Dallas, TX - A recent post hoc analysis [1] of cardiovascular and other outcomes in ALLHAT trial participants randomized to either the dihydropyridine calcium-channel blocker (CCB) amlodipine or the ACE inhibitor lisinopril should banish once and for all the controversy over the relative safety of CCBs, authors of an accompanying editorial write [2].

The study, by Dr Frans Leenen (University of Ottawa Heart Institute, ON) and colleagues, published in the September 2006 issue of Hypertension, found that while rates of fatal coronary heart disease (CHD) or nonfatal 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), 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," Leenen et al concluded.

In their accompanying editorial commentary, Dr Franz H Messerli (St Luke's-Roosevelt Hospital, NY) and Jan A Staessen (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."

In an interview with heartwire, 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 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," 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 told heartwire. "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."

In an unusual editorial gaffe on the part of the journal, Messerli and Staessen's commentary—written on the basis of a draft of ALLHAT analysis— quotes a statement by Leenen et al 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 with heartwire, study coauthor Dr Michael Alderman (Albert Einstein College of Medicine, Bronx, NY) emphasized that the authors had ultimately decided that they did not want to make sweeping statements about their findings and had removed this sentence.

There is no consistent important difference between these two drugs that could guide a general recommendation about their relative value.

"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 two drugs that could guide a general recommendation about their relative value."

In their commentary, 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.

To heartwire, Messerli recalled, "As little as six 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."

Clearly the pendulum has swung from calcium antagonists being the worst possible option to the safest and most efficacious possible option.

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."

Alderman, with more tempered enthusiasm, told heartwire: "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, Leenen emphasized to heartwire 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.

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 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.