Changes in Ventricular Size and Function in Patients Treated With Valsartan, Captopril, or Both After Myocardial Infarction
http://www.100md.com
《循环学杂志》
the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (S.D.S., H.S., N.S.A., M.B., M.A.P.)
Section of Cardiology, Department of Medicine, Central Hospital in Rogaland, Stavanger, Norway (S.B.)
Cardiac Centers of Louisiana, Shreveport (J.K.G.)
Foothills Hospital, Calgary, Alberta, Canada (J.W.W.)
St George Hospital, St Petersburg, Russia (M.K.)
London Health Sciences Center–Victoria Campus, London, Ontario, Canada (J.M.O.A.)
University Hospital N3, Saratov, Russia (Y.S.)
Duke University Medical Center, Durham, NC (E.J.V., R.M.C.)
Department of Cardiology, Western Infirmary, Glasgow, Scotland (J.V.M.).
Abstract
Background— Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI). Preclinical data suggest that angiotensin receptor blockers (ARBs) may have similar structural and functional effects after MI. The Valsartan in Acute Myocardial Infarction (VALIANT) Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV ejection fraction to a greater extent than captopril alone.
Methods and Results— Six hundred ten patients enrolled in the main VALIANT study who experienced MI and evidence of LV dysfunction, heart failure, or both were enrolled in the VALIANT Echo study. Patients were randomized to receive valsartan 160 mg PO BID, captopril 50 mg PO TID, or valsartan 80 mg PO BID plus captopril 50 mg PO TID between 1 and 10 days after MI. Six hundred three patients had echocardiograms of sufficient quality for quantitative analysis. Echocardiograms were digitized, and endocardial borders were traced manually from 2 short-axis and 2 apical views. Ventricular volumes, ejection fractions, combined areas, and infarct segment length were measured, and changes in echocardiographic measures from baseline to 20 months were compared between treatment groups. Baseline clinical and echocardiographic characteristics were similar in the 3 treatment arms. The changes from baseline to 20 months in all echocardiographic parameters were similar in all 3 treatment arms. Baseline echocardiographic measures of ejection fraction, end-diastolic volume, and infarct segment length were highly predictive of outcomes including total mortality, death or hospitalization for heart failure, or death or any cardiovascular event (heart failure, MI, stroke, resuscitated sudden death), even after adjustment for known covariates.
Conclusions— Treatment with the ACE inhibitor captopril, valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction, and infarct segment length between baseline and 20 months after MI. Baseline echocardiographic measures were powerfully and independently predictive of all major outcomes.
Key Words: echocardiography ; myocardial infarction ; remodeling ; angiotensin-converting enzyme inhibitors ; ventricular function
Introduction
Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI).1–3 Preclinical data with angiotensin receptor blockers (ARBs) suggest that this alternative method of inhibiting the renin-angiotensin system may result in similar structural and functional effects after experimental infarction.4–6 In heart failure patients, the combination of an ACE inhibitor and an ARB has been associated with greater attenuation of ventricular enlargement than either agent alone.7,8
The Valsartan in Acute Myocardial Infarction (VALIANT) study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with the proven ACE inhibitor captopril, would be superior or not inferior to a proven dose of captopril in reducing cardiovascular morbidity or mortality after MI and demonstrated that valsartan was as effective as captopril in reducing cardiovascular morbidity and mortality, but the combination was associated with increased adverse events without increased benefit.9 The VALIANT Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV function to a greater extent than captopril alone. Six hundred ten patients from the main VALIANT study were enrolled in the VALIANT Echo study. In this report we present the results of the VALIANT Echo study and the relationship between baseline echocardiographic assessment and outcomes after MI.
Methods
Patients
Clinical sites participating in the main VALIANT study were invited to enroll patients in the VALIANT Echo study, and patients enrolled in the VALIANT trial at these sites were eligible for inclusion in the VALIANT Echo study. Entry criteria were identical to those for the main VALIANT study: Patients were eligible if they had an MI and evidence of LV dysfunction (ejection fraction 35% on echocardiography or ventriculography, or ejection fraction 40% by radionuclide ventriculography), heart failure, or both. Patients were included regardless of infarct location or ST-segment characteristics. Patients were randomized and titrated to receive valsartan 160 mg BID, captopril 50 mg TID, or valsartan 80 mg BID plus captopril 50 mg TID between 0.5 day and 10 days after MI (mean=4.8 days) and received concomitant background therapy at the discretion of the treating physicians. Six hundred ten patients from the total VALIANT population (14 703) were enrolled in VALIANT Echo. Echocardiographic examinations were performed at baseline (before randomization), at 1 month, and at 20 months after MI. A total of 94 clinical sites in 13 countries participated in the VALIANT Echo study. Patients signed informed consent for inclusion in the VALIANT Echo study, and institutional review board approval was obtained by each site.
Echocardiographic Analysis
All echocardiographic studies were sent to a core laboratory at Brigham and Women’s Hospital. Studies were reviewed for quality, and 5 patients were excluded before analysis because of extremely poor study quality; 2 additional patients had insufficient echocardiographic images for assessment of ventricular volume and ejection fractions. In patients with echocardiographic studies of sufficient quality for quantitative analysis, defined as availability of all necessary views and sufficient image quality for endocardial border definition, echocardiographic analyses were performed at baseline (n=603), at 1 month (n=544), and at 20 months after MI (n=428). Fifty-nine patients in the initial cohort did not have 1-month echocardiograms, including 21 patients who died before the 1-month echo. One hundred seventy-five patients in the initial cohort did not have the 20-month echocardiogram, including 98 patients who died before the final visit. Five patients died after the 20-month echocardiograms, which were available in 146 patients in the captopril group, 140 patients in the combination group, and 142 patients in the valsartan group.
Echocardiograms from videotape were digitized, and analyses were performed with the use of an offline analysis workstation. LV endocardial borders were manually traced at end-diastole and end-systole at the mitral and papillary level short-axis and apical 4- and 2-chamber views from 3 separate cardiac cycles by a single experienced observer. LV volumes were derived according to the modified biplane Simpson’s rule in the apical 4-chamber and apical 2-chamber views, and ejection fraction was calculated in the standard fashion from ventricular volumes. Combined LV areas were calculated by summing the average areas from the apical and short-axis views.3 Infarct segment length was assessed by manual measurement of the infarct perimeter, defined as a severely hypokinetic, akinetic, or dyskinetic segment, and the average short-axis and apical infarct perimeter lengths were summed. The entire cavity perimeter length was measured in the apical and short-axis views, and the infarct segment length was expressed as a percentage of the total perimeter. Biplane volumes and ejection fractions were available at baseline in 603 patients; combined areas were available in 574 patients at baseline; infarct segment length measures were available in 552 patients at baseline.
