Valsartan, Captopril, or Both in Myocardial Infarction
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《新英格兰医药杂志》
To the Editor: In their assessment of treatment with valsartan, captopril, or both in patients with myocardial infarction complicated by heart failure or left ventricular dysfunction (Nov. 13 issue),1 Pfeffer et al. calculate a hazard ratio for their patients by using an "imputed placebo." Because they include this hazard ratio in a figure with hazard ratios from other trials that were placebo-controlled (Figure 3 of the article), the message is conveyed — since figures are powerful — that this trial was also placebo-controlled. It was not. Two references supporting this depiction are provided in the article.2,3 These, and a subsequent article,4 do not reveal a clear difference between patients in an "imputed placebo" group and historical controls. If this method of calculating hazard ratios is justified, it would seem unethical to submit patients to the risks of participating in future placebo-controlled clinical trials when a large number of historical controls are available for analysis.
John H. McAnulty, Jr., M.D.
Oregon Health and Science University
Portland, OR 97239
mcanultj@ohsu.edu
References
Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-1906.
Fisher LD. Active control trials: what about placebo? A method illustrated with clopidogrel, aspirin and placebo. J Am Coll Cardiol 1998;31:Suppl A:49A-49A. abstract.
Hasselblad V, Kong DF. Statistical methods for comparison to placebo in active-control trials. Drug Inf J 2001;35:435-449.
Fisher LD, Gent M, Buller HR. Active-control trials: how would a new agent compare with placebo? A method illustrated with clopidogrel, aspirin, and placebo. Am Heart J 2001;141:26-32.
To the Editor: Pfeffer et al. report that valsartan was as effective as captopril in reducing the rate of death and other cardiovascular outcomes in high-risk patients after myocardial infarction. Although the overall rate of complications was similar for valsartan and captopril, the rate of serious complications, including hypotension, renal dysfunction, and hyperkalemia, was significantly higher in the valsartan group than in the captopril group (21.3 percent vs. 15.8 percent). Thus, given the similar efficacy, captopril is the safer drug and should be used for these patients.
Reuven Moshenyat, M.D.
Yizhak Kupfer, M.D.
Sidney Tessler, M.D.
Maimonides Medical Center
Brooklyn, NY 11219
stessler@maimonidesmed.org
To the Editor: The absence of a late separation of the curves in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) strongly suggests that "escape" from the effect of angiotensin-converting–enzyme (ACE) inhibition may indeed not exist1 or may at best have negligible clinical consequences. The authors report that patients receiving valsartan "were less likely . . . to discontinue therapy because of a drug-related adverse event," suggesting a favorable safety and tolerability profile for the angiotensin-receptor blocker. Hypotension leading to discontinuation of the study drug, arguably a more serious adverse event than cough, occurred almost twice as often in patients receiving valsartan as in those receiving captopril (1.4 percent vs. 0.8 percent; P<0.05).
VALIANT indeed provides definitive evidence that valsartan (and, for that matter, probably any angiotensin-receptor blocker at an appropriate dose) is a clinically effective alternative to captopril in patients who are at high risk for cardiovascular events after myocardial infarction. However, serious adverse events were less frequent with ACE inhibitors. VALIANT thus removes two major rationales for favoring angiotensin-receptor blockers over ACE inhibitors, which clearly remain first-line therapy.
Ulrich P. Jorde, M.D.
New York University School of Medicine
New York, NY 10016
ulrich.jorde@med.nyu.med
References
Kokkonen JO, Saarinen J, Kovanen PT. Regulation of local angiotensin II formation in the human heart in the presence of interstitial fluid: inhibition of chymase by protease inhibitors of interstitial fluid and of angiotensin-converting enzyme by Ang-(1-9) formed by heart carboxypeptidase A-like activity. Circulation 1997;95:1455-1463.
The authors reply: Given the established mortality-related and other cardiovascular benefits of ACE inhibitors in patients with myocardial infarction who are at higher risk, random assignment to placebo was not an option. The "imputed placebo" analysis Dr. McAnulty refers to was conducted to support our noninferiority analysis. We did not mean to imply that an imputed placebo (or historical controls) could replace a direct and robust comparison between treatments in concurrently randomized patients, as in VALIANT. The similar mortality and morbidity rates in the valsartan and captopril groups (and, by inference, lower rates as compared with placebo in the valsartan group) do, however, provide the best available evidence that valsartan is as effective as a proven ACE inhibitor (and better than placebo).
