Disclosures: Donald Cutlip, MD Grant/Research/Clinical Trial Support: Celonova [coronary stents (bare metal stent)]; Boston Scientific [transcatheter aortic valve (transcatheter valve)]; Medtronic [coronary stent (drug eluting stent)]. Christopher P Cannon, MD Grant/Research Support: Accumetrics (Platelets and ACS [Verify Now platelet test]); Arisaph (Lipids); AstraZeneca (ACS, lipids, and GI [Ticagrelor, Rosuvastatin, PPI]); Boehringer-Ingelheim (AF [Dabigatran]); CSL Behring (Lipids); Essentialis (Lipids); GlaxoSmithKline (Lipids and DM); Janssen (AF and DM [Rivaroxaban and Cangliflozen); Merck (Lipids [Ezetimibe]); Regeneron (Lipids); Sanofi (Lipids and ACS [clopidogrel]); Takeda (DM [Pioglitazone]). Consultant/Advisory Boards: Bristol-Myers Squibb (AF [Apixaban]); Lipimedix (Lipids); Pfizer (AF, DM, and Lipids [Apixaban, Etrugliflozin, Atorvastatin]); Kowa (lipids). Stephan Windecker, MD Grant/Research/Clinical Trial Support: Abbott [Coronary stents (Xience)]; Boston Scientific [Coronary stents (Synergy)]; Edwards Lifesciences [Heart valves (Sapien)]; Medtronic Medicines [Coronary stents (CoreValve and Resolute)]; Medicines Company [Anticoagulants (Bivalirudin)]; St. Jude Medical [Optical coherence tomography]. Speaker's Bureau: Abbott [Coronary stents (Xience)]; Astra Zeneca [Antiplatelets (Ticagrelor)]; Eli Lilly [Antiplatelets (Prasugrel)]; Daiichi Sankyo [Antiplatelets (Prasugrel)]; Biotronik [Coronary stents (Orsiro)]; Boston Scientific [Coronary stents (Synergy)]; Bayer [Antithrombotics (rivaroxaban)]; Biosensors [Coronary stents (Biomatrix)]. Gordon M Saperia, MD, FACC Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Coronary artery stents, particularly drug-eluting stents (DES), are used in the majority of patients who undergo percutaneous coronary intervention to improve symptoms in patients with obstructive coronary artery disease. They function both to prevent abrupt closure of the stented artery soon after the procedure as well as to lower the need for repeat revascularization compared to balloon angioplasty alone (formerly referred to as percutaneous transluminal coronary angioplasty).
Stent thrombosis is an uncommon but serious complication of coronary artery stenting that often presents as death and is almost always accompanied by myocardial infarction, usually with ST-segment elevation. DAPT (DAPT; aspirin plus platelet P2Y12 receptor blocker) significantly lowers the risk of stent thrombosis. In the absence of DAPT, the period of high risk for stent thrombosis is longer with DES than bare metal stents (BMS) due to a delay in neointimal coverage with the former. The cumulative incidence of stent thrombosis appears to occur with similar frequency in patients with BMS or DES, as long as patients are treated with DAPT for the recommended duration for the particular stent.
This topic will discuss the use of antiplatelet therapy to reduce the risk of adverse outcomes related to stent thrombosis in patients with stable coronary artery disease. Other issues related to stent thrombosis, recommendations for therapy in patients with an acute coronary syndrome, and the use of antiplatelet drugs in the periprocedural period are discussed separately. (See "Coronary artery stent thrombosis: Incidence and risk factors" and "Antiplatelet agents in acute non-ST elevation acute coronary syndromes", section on 'Duration of therapy' and "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Aspirin' and "Antiplatelet agents in acute ST elevation myocardial infarction", section on 'Specifics of P2Y12 use' and "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'P2Y12 receptor blockers'.)
