Version May 2024
INTRODUCTION — Percutaneous coronary intervention (PCI) with placement of an intracoronary stent requires treatment with dual antiplatelet therapy (DAPT) for some period of time, which is as short as one month or as long as up to three years. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)
Such therapy improves outcomes of cardiac mortality and myocardial infarction (MI). Some of the improvement is attributable to a reduction in the incidence of stent thrombosis, a complication often associated with MI and death. However, DAPT is associated with an increased risk of major bleeding. For patients undergoing PCI who are identified as being at high risk of bleeding, shorter durations of DAPT reduce bleeding risk; however, the optimal management strategy is not known. This topic will discuss this issue in detail.
Other relevant topics include:
●(See "Noncardiac surgery after percutaneous coronary intervention".)
●(See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy".)
●(See "Gastrointestinal bleeding in patients undergoing percutaneous coronary intervention".)
●(See "Periprocedural bleeding in patients undergoing percutaneous coronary intervention".)
BACKGROUND AND DEFINITIONS
Definition of high bleeding risk — We use the definition for high bleeding risk (HBR) established in 2019 by the Academic Research Consortium for High Bleeding Risk (ARC-HBR) [1]. The definition states that HBR is present if one major or two minor criteria (risk factors) for major bleeding are present. Major bleeding is defined by the Bleeding Academic Research Consortium (BARC). A patient is felt to be at HBR if the risk of BARC 3 or BARC 5 bleeding (table 1) is predicted to occur at a rate of ≥4 percent at one year or the risk of an intracranial hemorrhage of ≥1 percent at one year is present.
The ARC specifies 20 clinical criteria that predict major bleeding. The ARC points out that as the number of risk factors increases, so does the risk. However, they felt the data were not strong enough to allow for point-based care that would account for the relative weight of HBR criterion. These criteria are presented in a table (table 2).
The ACR-HBR clinical and biochemical criteria have been validated in two studies of 16,580 "real-world" patients who underwent PCI [2,3]. In both studies, there was a stepwise (significant) increase in bleeding risk with the number of criteria present.
Incidence of bleeding after PCI — The incidence of bleeding after PCI in the broad population of patients receiving dual antiplatelet therapy has been relatively well studied [4]. The following studies are representative:
●In the 8582 individuals in the ADAPT-DES study, post-discharge bleeding occurred in 535 (6.2 percent) at a median time of 300 days after discharge [5]. Gastrointestinal bleeding (GI) was the most frequent source (62 percent). (See "Nonresponse and resistance to aspirin", section on 'Observations'.)
●In the EDUCATE registry of 2159 patients who underwent stenting with a second-generation drug-eluting stents (DES), the rate of bleeding by six months was approximately 2 percent [6]. (See 'Prognosis after bleeding' below.)
●In a registry study of 8137 patients who underwent stenting with first-generation DES, 4.8 percent had bleeding-related hospitalization after discharge, and the highest incidence occurred within 30 days of discharge [4]. The most common cause of bleeding was the GI tract. (See "Gastrointestinal bleeding in patients undergoing percutaneous coronary intervention".)
●In a second registry study of 22,798 patients who underwent stenting with first-generation DES, 2.5 percent of patients had bleeding-related hospitalization within 12 months after PCI (56 percent due to GI bleeding) [7].
Assessing individual patient risk — Although we do not routinely assess individual bleeding risk using a risk score (table 2), several are available and can be useful in some cases [8-10]. While there is prognostic value to assessing bleeding risk, such an evaluation does not dictate a particular treatment algorithm. Treatment needs to be individualized based on consideration of both bleeding and ischemic risks.
The PRECISE-DAPT score is a five-item risk score that provides a tool for the prediction of out-of-hospital bleeding during DAPT. The score is calculated from age, creatinine clearance, hemoglobin, white blood cell count, and previous spontaneous bleeding and has moderate ability to predict out-of-hospital TIMI major or minor bleeding (c-index 0.73 derivation cohort, 0.66 to 0.70 validation cohorts). Using a cutoff score of 25 or higher, patients at increased risk of bleeding on longer durations of DAPT are identified [11]. A web-based calculator is available [12].
The HAS-BLED score (table 3), which was developed to assess bleeding risk in atrial fibrillation patients, is a commonly-referred-to bleeding risk score. With HAS-BLED, a value of ≥3 is considered high. It has not been validated in patients receiving DAPT, and it is not used in clinical practice to evaluate bleeding risk in patients undergoing PCI.
