Version May 2024
INTRODUCTION — In patients with obstructive coronary artery disease who undergo percutaneous coronary intervention (PCI) to improve symptoms, drug-eluting stents (DES) are used most of the time, with fewer centers using bare metal stents (BMS). (See "Coronary artery stent thrombosis: Incidence and risk factors".)
Long-term antiplatelet therapy after coronary stenting significantly lowers the risk of stent thrombosis. Options for long-term antiplatelet therapy include dual antiplatelet therapy (DAPT; aspirin plus platelet P2Y12 receptor blocker) or single antiplatelet therapy (aspirin or P2Y12 receptor blocker). There is also some evidence to support the idea that long-term antiplatelet therapy strategies may impact the risk of ischemic events remote from the stented area. Considering the individual bleeding and ischemic risks, the benefits and risks with DAPT need to be carefully weighed.
This topic will discuss the use of antiplatelet therapy to reduce the risk of adverse outcomes after PCI in patients with stable coronary artery disease. Related topics include:
●(See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'P2Y12 use'.)
●(See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Duration'.)
OUR APPROACH — The following is our approach to the initial choice of long-term antiplatelet therapy in stable patients who have undergone percutaneous coronary intervention (PCI) with stenting, irrespective of stent type. (See 'Evidence' below and 'DAPT versus P2Y12 receptor blocker monotherapy trials' below.)
The first step is to estimate the patient's bleeding and ischemic risks during the first 6 to 12 months after PCI.
●A patient is felt to be at high bleeding risk if one major or two minor criteria (risk factors) for major bleeding are present [1]. These criteria are presented in a table (table 1). (See "High bleeding risk patients undergoing percutaneous coronary intervention", section on 'Definition of high bleeding risk'.)
●A patient is felt to be at high ischemic risk if certain angiographic/procedural or clinical factors are present (table 2).
With the estimates of bleeding and ischemic risk, the patient can be assigned to one of four broad categories. Our suggestions for the type and duration of DAPT are based on these categories (table 3).
We carefully individualize the decision to continue DAPT for more or less than 6 to 12 months, taking into account predictors of bleeding and ischemic events. Each practitioner and his/her patients must weigh the decrease in the risk of ischemic events with the increase in the rate of major bleeding. (See 'Treatment for longer than 12 months' below.)
In patients treated with ticagrelor monotherapy for between 3 and 12 months, some experts consider ticagrelor monotherapy for up to two years as a reasonable approach based on the GLOBAL LEADERS trial (see 'DAPT versus P2Y12 receptor blocker monotherapy trials' below).
RATIONALE FOR DUAL ANTIPLATELET THERAPY — There may be benefit from continuing indefinite antiplatelet therapy with aspirin (or with clopidogrel as an alternative) in patients with atherosclerotic cardiovascular disease (secondary prevention). (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)
The rationale for the use of dual antiplatelet therapy (DAPT), which is the combination of aspirin and a P2Y12 receptor blocker, as opposed to antiplatelet monotherapy, is derived from the known tendency of circulating blood to clot in the presence of many metals. This period of risk decreases after the metal portion of the stent is endothelialized [2-5]. More intense DAPT lowers the risk of stent thrombosis compared with aspirin alone, especially for the early period after stenting [6-10]. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'P2Y12 receptor blockers'.)
DAPT likely decreases the risk of these ischemic events by preventing stent thrombosis, as well as by lowering the risk of adverse events consequent to plaque rupture at sites remote from the stented location. (See "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Early and late stent thrombosis' and "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Risk factors' and "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Mechanisms'.)
Evidence supporting the role of DAPT for preventing non-stent-related events is suggested by the following:
●In patients with acute coronary syndromes treated medically (no percutaneous coronary intervention [PCI]), DAPT, compared with aspirin alone, reduces the rate of MI. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".)
●In the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial, which compared ticagrelor with placebo in stable patients who were one to three years away from their MI (83 percent with previous PCI), a composite end point of cardiovascular death, MI, or stroke occurred less often with ticagrelor than with placebo at three years. However, the risk of major bleeding was increased. (See 'Evidence' below.)
●In the DAPT trial (see 'Evidence' below), which showed that overall ischemic event rates and stent thrombosis were lower with 30 rather than 12 months of DAPT after stenting, the rate of MI not related to stenting was also lower (1.8 versus 2.9 percent; hazard ratio 0.59; p<0.001). This difference accounted for 55 percent of the total reduction in MI with prolonged DAPT. However, the risk of bleeding was increased.
EARLY POSTPROCEDURAL DECISIONS — After percutaneous coronary intervention (PCI), we prefer clopidogrel to prasugrel or ticagrelor for most stable patients requiring dual antiplatelet therapy (DAPT). In most randomized trials performed in patients with stable coronary artery disease, clopidogrel 75 mg daily was the P2Y12 receptor blocker tested. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Evidence regarding timing and dose'.).
With regard to aspirin, we suggest that patients who have undergone elective stent placement, irrespective of stent type, be discharged on 75 to 100 mg/day. There have been no randomized trials of differing aspirin doses in stable patients who undergo PCI in the stent era. However, the issue of the optimal dose of aspirin was addressed in a prespecified subgroup analysis of the 17,263 acute coronary syndrome (ACS) patients who underwent early PCI in the CURRENT-OASIS 7 trial. There was no significant difference in the primary outcome (cardiovascular death, MI, or stroke at 30 days) between those who were randomly assigned for 30 days to a dose of 300 to 325 mg compared with those given 75 to 100 mg (4.1 versus 4.2 percent, respectively) [11]. While there was no significant difference in the rate of major bleeding, the rate of minor bleeding was significantly higher in those who received the higher dose of aspirin (5.0 versus 4.3 percent; adjusted hazard ratio 1.18, 95% CI 1.03-1.36). In the analysis of all patients (n = 25,086) enrolled in the study, there was a small but significant increase in the rate of gastrointestinal bleeding with higher-dose aspirin (0.4 versus 0.2 percent; p = 0.04) [12].
