–Aliskiren raised regulatory pandemonium as it crashed in trials
When it comes to interrupting the renin-angiotensin system, the third time was definitely not the charm.
Following the enormous success of the ACE inhibitors and angiotensin-receptor blockers, there were early high expectations for a third class of drugs, the direct renin inhibitors. Those hopes were dashed when aliskiren (Tekturna), the first drug in the class, crashed and burned a few years ago.
Important information about one of those trials, ATMOSPHERE, was presented Monday at the American College of Cardiology meeting in Chicago and published simultaneously in the New England Journal of Medicine. In addition to the usual trial details, the NEJM publications contained a fascinating round of articles from the trial’s Data Monitoring Committee, executives from drug sponsor Novartis, and officials from European regulatory agencies, offering their perspectives on the pandemonium that ensued when the drug began to fall.
ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) randomized more than 7,000 heart failure patients to the ACE inhibitor enalapril (Vasotec), aliskiren, or the combination of the two. The trial was significantly modified midstream when major safety concerns in patients with diabetes emerged in two other trials testing the drug, ALTITUDE and ASTRONAUT. As a result, enrollment of diabetics was halted and diabetics already enrolled in the trial who were receiving aliskiren were taken off the drug.
After 3 years in ATMOSPHERE, there was no significant difference in the primary endpoint, which was the rate of death from cardiovascular causes or hospitalization for heart failure: 34.6% in patients who received enalapril alone, 33.8% in patients who got aliskiren alone, and 32.9% in patients who received both drugs. Compared with enalapril monotherapy, combination therapy was associated with a significant increase in hypotension, elevated serum creatinine, and elevated potassium.
The authors concluded that there was no benefit to either adding aliskiren to an ACE inhibitor or using aliskiren on its own.
“There seems to be a ceiling to the benefit that can be obtained with renin-angiotensin system blockers,” said John McMurray, MD, of the University of Glasgow, lead author of the study, in a press release. “Above a certain level of blockade, there are more adverse effects and no additional benefit. These findings also tell us that it is very hard to improve on the results obtained with ACE inhibitors.”
In a separate NEJM paper, members of the ATMOSPHERE Data Monitoring Committee— Karl Swedberg, Jeffrey Borer, Bertram Pitt, Stuart Pocock, and Jean Rouleau— issued a harsh condemnation of regulatory intervention in the trial. They wrote that they consider the regulatory action “to be a threat to the function of data monitoring committees [DMCs] and potentially to the integrity of monitored trials.”
Problems with aliskiren first emerged in the ALTITUDE trial, resulting in the early termination of the trial and a regulatory warning against use of the drug in diabetic patients. In response, the DMC members for ATMOSPHERE, who were also monitoring the ASTRONAUT trial, carefully scrutinized their trials. European regulators wanted to examine blinded data from the ongoing ATMOSPHERE trial but the DMC resisted, though they reassured the regulators that they were carefully monitoring the trial and that they had not found evidence to warrant discontinuation of aliskiren in diabetics. Although they had not seen the data from ATMOSPHERE, the regulators intervened and asked Novartis to discontinue the use of aliskiren in diabetic patients in the trial.
“Given the results of ALTITUDE and ASTRONAUT, the concerns of the regulators regarding patients in ATMOSPHERE were reasonable,” the DMC members wrote. But ATMOSPHERE was different, they maintained, because it included a run-in period to help identify patients who could not tolerate aliskiren.
The DMC authors wrote that it is appropriate for regulators to ask the DMC to pay special attention to emerging problems, but that it is inappropriate for them to ask for unblinded data during a trial. “We strongly recommend that the data monitoring committee in a clinical trial be allowed to act independently during the progress of the trial. If legitimate concerns arise regarding the safety of any intervention, as was the case here, sharing of data with regulators should be avoided. In special cases, the data monitoring committee’s statistical analysis plan to deal with these concerns should be shared with the regulators.”
Responding to the DMC authors, a group of European regulators wrote that the “proposal to share statistical analysis plans instead of unblinded data with regulators… seems reasonable,” though they went on to defend their actions in ATMOSPHERE. In a separate piece, Novartis officials described their experience of being caught between a rock and a hard place, i.e., the DMC and the European regulators.