Emergency Medicine

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

 

 

Trial of prasugrel vs clopidogrel

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

 

 

Low-molecular-weight heparins

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

 

 

Trial of prasugrel vs clopidogrel

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

 

 

Low-molecular-weight heparins

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

 

 

Trial of prasugrel vs clopidogrel

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

 

 

Low-molecular-weight heparins

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

In many ways, vascular disease in the leg is similar to that in the heart. The risk factors, underlying conditions, and pathogenetic processes are the same, and in many cases, patients have both conditions. And just as cardiologists and emergency physicians have learned that in acute myocardial infarction “time is muscle,” we are coming to appreciate that in many cases of limb ischemia, “time is limb.”

Most physicians well understand the clinical spectrum of coronary artery disease, which ranges from stable angina to ST-elevation myocardial infarction. In the leg, the same situation exists: at the more benign end of the spectrum, patients experience no symptoms, but often that is because they lead a sedentary lifestyle, modifying their activity level to avoid pain. As the disease worsens, they can develop claudication and critical leg ischemia, comparable to non-ST-elevation myocardial infarction. The most severe condition is acute limb ischemia, analagous to ST-elevation myocardial infarction.

Distinguishing acute from critical limb ischemia is essential in patients who present with leg problems, whether it be leg pain or ulcers. The farther along the clinical spectrum the patient’s condition is, the more important it is to be aggressive in diagnosis and treatment. The history and physical examination are the most important first steps, focusing on the onset of symptoms, history, risk factors, and past interventions.

Peripheral artery disease is increasingly becoming a worldwide problem that is now being emphasized by the World Health Organization. Unfortunately, not enough attention is paid to the problem, not only in less-developed countries but also in the United States. Patients with peripheral artery disease tend to be elderly, in the lowest economic classes, and uninsured, and they often do not understand the impact of the disease on their health.

LEG ULCERS: CAUSES AND COSTS

Finding the underlying cause of leg ulcers is important, and the differential diagnosis is large (Table 1). However, knowing the cause does not necessarily lead to healing; it is still essential to assess perfusion, infection, and wound care, and to arrest edema.

Causes of leg and foot ulcers include venous insufficiency (with an estimated 2.5 million cases annually),^1,2 diabetes (nearly 1 million cases),³ and pressure (ie, bedsores, occurring in up to 28% of patients in extended care),⁴ all at a cost in the billions of dollars.^5–7

In general, peripheral artery disease itself does not cause ulcers; it is an inciting factor. It is important to find what started the process. Ill-fitting shoes, poor sensation because of diabetes, or a cut when trimming toenails can all contribute to a wound, and peripheral artery disease makes it unable to heal. The healing process requires more nutrients and oxygen than poor circulation can provide.

ACUTE LIMB ISCHEMIA

Acute limb ischemia is defined as any sudden decrease in limb perfusion causing a potential threat to limb viability.⁸ Although it comes on suddenly, it does not imply that the patient has not had long-standing peripheral artery disease. It is important to determine what suddenly changed to cause the onset of symptoms.

History and physical examination: The six Ps

A good history includes a thorough evaluation of the present illness, including the pain’s time of onset, abruptness, location, intensity, and change over time, and whether it is present at rest. The medical history should focus on claudication, diabetes, smoking, heart disease, palpitations, atrial fibrillation, and previous ischemic symptoms.⁸

The physical examination should focus on the “six Ps”:

• Pain
• Pulselessness
• Paresthesia (numbness occurs in about half of patients)
• Pallor (obstruction is typically one joint above the level of demarcation of pallor)
• Paralysis (a bad sign, particularly if the calf is tight)
• Poikilothermia (inability to regulate temperature).

A good pulse examination includes measuring the ankle-brachial index and a Doppler examination of both legs. A neurologic examination focusing on sensory and motor function is critical for determining the level of ischemia and the urgency of intervention.

Classification of acute limb ischemia

If it is determined that a patient has acute leg ischemia, it is important to categorize the condition using the classification system devised by the Society of Vascular Surgery and International Society of Cardiovascular Surgery (Table 2).⁹ The category establishes the type and urgency of treatment. This classification system is simple and depends on factors that can be assessed easily by nonspecialists:

• Pulses—arterial and venous pulses assessed by Doppler ultrasonography
• Sensation—the patient closes the eyes and answers if he or she can feel the examiner’s touch
• Motor function—can the patient move his or her toes?

Venous pulses can be difficult to assess. However, if the arterial pulse is present, the venous pulse should be next to it. Knowing the other criteria can determine the category, so not being certain of the venous pulse should not deter a clinician from assessing the other factors.

Category I is “viable.” Patients have intact sensory and motor functions and audible pulses. Patients in this category should be admitted and possibly started on anticoagulation therapy and referred to a vascular specialist within hours.

Category IIa is “threatened.” Sensation is starting to be lost but motor function is still present. These patients are considered to have reversible ischemia, analogous to myocardial infarction of the leg, and they require immediate attention.

Category IIb is similar and it also requires immediate attention.

Category III is usually irreversible, with loss of motor function and sensation.

CAUSES OF ACUTE LIMB ISCHEMIA

Thrombosis accounts for about 50% of cases. Underlying causes of the thrombosis are artherosclerosis (native or bypass), aneurysm, trauma, vasculitis (eg, in a rheumatologic disease such as lupus), and hypercoagulable states (particularly in patients with cancer).

Embolism accounts for about 30% of cases. Emboli usually arise from plaque rupture in atherosclerotic arteries or a clot breaking off from an aneurysm or from within the heart in patients with atrial fibrillation or another underlying heart disease. Paradoxical embolism, caused by an embolism crossing the heart through an opening such as a patent foramen ovale, is rare.

Uncommon causes include arterial dissection following trauma, adventitial cystic disease, popliteal artery entrapment, ergotism (from consuming fungus-contaminated grains), and human immunodeficiency virus arteriopathy.

The physical examination provides clues to the origin: livedo reticularis (purple discoloration in a mottled pattern) and blue nail beds indicate that an embolus is likely. Tests, including electrocardiography, echocardiography, and computed tomography of the chest and abdomen to look for an aneurysm, can help identify the cause. Ultrasonography of the popliteal arteries should also be considered to search for an aneurysm.

CRITICAL LIMB ISCHEMIA

Critical limb ischemia is more likely than acute limb ischemia to be seen in a general practice. Many aspects need to be addressed simultaneously, by different specialists: vascular and endocrine systems, infection, and wound care. The most successful management strategy is a dynamic approach using every piece of information.¹⁰

The Rutherford classification of peripheral artery disease has six categories based on the clinical presentation, with categories I through III being mild to severe claudication. We discuss here only the more severe categories: IV (pain at rest), V (tissue loss), and VI (gangrene).

Strong indicators of pain at rest are that the patient has to get up at night to dangle the leg over the bed or walk a few steps, or sleeps in a chair, or refuses to elevate the leg because of pain. The affected leg tends to appear red when the patient is standing (dependent rubor), but pale when the foot is elevated (elevation pallor).

