OPTIME CHF and PRAISE II: Recent heart failure trials Clinical Trial Commentary Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

OPTIME CHF OPTIME CHF: Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure The OPTIME CHF trial was designed to evaluate whether intravenous treatment with milrinone (a bipyridine inotropic/vasodilator that improves hemodynamics in the short term), in addition to best medical therapy, in patients admitted with an exacerbation of CHF but not requiring pressor or inotrope support, would reduce the number of days of hospitalization for cardiovascular events in the intermediate (60-day) term. Study objective Mihai Gheorghiade MD (Northwestern University, Chicago, Illinois, USA)

OPTIME CHF OPTIME CHF was a prospective, randomized, double- blind placebo-controlled trial with a 60-day follow-up. 951 patients from 78 US centers were randomized within 48 hours of admission to intravenous milrinone 0.5 g/kg/min without a bolus dose (n=477) or placebo (n=472) for 48 hours. Primary endpoint: rehospitalization for cardiovascular events within 60 days of treatment Secondary endpoints: subjective improvement; length of initial hospitalization; treatment failures within the first 48 hours; proportion of patients reaching, and time to reach, the target dose of the ACE inhibitor; and mortality and adverse events Study design

OPTIME CHF Total mortality rates (in hospital and at 60 days) were not significantly different between the 2 groups. A subgroup analysis by cause of heart failure revealed a small trend favoring milrinone in the non-ischemic heart failure group, and the opposite in the ischemic heart disease group. Study results There was no significant difference in the primary endpoint (days of hospitalization for cardiovascular events within 60 days) IV milrinoneControls Number of patients Median hospital stay (days)67 Mean hospital stay (days)12.3 ± ± 14 Days until discharge5.7 ± ± 13

MilrinonePlacebop value Reduction in treatment failures or progression of CHF7.9%6.6%0.536 Number of complications12.6%2.1%<0.001 Treatment-related new atrial fibrillation4.6%1.5%0.004 Sustained hypotension10.7%3.2%<0.001 Myocardial infarcts1.5%0.4%0.178 OPTIME CHF Secondary endpoints

OPTIME CHF OPTIME CHF is the largest randomized trial of hospitalized patients with CHF conducted to date. Patients who are admitted for exacerbation of chronic CHF but are not believed to require inotropic support do not derive any additional benefit from milrinone therapy. The potential benefit that milrinone may have in non- ischemic heart failure needs further investigation. Caution should be exercised before making an early jump to aggressive therapy (ie, inotropes) in patients admitted with CHF but preserved blood pressures. Aggressive diuresis should be tried before initiating intravenous inotropic support. Study conclusions

Outcome-based trials It has always been assumed that improving the hemodynamics in acute heart failure is good for the patient in the long term. Because of this assumption, the FDA does not require clinical outcome trials in this area; this made it difficult to conduct the OPTIME CHF trial. Several types of agents are now being studied  neutral endopeptidase (NEP) inhibitors  and brain natriuretic peptide (BNP) ANP was turned down by the FDA recently in a study that looked at hemodynamics; an outcome-based clinical trial with ANP is currently being conducted. FDA requirements

PRAISE 1 PRAISE (Prospective Randomized Amlodipine Survival Evaluation): a randomized, placebo-controlled trial with more than 1100 cardiomyopathy patients, randomized to amlodipine (a calcium channel blocker), or placebo. The primary endpoint of the study (all-cause mortality or cardiovascular morbidity) was not significantly different between the 2 groups. Unexpected results Amlodipine was beneficial for patients with non-ischemic cardiomyopathy — a 31% risk reduction (95% CI 2%– 51%; p=0.04) in the primary endpoint. All-cause mortality (a secondary endpoint) was reduced by 46% (95% CI 21%–63%; p<0.001), a benefit not seen in the ischemic heart disease patients receiving amlodipine. Advanced heart failure patients

PRAISE 1 The study results were considered by many to be highly credible because the reduction in mortality was seen in a prospectively defined subgroup and the p value was very small (<0.001), in addition to the fact that mortality is an unbiased and incontrovertible endpoint. Critics argued that although prospectively defined, the subgroup was small (only 119 patients) and all-cause mortality was a secondary endpoint. Moreover, no plausible mechanisms could explain the risk reduction in patients with non-ischemic cardiomyopathy; risk reduction had been expected in the ischemic heart disease population. Trial results

PRAISE 2 PRAISE 2 was designed as a follow-up trial to evaluate prospectively the benefit of amlodipine seen in PRAISE 1. It was powered at 90% to detect a 25% difference in mortality between the treatment arms. Patients were randomized to double-blind therapy with amlodipine or placebo; amlodipine was started at 5 mg a day and then increased to 10 mg a day after 2 weeks. PRAISE 2 was designed to recruit 1800 patients and follow them for 36 months; enrollment in the trial was to continue until 263 deaths occurred in the placebo arm. In reality, the trial recruited 1652 patients and it took 48 months to record the required number of deaths in the placebo arm; recruitment was halted in January Non-ischemic heart failure patients Packer M, et al (Columbia University College of Physicians & Surgeons, New York, NY)