Some studies suggest that as many as 44 percent of patients who undergo PCI with current-generation stents are at high bleeding risk [2,13]. Risk prediction models that incorporate identified risk factors (table 2) are available [8-10]. When applied to an individual patient, differences from model to model in the risk of high bleeding risk (HBR) appear. This is likely attributable to the fact that the scores reflect heterogeneity in the patient populations studied, the variables assessed, and the bleeding definitions used in the development cohorts.
PROGNOSIS
Prognosis after percutaneous coronary intervention — High-bleeding-risk patients have worse outcomes after PCI compared with non-high-bleeding-risk patients. A 2020 analysis of 10,502 patients who received a current-generation (cobalt-chromium everolimus) drug-eluting stent (DES) in four all-comers postapproval registries evaluated long-term outcomes. Approximately one-third of patients were identified as high bleeding risk if they had one or more of the following risk predictors: age ≥75 years, history of major bleeding, history of stroke, chronic oral anticoagulant use, chronic kidney disease, anemia, or thrombocytopenia. Compared with non-high-bleeding-risk patients, those at high bleeding risk had more comorbidities, higher lesion complexity, and a higher risk of mortality at four years (15.7 versus 3.8 percent; hazard ratio 4.38, 95% CI 3.76-5.11).
Prognosis after bleeding — Any bleeding, and particularly major bleeding, after percutaneous coronary intervention (PCI) is a risk factor for death and myocardial infarction (MI). The prognosis after gastrointestinal bleeding is discussed separately. (See "Gastrointestinal bleeding in patients undergoing percutaneous coronary intervention", section on 'Outcomes'.)
The poor prognosis in patients who bleed after PCI has been demonstrated in multiple observational studies:
●In the EDUCATE registry of 2159 patients who underwent stenting with a second generation drug-eluting stent (DES), 9.6 percent reported nonadherence to dual antiplatelet therapy (DAPT). Development of a major bleeding event was the only independent correlate of nonadherence during the first six months (odds ratio 12.83) [6]. The risk for death or MI was significantly higher in patients with drug nonadherence associated with major bleeding (22 patients) than in those with drug nonadherence due to other factors (35 versus 7 percent; p<0.001).
●In the ADAPT-DES study (see 'Incidence of bleeding after PCI' above), post-discharge bleeding was associated with an increased rate of all-cause mortality (13 versus 3.2 percent; p<0.001) [5]. The risk of two-year mortality was increased after adjustment (hazard ratio [HR] 5.03; p<0.0001).
●In a retrospective cohort study of 32,906 patients who underwent PCI and survived the index hospitalization, 530 (1.6 percent) had bleeds between 7 and 365 days after discharge. Bleeding was associated with an increase rate of death (adjusted HR 1.61, 95% CI 1.62-2.25) [14].
●In a registry study of 8137 patients who underwent stenting with first generation DES, post-discharge bleeding-related hospitalization after stenting was associated with subsequent death or MI (HR 3.09, 95% CI 2.41-3.96) [4]. The highest risk occurred within 60 of bleeding.
●In a second registry study of 22,798 patients who underwent stenting with first generation DES, post-discharge bleeding was associated with significantly increased risks of death or MI (adjusted HR 2.39 and 3.38) [7].
●In an all-comers postapproval study of 10,502 patients who received DES (see 'Prognosis after percutaneous coronary intervention' above), the risk of death was increased after major bleeding (HR 4.92, 95% CI 3.82-6.35) [13]. The effect was consistent across the spectrum of bleeding risk.
COMPARING BLEEDING AND ISCHEMIC RISK — Dual antiplatelet therapy (DAPT) is given after percutaneous coronary intervention (PCI) in stable patients to reduce the risk of stent thrombosis. This risk is highest during the first 30 days but is quite low if the patient is taking DAPT. After 30 days, the daily risk continues to fall with time. However, the risk of bleeding due to DAPT and its consequences are relatively constant over time. Thus, the benefit from DAPT is greatest during the first 30 days and is smaller after six months.
The impact of bleeding and ischemic events after PCI was examined in a study of 8582 patients who underwent successful PCI with drug-eluting stents [15]. There were 1060 (12.4 percent of the entire cohort) episodes of definite or possible stent thrombosis (0.9 percent), clinical bleeding (8.1 percent), or myocardial infarction not related to stent thrombosis (3.4 percent). The risk of death within 30 days of each for these events was 38.5, 7.3, and 7.5 percent, respectively. This is consistent with much higher mortality risk but low frequency for stent thrombosis, whereas overall ischemic (stent thrombosis or myocardial infarction not related to stent thrombosis) and bleeding occur with similar frequency and carry similar mortality risk.
