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Heart Failure Outcomes Unaltered by Different Diuretic Strategies
In patients with acute decompensated heart failure, outcomes are essentially the same regardless of whether diuretic therapy is administered in continuous infusions or boluses, and at high or low doses, according to a report in the March 3 New England Journal of Medicine.
In a prospective, double-blind, randomized trial, both patients’ own global assessments of their symptoms and objective changes in several measures of renal and cardiac function were similar, regardless of diuretic treatment approach, said Dr. G. Michael Felker of Duke University Heart Center, Durham, N.C., and his associates in the Diuretic Optimization Strategies Evaluation (DOSE) study.
The National Heart, Lung, and Blood Institute funded the DOSE trial because even though intravenous loop diuretics are "an essential component of current treatment and are administered to approximately 90% of patients hospitalized with heart failure," there is still widespread uncertainty about the best type of dosing and mode of administration. "Despite decades of clinical experience with these agents, prospective data to guide the use of loop diuretics are sparse, and current guidelines are based primarily on expert opinion. As a result, clinical practice varies widely," the investigators said.
The 308 patients were hospitalized at 26 clinical sites in the United States and Canada for acute decompensated heart failure. The mean patient age was 66 years; 27% were women, and 25% were black. Approximately three-quarters of the subjects had been hospitalized for heart failure during the preceding year. Most had moderate renal dysfunction, elevated levels of natriuretic peptide, and a decreased ejection fraction.
The subjects were randomly assigned to either a low-dose strategy in which the total daily IV furosemide dose was equivalent to their total daily oral diuretic dose, or a high-dose strategy in which the total daily IV furosemide dose was equivalent to 2.5 times their total daily diuretic dose. They also were randomly assigned to receive furosemide by either an IV bolus every 12 hours or by a continuous IV infusion.
Patients were assessed at baseline, 72 hours, and 60 days. The primary efficacy end point was the patient’s global assessment of symptoms from baseline through 72 hours, and the primary safety end point was the change in serum creatinine level from baseline to 72 hours.
There were no significant differences among the four study groups in either of these end points. There also were no significant differences across a variety of secondary end points, including dyspnea, change in body weight, net fluid loss, percentage of patients affected by congestion, worsening renal function, worsening heart failure, or changes in several biomarkers, Dr. Felker and his colleagues said (N. Engl. J. Med. 2011;364:797-805).
There was a trend toward greater improvement of patient-reported global symptoms with the high-dose strategy, but this did not reach statistical significance. Moreover, this potential benefit was offset by a higher incidence of transient worsening renal function that also did not reach statistical significance.
The median length of stay was 5 days in all four groups. A total of 130 patients (42%) died, required rehospitalization, or required a visit to the emergency department within 60 days, but there were no significant differences among the treatment groups in this composite end point. The total number of patients who were alive and not hospitalized at 60 days also did not differ significantly among the four groups.
The DOSE study was funded by the National Heart, Lung, and Blood Institute. Dr. Felker and his associates reported numerous ties to drug and device companies, including those that manufacture diuretics.
Both of the main findings of this study are likely to change current practice, said Dr. Gregg C. Fonarow.
Since high-dose furosemide doesn’t have a worse effect than low-dose furosemide on renal function (other than the nonsignificant, transient worsening seen in some study subjects), many clinicians may switch to the high dose because it may relieve dyspnea more quickly. And since bolus infusion is as effective as continuous infusion, many clinicians may switch to bolus treatment because it is more convenient, he said.
The study by Dr. Felker and his associates also "underscores the dismal prognosis" for patients with acute decompensated HF. Even in this well-conducted study "performed at institutions that have highly regarded programs for patients with heart failure, there was an unacceptably high (43%) rate of death, rehospitalization, or emergency department visits within the first 60 days, irrespective of treatment assignment.
"Clearly, there is a crucial need to develop new agents and effective strategies for this patient population," Dr. Fonarow said.
Dr. Fonarow is at the Ahmanson-UCLA Cardiomyopathy Center, Los Angeles. He reported ties to Novartis and Scios/DCRI. These remarks were taken from his editorial accompanying Dr. Felker’s report (N. Engl. J. Med. 2011;364:877-8).
Both of the main findings of this study are likely to change current practice, said Dr. Gregg C. Fonarow.
Since high-dose furosemide doesn’t have a worse effect than low-dose furosemide on renal function (other than the nonsignificant, transient worsening seen in some study subjects), many clinicians may switch to the high dose because it may relieve dyspnea more quickly. And since bolus infusion is as effective as continuous infusion, many clinicians may switch to bolus treatment because it is more convenient, he said.
The study by Dr. Felker and his associates also "underscores the dismal prognosis" for patients with acute decompensated HF. Even in this well-conducted study "performed at institutions that have highly regarded programs for patients with heart failure, there was an unacceptably high (43%) rate of death, rehospitalization, or emergency department visits within the first 60 days, irrespective of treatment assignment.
"Clearly, there is a crucial need to develop new agents and effective strategies for this patient population," Dr. Fonarow said.
Dr. Fonarow is at the Ahmanson-UCLA Cardiomyopathy Center, Los Angeles. He reported ties to Novartis and Scios/DCRI. These remarks were taken from his editorial accompanying Dr. Felker’s report (N. Engl. J. Med. 2011;364:877-8).
Both of the main findings of this study are likely to change current practice, said Dr. Gregg C. Fonarow.
Since high-dose furosemide doesn’t have a worse effect than low-dose furosemide on renal function (other than the nonsignificant, transient worsening seen in some study subjects), many clinicians may switch to the high dose because it may relieve dyspnea more quickly. And since bolus infusion is as effective as continuous infusion, many clinicians may switch to bolus treatment because it is more convenient, he said.
The study by Dr. Felker and his associates also "underscores the dismal prognosis" for patients with acute decompensated HF. Even in this well-conducted study "performed at institutions that have highly regarded programs for patients with heart failure, there was an unacceptably high (43%) rate of death, rehospitalization, or emergency department visits within the first 60 days, irrespective of treatment assignment.
"Clearly, there is a crucial need to develop new agents and effective strategies for this patient population," Dr. Fonarow said.
Dr. Fonarow is at the Ahmanson-UCLA Cardiomyopathy Center, Los Angeles. He reported ties to Novartis and Scios/DCRI. These remarks were taken from his editorial accompanying Dr. Felker’s report (N. Engl. J. Med. 2011;364:877-8).
In patients with acute decompensated heart failure, outcomes are essentially the same regardless of whether diuretic therapy is administered in continuous infusions or boluses, and at high or low doses, according to a report in the March 3 New England Journal of Medicine.
In a prospective, double-blind, randomized trial, both patients’ own global assessments of their symptoms and objective changes in several measures of renal and cardiac function were similar, regardless of diuretic treatment approach, said Dr. G. Michael Felker of Duke University Heart Center, Durham, N.C., and his associates in the Diuretic Optimization Strategies Evaluation (DOSE) study.
The National Heart, Lung, and Blood Institute funded the DOSE trial because even though intravenous loop diuretics are "an essential component of current treatment and are administered to approximately 90% of patients hospitalized with heart failure," there is still widespread uncertainty about the best type of dosing and mode of administration. "Despite decades of clinical experience with these agents, prospective data to guide the use of loop diuretics are sparse, and current guidelines are based primarily on expert opinion. As a result, clinical practice varies widely," the investigators said.
The 308 patients were hospitalized at 26 clinical sites in the United States and Canada for acute decompensated heart failure. The mean patient age was 66 years; 27% were women, and 25% were black. Approximately three-quarters of the subjects had been hospitalized for heart failure during the preceding year. Most had moderate renal dysfunction, elevated levels of natriuretic peptide, and a decreased ejection fraction.
The subjects were randomly assigned to either a low-dose strategy in which the total daily IV furosemide dose was equivalent to their total daily oral diuretic dose, or a high-dose strategy in which the total daily IV furosemide dose was equivalent to 2.5 times their total daily diuretic dose. They also were randomly assigned to receive furosemide by either an IV bolus every 12 hours or by a continuous IV infusion.
Patients were assessed at baseline, 72 hours, and 60 days. The primary efficacy end point was the patient’s global assessment of symptoms from baseline through 72 hours, and the primary safety end point was the change in serum creatinine level from baseline to 72 hours.
There were no significant differences among the four study groups in either of these end points. There also were no significant differences across a variety of secondary end points, including dyspnea, change in body weight, net fluid loss, percentage of patients affected by congestion, worsening renal function, worsening heart failure, or changes in several biomarkers, Dr. Felker and his colleagues said (N. Engl. J. Med. 2011;364:797-805).
There was a trend toward greater improvement of patient-reported global symptoms with the high-dose strategy, but this did not reach statistical significance. Moreover, this potential benefit was offset by a higher incidence of transient worsening renal function that also did not reach statistical significance.
The median length of stay was 5 days in all four groups. A total of 130 patients (42%) died, required rehospitalization, or required a visit to the emergency department within 60 days, but there were no significant differences among the treatment groups in this composite end point. The total number of patients who were alive and not hospitalized at 60 days also did not differ significantly among the four groups.
The DOSE study was funded by the National Heart, Lung, and Blood Institute. Dr. Felker and his associates reported numerous ties to drug and device companies, including those that manufacture diuretics.
In patients with acute decompensated heart failure, outcomes are essentially the same regardless of whether diuretic therapy is administered in continuous infusions or boluses, and at high or low doses, according to a report in the March 3 New England Journal of Medicine.
In a prospective, double-blind, randomized trial, both patients’ own global assessments of their symptoms and objective changes in several measures of renal and cardiac function were similar, regardless of diuretic treatment approach, said Dr. G. Michael Felker of Duke University Heart Center, Durham, N.C., and his associates in the Diuretic Optimization Strategies Evaluation (DOSE) study.
The National Heart, Lung, and Blood Institute funded the DOSE trial because even though intravenous loop diuretics are "an essential component of current treatment and are administered to approximately 90% of patients hospitalized with heart failure," there is still widespread uncertainty about the best type of dosing and mode of administration. "Despite decades of clinical experience with these agents, prospective data to guide the use of loop diuretics are sparse, and current guidelines are based primarily on expert opinion. As a result, clinical practice varies widely," the investigators said.
The 308 patients were hospitalized at 26 clinical sites in the United States and Canada for acute decompensated heart failure. The mean patient age was 66 years; 27% were women, and 25% were black. Approximately three-quarters of the subjects had been hospitalized for heart failure during the preceding year. Most had moderate renal dysfunction, elevated levels of natriuretic peptide, and a decreased ejection fraction.
The subjects were randomly assigned to either a low-dose strategy in which the total daily IV furosemide dose was equivalent to their total daily oral diuretic dose, or a high-dose strategy in which the total daily IV furosemide dose was equivalent to 2.5 times their total daily diuretic dose. They also were randomly assigned to receive furosemide by either an IV bolus every 12 hours or by a continuous IV infusion.
