American Heart Journal
Volume 145, Issue 5 , Pages 754-757, May 2003

What did we learn from the OPTIMAAL trial? What can we expect from VALIANT?

  • Kenneth Dickstein

      Affiliations

    • University of Bergen, Central Hospital in Rogaland, Stavanger, Norway
    • Corresponding Author InformationReprint requests: Kenneth Dickstein,University of Bergen, Central Hospital in Rogaland, Stavanger, Norway.

Article Outline

 

The Optimal Trial In Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) results have been reported1 and the results from the Valsartan in Acute Myocardial Infarction Trial (VALIANT)2 will be presented in 2003. These 2 trials compared the effect of an angiotensin II receptor blocker (ARB) with the angiotensin-converting enzyme (ACE) inhibitor captopril (150 mg daily) on mortality and morbidity in similar populations. The extensive documentation for ACE inhibitors precludes placebo treatment in clinical trials involving high-risk patients after acute myocardial infarction (AMI).3 Both cohorts were recruited after AMI with clinical evidence of heart failure or substantial left ventricular dysfunction. Although the hypotheses and populations in both trials are similar, there are 2 major differences. First, VALIANT is testing high-dose ARB therapy (valsartan 160 mg twice daily), whereas OPTIMAAL tested low-dose ARB therapy (losartan 50 mg once daily). Secondly, VALIANT includes a third arm that evaluates the efficacy of the potent combination of ARB and ACE therapy (valsartan 80 mg twice daily plus captopril 50 mg three times daily). It’s a worthwhile exercise to evaluate what we have learned from OPTIMAAL and focus on what can we expect from VALIANT.

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OPTIMAAL results 

The OPTIMAAL trial results were presented at the European Society of Cardiology meeting in Berlin in September 2002 and published simultaneously in the Lancet.4 The trial was designed to test the hypothesis that losartan (50 mg) would be superior or noninferior to captopril (150 mg) in preventing all-cause death when started early post-MI in a high-risk population. A total of 5477 patients with AMI and clinical evidence of heart failure in the acute phase and/or Q-wave anterior AMI were included from 7 Western European countries. Patients were randomized a median of 3 days after the onset of symptoms, in contrast to a median of 5 days in VALIANT. The trial excluded patients currently treated with an ACE inhibitor or an angiotensin II antagonist before the index AMI. Therefore, few patients with symptomatic heart failure before the index AMI participated. This is in contrast to VALIANT, which included patients previously treated with an ACE inhibitor or ARB and thereby creating a slightly higher risk cohort.

Mortality and morbidity 

The OPTIMAAL trial showed a strong but nonsignificant trend (P = .069) in favor of captopril in the primary end point of all-cause mortality (n = 946). A single prespecified end point, cardiovascular death (a subgroup of the primary end point), did reach significance in favor of captopril (P = .035). However, the incidences of the other clinically important outcomes were essentially identical between the groups; reinfarction (P = .72), need for revascularisation (P = .62), stroke (P = .59), first, all-cause hospitalizations (P = .36) or all hospitalizations (P = .97). Losartan was significantly better tolerated, with fewer patients discontinuing study medication (P < .0001).

An important post hoc observation was derived from study of the Kaplan-Meier curves. Two differing patterns with regard to the treatment effect between losartan and captopril during the acute and chronic phases of the 40-month follow-up period were observed. Almost the entire difference in mortality developed during the first 210 days of therapy post-MI. This time point corresponded to the maximal separation of the survival curves and also identified the time when one half of the deaths had occurred. Although not conclusive, this finding may offer important insights into potential reasons for our findings. During the first 210 days, the relative risk (RR) between groups was 1.24 (1.04–1.50) favoring captopril, and subsequent to day 210 the relative risk was more evenly distributed, 1.02 (0.86–1.22). Of the 484 deaths during the final 33 months of follow-up, 243 occurred on losartan and 241 occurred on captopril. The pattern of mortality and morbidity suggests an early post-AMI remodeling phase and a stable mild chronic heart failure phase.

Tolerability 

Evaluated both by all-cause discontinuation and by adverse experience, tolerability was strongly in losartan’s favor. Fewer patients on losartan discontinued study medication for any reason (458 [17%] vs 624 [23%], RR 0.70 [0.62–0.79], P < .0001). Discontinuation due to adverse experience was also substantially less (202 [7%] vs 387 [14%], RR 0.50 [0.42–0.59], P < .0001). These data are almost identical with those reported in the Losartan Heart Failure Survival Study (ELITE) II heart failure trial (with identical dosages of losartan and captopril) and demonstrate consistency regarding tolerability.5

Subgroups 

There were no differences with regard to the treatment effects in the important subgroups with known hypertension (36%) and diabetes (18%) at baseline. All-cause death for hypertensive patients was 18.5% for losartan and 18.3% for captopril (P = .92). All-cause death for patients with diabetes was 21.7% for losartan and 22.6% for captopril (P = .97). There was no significant interaction between treatment (losartan vs captopril) and β-blocker use before randomization or at 1 month postrandomization. However, as expected, patients tolerant of β-blocker therapy had significantly better survival than untreated patients. Due to the design of the protocol, we did not test the combination of all 3 agents. The results of VALIANT should provide adequate data to assess any potential negative interaction when patients are treated with both ARBs and ACE inhibitors in addition to β-blockers.

