Patient and Physician Perspectives on the Benefits and Risks of Antiplatelet Therapy for Acute Coronary Syndrome

Antiplatelet therapies are prescribed for patients with ACS who have experienced an MI, to prevent blood clots from forming, particularly after percutaneous coronary intervention (PCI) [1]. Although these treatments can significantly lower the risk of recurrent ischemic events, they are associated with some potentially serious adverse effects, such as bleeding, which must be balanced against their benefits in order to manage patients appropriately [2, 3].

DAPT is the cornerstone of treatment for patients with ACS for the secondary prevention of cardiovascular events [1, 3‐5]. There are several classes of antiplatelet therapy, including platelet aggregation inhibitors such as the cyclooxygenase-1 inhibitor ASA, and oral P2Y12 inhibitors such as clopidogrel, prasugrel, and ticagrelor [4, 5]. Direct oral anticoagulants may also be prescribed during both the acute phase and for long-term management of ACS [3].

Different durations and combinations of antiplatelet therapies have been evaluated in a number of clinical trials for the management of patients with ACS (Tables 1 and 2). The pivotal PLATO trial compared the P2Y12 inhibitors clopidogrel and ticagrelor, each in combination with ASA, in patients who had been hospitalized for ACS, with or without ST-segment elevation [6]. PLATO demonstrated that, compared with DAPT consisting of clopidogrel and ASA, 12 months of DAPT consisting of ticagrelor and ASA significantly reduced the rate of death from vascular causes, MI, or stroke without an increase in the rate of major life-threatening bleeding, but with an increase in the rate of non-procedure-related bleeding (i.e., spontaneous bleeding, including gastrointestinal and intracranial bleeding) [6]. Since PLATO, several trials have evaluated DAPT followed by P2Y12 inhibitor monotherapy compared with continuing DAPT in patients who had been fitted with current-generation thin-strut stents [7‐11]. TWILIGHT evaluated the impact of ticagrelor alone compared with DAPT consisting of ticagrelor and ASA on the endpoint of clinically relevant bleeding in patients who were considered high risk for bleeding or ischemic events and had undergone PCI. Patients who received ticagrelor monotherapy had a lower incidence of clinically relevant bleeding than patients who received DAPT, with no increased risk of death, MI, or stroke [7]. GLOBAL LEADERS evaluated 2 years of treatment with ticagrelor monotherapy (in combination with ASA for the first month) compared with 1 year of DAPT consisting of ASA with clopidogrel or ticagrelor, followed by 1 year of ASA alone. Results demonstrated that neither treatment arm was superior in terms of the composite endpoint of all-cause mortality or new Q-wave MI after PCI, and rates of grade 3 or 5 bleeding were similar between the arms [8]. The TICO study demonstrated that, following 3 months of DAPT (consisting of ticagrelor and ASA), ticagrelor monotherapy resulted in a small yet significant reduction in the composite outcome of major bleeding and adverse cardiac and cerebrovascular events after 1 year in patients with ACS who had undergone PCI, compared with DAPT for 1 year [9].

Meta-analyses have confirmed that ticagrelor monotherapy results in a superior net clinical benefit compared with DAPT (consisting of ticagrelor and ASA) through a significant reduction in major bleeding without an increase in ischemic risk [12]. One meta-analysis evaluated the benefits and risks of 1–3 months of DAPT followed by ticagrelor monotherapy compared with 12 months of DAPT in patients who had undergone complex PCI. The analysis found a weak association between shorter duration of DAPT and reduced risk of bleeding events and no significant difference in terms of all-cause mortality, MI, stent thrombosis, target vessel revascularization, or stroke [13]. The T-PASS trial found ticagrelor monotherapy was superior to DAPT for the 1-year composite outcome of death, major bleeding, MI, stent thrombosis, and stroke, in patients with ACS who had undergone PCI [14].

PEGASUS-TIMI 54 evaluated two different doses of ticagrelor compared with placebo, in addition to ASA, in more than 21,000 patients who had experienced an MI 1–3 years before enrollment. Ticagrelor plus ASA was superior to placebo plus ASA for reducing the incidence of cardiovascular death, MI, or stroke, although rates of major bleeding, using definitions based on the Thrombolysis in Myocardial Infarction (TIMI) criteria, were higher for those treated with ticagrelor than for those receiving placebo [15].

The other potent P2Y12 inhibitor, prasugrel, has also been extensively evaluated in clinical trials. TRITON-TIMI 38 evaluated prasugrel compared with clopidogrel, both in combination with ASA, in patients with moderate-to-high-risk ACS who were scheduled to undergo PCI. Prasugrel plus ASA was associated with reduced rates of ischemic events but an increased risk of major bleeding, including fatal bleeding compared with clopidogrel plus ASA [16].

