Subscribe to RSS
DOI: 10.1055/s-0042-1750419
Resumption of Antiplatelet Therapy after Major Bleeding
- Abstract
- Clinical Impact of Bleeding
- Conclusion
- References
Abstract
Major bleeding is a common threat in patients requiring antiplatelet therapy. Timing and intensity with regard to resumption of antiplatelet therapy represent a major challenge in clinical practice. Knowledge of the patient's bleeding risk, defining transient/treatable and permanent/untreatable risk factors for bleeding, and weighing these against thrombotic risk are key to successful prevention of major adverse events. Shared decision-making involving various disciplines is essential to determine the optimal strategy. The present article addresses clinically relevant questions focusing on the most life-threatening or frequently occurring bleeding events, such as intracranial hemorrhage and gastrointestinal bleeding, and discusses the evidence for antiplatelet therapy resumption using individual risk assessment in high-risk cardiovascular disease patients.
#
Keywords
bleeding - antiplatelet therapy - resumption of antiplatelet therapy - intracranial bleeding - gastrointestinal bleeding - aspirin - dual antiplatelet therapyClinical Impact of Bleeding
Risk Factors for Bleeding on Antiplatelet Therapy
Bleeding under antiplatelet therapy (APT) can occur in the early phase postprocedure (e.g., after coronary or valve interventions), in the intermediate phase from discharge during the first year, or in the chronic phase after the first year of treatment. Major and minor risk factors for bleeding under APT have been recently issued by the Academic Research Consortium. A high bleeding risk (HBR) status is defined by the presence of at least one major or two minor risk criteria ([Fig. 1]).[1]
![](https://www.thieme-connect.de/media/10.1055-s-00035024/202302/thumbnails/10-1055-s-0042-1750419-i220100-1.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
#
Incidence and Case Fatality of Bleeding on Antiplatelet Therapy
Bleeding is associated with higher short-term, i.e., intrahospital, intermediate (up to 12 months), and long-term (beyond 12 months) mortality after the event, which is either caused by case fatality of the bleeding event itself or by thromboembolic complications after temporary or permanent discontinuation/disruption or modification of APT.[2] [3] [4] [5] [6] [7] In many cases, treating physicians tend to discontinue APT even after nonmajor bleeding events. Cessation of antithrombotic therapy has been defined in the literature as discontinuation (physician-recommended withdrawal), interruption (temporary cessation of antiplatelet treatment due to surgical necessity with resumption within 14 days), or disruption (cessation of antiplatelet treatment due to bleeding or noncompliance).[8] [9] In the Patterns of nonadherence to Antiplatelet Regimens In Stented patients (PARIS) registry,[8] the risk of major adverse cardiovascular events (MACE) was approximately sevenfold higher in the first week after disruption of dual antiplatelet therapy (DAPT). An observational cohort study suggested that those who discontinued P2Y12 inhibitor after 3 months or had poor initial adherence had higher MACE risk compared with those with persistently good adherence over 12 months.[10]
If a patient has a bleeding tendency, the majority of major bleeding events occur early (within 3 months) after initiation of DAPT. Shortening of DAPT duration (from 3 to 1 month) is associated with a significant decrease of major bleeding in patients with a HBR (2.1 vs. 1.0%).[11] Although the rates of major bleeding decrease over time, there remains a persistent annual major bleeding rate of approximately 0.4% with low-dose acetyl salicylic acid (ASA) and 0.6 to 0.9% with DAPT in the chronic phase beyond 1 year.[12] Among patients treated with DAPT, gastrointestinal bleeding (GIB) accounts for about two-thirds of all bleeding events.[13] GIB occurs in 3 to 4% of cases in the first year of DAPT.[13] The bleeding rates reported in randomized trials need to be evaluated with caution when translating into the real world. In clinical trials, patients often either underwent a run-in period of event-free DAPT to be included or were excluded due to bleeding risk criteria ([Table 1]). Precise numbers of major and clinically relevant nonmajor bleeding events in true all-comer populations are sparse but likely higher than in well-controlled clinical trials.