Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Cannon and colleagues (April 8 issue)1 report the results of the PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) study of an intensive lipid-lowering statin regimen. In contrast to the conclusions of the Heart Protection Study Collaborative Group,2 their call for aggressive lowering of low-density lipoprotein (LDL) cholesterol is not fully supported by their data. Considering the high-risk population in the study by Cannon et al., we expected a beneficial effect with more aggressive lipid lowering, irrespective of the baseline lipid level. Although subgroup analysis is a thorny area, Figure 5 of the article indicates that the favorable effect of atorvastatin over pravastatin seems to be influenced by the baseline LDL cholesterol concentration. The superiority of atorvastatin over pravastatin was demonstrated only in the 27 percent of patients who had a baseline LDL cholesterol level of 125 mg per deciliter or higher. This finding is in keeping with the threshold baseline LDL cholesterol level suggested in the CARE (Cholesterol and Recurrent Events) study — 125 mg per deciliter, below which a benefit is not apparent.3 We await a more detailed analysis of the PROVE IT–TIMI 22 results, in accordance with that provided for the WOSCOPS (West of Scotland Coronary Prevention Study) data,4 to see whether the relation between the baseline LDL cholesterol level and outcome or between the change in LDL cholesterol level and outcome is linear.
Pim van der Harst, M.D.
Adriaan A. Voors, M.D., Ph.D.
Dirk J. van Veldhuisen, M.D., Ph.D.
University Hospital Groningen
9700RB Groningen, the Netherlands
p.van.der.harst@thorax.azg.nl
References
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504.
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009.
Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440-1445.
To the Editor: Cannon et al. report greater protection against cardiovascular events and death in patients treated with 80 mg of atorvastatin per day than in those treated with 40 mg of pravastatin per day after an acute coronary syndrome. This result is based in large part on the greater median reduction in the LDL cholesterol level among the atorvastatin-treated patients. However, at the doses studied, atorvastatin also exerts a greater reduction in triglyceride levels than does pravastatin.1 Although the median baseline triglyceride levels were reported, data on the triglyceride levels after treatment were, surprisingly, omitted. Because both LDL cholesterol and triglycerides are represented in calculations of non–high-density lipoprotein (non-HDL) cholesterol, and because triglycerides are a secondary therapeutic target in the guidelines of the Third Adult Treatment Panel of the National Cholesterol Education Program (NCEP),2 it would be useful to know the relative contributions of triglyceride reductions and reductions in non-HDL cholesterol with respect to the rates of cardiovascular events in this study.
Michael Miller, M.D.
University of Maryland Medical Center
Baltimore, MD 21201
mmiller@heart.umaryland.edu
Editor's note: Dr. Miller reports having received grant support and lecture fees from Bristol-Myers Squibb and Pfizer.
References
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071-1080.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.
To the Editor: I concur with Dr. Topol, who suggests in an editorial1 accompanying the article by Cannon et al. that more study is needed to confirm any clinical relevance of "pleiotropic" statin effects in the PROVE IT–TIMI 22 study. Indeed, the results of the study seem to support an interpretation that minimizes any such effect. Its nonsuperiority design implicitly suggests that doses of atorvastatin and pravastatin that clearly are not equipotent for lipid modification would have effects independent of their lipid-modifying efficacy that would make them equally beneficial with respect to coronary risk. Instead, PROVE IT–TIMI 22 shows that aggressive reduction of LDL cholesterol (by 42 percent) to a level of 62 mg per deciliter during treatment with a high-dose statin translates into a significantly greater clinical benefit than does moderate reduction of LDL cholesterol (by 10 percent) to a level of 95 mg per deciliter during treatment with a lower-dose statin in patients with an acute coronary syndrome. This important finding suggests that an even lower goal for secondary prevention than that currently recommended by the Third Adult Treatment Panel of the NCEP (LDL cholesterol, less than 100 mg per deciliter) may be preferable.2 The results of the PROVE IT–TIMI 22 study provide valuable new information about the optimal management of LDL cholesterol in patients with an acute coronary syndrome.