Patients were assessed at baseline, 72 hours, and 60 days. The primary efficacy end point was the patient’s global assessment of symptoms from baseline through 72 hours, and the primary safety end point was the change in serum creatinine level from baseline to 72 hours.
There were no significant differences among the four study groups in either of these end points. There also were no significant differences across a variety of secondary end points, including dyspnea, change in body weight, net fluid loss, percentage of patients affected by congestion, worsening renal function, worsening heart failure, or changes in several biomarkers, Dr. Felker and his colleagues said (N. Engl. J. Med. 2011;364:797-805).
There was a trend toward greater improvement of patient-reported global symptoms with the high-dose strategy, but this did not reach statistical significance. Moreover, this potential benefit was offset by a higher incidence of transient worsening renal function that also did not reach statistical significance.
The median length of stay was 5 days in all four groups. A total of 130 patients (42%) died, required rehospitalization, or required a visit to the emergency department within 60 days, but there were no significant differences among the treatment groups in this composite end point. The total number of patients who were alive and not hospitalized at 60 days also did not differ significantly among the four groups.
The DOSE study was funded by the National Heart, Lung, and Blood Institute. Dr. Felker and his associates reported numerous ties to drug and device companies, including those that manufacture diuretics.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: After 72 hours of hospitalization for acute decompensated heart failure, patients’ symptoms and creatinine levels were not significantly different, regardless of whether they had received high-dose or low-dose diuretic therapy and regardless of whether they had received continuous IV infusion or twice-a-day IV boluses of diuretics.
Data Source: A prospective, double-blind, randomized clinical trial involving 308 patients treated at 26 clinical centers in the U.S. and Canada for acute decompensated HF.
Disclosures: The DOSE study was funded by the National Heart, Lung, and Blood Institute. Dr. Felker and his associates reported numerous ties to drug and device companies.
Study: Esomeprazole Plus Clopidogrel Can Safely Prevent Peptic Ulcers
For patients who must take clopidogrel for atherosclerosis but have a history of peptic ulcer, the addition of esomeprazole to the antiplatelet therapy can prevent recurrent peptic ulcer, Dr. Ping-I Hsu and colleagues reported in the March issue of Gastroenterology.
Esomeprazole did not interfere with clopidogrel’s antiplatelet action when the two drugs were taken 14-16 hours apart every day, said Dr. Hsu of Kaohsiung (Taiwan) Veterans General Hospital and National Yang-Ming University in Taipei, Taiwan, and his associates.
Research has shown that a significant number of patients with atherosclerosis who have a history of peptic ulcer will develop recurrent ulcers during treatment with clopidogrel. Moreover, some data have raised concerns that proton pump inhibitors (PPIs) such as esomeprazole might inhibit the conversion of clopidogrel to its active form, interfering with its efficacy.
"Both the U.S. Food and Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary," Dr. Hsu and his colleagues noted.
They examined these issues in a 6-month, prospective, randomized clinical trial involving 165 patients who had atherosclerosis and a history of peptic ulcer confirmed by endoscopy. In the open-label study, 82 subjects were randomly assigned to take daily clopidogrel (75 mg) alone and 83 to take esomeprazole (20 mg) before breakfast and clopidogrel at bedtime every day (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.056]).
The study subjects were allowed to take antacids for dyspeptic symptoms but were not permitted to take anticoagulants, cyclooxygenase-2 (COX-2) inhibitors, NSAIDs, over-the-counter analgesics, corticosteroids, misoprostol, histamine H2 receptor antagonists, or sucralfate.
In the intention-to-treat analysis, there were 10 cases of recurrent peptic ulcer in patients taking clopidogrel alone, for a cumulative incidence of 11%. In contrast, only one patient taking clopidogrel plus esomeprazole developed recurrent peptic ulcer, for a cumulative incidence of only 1%.
In the per-protocol analysis of 129 patients who completed the study, the respective incidences were very similar, at 12% and 2%.
These results "confirm our hypothesis that esomeprazole can effectively prevent recurrent ulcer in clopidogrel users who have a peptic ulcer history," the investigators said.
The rates of loss to follow-up or to medication intolerance were similar between the two groups, at approximately 5% each. Also similar were rates of dyspeptic symptoms (23% with combined treatment and 28% with clopidogrel alone) and consumption of antacids (51 tablets and 66 tablets, respectively).
A subset of 42 patients (21 in each treatment group) underwent pharmacodynamic testing to examine whether esomeprazole interfered with clopidogrel’s antiplatelet action. There were no differences between the two groups in the results of platelet aggregation tests.
Moreover, the rates of cardiovascular events including unstable angina, acute MI, and ischemic stroke were not significantly different between the two groups.
"It is important to note that we widely separated the administration of esomeprazole and clopidogrel in this study," the researchers said.
The half-lives of both drugs are very short, so the 14- to 16-hour separation likely minimized any potential interactions. This study could not address potential drug interactions if the two agents are given closer together, Dr. Hsu and his associates said.
The specific reasons for recurrence of peptic ulcers in the study remain unclear. "Nonetheless, it should be noted that most of our patients had advanced age and comorbid diseases," both of which have been shown to predispose patients to the development of ulcers "even in the absence of [Helicobacter] pylori infection or the use of NSAIDs," they added.
The investigators emphasized that their results pertain only to clopidogrel monotherapy and cannot be generalized to the majority of patients who take clopidogrel in combination with low-dose aspirin (dual antiplatelet therapy).
This study was funded by the research fund of the Kaohsiung Veterans General Hospital. No financial conflicts of interest were reported.
For patients who must take clopidogrel for atherosclerosis but have a history of peptic ulcer, the addition of esomeprazole to the antiplatelet therapy can prevent recurrent peptic ulcer, Dr. Ping-I Hsu and colleagues reported in the March issue of Gastroenterology.
Esomeprazole did not interfere with clopidogrel’s antiplatelet action when the two drugs were taken 14-16 hours apart every day, said Dr. Hsu of Kaohsiung (Taiwan) Veterans General Hospital and National Yang-Ming University in Taipei, Taiwan, and his associates.
Research has shown that a significant number of patients with atherosclerosis who have a history of peptic ulcer will develop recurrent ulcers during treatment with clopidogrel. Moreover, some data have raised concerns that proton pump inhibitors (PPIs) such as esomeprazole might inhibit the conversion of clopidogrel to its active form, interfering with its efficacy.
"Both the U.S. Food and Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary," Dr. Hsu and his colleagues noted.
They examined these issues in a 6-month, prospective, randomized clinical trial involving 165 patients who had atherosclerosis and a history of peptic ulcer confirmed by endoscopy. In the open-label study, 82 subjects were randomly assigned to take daily clopidogrel (75 mg) alone and 83 to take esomeprazole (20 mg) before breakfast and clopidogrel at bedtime every day (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.056]).
The study subjects were allowed to take antacids for dyspeptic symptoms but were not permitted to take anticoagulants, cyclooxygenase-2 (COX-2) inhibitors, NSAIDs, over-the-counter analgesics, corticosteroids, misoprostol, histamine H2 receptor antagonists, or sucralfate.
In the intention-to-treat analysis, there were 10 cases of recurrent peptic ulcer in patients taking clopidogrel alone, for a cumulative incidence of 11%. In contrast, only one patient taking clopidogrel plus esomeprazole developed recurrent peptic ulcer, for a cumulative incidence of only 1%.
In the per-protocol analysis of 129 patients who completed the study, the respective incidences were very similar, at 12% and 2%.
These results "confirm our hypothesis that esomeprazole can effectively prevent recurrent ulcer in clopidogrel users who have a peptic ulcer history," the investigators said.
The rates of loss to follow-up or to medication intolerance were similar between the two groups, at approximately 5% each. Also similar were rates of dyspeptic symptoms (23% with combined treatment and 28% with clopidogrel alone) and consumption of antacids (51 tablets and 66 tablets, respectively).
A subset of 42 patients (21 in each treatment group) underwent pharmacodynamic testing to examine whether esomeprazole interfered with clopidogrel’s antiplatelet action. There were no differences between the two groups in the results of platelet aggregation tests.
Moreover, the rates of cardiovascular events including unstable angina, acute MI, and ischemic stroke were not significantly different between the two groups.
"It is important to note that we widely separated the administration of esomeprazole and clopidogrel in this study," the researchers said.
The half-lives of both drugs are very short, so the 14- to 16-hour separation likely minimized any potential interactions. This study could not address potential drug interactions if the two agents are given closer together, Dr. Hsu and his associates said.
The specific reasons for recurrence of peptic ulcers in the study remain unclear. "Nonetheless, it should be noted that most of our patients had advanced age and comorbid diseases," both of which have been shown to predispose patients to the development of ulcers "even in the absence of [Helicobacter] pylori infection or the use of NSAIDs," they added.
The investigators emphasized that their results pertain only to clopidogrel monotherapy and cannot be generalized to the majority of patients who take clopidogrel in combination with low-dose aspirin (dual antiplatelet therapy).
This study was funded by the research fund of the Kaohsiung Veterans General Hospital. No financial conflicts of interest were reported.
For patients who must take clopidogrel for atherosclerosis but have a history of peptic ulcer, the addition of esomeprazole to the antiplatelet therapy can prevent recurrent peptic ulcer, Dr. Ping-I Hsu and colleagues reported in the March issue of Gastroenterology.
Esomeprazole did not interfere with clopidogrel’s antiplatelet action when the two drugs were taken 14-16 hours apart every day, said Dr. Hsu of Kaohsiung (Taiwan) Veterans General Hospital and National Yang-Ming University in Taipei, Taiwan, and his associates.
Research has shown that a significant number of patients with atherosclerosis who have a history of peptic ulcer will develop recurrent ulcers during treatment with clopidogrel. Moreover, some data have raised concerns that proton pump inhibitors (PPIs) such as esomeprazole might inhibit the conversion of clopidogrel to its active form, interfering with its efficacy.
"Both the U.S. Food and Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary," Dr. Hsu and his colleagues noted.
They examined these issues in a 6-month, prospective, randomized clinical trial involving 165 patients who had atherosclerosis and a history of peptic ulcer confirmed by endoscopy. In the open-label study, 82 subjects were randomly assigned to take daily clopidogrel (75 mg) alone and 83 to take esomeprazole (20 mg) before breakfast and clopidogrel at bedtime every day (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.056]).
The study subjects were allowed to take antacids for dyspeptic symptoms but were not permitted to take anticoagulants, cyclooxygenase-2 (COX-2) inhibitors, NSAIDs, over-the-counter analgesics, corticosteroids, misoprostol, histamine H2 receptor antagonists, or sucralfate.
In the intention-to-treat analysis, there were 10 cases of recurrent peptic ulcer in patients taking clopidogrel alone, for a cumulative incidence of 11%. In contrast, only one patient taking clopidogrel plus esomeprazole developed recurrent peptic ulcer, for a cumulative incidence of only 1%.
In the per-protocol analysis of 129 patients who completed the study, the respective incidences were very similar, at 12% and 2%.
These results "confirm our hypothesis that esomeprazole can effectively prevent recurrent ulcer in clopidogrel users who have a peptic ulcer history," the investigators said.