Statistical Analysis
The primary end point of the study was the change in ventricular size (end-diastolic volume) from baseline to 20 months. A sample size of 600 patients was determined necessary to detect, with 90% power, a 7.6-mL difference in end-diastolic volume between treatment groups on the basis of data from previous post-MI studies.10 This difference was considered both clinically meaningful and large enough to be greater than the limits of measurement error. A statistical adjustment was planned to account for the 3-group comparison in the event of a treatment difference. To assess reproducibility, 52 patient studies were randomly chosen and reanalyzed with the observer blinded to the initial results for the primary end point of end-diastolic volume. The mean signed differences and the SD of the differences between measurements were calculated (Bland-Altman method), and the variability was expressed as the SD of the difference divided by the mean measurement. Clinical characteristics in the Echo cohort and the remainder of the VALIANT cohort were compared. LV volumes, areas, and ejection fractions were compared at baseline and at 20 months, and the changes in these parameters between time points were compared between the 3 treatment groups.
Baseline echocardiographic assessments, including LV volume, ejection fraction, and infarct segment length, were related to clinical outcomes, including total mortality and cardiovascular morbidity, with Cox proportional hazards models. In patients who survived to the 20-month echocardiogram, changes in ventricular size and function were related to clinical outcomes throughout the study period. Continuous variables were compared with the Student t test. Categorical variables were compared with the 2 test. To determine the independent value of echocardiographic measures, we used a multivariable Cox proportional hazards model with the 10 most powerful covariate predictors of mortality identified from the overall VALIANT study using stepwise backward selection of a 70-covariate model.
Results
Baseline Characteristics
The VALIANT Echo cohort was similar to the VALIANT cohort as a whole (Table 1) and differed from the main cohort minimally with respect to age (63.8±12.3 versus 64.9±11.8 years; P=0.02) and baseline blood pressure (systolic blood pressure, 121.1±14.9 versus 122.7±17.1 mm Hg; P=0.02; diastolic blood pressure, 70.5±10.9 versus 72.4±11.3 mm Hg; P=0.0001). There were no other significant differences in baseline characteristics or prerandomization medications between the Echo cohort and the remainder of the VALIANT cohort. There were no differences in baseline characteristics or medications in patients randomized to any of the 3 treatment arms in the VALIANT Echo study. The overall coefficient of variability of the primary end point (end-diastolic volume) based on the reproducibility assessment was 8.3%.
Changes From Baseline to 20 Months
In the 428 patients with paired echocardiographic studies between baseline and 20 months, overall diastolic volume increased by 2.4±17.6 mL (P=0.005), systolic volume decreased by 0.45±16.7 mL (P=0.56), and ejection fraction increased by 2.0±7.22% (P<0.0001). Table 3 shows baseline, 1-month, and 20-month echocardiographic measures in the 3 treatment arms. There were no significant differences in the magnitude of the change in any of the echocardiographic end points, including volumes, areas, ejection fractions, or infarct segment lengths between patients receiving either valsartan, captopril, or the combination (Table 3).
Echocardiographic Measures and Outcomes
Changes in ventricular size or function from baseline to 1 month did not predict subsequent cardiovascular outcomes. Of patients who survived to the 20-month echocardiogram, those who experienced an adverse cardiovascular event (n=76), including hospitalization for heart failure, MI, resuscitated sudden death, or stroke before or after the final echocardiogram or death after the final echocardiogram, had a greater increase in end-diastolic volume (7.5±19.9 versus 1.3±16.9 mL; P=0.005), a greater decrease in ejection fraction (–0.68±7.0% versus 2.5±7.1%; P=0.0004), and a lesser improvement in infarct segment length (0.06±3.1% versus –1.04±2.2%; P=0.005) compared with patients who did not experience adverse events.
Discussion
ACE inhibition has been shown to attenuate ventricular enlargement and has been associated with improvement in ventricular function in patients after MI. The results of the VALIANT Echo study suggest that in a contemporary population of patients with MI and LV dysfunction, heart failure, or both, treatment with the ACE inhibitor captopril, the ARB valsartan, or the combination of valsartan and captopril resulted in similar changes in ventricular size and function. These findings suggest that combination therapy with an ACE inhibitor and ARB is not superior to either strategy alone for improving ventricular function or attenuating enlargement after MI complicated by LV dysfunction or heart failure. These findings are consistent with the primary results of the VALIANT trial, in which neither arm was more effective in reducing mortality or cardiovascular morbidity.
Early observations from experimental infarct studies demonstrating that ACE inhibitors could attenuate subsequent progressive LV enlargement (remodeling) provided the initial rationale for the use of ACE inhibitors after MI.11–13 LV enlargement, either limited or progressive, has been demonstrated in a significant proportion of patients after MI,14 is dependent on initial infarct size, and is associated with a significant increase in the risk of subsequent morbidity and mortality.15 Although the improvement in survival associated with ACE inhibitor use after MI in multiple large clinical trials cannot be explained entirely by attenuation of LV enlargement alone, ventricular enlargement after MI has been associated with an increased risk for adverse events.3
A number of experimental studies have suggested that ARBs may attenuate ventricular enlargement to an extent similar to that of ACE inhibitors. In animal models, angiotensin receptor blockade has been associated with inhibition of LV hypertrophy, ventricular dilatation, and collagen deposition compared with placebo.16 Experimental models of MI have shown similar antiremodeling effects of the ARB losartan and the ACE inhibitor ramipril.17 Zornoff et al4 have shown similar overall attenuation of ventricular enlargement in rats treated with losartan, captopril, or the combination after MI.
