Valsartan in Acute Myocardial Infarction Trial (VALIANT): Rationale and design☆☆☆★

Article Outline

• Abstract
• The VALIANT protocol
• Efficacy measures
• Safety and tolerability measures
• Statistical section
• Substudies
• Study organization
• Discussion
• Conclusion
• Appendix: Participating centers
• References
• Copyright

Abstract 

Background Survivors of acute myocardial infarction (MI) complicated by heart failure and/or resulting in left ventricular dysfunction are at heightened risk for subsequent death and major nonfatal cardiovascular events. Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor has consistently been demonstrated to result in reductions in these risks by approximately 20%. The development of angiotensin II receptor blockers offers a new, more specific, and theoretically more complete pharmacologic mode to inhibit the adverse influence of angiotensin II. Methods Valsartan in Acute Myocardial Infarction (VALIANT) is a multicenter, double-blind, randomized, active controlled parallel group study comparing the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after MI. The trial is designed with 3 arms, giving equal statistical consideration to survival comparisons of captopril versus the angiotensin II receptor blocker valsartan, as well as the combination of captopril plus valsartan, compared with a proven effective dose of captopril. This 14,500-patient trial is designed with an 86% power to detect a 15% reduction in mortality rate with either use of valsartan compared with captopril. The trial encourages optimal individualization of other proven therapies in acute and chronic infarction, and the international patient body ensures good representation of multiple practice patterns. Conclusion VALIANT is a large international investigative effort that will evaluate the role of valsartan in the management of patients with MI associated with heart failure and/or left ventricular dysfunction. The use of a proven dose of captopril and the comparator arms with valsartan alone or in combination with captopril provides a unique test of whether the angiotensin II receptor blocker can make an additional improvement in clinical outcomes beyond angiotensin-converting enzyme inhibitors. (Am Heart J 2000;140:727-34.)

Cumulative advances in the management of the acute and chronic phases of a myocardial infarction have led to progressive reductions in the risk of death and the risk of serious cardiovascular complications after a myocardial infarction. β-Blockers were the first pharmacologic therapy proven to be effective in improving survival in myocardial infarction.¹ The next major life-saving advances were thrombolytic or reperfusion strategies along with the independent benefits of aspirin therapy.² The benefits of reperfusion were shown to be particularly sensitive to time of initiation, and have made a tremendous impact in the triage and management of patients with acute myocardial infarction.³

The initial rationale for evaluation of the use of angiotensin-converting enzyme (ACE) inhibitors in patients with myocardial infarction was derived from animal studies that demonstrated that for comparable myocardial infarction size, this therapy could attenuate long-term changes in ventricular remodeling and prolong survival.⁴ As such, ACE inhibitor use in myocardial infarction was complementary to the other proven therapies and was considered as a long-term therapy to reduce the risk of death and the development of heart failure after myocardial infarction.

From a series of internationally conducted, randomized, placebo-controlled clinical trials involving more than 100,000 patients, the survival benefit of ACE inhibitors in patients with acute⁵ and chronic⁶ myocardial infarction has been definitively established. The greatest relative and absolute benefits were seen in the trials that selected patients for higher risk, based on subjective or objective evidence of left ventricular dysfunction.⁷ In studies such as SAVE (Survival And Ventricular Enlargement), AIRE (Acute Infarction Ramipril Efficacy), and TRACE (Trandolapril Cardiac Evaluation), the odds ratio for ACE-inhibitor attributed reduction in all-cause mortality was 0.74% (95% confidence interval [CI], 0.66%-0.83%), with comparable benefits achieved when other major, initially nonfatal cardiovascular events (hospitalization for heart failure 0.73% [95% CI, 0.63%-0.85%] and recurrent myocardial infarction 0.80% [95% CI, 0.69%-0.94%]) were considered.⁶, ⁸, ⁹, ¹⁰

