According to the HOPE* study published in early 2000, the ACE inhibitor ramipril (e.g. DELIX) is said to be useful for a wide range of patients with high cardiovascular risk in addition to its efficacy in hypertension and heart failure (1). Despite the placebo-controlled design, patients with hypertension and left ventricular dysfunction were not excluded reliably. Therefore - apart from the ethical problem of under-treatment in the placebo group - it cannot be derived from the HOPE trial that there is a benefit outside these two indications, in which ACE inhibitors have been of proven efficacy (a-t 1999; No. 12: 127 and 2000; 31: 21-2). However, the concept of the marketing study was successful. On the basis of the HOPE study, ramipril has now been licensed in the USA and also in Germany for a wider range of indications (2,3).

A similar concept underlies the recently published EUROPA* trial (4), which was designed to examine the benefit of perindopril (COVERSUM) in addition to standard therapy of stable coronary heart disease. After a four-week drug run-in phase, 12.218 patients with an average age of 60 years were randomised to treatment with (4 mg to) 8 mg perindopril daily or placebo. 65% had a previous history of myocardial infarction. Patients with asymptomatic heart failure were not excluded deliberately although it has been proven that they would benefit from an ACE inhibitor.

The same applies to patients with high blood pressure, who were able to take part with levels of up to 180/100 mmHg and whose treatment remained unclear. Furthermore, not all hypertensive patients were even recorded as such because of the study definition of hypertension as blood pressure above 160/95 mmHg, which contradicts the WHO definition that has been in force since the start of the 1990s (levels of 140/90 mmHg or higher). However, 27% of the participants had blood pressure levels above 160/95 mmHg or were taking antihypertensive drugs and were therefore regarded as hypertensive. With an average blood pressure being 5/2 mmHg higher the antihypertensive therapy in the placebo arm was poorer than in the perindopril group. The absolute blood pressure level remains unclear.

The primary endpoint, a combination of total mortality, myocardial infarction, unstable angina and cardiac arrest, was changed shortly before the end of the originally planned follow-up period. Total mortality was exchanged for the bias-prone endpoint of cardiovascular mortality, and unstable angina was dropped. At the same time, the study was prolonged by more than a year. The later added combination endpoint applied to 8% in the drug group(488 of 6.110 patients) compared to 9.9% in the placebo arm (603 of 6.108) after an average of 4.2 years (Number Needed to Treat [NNT] = 53). The benefit was based mainly on the prevention of non-fatal myocardial infarctions (4.8% versus 6.2%; NNT = 72). Cardiovascular mortality (3.5% vs. 4.1%) and incidence of cardiac arrest (0.1% vs. 0.2%) did not differ significantly, neither did the overall mortality (6.1% vs. 6.9%).

	The EUROPA trial is said to show a benefit of the ACE inhibitor perindopril (COVERSUM) in all patients with stable coronary heart disease.
	Patients with asymptomatic heart failure or with hypertension, that is, with an urgent indication for an ACE inhibitor or antihypertensive therapy, were not excluded and were undertreated if they were allocated to placebo. Because of this ethically indefensible design, however, the question of whether perindopril is also effective outside the licensed indications cannot be answered by the study.
	The change of primary endpoint shortly before the end of the trial with prolongation of the follow-up period raises the suspicion that a possibly negative outcome was to be averted.
	We regard the EUROPA trial as an ethically and methodically dubious and unreliable marketing study to expand perindopril's range of indications.

(R = randomised study)

1

The Heart Outcomes Prevention Evaluation Study Investigators: N. Engl. J. Med. 2000; 342: 145-53

2

American product information ALTACE (ramipril), status in Feb. 2003
http://www.wyeth.com/content/ShowLabeling.asp?id=87

3

Aventis Pharma: DELIX SPC, status June 2003

4

The European trial on reduction of cardiac events with perindopril in stable
coronary artery disease investigators: Lancet 2003; 362: 782-8

HOPE = Heart Outcomes Prevention Evaluation

EUROPA = European trial On reduction of cardiac events with Perindopril
in stable coronary Artery disease