For patients with an ACS, we prefer a more potent P2Y12 receptor blocker (prasugrel or ticagrelor) to clopidogrel for one year. Our approach to long-term antiplatelet therapy in patients with ACS is presented separately. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Duration of dual antiplatelet therapy' and "Clopidogrel resistance and clopidogrel treatment failure", section on 'Acute coronary syndrome' and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".)
DURATION AND TYPE OF ANTIPLATELET TREATMENT — The optimal duration of dual antiplatelet therapy (DAPT) after placement of intracoronary stents in stable patients depends on patient-specific ischemic and bleeding risks (table 3). For many patients, a course of DAPT for 6 to 12 months is a reasonable duration, although the evidence for this specific duration, especially with newer-generation DES, is limited and is based mostly on expert consensus [13]. For patients at higher bleeding risk, especially if with a lower ischemic risk, a shorter course of DAPT followed by antiplatelet monotherapy may be appropriate, while for patients at higher ischemic risk, especially if with a lower bleeding risk, a longer course of DAPT may be reasonable.
The MASTER DAPT trial reported that in high-bleeding-risk patients who had a biodegradable-polymer sirolimus-eluting stent placed for acute or chronic coronary syndrome, one month of DAPT was noninferior to continuing the therapy for at least two additional months with respect to major adverse cardiovascular events and was superior with respect to reduced bleeding [14]. In this study, 4434 patients were randomly assigned to discontinuing DAPT at one month after intracoronary stent placement or continuing it for at least five more months if not also taking an oral anticoagulant or two more months if also taking an oral anticoagulant. Monotherapy in the abbreviated DAPT group was clopidogrel in 53.9 percent of subjects. Major or clinically relevant bleeding was lower in patients immediately discontinuing DAPT compared with standard therapy (6.5 versus 9.4 percent). Major adverse cardiac events (including a composite of death from any cause, myocardial infarction, or stroke) did not differ between the immediately discontinuing versus the standard therapy groups (6.1 versus 5.9 percent), nor did net adverse events differ between treatment groups (bleeding or major cardiac events; 7.5 versus 7.7 percent).
A summary of our approach to selecting the length of DAPT treatment is presented above. (See 'Our approach' above.)
Bleeding is the most frequent complication of DAPT. Risk predictors are presented in a table (table 1). The risk is higher with clopidogrel plus aspirin compared with aspirin alone [15] or compared with clopidogrel alone [16]. In addition, the risk is higher with more potent P2Y12 receptor blockers (such as prasugrel and ticagrelor) than with clopidogrel. (See "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies", section on 'P2Y12 receptor blockers' and "High bleeding risk patients undergoing percutaneous coronary intervention".)
During the first months after percutaneous coronary intervention (PCI), the reduction in ischemic events with DAPT outweighs the bleeding risk. Longer DAPT therapy (variably defined as >1 to 12 months), compared with aspirin or P2Y12 monotherapy, has uncertain benefit for reducing ischemic events in contemporary clinical practice. This benefit is likely restricted to those patients with highest-risk clinical or lesion characteristics [17]. The cumulative risk of bleeding begins to outweigh the benefit in many patients, especially those at higher bleeding risk [18]. P2Y12 receptor blocker monotherapy after a course of DAPT decreases bleeding risk without compromising ischemic risk for many patients. (See 'DAPT versus P2Y12 receptor blocker monotherapy trials' below and 'Our approach' above.)
Evidence — Early generation intracoronary stents had a higher rate of stent thrombosis than current generation stents, especially when these devices were translated into routine practice. Thus, recommendations for DAPT duration were longer. With time, trials of shorter duration DAPT have been performed. In these trials of shorter duration, DAPT has been followed by either monotherapy with aspirin or monotherapy with a P2Y12 receptor blocker. (See "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Drug-eluting stents' and 'Rationale for dual antiplatelet therapy' above.)
Our approach to the duration of DAPT after stenting with drug-eluting stents (see 'Our approach' above) is supported by a 2020 network meta-analysis of 24 randomized trials (including 79,073 patients with a median follow-up of 18 months), many of which are discussed in sections of this topic below [19]. The study compared short-term (<6 months) DAPT followed by aspirin or P2Y12 inhibitor monotherapy, midterm (six-month) DAPT, 12-month DAPT, and extended-term (>12-month) DAPT. The meta-analysis supports the broad concept that longer-duration DAPT is associated with a higher rate of bleeding and a lower rate of MI. The following findings were reported:
●Extended-term DAPT was associated with reduced risk of MI in comparison with 12-month DAPT (absolute risk difference [ARD], -3.8 incident cases per 1000 person-years; relative risk [RR] 0.68, 95% CI 0.54-0.87), midterm DAPT (ARD -4.6 incident cases per 1000 person-years; RR 0.61, 95% CI 0.45-0.83), and short-term DAPT followed aspirin monotherapy (ARD -6.1 incident cases per 1000 person-years; RR 0.55, 95% CI 0.37-0.830) or P2Y12 monotherapy (ARD -3.7 incident cases per 1000 person-years, RR 0.69, 95% CI 0.51-0.95).
●Extended-term DAPT was associated with a higher risk of major bleeding compared with all other DAPT groups.