Antonio M. Gotto, Jr., M.D., D.Phil.
Weill Medical College of Cornell University
New York, NY 10021
amg_editorial@med.cornell.edu
Editor's note: Dr. Gotto reports having served as a consultant to AstraZeneca, Bristol-Myers Squibb, Kowa, Merck, Novartis, Pfizer, and Reliant Pharmaceuticals.
References
Topol EJ. Intensive statin therapy -- a sea change in cardiovascular prevention. N Engl J Med 2004;350:1562-1564.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.
To the Editor: The PROVE IT–TIMI 22 trial clearly establishes the benefits of aggressive lipid-lowering therapy with 80 mg of atorvastatin per day as compared with conventional therapy with 40 mg of pravastatin per day in reducing the risk of coronary heart disease. However, the rates of withdrawal in this two-year trial (33.0 percent in the pravastatin group and 30.4 percent in the atorvastatin group) are higher than those in previous trials of these drugs. According to the authors, the reasons for discontinuation of treatment were "an adverse event or the patient's preference or . . . other reasons." The LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) Study Group reported a 19 percent withdrawal rate after 6.1 years among patients who had taken 40 mg of pravastatin per day.1 In the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, which lasted 18 months, the reported withdrawal rates were 6.4 percent in the group assigned to 40 mg of pravastatin per day and 6.7 percent in the group assigned to 80 mg of atorvastatin per day.2
Withdrawal rates in real-life clinical practice are higher than those reported in clinical trials.3 It is therefore important that reasons for withdrawal are reported in greater detail than they are by the authors of the PROVE IT–TIMI 22 trial.
Jean-Michel Paradis, M.D.
Jacques LeLorier, M.D., Ph.D.
Centre Hospitalier de l'Université de Montréal
Montreal, QC H2W 1T7, Canada
jacques.le.lorier@umontreal.ca
Editor's note: Dr. LeLorier reports having served as a paid speaker or consultant for the following manufacturers of statins: Merck Frosst Canada, Pfizer Canada, AstraZeneca, and Bristol-Myers Squibb.
References
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357.
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071-1080.
Catalan VS, LeLorier J. Predictors of long-term persistence on statins in a subsidized clinical population. Value Health 2000;3:417-426.
To the Editor: Cannon and colleagues report that among patients who had recently been hospitalized for an acute coronary syndrome, an intensive lipid-lowering statin regimen provided a 16 percent reduction in clinical events when compared with a standard regimen. Are these data compelling enough to change clinical practice?1 Beyond costs, a strategy based on the use of very high statin doses as a standard regimen has implications for potential adverse effects. Despite a select study population, with the exclusion of patients at risk for statin-induced toxic effects, Cannon et al. report more liver-related side effects with high-dose atorvastatin than with standard-dose pravastatin. In clinical practice, patients with additional existing conditions may be at much higher risk for adverse effects induced by a high-dose statin.2
Safety data from several large, long-term clinical trials are needed to establish a high level of clinical confidence for the use of high statin doses as standard therapy. Until these data are available, it seems prudent to treat patients who have coronary artery disease with a statin at an intensity appropriate for achieving the recommended LDL cholesterol goals, as suggested by current guidelines.3,4
Johann Auer, M.D.
Thomas Weber, M.D.
Bernd Eber, M.D.
General Hospital Wels
A-4600 Wels, Austria
johann.auer@khwels.at
References
Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ 2002;324:1570-1576.
Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40:567-572.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-3421.
De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease and prevention in clinical practice. Atherosclerosis 2004;173:381-391.
The authors reply: We concur with Dr. Gotto that the PROVE IT–TIMI 22 trial provides evidence that aggressive lowering of LDL cholesterol, to levels well below those currently recommended by the Third Adult Treatment Panel of the NCEP, is likely to be beneficial in preventing death and major cardiac events. One surprise in the results, as Dr. Topol notes in his editorial, was how rapidly the benefit of high-dose atorvastatin was observed: at 30 days, there was already a 17 percent reduction in the primary end point as well as a significant (33 percent) reduction in the rate of death, myocardial infarction, or urgent revascularization. Actually, the event-rate curves began to separate within a few days after the start of treatment — a period that is consistent with findings in studies in animals of the pleiotropic effects of statins. Future mechanistic studies should help determine whether there is a dose response associated with these pleiotropic effects, as has been seen with respect to LDL cholesterol levels and clinical effects.