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OPTIMAAL dosage? 

The critical question of the optimal dose of losartan is perhaps most important. Indeed, this question may yet be unresolved for ACE inhibitors.6 Most studies with losartan in heart failure used 50 mg as the target dose. However, doses of losartan ranging from 5 to 150 mg in patients with heart failure resulted in a step-wise increase in plasma renin activity and angiotensin II levels, indicating more potent negative feedback at the highest doses.7

The substantial event rate during the early post-MI phase in the OPTIMAAL trial emphasizes the potential importance of rapid titration and adequate dosage, especially during the early remodeling phase. Indeed, evidence from post-MI studies with ACE inhibitors would suggest that over half of the benefits of these agents in the first 30 days post-MI occur within the first week.8 The relatively slow dose uptitration of losartan in OPTIMAAL would have compounded any problems related to a suboptimal dose of losartan compared with adequate doses of captopril administered 3 times daily. Inadequate dosage compounded with slow uptitration would be consistent with the early separation of the mortality curves, the significantly greater increase in serum creatinine from baseline to 1 month with captopril compared with losartan (P < .0001), and the greater first-dose blood-pressure lowering effect of captopril compared with losartan. Losartan resulted in fewer adverse experiences of hypotension during follow-up (13.2 vs 26.3%, P = .002), which also suggests a difference in the pharmacodynamic effect of the 2 agents at the dosages used.

Two recently completed positive trials with losartan, Reduction of Endpoints in Non-insulin-dependent diabetes mellitus with Angiotensin II Antagonist Losartan (RENAAL),9 in patients with type 2 diabetes with nephropathy, and Losartan Intervention For Endpoint reduction in hypertension (LIFE),10 in patients with hypertension and left ventricular hypertrophy, where patients could be uptitrated to 100 mg, support the use of a higher dose in those populations. An ongoing mortality and morbidity trial, Heart Failure Endpoint Evaluation with the Angiotensin II Antagonist Losartan (HEAAL), is comparing 2 doses of losartan, 50 mg and 150 mg, in a heart failure population intolerant of ACE inhibition, and should shed additional light on the issue of optimal dosage.

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Implications for patients after complicated MI 

It is essential to interpret the results of OPTIMAAL in light of the fact that losartan was compared with an efficacious, active control at an adequate dose (captopril 150 mg). Captopril is indicated for the treatment of patients with chronic heart failure and patients after AMI in most countries, is off patent, and is used widely. Convincing documentation exists for the use of ACE inhibitors in selected patients after AMI.11 Because this trial demonstrated neither superiority nor noninferiority of losartan relative to captopril, ACE inhibitors should remain the therapy of first choice in patients after complicated AMI. However, losartan was better tolerated than captopril and was associated with significantly fewer discontinuations due to adverse experience. Keeping patients on long-term therapy in everyday practice is a major problem for primary care physicians, and tolerability translates into improved compliance. However, at present, these 2 modes of inhibiting the renin-angiotensin system cannot be considered equal for high-risk MI patients.

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Implications for patients intolerant of ACE inhibitors 

In the Valsartan Heart Failure Trial (ValHeFT)12 in patients with chronic heart failure, valsartan markedly improved survival and reduced hospitalization in patients not treated with an ACE inhibitor. These findings in the subgroup without ACE inhibitor treatment (n = 366) may represent the strongest evidence to date that angiotensin II antagonists are comparable in efficacy to ACE inhibitors regarding mortality and morbidity.13 The FDA recently approved the indication for valsartan in the ACE-intolerant population on the basis of these data.14 The question of the role of ARBs in chronic heart failure in patients intolerant of ACE inhibitors and their superiority or not to placebo should definitely be answered in the near future when the Candesartan in Heart failure—Assessment of Reduction in Mortality (CHARM)15 trial reports. The CHARM trial is near completion and will be presented at the European Society of Cardiology meeting in Vienna in 2003. This trial included an arm with candesartan (32 mg) versus placebo in patients intolerant of ACE inhibitors (n = 2028) with an ejection fraction <40%.