STENT SPECIFIC CONSIDERATIONS
BMS versus DES — There is no strong evidence to suggest that the use of bare metal stents (BMS) compared with drug-eluting stents (DES) allows for a shorter period of dual antiplatelet therapy (DAPT). In addition, there is evidence suggesting that cardiovascular outcomes are better with DES when DAPT is used for as short a period as 30 days, such as what might be considered in patients at high bleeding risk. The following trials support this concept:
●In the Zotarolimus-eluting Endeavor sprint stent in Uncertain DES candidates (ZEUS) trial, 1606 patients (with stable or unstable symptoms) for whom it was not clear whether DES or BMS was a superior choice (eg, high bleeding risk, low restenosis risk, or high stent thrombosis risk) were randomly assigned to a zotarolimus-eluting stent (ZES) or BMS and treated with DAPT for at least 30 days, after which they received either aspirin or P2Y12 monotherapy [16]. The total duration of DAPT was prespecified based on the reason for inclusion, and the mean duration was 32 days. The primary end point of 12-month major adverse cardiovascular events (including death, myocardial infarction [MI], or target vessel revascularization) occurred less often with ZES (17.5 versus 22.1 percent; hazard ratio [HR] 0.76, 95% CI 0.61-0.95). This was driven by lower rates of MI and target vessel revascularization. The rate of definite or probable stent thrombosis was significantly reduced in ZES patients (2 versus 4.1 percent).
A prespecified analysis evaluated outcomes in 828 patients at high bleeding risk who had at least one of the following: age older than 80 years, clinical indication for treatment with oral anticoagulant agents, recent bleeding episodes that required medical attention or hospitalization, systemic conditions associated with increased bleeding risk, known anemia, and the need for long-term treatment with steroids or nonsteroidal antiinflammatory drugs (NSAIDs) [17]. The primary end point occurred less often with ZES (22.6 versus 29 percent; HR 0.75, 95% CI 0.57-0.98).
●In the LEADERS FREE trial, 2466 patients who were candidates for a BMS rather than a DES due to high bleeding risk were randomly assigned to a polymer- and carrier-free drug-coated stent that transfers umirolimus (biolimus A9) into the vessel wall over one month or a similar BMS [18] (see "Intracoronary stents: Stent types", section on 'Bioresorbable polymer drug-eluting stents'). All patients received DAPT for one month followed by aspirin alone. The primary safety end point (a composite of cardiac death, MI, or stent thrombosis) occurred less often in the drug-coated group at 390 days (9.4 versus 12.9 percent; p = 0.005 for superiority), owing to a difference in spontaneous and type 4C (restenosis-related) MI during follow-up. The primary efficacy end point of target lesion revascularization occurred less often in the drug-coated stent group (5.1 versus 9.8 percent; p<0.001).
●The SENIOR trial randomly assigned 1200 patients aged 75 years or older scheduled to undergo PCI to either a bioresorbable polymer DES or similar thin-strut BMS [19]. DAPT was given for one month in stable patients and six months in those with an acute coronary syndrome. The composite primary end point (all-cause mortality, MI, stroke, or ischemia–driven target lesion revascularization at one year) occurred less often in the DES group (12 versus 16 percent; relative risk 0.71, 95% CI 0.52-0.94).
The ZEUS, LEADERS FREE, and SENIOR trials suggest that even in patients who receive DAPT for as short as 30 days, outcomes are better with some DES compared with BMS. The trials have several limitations including varying definitions of high bleeding risk, lack of power to detect differences in individual endpoints (including stent thrombosis and heterogeneous population), and limited ability to define subgroups that may have different outcomes. A longer course of DAPT in high bleeding risk patients may be considered in complex anatomic anatomy such as left main or bifurcation stenting. In addition, two of the three trials used bioresorbable polymer DES, one of which is not US Food and Drug Administration (FDA) approved. We believe that, despite trial limitations, current generation, thin strut DES with biocompatible durable or bioresorbable polymers should be favored over BMS in most patients at high bleeding risk even when DAPT may be limited to 30 days [20].
DES and DAPT duration — Studies suggest that for high-bleeding-risk patients treated with current-generation DES platforms, short DAPT durations of one to three months, with continuation of a single antiplatelet (aspirin or ticagrelor) out to 12 months, reduce bleeding risk without increasing risk of ischemic events, even among patients with acute coronary syndromes.
Definitions of DAPT regimens are as follows:
●Abbreviated – One to <3 months DAPT with 11 months of single APT (five months in patients with oral anticoagulants).