There is a compelling rationale for considering AT1 receptor blockers as an alternative therapy to ACE inhibitors for attenuation of ventricular enlargement and improvement in ventricular function after MI. ACE inhibitors are poorly tolerated in a finite number of patients. Moreover, the effect of ACE inhibition on enlargement may diminish over time; in the Survival and Ventricular Enlargement (SAVE) study, no further attenuation of enlargement was observed after 1 year.18 Elevations in the levels of circulating angiotensin II and aldosterone can occur relatively soon after administration of ACE inhibitors,19,20 suggesting that blockade at the AT1 receptor level may provide more complete inhibition of the renin-angiotensin-aldosterone system. Although there are limited experimental data suggesting a benefit of combination therapy over single-agent therapy with an ACE inhibitor or ARB after infarction, there are substantial mechanistic and clinical trial data suggesting a benefit of combination therapy in heart failure patients treated with ARBs on a background of ACE inhibitor therapy.21–23 The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study showed improvement in enlargement in heart failure patients treated with a combination of candesartan and enalapril compared with either agent alone.7 Similarly, in the Valsartan Heart Failure Trial (Val-HeFT), addition of the ARB valsartan was associated with further improvements in ventricular size and function after MI.8 It must be noted, however, that both RESOLVD and Val-HeFT, in contrast to VALIANT, were studies of chronic heart failure patients. Additionally, although most patients (92%) in Val-HeFT received ACE inhibitors, the ACE inhibitor dose was not controlled.
In the present study we did not observe any benefit with respect to changes in ventricular size and function with valsartan therapy compared with captopril or the combination of the 2 agents. These findings are consistent with the primary VALIANT results, which failed to distinguish between the 3 arms with respect to mortality or morbidity end points. The dose of captopril used in VALIANT was the same as that used in the SAVE trial, a placebo-controlled trial that enrolled similar patients in the early 1990s and that demonstrated attenuation of ventricular enlargement in follow-up. In VALIANT, we cannot directly assess the effect of the ARB relative to placebo on ventricular enlargement and ventricular function. Nevertheless, these findings suggest that treatment with the ARB is associated with similar effects on ventricular enlargement and ventricular function. Whereas VALIANT was powered to test the noninferiority hypothesis, the VALIANT Echo study was designed and powered to assess whether either arm was superior to the others with respect to changes in ventricular size and function. We cannot therefore specifically address the issue of "noninferiority," although we observed no clinically meaningful or statistically significant differences in change in any of the echocardiographic measures from baseline to 20 months based on treatment assignment. Of note, ;-blocker use at the time of randomization was extremely high in the VALIANT population. In heart failure trials, the effect of ;-blocker use on ventricular enlargement is extremely robust, with significantly greater attenuation of enlargement than observed in ACE inhibitor studies.24 Additionally, ;-blocker therapy in the setting of ACE inhibition has been shown to directly lower angiotensin II levels in heart failure patients.25 It is possible, therefore, that ;-blockers might have attenuated any differences among the treatment groups. We also cannot exclude the possibility that the addition of an ARB to chronic ACE inhibitor therapy would be substantively different from simultaneous initiation and titration of the 2 drugs, as performed in VALIANT. In the overall VALIANT study, combination therapy was associated with an increase in adverse events, predominantly discontinuation for hypotension or renal dysfunction. We did not observe any echocardiographic correlates of these adverse events in this substudy. We also did not observe any differential benefit with respect to these echocardiographic parameters depending on infarct location.
The Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL) echocardiographic substudy was most comparable in design to the VALIANT Echo study.26 OPTIMAAL compared losartan 50 mg/d with captopril 50 mg TID. The Echo substudy demonstrated a small but significant decrease in wall motion score index in patients receiving captopril. These findings are consistent with the overall small, though nonsignificant, reduction in events in patients receiving captopril in OPTIMAAL. Although we cannot directly compare the global assessments made in the VALIANT Echo study with the wall motion assessments made in OPTIMAAL, the OPTIMAAL echocardiographic findings are consistent with the notion that the relatively low dose of the ARB and relatively slow uptitration used in OPTIMAAL may have contributed to the observed benefits of the ACE inhibitor. Similarly, in the Evaluation of Losartan in the Elderly (ELITE) trial, there were no differences in the change in ventricular volumes observed with either losartan or captopril therapy.27 In each of these studies, the imaging data paralleled the main study findings.
Baseline echocardiographic measures of ventricular size and function in our cohort were extremely predictive of cardiovascular outcomes, including total mortality, cardiovascular mortality, hospitalization for heart failure, and stroke. Of the major cardiovascular outcomes in VALIANT, only MI was not influenced by baseline measures of cardiac size and function, a finding previously observed in the SAVE cohort. Although the relationship between ejection fraction and outcomes appears relatively linear, we observed a minimal increase in risk below the median for volumes or infarct segment length. Nevertheless, even after adjustment for clinical baseline variables that were most predictive of outcome in this cohort, these echocardiographic measures remained independently predictive of all major outcomes. These data are consistent with prior studies and provide precise information on the prognostic value of specific echocardiographic measures as surrogate end points in an MI clinical trial, data that we believe will be useful in the design of future clinical trials.
In patients who survived to the 20-month echocardiogram, those with nonfatal interim events (heart failure, MI, stroke, resuscitated sudden death) were more likely to experience LV dilatation or reduction in ventricular function. These findings are consistent with prior studies demonstrating a relationship between cardiovascular events and alterations in ventricular size and function.3 Nevertheless, the number of deaths between baseline and 20 months complicates the relationship between changes in ventricular size or function and outcomes in this population. Because there was very little follow-up time after the final echocardiogram, we could not assess the influence of changes in ventricular size or function on subsequent outcomes. That changes occurring in the first month after MI did not predict outcome may be explained by the fact that baseline echocardiograms in this study were obtained at a median of 5 days after MI and may reflect a more "stable" assessment of cardiac size and function than would be obtained in the early postinfarct period.
Some limitations of the present study should be noted. A significant number of patients enrolled in the VALIANT Echo study died before the final echocardiogram. We expect, therefore, that some degree of survivor bias influenced the findings. Indeed, we cannot exclude the possibility that the slight improvement observed in LV function over the 20-month period might be secondary to survivor bias. It is unlikely, however, that survivor bias might have influenced the relative changes in ventricular size and function in each of the 3 treatment arms because in the overall trial, and in the Echo cohort, the number of deaths were similar, as were the number of patients available for paired studies, in each arm. Echocardiograms were obtained, on average, 4.8 days after MI and as many as 10 days after MI. Our baseline echocardiogram, therefore, may have occurred after substantial recovery of function or after significant ventricular enlargement, both of which can occur during this time period.10,28 The relatively simple measures of ventricular size and function that we report are not the only measurements that may relate to outcomes after infarction, and it is conceivable that other measures may be more sensitive. Finally, although background therapy was similar in all 3 groups, we cannot rule out the possibility that any aspect of the patients’ management, including background therapy or reperfusion therapy, may have altered the natural history of ventricular enlargement in this population and may have attenuated any potential therapeutic effect.