●In comparison with 12-month DAPT, no significant differences in the risks of ischemic endpoints or major bleeding were observed with mid- or short-term DAPT followed by aspirin monotherapy. However, in this comparison, short-term DAPT followed by P2Y12 inhibitor monotherapy was associated with a reduced risk of major bleeding (ARD -3.7 incident cases per 1000 person-years; RR 0.69, 95% CI 0.50-0.96).
In patients at high bleeding risk post-PCI, a meta-analysis including 11 trials and >9000 patients showed that the utilization of DAPT for one to three months followed by monotherapy reduced major or clinically relevant nonmajor bleeding (RR 0.76; 95% CI 0.61-0.94), major bleeding (RR 0.80; 95% CI 0.64-0.99), and cardiovascular mortality (RR 0.79; 95% CI 0.65-0.95) compared with standard DAPT [20].
Specifically for patients >74 years of age, a consensus recently published recommended the utilization of DAPT (aspirin plus clopidogrel) for one to three months followed by monotherapy post-PCI for patients with high bleeding risk, and six months of DAPT with aspirin plus clopidogrel followed by monotherapy for those without high bleeding risk [21].
Treatment for longer than 12 months — The initial clinical practice of treating with DAPT for 12 months was derived in part from the early PCI-CURE and Clopidogrel for the Reduction of Events During Observation (CREDO) trials, which used bare metal stents (BMS). The benefit from clopidogrel plus aspirin compared with aspirin alone increased over time, with no evidence of a plateau at one year (figure 1) [22,23].
This issue of whether DAPT for longer than one year improves ischemic outcomes was evaluated in the DAPT trial, which randomly assigned 9961 patients with DES implantation, who had been successfully treated with 12 months of aspirin and a P2Y12 receptor blocker (either clopidogrel or prasugrel) with good compliance and without any adverse serious events, to continue receiving the P2Y12 receptor blocker or placebo for another 18 months (randomization was performed one year after the index hospitalization); all patients continued aspirin [24]. Enrolled patients had either stable (38 percent) or unstable disease. Exclusion criteria included a major adverse cardiovascular or cerebrovascular event, repeat revascularization, or moderate or severe bleeding within the first 12 months after the index procedure. The new-generation everolimus-eluting XIENCE stent was used in approximately half of the patients, whereas first-generation stents were used in the remainder. The following findings were reported:
●The rates for each of the coprimary end points of stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death from any cause, MI, or stroke) were lower with continued P2Y12 therapy (0.4 versus 1.4 percent; hazard ratio [HR] 0.29, 95% CI 0.17-0.48 and 4.3 versus 5.9 percent; HR 0.71, 95% CI 0.59-0.85, respectively). The reduction in events with continued DAPT was mostly attributable to a lower rate of MI (2.1 versus 4.1 percent; HR 0.47, p<0.001), which represents 20 fewer MIs per 1000 treated patients per year.
●The rate of the primary safety end point of moderate or severe bleeding applying the Global Use of Strategies to Open Occluded Arteries (GUSTO) criteria (table 4) was increased with continued DAPT (2.5 versus 1.6 percent, p = 0.001), which represents nine more major bleeds per 1000 treated patients per year.
●The rate of death from any cause was higher in the DAPT group (2.0 versus 1.5 percent; HR 1.36, 95% CI 1.00-1.85). This increase was due to an increase in noncardiac deaths (1.0 versus 0.5 percent, p = 0.002), which represents five more deaths per 1000 treated patients per year.
●Regarding the primary end point, a prespecified sub-group analysis suggested a greater benefit of longer duration of DAPT in patients with an MI compared with those without an MI (3.9 versus 6.8 percent compared with 4.4 versus 5.3 percent; p-interaction = 0.03) [25].
●In a post-hoc analysis of 4703 patients treated with the second-generation everolimus eluting stent, the results were similar to the results of the overall DAPT trial [26]. Continued P2Y12 therapy reduced the rate of stent thrombosis (0.3 versus 0.7 percent; HR 0.38, 95% CI 0.15-0.97) and MI (2.1 versus 3.2 percent; HR 0.63, 95% CI 0.44-0.91), while the rate of moderate/severe bleeding was increased (2.5 versus 1.3 percent, HR 1.79, 95% CI 1.15-2.80).
As new-generation stents are used in the majority of cases, the results in this subgroup are particularly important. Given the smaller (compared with the entire study group) absolute reductions in ischemic events, significant consideration to the relative hazards of ischemic events and bleeding events is warranted before determining a long-term DAPT strategy in the individual patient receiving everolimus-eluting stents.
The DAPT trial is the largest of the randomized trials that have compared longer (than 12 months) DAPT with 12 months of DAPT after DES placement. Other randomized trials such as PRODIGY, DES-LATE, and ARCTIC-Interruption did not show a decrease in ischemic events with longer therapy [27-29]. However, they had design limitations that may have prevented the demonstration of benefit.
