CME Author: Vicki Brower
Study Authors: Tracy Y. Wang, Lisa A. Kaltenbach, et al; and Cynthia A. Jackevicius, Dennis T. Ko (editorial)
Target Audience and Goal Statement:
Cardiologists, internists, family medicine specialists, public policy experts
The goal was to determine if removing co-payment barriers increased use of newer P2Y12 antiplatelet inhibitors among patients who recently had a myocardial infarction (MI), and whether this drug class lowered the risk of subsequent major adverse cardiovascular events (MACE).
- What is the effect, if any, of giving patients vouchers to offset co-payment costs of P2Y12 inhibitors on compliance?
- Did use of this class of antiplatelet drugs reduce the rates of MACE in patients who had recently suffered an MI?
Study Synopsis and Perspective:
Removing the cost barrier for a newer class of antiplatelet drugs, P2Y12 inhibitors, resulted in only a small increase in their use by patients who had recently had an MI, according to results of the Affordability and Real-world Antiplatelet Treatment Effectiveness After Myocardial Infarction Study (ARTEMIS).
Compared with patients who did not receive vouchers, those who accepted and filled prescriptions using vouchers had a 3.3% absolute increase in using the drugs, reported Tracy Wang, MD, MHS, MSc, of Duke Clinical Research Institute in Durham, North Carolina, and colleagues. However, this did not result in a significant reduction in MACE outcomes at 1-year post-MI, the team wrote in their study online in JAMA.
For the study, the researchers randomized 301 hospitals to either withhold or distribute co-payment vouchers to their patients, providing a 1 year supply of clopidogrel or ticagrelor to the intervention group at zero out-of-pocket cost for the patient (the median voucher value for a 30-day supply was $137). There were no refill reminders or other interventions to improve medication adherence, and the rates of bleeding were similar in the two groups.
The study enrolled 11,001 adults (median age 62, 31% women), all of whom had been discharged following an acute MI and received a prescription for a P2Y12 inhibitor from their physician. Patients with all insurance types, including Medicare, were included.
“These results suggest that multifactor interventions are likely needed to achieve population-level health benefits,” Wang and co-authors concluded. “Co-payment reductions may be considered part of broader-scale strategies to incentivize risk-based treatment selection and promote adherence to guideline-recommended therapies.”
Current guidelines from the American College of Cardiology (ACC) and the American Heart Association state that ticagrelor or prasugrel is preferred over clopidogrel since these more potent agents better reduce event rates after MI. However, nonadherence to antiplatelet therapy remains a problem, Wang and colleagues noted, prompting them to investigate the reasons and attempt to find ways to increase compliance.
Study limitations, the researchers said, were that the trial might have been underpowered to detect a difference in adverse events, since there were many patients in the intervention group who never used the voucher.
“For dual antiplatelet therapy to be effective, a threshold of exposure may be required before clinical benefits will be manifest, and that threshold likely exceeds the 55% objectively documented adherence rates seen in the ARTEMIS trial,” wrote Cynthia Jackevicius, PharmD, MSc, of Western University of Health Sciences in Pomona, California, and Dennis Ko, MD, MSc, of Sunnybrook Health Sciences Centre in Toronto, in an accompanying editorial. They noted that since only 72% of intervention patients used the voucher, the clinical effects of the drugs may have been attenuated.
The editorialists compared the ARTEMIS study with the PLATO trial, which needed nearly double the sample size and a 78% difference in interventions between groups to find a 16% relative reduction in MACE with ticagrelor compared with clopidogrel, and which had absolute MACE rates of 9.8% versus 11.7%, respectively. One year adherence in that trial was 83%. Given the parameters of ARTEMIS, “it may not be entirely surprising that ARTEMIS did not improve clinical outcomes,” Jackevicius and Ko wrote.
In addition, they stated, greater use of ticagrelor in the treatment group may have resulted in greater negative consequences of P2Y12 inhibitor nonadherence on clinical outcomes due to pharmacokinetic and pharmacodynamic differences between drugs.