DEFINITIONS OF STENT THROMBOSIS AND RESTENOSIS — After a successful procedure, coronary stents can fail to maintain vessel patency due to stent thrombosis or stent restenosis. Stent thrombosis is an abrupt thrombotic occlusion of a previously patent stent. It is a serious complication that presents as sudden death or myocardial infarction (MI) in most patients. Despite successful repeat revascularization, the six-month mortality is high. Earlier randomized clinical trials that evaluated the frequency of stent thrombosis did not use a uniform definition in their protocols, leading to difficulty in comparing the different studies. The following definitions were used in most studies and will be referred to as the historical definition :
●Events occurring within the first 30 days were considered to represent acute or subacute stent thrombosis if there was angiographic vessel occlusion, any new Q-wave MI in an area supplied by the stented vessel, and/or unexplained death from a cardiac cause.
●Events occurring after 30 days were considered to represent late stent thrombosis if there was a new MI with occlusion of the stented artery on angiography. This definition underestimates the incidence of stent thrombosis since unexplained MI in the territory of the stented vessels and late deaths, which may have been due to stent thrombosis, were usually not included.
Another problem is that in some clinical trials, stent thrombosis occurring in a patient who had previously undergone repeat target lesion revascularization was not counted. Since this is more likely to occur in a patient with a bare metal stent due to the more frequent need for repeat revascularization, there is a potential for bias against drug-eluting stents.
In an attempt to standardize the definition, an academic research consortium (ARC) proposed the following criteria for stent thrombosis :
●Definite – Angiographic confirmation of a thrombus that originates in the stent or in the segment 5 mm proximal or distal to the stent, with or without vessel occlusion, which is associated with acute onset of ischemic symptoms at rest or electrocardiogram (ECG) signs of acute ischemia or typical rise and fall of in cardiac biomarkers within 48 hours of angiography OR pathologic confirmation of stent thrombosis determined at autopsy or from tissue obtained following thrombectomy.
●Probable – Unexplained death occurring within 30 days after the index procedure, or an MI occurring at any time after the index procedure that was documented by ECG or imaging to occur in an area supplied by the stented vessel in the absence of angiographic confirmation of stent thrombosis or other culprit lesion.
●Possible – Unexplained death occurring more than 30 days after the index procedure
In the discussion that follows, studies will be identified as having used either the historical or the ARC definition. Most studies published after 2010 use only the ARC definition.
Restenosis is a gradual re-narrowing of the stented segment that occurs mostly between 3 to 12 months after stent placement. It usually presents as recurrent angina but can present as acute MI in approximately 10 percent of patients. (See "Intracoronary stent restenosis".)
PERIPROCEDURAL ANTIPLATELET THERAPY — Recommendations for the periprocedural use of antithrombotic therapy, including antiplatelet therapy, are found elsewhere (see "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Summary and recommendations'), as are recommendations for their use at the time of percutaneous coronary intervention in patients with acute coronary syndromes. (See "Antiplatelet agents in acute ST elevation myocardial infarction", section on 'Summary and recommendations' and "Antiplatelet agents in acute non-ST elevation acute coronary syndromes", section on 'Invasive approach'.)
LONG-TERM DUAL ANTIPLATELET THERAPY — The benefit from long-term antiplatelet therapy with aspirin in patients with atherosclerotic cardiovascular disease (secondary prevention) is well established. (See "Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease", section on 'Efficacy'.)
All patients who undergo percutaneous coronary intervention (PCI), including those treated with balloon angioplasty without stenting, receive dual antiplatelet therapy (DAPT), which is the combination of aspirin and a P2Y12 receptor blocker to reduce the risk of myocardial infarction (MI) or death. For patients with stable coronary artery disease, we recommend aspirin 75 to 100 mg daily plus clopidogrel 75 mg daily for at least 12 months. For patients who have tolerated this therapy, we suggest continuing for an additional 18 months. (See 'Duration' below.)
Many of these adverse episodes of death and MI are attributable to stent thrombosis. (See "Coronary artery stent thrombosis: Incidence and risk factors".) However, we believe the benefit from DAPT in stented patients is also attributable to the prevention of adverse events consequent to plaque rupture at sites remote from the stented location (events not related to stent placement). Evidence supporting the role of DAPT in this regard is suggested by the following:
●In patients with acute coronary syndromes treated medically (no percutaneous coronary intervention), DAPT, compared to aspirin alone, reduces the rate of MI (figure 1). (See "Antiplatelet agents in acute non-ST elevation acute coronary syndromes", section on 'Platelet P2Y12 receptor blockers'.)