Other evidence to support a recommendation for more than 12 months of DAPT comes from the PEGASUS-TIMI 54 trial. PEGASUS-TIMI 54 randomly assigned 21,162 patients with an MI one to three years earlier (median time 1.7 years) to one of two doses of ticagrelor (90 or 60 mg twice daily) or placebo [30]. The primary efficacy end point (a composite of cardiovascular death, MI, or stroke) occurred less often with both doses of ticagrelor than with placebo at three years (7.85, 7.77, and 9.04 percent, respectively; HRs 0.85, 95% CI 0.75-0.96 and 0.84, 95% CI 0.74-0.95). The rate of the primary safety end point of Thrombolysis in Myocardial Infarction (TIMI) major bleeding (table 4) was higher in the ticagrelor 90 and 60 mg groups (2.6, 2.3, and 1.06 percent, respectively; p<0.001 for each dose versus placebo), but there was no difference in the rates of fatal and nonfatal intracranial hemorrhage (0.63, 0.71, and 0.60 percent, respectively). Importantly, there was no significant difference in the rate of death from any cause (5.15, 4.69, and 5.15 percent, respectively; HR 0.89, 95% CI 0.76-1.04), and there was a trend toward a lower rate of cardiovascular death. In addition, ticagrelor lowered the risk of any stroke at the lower dose. More recently, a study showed that patients with a high bleeding risk assigned ticagrelor had a higher risk of bleeding and a similar absolute risk of cardiovascular death, MI, or stroke compared with the placebo group. For the 81 percent of the population with low bleeding risk, the difference was proportional to the number of ischemic risk factors, with -0.47 percent for patients with zero to one ischemic risk factor and up to -2.61 percent for those with three or more ischemic risk factors (P-trend = 0.076) [31].
A meta-analysis that included 33,145 stable patients with previous MI (most with PCI) showed a 22 percent (p<0.001) decrease in the rate of major cardiovascular events, a 15 percent (p = 0.03) decrease in cardiovascular death, a 30 percent (p = 0.003) decrease in MI, a 19 percent decrease in stroke (p = 0.02), and a 50 percent decrease (p = 0.02) in stent thrombosis, in favor of extended DAPT versus aspirin alone [32]. As expected, the rate of major bleeding was increased (risk ratio [RR] 1.73; p = 0.004). Another meta-analysis with more than 43,000 patients (including only the ticagrelor 60 mg dosing arm of PEGASUS) showed similar results, with an additional finding of a significant reduction in all-cause mortality [33]. The 60 mg dose is important in that the antiaggregant potency between the 60 and 90 mg doses is similar [34-36]. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Duration'.)
Multiple meta-analyses of randomized trials that evaluated DAPT therapy for more than 12 months have been performed [37-41]. These meta-analyses evaluated different durations of DAPT therapy. The largest of these was published in 2016 and included 10 trials with 33,051 patients who received predominantly newer-generation DES [41]. With regard to DAPT duration greater than one year: comparing 18 to 48 months with 6 to 12 months, there was no difference in the incidence of all-cause death (odds ratio [OR] 1.14, 95% CI -0.92 to 1.42), an increase in major hemorrhage (OR 1.58, 95% CI 1.20-2.09), a decrease in MI (OR 0.67, 95% CI 0.47-0.95), and a decrease in stent thrombosis (OR 0.42, 95% CI 0.24-0.74). Post-hoc analysis found a trend toward increased mortality with longer DAPT. This has been noted in other meta-analyses. Although complete explanations are not available, it is possible that the finding is related to complications of observed or unobserved bleeding and modified substantially by the relative risks of ischemic versus bleeding events in individual patients.
It is important to consider that results in real-world contemporary practice may differ from randomized clinical trials. In the EXTEND-DAPT study, in which results of the DAPT study were weighted according to clinical, lesion, and stent characteristics of a cohort derived from the NCDR CATH PCI registry, the benefit in reduction of major bleeding and adverse cardiac and cerebrovascular events (MACCE), stent thrombosis, or myocardial infarction for prolonged DAPT beyond 12 months in the overall population was no longer significant. However, the harm of increased bleeding persisted. Among subjects with a DAPT score ≥2, the benefit of prolonged DAPT for reduced stent thrombosis persisted without a significant increase in bleeding, showing the continued importance of stratification according to the balance of ischemic and bleeding risk.
Treatment for less than 12 months — There are two treatment options after earlier discontinuation of DAPT: stopping DAPT with continuation of aspirin or stopping with continuation of P2Y12 inhibitor monotherapy.
DAPT versus aspirin trials — In stable patients, there is evidence that ischemic outcomes are similar with three to six months of DAPT followed by aspirin compared with 12 months of DAPT:
●The SECURITY, ITALIC, ISAR-SAFE, OPTIMIZE, EXCELLENT, RESET, and PRODIGY trials compared six months of DAPT with 12 months or longer [42-47]. Each trial had one or more significant limitations, including small sample size and enrollment of lower-risk patients, and there was significant heterogeneity between the trials. In a meta-analysis (n = 8180) that included only studies comparing shorter duration (three to six months) with 12 months of therapy, there was no significant difference in the risk of all-cause death (HR 0.89, 95% CI 0.66-1.20) [39].
●The large 2016 meta-analysis of about 33,000 patients presented above looked at shorter duration of DAPT [41]. Comparing 12 with 3 to 6 months, there were no significant differences in the incidence of death (OR 1.17, 95% CI 0.85-1.63), major hemorrhage (OR 1.65, 95% CI 0.97-2.82), MI (OR 0.87, 95% CI 0.65-0.1.18), or stent thrombosis (OR 0.86, 95% 0.49-1.55). Selection bias for entry into shorter-duration trials cannot be excluded and again indicates the importance of individual assessment of bleeding and ischemic risk to determine DAPT strategy.
DAPT versus P2Y12 receptor blocker monotherapy trials — There is evidence to support the use of DAPT for one to three months followed by P2Y12 receptor blocker monotherapy rather than DAPT for 6 to 12 months. (See 'Our approach' above.)
The trials presented below enrolled patients with both stable and unstable coronary artery disease. We believe that the evidence can be used to support recommendations for both groups of patients.
Two 2020 meta-analyses of five randomized trials (over 30,000 patients) that evaluated this issue found the following when comparing P2Y12 receptor blocker monotherapy with DAPT after three months of DAPT [48,49]:
●A 40 percent lower risk of major bleeding.
●No significant difference in all-cause mortality or myocardial infarction.