The rates of loss to follow-up or to medication intolerance were similar between the two groups, at approximately 5% each. Also similar were rates of dyspeptic symptoms (23% with combined treatment and 28% with clopidogrel alone) and consumption of antacids (51 tablets and 66 tablets, respectively).
A subset of 42 patients (21 in each treatment group) underwent pharmacodynamic testing to examine whether esomeprazole interfered with clopidogrel’s antiplatelet action. There were no differences between the two groups in the results of platelet aggregation tests.
Moreover, the rates of cardiovascular events including unstable angina, acute MI, and ischemic stroke were not significantly different between the two groups.
"It is important to note that we widely separated the administration of esomeprazole and clopidogrel in this study," the researchers said.
The half-lives of both drugs are very short, so the 14- to 16-hour separation likely minimized any potential interactions. This study could not address potential drug interactions if the two agents are given closer together, Dr. Hsu and his associates said.
The specific reasons for recurrence of peptic ulcers in the study remain unclear. "Nonetheless, it should be noted that most of our patients had advanced age and comorbid diseases," both of which have been shown to predispose patients to the development of ulcers "even in the absence of [Helicobacter] pylori infection or the use of NSAIDs," they added.
The investigators emphasized that their results pertain only to clopidogrel monotherapy and cannot be generalized to the majority of patients who take clopidogrel in combination with low-dose aspirin (dual antiplatelet therapy).
This study was funded by the research fund of the Kaohsiung Veterans General Hospital. No financial conflicts of interest were reported.
FROM GASTROENTEROLOGY
Study: Esomeprazole Plus Clopidogrel Can Safely Prevent Peptic Ulcers
For patients who must take clopidogrel for atherosclerosis but have a history of peptic ulcer, the addition of esomeprazole to the antiplatelet therapy can prevent recurrent peptic ulcer, Dr. Ping-I Hsu and colleagues reported in the March issue of Gastroenterology.
Esomeprazole did not interfere with clopidogrel’s antiplatelet action when the two drugs were taken 14-16 hours apart every day, said Dr. Hsu of Kaohsiung (Taiwan) Veterans General Hospital and National Yang-Ming University in Taipei, Taiwan, and his associates.
Research has shown that a significant number of patients with atherosclerosis who have a history of peptic ulcer will develop recurrent ulcers during treatment with clopidogrel. Moreover, some data have raised concerns that proton pump inhibitors (PPIs) such as esomeprazole might inhibit the conversion of clopidogrel to its active form, interfering with its efficacy.
"Both the U.S. Food and Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary," Dr. Hsu and his colleagues noted.
They examined these issues in a 6-month, prospective, randomized clinical trial involving 165 patients who had atherosclerosis and a history of peptic ulcer confirmed by endoscopy. In the open-label study, 82 subjects were randomly assigned to take daily clopidogrel (75 mg) alone and 83 to take esomeprazole (20 mg) before breakfast and clopidogrel at bedtime every day (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.056]).
The study subjects were allowed to take antacids for dyspeptic symptoms but were not permitted to take anticoagulants, cyclooxygenase-2 (COX-2) inhibitors, NSAIDs, over-the-counter analgesics, corticosteroids, misoprostol, histamine H2 receptor antagonists, or sucralfate.
In the intention-to-treat analysis, there were 10 cases of recurrent peptic ulcer in patients taking clopidogrel alone, for a cumulative incidence of 11%. In contrast, only one patient taking clopidogrel plus esomeprazole developed recurrent peptic ulcer, for a cumulative incidence of only 1%.
In the per-protocol analysis of 129 patients who completed the study, the respective incidences were very similar, at 12% and 2%.
These results "confirm our hypothesis that esomeprazole can effectively prevent recurrent ulcer in clopidogrel users who have a peptic ulcer history," the investigators said.
The rates of loss to follow-up or to medication intolerance were similar between the two groups, at approximately 5% each. Also similar were rates of dyspeptic symptoms (23% with combined treatment and 28% with clopidogrel alone) and consumption of antacids (51 tablets and 66 tablets, respectively).
A subset of 42 patients (21 in each treatment group) underwent pharmacodynamic testing to examine whether esomeprazole interfered with clopidogrel’s antiplatelet action. There were no differences between the two groups in the results of platelet aggregation tests.
Moreover, the rates of cardiovascular events including unstable angina, acute MI, and ischemic stroke were not significantly different between the two groups.
"It is important to note that we widely separated the administration of esomeprazole and clopidogrel in this study," the researchers said.
The half-lives of both drugs are very short, so the 14- to 16-hour separation likely minimized any potential interactions. This study could not address potential drug interactions if the two agents are given closer together, Dr. Hsu and his associates said.
The specific reasons for recurrence of peptic ulcers in the study remain unclear. "Nonetheless, it should be noted that most of our patients had advanced age and comorbid diseases," both of which have been shown to predispose patients to the development of ulcers "even in the absence of [Helicobacter] pylori infection or the use of NSAIDs," they added.
The investigators emphasized that their results pertain only to clopidogrel monotherapy and cannot be generalized to the majority of patients who take clopidogrel in combination with low-dose aspirin (dual antiplatelet therapy).
This study was funded by the research fund of the Kaohsiung Veterans General Hospital. No financial conflicts of interest were reported.
For patients who must take clopidogrel for atherosclerosis but have a history of peptic ulcer, the addition of esomeprazole to the antiplatelet therapy can prevent recurrent peptic ulcer, Dr. Ping-I Hsu and colleagues reported in the March issue of Gastroenterology.
Esomeprazole did not interfere with clopidogrel’s antiplatelet action when the two drugs were taken 14-16 hours apart every day, said Dr. Hsu of Kaohsiung (Taiwan) Veterans General Hospital and National Yang-Ming University in Taipei, Taiwan, and his associates.
Research has shown that a significant number of patients with atherosclerosis who have a history of peptic ulcer will develop recurrent ulcers during treatment with clopidogrel. Moreover, some data have raised concerns that proton pump inhibitors (PPIs) such as esomeprazole might inhibit the conversion of clopidogrel to its active form, interfering with its efficacy.
"Both the U.S. Food and Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary," Dr. Hsu and his colleagues noted.
They examined these issues in a 6-month, prospective, randomized clinical trial involving 165 patients who had atherosclerosis and a history of peptic ulcer confirmed by endoscopy. In the open-label study, 82 subjects were randomly assigned to take daily clopidogrel (75 mg) alone and 83 to take esomeprazole (20 mg) before breakfast and clopidogrel at bedtime every day (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.056]).
The study subjects were allowed to take antacids for dyspeptic symptoms but were not permitted to take anticoagulants, cyclooxygenase-2 (COX-2) inhibitors, NSAIDs, over-the-counter analgesics, corticosteroids, misoprostol, histamine H2 receptor antagonists, or sucralfate.
In the intention-to-treat analysis, there were 10 cases of recurrent peptic ulcer in patients taking clopidogrel alone, for a cumulative incidence of 11%. In contrast, only one patient taking clopidogrel plus esomeprazole developed recurrent peptic ulcer, for a cumulative incidence of only 1%.
In the per-protocol analysis of 129 patients who completed the study, the respective incidences were very similar, at 12% and 2%.
These results "confirm our hypothesis that esomeprazole can effectively prevent recurrent ulcer in clopidogrel users who have a peptic ulcer history," the investigators said.
The rates of loss to follow-up or to medication intolerance were similar between the two groups, at approximately 5% each. Also similar were rates of dyspeptic symptoms (23% with combined treatment and 28% with clopidogrel alone) and consumption of antacids (51 tablets and 66 tablets, respectively).
A subset of 42 patients (21 in each treatment group) underwent pharmacodynamic testing to examine whether esomeprazole interfered with clopidogrel’s antiplatelet action. There were no differences between the two groups in the results of platelet aggregation tests.
Moreover, the rates of cardiovascular events including unstable angina, acute MI, and ischemic stroke were not significantly different between the two groups.
"It is important to note that we widely separated the administration of esomeprazole and clopidogrel in this study," the researchers said.
The half-lives of both drugs are very short, so the 14- to 16-hour separation likely minimized any potential interactions. This study could not address potential drug interactions if the two agents are given closer together, Dr. Hsu and his associates said.
The specific reasons for recurrence of peptic ulcers in the study remain unclear. "Nonetheless, it should be noted that most of our patients had advanced age and comorbid diseases," both of which have been shown to predispose patients to the development of ulcers "even in the absence of [Helicobacter] pylori infection or the use of NSAIDs," they added.
The investigators emphasized that their results pertain only to clopidogrel monotherapy and cannot be generalized to the majority of patients who take clopidogrel in combination with low-dose aspirin (dual antiplatelet therapy).
This study was funded by the research fund of the Kaohsiung Veterans General Hospital. No financial conflicts of interest were reported.
For patients who must take clopidogrel for atherosclerosis but have a history of peptic ulcer, the addition of esomeprazole to the antiplatelet therapy can prevent recurrent peptic ulcer, Dr. Ping-I Hsu and colleagues reported in the March issue of Gastroenterology.
Esomeprazole did not interfere with clopidogrel’s antiplatelet action when the two drugs were taken 14-16 hours apart every day, said Dr. Hsu of Kaohsiung (Taiwan) Veterans General Hospital and National Yang-Ming University in Taipei, Taiwan, and his associates.
Research has shown that a significant number of patients with atherosclerosis who have a history of peptic ulcer will develop recurrent ulcers during treatment with clopidogrel. Moreover, some data have raised concerns that proton pump inhibitors (PPIs) such as esomeprazole might inhibit the conversion of clopidogrel to its active form, interfering with its efficacy.
"Both the U.S. Food and Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary," Dr. Hsu and his colleagues noted.
They examined these issues in a 6-month, prospective, randomized clinical trial involving 165 patients who had atherosclerosis and a history of peptic ulcer confirmed by endoscopy. In the open-label study, 82 subjects were randomly assigned to take daily clopidogrel (75 mg) alone and 83 to take esomeprazole (20 mg) before breakfast and clopidogrel at bedtime every day (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.056]).
The study subjects were allowed to take antacids for dyspeptic symptoms but were not permitted to take anticoagulants, cyclooxygenase-2 (COX-2) inhibitors, NSAIDs, over-the-counter analgesics, corticosteroids, misoprostol, histamine H2 receptor antagonists, or sucralfate.
In the intention-to-treat analysis, there were 10 cases of recurrent peptic ulcer in patients taking clopidogrel alone, for a cumulative incidence of 11%. In contrast, only one patient taking clopidogrel plus esomeprazole developed recurrent peptic ulcer, for a cumulative incidence of only 1%.
In the per-protocol analysis of 129 patients who completed the study, the respective incidences were very similar, at 12% and 2%.
These results "confirm our hypothesis that esomeprazole can effectively prevent recurrent ulcer in clopidogrel users who have a peptic ulcer history," the investigators said.
