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Data point to amlodipine, atorvastatin synergy: evidence obtained from ASCOT may lead to more aggressive use of statins in hypertensive patients.

DALLAS -- Combined treatment with the calcium channel blocker amlodipine and atorvastatin appeared to have synergistic effects for cutting the rate of coronary heart disease events in a trial with about 10,000 patients.

A new analysis of data that was collected from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) demonstrated a "much more dramatic risk reduction in patients treated with amlodipine and atorvastatin, compared with those treated with atenolol and atorvastatin," Peter S. Sever, M.B., said at the annual scientific sessions of the American Heart Association.

The results suggested that physicians may need to be more aggressive about prescribing a statin to hypertensive patients regardless of their baseline serum level of LDL cholesterol.

"In the context of hypertension, you have to ask, why is my patient not on a statin, because the evidence is fairly convincing that most patients would benefit," said Dr. Sever, professor of clinical pharmacology and therapeutics at Imperial College in London.

ASCOT was sponsored by Pfizer Inc., which makes amlodipine (Norvasc), atorvastatin (Lipitor), and a combined formulation of both drugs (Caduet). Dr. Sever served as a consultant to and received honoraria, travel expenses, and research support from Pfizer.

"I think the evidence is very good," said Richard B. Devereux, M.D., professor of medicine at Cornell University in New York. "I use statins a fair amount of time in my patients [with hypertension] and now I'll use it in a few more. I'm sure that the [ASCOT] results will influence some guidelines" to recommend wider use of statins in hypertensive patients, said Dr. Devereux, who was not involved in the ASCOT study and does not have any financial relationship with Pfizer.

"The guideline should be that anyone who needs treatment for hypertension should also be on a statin," said Jay Cohn, M.D., professor of medicine at the University of Minnesota in Minneapolis. The results of the new ASCOT analysis are "very provocative," he said, although he added that the finding needs to be repeated to prove that it's real.

Still, he is convinced that statins, calcium channel blockers like amlodipine, and ACE inhibitors, which were used with amlodipine in ASCOT, "protect the arteries in patients with arterial disease," and that this effect goes beyond simply using these drugs to reach a target blood pressure or level of serum cholesterol. Dr. Cohn was not involved in ASCOT; he has received research support from and served as a consultant to Pfizer.

ASCOT randomized a total of more than 19,000 patients with hypertension to two different antihypertensive treatment strategies. One arm used amlodipine as the primary agent, followed by addition of the ACE inhibitor perindopril in patients who did not reach the target blood pressure. The second arm used the [beta]-blocker atenolol as the primary drug, with the diuretic bendroflumethiazide and potassium added when a second drug was needed.

The results of this comparison showed that amlodipine plus perindopril was more effective than atenolol plus the diuretic for reducing coronary heart disease events in this primary prevention population (Lancet 2005;366:895-906).

In addition, 10,305 patients with a non-fasting total serum cholesterol level of 250 mg/dL or lower were subjected to a second randomization to treatment with 10-mg atorvastatin daily or placebo. This aspect of the study showed that the atorvastatin regimen led to a reduction in coronary heart disease events (Lancet 2003;361:1149-58).

The new analysis looked at the interaction between the lipid-lowering and blood pressure-lowering regimens in a 2-by-2 factorial study. This additional analysis was prespecified in the study's original design.

The findings appeared to show an interaction. During almost 6 years of follow-up, 38 patients treated with amlodipine and atorvastatin had the study's primary end point--a nonfatal myocardial infarction or coronary heart disease death--compared with 80 patients with this end point among those who got amlodipine plus placebo, a 53% reduction in the patients on dual therapy compared with monotherapy. Among those treated with atenolol, there were 62 events in those who also received atorvastatin and 74 events in those treated with atenolol plus placebo, a 16% reduction in patients on dual therapy.

The P value for an interaction between the two treatments was .025, which was of borderline statistical significance because the threshold for statistical significance in this tertiary analysis was prespecified as .01.

"While this could be a chance finding, there is a plausible biologic explanation for a synergistic effect between amlodipine and atorvastatin for coronary events," Dr. Sever said.

He proposed the hypothesis that vascular smooth-muscle cells in atherosclerotic plaque are stimulated by cytokines to grow and dedifferentiate into synthetic cells that are unresponsive to calcium channel blockers. Statin treatment transforms the synthetic cells back to a differentiated phenotype that is again responsive to calcium channel blockers, he said.


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Title Annotation:Cardiovascular Medicine
Author:Zoler, Mitchel L.
Publication:Internal Medicine News
Geographic Code:1USA
Date:Dec 15, 2005
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