●Findings were consistent between patients with stable disease and an acute coronary syndrome.
Details of the five randomized trials are as follows:
●In the 2019 open label SMART-CHOICE trial, 2993 stable and unstable patients were randomly assigned to three months of DAPT followed by P2Y12 receptor blocker monotherapy or 12 months of DAPT [16]. Clopidogrel was the P2Y12 receptor blocker in 77 percent of patients. The primary end point of major adverse cardiac and cerebrovascular events (all-cause death, MI, or stroke at 12 months) occurred with similar frequency in both groups (2.9 versus 2.5 percent, respectively; hazard ratio [HR] 1.19, 95% CI 0.76-1.85). The rate of Bleeding Academic Research Consortium (BARC) types 2 to 5 bleeding (table 5) was lower with P2Y12 receptor blocker monotherapy (2.0 versus 3.4 percent; HR 0.58, 95% CI 0.36-0.92). This trial was limited by an open-label design and enrollment of a relatively low ischemic risk population.
●In the open label STOPDAPT-2 trial, 3045 stable and unstable patients at relatively low risk of an ischemic event undergoing PCI with a third generation stent were randomly assigned to one month of DAPT followed by clopidogrel monotherapy or followed by aspirin plus clopidogrel [50]. During the first month, 38 percent of patients received prasugrel rather than clopidogrel. The primary composite endpoint (cardiovascular death, MI, ischemic and hemorrhagic stroke, definite stent thrombosis, or TIMI major or minor bleeding at 12 months) occurred in 2.36 and 3.70 percent of patients, respectively (table 4) (HR 0.64, 95% CI 0.42-0.98). The major secondary bleeding endpoint occurred significantly less often with one month of DAPT (0.41 and 1.54 percent of patients, respectively). This trial was limited by a lower-than-expected event rate and enrollment of a relatively low ischemic risk population.
●The 2019 TWILIGHT trial enrolled patients who were at higher ischemic risk than either SMART-CHOICE or STOPDAPT-2 [51]. In TWILIGHT, 7119 patients with either stable coronary artery disease or a non-ST elevation acute coronary syndrome were randomly assigned to ticagrelor 90 mg twice daily plus either placebo or aspirin, after a three-month period of ticagrelor plus aspirin. Patients were required to have at least one clinical feature (eg, age of at least 65 years, female sex, troponin-positive acute coronary syndrome, established vascular disease, treated diabetes mellitus, and chronic kidney disease) and one angiographic feature (eg, multivessel coronary artery disease, a total stent length of more than 30 mm, a thrombotic target lesion, a bifurcation lesion treated with two stents, an obstructive left main or proximal left anterior descending lesion, and a calcified target lesion treated with atherectomy) associated with a high risk of ischemic or bleeding events. Between randomization and one year, the primary endpoint of BARC type 2, 3, or 5 bleeding (table 5) occurred in 4.0 and 7.1 percent (HR 0.56, 95% CI 0.45-0.68) of the ticagrelor plus placebo and ticagrelor plus aspirin groups, respectively. The secondary endpoint of death from any cause, nonfatal MI, or nonfatal stroke was similar in both groups.
Prespecified subgroup analyses of patients with diabetes (n = 2720) or complex PCI (n = 2342) have been published. In the diabetic subgroup, the primary endpoint occurred in 4.5 and 6.7 percent (HR 0.65, 95% CI 0.47-0.91) of the ticagrelor plus placebo and ticagrelor plus aspirin groups, respectively [52]. In the complex PCI subgroup, the primary endpoint occurred in 4.2 and 7.7 percent (HR 0.54, 95% CI 0.38-0.76) of the two groups, respectively [53]. There was no significant difference in the risk of ischemic events in either of these two subgroups. Additionally, subgroup analysis showed that the ticagrelor monotherapy reduced bleeding in comparison with DAPT in both higher- and lower-bleeding risk populations [54]. In a small mechanistic sub-study, it was shown that ticagrelor monotherapy had similar antithrombotic effect regarding ex-vivo blood thrombogenicity compared with DAPT [55].
●GLOBAL LEADERS evaluated outcomes in 15,968 patients with stable disease (53 percent) or acute coronary syndromes undergoing stenting with a biolimus A9-eluting stent [56] (see "Intracoronary stents: Stent types", section on 'Bioresorbable polymer drug-eluting stents'). Patients were randomly assigned to aspirin 75 to 100 mg daily plus ticagrelor 90 mg twice daily for one month, followed by 23 months of ticagrelor monotherapy, or standard DAPT with aspirin 75 to 100 mg daily plus either clopidogrel 75 mg daily (stable disease) or ticagrelor 90 mg twice daily (acute coronary syndrome) for 12 months, followed by aspirin monotherapy for 12 months. At two years, there was no significant difference between the two strategies for the primary composite endpoint of all-cause mortality or non-fatal, new Q wave MI (3.81 versus 4.37 percent, respectively; rate ratio [RR] 0.87, 95% CI 0.75-1.01). In addition, there was no difference in the rate of stent thrombosis. There was no significant difference between the two groups in the rate of BARC grade 3 or 5 bleeding (table 5). Prespecified landmark analyses showed a significant decrease of the primary end point (RR = 0.79, p = 0.028) for one-year follow-up, and similar results in the groups between 366 days and two years (RR 0.97, p = 0.790). A prespecified subgroup analysis suggested a benefit with the ticagrelor approach in patients with an acute coronary syndrome [57]. A post-hoc analysis of GLOBAL LEADERS showed a favorably balanced ischemic/bleeding risk with the utilization of DAPT for one month followed by ticagrelor only in patients with multivessel PCI [58].