The rates of loss to follow-up or to medication intolerance were similar between the two groups, at approximately 5% each. Also similar were rates of dyspeptic symptoms (23% with combined treatment and 28% with clopidogrel alone) and consumption of antacids (51 tablets and 66 tablets, respectively).
A subset of 42 patients (21 in each treatment group) underwent pharmacodynamic testing to examine whether esomeprazole interfered with clopidogrel’s antiplatelet action. There were no differences between the two groups in the results of platelet aggregation tests.
Moreover, the rates of cardiovascular events including unstable angina, acute MI, and ischemic stroke were not significantly different between the two groups.
"It is important to note that we widely separated the administration of esomeprazole and clopidogrel in this study," the researchers said.
The half-lives of both drugs are very short, so the 14- to 16-hour separation likely minimized any potential interactions. This study could not address potential drug interactions if the two agents are given closer together, Dr. Hsu and his associates said.
The specific reasons for recurrence of peptic ulcers in the study remain unclear. "Nonetheless, it should be noted that most of our patients had advanced age and comorbid diseases," both of which have been shown to predispose patients to the development of ulcers "even in the absence of [Helicobacter] pylori infection or the use of NSAIDs," they added.
The investigators emphasized that their results pertain only to clopidogrel monotherapy and cannot be generalized to the majority of patients who take clopidogrel in combination with low-dose aspirin (dual antiplatelet therapy).
This study was funded by the research fund of the Kaohsiung Veterans General Hospital. No financial conflicts of interest were reported.
FROM GASTROENTEROLOGY
Study: Half of Men Infected With Genital HPV
Approximately half of men of all ages were infected with genital human papillomavirus, according to a prospective study of three urban areas in the United States, Brazil, and Mexico.
In addition, men's risk for acquiring HPV did not decline with age as it does in women, but appeared to remain stable throughout their lifetimes, said Dr. Anna R. Giuliano of the risk assessment, detection, and intervention program at H. Lee Moffitt Cancer Center and Research Institute, Tampa, and her associates.
The Lancet published the study online March 1.
The researchers examined the incidence and clearance of genital HPV among men because little is known about the subject. Optimal strategies for preventing the disease both in men and in their sexual partners cannot be devised until more is known about its epidemiology in men, they wrote.
The prospective HPV in Men (HIM) study involved 1,427 men in Tampa, 1,443 in Sao Paulo, Brazil, and 1,429 in Cuernavaca, Mexico, who were examined for HPV infection at 6-month intervals for a median of 27.5 months. The men were aged 18-70 years at baseline, with a median age of 32 years. All subjects were HIV negative and had no history of cancer.
At each visit, three specimens of penile and scrotal cells were obtained from the coronal sulcus, glans penis, penile shaft, and scrotum for the detection of HPV DNA and for HPV genotyping. Sociodemographic and sexual behavior data were obtained using a questionnaire.
Dr. Giuliano and her colleagues reported findings for a subgroup of the first 1,159 study subjects they assessed. The overall rate of infection with any HPV type was 50%. The overall prevalence of oncogenic HPV subtypes was 30% and that of nononcogenic subtypes was 38%, they said (Lancet 2011 March 1:[doi:10.106/S0140-6736(10)62342-2]).
The incidence of acquisition of a new HPV infection was 38.4/1,000 person-months and did not change appreciably according to subject age. The reason for the lack of an age association such as that seen among women is not yet known. In the study cohort, men in three age groups – 18-30 years, 31-44 years, and 45-70 years – reported having similar numbers of sexual partners and of new sexual partners. Thus, it is possible that they have continued exposure to HPV as they age, the researchers noted.
"Another possible explanation is sex differences in the HPV immune response," Dr. Giuliano and her associates said. "HPV infection of keratinized epithelium, such as the penile skin, might generate lower and weaker immune responses than infection of mucosal epithelium such as the cervix or anal canal."
If men remain at high risk of developing new HPV infections throughout their lives, "then vaccination of older men might be warranted," they noted.
Acquisition of a new HPV infection strongly correlated with the patients' reported number of sexual partners, male or female. Compared with men who reported no more than 1 lifetime female sexual partner, men who reported they had 10-49 lifetime female sexual partners were 2.7 times as likely to be infected. Those who reported at least three male anal-sex partners in the past 3 months were 2.3 times as likely to develop an infection as those reporting no partners.
Similarly, acquisition of a new infection with an oncogenic HPV subtype correlated with the number of female sexual partners and of male partners who engaged in anal sex. Again, the risk was more than two times greater among men who reported 10 or more such partners than among those who reported no more than 1 partner. Those who reported at least three male anal-sex partners in the past 3 months were 2.6 times as likely to develop an oncogenic HPV infection as those reporting no partners.
The odds of clearing an existing HPV infection also showed a strong association with number of sexual partners. And, as has been reported among women, the odds of clearing an HPV infection in men varied according to HPV subtype. The median time to clearance for oncogenic HPV was 7.2 months, while the median time to clearance of nononcogenic HPV was 7.6 months. Infection clearance times shortened with increasing age.
"The results from this study provide much-needed data about the incidence and clearance of HPV infection in men; these data are essential for the development of realistic cost-effectiveness models for male HPV vaccination internationally," the investigators said.
The National Cancer Institute supported the study. Dr. Giuliano reported ties to Merck, the manufacturer of the HPV vaccine.
The HIM study brings to light "important new information, and draw[s] attention to differences between the natural histories of male and female HPV infections, and the need for further studies to better define HPV transmission, progression to disease, and epithelial sites in men," according to Dr. Joseph Monsonego.
It appears that men have high infection rates but low disease rates, whereas women have low infection rates and high disease rates. Apart from genital warts, HPV-linked genital neoplasia is rare in men. Penile intraepithelial neoplasia is 10-20 times less frequent than cervical intraepithelial neoplasia in women, and HPV-induced cancers of the penis are extremely rare, he noted.
The findings also have implications for vaccinating men against HPV. "The cost-benefit ratio of vaccinating men to protect women from cervical neoplasia has yet to be definitively established," he noted. "However, as more diseases are prevented through male vaccination, notably anal cancer, the greater the cost-effectiveness of routine vaccination of both sexes."
Dr. Monsonego is at the Institute of the Cervix, Paris. He reported that he is on the board of and receives grants from EUROGIN. These remarks were taken from his editorial comment accompanying Dr. Giuliano's report (Lancet 2011 March 1:[doi:10.1016/So140-6736(11)60277-8]).
The HIM study brings to light "important new information, and draw[s] attention to differences between the natural histories of male and female HPV infections, and the need for further studies to better define HPV transmission, progression to disease, and epithelial sites in men," according to Dr. Joseph Monsonego.
It appears that men have high infection rates but low disease rates, whereas women have low infection rates and high disease rates. Apart from genital warts, HPV-linked genital neoplasia is rare in men. Penile intraepithelial neoplasia is 10-20 times less frequent than cervical intraepithelial neoplasia in women, and HPV-induced cancers of the penis are extremely rare, he noted.
The findings also have implications for vaccinating men against HPV. "The cost-benefit ratio of vaccinating men to protect women from cervical neoplasia has yet to be definitively established," he noted. "However, as more diseases are prevented through male vaccination, notably anal cancer, the greater the cost-effectiveness of routine vaccination of both sexes."
Dr. Monsonego is at the Institute of the Cervix, Paris. He reported that he is on the board of and receives grants from EUROGIN. These remarks were taken from his editorial comment accompanying Dr. Giuliano's report (Lancet 2011 March 1:[doi:10.1016/So140-6736(11)60277-8]).
The HIM study brings to light "important new information, and draw[s] attention to differences between the natural histories of male and female HPV infections, and the need for further studies to better define HPV transmission, progression to disease, and epithelial sites in men," according to Dr. Joseph Monsonego.
It appears that men have high infection rates but low disease rates, whereas women have low infection rates and high disease rates. Apart from genital warts, HPV-linked genital neoplasia is rare in men. Penile intraepithelial neoplasia is 10-20 times less frequent than cervical intraepithelial neoplasia in women, and HPV-induced cancers of the penis are extremely rare, he noted.
The findings also have implications for vaccinating men against HPV. "The cost-benefit ratio of vaccinating men to protect women from cervical neoplasia has yet to be definitively established," he noted. "However, as more diseases are prevented through male vaccination, notably anal cancer, the greater the cost-effectiveness of routine vaccination of both sexes."
Dr. Monsonego is at the Institute of the Cervix, Paris. He reported that he is on the board of and receives grants from EUROGIN. These remarks were taken from his editorial comment accompanying Dr. Giuliano's report (Lancet 2011 March 1:[doi:10.1016/So140-6736(11)60277-8]).
Approximately half of men of all ages were infected with genital human papillomavirus, according to a prospective study of three urban areas in the United States, Brazil, and Mexico.
In addition, men's risk for acquiring HPV did not decline with age as it does in women, but appeared to remain stable throughout their lifetimes, said Dr. Anna R. Giuliano of the risk assessment, detection, and intervention program at H. Lee Moffitt Cancer Center and Research Institute, Tampa, and her associates.
The Lancet published the study online March 1.
The researchers examined the incidence and clearance of genital HPV among men because little is known about the subject. Optimal strategies for preventing the disease both in men and in their sexual partners cannot be devised until more is known about its epidemiology in men, they wrote.
The prospective HPV in Men (HIM) study involved 1,427 men in Tampa, 1,443 in Sao Paulo, Brazil, and 1,429 in Cuernavaca, Mexico, who were examined for HPV infection at 6-month intervals for a median of 27.5 months. The men were aged 18-70 years at baseline, with a median age of 32 years. All subjects were HIV negative and had no history of cancer.
At each visit, three specimens of penile and scrotal cells were obtained from the coronal sulcus, glans penis, penile shaft, and scrotum for the detection of HPV DNA and for HPV genotyping. Sociodemographic and sexual behavior data were obtained using a questionnaire.
Dr. Giuliano and her colleagues reported findings for a subgroup of the first 1,159 study subjects they assessed. The overall rate of infection with any HPV type was 50%. The overall prevalence of oncogenic HPV subtypes was 30% and that of nononcogenic subtypes was 38%, they said (Lancet 2011 March 1:[doi:10.106/S0140-6736(10)62342-2]).
The incidence of acquisition of a new HPV infection was 38.4/1,000 person-months and did not change appreciably according to subject age. The reason for the lack of an age association such as that seen among women is not yet known. In the study cohort, men in three age groups – 18-30 years, 31-44 years, and 45-70 years – reported having similar numbers of sexual partners and of new sexual partners. Thus, it is possible that they have continued exposure to HPV as they age, the researchers noted.
"Another possible explanation is sex differences in the HPV immune response," Dr. Giuliano and her associates said. "HPV infection of keratinized epithelium, such as the penile skin, might generate lower and weaker immune responses than infection of mucosal epithelium such as the cervix or anal canal."
If men remain at high risk of developing new HPV infections throughout their lives, "then vaccination of older men might be warranted," they noted.
