Ticagrelor vs Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: Insights From a Single Institution Registry

Abstract: Dual-antiplatelet therapy is recommended for all patients with acute coronary syndromes (ACS), regardless of performance of revascularization. Ticagrelor (T) was shown to be superior to clopidogrel (C) in a large, randomized clinical trial, but data from real-world practice are lacking. We identified ACS patients from our institutional registry who underwent percutaneous coronary intervention and received one of the two drugs at hospital discharge based on physician preference. Among 1439 patients, there were 774 patients (53.8%) in the C group and 665 patients (46.2%) in the T group. T and C patients were similar except for a higher incidence of ST-elevation myocardial infarction (MI) and lower frequency of prior MI in the T group (P<.05 for both). The primary endpoint – 1-year all-cause death – occurred in 58 C patients and 48 T patients (6.9% vs 7.9%, respectively; P=.42). Sixty percent of these deaths (n = 62; 31 C and 31 T) were considered cardiovascular in nature based on chart review. By multivariable logistic regression model, only dialysis (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.50-4.64; P=.01), age (HR, 1.83; 95% CI, 1.49-2.24 per 10 years; P<.001), and prior heart failure (HR, 1.78; 95% CI, 1.12-2.82; P=.02) were independent predictors of 1-year death. Treatment with T was not a predictor of death (HR, 1.21; 95% CI, 0.81-1.82; P=.35) or cardiovascular death (HR, 1.18; 95% CI, 0.72-1.94; P=.52). Landmark analysis from day 10 showed similar results (HR, 1.13; 95% CI, 0.71-1.84; P=.59). Thus, we conclude that C and T have similar rates of 1-year all-cause mortality, which is predominantly affected by age, end-stage renal disease, and pre-existing heart failure.

J INVASIVE CARDIOL 2019;31(8):235-238. Epub 2019 July 15.

Key words: acute coronary syndromes, clopidogrel, survival, ticagrelor

European and American professional guidelines recommend dual-antiplatelet therapy (DAPT) consisting of aspirin and a platelet P2Y₁₂ receptor inhibitor for all acute coronary syndrome (ACS) patients for 1 year, irrespective of revascularization strategy.^1,2 Since the publication of the pivotal randomized clinical trial Platelet Inhibition and Patient Outcomes (PLATO) in 2009³ comparing ticagrelor with clopidogrel for ACS patients, ticagrelor is preferred over clopidogrel because it reduces the incidence of cardiovascular death and myocardial infarction by nearly 20%. The adoption of this strategy has been incomplete. We sought to determine whether treating ACS patients with ticagrelor in routine clinical practice at a large tertiary institution would produce similar results to those observed in PLATO.

Methods

We enrolled patients presenting with ACS, ie, those with acute myocardial infarction with ST-segment elevation (STEMI) or without ST-segment elevation (NSTEMI) who underwent percutaneous coronary intervention (PCI) between October 1, 2011 and July 31, 2017. This interval started at the time ticagrelor was approved at our institution and ended to allow 1 year of follow-up, as in PLATO. Our ACS protocol recommends the utilization of ticagrelor in preference to clopidogrel for all ACS patients, including those receiving clopidogrel, unless they were already treated with prasugrel or received medications known to interact with ticagrelor, such as antiepileptic or HIV drugs. Unique patients were identified from an institutional registry that enrolls all patients undergoing PCI for mandatory reporting to the New York State Department of Health (NYSDOH) and is exempt from the need for patient consent if deidentification of data is maintained. We excluded PCI patents who did not have ACS, based on elevation in cardiac enzymes (troponin I and/or CK-MB) prior to procedure and indication for coronary angiography as STEMI or NSTEMI. We utilized the fields and definitions mandated by the NYSDOH (https://www.health.ny.gov/forms/cardiac_surgery/2017/doh-3331.pdf). Patients were categorized as belonging to the clopidogrel or ticagrelor groups based on the drug used up to hospital discharge. The study endpoint was death within 1 year, which was verified by reviewing medical records or by contacting primary care physicians or the patients themselves, when necessary (14% of cases). We also collected data on recurrent MI or hospitalization for bleeding in this interval. Since DAPT beyond 1 year after ACS is not a class I recommendation and is not well standardized, we did not collect follow-up data beyond this point.

Statistical analysis. Continuous variables are presented as medians with interquartile ranges and were compared with Wilcoxon’s rank-sum tests. Categorical variables are presented as proportions and were compared with Chi-square or Fisher’s exact tests. Event rates were estimated using the Kaplan-Meier time-to-event methodology and compared using log-rank tests. As sensitivity analysis, endpoints were landmarked from day 10 to eliminate events that are less affected by the choice of DAPT. A multivariable logistic regression model was developed to test the independent impact of DAPT regimen on clinical events during follow-up. The following covariates were considered: age; sex; left ventricular ejection fraction; STEMI; prior MI; prior heart failure; hypertension; diabetes; current dialysis; and prior stroke. The significance level was set at P<.05. All analyses were performed with SAS version 14.2 (STATA Inc).

Results

There were 1613 unique patients with ACS undergoing PCI during the study period. Vital status could not be established in 112 patients and there was no follow-up after hospital discharge in 62 patients. Thus, a total of 1439 patients were enrolled in this study. There were 774 patients (53.8%) in the clopidogrel group and 665 patients (46.2%) in the ticagrelor group. Baseline characteristics are shown in Table 1. The two groups were similar except for a higher incidence of STEMI and lower frequency of prior MI in the ticagrelor group (P<.05 for both). The distribution of culprit vessels was similar among the two groups (Table 2). Bivalirudin was used as anticoagulant in 57.4% of the clopidogrel group and 59.2% of the ticagrelor group (P=.51). Intraprocedural death occurred in 4 patients (2 in each group), while post-PCI coronary artery bypass graft surgery occurred in 11 clopidogrel patients and 2 ticagrelor patients (P=.03) prior to hospital discharge. Bleeding and transfusions were recorded in similar proportions in both groups (P=.55 and P=.37, respectively). MI after PCI was noted in 16 patients in each group (P=.66).

The primary endpoint of all-cause death  occurred in 58 clopidogrel patients and 48 ticagrelor patients (6.9% vs 7.9%, respectively; P=.42) (Figure 1). Two-thirds of these deaths (n = 62; 31 clopidogrel and 31 ticagrelor patients) were considered cardiovascular in nature based on chart review. MI events occurred in 8 clopidogrel patients and 3 ticagrelor patients in the first year after ACS (P=.21). Hospitalization for bleeding occurred in 4 clopidogrel patients and 1 ticagrelor patient).

In a multivariable logistic model predicting the use of ticagrelor vs clopidogrel (including: age; sex; STEMI [vs NSTEMI]; prior MI; prior heart failure; prior PCI or coronary artery bypass grafting; existing cerebrovascular, peripheral, or lung disease; dialysis; and hypertension), the c-statistic was 0.55 and only prior heart failure (odds ratio, 1.43; 95% confidence interval [CI], 1.05-1.96; P=.02) and STEMI (OR, 1.25; 95% CI, 1.00-1.55; P=.05) were weakly associated with its use. These data suggest a fairly random utilization of the two drugs.

By multivariable logistic regression model, only dialysis (hazard ratio [HR], 2.64; 95% CI, 1.50-4.64; P=.01), age (HR, 1.83; 95% CI, 1.49-2.24 per 10 years; P<.001), and prior heart failure (HR, 1.78; 95% CI, 1.12-2.82; P=.02) were independent predictors of 1-year death. Treatment with T was not a predictor of death (HR, 1.21; 95% CI, 0.81-1.82; P=.35) or cardiovascular death (HR, 1.18; 95% CI, 0.72-1.94; P=.52). Landmark analysis from day 10 showed similar results (HR, 1.13; 95% CI, 0.71-1.84; P=.59).

Discussion

From this real-world cohort of patients with ACS and treated with percutaneous coronary revascularization, we glean the following messages: (1) the adoption of guideline-recommended therapy with respect to DAPT is incomplete, despite the presence of institutional policies and care paths; (2) the selection of DAPT regimen seems random and we could not identify predictors of choice of therapy; (3) in over 1400 patients followed for 1 year, there was no advantage for ticagrelor over clopidogrel with respect to mortality. (it is unlikely that a larger cohort would have changed these results); and (4) the rate of other ischemic or hemorrhagic events leading to hospitalization was very low and similar in the two groups.