The predominantly early occurrence of cardiovascular events after acute myocardial infarction may make the analysis of time to a first event an insensitive tool with which to evaluate the clinical importance of "escape" from the long-term effects of ACE inhibition, an issue raised by Dr. Jorde. However, our post hoc analysis, which showed fewer cumulative hospitalizations for myocardial infarction and heart failure with combination valsartan-and-captopril treatment, supports the possibility of "ACE escape."
The most important adverse clinical outcomes were our efficacy measures — death and major cardiovascular events (death from cardiovascular causes, myocardial infarction, hospitalization for heart failure, resuscitation after cardiac arrest, or stroke) — the rates of which did not differ between the captopril group (33.4 percent) and the valsartan group (32.8 percent). The study drug–related reasons for down-titration and discontinuation that are discussed by Dr. Moshenyat and colleagues, as well as by Dr. Jorde, though not necessarily serious, underscore the importance of clinical monitoring when patients are receiving clinically effective (mortality-reducing doses) of either an ACE inhibitor or an angiotensin-receptor blocker.
Though, as we reported, renal problems and hyperkalemia were more common in the valsartan group, there was no excess in terms of hospitalizations for renal dysfunction or hyperkalemia. Hypotension serious enough to warrant discontinuation of study medication occurred more often in the valsartan group than in the captopril group (1.4 percent vs. 0.8 percent; excess, 6 per 1000; P<0.05). However, discontinuation because of any adverse event was more frequent in the captopril group (7.7 percent, vs. 5.8 percent in the valsartan group; excess, 19 per 1000; P<0.05). We are conducting a more detailed analysis to attempt to identify patient characteristics associated with a heightened risk of specific drug-related adverse events. The different side-effect profiles of these two effective alternative approaches should assist clinicians in individualizing therapy to extend the appropriate use of these livesaving interventions to more survivors of myocardial infarction.
Marc A. Pfeffer, M.D., Ph.D.
Brigham and Women's Hospital
Boston, MA 02115
mpfeffer@rics.bwh.harvard.edu
John J.V. McMurray, M.D.
Western Infirmary
Glasgow G11 6NT, Scotland
Robert M. Califf, M.D.
Duke University Medical Center
Durham, NC 27710
John H. McAnulty, Jr., M.D.
Oregon Health and Science University
Portland, OR 97239
mcanultj@ohsu.edu
References
Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-1906.
Fisher LD. Active control trials: what about placebo? A method illustrated with clopidogrel, aspirin and placebo. J Am Coll Cardiol 1998;31:Suppl A:49A-49A. abstract.
Hasselblad V, Kong DF. Statistical methods for comparison to placebo in active-control trials. Drug Inf J 2001;35:435-449.
Fisher LD, Gent M, Buller HR. Active-control trials: how would a new agent compare with placebo? A method illustrated with clopidogrel, aspirin, and placebo. Am Heart J 2001;141:26-32.
To the Editor: Pfeffer et al. report that valsartan was as effective as captopril in reducing the rate of death and other cardiovascular outcomes in high-risk patients after myocardial infarction. Although the overall rate of complications was similar for valsartan and captopril, the rate of serious complications, including hypotension, renal dysfunction, and hyperkalemia, was significantly higher in the valsartan group than in the captopril group (21.3 percent vs. 15.8 percent). Thus, given the similar efficacy, captopril is the safer drug and should be used for these patients.
Reuven Moshenyat, M.D.
Yizhak Kupfer, M.D.
Sidney Tessler, M.D.
