Antithrombotic Therapy in Elderly Patients with ACS: Comparison
Please note this is a comparison between Version 1 by Clara Bonanad and Version 2 by Jason Zhu.
Cardiovascular disease constitutes one of the leading causes of death worldwide. The incidence of acute coronary syndromes (ACS) is especially high in the elderly, who constitute up to one-third of patients. Age also associates with an increased risk of recurrent ischemic events and death. Antithrombotic therapy represents the main component of treatment in the setting of ACS. The focus is on antiplatelet therapy, but balancing the benefit in terms of reducing ischemic events with the bleeding risk is still complicated. In combination with aspirin, oral P2Y12 receptor inhibitors (clopidogrel, prasugrel, and ticagrelor) have been widely implemented as a first-line treatment strategy in patients with ACS and those undergoing percutaneous coronary intervention (PCI). However, the management of ACS in the elderly has turned out to be challenging, since compared with clopidogrel, prasugrel and ticagrelor involve an increased risk of bleeding, potentially offsetting their ischemic clinical benefit among more vulnerable patients.
  • acute coronary syndrome
  • elderly
  • antiplatelet therapy

1. Duration of Dual Antiplatelet Therapy in Elderly Patients

After a percutaneous coronary intervention (PCI) with drug-eluting stents, there are competing risks of bleeding and thrombotic events in patients requiring antithrombotic therapies. In these situations, it is required to perform DAPT with aspirin and a P2Y12 receptor inhibitor to prevent thrombotic events [1][34].
Many risk prediction tools have been recently developed to inform optimal decision making on DAPT duration after PCI [2][35]. The ESC guidelines endorse the use of risk scores to estimate the risk and benefits of different DAPT durations. Regarding the duration of DAPT, they recommend DAPT with a P2Y12 receptor inhibitor on top of aspirin for 12 months unless contraindicated (class of recommendation I, level of evidence A), although the possibility of shortening or lengthening the duration of DAPT is also contemplated according to the individual risk profile of each patient [3][4][7,9].
A meta-analysis including six randomized trials evaluated the optimal duration of DAPT (short duration of ≤6 months vs. long duration of 12 months) after drug-eluting stent implantation in elderly patients (defined, in this case, as ≥65 years). The study revealed the possible benefit of short-term DAPT in the elderly compared with people <65 years after implantation of new-generation DES due to a greater reduction in the risk of major bleeding [5][36].
Consistently with these results, the DAPT and PEGASUS-TIMI 54 studies showed that prolonged treatment with DAPT increased the risk of bleeding across all age subgroups [6][7][13,37]. Similarly, a population-based study [8][38] using the RENAMI registry, which included 12 European centers, compared long vs. short dual antiplatelet therapy in ACS patients treated with prasugrel or ticagrelor after coronary revascularization. Although only 185 (9.8%) out of the 1884 patients matched in the propensity score analysis were older than 75 years, the observed favorable effects of prolonged DAPT beyond 12 months on the reduction of MACE appeared to be diminished in older patients because of excess bleeds.
Other antithrombotic strategies have been developed with the intention to reduce the risk of hemorrhagic events, such as DAPT de-escalation or monotherapy with P2Y12 inhibitors [9][10][39,40]. However, a description of these strategies goes beyond the scope of this manuscript, and specific data on elderly patients regarding these regimens are still very scarce.
The clinical trials suggest that short-term DAPT treatment might be appropriate to avoid the increased risk of bleeding in elderly patients, especially those prone to hemorrhagic events. However, new evidence-based recommendations on the appropriate use and duration of DAPT in this cohort of patients are required, and further clinical trials are needed to support these recommendations. In fact, individualizing the duration of dual antithrombotic therapy in elderly patients remains reasonable.

2. Anticoagulation Therapy in Elderly Patients with Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia, and its incidence increases with age. Elderly patients are those with the highest risk of embolism events [11][41]. The comprehensive approach to AF patients currently focuses on two main anticoagulant treatment options, vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs). Even though the benefits of VKA have been demonstrated through extensive clinical experience, VKAs have several disadvantages, such as a narrow therapeutic window and variability of the coagulant effect, and regular controls of the International Index Normalized may limit its use in clinical practice. Thus, DOACs are the group of agents of choice in the elderly in the absence of contraindications [12][13][42,43]. Therapy with DOACs presents some advantages, such as the wide therapeutic window; it is not necessary to monitor anticoagulant activity, and they can be prescribed at fixed doses according to specific clinical characteristics [14][44]. Some clinical studies on anticoagulation in the AF population included a significant number of older patients. The RE-LY study included 7258 patients (40.1%) aged ≥75 years [15][45], the ROCKET AF study included 6229 patients (44%) aged ≥75 years with atrial fibrillation [16][46], and the ARISTOTLE trial included 31% of patients aged ≥75 years. The rates of stroke, all-cause death, and major bleeding were higher in the older age groups (p < 0.001 for all) [17][47]. Because of the higher risk at older age, these studies confirmed that DOACs showed superior or similar efficacy and safety with a lower rate of bleeding, especially intracranial, compared with VKA consistently across all age groups. Despite these efficacy data and the availability of more alternatives in the choice of drugs, anticoagulant treatment continues to be underused in patients with AF, especially in very elderly patients and in patients with disabilities, cognitive impairment, or high comorbidity. Moreover, there were relevant differences in the clinical profiles of patients aged 75 years or older included in these studies. These studies present some specifications, such as the narrow follow-up, that may not always be applicable to real-life situations, highlighting the need to conduct real-life studies. An updated meta-analysis, including 27 studies, clinical trials, and cohort studies, concluded that apixaban (HR, 0.66; 95%CI, 0.55–0.80) and dabigatran (HR, 0.83; 95%CI, 0.70–0.97) significantly reduced the major bleeding risk vs. warfarin. Furthermore, apixaban (HR, 0.56; 95%CI, 0.42–0.73), dabigatran (HR, 0.45; 95%CI, 0.39–0.51), and rivaroxaban (HR, 0.66; 95%CI, 0.49–0.88) significantly reduced the risk of intracranial bleeding vs. warfarin. The finding suggested that reduced doses of direct oral anticoagulants were associated with a slightly better safety profile but with a marked reduction in stroke prevention effectiveness [18][48]. In recent years, several studies have been published analyzing the use of DOACs in routine clinical practice [19][20][21][22][23][24][49,50,51,52,53,54]. In general, in elderly patients with nonvalvular AF, DOACs were effective and safe and showed superiority over VKA in elderly patients in terms of stroke or bleeding risk prevention. Nevertheless, some studies found that there was a tendency to use inadequate doses in elderly patients, generally due to underdosing, leading to inadequate protection against thromboembolic events and even increased mortality compared with correct anticoagulation. Thus, it is estimated that in the elderly population, approximately 30–40% of patients received inadequate doses of DOACs [25][26][27][28][29][30][55,56,57,58,59,60]. On the other hand, antiplatelet therapy presents low efficacy for preventing stroke, and therefore, its use for this indication is not justified. The evidence about the effectiveness of antiplatelet agents for stroke prevention in AF is minimal, and its use is not recommended [31][61].