Confirming that a patient has dependent rubor can be challenging, especially in people with dark skin. Classically, redness is seen when the leg is down and disappears with elevation, but in cellulitis, redness can also be reduced by elevating the leg. A foot that is hot to the touch is an indication of infection and not lack of perfusion alone.

The hemodynamic definition of critical limb ischemia is¹¹:

• Ankle-brachial pressure index less than 0.4
• Reduced toebrachial pressure index, ie, less than 0.7
• Reduced transcutaneous pressure of oxygen (Tcpo₂), ie, less than 40 mm Hg.

From 15% to 20% of patients with claudication will progress to critical ischemia over their lifetime, and in patients with claudication who also have diabetes, the risk is nearly 10 times higher. Without revascularization, the risk of amputation within 1 year is 73% for patients in Rutherford class IV and 95% for patients in class V or VI.

Revascularization and limb preservation

Preserving the limb is a prime goal. For patients who have an amputation, the mortality rate is 40% within 2 years.⁸ These patients tend to be elderly, and after an amputation, most will not learn to use a prosthesis and resume their previous level of activity. Other treatment objectives are to relieve pain, reduce cardiovascular risk, and minimize procedural complications.

Although limb preservation is not a controversial goal, best practices to preserve limbs are not universally available. Goodney et al¹² studied variation in the United States in the use of lower-extremity vascular procedures for critical limb ischemia. They defined “low-intensity” to “high-intensity” regions of the country depending on the proportion of patients who underwent a vascular procedure in the year before amputation. They found considerable variation, but even in the region of highest intensity, more than 40% of patients did not have a vascular procedure in the year before amputation.

Similarly, Jones et al¹³ mapped amputation rates by US state and found significant variation even after adjusting for risk factors such as tobacco use and obesity.

Controversy surrounds the specifics of revascularization treatment, as in many fields in vascular medicine. However, most experts agree that improved perfusion is the goal.

The Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Artery Disease recommends revascularization as the best treatment for patients with critical limb ischemia.⁸ In addition, the American College of Cardiology and American Heart Association Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) state that the tibial or pedal artery that is capable of providing continuous and uncompromised outflow to the foot should be used as the site of distal anastomosis.¹⁴ These guidelines do not yet mention endovascular therapy.

Angiosomes guide revascularization

In the past few years, the ability to facilitate healing of foot ulcers has improved. Angiosomes—regions of vascularization supplied by specific arteries—can be mapped on the skin, similar to the way dermatomes are mapped for neural innervation (Figure 1). The foot and lower leg region has six angiosomes perfused by three arteries that branch off the popliteal artery after it passes behind the knee:

• The anterior tibial artery supplies the dorsum of the foot and the front of the lower limb.
• The posterior tibial artery supplies the plantar surface of the foot via three branches—the medial plantar, lateral plantar, and calcaneal branches.
• The peroneal artery supplies the lateral part of the foot with collaterals to the anterior and posterior tibial arteries if they are compromised.

Studies have compared angiosome-based treatment vs revascularizing the best available artery (thus depending on collateral flow to compensate to surrounding areas). They have found that regardless of whether an endovascular or bypass method of revascularization was used, an angiosome-based approach led to significantly higher amputation-free survival rates.^15–17

Patients typically do not have blockage of only a single tibial artery. Graziani et al¹⁸ assessed the vascular lesions in 417 patients with critical limb ischemia and found that multiple below-knee arteries were frequently involved. This makes it difficult to decide where to target revascularization efforts, and the angiosome concept helps with that.

ASSESSING WOUND PERFUSION

Ankle- and toe-brachial indices assess perfusion

The ankle-brachial index¹⁹ is a good superficial assessment of perfusion. Multiple epidemiologic studies have shown the prognostic value of the ankle brachial index beyond the traditional risk factors and even the Framingham risk score.¹⁹ Values:

• Normal 1.1–1.30 (> 1.31 is abnormal and consistent with calcified vessels, and is an unreliable measure)
• Low normal 0.91–1.00
• Mild disease 0.71–0.90
• Moderate disease 0.41–0.70
• Severe disease ≤ 0.40.

However, the ankle-brachial index assesses perfusion only to the ankle, and many patients have ulcers in the toes and distal foot. The toe-brachial index must be specifically ordered in most institutions (if the first toe has an ulcer, the second toe should be assessed). The toe-brachial index is also important if the ankle-brachial index cannot be obtained because of calcified, noncompressible arteries in the ankle. A normal toe-brachial index is greater than 0.7.

The segmental blood pressure examination compares blood pressure measurements at multiple sites in the lower extremity. A drop of more than 20 mm Hg between segments indicates obstruction at that location. The test is simple and noninvasive and often can replace computed tomography.²⁰

Transcutaneous oximetry

Transcutaneous oximetry measures the Tcpo₂ from 1 to 2 mm deep in the skin from local capillaries. Measured adjacent to an ulcer, it is useful to predict wound healing and to assess the response to hyperbaric oxygen therapy.²¹ The values are:

• Normal > 70 mm Hg
• Impaired wound healing < 40 mm Hg
• Critical limb ischemia < 30 mm Hg.

Although most agree that a Tcpo₂ below 40 mm Hg requires revascularization, low values can arise from many causes other than peripheral artery disease, including high altitude, pulmonary disease, heart failure, edema, inflammation, callus, and skin diseases such as scleroderma.

Skin perfusion pressure better predicts healing

Skin perfusion pressure is a measure of the capillary opening pressure after occlusion and is another way to assess perfusion. This test is not routinely done and must be specially requested.

The test is performed by inflating a blood pressure cuff on the leg until blood flow is occluded, then using laser Doppler to determine reactive hyperemia, ie, the gradual return of blood flow during controlled pressure release. The pressure at which movement is detected is the skin perfusion pressure.²²

The laser Doppler probe emits and detects light scattered in the tissue. Light hitting moving blood cells undergoes a change in frequency, ie, a Doppler shift. An algorithm converts the optical information in the skin perfusion pressure by capturing the onset of capillary flow return and determining the pressure at which flow returns. Categories of results:

• > 50 mm Hg—normal
• 40–50 mm Hg—mild ischemia (wound healing probable)
• 30–40 mm Hg—moderate ischemia (wound healing uncertain)
• < 30 mm Hg—critical limb ischemia (wound healing unlikely).

Skin perfusion pressure testing has the advantages of not being affected by vessel calcification, thickened skin, or edema. It can be used on the plantar aspect of the foot and on digits. Recent small studies indicate that it is more sensitive for predicting wound healing than Tcpo₂ measures.

On the other hand, skin perfusion pressure testing is not useful for predicting response to hyperbaric oxygen therapy. Also, blood flow occlusion by the cuff may be painful.

Intraoperative fluorescence angiography

Intraoperative fluorescence angiography is used to assess flap viability during reconstructive surgery and is being studied to determine its usefulness for assessing tissue viability in limb ischemia.

