By Michael H. Crawford, MD, Editor
SYNOPSIS: The results of a subanalysis of the ISCHEMIA trial indicated about one-quarter of patients in both conservative and invasive strategy groups were nonadherent to recommended medical therapy at baseline. Nonadherence was associated with worse health status in both groups at baseline and after one year.
SOURCE: Garcia RA, Spertus JA, Benton MC, et al. Association of medication adherence with health outcomes in the ISCHEMIA trial. J Am Coll Cardiol 2022;80:755-765.
The creators of the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial randomized patients with chronic stable ischemic heart disease (IHD) and at least moderate ischemia by stress testing to an invasive vs. a conservative strategy. Both groups received guideline-directed medical therapy (GDMT). Garcia et al performed coronary CT angiography in all 4,480 patients randomized to identify left main coronary artery patients and confirm obstructive coronary lesions were present. Researchers excluded patients with left ventricular ejection fractions < 35%, left main disease, an acute coronary syndrome within two months, glomerular filtration rate less than 30 mL/min/1.73 m2, class III-IV heart failure, and those with refractory angina, since such patients would be better served by revascularization.
After a median 3.2 years of follow-up, both the primary and major secondary event rates did not differ, but those with angina at baseline exhibited better health status with the invasive approach. However, investigators noted 28% of patients did not take the recommended medications, as instructed. Garcia et al hypothesized the health status of the conservatively treated patients who adhered to their recommended medical regimen would be better than those who did not, and that this difference would favor the invasive strategy, since they underwent revascularization and received GDMT.
The primary outcome measure for the ISCHEMIA subanalysis was the Seattle Angina Questionnaire (SAQ), which is scored from 0-100, with 100 representing the best and 5 or higher considered clinically significant. Patients self-reported adherence at their baseline visits. Nonadherent patients scored worse on SAQs at baseline than adherent patients in the conservative group (73 ± 19 vs. 76 ± 18) and invasive group (71 ± 20 vs. 74 ± 19). Also, adherence was associated with a higher 12-month SAQ in both treatment groups — a mean difference with conservative therapy of 1.6 and invasive 1.9, with no interaction by treatment. The authors concluded medication nonadherence happened among about one-quarter of patients in ISCHEMIA and was associated with worse health status in both the conservative and invasive groups at baseline as well as at 12 months.
COMMENTARY
The issue of nonadherence affects the results of randomized, controlled trials, and might influence guideline updates eventually. Accounting for nonadherence is a worthwhile goal. Traditional ways to account for this differential nonadherence are to perform an intention-to-treat analysis or a per-protocol one. However, the strength of any conservative management study is adherence to the medications under investigation.
ISCHEMIA investigators expressed concern that among nonadherent patients, an invasive approach would seem justified, even if medical therapy was a reasonable or even optimal approach. However, this is unlikely since interventionalists fear the nonadherent patient who after coronary stenting does not take their dual antiplatelet therapy. In ISCHEMIA, the incremental benefit in health status from adherence to medications was the same in both the conservative and invasive arms. Thus, ISCHEMIA does not support the concept that nonadherent patients fare better with an invasive approach.
There were weaknesses to this subanalysis. Perhaps most important is adherence assessment happened only at baseline, not throughout the study period. It is conceivable that participating in a study improved adherence. Additionally, nonadherence was self-reported rather than objectively measured by pill counts or other methods. Also, nonadherence was a binary determination; patients either were adherent, or they were not. A more graded approach might have been better. In addition, 21% of those randomized to the invasive arm did not undergo an intervention. Finally, the authors excluded patients with severe angina who most likely would benefit from either approach. We need to develop better tactics for improving adherence to GDMT.
The results of a subanalysis of the ISCHEMIA trial indicated about one-quarter of patients in both conservative and invasive strategy groups were nonadherent to recommended medical therapy at baseline. Nonadherence was associated with worse health status in both groups at baseline and after one year.
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