●Nonabbreviated DAPT – DAPT for minimum three months.
Among high-bleeding-risk patients undergoing current-generation DES implantation, abbreviated DAPT reduced bleeding without an increased risk of death or MI compared with nonabbreviated DAPT [21]. A meta-analysis of DAPT duration in 16,848 high-bleeding-risk PCI patients compared abbreviated DAPT (≤3 months) followed by aspirin or P2Y12 inhibitor monotherapy with nonabbreviated DAPT (6 to 12 months). Six randomized trials and three propensity-matched studies were included. People who received abbreviated DAPT had a lower odds of major bleeding compared with nonabbreviated DAPT (odds ratio [OR] 0.68; 95% CI 0.51-0.89). Those receiving abbreviated DAPT had a similar risk of MI as those receiving nonabbreviated DAPT [OR 1.16; 95% CI 0.94-1.44]. There were also no differences in risks of death, stroke, or stent thrombosis between those receiving abbreviated versus nonabbreviated DAPT [21].
POBA — While it is theoretically possible that performance of plain old balloon angioplasty (POBA) might be a reasonable revascularization strategy to stenting for patients who cannot take DAPT for more than brief periods of time, this approach has not been evaluated. We perform POBA only in rare cases where a stent cannot be delivered or when DAPT cannot be administered for a minimum of 30 days.
Drug-coated balloon angioplasty — Percutaneous coronary intervention using a drug-coated (-eluting) balloon (DCB) offers the possibility of avoidance of long-term dual antiplatelet therapy using an antirestenotic intervention. DCBs are used (primarily in Europe) for the treatment of in-stent restenosis or de-novo lesions in small coronary arteries. There is currently no approved coronary DCB in the United States. (See "Percutaneous coronary intervention of specific coronary lesions", section on 'Small coronary arteries' and "Intracoronary stent restenosis", section on 'Management'.)
The DEBUT trial is the first study to evaluate the use of DCB in patients with large coronary arteries [22]. DEBUT randomly assigned 208 patients with de-novo lesions in a native coronary artery (measuring between 2.5 and 4.0 mm) or bypass graft and risk factors for bleeding to a paclitaxel- and iopromide-coated balloon or a bare metal stent. Exclusion criteria included (but were not limited to) ST-elevation MI, cardiogenic shock, bifurcation lesion requiring a two-stent technique, in-stent restenosis, left main coronary artery disease, or flow-limiting (Thrombolysis in Myocardial Infarction [TIMI] blood flow<3) (table 4) dissection or substantial recoil (>30 percent) of the target lesion after predilation. Both groups received clopidogrel 75 mg and aspirin 100 mg daily for one month in both stable and ACS patients.
The primary end point of cardiovascular adverse events (eg, cardiovascular mortality, non-fatal MI, or ischemia drive target-lesion revascularization at nine months) occurred less often with DCB (1 versus 14 percent, respectively; risk ratio 0.07 percent, 95% CI 0.01-0.52). At nine months, target-lesion revascularization occurred significantly less often with DCB (0 and 6 percent, respectively). Although more patients with diabetes were randomized to the bare metal stent group, adjusted cardiovascular mortality remained lower in the DCB group. Limitations of the trial include premature termination due to slow recruitment, a lower-than-predicted rate of major adverse cardiovascular events, use of bare metal stents as the comparator, and imbalance of randomization with regard to patients with diabetes.
Additional studies are necessary before we recommend the routine use of DCB with one month of dual antiplatelet therapy for patients at risk for bleeding.
MANAGEMENT OF BLEEDING — This issue is discussed separately. (See "Gastrointestinal bleeding in patients undergoing percutaneous coronary intervention", section on 'Treatment' and "Periprocedural bleeding in patients undergoing percutaneous coronary intervention", section on 'Management'.)
OUR APPROACH — For patients undergoing percutaneous coronary intervention (PCI) with stenting who are assessed to be at high bleeding risk (see 'Definition of high bleeding risk' above) for reasons other than long-term use of oral anticoagulant, we pay particular attention to the following two issues: the choice of P2Y12 receptor blocker as well as the duration of dual antiplatelet therapy (DAPT) and the timing of PCI in stable patients.
Our recommendations for patients receiving oral anticoagulant therapy for an indication such as atrial fibrillation, who are by definition at high risk, are found elsewhere. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Summary and recommendations'.)
In practically all clinical scenarios, we choose drug-eluting stents to bare metal stents. (See 'BMS versus DES' above.)
