August 26, 2012 (Munich, Germany) — New data from the ALTITUDE trial with the direct renin inhibitor aliskiren (Tekturna, Novartis) in diabetic patients were released today, shedding more light on why the trial was halted prematurely.

The trial, which was studying the effects of aliskiren on top of ACE-inhibitor or angiotensin-receptor-blocker (ARB) therapy in diabetic patients with renal disease (glomerular filtration rate <60 mL/min per 1.73 m2 or microalbuminuria), was stopped late last year by the data and safety monitoring board. The reason given was no apparent benefit and an increase in adverse events, including nonfatal stroke, renal complications, hyperkalemia, and hypotension.

Presenting the latest data from the study at the European Society of Cardiology (ESC) 2012 Congress, Dr Hans-Henrik Parving (University of Copenhagen, Denmark) said an increase in ischemic stroke was "prominent" in the decision to stop the trial. At the time the decision was made, the increase in stroke was significant in the aliskiren group, but as more data have come in, this finding is no longer statistically significant, although they still show a strong signal, he told heartwire.

Increase in Stroke of 25%

"There was a 25% relative increase in stroke risk in the aliskiren group, which is a warning signal that there could be harm here, but it could also be a chance finding," he said. He stressed that an increased risk of stroke is converse to what would be expected with a drug that lowers blood pressure and has not been seen in any studies of the drug in hypertension. "It is a very peculiar finding. It is certainly unique to have a blood-pressure–lowering medication that increases stroke risk."

Parving suggested that if the finding was real, it was probably specific to the diabetic population, whom he said had impaired autoregulation of blood flow to the brain. "This may mean that lowering blood pressure too much in this population could cause too little perfusion to the brain," he speculated. While the average reduction in blood pressure with aliskiren in the trial was just 1.3 mm Hg systolic and 0.6 mm Hg diastolic, Parving said that all the data had not yet been analyzed and it is possible that some patients had larger drops in pressure. "We are planning to analyze whether it is the patients with the largest drop in pressure who had the strokes, but this has not been done yet," he told heartwire .

Designated discussant of the trial, Dr Johannes Mann (Munich General Hospitals, Germany), said there was no hint of a stroke increase with dual inhibition of the renin angiotensin system in the ONTARGET trial (which compared a combination of an ACE inhibitor and an ARB with monotherapy). He noted that there were 3000 patients in ONTARGET with diabetic nephropathy, but there was no difference in stroke rate between these patients in the different groups. He concluded that the stroke increase in ALTITUDE was therefore not explained by a blood-pressure effect or dual inhibition but was more likely to be "either specific to aliskiren or the play of chance." He added that a clarifying study (APOLLO) had recently been stopped by the sponsor.

But it was not just the stroke risk that led to the trial being stopped. "Five of the seven elements of the primary composite end point were going in the wrong direction," Parving said. The two that were positive were unplanned hospitalization for heart failure and doubling of serum creatinine. The other five end points--cardiovascular death, resuscitated death, MI, stroke, onset of end-stage renal disease--were trending higher in the aliskiren group. The overall primary end point showed a nonsignificant trend toward a worse outcome in the aliskiren group (HR 1.08).

Hyperkalemia Another Major Issue

The other main concern was hyperkalemia, which occurred in 39% of the aliskiren group vs 29% of the placebo group, with severe hyperkalemia seen in 21% vs 16%. "There were no cases where the increase in potassium needed dialysis, but there was one case where raised potassium levels were specified as the cause of death."

He noted that raised potassium at baseline was a strong indicator of a worse outcome on aliskiren. "Patients without raised potassium at baseline did not show an increase in the primary, cardiovascular, or renal outcomes with the drug."

Parving concluded: "Adding aliskiren on top of ACE inhibitors/ARBs in the diabetic population is not recommended and may even be harmful." He added to heartwire that he would also now not recommend the addition of aliskiren to ACE-inhibitor or ARB treatment in hypertension. "ONTARGET showed no additional benefit of this strategy, but it is still fine to use aliskiren monotherapy in patients who cannot tolerate ACE inhibitors or ARBs." He said the only situation where it may still be useful to add aliskiren on top of ACE inhibitor/ARB treatment was in heart failure, where studies looking at this are currently under way.

The ALTITUDE study enrolled 8561 subjects randomized to aliskiren 300 mg once daily or placebo on top of a single renin-angiotensin blockade. The data presented here represent a median patient follow-up of 32 months. But Parving said these data were still preliminary as final results have yet to be collected.

ALTITUDE: Main End Points

End point Aliskiren (n=4274), % Placebo (n=4287), % HR (95% CI) p
Composite end point 17.9 16.8 1.08 (0.98–1.20) 0.142
CV death 5.6 5.0 1.13 (0.94–1.36) 0.184
Resuscitated sudden death 0.4 0.2 2.28 (0.99–5.23) 0.053
MI 3.3 3.3 1.02 (0.81–1.29) 0.858
Stroke 3.4 2.8 1.25 (0.98–1.60) 0.070
Unplanned hospitalization for CHF 4.7 5.1 0.93 (0.77–1.13) 0.462
Doubling of serum creatinine 4.8 5.0 0.96 (0.79–1.16) 0.650
End-stage renal disease or renal death 2.8 2.5 1.10 (0.85–1.43) 0.465
Death 8.8 8.3 1.07 (0.92–1.23) 0.388

ALTITUDE: Adverse Effects

Outcome Aliskiren (%) Placebo (%)
Hyperkalemia 38.7 28.6
K+ >5.5–6.0 mmol/L 21.0 16.0
K+ >6.0 mmol/L 8.8 5.6
Hypotension 12.1 8.0
Diarrhea 9.6 7.2
Falls 2.8 2.6

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