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Antihypertensive combination may save lives.

STOCKHOLM -- An antihypertensive combination of amlodipine plus perindopril was strikingly superior to a combination of atenolol and a thiazide diuretic in a major study that followed nearly 20,000 patients for 5.5 years.

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) "is a huge study and a big deal," commented Kenneth A. Jamerson, M.D., professor of medicine and a hypertension specialist at the University of Michigan in Ann Arbor.

The combination of the calcium-channel blocker amlodipine (Norvasc) and the ACE inhibitor perindopril (Aceon) "not only led to fewer cardiovascular events, but it also saved lives."

The ASCOT results "should make us rethink what we recommend" for blood pressure lowering, Dr. Jamerson told this newspaper.

"The results will influence clinical practice," commented Salim Yusuf, M.B., professor of medicine at McMaster University in Hamilton, Ont.

The results showed a coherence of data in favor of amlodipine, and are also consistent with those from other studies, he said.

The ASCOT study was stopped prematurely in October 2004 because of the significantly higher mortality among patients randomized to the atenolol-based regimen as well as worse outcomes on several secondary measures.

When all the data were tallied, all-cause mortality occurred at a rate of 13.9 per 1,000 patient-years in the amlodipine group and 15.5 per 1,000 patient-years in the atenolol group, an 11% relative reduction in favor of amlodipine that was statistically significant, Bjorn Dahlof, M.D., reported at the annual congress of the European Society of Cardiology.

Cardiovascular mortality was cut from a rate of 6.5 per 1,000 patient-years in the atenolol group to 4.9 per 1,000 patient-years in the amlodipine group, a 24% relative reduction that was also statistically significant.

The ASCOT results appeared to sharply break from those of ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial), which in a 2002 report showed that a calcium channel blocker or an ACE inhibitor was no better than the diuretic chlorthalidone for preventing events in patients with hypertension in 2002.

But experts pointed to major differences between the two studies. First, the patients enrolled into ASCOT had a much lower baseline risk for cardiovascular events than did those who were enrolled into ALL-HAT, said Peter S. Sever, M.B., an ASCOT coinvestigator and professor of clinical pharmacology and therapeutics at Imperial College in London.

Second, the ALLHAT study was designed to compare individual drugs, while ASCOT was designed to compare two forms of combination therapy, according to Dr. Jamerson.

ASCOT enrolled 19,342 patients with hypertension in the United Kingdom and five other northern European countries during 1998-2000.

Patients were eligible if they were 49-79 years old and had at least three of these cardiovascular risk factors: male gender, age of at least 55 years, smoking, total- to HDL-cholesterol ratio of at least 6, family history of premature coronary heart disease, left ventricular hypertrophy, type 2 diabetes, peripheral artery disease, or prior stroke or transient ischemic attack.

Patients were treated with either amlodipine, adding perindopril when needed to reach the blood pressure target, or with atenolol (Tenormin), adding bendroflumethiazide and potassium when needed to reach the goal pressure. Throughout the trial, an average of 50% of patients in the amlodipine arm were on both amlodipine and perindopril, and an average of 55% in the atenolol arm were on atenolol and the thiazide.

The study's primary end point was the rate of nonfatal myocardial infarctions and coronary heart disease deaths, but this difference just missed being statistically significant. The rate was 8.2 per 1,000 patient-years in the amlodipine group and 9.1 per 1,000 patient-years in the atenolol group, a 10% relative reduction.

Part of the reason why the primary end point set in 1998 failed to reach significance was that many physicians now take a more aggressive approach to vascular intervention, which probably prevented many of these events, Dr. Sever said.

A more appropriate reflection of current practice is to tally myocardial infarctions, coronary heart disease deaths, and coronary revascularizations, Dr. Sever said.

By this measure, the amlodipine regimen cut events by a relative 14%, a statistically significant difference.

The impact of the amlodipine and perindopril regimen was also notable for the range of events that it prevented.

In addition to deaths and myocardial infarctions, it also significantly dropped the rate of strokes and peripheral artery disease, as well as the incidence of new-onset diabetes and renal impairment.

Throughout the study, the amlodipine arm had a systolic pressure that averaged 2.7 mm Hg lower than the atenolol arm and a diastolic pressure that averaged 1.9 mm Hg lower.

A complex statistical analysis by the study team established that the difference in blood pressure reduction between the two arms of the study accounted for about half of the difference in coronary events and about 40% of the difference in stroke events, suggesting that some of the difference was because of effects of amlodipine and perindopril that go beyond blood pressure lowering.

Evidence from other studies has suggested that calcium channel blockers are especially effective at reducing stroke risk, and that ACE inhibitors are effective at lowering coronary disease risk, said Dr. Sever.

The study leaders, as well as Dr. Jamerson and Dr. Yusuf, all said that they were confident that the advantages seen for amlodipine and perindopril in the study represent class effects for calcium channel blockers and ACE inhibitors.

The ASCOT study was sponsored by Pfizer, which makes Norvasc, and the researchers who ran the study served as consultants to and received honoraria, travel expenses, and research support from Pfizer.

But the researchers emphasized that the study was designed, run, and analyzed independently of any input from the sponsor.

BY MITCHEL L. ZOLER

Philadelphia Bureau
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Author:Zoler, Mitchel L.
Publication:Clinical Psychiatry News
Geographic Code:1USA
Date:Nov 1, 2005
Words:958
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