●In the DAPT trial (see 'Drug-eluting stents' 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.
Compared to aspirin monotherapy — The rationale for the use of DAPT, 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 [3-6]. More intense antiplatelet therapy (DAPT) lowers the risk of stent thrombosis compared to aspirin alone. (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'.)
In early studies of patients who received bare metal stents (BMS), the rate of stent thrombosis was significantly lower with aspirin plus ticlopidine than with aspirin alone (or aspirin plus warfarin) [7-11]. For example, the efficacy of combined antiplatelet therapy was demonstrated in the STARS trial in which 1653 patients were randomly assigned to aspirin alone or in combination with warfarin or ticlopidine . The primary end point included all clinical events reflecting stent thrombosis within 30 days: death, revascularization of the target lesion, angiographically documented thrombosis, or MI. The rate of the primary end point was significantly lower with aspirin plus ticlopidine than with aspirin plus warfarin or aspirin alone (0.5 versus 2.7 or 3.6 percent, respectively). After one randomized trial demonstrated similar efficacy between ticlopidine and clopidogrel but a better side effect profile with the latter, the use of ticlopidine declined dramatically; it is now rarely used . (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'P2Y12 receptor blockers'.)
There are no studies that have compared dual to single antiplatelet therapy in stable patients who received drug-eluting stents (DES). However, we believe the rationale for DAPT (as opposed to antiplatelet monotherapy) after DES implantation is strong based on biologic plausibility, evidence of benefit in patients with BMS, and observations of adverse outcomes, including stent thrombosis, when DAPT is discontinued during the period of time when incomplete endothelialization is possible or probable.
Duration — For most stable patients (and for acute coronary syndrome patients as well) treated with either DES or BMS in whom surgery is not anticipated and the bleeding risk is not excessive (eg, requirement for systemic anticoagulants or history of recent major bleeding), we prescribe DAPT for 12 months. After 12 months, we re-evaluate the patient. For patients who have not had clinically significant bleeding and who continue to not be at excessive risk for bleeding, we continue DAPT for at least an additional 18 months.
Occasionally, patients may unexpectedly need to stop DAPT prior to 12 months. We believe the minimum duration of uninterrupted therapy (ie, before which every effort to not stop therapy should be made) is 30 days for patients who receive BMS and six months for patients who receive DES. (See 'Patients needing temporary discontinuation' below.)
The randomized trials presented below did not demonstrate a difference in relative benefit based on risk factors for stent thrombosis. This does not exclude the possibility that some patient groups may derive greater benefit, such as those with :
●Complex PCI (bifurcation or left main stenting, long lesions, saphenous vein grafts)
●Less than optimal stenting result (eg, stent malapposition, residual stenosis)
●Reduced left ventricular systolic function
●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')
Patients at high bleeding risk while on DAPT are considered for treatment of less than 12 months (as short as one month after BMS and six months after DES) duration . These patients include those with a history of transient ischemic attack or stroke, age ≥75 years, propensity to bleed (eg, recent trauma or surgery, recent or recurrent gastrointestinal bleeding, active peptic ulcer disease, severe hepatic impairment, body weight <60 kg [for prasugrel], or concomitant use of medications that increase risk [oral anticoagulants or nonsteroidal antiinflammatory drugs]) . (See "Antiplatelet agents in acute non-ST elevation acute coronary syndromes", section on 'Bleeding risk' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Risk factors' and 'Patients taking anticoagulants' below and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Risk factors'.)
Drug-eluting stents — The optimal duration of DAPT after placement of an intracoronary drug-eluting (and bare metal) stent is not known and it likely depends on patient-specific ischemic and bleeding risks. We recommend at least 12 months of DAPT. For patients who remain free of major (table 2) or moderate (need for transfusion) severity bleeding events after 12 months and who are able to continue this therapy, we suggest continuing DAPT for at least an additional 18 months. We prescribe DAPT for less than one year if a bleeding event occurs or the bleeding risk is high.