The test provides real-time assessment of capillary perfusion, determining surface tissue viability. The imaging head contains a digital camera, a laser light source, and a distance sensor. The test requires intravenous administration of indocyanine green, which binds to plasma proteins and is cleared through the liver, making it safe for patients with renal dysfunction. It cannot be used in patients with allergies to iodine contrast, penicillin, or sulfa.²³

PREVENTION TARGETS CARDIOVASCULAR RISK FACTORS

Preventive measures are the same as for cardiovascular disease, ie, aggressive risk-factor modification: quitting smoking, lowering low-density lipoprotein cholesterol, reducing blood pressure, controlling diabetes, and managing heart failure.

Dual antiplatelet therapy should be instituted with aspirin and clopidogrel (Plavix) in patients undergoing revascularization. One can also consider cilostazol (Pletal); however, the role of this agent in patients with critical limb ischemia is less defined.

BYPASS OR ANGIOPLASTY?

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial²⁴ randomly assigned 452 patients with severe limb ischemia due to infrainguinal atherosclerosis to receive either surgery-first or angioplasty-first care and followed them for 5.5 years.

No significant differences between the two groups were found in amputation-free survival, deaths, or health-related quality of life. However, hospital costs associated with the surgery-first strategy were about one-third higher. As expected, more patients in the surgery group developed a wound infection, and more patients in the angioplasty group required bypass surgery at some point.

The conclusion that can be reached from this study is that patients presenting with severe limb ischemia due to infrainguinal atherosclerotic occlusive disease who are suitable for both surgical and interventional procedures can be treated with either method. However, most experts consider endovascular therapy as the first option in many patients. The National Institutes of Health recently funded a study to compare contemporary endovascular therapy vs surgery in patients with critical limb ischemia.

TAKE-HOME POINTS

In the last decade, significant endovascular advances have been made. New devices and techniques have enhanced our ability to treat high-risk patients who have critical limb ischemia. The combination of risk factor modification, accurate diagnosis, and aggressive revascularization should prevent limb loss in many of these patients. For the primary care physician, a low threshold for assessing perfusion in patients with critical limb ischemia is important using a screening ankle-brachial index and toe-brachial index. These patients should promptly be referred to a vascular specialist for further evaluation and treatment.

In many ways, vascular disease in the leg is similar to that in the heart. The risk factors, underlying conditions, and pathogenetic processes are the same, and in many cases, patients have both conditions. And just as cardiologists and emergency physicians have learned that in acute myocardial infarction “time is muscle,” we are coming to appreciate that in many cases of limb ischemia, “time is limb.”

Most physicians well understand the clinical spectrum of coronary artery disease, which ranges from stable angina to ST-elevation myocardial infarction. In the leg, the same situation exists: at the more benign end of the spectrum, patients experience no symptoms, but often that is because they lead a sedentary lifestyle, modifying their activity level to avoid pain. As the disease worsens, they can develop claudication and critical leg ischemia, comparable to non-ST-elevation myocardial infarction. The most severe condition is acute limb ischemia, analagous to ST-elevation myocardial infarction.

Distinguishing acute from critical limb ischemia is essential in patients who present with leg problems, whether it be leg pain or ulcers. The farther along the clinical spectrum the patient’s condition is, the more important it is to be aggressive in diagnosis and treatment. The history and physical examination are the most important first steps, focusing on the onset of symptoms, history, risk factors, and past interventions.

Peripheral artery disease is increasingly becoming a worldwide problem that is now being emphasized by the World Health Organization. Unfortunately, not enough attention is paid to the problem, not only in less-developed countries but also in the United States. Patients with peripheral artery disease tend to be elderly, in the lowest economic classes, and uninsured, and they often do not understand the impact of the disease on their health.

LEG ULCERS: CAUSES AND COSTS

Finding the underlying cause of leg ulcers is important, and the differential diagnosis is large (Table 1). However, knowing the cause does not necessarily lead to healing; it is still essential to assess perfusion, infection, and wound care, and to arrest edema.

Causes of leg and foot ulcers include venous insufficiency (with an estimated 2.5 million cases annually),^1,2 diabetes (nearly 1 million cases),³ and pressure (ie, bedsores, occurring in up to 28% of patients in extended care),⁴ all at a cost in the billions of dollars.^5–7

In general, peripheral artery disease itself does not cause ulcers; it is an inciting factor. It is important to find what started the process. Ill-fitting shoes, poor sensation because of diabetes, or a cut when trimming toenails can all contribute to a wound, and peripheral artery disease makes it unable to heal. The healing process requires more nutrients and oxygen than poor circulation can provide.

ACUTE LIMB ISCHEMIA

Acute limb ischemia is defined as any sudden decrease in limb perfusion causing a potential threat to limb viability.⁸ Although it comes on suddenly, it does not imply that the patient has not had long-standing peripheral artery disease. It is important to determine what suddenly changed to cause the onset of symptoms.

History and physical examination: The six Ps

A good history includes a thorough evaluation of the present illness, including the pain’s time of onset, abruptness, location, intensity, and change over time, and whether it is present at rest. The medical history should focus on claudication, diabetes, smoking, heart disease, palpitations, atrial fibrillation, and previous ischemic symptoms.⁸

The physical examination should focus on the “six Ps”:

• Pain
• Pulselessness
• Paresthesia (numbness occurs in about half of patients)
• Pallor (obstruction is typically one joint above the level of demarcation of pallor)
• Paralysis (a bad sign, particularly if the calf is tight)
• Poikilothermia (inability to regulate temperature).

A good pulse examination includes measuring the ankle-brachial index and a Doppler examination of both legs. A neurologic examination focusing on sensory and motor function is critical for determining the level of ischemia and the urgency of intervention.

Classification of acute limb ischemia

If it is determined that a patient has acute leg ischemia, it is important to categorize the condition using the classification system devised by the Society of Vascular Surgery and International Society of Cardiovascular Surgery (Table 2).⁹ The category establishes the type and urgency of treatment. This classification system is simple and depends on factors that can be assessed easily by nonspecialists:

• Pulses—arterial and venous pulses assessed by Doppler ultrasonography
• Sensation—the patient closes the eyes and answers if he or she can feel the examiner’s touch
• Motor function—can the patient move his or her toes?

Venous pulses can be difficult to assess. However, if the arterial pulse is present, the venous pulse should be next to it. Knowing the other criteria can determine the category, so not being certain of the venous pulse should not deter a clinician from assessing the other factors.

Category I is “viable.” Patients have intact sensory and motor functions and audible pulses. Patients in this category should be admitted and possibly started on anticoagulation therapy and referred to a vascular specialist within hours.

Category IIa is “threatened.” Sensation is starting to be lost but motor function is still present. These patients are considered to have reversible ischemia, analogous to myocardial infarction of the leg, and they require immediate attention.

Category IIb is similar and it also requires immediate attention.

Category III is usually irreversible, with loss of motor function and sensation.

CAUSES OF ACUTE LIMB ISCHEMIA

Thrombosis accounts for about 50% of cases. Underlying causes of the thrombosis are artherosclerosis (native or bypass), aneurysm, trauma, vasculitis (eg, in a rheumatologic disease such as lupus), and hypercoagulable states (particularly in patients with cancer).