However, we do not recommend the use of ticagrelor plus aspirin for one month followed by 23 months of ticagrelor, as used in GLOBAL LEADERS, as a first-choice strategy in large part due to the significantly higher cost of ticagrelor for two years compared with clopidogrel for 6 to 12 months followed by aspirin monotherapy. We believe that the regimen of one to three months of DAPT with aspirin and ticagrelor followed by ticagrelor 90 mg twice daily monotherapy for up to two years may be considered for individuals who are at high bleeding risk and in selected patients with high risk ischemic features. (See 'Our approach' above.)
●The TICO trial compared three months of DAPT (ticagrelor 90 mg twice daily and aspirin 100 mg daily) followed by ticagrelor monotherapy (90 mg twice daily) with a strategy of 12 months of DAPT in patients with acute coronary syndromes [59]. Among the 3056 patients who were randomly assigned, 35 percent had NSTEMI. The primary composite outcome of major bleeding and adverse cardiac and cerebrovascular events (MACCE) was lower with 3.9 and 5.9 percent of the two groups, respectively (absolute difference -1.98 percent [95% CI -3.50 to -0.45 percent]; HR 0.66, 95% CI 0.49-0.92). Major bleeding occurred in 1.7 and 3 percent of the two groups, respectively (HR 0.56, 95% CI 0.34-0.91); there was no significant difference in the rate of MACCE (2.3 versus 3.4 percent, respectively). In evaluating the results of TICO, the lower-than-expected event rates need to be considered.
The SMART-CHOICE and STOPDAPT-2 trials enrolled individuals living in Japan.
Patients with BMS — For patients who require a very short period of DAPT, such as 30 days, there is no evidence that BMS are preferred to current-generation DES. (See "Intracoronary stents: Stent types", section on 'Bare metal stents'.)
However, for those patients who receive a BMS for reasons other than DAPT duration, our approach to DAPT duration is similar to that for DES. In an analysis of the 1687 patients in the DAPT trial (discussed above) treated with BMS, there were no significant differences in the rates of stent thrombosis, major adverse cardiovascular and cerebrovascular events (a composite of death from any cause, MI, or stroke), or major/severe bleeding (0.5 versus 1.11 percent [HR 0.49, 95% CI 0.15-1.64], 4.04 versus 4.69 [HR 0.92, 95% CI 0.57-1.47], and 2.01 versus 0.90 [p = .07]) [60]. There was no interaction in the analysis between DES and BMS, suggesting that the therapeutic benefit is similar independent of stent type.
Furthermore, in patients at high bleeding risk in whom a DAPT duration of only 30 days is desired, the LEADERS-FREE trial demonstrated superiority for efficacy and safety for DES compared with BMS [61]. (See "High bleeding risk patients undergoing percutaneous coronary intervention", section on 'BMS versus DES'.)
Patients with bioresorbable polymer stents — Bioresorbable (also referred to as "biodegradable") polymer DES have been developed in an attempt to minimize the duration of vascular inflammation associated with the polymer. The optimal duration of DAPT for these newer stents is not known. Our approach is similar to that for DES. (See 'Our approach' above.)
The I-LOVE-IT 2 trial randomly assigned 1829 patients with an implanted biodegradable polymer sirolimus-eluting stent (with a thin strut design) to receive 6 or 12 months of DAPT [62]. There was no significant difference in the primary outcome of the 12-month target lesion failure rate (a composite of cardiac death, target vessel MI, or clinically-indicated target lesion revascularization) between the two groups (6.8 versus 5.9 percent, respectively). The trial was not powered, however, to assess small differences in thrombotic events.
Patients who may benefit from longer therapy — Some patient groups may derive greater benefit than that seen in the randomized trials due to increased ischemic risk [63] (see 'Evidence' above):
●Complex PCI (eg, bifurcation or left main stenting, long lesions, saphenous vein grafts, ≥3 stents implanted, ≥3 lesions treated, three coronary vessels treated, or treatment of a chronic total occlusion). One study suggests that the use of long-term (12 or 24 months) compared with short-term (three or six months) DAPT is associated with improved ischemic outcomes but only in the absence of higher bleeding risk [64].
●Implantation of an older-generation DES, such as sirolimus, paclitaxel, or early-generation everolimus stent (table 6).
●Prior stent thrombosis or a cardiovascular ischemic event within the first 12 months of DAPT. (See "Coronary artery stent thrombosis: Clinical presentation and management", section on 'Long-term antiplatelet therapy'.)
●Diabetes. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Antiplatelet therapy'.)
Decision tools — Decision tools are available to assess ischemic and bleeding risks in patients who might be candidates for longer than 6 to 12 months of DAPT. In particular, some of our contributors use these often when considering DAPT for more than one year. We prefer the DAPT Risk Calculator, although other tools are available to guide patients and practitioners [65].
The DAPT score was developed using data from 11,648 patients who received either a DES or a BMS in the DAPT trial (see 'Evidence' above). The investigators developed a decision tool (prediction rule) to identify which patients would likely benefit from continuing DAPT from 12 to 30 months [66,67]. The DAPT Score [65] predicts the combined ischemic and bleeding risks (net clinical benefit) and includes the following factors: age, cigarette smoking within the last two years, prior MI or PCI, history of heart failure or left ventricular ejection fraction <30 percent, MI at presentation, stenting of a vein graft, type of stent, diabetes, or stent diameter <3 mm. Of these, age ≥75 years was the most important determinant of a worse outcome with longer therapy.