P2Y12 receptor blocker — In patients at high bleeding risk, the specific P2Y12 receptor blocker (and dose) and the duration of DAPT need to be considered carefully. As there is no strong evidence on which to make recommendations, we individualize decision making based on patient characteristics and preferences. As the risk of bleeding increases, we tend to shorten the duration of DAPT. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Summary and recommendations'.)
Agent — In the broad population of patients with stable disease undergoing PCI, clopidogrel (75 mg daily) is the preferred P2Y12 receptor blocker. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Summary and recommendations'.)
In the broad population of patients with acute coronary syndrome (ACS), a more potent P2Y12 inhibitor (ticagrelor or prasugrel) is preferred to clopidogrel due to the higher ischemic risk of these patients compared to stable patients. However, in these patients with ACS, the rate of non-coronary artery bypass graft surgery major bleeding with these more potent agents was higher in the PLATO and TRITON-TIMI 38 trials. In ACS patients at high bleeding risk (see 'Assessing individual patient risk' above) due to use of oral anticoagulants, most of our contributors choose clopidogrel over a more potent P2Y12 inhibitor (see "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Summary and recommendations'). In other high bleeding risk patients, the risks of ischemia and bleeding must be considered when deciding on the potency and duration of the P2Y12 inhibitor. However, age alone is rarely used as a deciding factor. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Invasive management' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Patients receiving primary PCI'.)
Duration — In the broad population of patients with either stable disease or ACS undergoing PCI, we continue DAPT for 6 to 12 months. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration and Type of Antiplatelet Treatment'.)
In high bleeding risk, stable patients, we consider limiting DAPT to as short as one to three months. After this period, either aspirin or P2Y12 inhibitor is discontinued. Our contributors believe the evidence is not sufficiently robust to allow for a recommendation that chooses between the two.
For patients with an ACS, we believe it is reasonable to extend the duration to six months based on the evidence that even unstented ACS patients derive benefit from one year of DAPT. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Duration'.)
Timing of percutaneous coronary intervention — Bleeding risk may decrease with time. Examples include patients who are taking oral anticoagulant for a limited period of time or the removal of upcoming surgery as a risk factor. For patients scheduled for elective PCI, consideration should be given to postponing PCI.
RECOMMENDATIONS OF OTHERS — The 2016 American College of Cardiology/American Heart Association Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease makes the following recommendations for patients treated with percutaneous coronary intervention at high bleeding risk [23]:
●Clopidogrel is the P2Y12 receptor blocker of choice in patients taking an oral anticoagulant.
●For patients with stable ischemic heart disease at high bleeding risk, discontinuation of P2Y12 receptor blocker at three months may be reasonable.
●For patients with an acute coronary syndrome at high bleeding risk, discontinuation of P2Y12 receptor blocker at six months may be reasonable.
The 2015 European guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation states that P2Y12 inhibitor administration for a shorter duration (than 12 months) of three to six months after drug-eluting stent implantation may be considered in patients deemed at high bleeding risk [24,25].
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".)
SUMMARY AND RECOMMENDATIONS
●Background – Multiple risk factors for bleeding after percutaneous coronary intervention (PCI) have been identified. Although we evaluate each patient for the presence of these risk factors, we do not use a formal bleeding risk score to guide therapy. (See 'Definition of high bleeding risk' above and 'Assessing individual patient risk' above.)
●Acute management in patients with high bleeding risk
•In the broad population of patients with stable disease undergoing PCI, clopidogrel (75 mg daily) is the preferred P2Y12 receptor blocker.
•In acute coronary syndrome (ACS) patients at high bleeding risk (see 'Assessing individual patient risk' above) due to use of oral anticoagulants, most of our contributors choose clopidogrel over a more potent P2Y12 inhibitor (ticagrelor or prasugrel). (See 'Agent' above.)
•In other high bleeding risk patients, the risks of ischemia and bleeding must be considered when deciding on the potency and duration of the P2Y12 inhibitor. However, age alone is rarely used as a deciding factor. (See 'Agent' above.)
•In high bleeding risk, stable patients, we consider limiting dual antiplatelet therapy (DAPT) to as short as one to three months. After this period, either aspirin or P2Y12 inhibitor is discontinued. Our contributors believe the evidence is not sufficiently robust to allow for a recommendation that chooses between the two. For patients with an ACS, we believe it is reasonable to extend the duration to six months based on the evidence that even unstented ACS patients derive benefit from one year of DAPT. (See 'Our approach' above.)
●Long-term management in patients with high bleeding risk – Our approach to antithrombotic therapy in stented patients receiving long-term oral anticoagulant therapy is presented separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Our approach'.)
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