In response to Dr. van der Harst and colleagues: more analysis of subgroups according to baseline LDL cholesterol levels is in progress. We have observed that in the subgroup with an LDL cholesterol level of 100 to 125 mg per deciliter, high-dose atorvastatin was associated with a 12 percent reduction in the primary end point and a 17 percent reduction in the rate of death, myocardial infarction, or urgent revascularization, and that in the subgroup with a baseline LDL cholesterol level below 100 mg per deciliter, the reductions with high-dose atorvastatin, as compared with pravastatin, were 3 percent and 16 percent, respectively. Mortality in the latter group was also lower with high-dose atorvastatin than with standard-dose pravastatin (2.7 percent vs. 3.4 percent at two years), although the difference in this subgroup was not significant. Because these subgroups are small, we look to the overall results of the PROVE IT–TIMI 22 study, which shows a benefit of intensive statin therapy, and we look forward to the results of ongoing, large trials that are addressing this question with adequate power.
In response to Dr. Miller: at 30 days, triglyceride levels had fallen by 30 percent with 80 mg of atorvastatin per day and by 8 percent with 40 mg of pravastatin per day (P<0.001). Thus, the levels of LDL cholesterol, triglycerides, and C-reactive protein fell to a greater extent with high-dose atorvastatin, whereas HDL cholesterol rose more with pravastatin. We are attempting to determine, in ongoing multivariate analyses, what component of the clinical benefit might relate to these variables (or to other inflammatory markers that have not yet been assayed). Future studies with more specific interventions (e.g., specific inhibitors of Rho kinase or drugs that elevate HDL cholesterol) should help identify the contributions of each variable.
In response to Drs. Paradis and LeLorier: we list the exact reasons for discontinuation of the study drug in Table 1. In response to Dr. Auer and colleagues: we agree that the benefit in terms of efficacy needs to be balanced by safety issues, although we would like to emphasize that the latter consist of transient abnormalities in blood-test results or myalgias that resolve by halving the dose or stopping the medication, whereas the efficacy benefit was the prevention of death or major cardiac events, which are irreversible complications of atherosclerotic disease.
Table 1. Reasons for the Discontinuation of Statin Treatment in the PROVE IT–TIMI 22 Study.
Christopher P. Cannon, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital
Boston, MA 02115
cpcannon@partners.org
Pim van der Harst, M.D.
Adriaan A. Voors, M.D., Ph.D.
Dirk J. van Veldhuisen, M.D., Ph.D.
University Hospital Groningen
9700RB Groningen, the Netherlands
p.van.der.harst@thorax.azg.nl
References
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504.
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009.
Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440-1445.
To the Editor: Cannon et al. report greater protection against cardiovascular events and death in patients treated with 80 mg of atorvastatin per day than in those treated with 40 mg of pravastatin per day after an acute coronary syndrome. This result is based in large part on the greater median reduction in the LDL cholesterol level among the atorvastatin-treated patients. However, at the doses studied, atorvastatin also exerts a greater reduction in triglyceride levels than does pravastatin.1 Although the median baseline triglyceride levels were reported, data on the triglyceride levels after treatment were, surprisingly, omitted. Because both LDL cholesterol and triglycerides are represented in calculations of non–high-density lipoprotein (non-HDL) cholesterol, and because triglycerides are a secondary therapeutic target in the guidelines of the Third Adult Treatment Panel of the National Cholesterol Education Program (NCEP),2 it would be useful to know the relative contributions of triglyceride reductions and reductions in non-HDL cholesterol with respect to the rates of cardiovascular events in this study.
Michael Miller, M.D.
University of Maryland Medical Center
Baltimore, MD 21201
mmiller@heart.umaryland.edu
Editor's note: Dr. Miller reports having received grant support and lecture fees from Bristol-Myers Squibb and Pfizer.