[14] In addition, bleeding rates differ with regard to bleeding definition, type of APT, and indication, timing and duration of APT ([Table 1]). In the PLATelet inhibition and patient Outcomes (PLATO) trial, non-coronary artery bypass graft (non-CABG)-related major bleeding occurred at similar rates under ticagrelor and clopidogrel (2.47 vs. 2.21%) during the first 30 days, and at a significantly higher rate of 2.17% versus 1.65% after 30 days until the end of study treatment with ticagrelor.[15] Similarly, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON)-Thrombolysis In Myocardial Infarction (TIMI) 38 trial, TIMI major non-CABG-related bleeding rates with prasugrel were similar to clopidogrel during the first 3 days (0.74 vs. 0.61%) but were significantly higher with the use of prasugrel from 3 days to the end of study drug treatment (1.71 vs. 1.23%).[16] In the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared with Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction (PEGASUS)-TIMI 54 trial, long-term DAPT with ticagrelor beyond 1 year post-myocardial infarction (MI) was associated with a 3-year major bleeding rate of 2.6% (90 mg bid) and 2.3% (60 mg bid) versus 1.1% with ASA alone and intracranial hemorrhage (ICH) rates of 0.56% (90 mg bid) and 0.61% (60 mg bid) versus 0.47% with ASA alone.[17] Similarly, moderate-to-severe bleeding events occurred in 2.0% of cases under long-term treatment with clopidogrel plus ASA in the DAPT trial. Case fatality was high with an annualized mortality rate after a bleeding event of 21.5 (95% confidence interval [CI): 15.4–29.1) per 100 person-years.[18]
Type of APT |
Indication |
Incidence/risk increase of major bleeding events |
Incidence of intracranial hemorrhage/fatal bleedings |
---|---|---|---|
SAPT |
|||
Low-dose ASA |
Primary prevention |
0.23 per 100 patient-years[86]; 29% increased risk of major bleeding (mostly gastrointestinal) in diabetics,[35] 87% increased risk of upper GIB in healthy elderly,[36] 37% increased risk for ICB versus control[87] |
0.3%, no increase versus control[36] |
Secondary prevention in CVD patients |
Major bleeding 1.9%[88]; ∼60% increased risk of major extracranial bleeds (mostly gastrointestinal) compared with placebo[89] [90] [91] |
FB: 0.1%[88] |
|
Clopidogrel monotherapy |
Secondary prevention in patients with a history of ischemic stroke, myocardial infarction, or symptomatic atherosclerotic peripheral arterial disease. |
Severe bleeding with clopidogrel versus ASA monotherapy: 1.38 versus 1.55% (nonsignificant); severe GIB (0.49 vs. 0.71%, p < 0.05)[38] |
Nonfatal primary ICH or FB: 0.39% in the clopidogrel group versus 0.53% in the aspirin group[38] |
Secondary prevention after PCI (event free under DAPT for 6–18 months) |
1.2% over 2 years (vs. 2.0% compared with ASA monotherapy)[39] |
ICH: 0.2% over 2 years FB: not reported separately |
|
Ticagrelor monotherapy |
PCI with high-risk criteria (event free under DAPT for 3 months) |
BARC bleeding 3–5 1.0% over 12 months[41] BARC 3 or 5 bleeding 1.6% over 12 months in HBR patients[82] |
ICH/FB: not reported separately |
DAPT |
|||
ASA + clopidogrel |
ACS ± PCI |
Non-CABG PLATO-major bleeding 3.8%, non-CABG TIMI-major bleeding 2.2%[15] |
FB: 0.3%[15] |
Chronic coronary syndromes |
Major bleeding 0.2 to 1.3% with short duration and 0.2 to 2.3% with long duration DAPT[92] |
||
Secondary prevention in patients with documented CAD, cerebrovascular disease, PAD, or multiple atherothrombotic risk factors |
GUSTO severe bleeding according 1.7% in the ASA + clopidogrel group and 1.3% in the ASA + placebo group (relative risk: 1.25; 95 CI: 0.97–1.61; p = 0.09)[93] |
Primary ICH 0.3 in both ASA + clopidogrel and ASA + placebo-treated patients FB: 0.3 (ASA + clopidogrel) versus 0.2% (ASA + placebo)[93] |
|
Extended therapy |
BARC 3 bleeding 2.6% during 18 months extended treatment[94] |
FB: 0.1%, no increase versus placebo[18] |
|
ASA + prasugrel |
ACS + PCI |
Non-CABG TIMI-major bleeding 2.4%[95] |
FB: 0.4%, increased versus ASA + clopidogrel (HR: 4.19)[95] |
ASA + ticagrelor 90 mg/bid |
ACS ± PCI |
Non-CABG major bleeding 4.5%[15] |
FB: 0.3%, no increase versus ASA + clopidogrel[15] |
ASA + ticagrelor 60 mg/bid |
Extended therapy (beyond 12 months, post-MI) |
Year 1: 0.86%; year 2: 0.86%; year 3: 0.6%[12] |
ICH: year 1: 0.15%; year 2: 0.18%; year 3: 0.28% FB: year 1: 0.11%; year 2: 0.04%; year 3: 0.11%[12] |
Abbreviations: ACS, acute coronary syndrome; ASA, acetyl salicylic acid; BARC, Bleeding Academic Research Consortium; CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; CVD, cardiovascular disease; FB, fatal bleeding; HR, hazard ratio; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction; UGIB, upper gastrointestinal bleeding.