Comparing high and low score groups, continued P2Y12 receptor blocker therapy compared with placebo was associated with a larger decrease in ischemic events (2.7 versus 5.7 percent; risk difference [RD] -3 percent, 95% CI -4.1 to -2 percent and 1.7 versus 2.3 percent; RD -0.7 percent, 95% CI -1.4 to 0.09 percent, respectively). In addition, continued therapy was associated with a smaller increase in bleeding in the high score compared with the low score group (1.8 versus 1.4 percent; RD -0.4 percent, 95% CI -1.3 to 1.0 percent and 3 versus 1.4 percent; RD 1.5 percent, 95% CI 0.8-2.3 percent, respectively). Derivation cohort models predicting ischemia and bleeding had modest accuracy with C statistics of 0.70 and 0.68, respectively. In a validation cohort with 8136 patients, the C statistics for ischemia and bleeding were 0.64 and 0.64; in another, with >41,000 patients, the C statistics were, respectively, 0.67 and 0.67.
At a lower DAPT score, there is a greater increase in bleeding and a smaller reduction in ischemia. At a higher score, there is a greater reduction in ischemia and a smaller increase in bleeding. The DAPT investigators concluded that patients with a score <2 have greater harm than benefit from continued therapy beyond 12 months, while those with a score of 2 or more derive benefit from treatment for an additional 18 months. This tool needs external validation before we can recommend its use widely and needs to be used in conjunction with clinical judgment.
The score is not intended to be applied to patients with the following characteristics: receiving oral anticoagulation, limited life expectancy, stent thrombosis, stroke, repeat revascularization, bleed, and those not compliant with DAPT during the first year. The score was derived from patients not receiving a paclitaxel-eluting stent (but included patients with BMS), since such stents are no longer commonly used in clinical practice. It was not evaluated in patients receiving ticagrelor.
Potential limitations of the DAPT score are that one-third of patients had an acute coronary syndrome, that the score derivation did not include individuals who had a cardiovascular event while taking DAPT during one year, that it did not include patients taking ticagrelor, and the fact that it was a post-hoc analysis. Some of our experts use the DAPT score, as they see it as the best available tool to supplement clinical judgment in decision making. Others await more evidence about its utility, considering that the utilization of DAPT score in real world has shown conflicting results [68,69].
As mentioned above, other decision tools have been evaluated [64,70]. The PRECISE-DAPT score is one such tool and includes age, creatinine clearance, hemoglobin, white-blood-cell count, and previous spontaneous bleeding as risk predictors. The PRECISE-DAPT score evaluated the effects of bleeding and ischemic risks on clinical outcomes in nearly 15,000 patients, including over 3000 complex cases, in eight randomized trials [71,72]. In this study, patients who underwent complex PCI benefitted from long-term DAPT only if high bleeding risk features were not present. This score can be used at hospital discharge and thus may be of benefit in high-bleeding-risk patients. (See 'Duration and Type of Antiplatelet Treatment' above.)
SPECIFIC PATIENT GROUPS
Patients with aspirin sensitivity or allergy — Two options for addressing the problem of patients with possible aspirin sensitivity or allergy are to consider P2Y12 receptor blocker monotherapy or aspirin desensitization [73]. (See "Acute coronary syndrome: Oral anticoagulation in medically treated patients", section on 'Rivaroxaban' and "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions", section on 'Our approach'.)
Patients taking anticoagulants — The management of patients taking oral anticoagulant and DAPT is found elsewhere. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Summary and recommendations'.)
Patients needing temporary discontinuation — Although we recommend DAPT for a minimum of 6 to 12 months in most patients who have received a coronary stent, temporary discontinuation (interruption) is necessary in some patients. Based on the evidence presented below and clinical experience, temporary discontinuation before 30 days is associated with high risk. We are uncertain of the risk between one and six months, but we believe that interruption or discontinuation of the P2Y12 receptor blocker after six months is safe as long as aspirin is continued. For patients who are at higher bleeding risk or require nondeferrable surgery, interruption or discontinuation of P2Y12 receptor blocker after three months are probably safe as long as aspirin is continued [74]. Some of our experts recommend interruption or discontinuation of P2Y12 receptor blocker as early as after one month in these patients. Interruptions of the P2Y12 receptor blocker require special consideration when using a regimen of P2Y12 receptor blocker monotherapy after earlier aspirin discontinuation.
Multiple studies have attempted to quantify the risk or early interruption (mostly involving interruption of P2Y12 receptor blocker and continuation of aspirin) [75-77]. In one study the PARIS registry (see 'Promotion of DAPT adherence' below and "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Early and late stent thrombosis'), the hazard ratio for major adverse cardiovascular events was nonsignificantly higher for patients with interruption (1.41, 95% CI 0.94-2.12) [75].
The causes of and predictors for premature discontinuation are discussed separately. (See "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Early and late stent thrombosis'.)
Noncardiac surgery or gastrointestinal endoscopy — Noncardiac surgery and gastrointestinal endoscopy are situations in which DAPT may need to be temporarily interrupted. Except for emergent settings in which surgery cannot be delayed, we recommend that a platelet P2Y12 receptor blocker and aspirin be continued for at least the minimum recommended duration for each stent type and that elective noncardiac surgical procedures requiring discontinuation of DAPT be deferred. For patients who require urgent surgery or endoscopy, we individualize care, taking into account the relative risks of bleeding and stent thrombosis. This issue is discussed in detail elsewhere. (See "Noncardiac surgery after percutaneous coronary intervention", section on 'Our approach'.)
Aspirin should be continued during surgery if possible and not be discontinued without confirming absolute necessity. (See "Perioperative medication management", section on 'Aspirin'.)
Similar issues arise in patients scheduled to undergo gastrointestinal endoscopy. This matter is discussed elsewhere. (See "Management of antiplatelet agents in patients undergoing endoscopic procedures".)