References
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071-1080.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.
To the Editor: I concur with Dr. Topol, who suggests in an editorial1 accompanying the article by Cannon et al. that more study is needed to confirm any clinical relevance of "pleiotropic" statin effects in the PROVE IT–TIMI 22 study. Indeed, the results of the study seem to support an interpretation that minimizes any such effect. Its nonsuperiority design implicitly suggests that doses of atorvastatin and pravastatin that clearly are not equipotent for lipid modification would have effects independent of their lipid-modifying efficacy that would make them equally beneficial with respect to coronary risk. Instead, PROVE IT–TIMI 22 shows that aggressive reduction of LDL cholesterol (by 42 percent) to a level of 62 mg per deciliter during treatment with a high-dose statin translates into a significantly greater clinical benefit than does moderate reduction of LDL cholesterol (by 10 percent) to a level of 95 mg per deciliter during treatment with a lower-dose statin in patients with an acute coronary syndrome. This important finding suggests that an even lower goal for secondary prevention than that currently recommended by the Third Adult Treatment Panel of the NCEP (LDL cholesterol, less than 100 mg per deciliter) may be preferable.2 The results of the PROVE IT–TIMI 22 study provide valuable new information about the optimal management of LDL cholesterol in patients with an acute coronary syndrome.
Antonio M. Gotto, Jr., M.D., D.Phil.
Weill Medical College of Cornell University
New York, NY 10021
amg_editorial@med.cornell.edu
Editor's note: Dr. Gotto reports having served as a consultant to AstraZeneca, Bristol-Myers Squibb, Kowa, Merck, Novartis, Pfizer, and Reliant Pharmaceuticals.
References
Topol EJ. Intensive statin therapy -- a sea change in cardiovascular prevention. N Engl J Med 2004;350:1562-1564.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.
To the Editor: The PROVE IT–TIMI 22 trial clearly establishes the benefits of aggressive lipid-lowering therapy with 80 mg of atorvastatin per day as compared with conventional therapy with 40 mg of pravastatin per day in reducing the risk of coronary heart disease. However, the rates of withdrawal in this two-year trial (33.0 percent in the pravastatin group and 30.4 percent in the atorvastatin group) are higher than those in previous trials of these drugs. According to the authors, the reasons for discontinuation of treatment were "an adverse event or the patient's preference or . . . other reasons." The LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) Study Group reported a 19 percent withdrawal rate after 6.1 years among patients who had taken 40 mg of pravastatin per day.1 In the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, which lasted 18 months, the reported withdrawal rates were 6.4 percent in the group assigned to 40 mg of pravastatin per day and 6.7 percent in the group assigned to 80 mg of atorvastatin per day.2
Withdrawal rates in real-life clinical practice are higher than those reported in clinical trials.3 It is therefore important that reasons for withdrawal are reported in greater detail than they are by the authors of the PROVE IT–TIMI 22 trial.
Jean-Michel Paradis, M.D.
Jacques LeLorier, M.D., Ph.D.
Centre Hospitalier de l'Université de Montréal
Montreal, QC H2W 1T7, Canada
jacques.le.lorier@umontreal.ca
Editor's note: Dr. LeLorier reports having served as a paid speaker or consultant for the following manufacturers of statins: Merck Frosst Canada, Pfizer Canada, AstraZeneca, and Bristol-Myers Squibb.
References
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357.
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071-1080.
Catalan VS, LeLorier J. Predictors of long-term persistence on statins in a subsidized clinical population. Value Health 2000;3:417-426.