Embolism accounts for about 30% of cases. Emboli usually arise from plaque rupture in atherosclerotic arteries or a clot breaking off from an aneurysm or from within the heart in patients with atrial fibrillation or another underlying heart disease. Paradoxical embolism, caused by an embolism crossing the heart through an opening such as a patent foramen ovale, is rare.

Uncommon causes include arterial dissection following trauma, adventitial cystic disease, popliteal artery entrapment, ergotism (from consuming fungus-contaminated grains), and human immunodeficiency virus arteriopathy.

The physical examination provides clues to the origin: livedo reticularis (purple discoloration in a mottled pattern) and blue nail beds indicate that an embolus is likely. Tests, including electrocardiography, echocardiography, and computed tomography of the chest and abdomen to look for an aneurysm, can help identify the cause. Ultrasonography of the popliteal arteries should also be considered to search for an aneurysm.

CRITICAL LIMB ISCHEMIA

Critical limb ischemia is more likely than acute limb ischemia to be seen in a general practice. Many aspects need to be addressed simultaneously, by different specialists: vascular and endocrine systems, infection, and wound care. The most successful management strategy is a dynamic approach using every piece of information.¹⁰

The Rutherford classification of peripheral artery disease has six categories based on the clinical presentation, with categories I through III being mild to severe claudication. We discuss here only the more severe categories: IV (pain at rest), V (tissue loss), and VI (gangrene).

Strong indicators of pain at rest are that the patient has to get up at night to dangle the leg over the bed or walk a few steps, or sleeps in a chair, or refuses to elevate the leg because of pain. The affected leg tends to appear red when the patient is standing (dependent rubor), but pale when the foot is elevated (elevation pallor).

Confirming that a patient has dependent rubor can be challenging, especially in people with dark skin. Classically, redness is seen when the leg is down and disappears with elevation, but in cellulitis, redness can also be reduced by elevating the leg. A foot that is hot to the touch is an indication of infection and not lack of perfusion alone.

The hemodynamic definition of critical limb ischemia is¹¹:

• Ankle-brachial pressure index less than 0.4
• Reduced toebrachial pressure index, ie, less than 0.7
• Reduced transcutaneous pressure of oxygen (Tcpo₂), ie, less than 40 mm Hg.

From 15% to 20% of patients with claudication will progress to critical ischemia over their lifetime, and in patients with claudication who also have diabetes, the risk is nearly 10 times higher. Without revascularization, the risk of amputation within 1 year is 73% for patients in Rutherford class IV and 95% for patients in class V or VI.

Revascularization and limb preservation

Preserving the limb is a prime goal. For patients who have an amputation, the mortality rate is 40% within 2 years.⁸ These patients tend to be elderly, and after an amputation, most will not learn to use a prosthesis and resume their previous level of activity. Other treatment objectives are to relieve pain, reduce cardiovascular risk, and minimize procedural complications.

Although limb preservation is not a controversial goal, best practices to preserve limbs are not universally available. Goodney et al¹² studied variation in the United States in the use of lower-extremity vascular procedures for critical limb ischemia. They defined “low-intensity” to “high-intensity” regions of the country depending on the proportion of patients who underwent a vascular procedure in the year before amputation. They found considerable variation, but even in the region of highest intensity, more than 40% of patients did not have a vascular procedure in the year before amputation.

Similarly, Jones et al¹³ mapped amputation rates by US state and found significant variation even after adjusting for risk factors such as tobacco use and obesity.

Controversy surrounds the specifics of revascularization treatment, as in many fields in vascular medicine. However, most experts agree that improved perfusion is the goal.

The Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Artery Disease recommends revascularization as the best treatment for patients with critical limb ischemia.⁸ In addition, the American College of Cardiology and American Heart Association Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) state that the tibial or pedal artery that is capable of providing continuous and uncompromised outflow to the foot should be used as the site of distal anastomosis.¹⁴ These guidelines do not yet mention endovascular therapy.

Angiosomes guide revascularization

In the past few years, the ability to facilitate healing of foot ulcers has improved. Angiosomes—regions of vascularization supplied by specific arteries—can be mapped on the skin, similar to the way dermatomes are mapped for neural innervation (Figure 1). The foot and lower leg region has six angiosomes perfused by three arteries that branch off the popliteal artery after it passes behind the knee:

• The anterior tibial artery supplies the dorsum of the foot and the front of the lower limb.
• The posterior tibial artery supplies the plantar surface of the foot via three branches—the medial plantar, lateral plantar, and calcaneal branches.
• The peroneal artery supplies the lateral part of the foot with collaterals to the anterior and posterior tibial arteries if they are compromised.

Studies have compared angiosome-based treatment vs revascularizing the best available artery (thus depending on collateral flow to compensate to surrounding areas). They have found that regardless of whether an endovascular or bypass method of revascularization was used, an angiosome-based approach led to significantly higher amputation-free survival rates.^15–17

Patients typically do not have blockage of only a single tibial artery. Graziani et al¹⁸ assessed the vascular lesions in 417 patients with critical limb ischemia and found that multiple below-knee arteries were frequently involved. This makes it difficult to decide where to target revascularization efforts, and the angiosome concept helps with that.

ASSESSING WOUND PERFUSION

Ankle- and toe-brachial indices assess perfusion

The ankle-brachial index¹⁹ is a good superficial assessment of perfusion. Multiple epidemiologic studies have shown the prognostic value of the ankle brachial index beyond the traditional risk factors and even the Framingham risk score.¹⁹ Values:

• Normal 1.1–1.30 (> 1.31 is abnormal and consistent with calcified vessels, and is an unreliable measure)
• Low normal 0.91–1.00
• Mild disease 0.71–0.90
• Moderate disease 0.41–0.70
• Severe disease ≤ 0.40.

However, the ankle-brachial index assesses perfusion only to the ankle, and many patients have ulcers in the toes and distal foot. The toe-brachial index must be specifically ordered in most institutions (if the first toe has an ulcer, the second toe should be assessed). The toe-brachial index is also important if the ankle-brachial index cannot be obtained because of calcified, noncompressible arteries in the ankle. A normal toe-brachial index is greater than 0.7.

The segmental blood pressure examination compares blood pressure measurements at multiple sites in the lower extremity. A drop of more than 20 mm Hg between segments indicates obstruction at that location. The test is simple and noninvasive and often can replace computed tomography.²⁰

Transcutaneous oximetry

Transcutaneous oximetry measures the Tcpo₂ from 1 to 2 mm deep in the skin from local capillaries. Measured adjacent to an ulcer, it is useful to predict wound healing and to assess the response to hyperbaric oxygen therapy.²¹ The values are:

• Normal > 70 mm Hg
• Impaired wound healing < 40 mm Hg
• Critical limb ischemia < 30 mm Hg.

Although most agree that a Tcpo₂ below 40 mm Hg requires revascularization, low values can arise from many causes other than peripheral artery disease, including high altitude, pulmonary disease, heart failure, edema, inflammation, callus, and skin diseases such as scleroderma.

Skin perfusion pressure better predicts healing

Skin perfusion pressure is a measure of the capillary opening pressure after occlusion and is another way to assess perfusion. This test is not routinely done and must be specially requested.