The consistent observation of a risk for stent thrombosis for as long as one year (and longer) after placement of a DES led to an early recommendation for at least one year of DAPT. (See "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Drug-eluting stents'.) Our approach to long-term antiplatelet therapy in patients who have undergone elective stenting is based on the following evidence.
The DAPT trial randomly assigned 9961 patients who had been successfully treated with 12 months of aspirin and a P2Y12 receptor blocker (either clopidogrel or prasugrel) to continue receiving the P2Y12 receptor blocker or placebo for another 18 months; all patients continued aspirin . 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 patients, whereas first generation stents were used in the remainder. The following findings were reported:
●The rates for each of the co-primary 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 GUSTO criteria (table 2) 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 non-cardiac deaths (1.0 versus 0.5 percent, p = 0.002), which represents five more deaths per 1000 treated patients per year.
The DAPT trial is the largest of the randomized trials that have compared longer to shorter duration 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 [15-17]. However, they had design limitations that may have prevented the demonstration of benefit.
Multiple meta-analyses, which have included up to 10 randomized trials, have found a significantly higher rate of bleeding and a significantly lower rate of MI or stent thrombosis with longer treatment [18-21]. A small increase in overall mortality with treatment longer than one year, as found in the DAPT trial, has been found in most but not all of these .
A 2015 meta-analysis (nine trials including 29,531 patients), which is representative, found the following comparing longer to shorter duration DAPT :
●A lower risk for MI (risk ratio [RR] 0.73, 95% CI 0.58-0.92). This represents eight fewer MIs per 1000 treated patients per year.
●A higher risk for major bleeding (RR 1.63, 95% CI 1.34-1.99). This represents six more major bleeds per 1000 patients treated per year.
●A higher risk for death (RR 1.18, 95% CI 1.04-1.36). This represents an excess of two deaths per 1000 treated patients per year. There was no increase in cardiovascular mortality.
Each practitioner and his/her patients must weigh the decrease in the risk of MI with the increase in the rate of major bleeding prior to deciding on continuing DAPT after one year. The burden of longer use of a P2Y12 receptor blocker as well as an apparent small increase in the risk of overall death need to be included in decision making.
Additional evidence to support a recommendation for long-term (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 . The primary efficacy end point (a composite of cardiovascular death, MI, or stroke) occurred less often with ticagrelor than with placebo at three years (7.85, 7.77, and 9.04 percent, respectively; hazard ratios 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 2) 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 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).
We do not recommend DAPT for less than one year except in patients at high bleeding risk. The SECURITY, ITALIC, ISAR-SAFE, OPTIMIZE, EXCELLENT, RESET, and PRODIGY trials compared six months of DAPT to 12 months or longer [24-29]. 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), which included only studies comparing shorter duration (three to six months) to 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) .
Bare metal stents — For patients who have received BMS, our recommendations are the same as for DES. (See 'Drug-eluting stents' above.)
If a bleeding event occurs or the bleeding risk is high, we consider limiting therapy to as short as one month in some cases. This is based on the fact that the risk of stent thrombosis with BMS is greatest in the first 14 to 30 days, perhaps because the majority of the process of endothelialization has occurred.
The best evidence regarding the duration of DAPT for more than 30 days in patients who receive BMS comes from the CREDO trial, in which 2116 patients were randomly assigned to a 300 mg loading dose of clopidogrel or placebo prior to PCI . All patients received clopidogrel 75 mg daily through day 28. From day 29 through 12 months, patients in the initial clopidogrel group received clopidogrel 75 mg daily and those in the control group received placebo. All patients received aspirin throughout the study. At one year, the risk of the composite primary outcome of death, MI, or stroke was significantly lower with continuation of clopidogrel (8.5 versus 11.5 percent; relative risk reduction 26.9, 95% CI 2.9-44.4). Indirect support for the use of DAPT for one year comes from the PCI-CURE trial of patients with acute coronary syndromes who underwent stenting with BMS. After one month of clopidogrel plus aspirin, patients were randomly assigned to aspirin plus clopidogrel or aspirin plus placebo for a mean of nine months . Findings were similar to those in CREDO.
