Early use of an ACE inhibitor reduces mortality in patients with acute myocardial infarction and signs of heart failure (1). The status of angiotensin (AT) II antagonists is uncertain. In chronic heart failure, it has not been shown that they are equivalent to ACE inhibitors. In an initial study in heart failure after myocardial infarction, losartan (LORZAAR) came off worse than captopril (e.g. LOPIRIN; OPTIMAAL study*; a-t 2002; 33: 90-1) (2).

A trial sponsored by the manufacturer Novartis has now been published in which the AT II receptor blocker valsartan (DIOVAN, PROVAS) or a combination of valsartan plus captopril was compared with captopril (VALIANT*, see also page 113). 14,808 patients with an average age of 65 years took 20 mg valsartan once a day, 6.25 mg captopril once a day or a combination of the two in addition to standard therapy, starting twelve hours to ten days after an acute myocardial infarction that was complicated by signs of heart failure, left ventricular dysfunction or both. The target dose was 160 mg valsartan twice daily - double the maximum licensed daily dose - or 50 mg captopril three times a day. In the combination regime, the dose of valsartan was only increased up to 80 mg twice a day. The study was designed primarily to show superiority of the AT II receptor blocker, but it also allowed for analysis of non-inferiority if superiority was not proven. The primary endpoint was total mortality (3).

After a median study duration of 24.7 months, 19.9% of the patients (979 out of 4,909) in the valsartan arm died compared to 19.5% (958 out of 4,909) on captopril and 19.3% (941 of 4,885) on the combination. Valsartan thus confers no benefit as an alternative or addition to captopril compared to the ACE inhibitor alone. If the two monotherapy arms are compared, the upper limit of the 97.5% confidence interval for the risk of dying (0.90 to 1.11, with a relative risk of 1) lies within the specified range of up to 1.13 for which non-inferiority is assumed. There is also no difference in secondary endpoints such as cardiovascular mortality or in any of the subgroup analyses according to age, gender or severity of heart failure. In contrast to ELITE II* and Val-HeFT*, but in accordance with CHARM* (a-t 2003; 34: 81-2), there is no evidence that the AT II receptor blocker has an unfavourable effect in the subgroup of those taking a beta blocker (70%) (3).

Valsartan was more frequently associated with a fall in blood pressure and renal damage, captopril more often with cough, rash or dysgeusia. The harmful effects were additive with the combination. It had to be stopped significantly more often because of unwanted effects than captopril alone, and captopril significantly more often than valsartan alone (3).

The authors conclude from the study that valsartan and captopril are equivalent (3). As the cause of the poorer results with the AT II receptor blocker losartan in similar patients in the OPTIMAAL study it is proposed that the target dose was too low (4). Since about every fifth participant stopped the medication prematurely in the VALIANT study and 0.9% of the patients were not known to be alive or dead at end of trial (3), in our opinion the result should have been confirmed, as in OPTIMAAL, by a per protocol analysis, which only includes patients who complete the study according to the protocol. There is no such analysis.* Moreover, the non-inferiority range is so broad that valsartan is still regarded as equivalent if it achieves only 55% of the mortality advantage that has been shown for captopril compared to placebo.

	ACE inhibitors such as captopril (e.g. LOPIRIN) reduce mortality after myocardial infarction with signs of heart failure or left ventricular dysfunction.
	In the VALIANT study, the angiotensin (AT) II antagonist valsartan (DIOVAN, PROVAS), alone or in combination with captopril, has no advantage compared to captopril in this indication. However, the combination is more poorly tolerated.
	The results of the VALIANT study appear to suggest that valsartan and captopril are equivalent. However, the reliability of this result cannot be assessed because of study deficiencies. In addition, considering the up-to-now data on AT II receptor blockers in heart failure, less contestable proof is required before equivalence can be assumed.
	The ACE inhibitors, which have been better investigated and are available generically, remain the agents of choice.

(R = randomised study)

1

RYAN, T.J. et al.: ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction, 1999 Updated ACC/AHA AMI Guideline; http://www.acc.org/clinical/guidelines/nov96/edits/amipdf99edits.pdf

2

DICKSTEIN, K. et al.: Lancet 2002; 360: 752-60

3

PFEFFER, M.A. et al.: N. Engl. J. Med. 2003; 349: 1893-906

4

MANN, D.L., DESWAL, A.: N. Engl. J. Med. 2003; 349: 1963-5

5

Committee For Proprietary Medicinal Products: Points To Consider On Switching Between Superiority And Non-Inferiority, 27 July 2000; http://www.emea.eu.int/pdfs/human/ewp/048299en.pdf

CHARM = Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity
ELITE = Evaluation of Losartan in the Elderly
OPTIMAAL = Optimal Trial in Myocardial Infarction with the Angiotensin-II-Antagonist Losartan
ValHeFT = Valsartan Heart Failure Trial
VALIANT = The Valsartan in Acute Myocardial Infarction Trial