The test is performed by inflating a blood pressure cuff on the leg until blood flow is occluded, then using laser Doppler to determine reactive hyperemia, ie, the gradual return of blood flow during controlled pressure release. The pressure at which movement is detected is the skin perfusion pressure.²²

The laser Doppler probe emits and detects light scattered in the tissue. Light hitting moving blood cells undergoes a change in frequency, ie, a Doppler shift. An algorithm converts the optical information in the skin perfusion pressure by capturing the onset of capillary flow return and determining the pressure at which flow returns. Categories of results:

• > 50 mm Hg—normal
• 40–50 mm Hg—mild ischemia (wound healing probable)
• 30–40 mm Hg—moderate ischemia (wound healing uncertain)
• < 30 mm Hg—critical limb ischemia (wound healing unlikely).

Skin perfusion pressure testing has the advantages of not being affected by vessel calcification, thickened skin, or edema. It can be used on the plantar aspect of the foot and on digits. Recent small studies indicate that it is more sensitive for predicting wound healing than Tcpo₂ measures.

On the other hand, skin perfusion pressure testing is not useful for predicting response to hyperbaric oxygen therapy. Also, blood flow occlusion by the cuff may be painful.

Intraoperative fluorescence angiography

Intraoperative fluorescence angiography is used to assess flap viability during reconstructive surgery and is being studied to determine its usefulness for assessing tissue viability in limb ischemia.

The test provides real-time assessment of capillary perfusion, determining surface tissue viability. The imaging head contains a digital camera, a laser light source, and a distance sensor. The test requires intravenous administration of indocyanine green, which binds to plasma proteins and is cleared through the liver, making it safe for patients with renal dysfunction. It cannot be used in patients with allergies to iodine contrast, penicillin, or sulfa.²³

PREVENTION TARGETS CARDIOVASCULAR RISK FACTORS

Preventive measures are the same as for cardiovascular disease, ie, aggressive risk-factor modification: quitting smoking, lowering low-density lipoprotein cholesterol, reducing blood pressure, controlling diabetes, and managing heart failure.

Dual antiplatelet therapy should be instituted with aspirin and clopidogrel (Plavix) in patients undergoing revascularization. One can also consider cilostazol (Pletal); however, the role of this agent in patients with critical limb ischemia is less defined.

BYPASS OR ANGIOPLASTY?

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial²⁴ randomly assigned 452 patients with severe limb ischemia due to infrainguinal atherosclerosis to receive either surgery-first or angioplasty-first care and followed them for 5.5 years.

No significant differences between the two groups were found in amputation-free survival, deaths, or health-related quality of life. However, hospital costs associated with the surgery-first strategy were about one-third higher. As expected, more patients in the surgery group developed a wound infection, and more patients in the angioplasty group required bypass surgery at some point.

The conclusion that can be reached from this study is that patients presenting with severe limb ischemia due to infrainguinal atherosclerotic occlusive disease who are suitable for both surgical and interventional procedures can be treated with either method. However, most experts consider endovascular therapy as the first option in many patients. The National Institutes of Health recently funded a study to compare contemporary endovascular therapy vs surgery in patients with critical limb ischemia.

TAKE-HOME POINTS

In the last decade, significant endovascular advances have been made. New devices and techniques have enhanced our ability to treat high-risk patients who have critical limb ischemia. The combination of risk factor modification, accurate diagnosis, and aggressive revascularization should prevent limb loss in many of these patients. For the primary care physician, a low threshold for assessing perfusion in patients with critical limb ischemia is important using a screening ankle-brachial index and toe-brachial index. These patients should promptly be referred to a vascular specialist for further evaluation and treatment.

In many ways, vascular disease in the leg is similar to that in the heart. The risk factors, underlying conditions, and pathogenetic processes are the same, and in many cases, patients have both conditions. And just as cardiologists and emergency physicians have learned that in acute myocardial infarction “time is muscle,” we are coming to appreciate that in many cases of limb ischemia, “time is limb.”

Most physicians well understand the clinical spectrum of coronary artery disease, which ranges from stable angina to ST-elevation myocardial infarction. In the leg, the same situation exists: at the more benign end of the spectrum, patients experience no symptoms, but often that is because they lead a sedentary lifestyle, modifying their activity level to avoid pain. As the disease worsens, they can develop claudication and critical leg ischemia, comparable to non-ST-elevation myocardial infarction. The most severe condition is acute limb ischemia, analagous to ST-elevation myocardial infarction.

Distinguishing acute from critical limb ischemia is essential in patients who present with leg problems, whether it be leg pain or ulcers. The farther along the clinical spectrum the patient’s condition is, the more important it is to be aggressive in diagnosis and treatment. The history and physical examination are the most important first steps, focusing on the onset of symptoms, history, risk factors, and past interventions.

Peripheral artery disease is increasingly becoming a worldwide problem that is now being emphasized by the World Health Organization. Unfortunately, not enough attention is paid to the problem, not only in less-developed countries but also in the United States. Patients with peripheral artery disease tend to be elderly, in the lowest economic classes, and uninsured, and they often do not understand the impact of the disease on their health.

LEG ULCERS: CAUSES AND COSTS

Finding the underlying cause of leg ulcers is important, and the differential diagnosis is large (Table 1). However, knowing the cause does not necessarily lead to healing; it is still essential to assess perfusion, infection, and wound care, and to arrest edema.

Causes of leg and foot ulcers include venous insufficiency (with an estimated 2.5 million cases annually),^1,2 diabetes (nearly 1 million cases),³ and pressure (ie, bedsores, occurring in up to 28% of patients in extended care),⁴ all at a cost in the billions of dollars.^5–7

In general, peripheral artery disease itself does not cause ulcers; it is an inciting factor. It is important to find what started the process. Ill-fitting shoes, poor sensation because of diabetes, or a cut when trimming toenails can all contribute to a wound, and peripheral artery disease makes it unable to heal. The healing process requires more nutrients and oxygen than poor circulation can provide.

ACUTE LIMB ISCHEMIA

Acute limb ischemia is defined as any sudden decrease in limb perfusion causing a potential threat to limb viability.⁸ Although it comes on suddenly, it does not imply that the patient has not had long-standing peripheral artery disease. It is important to determine what suddenly changed to cause the onset of symptoms.

History and physical examination: The six Ps

A good history includes a thorough evaluation of the present illness, including the pain’s time of onset, abruptness, location, intensity, and change over time, and whether it is present at rest. The medical history should focus on claudication, diabetes, smoking, heart disease, palpitations, atrial fibrillation, and previous ischemic symptoms.⁸

The physical examination should focus on the “six Ps”:

• Pain
• Pulselessness
• Paresthesia (numbness occurs in about half of patients)
• Pallor (obstruction is typically one joint above the level of demarcation of pallor)
• Paralysis (a bad sign, particularly if the calf is tight)
• Poikilothermia (inability to regulate temperature).

A good pulse examination includes measuring the ankle-brachial index and a Doppler examination of both legs. A neurologic examination focusing on sensory and motor function is critical for determining the level of ischemia and the urgency of intervention.