In summary, treatment with captopril, valsartan, and the combination of valsartan plus captopril in patients with MI complicated by LV dysfunction, heart failure, or both was associated with similar changes in ventricular size and function in the 20 months that followed. These data suggest that in the doses tested, the ARB valsartan has similar effects with respect to changes in cardiac structure and function as a dose of captopril previously shown to affect cardiac enlargement. Baseline echocardiographic measures of ventricular size, ejection fraction, and infarct segment length were powerfully and independently predictive of death and other cardiovascular outcomes, suggesting the value of echocardiography as a predictor of outcome after MI.
Acknowledgments
This study was supported by a grant from Novartis Pharmaceuticals.
Disclosure
Dr Solomon, Pfeffer, McMurray, Velazquez, Arnold, and Califf have received research funding from, have served on the Speakers’ Bureau of and/or received honoraria from, and have served as a consultant to Novartis Pharmaceuticals. Drs Ghali and Warnica have received research funding from and served on the Speakers’ Bureau of and/or received honoraria from Novartis Pharmaceuticals. Dr Pfeffer is named as a co-inventor on a patent awarded to the Brigham and Women’s Hospital with regard to the use of inhibitors of the renin-angiotensin system in selected survivors of myocardial infarction; there is a licensing agreement between Novartis and the Brigham and Women’s Hospital, which is not linked to sales.
References
Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling: concepts and clinical implications. J Am Coll Cardiol. 2000; 35: 569–582.
Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford JR, Wertheimer JH, Hawkins CM, for the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992; 327: 669–677.
St John Sutton M, Pfeffer MA, Plappert T, Rouleau JL, Moye LA, Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S, Menapace F, Parker JO, Lewis S, Sestier F, Gordon DF, McEwan P, Bernstein V, Braunwald E, for the SAVE Investigators. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction: the protective effects of captopril. Circulation. 1994; 89: 68–75.
Zornoff LA, Paiva SA, Matsubara BB, Matsubara LS, Spadaro J. Combination therapy with angiotensin converting enzyme inhibition and AT1 receptor inhibitor on ventricular remodeling after myocardial infarction in rats. J Cardiovasc Pharmacol Ther. 2000; 5: 203–209.
Nakamura Y, Yoshiyama M, Omura T, Yoshida K, Izumi Y, Takeuchi K, Kim S, Iwao H, Yoshikawa J. Beneficial effects of combination of ACE inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction. Cardiovasc Res. 2003; 57: 48–54.
Zhang G, Shen X, Pu S, Yang Y, Pan W, Chen H. Comparative effects of losartan and captopril on ventricular remodeling and function after myocardial infarction in the rat. Chin Med Sci J. 1998; 13: 32–36.
McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Rouleau J, Latini R, Maggioni A, Young J, Pogue J, for the RESOLVD Pilot Study Investigators. Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Circulation. 1999; 100: 1056–1064.
Wong M, Staszewsky L, Latini R, Barlera S, Volpi A, Chiang YT, Benza RL, Gottlieb SO, Kleemann TD, Rosconi F, Vandervoort PM, Cohn JN, for the Val-HeFT Heart Failure Trial Investigators. Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol. 2002; 40: 970–975.
Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003; 349: 1893–1906.
Pfeffer MA, Greaves SC, Arnold JM, Glynn RJ, LaMotte FS, Lee RT, Menapace FJ Jr, Rapaport E, Ridker PM, Rouleau JL, Solomon SD, Hennekens CH. Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction: the Healing and Early Afterload Reducing Therapy Trial. Circulation. 1997; 95: 2643–2651.
Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res. 1985; 57: 84–95.
Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med. 1988; 319: 80–86.
Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet. 1988; 1: 255–259.
Gaudron P, Eilles C, Ertl G, Kochsiek K. Early remodelling of the left ventricle in patients with myocardial infarction. Eur Heart J. 1990; 11 (suppl B): 139–146.
White HD, Norris RM, Brown MA, Brandt PWT, Whitlock RML, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. 1987; 76: 44–51.
Taylor K, Patten RD, Smith JJ, Aronovitz MJ, Wight J, Salomon RN, Konstam MA. Divergent effects of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism on myocardial cellular proliferation and collagen deposition after myocardial infarction in rats. J Cardiovasc Pharmacol. 1998; 31: 654–660.
Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure: role of kinins and angiotensin II type 2 receptors. J Clin Invest. 1997; 99: 1926–1935.
St John Sutton M, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E, for the SAVE Investigators. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation. 1997; 96: 3294–3299.
Biollaz J, Brunner HR, Gavras I, Waeber B, Gavras H. Antihypertensive therapy with MK 421: angiotensin II–renin relationships to evaluate efficacy of converting enzyme blockade. Cardiovasc Pharmacol. 1982; 4: 966–972.
Struthers AD. Aldosterone escape during angiotensin converting enzyme inhibitor therapy in chronic heart failure. J Card Failure. 1996; 2: 47–54.
Baruch L, Anand I, Cohen IS, Ziesche S, Judd D, Cohn JN, for the Vasodilator Heart Failure Trial (V-HeFT) Study Group. Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor therapy in patients with heart failure. Circulation. 1999; 99: 2658–2664.
Cohn JN, Tognoni G. Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345: 1667–1675.
McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003; 362: 767–771.
Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N, for the Australia-New Zealand Heart Failure Research Collaborative Group. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. J Am Coll Cardiol. 1997; 29: 1060–1066.
Campbell DJ, Aggarwal A, Esler M, Kaye D. Beta-blockers, angiotensin II, and ACE inhibitors in patients with heart failure. Lancet. 2001; 358: 1609–1610.
Moller JE, Dahlstrom U, Gotzsche O, Lahiri A, Skagen K, Andersen GS, Egstrup K, for the OPTIMAAL Study Group. Effects of losartan and captopril on left ventricular systolic and diastolic function after acute myocardial infarction: results of the Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL) echocardiographic substudy. Am Heart J. 2004; 147: 494–501.
Konstam MA, Patten RD, Thomas I, Ramahi T, La Bresh K, Goldman S, Lewis W, Gradman A, Self KS, Bittner V, Rand W, Kinan D, Smith JJ, Ford T, Segal R, Udelson JE. Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function substudy. Am Heart J. 2000; 139: 1081–1087.
Solomon SD, Glynn RJ, Greaves S, Ajani U, Rouleau JL, Menapace F, Arnold JM, Hennekens C, Pfeffer MA. Recovery of ventricular function after myocardial infarction in the reperfusion era: the Healing and Early Afterload Reducing Therapy Study. Ann Intern Med. 2001; 134: 451–458.(Scott D. Solomon, MD; Hic)
Section of Cardiology, Department of Medicine, Central Hospital in Rogaland, Stavanger, Norway (S.B.)