In the PCI-CURE and CREDO trials, the benefit of clopidogrel therapy increased over time, with no evidence of a plateau at one year (figure 2 and figure 3). Although neither trial assessed the specific outcome of stent thrombosis, both provide some evidence in favor of clopidogrel therapy for at least one year in patients with BMS.
In an analysis of the 1687 patients in the DAPT trial 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]) . There was no interaction in the analysis between DES and BMS, suggesting that the therapeutic benefit is similar independent of stent type.
Dose and agent — Clopidogrel, prasugrel, ticagrelor, and ticlopidine are platelet P2Y12 receptor blockers. Prasugrel and ticagrelor have been studied in patients with acute coronary syndromes. (See "Antiplatelet agents in acute non-ST elevation acute coronary syndromes", section on 'Platelet P2Y12 receptor blockers' and "Antiplatelet agents in acute ST elevation myocardial infarction", section on 'With fibrinolytic therapy'.) Ticlopidine is rarely used because of its adverse hematologic side effects.
In most randomized trials of stent placement for stable coronary artery disease, clopidogrel was the P2Y12 receptor blocker tested. Thus, we prefer clopidogrel to prasugrel or ticagrelor for most patients requiring DAPT. We recommend a dose of 75 mg daily, which was used in the clinical trials.
We suggest that patients who have undergone elective stenting, irrespective of type of stent, be discharged on 75 to 100 mg/day of aspirin. There have been no randomized trials of differing aspirin doses in stable patients who undergo PCI in the stent era. The issue of the optimal dose of aspirin was addressed in a prespecified subgroup analysis of the 17,263 acute coronary syndrome 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 to those given 75 to 100 mg (4.1 versus 4.2 percent, respectively) . 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 HR 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) .
SPECIFIC PATIENT GROUPS
Patients not likely to comply — Patients who are not likely to comply with a recommendation for one year of dual antiplatelet therapy (DAPT) or who have a planned procedure that requires early cessation of antiplatelet therapy may be better candidates for a bare metal stent (BMS) than a drug-eluting stent (DES) . (See 'Noncardiac surgery or GI endoscopy' below and 'Bare metal stents' above.)
Although DES have been shown to improve outcomes in most patient and lesion subsets, the decision to place a DES rather than a BMS requires careful assessment of the relative benefits and risks [35,36]. The lower rate of repeat target vessel revascularization with a DES must be weighed against the costs of longer-term platelet P2Y12 receptor blocker therapy to prevent stent thrombosis, including an increase in the risk of bleeding while on long-term DAPT and the potentially serious complications of noncompliance, which is often not predictable.
A discussion of the potential difference in the rate of stent thrombosis between stent types is found elsewhere. (See "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Late and cumulative one-year stent thrombosis'.)
Patients taking anticoagulants — Our experts prefer BMS to DES in most patients who require long-term anticoagulation in an attempt to reduce the exposure period to DAPT. The management of patients taking oral anticoagulant and DAPT is found elsewhere. (See "Triple antithrombotic therapy in patients with cardiovascular disease", section on 'Summary and recommendations'.)
Patients needing temporary discontinuation — Although we recommend DAPT for one year 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 and we believe that temporary discontinuation of the P2Y12 receptor blocker after six months may be safe as long as aspirin in continued.
At least four studies have attempted to quantify this risk:
●In the PARIS registry (see 'Premature cessation' below), the hazard ratio for major adverse cardiovascular events was non-significantly higher for patients with interruption (1.41, 95% confidence interval 0.94-2.12) .
●The ACDC study evaluated 1622 individuals who received a DES and were placed on aspirin and clopidogrel and followed for one year . During this time, 111 patients temporarily discontinued at least one antiplatelet agent: clopidogrel was stopped in 31, aspirin in 27, and both drugs in 53. The median duration of cessation was seven days. The rate of acute coronary syndrome was not significantly different between those who discontinued and those who did not.
●In a pooled analysis of data from 4896 individuals in studies of the Resolute zotarolimus-eluting stent (table 1), 1069 had interruption of DAPT: 166 in the first month and 903 between 1 and 12 months . Among those with interruption in the first month, there were six definite/probable stent thrombosis events (3.61 percent). There was one episode of stent thrombosis between 1 and 12 months, a rate that was comparable to those without interruption.
