CHICAGO, IL — Adding the renin inhibitor aliskiren (Tekturna, Novartis) to standard therapy of the ACE inhibitor enalapril increases adverse events but does not improve outcomes in patients with chronic heart failure and reduced ejection fraction, according to new research that some say questions the role of regulatory responsibility when it comes to safety[1].
The ATMOSPHERE trial included more than 7000 patients with NYHA class 2 to 4 HF and an LVEF <35%, all of whom were randomized to one of three arms: aliskiren monotherapy, aliskiren plus enalapril, or enalapril alone (control group). At roughly 4 years of follow-up, aliskiren was not found to be superior (in either the monotherapy or combination groups) or even significantly noninferior (in the monotherapy group) to enalapril by itself in rates of CV death or HF-related hospitalization (the primary composite outcome).
In addition, compared with the enalapril-monotherapy group, the combo group had a significantly higher risk of hypotensive symptoms (P=0.005) and elevated serum creatinine (P=0.009) and potassium levels (P<0 .001="" p="">
"Our combination-therapy results show that there is a ceiling in heart failure" when it comes to blocking the renin-angiotensin system (RAS), Dr John JV McMurray (University of Glasgow, Scotland) told attendees at the American College of Cardiology (ACC) 2016 Scientific Sessions. "Beyond that limit, there is no additional benefit," he said.
"This important study comes with a background of 2 decades of seeing whether increased inhibition [of the renin system] could improve outcomes. And all of these studies have really failed to make a mark," noted Dr Dennis McNamara (University of Pittsburgh, PA), after McMurray's presentation during a late-breaking clinical-trial session.
The findings were simultaneously published in the New England Journal of Medicine, along with a statement from the trial's data monitoring committee (DMC), a regulatory reply, and a response from Novartis.
Because of concerns about possible harms from aliskiren to diabetes patients, the Clinical Trial Facilitation Group (CTFG) of the Heads of Medicines Agencies in Europe stepped in during the trial to request that these patients stop taking the medication.
Following ALTITUDE and ASTRONAUT
ATMOSPHERE joins two other aliskiren-focused studies that were unsuccessful. The ALTITUDE trial was stopped prematurely for futility, while the ASTRONAUT trial showed no significant improvement in CV death or hospitalization. Both of these earlier trials also showed possible harm from the drug.
The investigators of the current study hoped to avoid this problem by including a two-part run-in period to eliminate those who couldn't tolerate the combination therapy.
In the first phase, 8835 patients were enrolled at 789 centers from March 2009 to December 2013. All received enalapril 5 mg twice daily for 1 to 4 weeks. If treatment-related adverse events were deemed "not unacceptable," they then had the dose upped to 10 mg twice daily. The second phase of the run-in included the addition of aliskiren 150 mg once daily. Only those who could tolerate the combination therapy moved on to randomisation.
After the run-in period, 7016 patients (78% men; mean age 63 years) were randomly assigned to aliskiren 300 mg once daily (n=2340); enalapril 5 or 10 mg twice daily (n=2336); or both treatments (combination therapy [n=2340]).
"Death of Aliskiren?"
At a mean of 36.6 months, CVD death or hospitalization occurred in 33.8% of the aliskiren-receiving patients vs 34.6% of the enalapril group (hazard ratio [HR] 0.99, 95% CI 0.90–1.10). The prespecified requirement of P <0.01 for noninferiority was not met.
In addition, the primary composite outcome occurred in 32.9% of the combination-therapy group (HR 0.93 vs enalapril monotherapy, 95% CI 0.85–1.03).
Symptomatic hypotension was found in 13.8% of the combo-therapy group vs 11% of the enalapril-monotherapy group; serum creatinine >2.5 mg/dL was found in 4.1% vs 2.7%, respectively; and serum potassium >5.5 mmol/L was found in 17.1% vs 12.5%. There were no significant differences in these measures between the aliskiren- vs enalapril-monotherapy groups.
Overall, in addition to finding no benefit from adding aliskiren to enalapril, "our findings also do not support the use of a renin inhibitor as an alternative to an ACE inhibitor," note the investigators.
After his presentation, McMurray was asked where the field goes from here. "Is this the death of aliskiren in heart-failure therapy?" asked Dr Emerson C Perin (Texas Heart Institute, Houston).