Classification of acute limb ischemia

If it is determined that a patient has acute leg ischemia, it is important to categorize the condition using the classification system devised by the Society of Vascular Surgery and International Society of Cardiovascular Surgery (Table 2).⁹ The category establishes the type and urgency of treatment. This classification system is simple and depends on factors that can be assessed easily by nonspecialists:

• Pulses—arterial and venous pulses assessed by Doppler ultrasonography
• Sensation—the patient closes the eyes and answers if he or she can feel the examiner’s touch
• Motor function—can the patient move his or her toes?

Venous pulses can be difficult to assess. However, if the arterial pulse is present, the venous pulse should be next to it. Knowing the other criteria can determine the category, so not being certain of the venous pulse should not deter a clinician from assessing the other factors.

Category I is “viable.” Patients have intact sensory and motor functions and audible pulses. Patients in this category should be admitted and possibly started on anticoagulation therapy and referred to a vascular specialist within hours.

Category IIa is “threatened.” Sensation is starting to be lost but motor function is still present. These patients are considered to have reversible ischemia, analogous to myocardial infarction of the leg, and they require immediate attention.

Category IIb is similar and it also requires immediate attention.

Category III is usually irreversible, with loss of motor function and sensation.

CAUSES OF ACUTE LIMB ISCHEMIA

Thrombosis accounts for about 50% of cases. Underlying causes of the thrombosis are artherosclerosis (native or bypass), aneurysm, trauma, vasculitis (eg, in a rheumatologic disease such as lupus), and hypercoagulable states (particularly in patients with cancer).

Embolism accounts for about 30% of cases. Emboli usually arise from plaque rupture in atherosclerotic arteries or a clot breaking off from an aneurysm or from within the heart in patients with atrial fibrillation or another underlying heart disease. Paradoxical embolism, caused by an embolism crossing the heart through an opening such as a patent foramen ovale, is rare.

Uncommon causes include arterial dissection following trauma, adventitial cystic disease, popliteal artery entrapment, ergotism (from consuming fungus-contaminated grains), and human immunodeficiency virus arteriopathy.

The physical examination provides clues to the origin: livedo reticularis (purple discoloration in a mottled pattern) and blue nail beds indicate that an embolus is likely. Tests, including electrocardiography, echocardiography, and computed tomography of the chest and abdomen to look for an aneurysm, can help identify the cause. Ultrasonography of the popliteal arteries should also be considered to search for an aneurysm.

CRITICAL LIMB ISCHEMIA

Critical limb ischemia is more likely than acute limb ischemia to be seen in a general practice. Many aspects need to be addressed simultaneously, by different specialists: vascular and endocrine systems, infection, and wound care. The most successful management strategy is a dynamic approach using every piece of information.¹⁰

The Rutherford classification of peripheral artery disease has six categories based on the clinical presentation, with categories I through III being mild to severe claudication. We discuss here only the more severe categories: IV (pain at rest), V (tissue loss), and VI (gangrene).

Strong indicators of pain at rest are that the patient has to get up at night to dangle the leg over the bed or walk a few steps, or sleeps in a chair, or refuses to elevate the leg because of pain. The affected leg tends to appear red when the patient is standing (dependent rubor), but pale when the foot is elevated (elevation pallor).

Confirming that a patient has dependent rubor can be challenging, especially in people with dark skin. Classically, redness is seen when the leg is down and disappears with elevation, but in cellulitis, redness can also be reduced by elevating the leg. A foot that is hot to the touch is an indication of infection and not lack of perfusion alone.

The hemodynamic definition of critical limb ischemia is¹¹:

• Ankle-brachial pressure index less than 0.4
• Reduced toebrachial pressure index, ie, less than 0.7
• Reduced transcutaneous pressure of oxygen (Tcpo₂), ie, less than 40 mm Hg.

From 15% to 20% of patients with claudication will progress to critical ischemia over their lifetime, and in patients with claudication who also have diabetes, the risk is nearly 10 times higher. Without revascularization, the risk of amputation within 1 year is 73% for patients in Rutherford class IV and 95% for patients in class V or VI.

Revascularization and limb preservation

Preserving the limb is a prime goal. For patients who have an amputation, the mortality rate is 40% within 2 years.⁸ These patients tend to be elderly, and after an amputation, most will not learn to use a prosthesis and resume their previous level of activity. Other treatment objectives are to relieve pain, reduce cardiovascular risk, and minimize procedural complications.

Although limb preservation is not a controversial goal, best practices to preserve limbs are not universally available. Goodney et al¹² studied variation in the United States in the use of lower-extremity vascular procedures for critical limb ischemia. They defined “low-intensity” to “high-intensity” regions of the country depending on the proportion of patients who underwent a vascular procedure in the year before amputation. They found considerable variation, but even in the region of highest intensity, more than 40% of patients did not have a vascular procedure in the year before amputation.

Similarly, Jones et al¹³ mapped amputation rates by US state and found significant variation even after adjusting for risk factors such as tobacco use and obesity.

Controversy surrounds the specifics of revascularization treatment, as in many fields in vascular medicine. However, most experts agree that improved perfusion is the goal.

The Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Artery Disease recommends revascularization as the best treatment for patients with critical limb ischemia.⁸ In addition, the American College of Cardiology and American Heart Association Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) state that the tibial or pedal artery that is capable of providing continuous and uncompromised outflow to the foot should be used as the site of distal anastomosis.¹⁴ These guidelines do not yet mention endovascular therapy.

Angiosomes guide revascularization

In the past few years, the ability to facilitate healing of foot ulcers has improved. Angiosomes—regions of vascularization supplied by specific arteries—can be mapped on the skin, similar to the way dermatomes are mapped for neural innervation (Figure 1). The foot and lower leg region has six angiosomes perfused by three arteries that branch off the popliteal artery after it passes behind the knee:

• The anterior tibial artery supplies the dorsum of the foot and the front of the lower limb.
• The posterior tibial artery supplies the plantar surface of the foot via three branches—the medial plantar, lateral plantar, and calcaneal branches.
• The peroneal artery supplies the lateral part of the foot with collaterals to the anterior and posterior tibial arteries if they are compromised.

Studies have compared angiosome-based treatment vs revascularizing the best available artery (thus depending on collateral flow to compensate to surrounding areas). They have found that regardless of whether an endovascular or bypass method of revascularization was used, an angiosome-based approach led to significantly higher amputation-free survival rates.^15–17

Patients typically do not have blockage of only a single tibial artery. Graziani et al¹⁸ assessed the vascular lesions in 417 patients with critical limb ischemia and found that multiple below-knee arteries were frequently involved. This makes it difficult to decide where to target revascularization efforts, and the angiosome concept helps with that.

ASSESSING WOUND PERFUSION

Ankle- and toe-brachial indices assess perfusion

The ankle-brachial index¹⁹ is a good superficial assessment of perfusion. Multiple epidemiologic studies have shown the prognostic value of the ankle brachial index beyond the traditional risk factors and even the Framingham risk score.¹⁹ Values:

• Normal 1.1–1.30 (> 1.31 is abnormal and consistent with calcified vessels, and is an unreliable measure)
• Low normal 0.91–1.00
• Mild disease 0.71–0.90
• Moderate disease 0.41–0.70
• Severe disease ≤ 0.40.