Maimonides Medical Center
Brooklyn, NY 11219
stessler@maimonidesmed.org
To the Editor: The absence of a late separation of the curves in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) strongly suggests that "escape" from the effect of angiotensin-converting–enzyme (ACE) inhibition may indeed not exist1 or may at best have negligible clinical consequences. The authors report that patients receiving valsartan "were less likely . . . to discontinue therapy because of a drug-related adverse event," suggesting a favorable safety and tolerability profile for the angiotensin-receptor blocker. Hypotension leading to discontinuation of the study drug, arguably a more serious adverse event than cough, occurred almost twice as often in patients receiving valsartan as in those receiving captopril (1.4 percent vs. 0.8 percent; P<0.05).
VALIANT indeed provides definitive evidence that valsartan (and, for that matter, probably any angiotensin-receptor blocker at an appropriate dose) is a clinically effective alternative to captopril in patients who are at high risk for cardiovascular events after myocardial infarction. However, serious adverse events were less frequent with ACE inhibitors. VALIANT thus removes two major rationales for favoring angiotensin-receptor blockers over ACE inhibitors, which clearly remain first-line therapy.
Ulrich P. Jorde, M.D.
New York University School of Medicine
New York, NY 10016
ulrich.jorde@med.nyu.med
References
Kokkonen JO, Saarinen J, Kovanen PT. Regulation of local angiotensin II formation in the human heart in the presence of interstitial fluid: inhibition of chymase by protease inhibitors of interstitial fluid and of angiotensin-converting enzyme by Ang-(1-9) formed by heart carboxypeptidase A-like activity. Circulation 1997;95:1455-1463.
The authors reply: Given the established mortality-related and other cardiovascular benefits of ACE inhibitors in patients with myocardial infarction who are at higher risk, random assignment to placebo was not an option. The "imputed placebo" analysis Dr. McAnulty refers to was conducted to support our noninferiority analysis. We did not mean to imply that an imputed placebo (or historical controls) could replace a direct and robust comparison between treatments in concurrently randomized patients, as in VALIANT. The similar mortality and morbidity rates in the valsartan and captopril groups (and, by inference, lower rates as compared with placebo in the valsartan group) do, however, provide the best available evidence that valsartan is as effective as a proven ACE inhibitor (and better than placebo).
The predominantly early occurrence of cardiovascular events after acute myocardial infarction may make the analysis of time to a first event an insensitive tool with which to evaluate the clinical importance of "escape" from the long-term effects of ACE inhibition, an issue raised by Dr. Jorde. However, our post hoc analysis, which showed fewer cumulative hospitalizations for myocardial infarction and heart failure with combination valsartan-and-captopril treatment, supports the possibility of "ACE escape."
The most important adverse clinical outcomes were our efficacy measures — death and major cardiovascular events (death from cardiovascular causes, myocardial infarction, hospitalization for heart failure, resuscitation after cardiac arrest, or stroke) — the rates of which did not differ between the captopril group (33.4 percent) and the valsartan group (32.8 percent). The study drug–related reasons for down-titration and discontinuation that are discussed by Dr. Moshenyat and colleagues, as well as by Dr. Jorde, though not necessarily serious, underscore the importance of clinical monitoring when patients are receiving clinically effective (mortality-reducing doses) of either an ACE inhibitor or an angiotensin-receptor blocker.
Though, as we reported, renal problems and hyperkalemia were more common in the valsartan group, there was no excess in terms of hospitalizations for renal dysfunction or hyperkalemia. Hypotension serious enough to warrant discontinuation of study medication occurred more often in the valsartan group than in the captopril group (1.4 percent vs. 0.8 percent; excess, 6 per 1000; P<0.05). However, discontinuation because of any adverse event was more frequent in the captopril group (7.7 percent, vs. 5.8 percent in the valsartan group; excess, 19 per 1000; P<0.05). We are conducting a more detailed analysis to attempt to identify patient characteristics associated with a heightened risk of specific drug-related adverse events. The different side-effect profiles of these two effective alternative approaches should assist clinicians in individualizing therapy to extend the appropriate use of these livesaving interventions to more survivors of myocardial infarction.
Marc A. Pfeffer, M.D., Ph.D.
Brigham and Women's Hospital
Boston, MA 02115
mpfeffer@rics.bwh.harvard.edu
John J.V. McMurray, M.D.
Western Infirmary
Glasgow G11 6NT, Scotland
Robert M. Califf, M.D.
Duke University Medical Center
Durham, NC 27710