To the Editor: Cannon and colleagues report that among patients who had recently been hospitalized for an acute coronary syndrome, an intensive lipid-lowering statin regimen provided a 16 percent reduction in clinical events when compared with a standard regimen. Are these data compelling enough to change clinical practice?1 Beyond costs, a strategy based on the use of very high statin doses as a standard regimen has implications for potential adverse effects. Despite a select study population, with the exclusion of patients at risk for statin-induced toxic effects, Cannon et al. report more liver-related side effects with high-dose atorvastatin than with standard-dose pravastatin. In clinical practice, patients with additional existing conditions may be at much higher risk for adverse effects induced by a high-dose statin.2
Safety data from several large, long-term clinical trials are needed to establish a high level of clinical confidence for the use of high statin doses as standard therapy. Until these data are available, it seems prudent to treat patients who have coronary artery disease with a statin at an intensity appropriate for achieving the recommended LDL cholesterol goals, as suggested by current guidelines.3,4
Johann Auer, M.D.
Thomas Weber, M.D.
Bernd Eber, M.D.
General Hospital Wels
A-4600 Wels, Austria
johann.auer@khwels.at
References
Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ 2002;324:1570-1576.
Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40:567-572.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-3421.
De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease and prevention in clinical practice. Atherosclerosis 2004;173:381-391.
The authors reply: We concur with Dr. Gotto that the PROVE IT–TIMI 22 trial provides evidence that aggressive lowering of LDL cholesterol, to levels well below those currently recommended by the Third Adult Treatment Panel of the NCEP, is likely to be beneficial in preventing death and major cardiac events. One surprise in the results, as Dr. Topol notes in his editorial, was how rapidly the benefit of high-dose atorvastatin was observed: at 30 days, there was already a 17 percent reduction in the primary end point as well as a significant (33 percent) reduction in the rate of death, myocardial infarction, or urgent revascularization. Actually, the event-rate curves began to separate within a few days after the start of treatment — a period that is consistent with findings in studies in animals of the pleiotropic effects of statins. Future mechanistic studies should help determine whether there is a dose response associated with these pleiotropic effects, as has been seen with respect to LDL cholesterol levels and clinical effects.
In response to Dr. van der Harst and colleagues: more analysis of subgroups according to baseline LDL cholesterol levels is in progress. We have observed that in the subgroup with an LDL cholesterol level of 100 to 125 mg per deciliter, high-dose atorvastatin was associated with a 12 percent reduction in the primary end point and a 17 percent reduction in the rate of death, myocardial infarction, or urgent revascularization, and that in the subgroup with a baseline LDL cholesterol level below 100 mg per deciliter, the reductions with high-dose atorvastatin, as compared with pravastatin, were 3 percent and 16 percent, respectively. Mortality in the latter group was also lower with high-dose atorvastatin than with standard-dose pravastatin (2.7 percent vs. 3.4 percent at two years), although the difference in this subgroup was not significant. Because these subgroups are small, we look to the overall results of the PROVE IT–TIMI 22 study, which shows a benefit of intensive statin therapy, and we look forward to the results of ongoing, large trials that are addressing this question with adequate power.
In response to Dr. Miller: at 30 days, triglyceride levels had fallen by 30 percent with 80 mg of atorvastatin per day and by 8 percent with 40 mg of pravastatin per day (P<0.001). Thus, the levels of LDL cholesterol, triglycerides, and C-reactive protein fell to a greater extent with high-dose atorvastatin, whereas HDL cholesterol rose more with pravastatin. We are attempting to determine, in ongoing multivariate analyses, what component of the clinical benefit might relate to these variables (or to other inflammatory markers that have not yet been assayed). Future studies with more specific interventions (e.g., specific inhibitors of Rho kinase or drugs that elevate HDL cholesterol) should help identify the contributions of each variable.
In response to Drs. Paradis and LeLorier: we list the exact reasons for discontinuation of the study drug in Table 1. In response to Dr. Auer and colleagues: we agree that the benefit in terms of efficacy needs to be balanced by safety issues, although we would like to emphasize that the latter consist of transient abnormalities in blood-test results or myalgias that resolve by halving the dose or stopping the medication, whereas the efficacy benefit was the prevention of death or major cardiac events, which are irreversible complications of atherosclerotic disease.
Table 1. Reasons for the Discontinuation of Statin Treatment in the PROVE IT–TIMI 22 Study.
Christopher P. Cannon, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital
Boston, MA 02115
cpcannon@partners.org