November 3rd, 2012
ALTITUDE Autopsy Shows What Went Wrong With Aliskiren
Larry Husten, PHD
In its short lifespan the direct renin inhibitor aliskiren (a.k.a., Rasilez or Tekturna) rapidly declined from being a highly promising, first-of-its kind drug to a major failure. The death blow was struck last December with the early termination of the ALTITUDE trial, after the data and safety monitoring committee found an increased risk in patients taking aliskiren. Now the final results of the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints have been presented at Kidney Week 2012 in San Diego and simultaneously published in the New England Journal of Medicine.
8,561 type 2 diabetics at high risk for cardiovascular and renal complications already receiving an ACE inhibitor or an angiotensin-receptor blocker were randomized to receive aliskiren or placebo. The primary outcome of a cardiorenal event (CV death, resuscitated death, MI, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline creatinine) occurred more often in the aliskiren group, although this difference did not achieve statistical significance:
- 18.3% for aliskiren versus 17.1% for placebo (hazard ratio, 1.08; 95% CI, 0.98-1.20; P=0.12).
A similar trend was observed for just cardiovascular outcomes:
- 13.8% versus 12.6%, respectively (hazard ratio, 1.11; 95% CI, 0.99-1.25; P=0.09)
Compared with placebo, patients on aliskiren had lower blood pressure and a greater reduction in the urinary albumin-to-cretinine ratio. But there was also a significantly higher risk of hyperkalemia (39.1% versus 29.9%; P<0.001) and hypotension (12.1% versus 6.3%, p<0.001).
The authors concluded that the addition of aliskiren to standard therapy in high risk type 2 diabetics “is not supported by these data and may even be harmful.” The result of ALTITUDE, they write, “underscores the need to go beyond surrogate biomarkers and obtain risk-benefit data from clinical end-point trials to better inform clinical decisions.”
4 Responses to “ALTITUDE Autopsy Shows What Went Wrong With Aliskiren”
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It seems that not making any conclusion when the results of a clinical trial show non-statistically significant differences has been a sane tradition since the times clinical trials started, some point as a pioneer “king Louis XVI” of France, who hired Benjamin Franklin to ascertain if the claims of Mesmer about “Animal magnetism” (a thing some would call today “Instant hypnosis” or “the will”) were a fake, and this was the final conclusion of the team that included Lavoisier, Guillotin and Bailly. Perhaps the detrimental effect of Aliskiren is not sufficiently supported, and taking into account that a significant improvement in Blood Pressure and in urinary Albumin-to-Creatinine ratio, two markers of long term outcome in Hypertension and Diabetes Mellitus connected kidney disease, some improvement may be guessed at a longer term. Hyperkalemia is a class side effect for ACEIs and ARBs, so finding this may be no surprise at all. Can be envisaged a longer follow up of the trial’s groups to ascertain if there’s a long term benefit with Aliskiren, or considering other endpoints such as Left Ventricular remodelling or GFR? The ball in the side of Health Regulatory Authorities and the sponsor and investigators in this trial.
I agree that surrogates (including BP reduction) should not be used for approval of drugs or to determine their clinical utility – because we clearly misunderstand them.
The results are very similar to ONTARGET trial: lower BP, lower albuminuria – worse renal outcomes and more side effects. In ALTITUDE we see even a hint of worse CV outcomes. This really spells death to dual/triple RAS inhibition paradigm and questions our understanding of (seemingly) basic pathophysiologic processes in HTN/CV disease.
It is also interesting that the trial was stopped before actual harm could be unequivocally shown, thus allowing manufacturer of Aliskiren (who is also the trial sponsor) to continue producing and marketing the drug.
Similar scenario played out with AIM-HIGH: stopped early for “futility”, depriving practitioners and patients of a chance to know if drug is really harmful or not. Is this a new norm for the design of clinical trials – both industry- and publicly-funded ones? “Primo no nocere” – with regard to the sponsors interests, not the patients or community?
The 95% confidence interval for the endpoint of cardiovascular events excluded all but a 1% benefit (hazard ratio, 1.11; 95% CI, 0.99-1.25; P=0.09). Why would you use this drug, other than to prevent vascular events? Cardiac arrest was doubled. In patients with K>=5.0 at baseline, there were significant increases in MI, stroke, etc. I agree with my colleague Dr Vasin that this really spells the death knell for the dual/triple RAS inhibition paradigm.
aliskiren is a major failure, no doubt about that. i think its position in the treatment of cardiovascular patients was chosen wrong at the beginning. full inhibition of RAAS was thought to be the key of decreasing cv mortatlity, but we know that one cannot fully inhibit this pathway without causing serious damage.
so aliskiren could take place of acei’s or arb’s. we need some head-to head trials about this. but i am not sure about any company would take a risk by designing that kind of trial, so for now, aliskiren should take a long vacation.