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 GI endoscopy — Noncardiac surgery or gastrointestinal endoscopy are examples of why DAPT may need to be 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 dual antiplatelet therapy be deferred. This issue is discussed in detail elsewhere. (See "Elective 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".)
CAUSES OF TREATMENT FAILURE — The strongest predictor of stent thrombosis between months 1 and 12 is the premature cessation of one or both antiplatelet agents. Other predictors include clopidogrel nonresponse and possibly the use of proton pump inhibitors.
Other predictors of stent thrombosis, including neoatherosclerosis, and its management 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'.)
Premature cessation — The single most important predictor of early and late (at least up to six to nine months) stent thrombosis is absence of one or both antiplatelet agents at the time of the event .
The relationship between cessation of dual antiplatelet therapy (DAPT) and cardiac events after percutaneous coronary intervention was studied using data from 5018 patients in the PARIS registry . At two years, the overall incidence of cessation for any reason was 57.3 percent; the rates of discontinuation (clinician recommended), interruption (stopping for less than 14 days for surgery), and disruption (due to bleeding or noncompliance) were 40.8, 10.5, and 14.4 percent, respectively. Compared to those on DAPT, the hazard ratio for major adverse cardiovascular events (a composite of cardiac death, definite or probable stent thrombosis, spontaneous myocardial infarction, or clinically indicated target lesion revascularization) was significantly higher only for those with disruption (1.50); it was significantly lower for those with discontinuation (0.63). It was non-significantly higher for patients with interruption (1.41, 95% CI 0.94-2.12). (See 'Patients needing temporary discontinuation' above.) The impact of disruption on the risk of stent thrombosis was greater in the first 30 days compared to after 30 days.
However, similar to many other preventative interventions, the optimal use of DAPT does not ensure that a patient will not experience stent thrombosis. For example, in an observational study of over 10,000 patients undergoing drug-eluting stent (DES) placement, those with early stent thrombosis were on DAPT 86 percent of the time and those with late stent thrombosis were on DAPT 57 percent of the time . Similar findings were noted in the PARIS registry, in which 80 percent of the cases of definite or probable stent thrombosis occurred in patients taking DAPT . In these patients, it is likely that one or more predisposing risk factors leading to a prothrombotic environment make it difficult for DAPT to be fully effective. (See "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Risk factors'.)
The timing of late (events from one month to one year) or very late stent thrombosis (events after one year) in relation to discontinuation of one or both antiplatelet agents was evaluated in a review of 161 published cases . At the time of stent thrombosis, 19 patients were on aspirin and thienopyridine, 94 were on aspirin only, 33 had aspirin and thienopyridine stopped simultaneously, and 15 had thienopyridine stopped first and then had aspirin discontinued. The following findings were noted in the 142 patients who had discontinued at least one drug:
●In 33 patients who stopped both antiplatelet agents simultaneously, the mean time to stent thrombosis was seven days.
●In 15 patients who had stopped a thienopyridine with no ill effect and then subsequently stopped aspirin, the median time to stent thrombosis was seven days from the discontinuation of aspirin.
●In the 48 patients who stopped both agents, 75 percent of cases occurred within 10 days.
●In 94 patients with prior discontinuation of thienopyridine but on aspirin, the median time to event was 122 days. In this group, only 6 percent of cases occurred within 10 days.
Clinicians who care for patients treated with DAPT should pay attention to the following issues:
●The risk of noncompliance with recommendations for DAPT must be assessed before the placement of a drug-eluting stent (DES). This should include a discussion in reasonable detail with the patient and relevant caregivers of the pros and cons of DES versus bare metal stents (BMS) and the likelihood of compliance with recommendations for DAPT for a minimum of one year, 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. BMS are preferred when compliance with DAPT is uncertain.
●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.
