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Medication News & Update

A definite end to the CCB controversy? New ALLHAT analysis

Shelley Wood

Medscape Medical News 2006. © 2006 Medscape

August 16, 2006 — A recent post hoc analysis of cardiovascular and other outcomes in ALLHAT trial participants randomized to either the dihydropyridine calcium-channel blocker (CCB) amlodipine or the angiotensin-converting-enzyme (ACE) inhibitor lisinopril should banish once and for all the controversy over the relative safety of CCBs, authors of an accompanying editorial write.

The study, by Frans Leenen, MD, from the University of Ottawa Heart Institute, Ontario,and colleagues, published in the September issue of Hypertension, found that while rates of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) in older hypertensive patients were similar in CCB- and ACE-inhibitor–treated patients, secondary outcomes differed: CCBs significantly increased the risk of heart failure (HF), while ACE inhibitors increased the risk of stroke, angina, peripheral artery disease (PAD), gastrointestinal (GI) bleeding, and angioedema.

"Because there were differences in opposite directions (mainly stroke and HF), the drug choice in a given patient should depend on how the clinician and patient assess the absolute risks and the importance of reducing those risks," Dr. Leenen and coauthors conclude.

In their accompanying editorial commentary, Franz H. Messerli, MD, from St. Luke's-Roosevelt Hospital, New York, and Jan A. Staessen, MD, from the University of Leuven, Belgium, take a stronger stance, saying the findings will be "prone to at least dent, if not shatter, the halo surrounding the ACE inhibitors."

Post hoc analysis focuses on CV and other outcomes

As Dr. Leenen and colleagues note in their paper, both during and following the active follow-up of ALLHAT, results largely from nonrandomized trials pointed to improved survival and reduced morbidity in ACE-inhibitor–treated patients with HF, left ventricular dysfunction, or coronary heart disease, while other studies suggested that CCBs might be associated with worse cardiovascular outcomes while increasing the risks of cancer and GI bleeding. To investigate these claims, Dr. Leenen and colleagues used the ALLHAT database to compare effects of lisinopril and amlodipine directly, something that was not a prespecified comparison in the original ALLHAT study.

The primary end point for the post hoc analysis, as with the main trial, was the combined incidence of fatal CHD or nonfatal MI by intention to treat: as Dr. Leenen and coauthors report, there were no differences in the primary end point between the 2 groups. Secondary outcomes were all-cause mortality, stroke, combined CHD (fatal CHD, nonfatal MI, coronary revascularization, or angina with hospitalization), or combined cardiovascular disease (CVD) (combined CHD plus stroke, treated angina without hospitalization, heart failure, and peripheral arterial disease), end-stage renal disease, cancer, and gastrointestinal bleeding. It is here that key differences emerged, the authors note. Overall, stroke rates were higher for ACE-inhibitor therapy, particularly in black patients and women. Rates of combined CVD were higher in lisinopril-treated patients, driven by higher rates of stroke, PAD, and angina, but slightly offset lower rates of HF. Angioedema also occurred more frequently in the lisinopril-treated patients (38 vs 3; P <0.001).

Six-year event rate per 100 persons

*Combined CVD indicates CHD death, nonfatal MI, stroke, coronary revascularization procedures, hospitalized or treated angina, treated or hospitalized HF, and peripheral arterial disease.

CI = confidence interval.

Teasing out findings

In an interview, Dr. Leenen emphasized the stroke findings, pointing out that blood pressure control was slightly less effective in the lisinopril arm, which might have influenced stroke rates. "Small differences in blood pressure can have an important effect on outcome, particularly in patients who have a high risk for stroke, such as black patients," he said. "This further highlights how crucial it is to lower BP below targets."

As well, said Dr. Leenen, the post hoc analysis helps tease out findings hinted at in the main ALLHAT results that might have been obscured by having "the diuretic in the middle," Dr. Leenen explained.