However, the ankle-brachial index assesses perfusion only to the ankle, and many patients have ulcers in the toes and distal foot. The toe-brachial index must be specifically ordered in most institutions (if the first toe has an ulcer, the second toe should be assessed). The toe-brachial index is also important if the ankle-brachial index cannot be obtained because of calcified, noncompressible arteries in the ankle. A normal toe-brachial index is greater than 0.7.

The segmental blood pressure examination compares blood pressure measurements at multiple sites in the lower extremity. A drop of more than 20 mm Hg between segments indicates obstruction at that location. The test is simple and noninvasive and often can replace computed tomography.²⁰

Transcutaneous oximetry

Transcutaneous oximetry measures the Tcpo₂ from 1 to 2 mm deep in the skin from local capillaries. Measured adjacent to an ulcer, it is useful to predict wound healing and to assess the response to hyperbaric oxygen therapy.²¹ The values are:

• Normal > 70 mm Hg
• Impaired wound healing < 40 mm Hg
• Critical limb ischemia < 30 mm Hg.

Although most agree that a Tcpo₂ below 40 mm Hg requires revascularization, low values can arise from many causes other than peripheral artery disease, including high altitude, pulmonary disease, heart failure, edema, inflammation, callus, and skin diseases such as scleroderma.

Skin perfusion pressure better predicts healing

Skin perfusion pressure is a measure of the capillary opening pressure after occlusion and is another way to assess perfusion. This test is not routinely done and must be specially requested.

The test is performed by inflating a blood pressure cuff on the leg until blood flow is occluded, then using laser Doppler to determine reactive hyperemia, ie, the gradual return of blood flow during controlled pressure release. The pressure at which movement is detected is the skin perfusion pressure.²²

The laser Doppler probe emits and detects light scattered in the tissue. Light hitting moving blood cells undergoes a change in frequency, ie, a Doppler shift. An algorithm converts the optical information in the skin perfusion pressure by capturing the onset of capillary flow return and determining the pressure at which flow returns. Categories of results:

• > 50 mm Hg—normal
• 40–50 mm Hg—mild ischemia (wound healing probable)
• 30–40 mm Hg—moderate ischemia (wound healing uncertain)
• < 30 mm Hg—critical limb ischemia (wound healing unlikely).

Skin perfusion pressure testing has the advantages of not being affected by vessel calcification, thickened skin, or edema. It can be used on the plantar aspect of the foot and on digits. Recent small studies indicate that it is more sensitive for predicting wound healing than Tcpo₂ measures.

On the other hand, skin perfusion pressure testing is not useful for predicting response to hyperbaric oxygen therapy. Also, blood flow occlusion by the cuff may be painful.

Intraoperative fluorescence angiography

Intraoperative fluorescence angiography is used to assess flap viability during reconstructive surgery and is being studied to determine its usefulness for assessing tissue viability in limb ischemia.

The test provides real-time assessment of capillary perfusion, determining surface tissue viability. The imaging head contains a digital camera, a laser light source, and a distance sensor. The test requires intravenous administration of indocyanine green, which binds to plasma proteins and is cleared through the liver, making it safe for patients with renal dysfunction. It cannot be used in patients with allergies to iodine contrast, penicillin, or sulfa.²³

PREVENTION TARGETS CARDIOVASCULAR RISK FACTORS

Preventive measures are the same as for cardiovascular disease, ie, aggressive risk-factor modification: quitting smoking, lowering low-density lipoprotein cholesterol, reducing blood pressure, controlling diabetes, and managing heart failure.

Dual antiplatelet therapy should be instituted with aspirin and clopidogrel (Plavix) in patients undergoing revascularization. One can also consider cilostazol (Pletal); however, the role of this agent in patients with critical limb ischemia is less defined.

BYPASS OR ANGIOPLASTY?

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial²⁴ randomly assigned 452 patients with severe limb ischemia due to infrainguinal atherosclerosis to receive either surgery-first or angioplasty-first care and followed them for 5.5 years.

No significant differences between the two groups were found in amputation-free survival, deaths, or health-related quality of life. However, hospital costs associated with the surgery-first strategy were about one-third higher. As expected, more patients in the surgery group developed a wound infection, and more patients in the angioplasty group required bypass surgery at some point.

The conclusion that can be reached from this study is that patients presenting with severe limb ischemia due to infrainguinal atherosclerotic occlusive disease who are suitable for both surgical and interventional procedures can be treated with either method. However, most experts consider endovascular therapy as the first option in many patients. The National Institutes of Health recently funded a study to compare contemporary endovascular therapy vs surgery in patients with critical limb ischemia.

TAKE-HOME POINTS

In the last decade, significant endovascular advances have been made. New devices and techniques have enhanced our ability to treat high-risk patients who have critical limb ischemia. The combination of risk factor modification, accurate diagnosis, and aggressive revascularization should prevent limb loss in many of these patients. For the primary care physician, a low threshold for assessing perfusion in patients with critical limb ischemia is important using a screening ankle-brachial index and toe-brachial index. These patients should promptly be referred to a vascular specialist for further evaluation and treatment.

ANSWER

The radiograph shows the lungs overall to be clear. There are some slight increased markings, perhaps suggestive of mild congestion, but no infiltrate or consolidation.

Of note is a small nodule within the middle portion of the left upper lobe that requires monitoring and further workup. Also, although it is incompletely imaged, there appears to be a fracture of the right humeral neck.

Additional imaging confirmed the fracture. Orthopedic consultation was obtained.

ANSWER

The radiograph shows the lungs overall to be clear. There are some slight increased markings, perhaps suggestive of mild congestion, but no infiltrate or consolidation.

Of note is a small nodule within the middle portion of the left upper lobe that requires monitoring and further workup. Also, although it is incompletely imaged, there appears to be a fracture of the right humeral neck.

Additional imaging confirmed the fracture. Orthopedic consultation was obtained.

ANSWER

The radiograph shows the lungs overall to be clear. There are some slight increased markings, perhaps suggestive of mild congestion, but no infiltrate or consolidation.

Of note is a small nodule within the middle portion of the left upper lobe that requires monitoring and further workup. Also, although it is incompletely imaged, there appears to be a fracture of the right humeral neck.

Additional imaging confirmed the fracture. Orthopedic consultation was obtained.

To the Editor: In the December 2013 Cleveland Clinic Journal of Medicine, Tehrani and Seto provide a review of the updated definitions of myocardial infarction (MI).¹ A key concept incorporated into the structured definitions is that cardiac biomarkers must be interpreted in a clinical context.² This in turn helps better align the laboratory and clinical findings with the pathophysiologic processes.

However, there is another dimension to the definitions that is sometimes overlooked and requires careful attention: translation of the definitions into codes and comparable databases. Accurate and consistent coding according to the International Statistical Classification of Diseases, ninth edition (ICD-9), and the ICD-10 is critically vital to the appropriate analysis of data, research, quality measurement, and reimbursement of services related to MI. Unfortunately, there is no straightforward translation of the definitions into ICD-9 codes, and the challenge is further confounded when it comes to ICD-10, which will be implemented in October 2014.