●Placement of BMS should be considered in patients in whom one or more risk factors for bleeding, particularly from the upper gastrointestinal tract, are present. In the event of major bleeding in a noncompressible area that begins in a patient on platelet P2Y12 receptor blocker therapy, the risks of platelet P2Y12 receptor blocker cessation must be weighed against the risk of prolonged bleeding. Consideration should be given to restarting platelet P2Y12 receptor blocker after bleeding has stopped or is controlled and to strategies to decrease the likelihood of bleeding. (See "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity".)
●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 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 . (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. The optimal approach to screening for or management of clopidogrel resistance/nonresponse is not known and we do not recommend either screening for clopidogrel resistance/nonresponse or using alternative antiplatelet strategies if resistance/nonresponse is found (in patients who are screened), as this strategy has not been shown to improve cardiovascular outcomes. These issues are discussed in detail elsewhere. (See "Clopidogrel resistance and clopidogrel treatment failure".)
Proton pump inhibitors — Gastrointestinal bleeding is a risk of DAPT with aspirin and clopidogrel, particularly at the time of placement of an intracoronary stent when other potent antithrombotic therapy may be used. Some studies have raised the possibility that proton pump inhibitors, which are used to prevent gastrointestinal bleeding in patients at high risk, interfere with clopidogrel’s ability to inhibit platelet function. This issue is discussed in detail elsewhere. (See "Periprocedural and long-term gastrointestinal bleeding in patients undergoing percutaneous coronary intervention", section on 'Prevention' and "Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease", section on 'Primary prevention of aspirin induced GI bleeding' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Proton pump inhibitors' and "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Bleeding'.)
RECOMMENDATIONS OF OTHERS — Our recommendations for the prevention of stent thrombosis after coronary artery stenting in stable patients are generally consistent with those made in guidelines from the American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) in 2011 and the European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) in 2014 [44-46].
It is worth noting that the ACCF/AHA/SCAI guideline makes a strong recommendation for at least 12 months of dual antiplatelet therapy (DAPT) for patients not at high risk of bleeding while the ESC/EACTS guideline recommends individualized treatment with six months of DAPT in most patients with stable coronary artery disease, a shorter duration (<six months) in patients at high bleeding risk, and a longer duration (>six months) in patients at high ischemic and low bleeding risk. Our recommendations expand on these guidelines based on the results of the DAPT trial, which were not available at the time of the previous guidelines.
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 information: Angioplasty and stenting for the heart (The Basics)")
●Beyond the Basics topics (see "Patient information: Angina treatment — medical versus interventional therapy (Beyond the Basics)" and "Patient information: Heart stents and angioplasty (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The risk of coronary artery stent thrombosis and its consequences of myocardial infarction or death are diminished by the use of dual antiplatelet therapy (DAPT) with aspirin and a platelet P2Y12 receptor blocker compared to the use of aspirin monotherapy. (See 'Long-term dual antiplatelet therapy' above and "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Comparison of DES and BMS'.)
●At the time of percutaneous coronary intervention, the choice between bare metal and drug-eluting stents (BMS and DES) should be made after taking into account the patient’s ability to comply with recommendations for the minimum uninterrupted duration of DAPT presented below and the higher risk of restenosis with BMS. (See 'Patients not likely to comply' above.)
●For stable patients treated with either DES or BMS who are not at high bleeding risk and who do not have planned noncardiac surgery within one year, we recommend DAPT for at least 12 months rather than a shorter treatment duration (Grade 1B). Practitioners should evaluate patients after the first 12 months of DAPT to be certain that there has not been major bleeding or other important difficulty related to DAPT. (See 'Duration' above.)
●After one year of successful therapy, practitioners should discuss with their patients the potential benefits and risks of continuing DAPT. For stable patients who have not had a significant complication with DAPT during the first 12 months, we suggest continuing such therapy for an additional 18 months (Grade 2B). It is reasonable for patients to decide to stop DAPT after 12 months if they are particularly concerned about the increased risk of death or bleeding or due to a hardship associated with continuing DAPT. (See 'Drug-eluting stents' above.)
●For patients treated with BMS at high bleeding risk or who have planned noncardiac surgery within one year, we recommend a minimum of one month of uninterrupted DAPT (Grade 1B). For such patients treated with DES, we recommend uninterrupted DAPT for a minimum of six months (Grade 1B). (See 'Duration' above.)