The CURE trial evaluated clopidogrel compared with placebo, each in combination with ASA, in patients with ACS without ST-segment elevation. A significantly lower proportion of patients treated with clopidogrel plus ASA experienced severe ischemic events or recurrent angina than those receiving placebo; however, there was a significantly greater proportion of major bleeding events in the clopidogrel group than in the placebo group [17]. In STOPDAPT-2, 1–2 months of DAPT (consisting of clopidogrel or prasugrel and ASA) followed by clopidogrel monotherapy failed to demonstrate non-inferiority for net clinical benefit compared with 12 months of DAPT in patients with ACS who had undergone PCI [18]. In STOPDAPT-3, patients with ACS or high bleeding risk were randomized to receive either prasugrel or DAPT with prasugrel plus ASA before undergoing PCI. Compared with DAPT, prasugrel monotherapy did not demonstrate superiority in reducing major bleeding events within 1 month of treatment, but was non-inferior for cardiovascular events (cardiovascular death, definite stent thrombosis, ischemic stroke, or MI) after the same period. A signal was detected, however, suggesting that the ASA-free approach was associated with excess coronary events compared with DAPT [19].

The ideal DAPT duration remains under consideration, with 2022 guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA), and the Society for Cardiovascular Angiography and Interventions (SCAI) recommending at least 12 months of DAPT for patients with ACS [1]. The guidelines advise that, after considering the risk of ischemia and bleeding, certain patients undergoing PCI may transition to P2Y12 inhibitor monotherapy after 1–3 months of DAPT [1, 7, 9‐11]; however, these and the 2016 guidelines note that physicians should balance the risk of bleeding and recurrent ischemia when prescribing DAPT medications [1, 20]. Furthermore, ACC/AHA/SCAI guidelines recommend that treatment decisions are patient-centered, with patient preferences and goals taken into account, and that the patient is made aware of the benefits and risks of treatments [1].

An expert editorial summarizing the recent evidence regarding DAPT duration stated that “most patients benefit from withdrawal of ASA between 2 weeks and 3 months after PCI, followed by P2Y12 inhibitor monotherapy” with the important caveat that “caution is warranted in discontinuing ASA before 3 months after PCI when there are concerns about suboptimal stent deployment or if clopidogrel is used as the platelet P2Y12 inhibitor” [21].

In addition to treatment guidelines, evidence from clinical trials supports treatment with a potent P2Y12 inhibitor (prasugrel or ticagrelor) over clopidogrel for patients who have undergone PCI [3, 20]. Indeed, treatment rates with prasugrel or ticagrelor appear to be increasing [22]; however, there still seems to be some inertia among physicians in prescribing the potent P2Y12 inhibitors, because a large proportion of patients with coronary artery disease (CAD) in the USA are still treated with clopidogrel [23, 24]. In addition, there appears to be an ongoing issue with treatment adherence among patients [22].

Nonadherence to P2Y12 inhibitors is associated with an increased risk of ischemic events [25]. Adherence to DAPT has been reported to decrease over time after patients have undergone PCI [26]. Factors associated with nonadherence were bleeding, lower education levels, immigrant status, and a lack of education regarding DAPT [26]. The PARIS study reported that approximately 10% of patients undergoing PCI with stent implantation stopped DAPT owing to bleeding or noncompliance after 1 year, which rose to about 14% of patients after 2 years, and that cardiovascular risk significantly increased after this [27]. Bleeding was classified using the TIMI, Acute Catheterization and Urgent Intervention Triage strategY (ACUITY), and Bleeding Academic Research Consortium (BARC) criteria [28, 29]. Among other variables, ACS was found to significantly increase the likelihood that patients who were receiving PCI would stop DAPT owing to bleeding or noncompliance [27].

Perspectives on the reasons for nonadherence may differ between patients and physicians [26], with patients describing barriers related to miscommunication surrounding their treatment and a lack of continuity between inpatient and outpatient care [30, 31], and physicians mentioning cost as the key reason for discontinuing antiplatelet therapy [31]. A study evaluating P2Y12 inhibitor adherence using the Non-adherence Academic Research Consortium (NARC) classification reported nonadherence in 17% of approximately 4000 patients treated with DAPT who were evaluated in the first year after PCI, with the main driver for nonadherence being physician decision relating to changes in risk profile [25].

Dr. Marc Cohen, the Chair of the Department of Medicine at Newark Beth Israel Medical Center and a Professor of Medicine at the Rutgers New Jersey Medical School, shares his experience of managing patients with ACS.