The ICD-10-CM Index to Diseases does not yet recognize this nomenclature. ST-elevation MI is the default for the unspecified term “acute MI.” Non-ST-elevation MI requires more explicit documentation and is classified based on whether it occurs during or after a variety of procedures. Type 2 MI is particularly challenging because of the several possible ways to code the condition—for example, as acute subendocardial MI (I21.4), demand ischemia (I24.8), or acute MI, unspecified (I21.9). Coding guidelines are assumed to standardize the approach to coding these conditions, but there is no guarantee that comparability of the data will endure biases of code assignment. Although extreme precision in disease capture by coding may not exist, other clinical conditions have better correlations with coding classifications, such as stages of chronic kidney disease ranging from stage 1 through end-stage renal disease (N18.1 through N18.6). Furthermore, ICD-10 codes are insufficient to clearly distinguish the type of acute MI.³

While the concept of acute MI applies when the stated date of onset is less than 8 weeks in ICD-9,⁴ it changes to 4 weeks in ICD-10. “Acute” can reference an initial or a subsequent MI in ICD-10, but it does not define the time frame of the MI.⁵ This is different than in ICD-9, where the concept of “subsequent” refers to a “subsequent episode of care.”

On the surface, these variations may not seem significant. However, the discriminatory efforts to better define a patient’s clinical condition using the new definitions may get diluted by the challenges of the coding process. The implications on comparability of quality metrics and reporting are not to be underestimated and need to be assessed on a national level.

To the Editor: In the December 2013 Cleveland Clinic Journal of Medicine, Tehrani and Seto provide a review of the updated definitions of myocardial infarction (MI).¹ A key concept incorporated into the structured definitions is that cardiac biomarkers must be interpreted in a clinical context.² This in turn helps better align the laboratory and clinical findings with the pathophysiologic processes.

However, there is another dimension to the definitions that is sometimes overlooked and requires careful attention: translation of the definitions into codes and comparable databases. Accurate and consistent coding according to the International Statistical Classification of Diseases, ninth edition (ICD-9), and the ICD-10 is critically vital to the appropriate analysis of data, research, quality measurement, and reimbursement of services related to MI. Unfortunately, there is no straightforward translation of the definitions into ICD-9 codes, and the challenge is further confounded when it comes to ICD-10, which will be implemented in October 2014.

The ICD-10-CM Index to Diseases does not yet recognize this nomenclature. ST-elevation MI is the default for the unspecified term “acute MI.” Non-ST-elevation MI requires more explicit documentation and is classified based on whether it occurs during or after a variety of procedures. Type 2 MI is particularly challenging because of the several possible ways to code the condition—for example, as acute subendocardial MI (I21.4), demand ischemia (I24.8), or acute MI, unspecified (I21.9). Coding guidelines are assumed to standardize the approach to coding these conditions, but there is no guarantee that comparability of the data will endure biases of code assignment. Although extreme precision in disease capture by coding may not exist, other clinical conditions have better correlations with coding classifications, such as stages of chronic kidney disease ranging from stage 1 through end-stage renal disease (N18.1 through N18.6). Furthermore, ICD-10 codes are insufficient to clearly distinguish the type of acute MI.³

While the concept of acute MI applies when the stated date of onset is less than 8 weeks in ICD-9,⁴ it changes to 4 weeks in ICD-10. “Acute” can reference an initial or a subsequent MI in ICD-10, but it does not define the time frame of the MI.⁵ This is different than in ICD-9, where the concept of “subsequent” refers to a “subsequent episode of care.”

On the surface, these variations may not seem significant. However, the discriminatory efforts to better define a patient’s clinical condition using the new definitions may get diluted by the challenges of the coding process. The implications on comparability of quality metrics and reporting are not to be underestimated and need to be assessed on a national level.

To the Editor: In the December 2013 Cleveland Clinic Journal of Medicine, Tehrani and Seto provide a review of the updated definitions of myocardial infarction (MI).¹ A key concept incorporated into the structured definitions is that cardiac biomarkers must be interpreted in a clinical context.² This in turn helps better align the laboratory and clinical findings with the pathophysiologic processes.

However, there is another dimension to the definitions that is sometimes overlooked and requires careful attention: translation of the definitions into codes and comparable databases. Accurate and consistent coding according to the International Statistical Classification of Diseases, ninth edition (ICD-9), and the ICD-10 is critically vital to the appropriate analysis of data, research, quality measurement, and reimbursement of services related to MI. Unfortunately, there is no straightforward translation of the definitions into ICD-9 codes, and the challenge is further confounded when it comes to ICD-10, which will be implemented in October 2014.

The ICD-10-CM Index to Diseases does not yet recognize this nomenclature. ST-elevation MI is the default for the unspecified term “acute MI.” Non-ST-elevation MI requires more explicit documentation and is classified based on whether it occurs during or after a variety of procedures. Type 2 MI is particularly challenging because of the several possible ways to code the condition—for example, as acute subendocardial MI (I21.4), demand ischemia (I24.8), or acute MI, unspecified (I21.9). Coding guidelines are assumed to standardize the approach to coding these conditions, but there is no guarantee that comparability of the data will endure biases of code assignment. Although extreme precision in disease capture by coding may not exist, other clinical conditions have better correlations with coding classifications, such as stages of chronic kidney disease ranging from stage 1 through end-stage renal disease (N18.1 through N18.6). Furthermore, ICD-10 codes are insufficient to clearly distinguish the type of acute MI.³

While the concept of acute MI applies when the stated date of onset is less than 8 weeks in ICD-9,⁴ it changes to 4 weeks in ICD-10. “Acute” can reference an initial or a subsequent MI in ICD-10, but it does not define the time frame of the MI.⁵ This is different than in ICD-9, where the concept of “subsequent” refers to a “subsequent episode of care.”

On the surface, these variations may not seem significant. However, the discriminatory efforts to better define a patient’s clinical condition using the new definitions may get diluted by the challenges of the coding process. The implications on comparability of quality metrics and reporting are not to be underestimated and need to be assessed on a national level.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

ANSWER

The radiograph shows moderate soft-tissue swelling with dislocation of the proximal interphalangeal joint. No definite fracture is seen. In addition, there are some metallic-appearing foreign bodies.

The patient was treated with closed ­reduction and splinting. He also received a referral to outpatient orthopedics for ­follow-up.

ANSWER

The radiograph shows moderate soft-tissue swelling with dislocation of the proximal interphalangeal joint. No definite fracture is seen. In addition, there are some metallic-appearing foreign bodies.

The patient was treated with closed ­reduction and splinting. He also received a referral to outpatient orthopedics for ­follow-up.

ANSWER

The radiograph shows moderate soft-tissue swelling with dislocation of the proximal interphalangeal joint. No definite fracture is seen. In addition, there are some metallic-appearing foreign bodies.

The patient was treated with closed ­reduction and splinting. He also received a referral to outpatient orthopedics for ­follow-up.