Acquisition of a new HPV infection strongly correlated with the patients' reported number of sexual partners, male or female. Compared with men who reported no more than 1 lifetime female sexual partner, men who reported they had 10-49 lifetime female sexual partners were 2.7 times as likely to be infected. Those who reported at least three male anal-sex partners in the past 3 months were 2.3 times as likely to develop an infection as those reporting no partners.
Similarly, acquisition of a new infection with an oncogenic HPV subtype correlated with the number of female sexual partners and of male partners who engaged in anal sex. Again, the risk was more than two times greater among men who reported 10 or more such partners than among those who reported no more than 1 partner. Those who reported at least three male anal-sex partners in the past 3 months were 2.6 times as likely to develop an oncogenic HPV infection as those reporting no partners.
The odds of clearing an existing HPV infection also showed a strong association with number of sexual partners. And, as has been reported among women, the odds of clearing an HPV infection in men varied according to HPV subtype. The median time to clearance for oncogenic HPV was 7.2 months, while the median time to clearance of nononcogenic HPV was 7.6 months. Infection clearance times shortened with increasing age.
"The results from this study provide much-needed data about the incidence and clearance of HPV infection in men; these data are essential for the development of realistic cost-effectiveness models for male HPV vaccination internationally," the investigators said.
The National Cancer Institute supported the study. Dr. Giuliano reported ties to Merck, the manufacturer of the HPV vaccine.
Approximately half of men of all ages were infected with genital human papillomavirus, according to a prospective study of three urban areas in the United States, Brazil, and Mexico.
In addition, men's risk for acquiring HPV did not decline with age as it does in women, but appeared to remain stable throughout their lifetimes, said Dr. Anna R. Giuliano of the risk assessment, detection, and intervention program at H. Lee Moffitt Cancer Center and Research Institute, Tampa, and her associates.
The Lancet published the study online March 1.
The researchers examined the incidence and clearance of genital HPV among men because little is known about the subject. Optimal strategies for preventing the disease both in men and in their sexual partners cannot be devised until more is known about its epidemiology in men, they wrote.
The prospective HPV in Men (HIM) study involved 1,427 men in Tampa, 1,443 in Sao Paulo, Brazil, and 1,429 in Cuernavaca, Mexico, who were examined for HPV infection at 6-month intervals for a median of 27.5 months. The men were aged 18-70 years at baseline, with a median age of 32 years. All subjects were HIV negative and had no history of cancer.
At each visit, three specimens of penile and scrotal cells were obtained from the coronal sulcus, glans penis, penile shaft, and scrotum for the detection of HPV DNA and for HPV genotyping. Sociodemographic and sexual behavior data were obtained using a questionnaire.
Dr. Giuliano and her colleagues reported findings for a subgroup of the first 1,159 study subjects they assessed. The overall rate of infection with any HPV type was 50%. The overall prevalence of oncogenic HPV subtypes was 30% and that of nononcogenic subtypes was 38%, they said (Lancet 2011 March 1:[doi:10.106/S0140-6736(10)62342-2]).
The incidence of acquisition of a new HPV infection was 38.4/1,000 person-months and did not change appreciably according to subject age. The reason for the lack of an age association such as that seen among women is not yet known. In the study cohort, men in three age groups – 18-30 years, 31-44 years, and 45-70 years – reported having similar numbers of sexual partners and of new sexual partners. Thus, it is possible that they have continued exposure to HPV as they age, the researchers noted.
"Another possible explanation is sex differences in the HPV immune response," Dr. Giuliano and her associates said. "HPV infection of keratinized epithelium, such as the penile skin, might generate lower and weaker immune responses than infection of mucosal epithelium such as the cervix or anal canal."
If men remain at high risk of developing new HPV infections throughout their lives, "then vaccination of older men might be warranted," they noted.
Acquisition of a new HPV infection strongly correlated with the patients' reported number of sexual partners, male or female. Compared with men who reported no more than 1 lifetime female sexual partner, men who reported they had 10-49 lifetime female sexual partners were 2.7 times as likely to be infected. Those who reported at least three male anal-sex partners in the past 3 months were 2.3 times as likely to develop an infection as those reporting no partners.
Similarly, acquisition of a new infection with an oncogenic HPV subtype correlated with the number of female sexual partners and of male partners who engaged in anal sex. Again, the risk was more than two times greater among men who reported 10 or more such partners than among those who reported no more than 1 partner. Those who reported at least three male anal-sex partners in the past 3 months were 2.6 times as likely to develop an oncogenic HPV infection as those reporting no partners.
The odds of clearing an existing HPV infection also showed a strong association with number of sexual partners. And, as has been reported among women, the odds of clearing an HPV infection in men varied according to HPV subtype. The median time to clearance for oncogenic HPV was 7.2 months, while the median time to clearance of nononcogenic HPV was 7.6 months. Infection clearance times shortened with increasing age.
"The results from this study provide much-needed data about the incidence and clearance of HPV infection in men; these data are essential for the development of realistic cost-effectiveness models for male HPV vaccination internationally," the investigators said.
The National Cancer Institute supported the study. Dr. Giuliano reported ties to Merck, the manufacturer of the HPV vaccine.
FROM THE LANCET
Major Finding: The incidence of genital HPV infection was 50% among men of all ages in three cities in the Western Hemisphere.
Data Source: A prospective epidemiologic study of HPV infection in men aged 18-70 years living in Tampa, Fla.; Sao Paulo, Brazil; and Cuernavaca, Mexico.
Disclosures: The National Cancer Institute supported the study. Dr. Giuliano reported ties to Merck, the manufacturer of the HPV vaccine.
Subset of HIV/HCV Co-infected at Risk for Hepatic Steatosis
In patients co-infected with HIV and hepatitis C virus, alcohol use and a high body mass index are associated with progression of hepatic steatosis, whereas exposure to certain antiretrovirals and a high baseline CD4 count appear to be protective against steatosis, Dr. Tinsay A. Woreta and her colleagues reported in the March issue of Gastroenterology.
In their study of 222 patients who were co-infected with HIV and HCV, more than 90% showed no progression of steatosis during nearly 3 years of follow-up.
The findings indicate that efforts to diagnose and prevent hepatic steatosis "should be focused on persons with a high body mass index and excessive alcohol intake," said Dr. Woreta of Johns Hopkins University, Baltimore, and her associates (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.052]).
Hepatitis C virus is not uncommon in patients with HIV infection, and hepatic steatosis affects 30%-70% of those with both infections. The steatosis is associated with hepatic fibrosis and is thought to contribute to the more rapid progression of liver disease in co-infected patients than in those who don’t have concomitant HIV.
"The natural history of hepatic steatosis is incompletely understood" because most studies have been cross-sectional rather than longitudinal," wrote Dr. Woreta and her colleagues. They performed their longitudinal study to prospectively examine the natural history of steatosis, using data from HIV/HCV–co-infected patients who underwent serial liver biopsies while attending an urban HIV clinic.
There were 345 pairs of serial biopsies available for analysis. The study subjects had a median age of 44 years; 66% were men and 87% were black. Nearly half were overweight or obese. Almost all (94%) had HCV genotype 1.
Most patients (194, or 87%) had no or only trivial hepatic steatosis at baseline, and it did not progress during follow-up in 165 (74%) of them. The other 29 patients who had no or only trivial hepatic steatosis at baseline progressed to significant steatosis during follow-up.
In all, 28 patients had significant hepatic steatosis at baseline, and the steatosis actually regressed in 21 (75%) of them. The other seven patients who had significant hepatic steatosis at baseline maintained that steatosis.
Persistence or progression of steatosis was strongly associated with a history of alcohol abuse. Although few patients reported current alcohol abuse, the medical records showed chronic alcoholism or abuse in approximately half. Many study subjects were probably underreporting their current exposure, particularly because they were aware that they were participating in a study of liver outcomes. "Clinicians evaluating fatty liver disease in HIV-infected patients should remain cognizant about the likelihood of underreporting of alcohol consumption," the investigators noted.
Obesity also was strongly associated with persistent or progressive steatosis, which was not unexpected. Although HIV infection was, until a short time ago, "a progressively fatal disease characterized by severe wasting, the advent of HAART [highly active antiretroviral therapy] has transformed HIV into a chronic disease with an increase in the prevalence of obesity."
"These data underscore the importance of measures to prevent and treat obesity in HIV/HCV–co-infected patients, [given] the development or worsening of hepatic steatosis in these patients," the researchers said.
Longer exposure to antiretroviral therapy appeared to be protective against persistent or progressive steatosis. One possible mechanism for this finding is that HIV infection may promote steatosis by facilitating HCV replication in hepatocytes, so reducing the HIV load would ease steatosis.
"Another possibility is that HIV acts synergistically with HCV to disrupt lipid metabolism. Thus, direct inhibition of HIV viral replication could decrease steatosis, particularly if the antiretroviral agent [has] minimal impact on mitochondrial replication and function," Dr. Woreta and her colleagues said.
They emphasized that stavudine, which has been designated as a "nonpreferred" antiretroviral agent because it was thought to contribute to steatosis, was used by only 6% of patients in this study, so the authors were unable to assess its effects.
A higher CD4 cell count at baseline also appeared to be protective against steatosis. The investigators did not offer any possible explanations for this effect. No association was found between steatosis progression and patient age, sex, race, diabetes status, HCV genotype, fibrosis status, or HCV therapy, they noted.
This study was supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Center for Complementary and Alternative Medicine, the Agency for Healthcare Policy and Research, and the clinical research unit at the Johns Hopkins Medical Institutions. The investigators reported that they had no financial conflicts of interest.
In patients co-infected with HIV and hepatitis C virus, alcohol use and a high body mass index are associated with progression of hepatic steatosis, whereas exposure to certain antiretrovirals and a high baseline CD4 count appear to be protective against steatosis, Dr. Tinsay A. Woreta and her colleagues reported in the March issue of Gastroenterology.
In their study of 222 patients who were co-infected with HIV and HCV, more than 90% showed no progression of steatosis during nearly 3 years of follow-up.
The findings indicate that efforts to diagnose and prevent hepatic steatosis "should be focused on persons with a high body mass index and excessive alcohol intake," said Dr. Woreta of Johns Hopkins University, Baltimore, and her associates (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.052]).
Hepatitis C virus is not uncommon in patients with HIV infection, and hepatic steatosis affects 30%-70% of those with both infections. The steatosis is associated with hepatic fibrosis and is thought to contribute to the more rapid progression of liver disease in co-infected patients than in those who don’t have concomitant HIV.
"The natural history of hepatic steatosis is incompletely understood" because most studies have been cross-sectional rather than longitudinal," wrote Dr. Woreta and her colleagues. They performed their longitudinal study to prospectively examine the natural history of steatosis, using data from HIV/HCV–co-infected patients who underwent serial liver biopsies while attending an urban HIV clinic.
There were 345 pairs of serial biopsies available for analysis. The study subjects had a median age of 44 years; 66% were men and 87% were black. Nearly half were overweight or obese. Almost all (94%) had HCV genotype 1.
Most patients (194, or 87%) had no or only trivial hepatic steatosis at baseline, and it did not progress during follow-up in 165 (74%) of them. The other 29 patients who had no or only trivial hepatic steatosis at baseline progressed to significant steatosis during follow-up.