Cardiac Centers of Louisiana, Shreveport (J.K.G.)
Foothills Hospital, Calgary, Alberta, Canada (J.W.W.)
St George Hospital, St Petersburg, Russia (M.K.)
London Health Sciences Center–Victoria Campus, London, Ontario, Canada (J.M.O.A.)
University Hospital N3, Saratov, Russia (Y.S.)
Duke University Medical Center, Durham, NC (E.J.V., R.M.C.)
Department of Cardiology, Western Infirmary, Glasgow, Scotland (J.V.M.).
Abstract
Background— Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI). Preclinical data suggest that angiotensin receptor blockers (ARBs) may have similar structural and functional effects after MI. The Valsartan in Acute Myocardial Infarction (VALIANT) Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV ejection fraction to a greater extent than captopril alone.
Methods and Results— Six hundred ten patients enrolled in the main VALIANT study who experienced MI and evidence of LV dysfunction, heart failure, or both were enrolled in the VALIANT Echo study. Patients were randomized to receive valsartan 160 mg PO BID, captopril 50 mg PO TID, or valsartan 80 mg PO BID plus captopril 50 mg PO TID between 1 and 10 days after MI. Six hundred three patients had echocardiograms of sufficient quality for quantitative analysis. Echocardiograms were digitized, and endocardial borders were traced manually from 2 short-axis and 2 apical views. Ventricular volumes, ejection fractions, combined areas, and infarct segment length were measured, and changes in echocardiographic measures from baseline to 20 months were compared between treatment groups. Baseline clinical and echocardiographic characteristics were similar in the 3 treatment arms. The changes from baseline to 20 months in all echocardiographic parameters were similar in all 3 treatment arms. Baseline echocardiographic measures of ejection fraction, end-diastolic volume, and infarct segment length were highly predictive of outcomes including total mortality, death or hospitalization for heart failure, or death or any cardiovascular event (heart failure, MI, stroke, resuscitated sudden death), even after adjustment for known covariates.
Conclusions— Treatment with the ACE inhibitor captopril, valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction, and infarct segment length between baseline and 20 months after MI. Baseline echocardiographic measures were powerfully and independently predictive of all major outcomes.
Key Words: echocardiography ; myocardial infarction ; remodeling ; angiotensin-converting enzyme inhibitors ; ventricular function
Introduction
Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI).1–3 Preclinical data with angiotensin receptor blockers (ARBs) suggest that this alternative method of inhibiting the renin-angiotensin system may result in similar structural and functional effects after experimental infarction.4–6 In heart failure patients, the combination of an ACE inhibitor and an ARB has been associated with greater attenuation of ventricular enlargement than either agent alone.7,8
The Valsartan in Acute Myocardial Infarction (VALIANT) study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with the proven ACE inhibitor captopril, would be superior or not inferior to a proven dose of captopril in reducing cardiovascular morbidity or mortality after MI and demonstrated that valsartan was as effective as captopril in reducing cardiovascular morbidity and mortality, but the combination was associated with increased adverse events without increased benefit.9 The VALIANT Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV function to a greater extent than captopril alone. Six hundred ten patients from the main VALIANT study were enrolled in the VALIANT Echo study. In this report we present the results of the VALIANT Echo study and the relationship between baseline echocardiographic assessment and outcomes after MI.
Methods
Patients
Clinical sites participating in the main VALIANT study were invited to enroll patients in the VALIANT Echo study, and patients enrolled in the VALIANT trial at these sites were eligible for inclusion in the VALIANT Echo study. Entry criteria were identical to those for the main VALIANT study: Patients were eligible if they had an MI and evidence of LV dysfunction (ejection fraction 35% on echocardiography or ventriculography, or ejection fraction 40% by radionuclide ventriculography), heart failure, or both. Patients were included regardless of infarct location or ST-segment characteristics. Patients were randomized and titrated to receive valsartan 160 mg BID, captopril 50 mg TID, or valsartan 80 mg BID plus captopril 50 mg TID between 0.5 day and 10 days after MI (mean=4.8 days) and received concomitant background therapy at the discretion of the treating physicians. Six hundred ten patients from the total VALIANT population (14 703) were enrolled in VALIANT Echo. Echocardiographic examinations were performed at baseline (before randomization), at 1 month, and at 20 months after MI. A total of 94 clinical sites in 13 countries participated in the VALIANT Echo study. Patients signed informed consent for inclusion in the VALIANT Echo study, and institutional review board approval was obtained by each site.
Echocardiographic Analysis
All echocardiographic studies were sent to a core laboratory at Brigham and Women’s Hospital. Studies were reviewed for quality, and 5 patients were excluded before analysis because of extremely poor study quality; 2 additional patients had insufficient echocardiographic images for assessment of ventricular volume and ejection fractions. In patients with echocardiographic studies of sufficient quality for quantitative analysis, defined as availability of all necessary views and sufficient image quality for endocardial border definition, echocardiographic analyses were performed at baseline (n=603), at 1 month (n=544), and at 20 months after MI (n=428). Fifty-nine patients in the initial cohort did not have 1-month echocardiograms, including 21 patients who died before the 1-month echo. One hundred seventy-five patients in the initial cohort did not have the 20-month echocardiogram, including 98 patients who died before the final visit. Five patients died after the 20-month echocardiograms, which were available in 146 patients in the captopril group, 140 patients in the combination group, and 142 patients in the valsartan group.
Echocardiograms from videotape were digitized, and analyses were performed with the use of an offline analysis workstation. LV endocardial borders were manually traced at end-diastole and end-systole at the mitral and papillary level short-axis and apical 4- and 2-chamber views from 3 separate cardiac cycles by a single experienced observer. LV volumes were derived according to the modified biplane Simpson’s rule in the apical 4-chamber and apical 2-chamber views, and ejection fraction was calculated in the standard fashion from ventricular volumes. Combined LV areas were calculated by summing the average areas from the apical and short-axis views.3 Infarct segment length was assessed by manual measurement of the infarct perimeter, defined as a severely hypokinetic, akinetic, or dyskinetic segment, and the average short-axis and apical infarct perimeter lengths were summed. The entire cavity perimeter length was measured in the apical and short-axis views, and the infarct segment length was expressed as a percentage of the total perimeter. Biplane volumes and ejection fractions were available at baseline in 603 patients; combined areas were available in 574 patients at baseline; infarct segment length measures were available in 552 patients at baseline.