The development of the angiotensin II receptor blockers (ARBs) provides a new, more specific pharmacologic tool to inhibit the renin-angiotensin cascade.¹¹ The generation of angiotensin II by nonconverting enzyme pathways in cardiovascular tissues makes it likely that blockade at the AT₁ receptor may result in more complete inhibition of the adverse cardiovascular influences of angiotensin II.¹² Although the biologic significance of the AT₂ receptor is an active area of investigation, current opinion holds that “unopposed” AT₂ receptor stimulation promotes favorable long-term cardiovascular structural alterations and thus offers an additional advantage of AT₁ receptor blockade over ACE inhibitors.¹³ Another distinguishing feature between ACE inhibitors and ARBs is the concomitant potentiation of bradykinin produced by ACE inhibitors because kinase II and converting enzyme are one in the same. Although some of the side effects attributed to ACE inhibitors may involve bradykinin pathways, it is also conceivable that favorable bradykinin-dependent mechanisms mediated through nitric oxide, prostaglandins, and endothelially derived hyperpolarizing factor may contribute to the clinical effectiveness of ACE inhibitors.¹⁴ These actions may not be quantitatively shared with ARBs but raise the important possibility that the combination of both an ACE inhibitor and an ARB may be superior to either alone. Coadministration would be anticipated to more completely inhibit the actions of angiotensin II while preserving and possibly enhancing the bradykinin-dependent mechanisms. Additive benefits of these 2 modes on inhibiting the renin-angiotensin system have been observed in experimentally induced heart failure¹⁵ as well as on exercise capacity in patients with severe heart failure.¹⁶ The clinical significance of these and other hypothetical considerations will only be resolved by appropriate clinical outcome trials.

The Valsartan in Acute Myocardial Infarction Trial (VALIANT) is a multinational, multicenter, double-blind, randomized, active controlled, parallel group study comparing the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after myocardial infarction. By targeting a population in whom ACE inhibitor therapy has been clearly established and comparing the ARB valsartan against a proven agent and dosage regimen, VALIANT will determine whether valsartan offers additional clinical advantages over an ACE inhibitor. The 3-arm trial design with equal statistical weight given to the survival comparisons of ACE inhibitor to ARB therapy, as well as the combination ACE inhibitor plus ARB to ACE inhibitor alone, should provide unique and definitive data regarding the most beneficial clinical strategy for inhibiting the renin-angiotensin system in high-risk myocardial infarction patients.

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The VALIANT protocol 

VALIANT is a prospective multinational (24 countries), multicenter, double-blind, randomized, active controlled study with 3 parallel treatment groups. Men and women who are not of childbearing potential, aged 18 or older, with an acute myocardial infarction (between 12 hours and 10 days) complicated by either clinical or radiologic signs of heart failure and/or evidence of left ventricular systolic dysfunction, are eligible for this study. The goal of the study enrollment criteria is to simulate the type of criteria that would lead a practitioner to initiate ACE inhibitor therapy according to current guidelines while also producing a population of patients matching the composite population of SAVE, TRACE, and AIRE. The protocol is designed to have minimal interference with usual clinical practice as recommended by professional society guidelines.

The acute myocardial infarction forming the criterion for patient entry is characterized by clinical presentation and/or typical electrocardiographic changes and must be supported by abnormal cardiac markers. The criteria of heart failure and/or left ventricular dysfunction are a compilation of the SAVE, AIRE, and TRACE inclusions (Table I). Within this broad population, the trial is seeking to exclude only those patients with a contraindication to blockade of the renin-angiotensin system or a confounding factor that would make interpretation of the outcome data uncertain (Table I).

Table I. Inclusion and exclusion criteria

Consenting eligible patients are randomly assigned in a 1:1:1 ratio to either captopril monotherapy, valsartan monotherapy, or a valsartan and captopril combination. Randomization must occur between 12 hours and 10 days of the onset of the acute myocardial infarction. The study algorithm and drug titration regimens are presented in Figures 1 and 2, respectively.

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• Fig. 1. 

  Titration scheme regimens.

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• Fig. 2. 

  Study design.

The titrations are as clinically tolerated with a target of step 3 by hospital discharge and step 4 during the outpatient phase. Subsequent backtitrations and uptitrations are at the discretion of the investigators according to the patient’s clinical status. The captopril arms follow the protocol leading to a target dose used in the SAVE study.

Scheduled follow-up visits occur at 2 weeks and at 1, 3, 6, 9, and 12 months and thereafter at 4-month intervals for ascertainment of vital signs, evaluation for study end points, drug safety and tolerability, quality of life, and pharmacoeconomic assessments. This visit schedule is designed to be in accordance with a typical visit schedule of a high-risk patient after infarction.

