Introduction

The ACC/AHA 2007 guidelines recommend 12 months of dual antiplatelet therapy (DAPT) after placement of a drug-eluting stent (DES)¹ based on the increased risk of stent thrombosis observed in first generation DESs as compared to bare metal stents.² It is unknown if the same risks hold true with the advent of newer generation drug-eluting stents. In clinical practice patients may not adhere to the recommended 12 month treatment course, for a variety of reasons. The study "Thrombotic Complications Associated With Early and Late Nonadherence to Dual Antiplatelet Therapy" was designed to assess the frequency and clinical consequences of this nonadherence.³

Methods

This was a prospective registry based study using data from the multicenter EDUCATE (Endeavor Drug-Eluting Stenting: Understanding Care Antiplatelet Agents and Thrombotic Events) registry. 2,159 patients undergoing coronary stenting with an Endeavor zotarolimus-eluting stent and meeting criteria for the run in phase of the DAPT trial⁴ were included. Nonadherence and events were analyzed in the 12-month period prior to randomization.

Any nonadherence (ANA) was defined as missing ≥1 days of DAPT, and severe nonadherence as missing 14 or more consecutive days. The study endpoints were all-cause mortality, cardiac death myocardial infarction, stent thrombosis, GUSTO trial defined major bleeding,⁵ and the composite endpoint of death or myocardial infarction.

Results

At 6 months, 208 patients (9.6%) were noted to have ANA including severe nonadherence in 112 (5.2%). In the time period between 6 and 12 months, an additional 170 patients (7.9%) were noted to have ANA. Analysis of the baseline characteristics at the 6-month mark revealed that as compared to patients with full adherence to DAPT, patients with ANA were slightly older and had a higher prevalence of diabetes, heart failure, previous stroke/TIA, peripheral vascular disease, and warfarin use. The only measured significant independent predictor of ANA in the first 6 months was the development of a major bleeding event (odds ratio 12.83, 95% confidence interval 7.55 to 21.80, p < 0.001).

At 6 months, the individual endpoints of all-cause mortality, cardiac death, MI, major bleeding, and stroke were all more frequent in the group with ANA as compared to full adherence group (p = 0.001, p = 0.028, p = 0.002, p < 0.001, p < 0.001 respectively). The end point of stent thrombosis was also non-significantly increased (p = 0.123). The composite end point of death or MI was significantly more common in the group with ANA at 6 months (7.6% vs. 3.0%, p <0.001). Patients who demonstrated ANA between 6 months and 12 months after an initial 6 month period of full adherence did not have an increased risk for the composite end point of death or MI as compared to those will a full 12 months of adherence (1.1% vs 1.3%).

Conclusions

ANA to DAPT is common, with estimated 9.6% of patients demonstrating ANA in the 6 months after DES placement. Major bleeding is a clinical factor significantly associated with DAPT ANA. ANA within 6 months after DES placement is associated increased all-cause mortality, cardiac mortality, and adverse cardiovascular outcomes.

Commentary/Perspective

This study is an elegant use of EDUCATE registry to shed light on the clinically relevant issue of the role of nonadherence to DAPT in adverse outcomes in the era of second generation drug-eluting stents. It is recognized that certain contingencies can impede patient and/or clinician adherence to guidelines regarding treatment duration of DAPT. Understanding the consequences and factors associated with nonadherence is an important step that may lead to improved patient selection for DES placement, as well as targeted strategies to improve adherence.

In this study, ANA to DAPT was observed in almost 1 out of every 10 patients within 6 months of DES placement, the time when the risk for adverse events was the highest. This is an alarming statistic which is likely an underestimate of real world clinical practice due to the exclusion criteria employed for the DAPT study and the general selection bias associated with enrollment in clinical trials. The particular importance of adherence in the first 6 months of DAPT is a finding that is congruent with a landmark analysis of the previous PARIS registry based 2-year study which included bare metal stents and first generation drug-eluting stents in addition to the second generation drug-eluting stents.⁶

The main limitation of this study, noted by the study authors, is the existence of confounders that were not studied. The confounders omitted were psychosocial factors. These factors were noted in a previous systematic review which found that in addition to the aforementioned bleeding, that lower education level, immigrant status, and lack of education about DAPT are also associated with nonadherence.⁷

The prevalence of nonadherence to DAPT and the associated adverse cardiovascular events highlight the importance of patient selection prior to DES placement. Clinicians will need to weigh the potential bleeding risk vs. benefits of stent placement. In the current era of the second generation DES, efforts and resources are needed to combat nonadherence, especially in the first 6 months of DAPT.

References

1. Grines CL, Bonow RO, Casey DE Jr., et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Catheter Cardiovasc Interv 2007;69:334–40.
2. Farb A, Boam AB. Stent thrombosis redux—the FDA perspective. New Engl J Med 2007; 356:984–7.
3. Cutlip DE, Kereiakes DJ, Mauri L, et al. Thrombotic Complications Associated With Early and Late Nonadherence to Dual Antiplatelet Therapy. JACC Cardiovascular Interventions 2015; 8:404-10.
4. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents. N Engl J Med 2014; 371:2155-2166.
5. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. New Engl J Med 1993;329:673–82.
6. Mehran R, Baber U, Steg PG, et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet 2013; 382:1714–22.
7. Czarny MJ, Nathan AS, Yeh RW, et al. Adherence to dual antiplatelet therapy after coronary stenting: a systematic review. Clin Cardiol. 2014 Aug; 37(8):505-13.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Acute Heart Failure, Interventions and ACS, Interventions and Vascular Medicine

Keywords: Acute Coronary Syndrome, Diabetes Mellitus, Drug-Eluting Stents, Heart Failure, Hemorrhage, Myocardial Infarction, Patient Selection, Peripheral Vascular Diseases, Platelet Aggregation Inhibitors, Prevalence, Prospective Studies, Random Allocation, Registries, Selection Bias, Sirolimus, Stroke, Thrombosis, Warfarin

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