Source References: JAMA, Jan. 1/8, 2019; 321(1): 44-55; and JAMA, Jan. 1/8, 2019; 321(1): 37-39
Study Highlights: Explanation of Findings
Wang presented an abstract of the ARTEMIS results at the 2018 ACC annual meeting in 2018, emphasizing then that the payment vouchers, by eliminating price differences between clopidogrel and ticagrelor (the latter usually having higher out-of-pocket costs), made physicians more likely to prescribe ticagrelor. That analysis also showed a small overall increase in adherence, as well as little impact on clinical outcomes with the monetary subsidy.
As noted in the JAMA report, clopidogrel was the P2Y12 inhibitor of choice in 36.0% of the intervention group and 54.7% of the usual-care group. There was less ticagrelor but more prasugrel (Effient) prescribed in the latter.
Patients reported that they complied with P2Y12 inhibitor therapy for 1 year if they had been discharged from hospitals that gave out clopidogrel (Plavix) and ticagrelor (Brilinta) vouchers (87.0% vs 83.8% with no voucher, adjusted OR 1.19, 95% CI 1.02-1.40). However, that small absolute difference in medication adherence did not translate into a significant MACE reduction over the year (10.2% vs 10.6%, adjusted HR 1.07, 95% CI 0.93-1.25), Wang and colleagues said.
Patients included in the study were adults discharged after an acute MI who were prescribed a P2Y12 inhibitor. Even when the co-pay was eliminated for the intervention group, only 72% of patients who received the voucher used it at least once over the course of 1 year, which translates into “a modest 20% difference between groups in use of the guideline-preferred P2Y12 inhibitors ticagrelor and prasugrel (64% for intervention vs 45%$ for usual care), diminishing the magnitude of the intervention,” the researchers wrote.
When pharmacy records were used instead of patient self-reporting, the adherence rates favored the intervention group more, but were lower in both groups, at 55.2% and 46.3%, respectively (adjusted OR 1.47, 95% CI 1.29-1.66).
Most patients who didn’t use the voucher also didn’t note any barrier to use, suggesting that they didn’t need the voucher or chose not to use it, Wang and colleagues commented.
Jackevicius and Ko pointed out in the editorial that patients who used the voucher were more likely to be male, white, employed with private insurance, have a higher income, and have fewer comorbidities, suggesting that perhaps patients who could have benefited the most from the voucher were those who didn’t use it.
Perhaps the co-pay was not the actual barrier, but rather a marker for a patient who is at risk of nonadherence, regardless of financial circumstances, Jackevicius and Ko suggested.
The key remaining areas of research, they added, include identifying patients at risk of nonadherence, determining the type or reasons of nonadherence, and designing and implementing multipronged targeted interventions so that patients stick to their medications.
Nonadherence to prescribed medication “is a complex intersection of intentional and non-intentional nonadherence and has been categorized by the World Health Organization into five dimensions that involve patient-related, condition-related, therapy-related, health system-related, and social and economic factors,” the editorial explained. “Medication adherence thus requires a combination of interventions targeting information, health beliefs, self-efficacy, simplification, and barrier reduction to be successful. Success requires more than reducing cost barriers, which are only one part of a larger, and more complex story.”
“Adherence is primarily a behavioral matter that can be exacerbated by a health system, drug policy, or co-payment barriers,” the editorial continued. Therefore, a multi-modal approach and timely intervention will be necessary to change nonadherence. An improved ability to target those patients at risk for being nonadherent, discern what type of nonadherence may be involved, and design and implement multipronged targeted interventions is vital, Jackevicius and Ko stated.
Finally, they recommended that future research consider exploring “a shared decision-making, personalized medicine approach that incorporates patients’ values and preferences.” A one-size-fits-all approach without considering a patient’s specific needs and interests will not work, the editorial concluded.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco