Dual Antiplatelet Therapy in Patients Aged 75 Years and Older with Coronary Artery Disease: A Meta-Analysis and Systematic Review

Objectives This systematic review and meta-analysis evaluates the safety and efficacy of dual antiplatelet therapy (DAPT) in elderly patients with acute coronary syndrome (ACS). Background The safety and efficacy of DAPT in elderly patients with ACS is not well characterized. Methods We performed a systematic literature review to identify clinical studies that reported safety and efficacy outcomes after DAPT for ACS in elderly patients. The primary outcomes of primary efficacy endpoint rates and bleeding event rates were reported as random effects risk ratio (RR) with 95% confidence interval. No prior ethical approval was required since all data are public. Results Our search yielded 660 potential studies. We included 8 studies reporting on 29,217 patients. There was a higher risk of bleeding event rates in elderly patients treated with prasugrel or ticagrelor when compared to clopidogrel with a risk ratio of 1.17 (95% CI 1.08 to 1.27, p < 0.05). There was no difference in primary efficacy endpoint rates between elderly patients treated with prasugrel or ticagrelor when compared to clopidogrel with a risk ratio of 0.85 (95% CI 0.68 to 1.07, p=0.17). Conclusions This systematic review and meta-analysis suggests that DAPT with prasugrel or ticagrelor compared to clopidogrel is associated with a higher risk of bleeding events in elderly patients with ACS. There was no difference in the primary efficacy endpoints between the two treatment groups.


Introduction
Dual oral antiplatelet therapy (DAPT) with aspirin and P2Y12 receptor inhibitors has had a key role in the management of patients with acute coronary syndrome (ACS) and remains the treatment of choice to prevent in-stent thrombosis [1]. In patients with ACS undergoing percutaneous coronary intervention (PCI), a loading dose of DAPT (either aspirin + clopidogrel or aspirin + ticagrelor) is recommended as early as possible by the latest ESC guidelines [2]. Although current guidelines recommend the new and more predictable P2Y12 receptor inhibitors ticagrelor and prasugrel in ACS patients given their superiority to clopidogrel in preventing major adverse cardiovascular events (MACE), they have been associated with higher risk of bleeding especially in elderly patients [3].
Elderly patients contribute to a large proportion of patients with ACS and have often been underrepresented in the randomized trials that provided evidence for guidelines [4]. For example, in the TRITON TIMI 38 (Trial to Assess Improvement in erapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-rombolysis in Myocardial Infarction 38) and PLATO (Platelet Inhibition and Patient Outcomes) trials, elderly patients (age >75 years) accounted for only 13% and 15% of the study populations, respectively [5,6]. Elderly patients are more susceptible to the adverse effects of DAPT with bleeding being one of the most common complications associated with prolonged hospitalization and increased mortality. However, investigations about the safety and efficacy of DAPT in this group are scarce [7].
In this meta-analysis and systematic review, we evaluate the impact of DAPT on clinical and bleeding outcomes in elderly patients with ACS.

Methods
e main objective of this review was to assess the safety and efficacy of ticagrelor or prasugrel compared to clopidogrel in elderly patients with ACS. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement extension for network meta-analysis. e PRISMA flow diagram was used to depict the four phases of the review including identification, screening, eligibility, and inclusion. e PRISMA statement contains a checklist of items required of systematic reviews and meta-analyses. e review was not registered a priori. No ethical approval was required since this meta-analysis uses only public published data.

Search Strategy.
We performed a systematic literature review to identify randomized and non-randomized clinical studies that reported the use of DAPT in elderly patients with ACS. Searches were limited to peer-reviewed primary research articles published in English up to December 1 st , 2021. is research involved human subjects and described the clinical impact of DAPT in elderly patients with ACS. We developed the search strategy according to available guidance from the Cochrane Collaboration. e search strategy in PubMed explored Medical Subject Heading (MeSH) terms related to elderly patients with ACS treated with DAPT. e articles found to be relevant during the search were stored in EndNote. Selected articles underwent full evaluation to assess their potential inclusion in the systematic review.

Study Selection.
Articles were selected for inclusion based on predefined criteria, which included age, sex, DAPT, bleeding, MACE events, and the primary or secondary outcomes being mortality, bleeding, and efficacy outcomes. Exclusion criteria were patients with elective PCI without ACS. We excluded case reports and studies with fewer than 10 subjects.
Two authors (GS and SL) independently read the trials and screened the abstracts to choose potentially relevant articles. Selected articles underwent full evaluation to assess their potential inclusion in the systematic review.

Definition of Elderly Patients.
Each study defined elderly patients based on an arbitrary age. An age greater than 75 years old was defined as elderly in 5 of the included studies.
Ages greater than 65, 70, and 80 were each used as cutoffs by 3 of the included studies.

Definition of Outcomes.
Primary efficacy outcomes were defined separately by each included study. Most studies used a composite of death, myocardial infarction, or stroke during the follow-up period.
Bleeding events were defined separately by each included study. Most studies used TIMI major or minor bleeding or PLATO major or minor bleeding, as previously defined [8,9].

Risk of Bias.
e risk of bias was assessed using the Cochrane tool for assessing the risk of bias in randomized controlled trials (RCTs) [10]. e risk of bias was assessed by two independent reviewers (GS and SL).

Statistical
Analysis. Data were analyzed using Review Manager Software 5.4. We used fixed effects to assess the combined risk estimates according to I2 statistics. Analysis to determine sensitivity and publication bias was detected by funnel plots. p < 0.05 was considered statistically significant.

Literature Search.
Our search yielded 660 potential studies. We excluded 626 studies at the abstract level and selected 34 full-text articles for detailed assessment; 8 studies were ultimately included in our systematic review and metaanalysis. Figure 1 describes the flowchart of included studies. Table 1 shows the baseline characteristics of the included studies. All studies were published between 2007 and 2020. e 8 studies reported on 29,217 patients. Several of the included studies did not provide demographic data stratified by age, so the comparison of baseline characteristics in our target population of elderly patients is limited.

Risk of Bias.
e risk of bias revealed adequate randomization, allocation concealment, and blinding in the 6 RCTs included in this study. e 2 non-RCTs included in this study were registry analyses that had appropriate selection and ascertainment approaches, while confounding adjustments were limited due to the observational design. Overall, the risk of bias for clinical outcomes was low in the RCTs and high in the non-RCTs.

Primary Efficacy Outcomes and Bleeding Events in Elderly
Patients with CAD. Meta-analysis of the included studies revealed a higher risk of bleeding event rates in elderly patients treated with prasugrel or ticagrelor when compared to clopidogrel with a risk ratio of 1.17 (95% CI 1.08 to 1.27, p < 0.05). e forest plot for this comparison is shown in Figure 2. ere was no difference in primary efficacy endpoint rates between elderly patients treated with prasugrel or ticagrelor when compared to clopidogrel with a risk ratio of 0.85 (95% CI 0.68 to 1.07, p � 0.17). e forest plot for this comparison is shown in Figure 3. Meta-analysis with the non-RCT excluded revealed similar results as shown in Figures 4 and 5. e statistical heterogeneity for bleeding events was low with an I 2 value of 0%. e statistical heterogeneity for primary efficacy endpoints was high with an I 2 value of 94%.

Discussion
is systematic review and meta-analysis suggests that DAPT with prasugrel or ticagrelor compared to clopidogrel is associated with a higher risk of bleeding events in elderly patients with ACS. Our findings are derived from 8 studies reporting clinical outcomes in 29,217 patients [5,9,[11][12][13][14][15][16].
ere was no difference in the primary efficacy endpoints in DAPT with prasugrel or ticagrelor compared to clopidogrel in this patient population. ese findings provide a better understanding of the overall safety of DAPT in elderly patients assessed in various clinical trials. e CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial demonstrated that clopidogrel was more effective than placebo in patients with ACS at the cost of increased risk of major bleeding regardless of age [17]. e benefit of prasugrel therapy compared to the risk of bleeding in elderly patients with ACS was shown to have a neutral net clinical benefit in the TRITON-TIMI 38 (Trial to Assess Improvement in erapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-rombolysis in Myocardial Infarction 38) trial [5]. Low-dose prasugrel and clopidogrel were shown to have similar efficacy and bleeding outcomes in elderly patients in the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) study [11]. In the ELDERLY ACS II (Elderly Acute Coronary Syndrome 2) trial, low-dose prasugrel and clopidogrel showed similar primary endpoints in elderly patients with ACS [13]. In a substudy of elderly patients in the PLATO (Platelet Inhibition and Patient Outcomes) trial, there was no significant difference in major bleeding events between patients treated with ticagrelor versus clopidogrel [6]. In a more recent analysis, clopidogrel was shown to have decreased bleeding events with similar efficacy rates when compared to ticagrelor in elderly patients with ACS in the POPular AGE (Ticagrelor or Prasugrel Versus Clopidogrel     [16]. Ticagrelor was shown to decrease major ischemic events without increasing bleeding events in elderly patient with STEMI in the Bremen STEMI registry [14]. However, in the SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended erapies) trial, ticagrelor was associated with a higher risk of bleeding and death when compared to clopidogrel in elderly patients with MI [15].
Additional studies have evaluated DAPT in elderly patients for extended periods of time over 1 year after the index event. DAPTextended for 30 months versus aspirin only was associated with decreased ischemic events and stent thrombosis at the expense of increased bleeding events in the DAPT (Dual Antiplatelet erapy) trial. However, the benefit of prolonged DAPT was decreased and the bleeding event rates increased when stratified by age [18]. In the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-rombolysis In Myocardial Infarction 54) trial, ticagrelor and aspirin were shown to have a benefit on the 3-year primary ischemic outcome at the expense of a 150% increase in bleeding events in elderly patients 1 to 3 years after a prior MI [19]. e use of ticagrelor and aspirin in patients with diabetes mellitus and stable CAD was shown to have a modest benefit on the primary ischemic outcome at the expense of increased bleeding rates in the THEMIS ( e Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) trial. is benefit was not significant when stratified by elderly patients over 75 years of age [20]. An analysis of the RENAMI (REgistry of New Antiplatelets in patients with Myocardial Infarction) registry showed reduced fatal and non-fatal ischemic events by extending DAPT with prasugrel or ticagrelor beyond 12 months. However, this benefit was reduced in patients older than 75 years due to an increased risk of bleeding [21].
is systematic review and meta-analysis provides important insights on DAPT for elderly patients with ACS that may inform decisions in clinical practice. Elderly patients with ACS have an increased risk for bleeding events that can offset the ischemic benefit of DAPT. A risk assessment should be completed before initiating DAPT and new guideline recommendations indicate that bleeding risk should be the priority for informing decision making [22]. Individual risk assessments that account for quantitative and qualitative metrics are required since the causes of bleeding are variable and multifactorial within the elderly population [23]. e PRECISE-DAPT and PARIS risk scores have shown modest accuracy in predicting bleeding risk in elderly patients [24]. As drug-eluting stents continue to improve, the use of a shorter duration of DAPT offers a potential bleeding risk mitigation strategy for elderly patients [25,26] Heterogeneity: Tau 2 = 0.00; Chi 2 = 5.31, df = 6 (P = 0.51); I 2 = 0% Test for overall effect: Z = 3.70 (P = 0.0002) Figure 2: Forest plot of bleeding event rates for prasugrel or ticagrelor versus clopidogrel in elderly patients with acute coronary syndrome (CI � confidence interval).  strategy to reduce bleeding events in elderly patients with CAD currently being investigated [27,28]. Genotype-guided P2Y 12 inhibitor selection is another area of research that may provide clinical benefits to elderly patients [29]. e limitations of this systematic review and metaanalysis are influenced by the limitations of the included studies. All of the included studies are likely influenced by between-center variability and the lack of centralized independent assessment of procedural results and outcomes. Antiplatelet therapy regimens and follow-up time also differ in each study and limit the generalizability of the aggregate data. e statistical heterogeneity of the meta-analysis varied by outcome likely due to clinical and methodological diversity between studies.

Conclusion
is systematic review and meta-analysis suggests that DAPT with prasugrel or ticagrelor compared to clopidogrel is associated with a higher risk of bleeding events in elderly patients with acute coronary syndrome. ere was no difference in the primary efficacy endpoints between the two treatment groups.
Data Availability e data used are included within the article.