PRAISE 2 No differences were seen in different subgroups of the study population (age, sex, NYHA class, ejection fraction). Study results PRAISE 2PRAISE 1 and 2 AmlodipinePlaceboAmlodipinePlacebo Patients Deaths262*278479†466 Mortality31.7%33.6%34.0%33.4% *Odds ratio = 1.09 (p=0.28) †Odds ratio = 0.98

PRAISE 2 The results of PRAISE 2 do not confirm the survival benefit of amlodipine seen in non-ischemic cardiomyopathy in the PRAISE 1 trial. The favorable survival benefit of amlodipine seen in PRAISE 1 was likely due to chance, despite the fact that mortality is an unequivocal endpoint; the benefit was seen in a prespecified subgroup and the p value for the subgroup was very small. The combined results of PRAISE 1 and PRAISE 2 indicate that long-term treatment with amlodipine is neither beneficial nor harmful in patients with severe chronic heart failure. The results of PRAISE 2 emphasize the need for replication, even when the results define a mortality benefit and are associated with low p values. Conclusions

ELITE I ACE inhibitor-naive patients (aged 65 years or more) with NYHA class II–IV heart failure and ejection fractions  40% were randomly assigned to losartan titrated to 50 mg daily or captopril titrated to 50 mg 3 times daily, for 48 weeks. Pitt B, et al. Lancet 1997;349(9054): Evaluation of Losartan in the Elderly Treatment with losartan was associated with an unexpected lower mortality than treatment with captopril. Losartan (n=352) Captopril (n=370) p value Increase in serum creatinine10.5% Discontinuation of therapy because of side effects12.2%20.8%0.002 Death and/or hospital admission for heart failure9.4%13.2%0.075 All-cause mortality4.8%8.7%0.035

ELITE II Pitt B, Lancet 2000;355(9215): Losartan (n=1578) Captopril (n=1574)p value All-cause mortality11.7%10.4%0.16 Sudden death or resuscitated arrests9.0%7.3%0.16 Discontinuation of therapy because of side effects9.7%14.7%<0.001 Confirmatory study of ELITE I There were no significant differences in the primary endpoint of all-cause mortality or the secondary endpoint of sudden death or resuscitated arrests between the 2 treatment groups (hazard ratios 1.13 [95% CI 0.95–1.35], p=0.16 and 1.25 [95% CI 0.98–1.60], p=0.16 ).

Clinical trial results Large trials with many events are optimal, but biologic plausibility and a foundation are also desirable. In the PRAISE trials, there was no good explanation of why patients with non-ischemic heart failure would specifically benefit. All too often, explanations that fit the data are used, rather than pathophysiological confirmations of the results. Understanding pathophysiology

Omapatrilat A new drug approval (NDA) application was submitted to the FDA with data on patients who had taken omapatrilat. Omapatrilat had been given fast-track status and was scheduled for review by an FDA advisory committee at the beginning of May 2000; approval was expected a few months later. Among the 7000 patients, there were 44 cases of angioedema, 4 of which were classed as severe (requiring intubation). The incidence of angioedema is no higher than that seen with ACE inhibitors; angioedema occurs with ACE inhibitors in about 0.3%–0.5% of white patients and about 3 times more frequently in black patients. Because omapatrilat has an ACE inhibitor component, the presence of this side effect is not surprising. New drug approval application

Omapatrilat Having been criticized in the past for not being concerned about rare side effects; the FDA now wants to see safety data from more patients. As with ACE inhibitors, angioedema with omapatrilat normally occurred with the first dose of the drug, and seems to be dose related; it is more likely to occur at a starting dose of 20 mg than at 10 mg. The incidence of angioedema should be kept to a minimum if patients are started on the lowest dose, and gradually titrated up. Another 2000 patients have already been enrolled in the 2 major clinical trials underway in hypertension and heart failure. NDA application withdrawn

11 patients developed TTP TTP and clopidogrel 6 women and 5 men, aged 35 to 70 years (median=55) 6 patients received clopidogrel for coronary artery disease, 3 of whom received clopidogrel after placement of a coronary artery stent 10 patients used clopidogrel for fewer than 14 days, 1 patient used clopidogrel for 330 days Concomitant medications 5 patients were taking atorvastatin or simvastatin, 2 of whom began taking the cholesterol-lowering drug 3 weeks before TTP onset 3 patients were on long-term atenolol therapy 1 kidney-pancreas transplantation patient was on long- term cyclosporine therapy Bennett CL, Connors JM, Carwile JM, et al. N Engl J Med 2000 (June 15)

TTP and clopidogrel The 11 cases were scrutinized by TTP experts, who determined that at least 5 of them were not TTP. The incidence of clopidogrel-induced TTP is no higher than the incidence of TTP the general population. The incidence of clopidogrel-induced TTP is much lower than that seen with ticlopidine, which has been reported to be from 1 in patients to 1 in patients. Because the chemical structure between clopidogrel and ticlopidine is similar, an association with TTP was not surprising. Rare side effects, which have also been seen recently with Rezulin (troglitazone) and Posicor (mibefradil dihydrochloride), can limit the availability of agents that could be useful to specific patients. False alarm? 1. Bennett CL, et al. Arch Intern Med 1999 Nov 22;159(21): Steinhubl SR, et al. JAMA 1999 Mar 3;281(9):