Heart failure late-breaking science
Trials highlight aspirin-free LVAD regimen, TEAMMATE and POCKET-COST-HF.
Saturday’s Late-Breaking Science Session, Heart Failure — VADS, Kids and Money, found that:
- Removing aspirin from LVAD medical regimen reduces bleeding events and costs, without increasing risk of thromboembolic events.
- TEAMMATE shows everolimus is safe in children, young adults following heart transplant.
- Heart failure medication cost information affects treatment discussions and costs.
Aspirin-free LVAD regimen reduced bleeding events and costs
The first international trial comparing the use of a modern left ventricular assist device (LVAD) with and without aspirin as part of an antithrombotic regimen found that removing aspirin reduced non-surgical bleeding events (relative risk=0.66, p=0.002) with no increase in stroke or other thromboembolic events.
Aspirin avoidance was also associated with a 41% reduction in the cost of care related to bleeding complications.
“This is a huge step forward for the benefit of patients supported with LVADs, that the simple removal of aspirin from LVAD antithrombotic regimens improves the lives of patients,” said Mandeep R. Mehra, MBBS, MSc, FRCP, the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine, executive director of the Center for Advanced Heart Disease at Brigham and Women’s Hospital, and professor of medicine at Harvard Medical School.
“We can reduce bleeding complications by 44% by simply removing aspirin with no increase in stroke risk, pump malfunction or thromboembolic events,” he said.
The global ARIES-HM3 trial randomized 628 patients with advanced heart failure implanted with a fully magnetically levitated LVAD to receive either aspirin 100 mg daily (314 patients) or placebo (314 patients), in addition to a vitamin K antagonist with target INR between 2.0-3.0.
The study was conducted at 51 centers across nine countries. The mean age of patients was 60, 18% were female and 39% non-White (ARIES 1), the majority of patients (85%) were enrolled in North America.
The primary non-inferiority endpoint was a survival free of a major nonsurgical hemocompatibility-related adverse event, including stroke, pump thrombosis, major bleeding or arterial peripheral thromboembolism, at 12 months after LVAD implantation. The principal secondary endpoint was nonsurgical bleeding events.
ARIES-HM3 clearly demonstrated non-inferiority for the aspirin-free regimen with a between-group difference of 6.04% (p<0.001), Dr. Mehra said. The aspirin-free regimen showed a reduction of 14.5 bleeding events per 100 patient years of follow-up.
“We have always used aspirin for decades as part of ventricular assist device therapy, but it has never been adequately tested in a conclusive, randomized trial before,” Dr. Mehra said. “Our subgroup analysis also fully supports aspirin removal even in those with prior bypass surgery, stroke, coronary stent or diabetes, characteristics you would think are associated with higher thrombosis risk. This is a huge win for patients on LVAD.”
ARIES-HM3 was published simultaneously in the Journal of the American Medical Association.
TEAMMATE shows everolimus is safe in children, young adults following heart transplant
The first clinical trial of everolimus to prevent rejection in children and young adults after heart transplant found the agent is similarly safe as standard immunosuppression when initiated six months after transplant. Everolimus, a proliferation signal inhibitor, has been shown to reduce the risk of rejection and other transplant complications, but carries a black box warning against use in heart transplant due to an increased risk of mortality due to infection when initiated early.
“Everolimus combined with low-dose tacrolimus is safe in children and young adults when initiated at 6 months after transplant,” said Christopher S. Almond, MD, MPH, professor of pediatrics at Stanford University. “The primary strategy to prevent rejection, a combination of tacrolimus and mycophenolate mofetil (MMF), has a median survival of just 18 years, which means many who are transplanted as children fail to survive to adulthood.”
The TEAMMATE trial randomized 211 heart transplant patients at 25 children’s hospitals across the U.S. to everolimus + low-dose tacrolimus (EVL group, 107) or standard-dose tacrolimus + MMF (MMF group, 104) and followed them for 30 months. The primary efficacy endpoint was the Major Adverse Transplant Event (MATE-3) score, a composite of biopsy-proven acute cellular rejection, cardiac allograft vasculopathy, chronic kidney disease. The primary safety endpoint was the MATE-6 score, MATE-3 plus serious infection, post-transplant lymphoproliferative disorder (PTLD), and antibody-mediated rejection.
The mean age of patients was 8.2 years, half were female, 20% non-White, and 25% Hispanic. Half the cohort was transplanted for cardiomyopathy and 49% had public insurance.
At 30 months, there was no significant safety difference in MATE-6 score between the two groups. EVL had a numerically lower score for cardiac allograft vasculopathy, chronic kidney disease, and rejection with a higher score for infection and PTLD.
Nor was there a significant difference in efficacy by MATE-3 score. EVL had a numerically lower score for cardiac allograft vasculopathy and chronic kidney disease and a higher score for cellular rejection. The cumulative burden of cardiac allograft vasculopathy, chronic kidney disease, cellular rejection, and CMV infection was 30% lower in the EVL group versus the MMF group (p=0.03). Stomatitis was more common in the EVL group, 32% versus 7%, and drug discontinuation due to adverse events was more common in the MMF group, 21% versus 12% (p<0.001 for both).
Adding cost information can affect patient-clinician treatment discussions, decisions in heart failure
POCKET-COST-HF, the first randomized trial of adding cost information to patient-clinician discussions of heart failure therapy, showed a modest but important effect on treatment decisions and adherence.
When patients and clinicians were provided with out-of-pocket costs of recommended heart failure medications, cost issues were included in treatment discussions 19% more often than when patients and clinicians were unaware of potential out-of-pocket costs.
Patients also may be less likely to defer decisions and start the medications that they decide on with their clinicians when they know those costs.
“Out-of-pocket cost is a huge concern in general related to medications and to heart failure in particular,” said Neal Dickert, MD, PhD, associate professor and Thomas R. Williams Professor of Medicine at Emory University School of Medicine and interim director of the Emory Health Services Research Center.
“Guidelines now recommend a number of medications that can have appreciable out-of-pocket costs. What used to be an inexpensive set of a few generic drugs for heart failure with reduced ejection fraction is now a bigger set of drugs, some of which can have appreciable costs.”
Researchers randomized 240 patients at three academic clinical sites in Georgia and three in Colorado. All patients and clinicians had the same list of recommended heart failure medications. Half of the patients and clinicians also had the out-of-pocket costs of each of the non-generic medications, while a control group had the checklist without out-of-pocket cost information. All patient encounters were recorded and transcribed.
The primary endpoint was cost-informed decision-making, defined by the presence or absence of heart failure medication cost discussions. Secondary endpoints included the nature and quality of medication/cost discussions, patient satisfaction, medication changes and adherence, the value of cost conversations and perceptions regarding the checklist and costs of medications.
Inclusion of out-of-pocket cost information showed a nonsignificant 10% increase in cost discussions in unadjusted analysis, 55% in the control group versus 65% in the intervention group (p=0.131).
Adjusting differences for patients’ financial well-being, time of year, age, sex, race, payer status, copay and other factors showed a 19% increase (p=0.021) in cost discussions, 49% in the control group versus 68% in the intervention group.
Initial results showed that 36% of control patients started a new medication versus 21% in the intervention group. But while 78% of control patients reported remaining on their new medication two weeks later, 92% of intervention patients said they were still taking the new medication.
“If you provide this information, patients and clinicians talk about it and use it,” Dr. Dickert said. “And while the intervention group made fewer medication changes, they seem to be more likely to follow through with those changes. We are eager to see the longer-term trends related to adherence.”