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Getting Rid of Co-Pays Doesn’t Fix Antiplatelet Nonadherence

Taking away the cost barrier improved post-MI adherence to P2Y12 inhibitor therapy only slightly in the randomized ARTEMIS trial.

Patients were more likely to say that they stuck 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 benefit in major adverse cardiovascular events over the year (10.2% vs 10.6%, adjusted HR 1.07, 95% CI 0.93-1.25).

Rates of actionable bleeding were similar between groups as well, researchers led by Tracy Wang, MD, MHS, MSc, of Duke Clinical Research Institute in Durham, North Carolina, reported in the January 1/8 issue of JAMA.

“These results suggest that multifactor interventions are likely needed to achieve population-level health benefits. Co-payment reductions may be considered part of broader-scale strategies to incentivize risk-based treatment selection and promote adherence to guideline-recommended therapies,” the authors concluded.

ARTEMIS was first reported at the American College of Cardiology meeting in 2018, where investigators emphasized 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 (about 3 percentage points for non-persistence) and little impact on clinical outcomes with the monetary subsidy.

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.

Current guidelines show a preference of ticagrelor or prasugrel over clopidogrel because these more potent agents better reduce event rates after MI. However, nonadherence to antiplatelet therapy remains a problem, prompting researchers to investigate reasons for it and ways to reduce it.

The more than 10,000 patients enrolled in ARTEMIS were adults discharged alive after an acute MI who were prescribed a P2Y12 inhibitor. Patients with all insurance types, including Medicare, were included.

Investigators had randomized 301 hospitals to withhold or to give out 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 (median voucher value for 30-day supply $137). There were no refill reminders or other interventions to improve medication adherence.

Even with the co-pay eliminated for the intervention group, only 72% of these patients used the voucher at least once over 1 year.

ARTEMIS investigators acknowledged that, among other limitations, the trial might have been underpowered to detect a difference in adverse events because of the large number of patients in the intervention group who never used the voucher.

And when pharmacy records were used instead of patient self-report, 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 didn’t describe any barrier to use, suggesting that they didn’t need it or chose not to use it, Wang and colleagues commented.

“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 benefitted the most from the voucher were the ones who did not use it,” noted Cynthia Jackevicius, BScPhm, PharmD, MSc, of Western University of Health Sciences in Pomona, California, and Dennis Ko, MD, MSc, of Sunnybrook Health Sciences Centre in Toronto.

In ARTEMIS, perhaps the co-pay wasn’t the actual barrier but a marker for a patient who is at risk of nonadherence regardless of financial circumstances, they suggested in an accompanying editorial.

“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,” Jackevicius and Ko said.

According to the editorialists, the key remaining areas of research include how to identify patients at risk of nonadherence, to “diagnose” the type or reasons of nonadherence, and to the design and implementation of multipronged targeted interventions so that patients stick to their medications.

ARTEMIS was supported by an institutional grant from AstraZeneca.

Wang disclosed institutional grant support from Amgen, AstraZeneca, Bristol-Myers Squibb, Cryolife, Novartis, Pfizer, Portola, and Regeneron; and receiving consulting honoraria from Grifols and Gilead.

Jackevicius is an associate editor for Circulation: Cardiovascular Quality and Outcomes.

Ko reported no disclosures.


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