Statistical Analysis
The primary end point of the study was the change in ventricular size (end-diastolic volume) from baseline to 20 months. A sample size of 600 patients was determined necessary to detect, with 90% power, a 7.6-mL difference in end-diastolic volume between treatment groups on the basis of data from previous post-MI studies.10 This difference was considered both clinically meaningful and large enough to be greater than the limits of measurement error. A statistical adjustment was planned to account for the 3-group comparison in the event of a treatment difference. To assess reproducibility, 52 patient studies were randomly chosen and reanalyzed with the observer blinded to the initial results for the primary end point of end-diastolic volume. The mean signed differences and the SD of the differences between measurements were calculated (Bland-Altman method), and the variability was expressed as the SD of the difference divided by the mean measurement. Clinical characteristics in the Echo cohort and the remainder of the VALIANT cohort were compared. LV volumes, areas, and ejection fractions were compared at baseline and at 20 months, and the changes in these parameters between time points were compared between the 3 treatment groups.
Baseline echocardiographic assessments, including LV volume, ejection fraction, and infarct segment length, were related to clinical outcomes, including total mortality and cardiovascular morbidity, with Cox proportional hazards models. In patients who survived to the 20-month echocardiogram, changes in ventricular size and function were related to clinical outcomes throughout the study period. Continuous variables were compared with the Student t test. Categorical variables were compared with the 2 test. To determine the independent value of echocardiographic measures, we used a multivariable Cox proportional hazards model with the 10 most powerful covariate predictors of mortality identified from the overall VALIANT study using stepwise backward selection of a 70-covariate model.
Results
Baseline Characteristics
The VALIANT Echo cohort was similar to the VALIANT cohort as a whole (Table 1) and differed from the main cohort minimally with respect to age (63.8±12.3 versus 64.9±11.8 years; P=0.02) and baseline blood pressure (systolic blood pressure, 121.1±14.9 versus 122.7±17.1 mm Hg; P=0.02; diastolic blood pressure, 70.5±10.9 versus 72.4±11.3 mm Hg; P=0.0001). There were no other significant differences in baseline characteristics or prerandomization medications between the Echo cohort and the remainder of the VALIANT cohort. There were no differences in baseline characteristics or medications in patients randomized to any of the 3 treatment arms in the VALIANT Echo study. The overall coefficient of variability of the primary end point (end-diastolic volume) based on the reproducibility assessment was 8.3%.
Changes From Baseline to 20 Months
In the 428 patients with paired echocardiographic studies between baseline and 20 months, overall diastolic volume increased by 2.4±17.6 mL (P=0.005), systolic volume decreased by 0.45±16.7 mL (P=0.56), and ejection fraction increased by 2.0±7.22% (P<0.0001). Table 3 shows baseline, 1-month, and 20-month echocardiographic measures in the 3 treatment arms. There were no significant differences in the magnitude of the change in any of the echocardiographic end points, including volumes, areas, ejection fractions, or infarct segment lengths between patients receiving either valsartan, captopril, or the combination (Table 3).
Echocardiographic Measures and Outcomes
Changes in ventricular size or function from baseline to 1 month did not predict subsequent cardiovascular outcomes. Of patients who survived to the 20-month echocardiogram, those who experienced an adverse cardiovascular event (n=76), including hospitalization for heart failure, MI, resuscitated sudden death, or stroke before or after the final echocardiogram or death after the final echocardiogram, had a greater increase in end-diastolic volume (7.5±19.9 versus 1.3±16.9 mL; P=0.005), a greater decrease in ejection fraction (–0.68±7.0% versus 2.5±7.1%; P=0.0004), and a lesser improvement in infarct segment length (0.06±3.1% versus –1.04±2.2%; P=0.005) compared with patients who did not experience adverse events.
Discussion
ACE inhibition has been shown to attenuate ventricular enlargement and has been associated with improvement in ventricular function in patients after MI. The results of the VALIANT Echo study suggest that in a contemporary population of patients with MI and LV dysfunction, heart failure, or both, treatment with the ACE inhibitor captopril, the ARB valsartan, or the combination of valsartan and captopril resulted in similar changes in ventricular size and function. These findings suggest that combination therapy with an ACE inhibitor and ARB is not superior to either strategy alone for improving ventricular function or attenuating enlargement after MI complicated by LV dysfunction or heart failure. These findings are consistent with the primary results of the VALIANT trial, in which neither arm was more effective in reducing mortality or cardiovascular morbidity.
Early observations from experimental infarct studies demonstrating that ACE inhibitors could attenuate subsequent progressive LV enlargement (remodeling) provided the initial rationale for the use of ACE inhibitors after MI.11–13 LV enlargement, either limited or progressive, has been demonstrated in a significant proportion of patients after MI,14 is dependent on initial infarct size, and is associated with a significant increase in the risk of subsequent morbidity and mortality.15 Although the improvement in survival associated with ACE inhibitor use after MI in multiple large clinical trials cannot be explained entirely by attenuation of LV enlargement alone, ventricular enlargement after MI has been associated with an increased risk for adverse events.3
A number of experimental studies have suggested that ARBs may attenuate ventricular enlargement to an extent similar to that of ACE inhibitors. In animal models, angiotensin receptor blockade has been associated with inhibition of LV hypertrophy, ventricular dilatation, and collagen deposition compared with placebo.16 Experimental models of MI have shown similar antiremodeling effects of the ARB losartan and the ACE inhibitor ramipril.17 Zornoff et al4 have shown similar overall attenuation of ventricular enlargement in rats treated with losartan, captopril, or the combination after MI.
There is a compelling rationale for considering AT1 receptor blockers as an alternative therapy to ACE inhibitors for attenuation of ventricular enlargement and improvement in ventricular function after MI. ACE inhibitors are poorly tolerated in a finite number of patients. Moreover, the effect of ACE inhibition on enlargement may diminish over time; in the Survival and Ventricular Enlargement (SAVE) study, no further attenuation of enlargement was observed after 1 year.18 Elevations in the levels of circulating angiotensin II and aldosterone can occur relatively soon after administration of ACE inhibitors,19,20 suggesting that blockade at the AT1 receptor level may provide more complete inhibition of the renin-angiotensin-aldosterone system. Although there are limited experimental data suggesting a benefit of combination therapy over single-agent therapy with an ACE inhibitor or ARB after infarction, there are substantial mechanistic and clinical trial data suggesting a benefit of combination therapy in heart failure patients treated with ARBs on a background of ACE inhibitor therapy.21–23 The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study showed improvement in enlargement in heart failure patients treated with a combination of candesartan and enalapril compared with either agent alone.7 Similarly, in the Valsartan Heart Failure Trial (Val-HeFT), addition of the ARB valsartan was associated with further improvements in ventricular size and function after MI.8 It must be noted, however, that both RESOLVD and Val-HeFT, in contrast to VALIANT, were studies of chronic heart failure patients. Additionally, although most patients (92%) in Val-HeFT received ACE inhibitors, the ACE inhibitor dose was not controlled.