In all, 28 patients had significant hepatic steatosis at baseline, and the steatosis actually regressed in 21 (75%) of them. The other seven patients who had significant hepatic steatosis at baseline maintained that steatosis.
Persistence or progression of steatosis was strongly associated with a history of alcohol abuse. Although few patients reported current alcohol abuse, the medical records showed chronic alcoholism or abuse in approximately half. Many study subjects were probably underreporting their current exposure, particularly because they were aware that they were participating in a study of liver outcomes. "Clinicians evaluating fatty liver disease in HIV-infected patients should remain cognizant about the likelihood of underreporting of alcohol consumption," the investigators noted.
Obesity also was strongly associated with persistent or progressive steatosis, which was not unexpected. Although HIV infection was, until a short time ago, "a progressively fatal disease characterized by severe wasting, the advent of HAART [highly active antiretroviral therapy] has transformed HIV into a chronic disease with an increase in the prevalence of obesity."
"These data underscore the importance of measures to prevent and treat obesity in HIV/HCV–co-infected patients, [given] the development or worsening of hepatic steatosis in these patients," the researchers said.
Longer exposure to antiretroviral therapy appeared to be protective against persistent or progressive steatosis. One possible mechanism for this finding is that HIV infection may promote steatosis by facilitating HCV replication in hepatocytes, so reducing the HIV load would ease steatosis.
"Another possibility is that HIV acts synergistically with HCV to disrupt lipid metabolism. Thus, direct inhibition of HIV viral replication could decrease steatosis, particularly if the antiretroviral agent [has] minimal impact on mitochondrial replication and function," Dr. Woreta and her colleagues said.
They emphasized that stavudine, which has been designated as a "nonpreferred" antiretroviral agent because it was thought to contribute to steatosis, was used by only 6% of patients in this study, so the authors were unable to assess its effects.
A higher CD4 cell count at baseline also appeared to be protective against steatosis. The investigators did not offer any possible explanations for this effect. No association was found between steatosis progression and patient age, sex, race, diabetes status, HCV genotype, fibrosis status, or HCV therapy, they noted.
This study was supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Center for Complementary and Alternative Medicine, the Agency for Healthcare Policy and Research, and the clinical research unit at the Johns Hopkins Medical Institutions. The investigators reported that they had no financial conflicts of interest.
In patients co-infected with HIV and hepatitis C virus, alcohol use and a high body mass index are associated with progression of hepatic steatosis, whereas exposure to certain antiretrovirals and a high baseline CD4 count appear to be protective against steatosis, Dr. Tinsay A. Woreta and her colleagues reported in the March issue of Gastroenterology.
In their study of 222 patients who were co-infected with HIV and HCV, more than 90% showed no progression of steatosis during nearly 3 years of follow-up.
The findings indicate that efforts to diagnose and prevent hepatic steatosis "should be focused on persons with a high body mass index and excessive alcohol intake," said Dr. Woreta of Johns Hopkins University, Baltimore, and her associates (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.052]).
Hepatitis C virus is not uncommon in patients with HIV infection, and hepatic steatosis affects 30%-70% of those with both infections. The steatosis is associated with hepatic fibrosis and is thought to contribute to the more rapid progression of liver disease in co-infected patients than in those who don’t have concomitant HIV.
"The natural history of hepatic steatosis is incompletely understood" because most studies have been cross-sectional rather than longitudinal," wrote Dr. Woreta and her colleagues. They performed their longitudinal study to prospectively examine the natural history of steatosis, using data from HIV/HCV–co-infected patients who underwent serial liver biopsies while attending an urban HIV clinic.
There were 345 pairs of serial biopsies available for analysis. The study subjects had a median age of 44 years; 66% were men and 87% were black. Nearly half were overweight or obese. Almost all (94%) had HCV genotype 1.
Most patients (194, or 87%) had no or only trivial hepatic steatosis at baseline, and it did not progress during follow-up in 165 (74%) of them. The other 29 patients who had no or only trivial hepatic steatosis at baseline progressed to significant steatosis during follow-up.
In all, 28 patients had significant hepatic steatosis at baseline, and the steatosis actually regressed in 21 (75%) of them. The other seven patients who had significant hepatic steatosis at baseline maintained that steatosis.
Persistence or progression of steatosis was strongly associated with a history of alcohol abuse. Although few patients reported current alcohol abuse, the medical records showed chronic alcoholism or abuse in approximately half. Many study subjects were probably underreporting their current exposure, particularly because they were aware that they were participating in a study of liver outcomes. "Clinicians evaluating fatty liver disease in HIV-infected patients should remain cognizant about the likelihood of underreporting of alcohol consumption," the investigators noted.
Obesity also was strongly associated with persistent or progressive steatosis, which was not unexpected. Although HIV infection was, until a short time ago, "a progressively fatal disease characterized by severe wasting, the advent of HAART [highly active antiretroviral therapy] has transformed HIV into a chronic disease with an increase in the prevalence of obesity."
"These data underscore the importance of measures to prevent and treat obesity in HIV/HCV–co-infected patients, [given] the development or worsening of hepatic steatosis in these patients," the researchers said.
Longer exposure to antiretroviral therapy appeared to be protective against persistent or progressive steatosis. One possible mechanism for this finding is that HIV infection may promote steatosis by facilitating HCV replication in hepatocytes, so reducing the HIV load would ease steatosis.
"Another possibility is that HIV acts synergistically with HCV to disrupt lipid metabolism. Thus, direct inhibition of HIV viral replication could decrease steatosis, particularly if the antiretroviral agent [has] minimal impact on mitochondrial replication and function," Dr. Woreta and her colleagues said.
They emphasized that stavudine, which has been designated as a "nonpreferred" antiretroviral agent because it was thought to contribute to steatosis, was used by only 6% of patients in this study, so the authors were unable to assess its effects.
A higher CD4 cell count at baseline also appeared to be protective against steatosis. The investigators did not offer any possible explanations for this effect. No association was found between steatosis progression and patient age, sex, race, diabetes status, HCV genotype, fibrosis status, or HCV therapy, they noted.
This study was supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Center for Complementary and Alternative Medicine, the Agency for Healthcare Policy and Research, and the clinical research unit at the Johns Hopkins Medical Institutions. The investigators reported that they had no financial conflicts of interest.
Subset of HIV/HCV Co-infected at Risk for Hepatic Steatosis
In patients co-infected with HIV and hepatitis C virus, alcohol use and a high body mass index are associated with progression of hepatic steatosis, whereas exposure to certain antiretrovirals and a high baseline CD4 count appear to be protective against steatosis, Dr. Tinsay A. Woreta and her colleagues reported in the March issue of Gastroenterology.
In their study of 222 patients who were co-infected with HIV and HCV, more than 90% showed no progression of steatosis during nearly 3 years of follow-up.
The findings indicate that efforts to diagnose and prevent hepatic steatosis "should be focused on persons with a high body mass index and excessive alcohol intake," said Dr. Woreta of Johns Hopkins University, Baltimore, and her associates (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.052]).
Hepatitis C virus is not uncommon in patients with HIV infection, and hepatic steatosis affects 30%-70% of those with both infections. The steatosis is associated with hepatic fibrosis and is thought to contribute to the more rapid progression of liver disease in co-infected patients than in those who don’t have concomitant HIV.
"The natural history of hepatic steatosis is incompletely understood" because most studies have been cross-sectional rather than longitudinal," wrote Dr. Woreta and her colleagues. They performed their longitudinal study to prospectively examine the natural history of steatosis, using data from HIV/HCV–co-infected patients who underwent serial liver biopsies while attending an urban HIV clinic.
There were 345 pairs of serial biopsies available for analysis. The study subjects had a median age of 44 years; 66% were men and 87% were black. Nearly half were overweight or obese. Almost all (94%) had HCV genotype 1.
Most patients (194, or 87%) had no or only trivial hepatic steatosis at baseline, and it did not progress during follow-up in 165 (74%) of them. The other 29 patients who had no or only trivial hepatic steatosis at baseline progressed to significant steatosis during follow-up.
In all, 28 patients had significant hepatic steatosis at baseline, and the steatosis actually regressed in 21 (75%) of them. The other seven patients who had significant hepatic steatosis at baseline maintained that steatosis.
Persistence or progression of steatosis was strongly associated with a history of alcohol abuse. Although few patients reported current alcohol abuse, the medical records showed chronic alcoholism or abuse in approximately half. Many study subjects were probably underreporting their current exposure, particularly because they were aware that they were participating in a study of liver outcomes. "Clinicians evaluating fatty liver disease in HIV-infected patients should remain cognizant about the likelihood of underreporting of alcohol consumption," the investigators noted.
Obesity also was strongly associated with persistent or progressive steatosis, which was not unexpected. Although HIV infection was, until a short time ago, "a progressively fatal disease characterized by severe wasting, the advent of HAART [highly active antiretroviral therapy] has transformed HIV into a chronic disease with an increase in the prevalence of obesity."
"These data underscore the importance of measures to prevent and treat obesity in HIV/HCV–co-infected patients, [given] the development or worsening of hepatic steatosis in these patients," the researchers said.
Longer exposure to antiretroviral therapy appeared to be protective against persistent or progressive steatosis. One possible mechanism for this finding is that HIV infection may promote steatosis by facilitating HCV replication in hepatocytes, so reducing the HIV load would ease steatosis.
"Another possibility is that HIV acts synergistically with HCV to disrupt lipid metabolism. Thus, direct inhibition of HIV viral replication could decrease steatosis, particularly if the antiretroviral agent [has] minimal impact on mitochondrial replication and function," Dr. Woreta and her colleagues said.
They emphasized that stavudine, which has been designated as a "nonpreferred" antiretroviral agent because it was thought to contribute to steatosis, was used by only 6% of patients in this study, so the authors were unable to assess its effects.
A higher CD4 cell count at baseline also appeared to be protective against steatosis. The investigators did not offer any possible explanations for this effect. No association was found between steatosis progression and patient age, sex, race, diabetes status, HCV genotype, fibrosis status, or HCV therapy, they noted.
This study was supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Center for Complementary and Alternative Medicine, the Agency for Healthcare Policy and Research, and the clinical research unit at the Johns Hopkins Medical Institutions. The investigators reported that they had no financial conflicts of interest.
In patients co-infected with HIV and hepatitis C virus, alcohol use and a high body mass index are associated with progression of hepatic steatosis, whereas exposure to certain antiretrovirals and a high baseline CD4 count appear to be protective against steatosis, Dr. Tinsay A. Woreta and her colleagues reported in the March issue of Gastroenterology.
In their study of 222 patients who were co-infected with HIV and HCV, more than 90% showed no progression of steatosis during nearly 3 years of follow-up.
The findings indicate that efforts to diagnose and prevent hepatic steatosis "should be focused on persons with a high body mass index and excessive alcohol intake," said Dr. Woreta of Johns Hopkins University, Baltimore, and her associates (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.052]).