3. Patients with AF and Coronary Artery Disease

Current guidelines for AF recommend that most patients with AF and patients with chronic CAD without events in 1 year should receive monotherapy with DOACs, which are considered a safe and effective standard therapy for long-term management [3][32][7,62]. As per the EHRA guidelines, they should be considered only as an additional antiplatelet agent in individual patients at very high ischemic risk and a low bleeding risk [32][62]. Until recently, there were only indirect data from the pivotal phase 3 trials using DOACs and some observational data on whether it might be safe to transition to DOAC monotherapy in patients with CAD. In elderly patients, concomitant use of DOACs with strong platelet inhibitors (prasugrel, ticagrelor), dual platelet inhibition, or nonsteroidal anti-inflammatory drugs (NSAIDs) should be restricted to the minimal duration considered crucial in order to prevent ischemic events. Concomitant antiplatelet drugs appeared to increase the risk for significant bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Patients with high coronary risk, such as elderly patients, may be at risk for perioperative cardiovascular events during DOAC interruption due to the absence of antithrombotic therapy [32][62]. A meta-analysis that included six trials (a total of 8855 patients with nonvalvular AF and stable CAD but generally including patients at low ischemic risk) compared DOAC monotherapy vs. DOAC plus single antiplatelet therapy. It showed that DOAC monotherapy provided more efficacy than DOAC plus single antiplatelet therapy with lower bleeding risk. There was no significant difference in MACE in AF patients treated using DOAC plus single antiplatelet therapy compared with those treated with DOAC monotherapy (HR 1.09; 95% CI, 0.92–1.29). On the other hand, DOAC plus antiplatelet therapy was associated with a significantly higher risk of major bleeding compared with DOAC monotherapy (HR 1.61; 95% CI, 1.38–1.87), as well as higher risk of net adverse events (NAE) (HR, 1.21; 95% CI, 1.02–1.43). Although these results were the main data we found in this scenario, researcherswe must take into account the methodological limitations of the AFIRE study and the premature stopping of the trial due to an increase in mortality in the combination therapy arm in the interpretation of the results [33][34][63,64]. These results support that DOAC alone may confer the same benefits with fewer risks in patients without a high risk of ischemic events, suggesting that there is a large subgroup of patients with stable CAD for whom antiplatelet therapy should not be prescribed as a preventive medication. However, an individualized approach is still mandatory when deciding the optimal combination and duration of antithrombotic agents.

4. Dual Antiplatelet Therapy (DAPT) Strategy in Elderly ACS Patients Undergoing Coronary Artery Bypass Grafting (CABG)

Coronary artery bypass graft surgery (CABG) is an effective treatment for patients with ischemic heart disease but presents a high risk of occlusion after bypass surgery. By ten years after surgery, the majority of vein grafts—main used tube—either occlude or develop a heavy burden of atherosclerosis, leading the patients who have undergone CABG to a subsequent high risk of an ischemic event, including myocardial infarction (MI), stroke, or death [35][36][65,66]. However, in the elderly, CABG seems to be more beneficial than PCI in terms of survival [37][67] and development of an MI or stroke or subsequent revascularization [38][68]. Even if guidelines recommend DAPT after CABG for patients with ACS, the evidence for these recommendations is limited [4][39][40][9,69,70], a fortiori in elderly patients, in whom DAPT use is suboptimal for patients undergoing CABG [41][71]. There are several gaps in the current evidence about DAPT in elderly ACS patients undergoing CABG, particularly whether DAPT should be started after CABG, when the postoperative DAPT should restart, and the optimal point of DAPT discontinuation [4][9]. Indeed, the main concern of this therapy in a CABG context is about the perioperative bleeding risk, given that continuing DAPT until CABG highly increases this risk [4][9]. The American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) recommend specific interruption and resumption of DATP on a patient undergoing CABG [4][42][9,72]. The Society of Thoracic Surgeons (STS) recommends that precisely restarting the DAPT drug as soon as the bleeding risk is diminished may have a secondary benefit of increasing early vein graft patency [43][73]. The STS also suggests that it could be more relevant for patients already on DAPT to make decisions about surgical timing based on platelet inhibitions tests rather than applying a prespecified period of surgical delay [44][74]. Nevertheless, these recommendations should be individualized for the elderly population, a particular category of patients with higher bleeding risk [45][22].
Video Production Service