"If we believe in evidence-based medicine, I don't see how aliskiren helps," answered McMurray.
However, he noted that the trial did have an additional—and controversial—wrinkle thrown in.
New Regulatory Mandate
Because of the ALTITUDE trial's possible harm specifically in the participants who had diabetes, the CTFG announced in 2013 that any trial participant with baseline diabetes should immediately be switched from aliskiren to standard therapy—and no further diabetes patients could be enrolled.
"This decision was executed worldwide in a protocol amendment issued in April 2013," report the current researchers.
A total of 665 of their 2340 participants randomized to combination therapy had diabetes, as did 627 of the 2340 aliskiren-monotherapy group and 652 of the 2336 enalapril group. Before their follow-up was truncated, the diabetes patients in the aliskiren group received the treatment for a mean of 24 months.
Interestingly, an analysis that included only data after regulatory censoring showed consistent results with the above-mentioned outcomes.
Of those without diabetes, 34.3% of the combination-therapy group vs 35.2% of the enalapril group experienced the primary composite outcome. Of those with diabetes, 29.5% vs 33.1%, respectively, met the outcome.
Still, a statement from the trial's data and safety monitoring board regarding the regulatory intervention accompanied publication of the study[2].
Published Replies
"New pharmaceutical agents are best evaluated in randomized, controlled clinical trials in which both the safety of participants and the adequacy of conduct are monitored by an independent data monitoring committee [DMC]," write Dr Karl Swedberg (University of Gothenburg, Sweden) and colleagues, noting that regulatory interference calls into question how to run clinical trials.
Swedberg et al report that the ATMOSPHERE DMC recommended trial continuation in February 2012 and January 2013, even after considering the results of ALTITUDE and ASTRONAUT. They add that the DMC had increased its frequency of reviews and was carefully monitoring those with diabetes or renal dysfunction
At that latter review, "there were numerically fewer" HF hospitalizations, CV deaths, MIs, and strokes in the combination-therapy group vs the enalapril-monotherapy group, they write. But 1 month later, the CTFG requested that ATMOSPHERE patients with diabetes stop receiving aliskiren based on data from ALTITUDE and ASTRONAUT "but without knowledge of the unblinded ATMOSPHERE results." The trial committee complied with the request.
The DMC conducted a last data review in March 2015 and recommended continuing the trial to its planned ending of July 2015. These overall results were what were reported at the ACC meeting and published.
The committee notes that although the concerns raised were reasonable, the run-in period, which did not occur in the other two trials, and multiple safety reviews should have kept the regulators from stepping in.
In a regulatory reply to the DMC's statement[3], Dr Tomas Salmonson (Medical Products Agency, Uppsala, Sweden), Heidi Janssen (European Medicines Agency, London, UK), and Drs Thomas Sudhop and Elke Stahl (German Federal Institute for Drugs and Medical Devices [BfArM], Bonn) write that they agree that a DMC "should be allowed to act independently during the progress of a trial."
However, they note that when the BfArM contacted ATMOSPHERE's DMC with concerns because of the previous two trials, they weren't reassured that the new trial's monitoring measures were adequate and asked for unblinded data, which were not provided. That's when they asked the CTFG to step in.
Swedberg et al note that releasing unblinded ATMOSPHERE data could have compromised the trial's integrity. This type of sharing to several regulators "could lead to a variety of interpretations, with consequent confusion," they write.
Journal's Response
New England Journal of Medicine's deputy editor Dr John Jarcho (Brigham and Women's Hospital, Boston, MA) admitted to heartwire that publishing the two responses with the study, as well as a reply from Novartis[4], was "a bit unusual." However, the circumstances themselves were unusual, he said.
"To be fair to the regulators, they have a very difficult job because part of their responsibility is ensuring patient safety while people are conducting clinical trials," said Jarcho. "One thing that often happens is that while you're conducting a trial, someone else discovers something in a different trial that influences data." And this has led to some past studies being stopped.
In this case, "there was a difference in views between the regulators and the members of the data and safety monitoring board, who know things that nobody else does. The board was not happy and said, 'You are usurping our authority to make judgments about what's safe,' " said Jarcho.
"I think what has come out of this discussion is, I hope, a desire to try to find ways for these boards and safety regulators to work together to ensure the safety of patients in ongoing trials without having to stop trials or alter their progress, if at all possible."
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