PROMOTION OF DAPT ADHERENCE — Patients who cannot complete a recommended duration of dual antiplatelet therapy (DAPT) are at risk for stent thrombosis (see 'Rationale for dual antiplatelet therapy' above). Issues related to treatment failure are discussed separately. (See "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Early and late stent thrombosis' and "Coronary artery stent thrombosis: Clinical presentation and management", section on 'Long-term antiplatelet therapy'.)
Clinicians who care for patients treated with DAPT should pay attention to the following issues in an attempt to minimize the risk of stent thrombosis:
●The risk of noncompliance with recommendations for DAPT must be assessed before stent placement. This should include a discussion in reasonable detail with the patient and relevant caregivers of the likelihood of compliance with recommendations for DAPT for a minimum of 6 to 12 months, including issues of cost/insurance coverage, assessment of the likelihood of noncardiac surgery in the next 12 months, and the consequences of premature cessation of therapy.
●Office-based practitioners, such as primary care clinicians or dentists, need to be properly educated about the importance of not discontinuing antiplatelet therapy unless absolutely necessary.
●Rash or other manifestations of a hypersensitivity reaction to clopidogrel may develop in up to 4 percent of patients and possibly lead to drug discontinuation. This issue is discussed in detail separately. (See "Hypersensitivity reactions to clopidogrel".)
●In the unusual case in which aspirin must be discontinued (in addition to the P2Y12 inhibitor) due to a procedure where there is a significant risk of uncontrollable bleeding, we discuss this decision with the clinician performing the procedure to verify that continuing aspirin is truly a significant risk. There are very few situations that require discontinuing low-dose aspirin. As examples, aspirin can be continued with both coronary artery bypass graft surgery and cataract surgery [78]. (See "Perioperative medication management", section on 'Aspirin'.)
●Cessation of antiplatelet therapy may be required for reasons such as urgent surgery or major bleeding. However, minor bleeding is also a risk factor for antiplatelet therapy cessation. This issue is discussed separately. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Bleeding'.)
Clopidogrel resistance/nonresponse — Clopidogrel resistance/nonresponse is associated with stent thrombosis. This issue is discussed separately. (See "Clopidogrel resistance and clopidogrel treatment failure".)
RECOMMENDATIONS OF OTHERS — Recommendations for the prevention of stent thrombosis after coronary artery stenting in stable patients are found in guidelines from the American College of Cardiology Foundation/American Heart Association in 2016 and the European Society of Cardiology/European Association for Cardio-Thoracic Surgery in 2014 [79,80].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Percutaneous coronary intervention".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Stenting for the heart (The Basics)")
●Beyond the Basics topics (see "Patient education: Angina treatment — medical versus interventional therapy (Beyond the Basics)" and "Patient education: Stenting for the heart (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Rationale for dual antiplatelet therapy (DAPT) – The risks of stent thrombosis, a potentially lethal complication of intracoronary artery stent placement, and major adverse cardiovascular events such as cardiac death, myocardial infarction, or stroke, are diminished by the use of dual antiplatelet therapy (DAPT) with aspirin and a platelet P2Y12 receptor blocker compared with the use of aspirin monotherapy. (See 'Duration and Type of Antiplatelet Treatment' above and "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Comparison of DES and BMS'.)
●Therapy for most patients
•For stable patients treated with intracoronary stents who are not at high bleeding risk and who do not have planned noncardiac surgery within one year, we recommend aspirin and a platelet P2Y12 receptor blocker for at least 6 months after stent placement rather than a shorter treatment duration (Grade 1B). (See 'Evidence' above.)
•Clopidogrel is the preferred P2Y12 receptor blocker in most stable patients and the dose of clopidogrel is 75 mg daily. We suggest aspirin 75 to 100 mg daily rather than higher doses. (See 'Early postprocedural decisions' above.)
●Patients at high ischemic risk – For stable patients assessed to be at high bleeding or ischemic risk, such as those enrolled in the TWILIGHT trial, we consider treatment with ticagrelor plus aspirin for three months followed by ticagrelor alone for at least an additional year. (See 'DAPT versus P2Y12 receptor blocker monotherapy trials' above.)
●Duration of long-term DAPT – The optimal duration of DAPT after placement of intracoronary stents in stable patients depends on patient-specific ischemic and bleeding risks (table 3). In patients with high ischemic risk and low to average bleeding risk, after 6 to 12 months of successful DAPT therapy, practitioners should discuss with their patients the potential benefits and risks of continuing DAPT instead of changing to monotherapy.(See 'Our approach' above.)
For stable patients who have not had a significant complication with DAPT during the first 6 to 12 months, especially those with higher ischemic risk and low bleeding risk, we suggest continuing such therapy, rather than monotherapy, for an additional 18 months (Grade 2B). It is reasonable for patients to stop DAPT after 6 to 12 months if they are particularly concerned about the increased risk of bleeding, if the bleeding risk exceeds ischemic benefit (eg, DAPT score <2), or if there is a hardship associated with continuing DAPT.
Prolonged DAPT regimens may include clopidogrel, ticagrelor, or prasugrel. If ticagrelor is chosen, we favor the 60 mg twice-daily dose for continuation of DAPT beyond 12 months. (See 'Evidence' above.)
●Duration of single antiplatelet therapy – For patients who are stented and who have no high bleeding risk and no indication for long-term oral anticoagulant therapy, we recommend continuing single antiplatelet therapy (usually aspirin or clopidogrel) indefinitely (Grade 1A). In patients who require long-term oral anticoagulant therapy (eg, patients with atrial fibrillation), a more nuanced approach to antiplatelet therapy is required. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease" and 'Evidence' above and "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Our approach'.)
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