ALTITUDE Autopsy Shows What Went Wrong With Aliskiren Reply

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.”

First Detailed Look At Why Aliskiren Failed To Gain ALTITUDE 2

Last December the once-promising direct renin inhibitor aliskiren (Rasilez, Tekturna) suffered a fatal setback with the early termination of the ALTITUDE trial. The trial was stopped when the Data Monitoring Committee (DMC) found an increased risk for non-fatal stroke, renal complications, hyperkalemia, and hypotension in patients taking aliskiren after 18-24 months.

At the ESC in Munich ALTITUDE investigator Hans-Henrik Parving presented the first detailed but preliminary results from the trial, which compared aliskiren to placebo in 8,561 type 2 diabetics at high risk for cardiovascular and renal complications already receiving single RAAS blockade.

After 32 months of followup, the composite endpoint (CV death, resuscitated death, MI, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline creatinine) was not significantly different between the two groups, though Parving noted that the numbers went in the wrong direction for aliskiren, including a trend suggesting more strokes associated with the treatment drug:

  • Composite endpoint: 17.9% for aliskiren versus 16.8% for placebo (HR 1.08, 0.98-1.20, p=0.142)
  • Stroke: 3.4% versus 2.8%, HR 1.25 (o.98-1.60, p=0.70)

Aliskiren-treated patients also had higher potassium levels and were more likely to develop hyperkalemia, hypotension, and diarrhea.

Republished with permission from CardioExchange, a NEJM group publication.

Click here to read the ESC press release…

Aliskiren (Tekturna) Gets New Warning and Contraindication From FDA Reply

The FDA has issued new warnings about antihypertensive drugs containing the direct renin inhibitor aliskiren (including Tekturna, Amturnide, Takamio, and Valturna) when used in combination with ACE inhibitors or angiotensin receptor blockers (ARBs). The FDA now states that these drug combinations are contraindicated in patients with diabetes, and it is adding a new warning to avoid the use of this combination in patients with moderate to severe renal impairment (GFR <60 mL/min).

The new warnings are based on preliminary data from the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) clinical trial. As previously reported here, ALTITUDE was terminated last December when the independent Data Monitoring Committee (DMC) found an increased risk for non-fatal stroke, renal complications, hyperkalemia, and hypotension in patients taking aliskiren after a median followup of about 27 months. More than 8,500 patients  with type 2 diabetes and renal disease were randomized to receive aliskiren or placebo in addition to an ACE inhibitor or an ARB.

Click here to read the FDA Drug Safety Communication.