"In the main ALLHAT trial results, all comparisons were vs the diuretic, and small differences up or down could have been hidden," he said. "Particularly for the stroke end point, it becomes much clearer because, compared with the diuretic, the dihydropyridine was indeed somewhat lower, but this difference was not significant, and for the ACE inhibitor compared with the diuretic there was already a higher stroke rate. But now this direct comparison shows a more prominent difference, and that's a new finding."

No sweeping statements

In an unusual editorial gaffe on the part of the journal, Drs. Messerli and Staessen's commentary — written on the basis of a draft of ALLHAT analysis — quotes a statement by Dr. Leenen and colleagues that was subsequently removed from the final version of their paper. The phrase, quoted in the commentary, read: "Considering the totality of outcome measures in ALLHAT, amlodipine appeared to have advantages over lisinopril." Yet, in an interview, study coauthor Michael Alderman, MD, from the Albert Einstein College of Medicine, Bronx, New York, emphasized that the authors had ultimately decided that they did not want to make sweeping statements about their findings and had removed this sentence.

"We tried to avoid making a global conclusion because we felt that the data didn't support that. There were no differences in the primary outcome, there were differences in the secondary end points — most important, heart failure on one side and stroke on the other — and there were also differences in blood pressure control that had an important impact, particularly in terms of race. Overall we felt that these data would indicate that there is no consistent important difference between these 2 drugs that could guide a general recommendation about their relative value."

An end to the CCB controversy?

In their commentary, Drs. Messerli and Staessen also emphasize the importance of lowering blood pressure to prevent MI and stroke and stress that the shadow that once hovered over CCBs should now be lifted: "The analysis of Leenen et al puts a definite end to what was called the CCB controversy, which flourished for more than a decade," they write.

In an interview, Dr. Messerli recalled, "As little as 6 years ago, New York Times headlines stated that calcium antagonists were causing something like 85,000 heart attacks per year and cases of congestive heart failure. These headlines were scaring patients and frustrating physicians. At that time, CCBs were considered one of the worst options in CV medicine, and this is what all of the controversy was about. Now this study, directly comparing an ACE inhibitor with a calcium antagonist, shows that, if anything, CCBs are safer and better tolerated. Clearly the pendulum has swung from calcium antagonists being the worst possible option to the safest and most efficacious possible option."

Dr. Messerli says that many, though not all, physicians are now using CCBs without misgivings. "I think the . . . physician has realized that the calcium-blocker controversy was mostly heat and no light and has realized that calcium antagonists are a very safe option. . . . But there are still a lot of physicians who think of the CCB as third-line, and it's hard to change habits."

Dr. Alderman, with more tempered enthusiasm, said: "I think that this paper along with other data suggest that the concerns about the hazards of calcium antagonists have not been sustained."

For his part, Dr. Leenen emphasized that the post hoc analysis should not detract from the primary ALLHAT findings and the value of diuretics. However, physicians should feel comfortable knowing that they can also choose between an ACE inhibitor and a CCB, particularly as add-on therapy, based on the individual risks of the patient in question. "You would still want to make sure that the blood pressure is being well-controlled and in blacks, control of blood pressure by an ACE inhibitor would clearly be not as effective as compared with the dihydropyridine," he said.

Dr. Alderman adds that there are circumstances in which a diuretic may not be the first choice. "Sometimes in individual cases there are strong reasons to use a converting enzyme inhibitor, and there are some situations in which a calcium antagonist might be the first choice as well."

It's a point of view that Dr. Messerli calls "fair" but notes that ACE inhibitors still appear to have "more baggage" to be taken into account. "Cough is minor, but angioedema is potentially fatal," he stated.

The editorial notes that Drs. Messerli and Staessen have received funding from and are "ad hoc consultants for pharmaceutical companies with commercial interest in CCBs and ACE inhibitors." Dr. Leenen is listed in the paper as having "ownership interest" in Bristol-Myers Squibb, Johnson & Johnson, Merck, Pfizer, and Schering-Plough. Dr. Alderman reports receiving speakers' bureau honoraria from Merck and Bristol-Myers Squibb totaling "well less" than $10 000.

Hypertension. Published online July 24, 2006.

Hypertension. 2006;48:359-361.

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