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Efficacy measures 

The primary efficacy parameter is all-cause mortality (time to death). The critical secondary efficacy parameter is the composite of cardiovascular death or emergency treatment or hospitalization for new or worsening heart failure. Other secondary end points will provide a more complete picture of the relative efficacy of the therapeutic regimens being tested. Table II details the major study end points.

Table II. Major end points

An end points committee, blinded to treatment assignments, will adjudicate deaths, recurrent nonfatal myocardial infarctions, and hospitalizations for heart failure by predefined criteria.

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Safety and tolerability measures 

Safety and tolerability assessments will determine the incidence of symptomatic hypotension, renal dysfunction (need for dialysis, renal transplant, or discontinuation of study medication because of an increase in creatinine), dry cough, angioedema, and any other serious adverse event. In addition, the incidence of study drug discontinuation will be assessed in each of the 3 groups.

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Statistical section 

The trial is designed with adequate power to address several questions within a single study design. The study will determine whether valsartan reduces the risk of all-cause mortality compared with captopril. With equal statistical weight, the study will determine whether the combination of captopril and valsartan is superior to captopril monotherapy. If valsartan is not found to be superior to captopril, VALIANT is designed with a prespecified noninferiority analysis to determine whether its use results in comparable survival to the previously proven ACE inhibitor regimen. To test each of these hypotheses, the Cox proportional hazards model will be used with all-cause mortality as the dependent variable.

The first test will be a superiority comparison of the monotherapies. According to the trial assumptions, when 2700 deaths have accrued, the study will have 95% power to detect a 17.5% reduction in mortality rate and 86% power to detect a 15% reduction in mortality rate. If this test is positive, the test for noninferiority will, of course, also be significant. On the other hand, if the monotherapy superiority test is negative, a noninferiority test will be done; this test has a 74% power to declare noninferiority if the mortality rate in both arms is, in fact, equal. However, if the mortality rate is modestly, but not significantly, lower in the valsartan-treated patients, higher power exists to declare noninferiority (as good as a previously proven therapy).

To generate the criteria for noninferiority, a formal exercise was undertaken involving the steering committee, the coordinating center, the sponsor, and the independent data and safety monitoring center coordinating group. All trials comparing ACE inhibition and placebo after acute myocardial infarction were reviewed. Three trials (SAVE, TRACE, and AIRE) were found that made this comparison in patients with heart failure and/or systolic left ventricular dysfunction after definite myocardial infarction. A systematic overview was performed, demonstrating a benefit of all-cause mortality with a pooled odds ratio of 0.74 (95% CI, 0.66-0.83) and a similar effect on key secondary end points of death or time to first hospitalization for heart failure (0.73; 95% CI, 0.63-0.85).⁶ No heterogeneity was evident, so that the pooled estimate was considered to be representative of the ACE inhibitors used in these studies.

The importance of the noninferiority analysis necessitated a comparator ACE inhibitor used in one of the 3 reference trials. Captopril was chosen because it represents the ACE inhibitor evaluated in the most studies and the most commonly used ACE inhibitor worldwide. Indeed, captopril is the only ACE inhibitor with proven survival benefits in the early¹⁷ and late⁸ stages of myocardial infarction. Recently, the ELITE II (Evaluation of Losartan in the Elderly II) trial,¹⁸ the first mortality study to compare an ACE inhibitor and ARB, found the point estimate for mortality favored captopril, adding further credence to the validity of captopril as an appropriate comparator. Therefore the criterion for the noninferiority test was chosen to ensure that, if satisfied, valsartan would preserve the majority of the estimated benefit of captopril.

To have adequate power to address each of these questions, a large sample size is required. In addition, 2 formal interim analyses are planned; one is planned at the occurrence of 900 deaths and the second is planned after 1800 deaths have occurred. An O’Brien-Fleming¹⁹ approach is being taken to preserve power after accounting for these interim analyses. To accommodate all these issues, a total sample size of 14,500 patients will be enrolled to accrue the 2700 deaths that will be required to achieve adequate power. The study is designed as an “event-driven” trial unless the duration of follow-up exceeds 6 years.

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Substudies 

The VALIANT study is also designed to address quantitative quality of life as well as pharmacoeconomic issues. Additional data will be collected on a subset of patients for neurohormone profiling, cytokine, and other inflammatory markers as well as DNA analysis for functional polymorphisms. A quantitative echocardiographic study for left ventricular remodeling and other indices of ventricular function will be conducted in approximately 1200 patients. This study will use Optison (Mallinckrodt) in a subset of patients to enhance ultrasound imaging and improve definition of the cavity dimensions.