Hepatitis C virus is not uncommon in patients with HIV infection, and hepatic steatosis affects 30%-70% of those with both infections. The steatosis is associated with hepatic fibrosis and is thought to contribute to the more rapid progression of liver disease in co-infected patients than in those who don’t have concomitant HIV.
"The natural history of hepatic steatosis is incompletely understood" because most studies have been cross-sectional rather than longitudinal," wrote Dr. Woreta and her colleagues. They performed their longitudinal study to prospectively examine the natural history of steatosis, using data from HIV/HCV–co-infected patients who underwent serial liver biopsies while attending an urban HIV clinic.
There were 345 pairs of serial biopsies available for analysis. The study subjects had a median age of 44 years; 66% were men and 87% were black. Nearly half were overweight or obese. Almost all (94%) had HCV genotype 1.
Most patients (194, or 87%) had no or only trivial hepatic steatosis at baseline, and it did not progress during follow-up in 165 (74%) of them. The other 29 patients who had no or only trivial hepatic steatosis at baseline progressed to significant steatosis during follow-up.
In all, 28 patients had significant hepatic steatosis at baseline, and the steatosis actually regressed in 21 (75%) of them. The other seven patients who had significant hepatic steatosis at baseline maintained that steatosis.
Persistence or progression of steatosis was strongly associated with a history of alcohol abuse. Although few patients reported current alcohol abuse, the medical records showed chronic alcoholism or abuse in approximately half. Many study subjects were probably underreporting their current exposure, particularly because they were aware that they were participating in a study of liver outcomes. "Clinicians evaluating fatty liver disease in HIV-infected patients should remain cognizant about the likelihood of underreporting of alcohol consumption," the investigators noted.
Obesity also was strongly associated with persistent or progressive steatosis, which was not unexpected. Although HIV infection was, until a short time ago, "a progressively fatal disease characterized by severe wasting, the advent of HAART [highly active antiretroviral therapy] has transformed HIV into a chronic disease with an increase in the prevalence of obesity."
"These data underscore the importance of measures to prevent and treat obesity in HIV/HCV–co-infected patients, [given] the development or worsening of hepatic steatosis in these patients," the researchers said.
Longer exposure to antiretroviral therapy appeared to be protective against persistent or progressive steatosis. One possible mechanism for this finding is that HIV infection may promote steatosis by facilitating HCV replication in hepatocytes, so reducing the HIV load would ease steatosis.
"Another possibility is that HIV acts synergistically with HCV to disrupt lipid metabolism. Thus, direct inhibition of HIV viral replication could decrease steatosis, particularly if the antiretroviral agent [has] minimal impact on mitochondrial replication and function," Dr. Woreta and her colleagues said.
They emphasized that stavudine, which has been designated as a "nonpreferred" antiretroviral agent because it was thought to contribute to steatosis, was used by only 6% of patients in this study, so the authors were unable to assess its effects.
A higher CD4 cell count at baseline also appeared to be protective against steatosis. The investigators did not offer any possible explanations for this effect. No association was found between steatosis progression and patient age, sex, race, diabetes status, HCV genotype, fibrosis status, or HCV therapy, they noted.
This study was supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Center for Complementary and Alternative Medicine, the Agency for Healthcare Policy and Research, and the clinical research unit at the Johns Hopkins Medical Institutions. The investigators reported that they had no financial conflicts of interest.
In patients co-infected with HIV and hepatitis C virus, alcohol use and a high body mass index are associated with progression of hepatic steatosis, whereas exposure to certain antiretrovirals and a high baseline CD4 count appear to be protective against steatosis, Dr. Tinsay A. Woreta and her colleagues reported in the March issue of Gastroenterology.
In their study of 222 patients who were co-infected with HIV and HCV, more than 90% showed no progression of steatosis during nearly 3 years of follow-up.
The findings indicate that efforts to diagnose and prevent hepatic steatosis "should be focused on persons with a high body mass index and excessive alcohol intake," said Dr. Woreta of Johns Hopkins University, Baltimore, and her associates (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.052]).
Hepatitis C virus is not uncommon in patients with HIV infection, and hepatic steatosis affects 30%-70% of those with both infections. The steatosis is associated with hepatic fibrosis and is thought to contribute to the more rapid progression of liver disease in co-infected patients than in those who don’t have concomitant HIV.
"The natural history of hepatic steatosis is incompletely understood" because most studies have been cross-sectional rather than longitudinal," wrote Dr. Woreta and her colleagues. They performed their longitudinal study to prospectively examine the natural history of steatosis, using data from HIV/HCV–co-infected patients who underwent serial liver biopsies while attending an urban HIV clinic.
There were 345 pairs of serial biopsies available for analysis. The study subjects had a median age of 44 years; 66% were men and 87% were black. Nearly half were overweight or obese. Almost all (94%) had HCV genotype 1.
Most patients (194, or 87%) had no or only trivial hepatic steatosis at baseline, and it did not progress during follow-up in 165 (74%) of them. The other 29 patients who had no or only trivial hepatic steatosis at baseline progressed to significant steatosis during follow-up.
In all, 28 patients had significant hepatic steatosis at baseline, and the steatosis actually regressed in 21 (75%) of them. The other seven patients who had significant hepatic steatosis at baseline maintained that steatosis.
Persistence or progression of steatosis was strongly associated with a history of alcohol abuse. Although few patients reported current alcohol abuse, the medical records showed chronic alcoholism or abuse in approximately half. Many study subjects were probably underreporting their current exposure, particularly because they were aware that they were participating in a study of liver outcomes. "Clinicians evaluating fatty liver disease in HIV-infected patients should remain cognizant about the likelihood of underreporting of alcohol consumption," the investigators noted.
Obesity also was strongly associated with persistent or progressive steatosis, which was not unexpected. Although HIV infection was, until a short time ago, "a progressively fatal disease characterized by severe wasting, the advent of HAART [highly active antiretroviral therapy] has transformed HIV into a chronic disease with an increase in the prevalence of obesity."
"These data underscore the importance of measures to prevent and treat obesity in HIV/HCV–co-infected patients, [given] the development or worsening of hepatic steatosis in these patients," the researchers said.
Longer exposure to antiretroviral therapy appeared to be protective against persistent or progressive steatosis. One possible mechanism for this finding is that HIV infection may promote steatosis by facilitating HCV replication in hepatocytes, so reducing the HIV load would ease steatosis.
"Another possibility is that HIV acts synergistically with HCV to disrupt lipid metabolism. Thus, direct inhibition of HIV viral replication could decrease steatosis, particularly if the antiretroviral agent [has] minimal impact on mitochondrial replication and function," Dr. Woreta and her colleagues said.
They emphasized that stavudine, which has been designated as a "nonpreferred" antiretroviral agent because it was thought to contribute to steatosis, was used by only 6% of patients in this study, so the authors were unable to assess its effects.
A higher CD4 cell count at baseline also appeared to be protective against steatosis. The investigators did not offer any possible explanations for this effect. No association was found between steatosis progression and patient age, sex, race, diabetes status, HCV genotype, fibrosis status, or HCV therapy, they noted.
This study was supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Center for Complementary and Alternative Medicine, the Agency for Healthcare Policy and Research, and the clinical research unit at the Johns Hopkins Medical Institutions. The investigators reported that they had no financial conflicts of interest.
Subset of HIV/HCV Co-infected at Risk for Hepatic Steatosis
In patients co-infected with HIV and hepatitis C virus, alcohol use and a high body mass index are associated with progression of hepatic steatosis, whereas exposure to certain antiretrovirals and a high baseline CD4 count appear to be protective against steatosis, Dr. Tinsay A. Woreta and her colleagues reported in the March issue of Gastroenterology.
In their study of 222 patients who were co-infected with HIV and HCV, more than 90% showed no progression of steatosis during nearly 3 years of follow-up.
The findings indicate that efforts to diagnose and prevent hepatic steatosis "should be focused on persons with a high body mass index and excessive alcohol intake," said Dr. Woreta of Johns Hopkins University, Baltimore, and her associates (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.052]).
Hepatitis C virus is not uncommon in patients with HIV infection, and hepatic steatosis affects 30%-70% of those with both infections. The steatosis is associated with hepatic fibrosis and is thought to contribute to the more rapid progression of liver disease in co-infected patients than in those who don’t have concomitant HIV.
"The natural history of hepatic steatosis is incompletely understood" because most studies have been cross-sectional rather than longitudinal," wrote Dr. Woreta and her colleagues. They performed their longitudinal study to prospectively examine the natural history of steatosis, using data from HIV/HCV–co-infected patients who underwent serial liver biopsies while attending an urban HIV clinic.
There were 345 pairs of serial biopsies available for analysis. The study subjects had a median age of 44 years; 66% were men and 87% were black. Nearly half were overweight or obese. Almost all (94%) had HCV genotype 1.
Most patients (194, or 87%) had no or only trivial hepatic steatosis at baseline, and it did not progress during follow-up in 165 (74%) of them. The other 29 patients who had no or only trivial hepatic steatosis at baseline progressed to significant steatosis during follow-up.
In all, 28 patients had significant hepatic steatosis at baseline, and the steatosis actually regressed in 21 (75%) of them. The other seven patients who had significant hepatic steatosis at baseline maintained that steatosis.
Persistence or progression of steatosis was strongly associated with a history of alcohol abuse. Although few patients reported current alcohol abuse, the medical records showed chronic alcoholism or abuse in approximately half. Many study subjects were probably underreporting their current exposure, particularly because they were aware that they were participating in a study of liver outcomes. "Clinicians evaluating fatty liver disease in HIV-infected patients should remain cognizant about the likelihood of underreporting of alcohol consumption," the investigators noted.
Obesity also was strongly associated with persistent or progressive steatosis, which was not unexpected. Although HIV infection was, until a short time ago, "a progressively fatal disease characterized by severe wasting, the advent of HAART [highly active antiretroviral therapy] has transformed HIV into a chronic disease with an increase in the prevalence of obesity."
"These data underscore the importance of measures to prevent and treat obesity in HIV/HCV–co-infected patients, [given] the development or worsening of hepatic steatosis in these patients," the researchers said.
Longer exposure to antiretroviral therapy appeared to be protective against persistent or progressive steatosis. One possible mechanism for this finding is that HIV infection may promote steatosis by facilitating HCV replication in hepatocytes, so reducing the HIV load would ease steatosis.
"Another possibility is that HIV acts synergistically with HCV to disrupt lipid metabolism. Thus, direct inhibition of HIV viral replication could decrease steatosis, particularly if the antiretroviral agent [has] minimal impact on mitochondrial replication and function," Dr. Woreta and her colleagues said.
They emphasized that stavudine, which has been designated as a "nonpreferred" antiretroviral agent because it was thought to contribute to steatosis, was used by only 6% of patients in this study, so the authors were unable to assess its effects.
A higher CD4 cell count at baseline also appeared to be protective against steatosis. The investigators did not offer any possible explanations for this effect. No association was found between steatosis progression and patient age, sex, race, diabetes status, HCV genotype, fibrosis status, or HCV therapy, they noted.
