Impact of provincial and national implementation strategies on P2Y12 inhibitor utilization for acute coronary syndrome in the elderly: an interrupted time series analysis from 2008 to 2018

Based on large, multi-center randomized controlled trials (RCTs), guidelines recommend dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and a P2Y12 inhibitor for 12 months after an acute coronary syndrome (ACS), regardless of management strategy: medical management, percutaneous intervention (PCI), or coronary artery bypass grafting (CABG) [1‐10]. Specifically, the 2010 Canadian Cardiovascular Society (CCS) Antiplatelet Therapy Guidelines recommended DAPT with ticagrelor or clopidogrel and ASA for all ACS patients. Soon after, a focused update was released in 2013, exclusively recommending ticagrelor and ASA for all ACS patients [10, 11]. Despite these recommendations and available evidence, appropriate DAPT use remains variable. For example, the ACS Reflective Program—a multicenter national observational registry conducted from 2011 to 2013—found that clopidogrel remained the most common prescribed P2Y12 inhibitor across Canada at a rate of 82%, compared to only 9% for ticagrelor. Further, the prospective Canadian Observational Antiplatelet Study (COAPT) demonstrated that despite RCTs and guideline recommendations, only a minority of ACS patients were discharged on ticagrelor (11.1%) or prasugrel (5.7%), compared to clopidogrel, after PCI [12, 13]. DAPT is particularly underused in patients undergoing CABG. In a cohort of patients with ACS, CABG was an independent predictor for DAPT underutilization (odds ratio [OR] 0.09, 95%CI 0.05–0.14) [14‐16].

Suboptimal evidence implementation is not unique to antiplatelet therapy and ACS patients. Glynn et al. reviewed random patient samples from 12 metropolitans in the United States (U.S.) and found that less than 55% received guideline-recommended care [17]. More specific to cardiovascular health, a review of care gaps (defined as under-utilization or under-dosing of proven treatments) found that only 34 to 60% of eligible outpatients in Europe, Canada, and U.S. received appropriate medications for heart failure, coronary artery disease, or atrial fibrillation [18]. As such, implementation science strategies are paramount in improving healthcare delivery and quality of care.

To address the knowledge-implementation gap around antiplatelet therapy and ACS, we used provincial administrative data to examine how—if at all—government approval, guideline recommendations, and publicly funded medication plan coverage impacted P2Y12 inhibitor utilization among the elderly ACS patients managed medically, with PCI or CABG.

We analyzed P2Y12 inhibitor utilization data on 114,142 elderly ACS patients and identified three key evidence-practice gaps. First, the uptake of evidence is slow and although the proportion of patients receiving P2Y12 inhibitors after an ACS has improved in the last decade, the proportion of patients receiving guideline-directed therapy with ticagrelor remains low. Second, DAPT use is suboptimal for patients who undergo CABG. Third, and perhaps most importantly, policies have the biggest influence on changing practice. Drug coverage by a publicly funded medication plan and guideline updates had the largest impact on appropriate medication utilization.

DAPT has proven benefit for ACS patients undergoing medical management, PCI or CABG [6, 7]. An RCT of 18,624 patients randomized to ASA and ticagrelor demonstrated that the latter reduced the primary composite outcome of vascular mortality, myocardial ischemia (MI), or cerebrovascular accidents (CVA)—9.8% with ASA and ticagrelor vs 11.75% with ASA and clopidogrel (HR 0.84; 95%CI 0.77–0.92) at 12 months [6]. Previously, Yusuf et al. compared DAPT with ASA and clopidogrel with ASA monotherapy and demonstrated that a composite of death from cardiovascular causes, non-fatal MI or stroke occurred in 9.3% of patients receiving DAPT and in 11.4% of patients receiving ASA only (RR 0.80; 95% CI 0.72–0.90; p<0.001) [7]. The results of CABG subgroups from both above trials were also consistent with above findings, demonstrating a reduction in major adverse cardiovascular events (MACE) when using more potent antiplatelet therapy regimens [28, 29]. Recently, Zhao et al. randomized 500 CABG patients to 1:1:1 (ticagrelor and ASA: ticagrelor monotherapy: ASA monotherapy) and reported a statistically significant increase in vein graft patency when comparing DAPT with ticagrelor and ASA to ASA monotherapy alone (12.2% [95% CI, 5.2% to 19.2%]; p<0.001) [9]. In a recent network meta-analysis, Gupta et al. studied the safety and efficacy of various antiplatelet regimens in 15,511 CABG patients and reported that DAPT with ASA and ticagrelor, compared to ASA monotherapy, reduced SVG stenosis (OR 0.40; 95% credible interval (CrI) 0.21, 0.74), mortality (OR 0.52; 95% CrI 0.30, 0.87) and MACE (OR 0.63; 95% CrI 0.44, 0.91) [30, 31]. As such, DAPT is an evidence-based and guideline-recommended treatment for patients with ACS regardless of the management approach.