The evidence supporting the net clinical benefit of DAPT and the relative efficacy of the potent P2Y12 inhibitors is unequivocal. The results of the pivotal PLATO trial and the PEGASUS-TIMI 54 trial, which evaluated the efficacy and safety of ticagrelor, were published in 2009 and 2015, respectively [6, 15]; however, the findings of these studies, as well as other large clinical trials, have not fully translated into clinical practice. There appears to be considerable treatment inertia among cardiologists who continue to prescribe the less potent P2Y12 inhibitor clopidogrel over prasugrel or ticagrelor, and there is a lack of acceptance of this evidence-based science from some patients.

From a clinical perspective, I follow the PLATO strategy: ticagrelor at a loading dose of 180 mg followed by 90 mg twice daily [6] during the first year after ACS diagnosis in both high-risk and non-high-risk patients with bifurcations or left main artery stents, unless there is a reason for early discontinuation. If this is effective and well tolerated for 12 months, I consider strategies following the PEGASUS-TIMI 54 (ticagrelor) [15] or COMPASS (rivaroxaban) [32] trials. In brief, the PEGASUS-TIMI 54 regimen consists of ticagrelor 90 mg or 60 mg twice daily in combination with low-dose ASA [15], whereas the COMPASS strategy consists of treatment with the factor Xa inhibitor rivaroxaban 2.5 mg twice daily plus ASA 100 mg once daily [32]. From my clinical perspective, the choice to continue ticagrelor or to switch to rivaroxaban is based on individual patient characteristics.

Similarly, I value the results of post hoc analyses of key clinical trials when considering the level of risk of patients. Post hoc analyses of PEGASUS-TIMI 54 categorized patients with low bleeding risk by ischemic risk factors, including type 2 diabetes mellitus, non-end-stage chronic kidney disease, multivessel coronary disease, and multiple prior MIs; patients were grouped by having 0–1, 2, or at least 3 ischemic risk factors [33]. Subgroup analyses of the COMPASS trial stratified patients into risk categories based on the REACH (REduction of Atherothrombosis for Continued Health) risk score, centered around vascular disease or high risk of ischemic vascular events, and CART (Classification and Regression Tree) analysis, used to identify high-risk patients treated with ASA [34].

Although assessing the risk of bleeding (using validated bleeding risk score tools [35]) and further ischemic events is important, bleeding risk rarely prevents me from initiating DAPT. In my experience, major bleeding events are extremely rare and the benefits of DAPT clearly outweigh the potential risks. From my point of view, the value of bleeding risk scores becomes most relevant when considering approaches to de-escalation or shortening the duration of DAPT. Patients who have comorbidities resulting in anemia and those with severe liver disease would be more likely to be considered for de-escalation after 3 months than patients without these characteristics.

Irrespective of the evidence base, the effectiveness of any treatment regimen is equivalent only to the level of medication persistence and adherence of patients receiving that medication. As part of the shared decision-making process between patients and their care teams, it is of great importance to emphasize the value of secondary prevention and to contextualize the risks versus the benefits using accessible metrics such as number needed to harm or to treat. Indeed, analysis of the PLATO trial demonstrated that there was no significant effect of ticagrelor on the number needed to harm compared with clopidogrel [2]. Furthermore, for both prasugrel and ticagrelor, the benefits are considered to outweigh the risks regarding number needed to treat versus number needed to harm [36]. From my perspective, the reason for prescribing ticagrelor as a first-line antiplatelet therapy over the less potent P2Y12 inhibitor clopidogrel is clear: ticagrelor treatment more effectively reduces the risk of future events, is associated with fewer serious adverse events, and the risk profile is very minimally elevated.

In my view, adherence to treatment after having PCI is challenging for patients owing to several factors, some of which have become more relevant in recent years, including cognitive load relating to the amount of information that patients may be given and required to understand, minor adverse events, cost, pill burden and dosing schedule, a lack of tangible benefits to patients, and misleading information from various sources such as social media and the Internet.

Although not serious, the minor adverse events from antiplatelet therapy, such as transient dyspnea and unsightly bruising (i.e., minor bleeding), can be distressing for patients; however, in the context of preventing a potentially fatal MI, these side effects should not be causes for stopping antiplatelet therapy. For patients, however, the side effects are tangible and immediate, whereas the benefits can be harder to appreciate, especially if the patient feels well. These factors increase the importance of patient education and clear communication in terms of improving patients’ understanding and resultant adherence to medication. In particular, I believe it is important to discuss the risk of dyspnea, because this transient side effect may cause alarm and concern for patients, particularly if they are not forewarned of its possible association with ticagrelor or clopidogrel use.