This study was supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Center for Complementary and Alternative Medicine, the Agency for Healthcare Policy and Research, and the clinical research unit at the Johns Hopkins Medical Institutions. The investigators reported that they had no financial conflicts of interest.
In patients co-infected with HIV and hepatitis C virus, alcohol use and a high body mass index are associated with progression of hepatic steatosis, whereas exposure to certain antiretrovirals and a high baseline CD4 count appear to be protective against steatosis, Dr. Tinsay A. Woreta and her colleagues reported in the March issue of Gastroenterology.
In their study of 222 patients who were co-infected with HIV and HCV, more than 90% showed no progression of steatosis during nearly 3 years of follow-up.
The findings indicate that efforts to diagnose and prevent hepatic steatosis "should be focused on persons with a high body mass index and excessive alcohol intake," said Dr. Woreta of Johns Hopkins University, Baltimore, and her associates (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.052]).
Hepatitis C virus is not uncommon in patients with HIV infection, and hepatic steatosis affects 30%-70% of those with both infections. The steatosis is associated with hepatic fibrosis and is thought to contribute to the more rapid progression of liver disease in co-infected patients than in those who don’t have concomitant HIV.
"The natural history of hepatic steatosis is incompletely understood" because most studies have been cross-sectional rather than longitudinal," wrote Dr. Woreta and her colleagues. They performed their longitudinal study to prospectively examine the natural history of steatosis, using data from HIV/HCV–co-infected patients who underwent serial liver biopsies while attending an urban HIV clinic.
There were 345 pairs of serial biopsies available for analysis. The study subjects had a median age of 44 years; 66% were men and 87% were black. Nearly half were overweight or obese. Almost all (94%) had HCV genotype 1.
Most patients (194, or 87%) had no or only trivial hepatic steatosis at baseline, and it did not progress during follow-up in 165 (74%) of them. The other 29 patients who had no or only trivial hepatic steatosis at baseline progressed to significant steatosis during follow-up.
In all, 28 patients had significant hepatic steatosis at baseline, and the steatosis actually regressed in 21 (75%) of them. The other seven patients who had significant hepatic steatosis at baseline maintained that steatosis.
Persistence or progression of steatosis was strongly associated with a history of alcohol abuse. Although few patients reported current alcohol abuse, the medical records showed chronic alcoholism or abuse in approximately half. Many study subjects were probably underreporting their current exposure, particularly because they were aware that they were participating in a study of liver outcomes. "Clinicians evaluating fatty liver disease in HIV-infected patients should remain cognizant about the likelihood of underreporting of alcohol consumption," the investigators noted.
Obesity also was strongly associated with persistent or progressive steatosis, which was not unexpected. Although HIV infection was, until a short time ago, "a progressively fatal disease characterized by severe wasting, the advent of HAART [highly active antiretroviral therapy] has transformed HIV into a chronic disease with an increase in the prevalence of obesity."
"These data underscore the importance of measures to prevent and treat obesity in HIV/HCV–co-infected patients, [given] the development or worsening of hepatic steatosis in these patients," the researchers said.
Longer exposure to antiretroviral therapy appeared to be protective against persistent or progressive steatosis. One possible mechanism for this finding is that HIV infection may promote steatosis by facilitating HCV replication in hepatocytes, so reducing the HIV load would ease steatosis.
"Another possibility is that HIV acts synergistically with HCV to disrupt lipid metabolism. Thus, direct inhibition of HIV viral replication could decrease steatosis, particularly if the antiretroviral agent [has] minimal impact on mitochondrial replication and function," Dr. Woreta and her colleagues said.
They emphasized that stavudine, which has been designated as a "nonpreferred" antiretroviral agent because it was thought to contribute to steatosis, was used by only 6% of patients in this study, so the authors were unable to assess its effects.
A higher CD4 cell count at baseline also appeared to be protective against steatosis. The investigators did not offer any possible explanations for this effect. No association was found between steatosis progression and patient age, sex, race, diabetes status, HCV genotype, fibrosis status, or HCV therapy, they noted.
This study was supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Center for Complementary and Alternative Medicine, the Agency for Healthcare Policy and Research, and the clinical research unit at the Johns Hopkins Medical Institutions. The investigators reported that they had no financial conflicts of interest.
In patients co-infected with HIV and hepatitis C virus, alcohol use and a high body mass index are associated with progression of hepatic steatosis, whereas exposure to certain antiretrovirals and a high baseline CD4 count appear to be protective against steatosis, Dr. Tinsay A. Woreta and her colleagues reported in the March issue of Gastroenterology.
In their study of 222 patients who were co-infected with HIV and HCV, more than 90% showed no progression of steatosis during nearly 3 years of follow-up.
The findings indicate that efforts to diagnose and prevent hepatic steatosis "should be focused on persons with a high body mass index and excessive alcohol intake," said Dr. Woreta of Johns Hopkins University, Baltimore, and her associates (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.052]).
Hepatitis C virus is not uncommon in patients with HIV infection, and hepatic steatosis affects 30%-70% of those with both infections. The steatosis is associated with hepatic fibrosis and is thought to contribute to the more rapid progression of liver disease in co-infected patients than in those who don’t have concomitant HIV.
"The natural history of hepatic steatosis is incompletely understood" because most studies have been cross-sectional rather than longitudinal," wrote Dr. Woreta and her colleagues. They performed their longitudinal study to prospectively examine the natural history of steatosis, using data from HIV/HCV–co-infected patients who underwent serial liver biopsies while attending an urban HIV clinic.
There were 345 pairs of serial biopsies available for analysis. The study subjects had a median age of 44 years; 66% were men and 87% were black. Nearly half were overweight or obese. Almost all (94%) had HCV genotype 1.
Most patients (194, or 87%) had no or only trivial hepatic steatosis at baseline, and it did not progress during follow-up in 165 (74%) of them. The other 29 patients who had no or only trivial hepatic steatosis at baseline progressed to significant steatosis during follow-up.
In all, 28 patients had significant hepatic steatosis at baseline, and the steatosis actually regressed in 21 (75%) of them. The other seven patients who had significant hepatic steatosis at baseline maintained that steatosis.
Persistence or progression of steatosis was strongly associated with a history of alcohol abuse. Although few patients reported current alcohol abuse, the medical records showed chronic alcoholism or abuse in approximately half. Many study subjects were probably underreporting their current exposure, particularly because they were aware that they were participating in a study of liver outcomes. "Clinicians evaluating fatty liver disease in HIV-infected patients should remain cognizant about the likelihood of underreporting of alcohol consumption," the investigators noted.
Obesity also was strongly associated with persistent or progressive steatosis, which was not unexpected. Although HIV infection was, until a short time ago, "a progressively fatal disease characterized by severe wasting, the advent of HAART [highly active antiretroviral therapy] has transformed HIV into a chronic disease with an increase in the prevalence of obesity."
"These data underscore the importance of measures to prevent and treat obesity in HIV/HCV–co-infected patients, [given] the development or worsening of hepatic steatosis in these patients," the researchers said.
Longer exposure to antiretroviral therapy appeared to be protective against persistent or progressive steatosis. One possible mechanism for this finding is that HIV infection may promote steatosis by facilitating HCV replication in hepatocytes, so reducing the HIV load would ease steatosis.
"Another possibility is that HIV acts synergistically with HCV to disrupt lipid metabolism. Thus, direct inhibition of HIV viral replication could decrease steatosis, particularly if the antiretroviral agent [has] minimal impact on mitochondrial replication and function," Dr. Woreta and her colleagues said.
They emphasized that stavudine, which has been designated as a "nonpreferred" antiretroviral agent because it was thought to contribute to steatosis, was used by only 6% of patients in this study, so the authors were unable to assess its effects.
A higher CD4 cell count at baseline also appeared to be protective against steatosis. The investigators did not offer any possible explanations for this effect. No association was found between steatosis progression and patient age, sex, race, diabetes status, HCV genotype, fibrosis status, or HCV therapy, they noted.
This study was supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Center for Complementary and Alternative Medicine, the Agency for Healthcare Policy and Research, and the clinical research unit at the Johns Hopkins Medical Institutions. The investigators reported that they had no financial conflicts of interest.
Half of Recurrent ACS Due to Existing 'Mild' Lesions
It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.
“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.
The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.
The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.
The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.
Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.
The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.
“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.
“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.
“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.
RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.
“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”
Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.
“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.
“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.
However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).
First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.
“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.
Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.
Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.
While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”
Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.
The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.
In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.
These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.
For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.
“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”
Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”
“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.
PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.
Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.
It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.
“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.
The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.
The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.
The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.
Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.
The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.
“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.
“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.
“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.
RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.
“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”
Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.
“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.
“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.
However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).
First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.
“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.
Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.
Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.
While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”
Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.
The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.
In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.
These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.
For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.
“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”
Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”
“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.
PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.
Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.
It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.
“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.
The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.
The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.
The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.
Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.
The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.
“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.
“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.
“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.
RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.
“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”
Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.
“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.
“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.
However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).
First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.
“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.
Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.
Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.
While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”
Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.
The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.
In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.
These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.
For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.
“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”
Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”
“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.
PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.
Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.
Half of Recurrent ACS Due to Existing 'Mild' Lesions
It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.
“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.
The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.
The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.
The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.
Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.
The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.
“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.
“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.
“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.
RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.
“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”
Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.
“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.
“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.
However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).
First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.
“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.
Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.
Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.
While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”
Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.
The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.
In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.
These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.
For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.
“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”
Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”
“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.
PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.
Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.
It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.
“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.
The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.
The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.
The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.
Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.
The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.
“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.
“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.
“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.
RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.
“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”
Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.
“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.
“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.
However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).
First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.
“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.
Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.
Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.
While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”
Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.
The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.
In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.
These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.
For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.
“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”
Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”
“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.
PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.
Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.
It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.
“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.
The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.
The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.
The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.
Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.
The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.
“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.
“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.
“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.
RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.
“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”
Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.
“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.
“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.
However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).
First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.
“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.
Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.
Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.
While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”
Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.
The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.
In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.
These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.
For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.
“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”
Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”
“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.
PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.
Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.
Half of Recurrent ACS Due to Existing 'Mild' Lesions
It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.
“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.
The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.
The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.
The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.
Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.
The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.
“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.
“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.
“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.
RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.
“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”
Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.
“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.
“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.
However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).
First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.
“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.
Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.
Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.
While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”
Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.
The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.
In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.
These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.
For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.
“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”
Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”
“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.
PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.
Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.
It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.
“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.
The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.
The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.
The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.
Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.
The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.
“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.
“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.
“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.
RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.
“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”
Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.
“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.
“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.
However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).
First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.
“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.
Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.
Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.
While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”
Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.
The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.
In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.
These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.
For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.
“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”
Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”
“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.
PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.
Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.
It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.
“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.
The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.
The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.
The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.
Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.
The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.
“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.
“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.
“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.
RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.
“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”
Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.
“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.
“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.
However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).
First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.
“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.
Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.
Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.
While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”
Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.
The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.
In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.
These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.
For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.
“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”
Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”
“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.
PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.
Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.