Despite this, P2Y12 inhibitor prescription practices lag globally; our data corroborate this. We demonstrated that at end of our accrual window in March 2018, only 86.9% of PCI patients were discharged with P2Y12 inhibitors. This is not dissimilar to the previously published real-world data; Schwalm et al. reported a 92% compliance in P2Y12 inhibitor prescriptions after PCI in a cluster RCT, while and Turgeon et al. demonstrated a 80.5% compliance rate in their cohort of 13,897 ACS patients treated with PCI in Alberta from 2012 to 2016 [32, 33]. Esposti et al. analyzed discharge prescriptions of 1882 ACS patients in Italy. Of the 83% of patients who were discharged on any antiplatelet therapy, 57% were prescribed ASA and clopidogrel and only 0.1% of patients were discharged on ASA and ticagrelor [34]. DAPT is even further underutilized in ACS patients who undergo CABG compared to PCI. In a retrospective study of 8939 ACS patients in Australia, CABG was an independent predictor for DAPT underutilization; OR 0.09, 95%CI 0.05–0.14 [14]. A recent survey evaluating the practice patterns of 75 Canadian cardiac surgeons around postoperative antiplatelet management found that only 45% of cardiac surgeons would restart DAPT in patients who suffered a recent ACS. Interestingly, they were more likely to initiate DAPT in patients who had previous stents to vessels that were not bypassed, required endarterectomy, or suffered a peri-operative MI. Respondents (81%) were more concerned with preventing bleeding than recurrent ischemic events [35].

While underutilization of ticagrelor post-ACS in our cohort may appear concerning, we must note that our population is elderly, with a mean age over 74, and use of clopidogrel may be justified. Recently, the POPular AGE Trial (Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome) demonstrated that ticagrelor was prematurely discontinued in 47% of patients (due to bleeding and dyspnea) compared to clopidogrel, which was only discontinued in 22% of patients. The authors also concluded that clopidogrel was an appropriate alternative to ticagrelor among ACS patients aged 70 years or older [36]. Within Canada, the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry evaluated clopidogrel versus ticagrelor prescriptions and outcomes in ACS patients who were discharged after a PCI. In their cohort of 11,185 PCI patients, compared with clopidogrel, ticagrelor was not associated with lower risk of MACE (aHR 0.97; 95% CI 0.85–1.10), but was associated with an increased risk of major bleeding (aHR 1.51; 95% CI 1.29–1.78) and dyspnea (aHR 1.98; 95% CI 1.47–2.65) [33]. These findings introduce a nuance to bleeding and dyspneic risk with ticagrelor, which seems particularly pronounced among the elderly, potentially explaining why clopidogrel remains so widely used in our cohort.

Additionally, it should be noted that evidence for use of DAPT after CABG has significant limitations—RCTs are small or are sub-studies of larger RCTs. Furthermore, there is significant population heterogeneity within the RCTs on whether patients underwent off-pump CABG (OPCAB) or CABG with cardiopulmonary bypass. In fact, a large majority of patients randomized in the two trials demonstrating DAPT superiority over ASA monotherapy underwent OPCAB [9, 37]. The available evidence does not evaluate the use of DAPT in patients undergoing multiple arterial grafting, which are associated with significantly better patency rates and clinical outcomes compared with vein grafts and the effect DAPT has on the latter may not apply to arterial grafts [38, 39]. Given the limitation of existing evidence, physicians and surgeons are more concerned with post-procedural bleeding risk, lack of dedicated robust evidence in CABG patients.

Given the above findings and real-world data, the discordance between guidelines and practice is likely multifactorial. The underutilization of ticagrelor may be due to some of the barriers to physician adherence discussed by Cabana et al. Specifically, with ever-expanding research, physicians may find it challenging to keep abreast with updated guidelines or apply them due to previous practice inertia. While lack of familiarity with ticagrelor (pharmacology and evidence around it) or external barriers (perceived issues with costs and drug coverage) may play a role, the most likely factors are likely due to lack of outcome expectancy (belief in efficacy) and lack of agreement (belief in safety, especially fear of increased bleeding, and belief in strength of recommendations) [40]. In fact, the fear of post-procedural bleeding may also explain why all P2Y12 inhibitor utilization among CABG patients declined significantly after the 2012 CCS Antiplatelet Therapy Guidelines were published. Despite strong recommendations for ASA and ticagrelor, surgeons were likely not convinced of the efficacy and safety in this population [12].

Our observation that provincial coverage increases prescription practice is aligned with the results of other studies and highlights the importance of health benefits and provincial formulary coverage. In 2011, Quebec became the first province in Canada to cover ticagrelor and prasugrel after an ACS; on discharge, Quebec showed increased use of ticagrelor and prasugrel (37.1%) compared to rest of Canada (19.2%) [12]. In 2008, Jackevicius et al. published on the impact of ODB coverage and clopidogrel use among patients who underwent PCI after an acute MI in Ontario; demonstrating an increase from 35% utilization before coverage to 88% after coverage in the first 30 days after discharge (p<0.001) [41]. Though adherence to guideline-directed use of DAPT following ACS will never reach 100%, targeted knowledge translation strategies are required to improve antiplatelet management for ACS patients in Ontario and around the world. As per the practical knowledge translation framework, a national survey to understand barriers towards appropriate antiplatelet prescription is required [42]. First, this would help address the underutilization of ticagrelor as compared to clopidogrel, and would aim to address the subset of ACS patients undergoing CABG, where surgeons are least adherent to prescribing guideline-directed DAPT. Increased prescription compliance in this population could close the practice gap and improve secondary prevention for these patients. Lastly, knowledge translation strategies should be developed during the medication study period (the pre-trial results stage) to expedite uptake if the study is positive.

Our study shows an overall increase in utilization of all available P2Y12 inhibitors for elderly ACS patients compared to previous Canadian national registries. Government-led policy changes, such as public funding, appear to be most effective at moving clinicians towards guideline-directed medical therapy.

Compared to ACS patients who underwent CABG or medical management, patients who underwent PCI had a substantially greater increase in appropriate P2Y12 inhibitor utilization after implementation strategies. Future research must focus on the barriers to appropriate antiplatelet therapy in ACS patients, especially among those managed surgically.