OPTIMAAL does not provide decisive information regarding the value in ARBs in ACE-inhibitor intolerant patients after complicated AMI. The results fail to show conclusively that losartan is better than placebo (as it would have if the noninferiority criteria had been met), but they did not show that losartan is no better than placebo. The noninferiority hypothesis was designed such that a finding of noninferiority would imply that there is great confidence that losartan is superior to placebo with regard to the primary end point, all-cause death. We prospectively performed a meta-analysis of placebo-controlled trials of ACE inhibitors in patients with AMI to define the margin that we could expect between losartan and placebo, had this been a placebo-controlled trial. Data from trials, which required patients to have heart failure or left ventricular dysfunction and data on patients with anterior AMI, were pooled.16, 17, 18, 19, 20, 21, 22, 23 We conservatively estimated the effect of captopril relative to placebo to be 19.5%, or a relative risk of 0.805. In order to estimate the effect of losartan relative to placebo, this 19.5% relative risk was multiplied by the relative risk of OPTIMAAL to obtain 0.805 × 1.126 = 0.906 (ie, we estimate that losartan reduced total mortality relative to placebo by 9.4%).

It should also be emphasized that there was a large number of important clinical outcomes with regard to morbid events that occur frequently in high-risk patients after AMI: reinfarctions (n = 763), revascularisations (n = 1672), strokes (n = 272) and hospitalizations (n = 9183). Here the similarities between treatments are striking, even with the low dose of losartan. These findings suggest that an ARB may be a reasonable alternative in such patients intolerant of ACE inhibitors.

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What did OPTIMAAL teach us about clinical trial conduct? 

First, the good news. It is possible to keep >80% of patients on study medication in a large multinational effort (19.5 overall discontinuation during a 40-month follow-up). This requires vigilance and commitment from the entire study organization. Dedicated investigators can often restart study medication with a little extra effort. The only good reason for permanent discontinuation is drug-related adverse experience. Similarly, it is just as important to never give up searching for patients lost to follow-up (only a single patient was lost to follow-up in OPTIMAAL). Again, this requires serious dedication from the study monitors, nurses and investigators. A trial’s power to test its hypothesis depends on the assumption that patients stay on treatment, and accurate intention-to-treat analysis assumes that you know what happened to all the patients at the end of the trial.

The most frustrating lesson from OPTIMAAL was our inability to respond to our growing suspicion that the dose of losartan was too low. It is obviously imperative that any pharmacologic intervention in a large clinical trial is administered at the most efficacious dose possible. This is especially true of trials with an active comparator and no placebo control. Megatrials represent a major effort and expense and we owe it to ourselves and our patients to make sure the design represents our best shot. Logistic considerations usually limit comparisons to evaluation of a single dose. It is the intellectual responsibility of the steering committee to assure that trials are not initiated prematurely and only proceed when adequate dose-finding and safety data exist. In clinical research the temptation to move forward quickly is real and the competition for individual and commercial success are fierce. However, it is prudent to invest adequate time and resources in the dose-finding stage of drug development.

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Hotline sessions 

I know the next bit is controversial. But it should also be possible for the primary publication to be available at the time of the first official presentation (or at least very soon afterwards). It is good practice, limits rumor, and provides interested parties with the opportunity to examine the methodology, digest a complete dataset, and read the authors’ discussion of the results. The OPTIMAAL results were presented at a hotline session and published on the same day. Although hotline sessions are popular, they frequently contain only headlines and abbreviated data that do not permit adequate interpretation of the results (the OPTIMAAL slot was 8 minutes). Uncertainty and some confusion often prevail among clinicians. Temporary results do not belong in the public domain, and the main publication and hotline presentation must contain identical results. Results should be presented only when the primary publication is around the corner. This obviously represents a challenge for the editors of medical journals and requires mutual effort and cooperation with authors in order to facilitate a rapid publication process.

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What can we expect from VALIANT? 

From VALIANT we can probably expect the answers to most of the important questions. The VALIANT trial is designed to test the potential superiority of valsartan compared to captopril, and is well powered (95% power to detect a 15% difference) with 14,703 patients. It contains 3 arms, including an arm of the combination of an ARB and ACE inhibitor. The comparator is identical to that of OPTIMAAL (captopril 50 mg 3 times daily). VALIANT is, however, testing a relatively large dose of the ARB valsartan: 160 mg twice daily in the stand-alone arm, and 80 mg twice daily in the combination arm with captopril. The titration of these agents was performed as rapidly as the investigator deemed fit.

VALIANT also contains a noninferiority hypothesis with a noninferiority margin similar to OPTIMAAL; an upper 1-sided 95% boundary for the relative risk of valsartan relative to captopril was set to a prespecified clinically important difference between the therapies. For example, in VALIANT, if the observed relative risk were 0.95 (corresponding to an estimated 5% risk reduction) with an upper confidence bound of 1.05 (corresponding to a 5% risk increase), then valsartan would be declared noninferior to captopril.

The trial will therefore address the important questions that OPTIMAAL left unanswered: are ARBs better than ACE inhibitors? If not, are they as good? How efficacious and well tolerated is the combination? Assuming that valsartan alone will be far better tolerated than captopril (as assessed by both discontinuation and adverse experience), even comparable efficacy would represent real progress in the management of patients after AMI complicated with left ventricular dysfunction.

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References 

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PII: S0002-8703(03)00168-6

doi:10.1016/S0002-8703(03)00168-6

American Heart Journal
Volume 145, Issue 5 , Pages 754-757, May 2003

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