An international registry will be conducted to give insight into the reasons for nonenrollment of eligible patients and treatment patterns of nonenrolled and enrolled patients. Ultimately, the registry should give a more complete picture of the overall patient population seen at VALIANT centers and the degree to which enrolled patients represent this intended population.

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Study organization 

The trial is lead by an executive committee, which is composed of academic leaders and the sponsor, Novartis Pharma AG. The steering committee consists of academic leaders from each country involved in the trial. The large number of countries brings a special flavor of international interaction, including countries with vastly different allocations of financial support to health care. Subcommittees of the steering committee have been selected to comprise an ancillary trials committee and an end points adjudication committee. Separate neurohormone and echocardiographic core laboratories have been established for these specialized procedures. The chair of the data safety and monitoring board was involved in the protocol design. This group maintains unblinded data that are not available to the data coordinating center, sponsor, or investigators. The trial also includes more than 950 clinical sites and uses multiple international organizations for site monitoring, randomization, drug distribution, and coordination. These groups are denoted in the Appendix.

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Discussion 

The VALIANT trial has been organized to address the interaction between 2 critical elements of cardiovascular therapeutics: renin-angiotensin blockade and postinfarction left ventricular dysfunction. Because blockade of the renin-angiotensin system has become an important component of therapy for a variety of cardiovascular disorders, it becomes critical to determine the most effective pharmacologic approach to inhibit this system. Despite progress in the management of the acute phase of a myocardial infarction, post–myocardial infarction left ventricular dysfunction continues to be a major cause of death and disability. From a series of well-conducted clinical trials, ACE inhibitors have proven their value as an important adjunctive therapy to improve clinical outcome in acute and chronic myocardial infarction, especially in patients at higher risk because of signs and symptoms of failure or left ventricular dysfunction.

The development of ARBs offers the opportunity to inhibit more selectively the renin-angiotensin system at the AT₁ receptor level.¹¹, ¹³ These agents have already gained widespread acceptance as effective and well-tolerated antihypertensive agents.²⁰ Mechanistic studies and theoretical constructs suggest that ARBs may provide a more effective means of inhibiting the deleterious effects of angiotensin II.²¹ The determination of whether these agents confer additional clinical benefits is the subject of a variety of ongoing clinical trials.²² Given the established record of ACE inhibitors in reducing rates of mortality and morbidity, the ARBs have to prove a range of clinical benefits that are either superior or not inferior to ACE inhibitors. Indeed, in ELITE II, the first major direct, clinical outcomes comparison of ACE inhibitor and ARB treatments of patients with symptomatic heart failure, no benefits of ARBs were reported.¹⁸ In fact, the confidence intervals for both survival and hospitalizations for heart failure tended to favor the ACE inhibitor captopril. The recently completed HOPE (Heart Outcomes Prevention Evaluation) trial,²³ demonstrating a reduction in death, stroke, and myocardial infarction in patients with a variety of vascular disease presentations treated with ACE inhibitors, further underscores the importance of basing therapeutic decisions on available evidence.

Determining whether an ARB, when used alone or in combination with an ACE inhibitor, offers a therapeutic advantage over an ACE inhibitor is a particularly important question in the high-risk population after myocardial infarction. Patients who have signs and symptoms of failure develop or even asymptomatic left ventricular dysfunction after myocardial infarction have such a high risk of death, rehospitalization, and disability that even a small incremental benefit translates into substantial societal benefit. For death alone, the use of an ACE inhibitor in SAVE, AIRE, and TRACE translates to approximately 50 to 70 premature deaths prevented per thousand patients treated. The addition of the impressive reductions in new or recurrent episodes of symptomatic heart failure and myocardial infarction further underscores the need for use of this inhibitor of the renin-angiotensin system in these patients. It is therefore important to determine whether ARBs offer any additional advantage to this patient population.