●We recommend that aspirin be continued indefinitely in all stented patients (Grade 1A). (See "Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease", section on 'Summary and recommendations'.)
●With regard to dosing (see 'Dose and agent' above):
•The dose of clopidogrel is 75 mg daily.
- Spaulding C, Daemen J, Boersma E, et al. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007; 356:989.
- Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115:2344.
- Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007; 116:745.
- Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006; 113:1108.
- Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation 2006; 113:2803.
- Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005; 293:2126.
- Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339:1665.
- Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334:1084.
- Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study. Circulation 1998; 98:1597.
- Urban P, Macaya C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation 1998; 98:2126.
- Bertrand ME, Rupprecht HJ, Urban P, et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102:624.
- Sibbing D, Massberg S. Dual antiplatelet treatment after stenting: is longer better? Lancet 2014; 384:1553.
- Ducrocq G, Amarenco P, Labreuche J, et al. A history of stroke/transient ischemic attack indicates high risks of cardiovascular event and hemorrhagic stroke in patients with coronary artery disease. Circulation 2013; 127:730.
- Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371:2155.
- Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014; 129:304.
- Collet JP, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet 2014; 384:1577.
- Campo G, Tebaldi M, Vranckx P, et al. Short- versus long-term duration of dual antiplatelet therapy in patients treated for in-stent restenosis: a PRODIGY trial substudy (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia). J Am Coll Cardiol 2014; 63:506.
- Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015; 385:2371.
- Giustino G, Baber U, Sartori S, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol 2015; 65:1298.
- Palmerini T, Sangiorgi D, Valgimigli M, et al. Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis. J Am Coll Cardiol 2015; 65:1092.
- Spencer FA, Prasad M, Vandvik PO, et al. Longer- Versus Shorter-Duration Dual-Antiplatelet Therapy After Drug-Eluting Stent Placement: A Systematic Review and Meta-analysis. Ann Intern Med 2015; 163:118.
- Elmariah S, Mauri L, Doros G, et al. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. Lancet 2015; 385:792.
- Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372:1791.
- Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013; 310:2510.
- Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125:505.
- Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; 60:1340.
- Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014; 64:2086.
- Gilard M, Barragan P, Noryani AA, et al. 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol 2015; 65:777.
- Schulz-Schüpke S, Byrne RA, Ten Berg JM, et al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J 2015; 36:1252.
- Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288:2411.
- Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358:527.
- Kereiakes DJ, Yeh RW, Massaro JM, et al. Antiplatelet therapy duration following bare metal or drug-eluting coronary stents: the dual antiplatelet therapy randomized clinical trial. JAMA 2015; 313:1113.
- Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010; 376:1233.
- CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363:930.
- Farb A, Boam AB. Stent thrombosis redux--the FDA perspective. N Engl J Med 2007; 356:984.
- Grines CL, Bonow RO, Casey DE Jr, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007; 115:813.
- Mehran R, Baber U, Steg PG, et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet 2013; 382:1714.
- Ferreira-González I, Marsal JR, Ribera A, et al. Double antiplatelet therapy after drug-eluting stent implantation: risk associated with discontinuation within the first year. J Am Coll Cardiol 2012; 60:1333.
- Silber S, Kirtane AJ, Belardi JA, et al. Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following resolute zotarolimus-eluting stent implantation. Eur Heart J 2014; 35:1949.
- van Werkum JW, Heestermans AA, Zomer AC, et al. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry. J Am Coll Cardiol 2009; 53:1399.
- Kimura T, Morimoto T, Nakagawa Y, et al. Antiplatelet therapy and stent thrombosis after sirolimus-eluting stent implantation. Circulation 2009; 119:987.
- Eisenberg MJ, Richard PR, Libersan D, Filion KB. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation 2009; 119:1634.
- Mangano DT, Multicenter Study of Perioperative Ischemia Research Group. Aspirin and mortality from coronary bypass surgery. N Engl J Med 2002; 347:1309.
- Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011; 124:2574.
- Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011; 124:e574.
- Authors/Task Force members, Windecker S, Kolh P, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35:2541.