It is notable that in PLATO (which unlike our study also included high-risk unstable angina patients), the 1-year all-cause mortality was 5.9% and 4.5% for clopidogrel and ticagrelor patients, respectively (P<.001 by Kaplan-Meier estimates). These rates are substantially lower than in our study, reflecting the nearly double incidence of diabetes and more advanced age in our study cohort. More deaths in PLATO were cardiovascular in nature (~80% vs ~60% in our study).

Sweden had been among the more ardent adopters of ticagrelor for real-world practice among PLATO countries. Sahlen et al reported in 2016 on more than 45,000 ACS patients enrolled in the Swedish Web system for Enhancement and Development of Evidence-based care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry from 2010 to 2013. There were 33,119 clopidogrel patients (61.2%) and 11,594 ticagrelor patients (38.8%), of which 78% underwent PCI. At 1 year, the incidence of all-cause death and readmission for MI or stroke was reduced by 15% with ticagrelor (HR, 0.85; 95% CI, 0.77-0.94) and the risk of death was reduced by 17% (HR, 0.83; 95% CI, 0.75-0.92), with P<.01 for both (adjusted for year of enrollment, age, gender, cardiac risk factors, and revascularization).⁴ Unlike our study, the two cohorts were very dissimilar in baseline characteristics and risk factors. Yet, this large cohort of ACS patients treated in routine clinical practice reproduced the benefit of ticagrelor seen in PLATO.

In a small cohort of STEMI patients (n = 411),  Vercellino et al⁵ showed that ticagrelor reduced 1-year mortality rate compared with clopidogrel after adjusting for propensity to receive either drug (HR, 0.29; 95% CI, 0.08-0.99; P=.048).

To our knowledge, there is no other comparison in real-world practice of these commonly utilized care paths for ACS patients with extended follow-up. Ticagrelor and clopidogrel were compared in patient subsets from the PLATO trial, showing in general that the benefit of ticagrelor is consistent across many groups and congruent with the results of the main study.^6-12

Theoretically, ticagrelor offers many advantages. As compared with clopidogrel, it is a directly acting drug bypassing the need for metabolic transformation,¹³ has higher and more consistent levels of platelet P2Y₁₂ inhibition,¹⁴ and may benefit from pleiotropic effects related to increased levels of circulating adenosine in the blood stream.^15,16 Importantly, ticagrelor seems to be safe and more efficacious than clopidogrel in elderly patients.¹⁷ Yet, these putative benefits may not be critical enough to lead to reduction in death rate, as observed in our series.

Study limitations. We recognize important limitations to our observations and conclusions. Foremost is the relatively small number of patients enrolled at a single center, when compared with randomized clinical trials. While the selection of the appropriate patients is robust and verifiable, the treatment received by patients between hospital discharge and 1 year and its duration is difficult to monitor. It is possible that a substantial number of patients switched from ticagrelor to clopidogrel because of side effects, cost, or preference.^18,19 Such a switch would tend to eliminate possible differences between clopidogrel and ticagrelor. Furthermore, a little more than 10% of identified patients had to be excluded because of lack of reliable follow-up. It is unlikely, though, based on sensitivity analysis, that these patients would have dramatically altered the results of the study. Finally, as is typical of clinical registries, the rate of events such as MI or bleeding is lower than reported in randomized clinical trials with stringent definitions and monitoring. It is possible that more events occurred, but patients were treated at other institutions and we could not review those records. Moreover, we did not have reliable data on stent thrombosis (predominantly captured by recurrent MI).

Conclusion

Despite these limitations, and considering the limited data comparing clopidogrel and ticagrelor in real-world practice, we conclude that in a cohort of ACS patients treated with contemporary medical therapy and prompt revascularization, clopidogrel and ticagrelor have similar rates of 1-year all-cause mortality, which is predominantly affected by age, end-stage renal disease, and pre-existing heart failure.

References

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From the New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Brener reports speakers’ bureau income from AstraZeneca. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted April 9, 2019, provisional acceptance given April 15, 2019, final version accepted April 23, 2019.

Address for correspondence: Sorin J. Brener, MD, New York-Presbyterian Brooklyn Methodist Hospital, 506 6th Street, Brooklyn, NY 11215. Email: sjb9005@nyp.org