Two major ARB trials are currently under way in patients with post–myocardial infarction left ventricular dysfunction. In the OPTIMAAL (Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan),²⁴ 5000 such high-risk patients have been randomly assigned to either the ARB losartan or the ACE inhibitor captopril. The study is powered to detect a 20% reduction in all-cause mortality with either of these agents compared with the other. The VALIANT study has taken a somewhat different track of addressing whether the use of the ARB valsartan confers an additional mortality benefit over and above that achieved with captopril alone. As described, this study is designed to detect a 15% difference between captopril and the valsartan-treated group. Moreover, this study devotes the same statistical weight to detect whether the combination of valsartan and captopril is superior to captopril alone in the treatment of these high-risk patients with myocardial infarction.

The study also prospectively defines a margin for making a noninferiority (comparability) comparison that would have adequate statistical power to test whether the use of valsartan, if not different from captopril, can be considered comparable and therefore superior to placebo. The issue of noninferiority, although not familiar to most practitioners, is becoming a major issue for therapeutic decision-making.²⁵ Why would a practitioner care if a new therapy was noninferior to ACE inhibition? The main reason is that it would be important to know that, when a patient is switched from an ACE inhibitor to an ARB because of side effects, the mortality benefit of ACE inhibition is not being lost. Although ACE inhibitors are generally well-tolerated, a significant share of patients has a bothersome cough that makes it difficult to stay on an ACE inhibitor.²⁶

For both the tests of superiority and noninferiority a distinguishing feature of VALIANT is the magnitude of the difference that should be considered clinically important. In this high-risk population, a small difference in outcome attributable to a therapy could prevent a large number of events. Given the underlying risk of 21% of deaths over a 3-year period, the VALIANT investigators believe that a difference of 15% in the risk of death would be clinically important enough to cause a shift in the choice of pharmacologic therapy. Other studies have chosen a larger difference, leaving open the possibility that a clinically important benefit attributed to one or the other therapy could be insignificant in statistical terms.

In comparing the new mode of inhibiting the renin-angiotensin system, ARBs to an ACE inhibitor, it is of fundamental importance to evaluate against an ACE inhibitor regimen that has been proven, in the specific patient population, to demonstrate clinical effectiveness. For reductions in mortality rate in high-risk patients after myocardial infarction, one can turn to placebo-controlled blinded studies that used ramipril as in AIRE,⁹ trandolapril as in TRACE,¹⁰ and captopril as in the SAVE study.⁸ Each of these studies led to regulatory approval and registration and, importantly, each provided a dose regimen that resulted in statistical improvements in survival. Each of these agents would have therefore been a satisfactory comparator for a long-term study of high-risk patients with myocardial infarction. Because VALIANT initiates therapy in as early as 12 hours, an agent had to be chosen that also had substantial experience and clinical efficacy in the first 24 hours of the infarct period. The combination of the experience from ISIS-4 and SAVE made captopril the best-studied, proven ACE inhibitor with extensive experience in both early and long-term infarcts.⁸, ¹⁷ It is important to note that in all the regimens that use captopril in VALIANT (captopril alone or in combination with valsartan), the target dose for titration leads to the captopril dose of 50 mg 3 times daily that was used in the long term in the SAVE population.

By combining the information from the echocardiography and blood substudies, VALIANT will provide mechanistic insights into the clinical outcomes and treatment effects in the trial. Whether monotherapy or the combination exerts a more beneficial effect through an impact on ventricular remodeling, neurohormonal modulation, cytokine modulation, functional DNA polymorphisms, hemodynamic effects, or some combination of these or other factors should be elucidated.

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Conclusion 

Despite the major advances in the care of patients with myocardial infarction, including ACE inhibitors, those who sustain an acute infarct and have signs or symptoms of failure or even asymptomatic left ventricular dysfunction remain at high risk for further cardiovascular events. The VALIANT study, by its magnitude and design of looking for even small differences between the ACE inhibitor and the ARB and in studying the combination of adding valsartan to the proven dose of an ACE inhibitor, offers several unique features. As such, we believe VALIANT is designed with sufficient statistical power to generate the most definitive comparisons of these pharmacologic modes of inhibiting the renin-angiotensin system. The use of a proven dose of the ACE inhibitor in the equally powered combination therapy comparison renders VALIANT well-positioned to detect whether there is added clinical value from combination therapy. The global distribution of VALIANT investigative sites will improve the generalizability of the findings and allow for an assessment of regional variations in practice patterns.

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Appendix: Participating centers 

Appendix: Participating centers

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