In the present study we did not observe any benefit with respect to changes in ventricular size and function with valsartan therapy compared with captopril or the combination of the 2 agents. These findings are consistent with the primary VALIANT results, which failed to distinguish between the 3 arms with respect to mortality or morbidity end points. The dose of captopril used in VALIANT was the same as that used in the SAVE trial, a placebo-controlled trial that enrolled similar patients in the early 1990s and that demonstrated attenuation of ventricular enlargement in follow-up. In VALIANT, we cannot directly assess the effect of the ARB relative to placebo on ventricular enlargement and ventricular function. Nevertheless, these findings suggest that treatment with the ARB is associated with similar effects on ventricular enlargement and ventricular function. Whereas VALIANT was powered to test the noninferiority hypothesis, the VALIANT Echo study was designed and powered to assess whether either arm was superior to the others with respect to changes in ventricular size and function. We cannot therefore specifically address the issue of "noninferiority," although we observed no clinically meaningful or statistically significant differences in change in any of the echocardiographic measures from baseline to 20 months based on treatment assignment. Of note, ;-blocker use at the time of randomization was extremely high in the VALIANT population. In heart failure trials, the effect of ;-blocker use on ventricular enlargement is extremely robust, with significantly greater attenuation of enlargement than observed in ACE inhibitor studies.24 Additionally, ;-blocker therapy in the setting of ACE inhibition has been shown to directly lower angiotensin II levels in heart failure patients.25 It is possible, therefore, that ;-blockers might have attenuated any differences among the treatment groups. We also cannot exclude the possibility that the addition of an ARB to chronic ACE inhibitor therapy would be substantively different from simultaneous initiation and titration of the 2 drugs, as performed in VALIANT. In the overall VALIANT study, combination therapy was associated with an increase in adverse events, predominantly discontinuation for hypotension or renal dysfunction. We did not observe any echocardiographic correlates of these adverse events in this substudy. We also did not observe any differential benefit with respect to these echocardiographic parameters depending on infarct location.
The Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL) echocardiographic substudy was most comparable in design to the VALIANT Echo study.26 OPTIMAAL compared losartan 50 mg/d with captopril 50 mg TID. The Echo substudy demonstrated a small but significant decrease in wall motion score index in patients receiving captopril. These findings are consistent with the overall small, though nonsignificant, reduction in events in patients receiving captopril in OPTIMAAL. Although we cannot directly compare the global assessments made in the VALIANT Echo study with the wall motion assessments made in OPTIMAAL, the OPTIMAAL echocardiographic findings are consistent with the notion that the relatively low dose of the ARB and relatively slow uptitration used in OPTIMAAL may have contributed to the observed benefits of the ACE inhibitor. Similarly, in the Evaluation of Losartan in the Elderly (ELITE) trial, there were no differences in the change in ventricular volumes observed with either losartan or captopril therapy.27 In each of these studies, the imaging data paralleled the main study findings.
Baseline echocardiographic measures of ventricular size and function in our cohort were extremely predictive of cardiovascular outcomes, including total mortality, cardiovascular mortality, hospitalization for heart failure, and stroke. Of the major cardiovascular outcomes in VALIANT, only MI was not influenced by baseline measures of cardiac size and function, a finding previously observed in the SAVE cohort. Although the relationship between ejection fraction and outcomes appears relatively linear, we observed a minimal increase in risk below the median for volumes or infarct segment length. Nevertheless, even after adjustment for clinical baseline variables that were most predictive of outcome in this cohort, these echocardiographic measures remained independently predictive of all major outcomes. These data are consistent with prior studies and provide precise information on the prognostic value of specific echocardiographic measures as surrogate end points in an MI clinical trial, data that we believe will be useful in the design of future clinical trials.
In patients who survived to the 20-month echocardiogram, those with nonfatal interim events (heart failure, MI, stroke, resuscitated sudden death) were more likely to experience LV dilatation or reduction in ventricular function. These findings are consistent with prior studies demonstrating a relationship between cardiovascular events and alterations in ventricular size and function.3 Nevertheless, the number of deaths between baseline and 20 months complicates the relationship between changes in ventricular size or function and outcomes in this population. Because there was very little follow-up time after the final echocardiogram, we could not assess the influence of changes in ventricular size or function on subsequent outcomes. That changes occurring in the first month after MI did not predict outcome may be explained by the fact that baseline echocardiograms in this study were obtained at a median of 5 days after MI and may reflect a more "stable" assessment of cardiac size and function than would be obtained in the early postinfarct period.
Some limitations of the present study should be noted. A significant number of patients enrolled in the VALIANT Echo study died before the final echocardiogram. We expect, therefore, that some degree of survivor bias influenced the findings. Indeed, we cannot exclude the possibility that the slight improvement observed in LV function over the 20-month period might be secondary to survivor bias. It is unlikely, however, that survivor bias might have influenced the relative changes in ventricular size and function in each of the 3 treatment arms because in the overall trial, and in the Echo cohort, the number of deaths were similar, as were the number of patients available for paired studies, in each arm. Echocardiograms were obtained, on average, 4.8 days after MI and as many as 10 days after MI. Our baseline echocardiogram, therefore, may have occurred after substantial recovery of function or after significant ventricular enlargement, both of which can occur during this time period.10,28 The relatively simple measures of ventricular size and function that we report are not the only measurements that may relate to outcomes after infarction, and it is conceivable that other measures may be more sensitive. Finally, although background therapy was similar in all 3 groups, we cannot rule out the possibility that any aspect of the patients’ management, including background therapy or reperfusion therapy, may have altered the natural history of ventricular enlargement in this population and may have attenuated any potential therapeutic effect.
