Hypertension rebels voice doubts about aliskiren

May 16, 2007

New York, NY - Doubts about the effectiveness of the new renin inhibitor antihypertensive aliskiren (Tektura, Novartis) have been voiced in a somewhat controversial review article in the May 2007 issue of the American Journal of Hypertension[1].

The authors, Dr John Laragh (editor of the journal) and his wife and fellow hypertension researcher Dr Jean Sealey (New York Hospital/Cornell University Medical Center, New York), say that aliskiren is no more effective than current antihypertensives and suggest that its ability to lower blood pressure may be limited by reactive renin secretion, an effect that may actually increase blood pressure in certain patient groups.

In an interview with heart wire , Laragh said: "We don't have an urgent need for a new drug like this. It is not a breakthrough. It is a weak antihypertensive drug. It is no better than what we already have, and it will be much more expensive. In addition, aliskiren causes a greater reactive rise in renin production than any other antihypertensive, which could be dangerous for patients with the most highly reactive renin systems."

Laragh and Sealey are no strangers to controversy, having been at the center of a bitter row with the American Society of Hypertension (ASH), which resulted in the American Journal of Hypertension no longer being the official journal of ASH and the end of Laragh's and Sealey's involvement with ASH.

Their current views on aliskiren have received a mixed response from other hypertension experts. While most agree that aliskiren may not offer much of an improvement over current agents, they also point out that any new antihypertensive has to be welcomed, as it widens the choice available. And the main reaction to the idea that by increasing renin levels aliskiren may be harmful to some is one of caution, with most experts pointing out that this is just a theory.

"Theoretical mumbo jumbo"?

Of those asked to comment on Laragh and Sealey's article, Dr Matthew Weir (University of Maryland School of Medicine, Baltimore), who is the author of several studies with aliskiren, was the most outspoken, calling the renin discussions "theoretical mumbo jumbo."

"This is all hogwash. The blood-pressure-lowering data with aliskiren are similar to all other marketed drugs. The FDA agrees. It does lots of good things—lowers proteinuria, regresses left ventricular hypertrophy, etc—and outcome trials are currently under way with it. The theory about higher renin levels is just that—a theory. If anything, it provides better biochemical suppression of the [renin-angiotensin-aldosterone system] RAAS than an ACE inhibitor or [angiotensin receptor blocker] ARB. It is shortsighted to base an entire premise on theories that are unsubstantiated. I'm struggling to understand why Laragh would believe such nonsense. I suspect this may be a personal vendetta rather than a scientific opinion; otherwise, he would have published this in another journal rather than his own," Weir fired. "This drug does work, and Dr Laragh needs to remember that not everyone responds to the same drug. One third to one half of hypertension patients are not getting their blood pressure under control, and anything that helps in this regard should be welcomed," he added.

Dr Joseph Izzo (State University of NY at Buffalo) was also supportive of the new drug. "Aliskiren appears to be at least as effective for blood-pressure lowering as ACE inhibitors or ARBs when sufficient doses of each agent are used in similar populations. As with ACE inhibitors or ARBs, renin inhibitors can be combined effectively with a diuretic or calcium antagonist to achieve greater blood-pressure lowering. Aliskiren decreases plasma renin activity but increases plasma renin concentration; renin has no proven direct effect on human organ function or disease. Because aliskiren is specific for human renin, extrapolation of transgenic animal data may not be fully indicative of the long-term effects of the drug in humans; such studies are currently in progress," he told heart wire .

Others were more sympathetic to Laragh and Sealey's view. These included Dr William Kannel (Boston University School of Medicine, MA), who said he agreed with their comments, and Dr Franz Messerli (St Luke's-Roosevelt Hospital, New York), who took a slightly more neutral stance.

Messerli says he agrees somewhat with views of Laragh and Sealey in that he is not convinced that another blocker of the renin angiotensin system is absolutely necessary, but he is skeptical about the theory that higher renin levels would have an antagonistic effect on blood pressure. "It is true that the dose-response curve of aliskiren is relatively shallow, but this is true for all blockers of the renin angiotensin system. We should of course consider that there is always space for a new drug class in hypertension, since many patients have side effects (real or perceived) on numerous antihypertensive drugs," he commented to heart wire .

In their article, Sealey and Laragh analyze data from clinical trials involving more than 5000 hypertensive patients, which they say show that aliskiren was not more effective as an antihypertensive agent than ACE inhibitors, ARBs, or diuretics and that it has a limited antihypertensive dose-response curve. Although aliskiren lowered blood pressure to a greater extent when combined with an ACE inhibitor, an ARB, or a diuretic, blood-pressure control was achieved by less than 50% of patients, they report. Because aliskiren stimulates kidney renin secretion to a greater degree than do ACE inhibitors or ARBs, its antihypertensive capabilities can be counteracted by large reactive increases in renin secretion; this is particularly likely at a higher dosage and may explain why the drug appears weak, they add.

"Aliskiren's pervasive stimulation of varying degrees of renin secretion could especially be a problem for those hypertensive patients who have hyperreactive renin systems, such as patients with renovascular, advanced, or malignant hypertension, all of whom were excluded from the trials. Their reactive renin responses might be so great as to induce a rise in blood pressure. Until the possibility of aliskiren inducing increases in blood pressure is eliminated, it seems safer, simple, and wiser to stick to the less expensive, equally effective, and widely available generic drugs for treating hypertensive disorders," they write.

Not a witch hunt

Laragh commented to heart wire : "Our analysis is not a witch hunt. But we have to live with the fact that they didn't show very good results." He added that the issues he has raised about reactive renin could be easily addressed if the individual data from the aliskiren trials were made public and if the drug were systematically studied in patients with hyperreactive renin systems. "All my concerns could be obliterated with such data," he said.


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