In summary, treatment with captopril, valsartan, and the combination of valsartan plus captopril in patients with MI complicated by LV dysfunction, heart failure, or both was associated with similar changes in ventricular size and function in the 20 months that followed. These data suggest that in the doses tested, the ARB valsartan has similar effects with respect to changes in cardiac structure and function as a dose of captopril previously shown to affect cardiac enlargement. Baseline echocardiographic measures of ventricular size, ejection fraction, and infarct segment length were powerfully and independently predictive of death and other cardiovascular outcomes, suggesting the value of echocardiography as a predictor of outcome after MI.
Acknowledgments
This study was supported by a grant from Novartis Pharmaceuticals.
Disclosure
Dr Solomon, Pfeffer, McMurray, Velazquez, Arnold, and Califf have received research funding from, have served on the Speakers’ Bureau of and/or received honoraria from, and have served as a consultant to Novartis Pharmaceuticals. Drs Ghali and Warnica have received research funding from and served on the Speakers’ Bureau of and/or received honoraria from Novartis Pharmaceuticals. Dr Pfeffer is named as a co-inventor on a patent awarded to the Brigham and Women’s Hospital with regard to the use of inhibitors of the renin-angiotensin system in selected survivors of myocardial infarction; there is a licensing agreement between Novartis and the Brigham and Women’s Hospital, which is not linked to sales.
References
Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling: concepts and clinical implications. J Am Coll Cardiol. 2000; 35: 569–582.
Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford JR, Wertheimer JH, Hawkins CM, for the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992; 327: 669–677.
St John Sutton M, Pfeffer MA, Plappert T, Rouleau JL, Moye LA, Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S, Menapace F, Parker JO, Lewis S, Sestier F, Gordon DF, McEwan P, Bernstein V, Braunwald E, for the SAVE Investigators. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction: the protective effects of captopril. Circulation. 1994; 89: 68–75.
Zornoff LA, Paiva SA, Matsubara BB, Matsubara LS, Spadaro J. Combination therapy with angiotensin converting enzyme inhibition and AT1 receptor inhibitor on ventricular remodeling after myocardial infarction in rats. J Cardiovasc Pharmacol Ther. 2000; 5: 203–209.
Nakamura Y, Yoshiyama M, Omura T, Yoshida K, Izumi Y, Takeuchi K, Kim S, Iwao H, Yoshikawa J. Beneficial effects of combination of ACE inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction. Cardiovasc Res. 2003; 57: 48–54.
Zhang G, Shen X, Pu S, Yang Y, Pan W, Chen H. Comparative effects of losartan and captopril on ventricular remodeling and function after myocardial infarction in the rat. Chin Med Sci J. 1998; 13: 32–36.
McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Rouleau J, Latini R, Maggioni A, Young J, Pogue J, for the RESOLVD Pilot Study Investigators. Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Circulation. 1999; 100: 1056–1064.
Wong M, Staszewsky L, Latini R, Barlera S, Volpi A, Chiang YT, Benza RL, Gottlieb SO, Kleemann TD, Rosconi F, Vandervoort PM, Cohn JN, for the Val-HeFT Heart Failure Trial Investigators. Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol. 2002; 40: 970–975.
Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003; 349: 1893–1906.
Pfeffer MA, Greaves SC, Arnold JM, Glynn RJ, LaMotte FS, Lee RT, Menapace FJ Jr, Rapaport E, Ridker PM, Rouleau JL, Solomon SD, Hennekens CH. Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction: the Healing and Early Afterload Reducing Therapy Trial. Circulation. 1997; 95: 2643–2651.
Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res. 1985; 57: 84–95.
Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med. 1988; 319: 80–86.
Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet. 1988; 1: 255–259.
Gaudron P, Eilles C, Ertl G, Kochsiek K. Early remodelling of the left ventricle in patients with myocardial infarction. Eur Heart J. 1990; 11 (suppl B): 139–146.
White HD, Norris RM, Brown MA, Brandt PWT, Whitlock RML, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. 1987; 76: 44–51.
Taylor K, Patten RD, Smith JJ, Aronovitz MJ, Wight J, Salomon RN, Konstam MA. Divergent effects of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism on myocardial cellular proliferation and collagen deposition after myocardial infarction in rats. J Cardiovasc Pharmacol. 1998; 31: 654–660.
Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure: role of kinins and angiotensin II type 2 receptors. J Clin Invest. 1997; 99: 1926–1935.
St John Sutton M, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E, for the SAVE Investigators. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation. 1997; 96: 3294–3299.
Biollaz J, Brunner HR, Gavras I, Waeber B, Gavras H. Antihypertensive therapy with MK 421: angiotensin II–renin relationships to evaluate efficacy of converting enzyme blockade. Cardiovasc Pharmacol. 1982; 4: 966–972.
Struthers AD. Aldosterone escape during angiotensin converting enzyme inhibitor therapy in chronic heart failure. J Card Failure. 1996; 2: 47–54.
Baruch L, Anand I, Cohen IS, Ziesche S, Judd D, Cohn JN, for the Vasodilator Heart Failure Trial (V-HeFT) Study Group. Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor therapy in patients with heart failure. Circulation. 1999; 99: 2658–2664.
Cohn JN, Tognoni G. Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345: 1667–1675.
McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003; 362: 767–771.
Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N, for the Australia-New Zealand Heart Failure Research Collaborative Group. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. J Am Coll Cardiol. 1997; 29: 1060–1066.
Campbell DJ, Aggarwal A, Esler M, Kaye D. Beta-blockers, angiotensin II, and ACE inhibitors in patients with heart failure. Lancet. 2001; 358: 1609–1610.
Moller JE, Dahlstrom U, Gotzsche O, Lahiri A, Skagen K, Andersen GS, Egstrup K, for the OPTIMAAL Study Group. Effects of losartan and captopril on left ventricular systolic and diastolic function after acute myocardial infarction: results of the Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL) echocardiographic substudy. Am Heart J. 2004; 147: 494–501.
Konstam MA, Patten RD, Thomas I, Ramahi T, La Bresh K, Goldman S, Lewis W, Gradman A, Self KS, Bittner V, Rand W, Kinan D, Smith JJ, Ford T, Segal R, Udelson JE. Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function substudy. Am Heart J. 2000; 139: 1081–1087.
Solomon SD, Glynn RJ, Greaves S, Ajani U, Rouleau JL, Menapace F, Arnold JM, Hennekens C, Pfeffer MA. Recovery of ventricular function after myocardial infarction in the reperfusion era: the Healing and Early Afterload Reducing Therapy Study. Ann Intern Med. 2001; 134: 451–458.(Scott D. Solomon, MD; Hic)