#
Trade-Off between Bleeding and Ischemic Risk
Clear classification of the bleeding severity according to established bleeding risk classifications (i.e., Bleeding Academic Research Consortium [BARC], International Society of Thrombosis and Haemostasis [ISTH] bleeding classification; [Table 2]) and the individual assessment of bleeding recurrence and thrombotic risk are of utmost importance. In a retrospective study of the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, the risk for mortality after major bleeding (BARC 3b + c) was almost equal to the mortality risk after MI. However, compared with bleeding with lower severity (BARC 2 and 3a), the mortality after MI clearly outweighed the bleeding-associated mortality risk.[19] Thus, the trade-off between cardiovascular versus bleeding-associated mortality needs to be clearly defined ([Fig. 2]). Although scores that weigh the antithrombotic benefit against the bleeding risk of continued DAPT have not been evaluated up to now in acute bleeding situations, they might aid decision-making about the net benefit of prolonged APT in HBR patients. Several contemporary scores evaluate the bleeding risk and trade-off between bleeding and ischemic risk, and weigh the net benefit of prolonged versus shortened DAPT. Their utility in clinical routine is limited by their inability to discriminate between bleeding and ischemic risks as well as by the characteristics of the patient population and APT in the derivation cohorts[1] [20] [21] [22] [23] [24] [25] ([Table 3]).
![](https://www.thieme-connect.de/media/10.1055-s-00035024/202302/thumbnails/10-1055-s-0042-1750419-i220100-2.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
Abbreviations: BARC, Bleeding Academic Research Consortium; ISTH, International Society on Thrombosis and Haemostasis.
Score |
Patient population/predominant type of APT |
Risk factors in the primary model |
Correlation with bleeding in the derivation cohort |
Trade-off between bleeding and ischemic risk |
Clinical utility/validity in real world |
---|---|---|---|---|---|
DAPT (total score range: −2 to 10)[22] |
PCI patients completing 12-month DAPT (60% ASA + clopidogrel, 40% ASA + prasugrel) |
Age (categorized) Smoking Diabetes mellitus MI at presentation Prior PCI or MI Paclitaxel-eluting stent Stent diameter < 3 mm CHF or LVEF < 30 Vein graft stent |
AUC 0.68 for moderate to severe bleedings (GUSTO) between 12 and 30 months under of prolonged DAPT. |
Score ≥2 is associated with a favorable benefit/risk ratio for prolonged DAPT, whereas a score <2 is associated with an unfavorable benefit/risk ratio |
Ability to stratify ischemic benefit across different DAPT patient cohorts[99] [100] [101] [102] |
PARIS (range: 0–14)[23] |
PCI + drug-eluting stent (>90% ASA + clopidogrel) |
Score for bleeding (PARIS MB): age (percentiles > 50 years) BMI Current smoking Anemia CrCl < 60 mL/min Triple therapy on discharge |
AUC for major bleeding (BARC 3 or 5) at 2 years: 0.72 |
AUC 0.64 validation cohort (ADAPT-DES)[103] |
|
PRECISE-DAPT (range: 0–100)[20] |
PCI + stent (ASA + clopidogrel (88%)) |
Age (continuous), creatinine clearance, hemoglobin, previous bleeding, and white blood cell count (simplified version excluding white blood cell count[104] |
AUC 0.71 for TIMI major bleedings within 12 months |
Longer DAPT duration reduced the composite ischemic endpoint (MI, definite ST, stroke, or target vessel revascularization) in those at non-high bleeding risk |
Recommended in current guidelines,[7] [31] reproducible in real-world cohorts, limited usefulness in patients with MI and pre-existing risk factors for bleeding[103] [105] [106] |
PRAISE[24] |
ACS (ASA + clopidogrel (64%), + ticagrelor (21%), + prasugrel (15%)) |
16 clinical variables[a], five therapeutic variables[b], two angiographic variables[c], and two procedural variables[d] |
AUC for major bleeding within 12 months: 0.70 in the internal validation cohort |
Robust hypothetical trade-offs in the occurrence of ischemic and bleeding events according to individual MI and major bleeding score classes[24] |
High predictability and good discrimination of the trade-off (AUC >0.8 for mortality, MI, and major bleeding in an external validation cohort).[24] Allowing for differentiation of the use of potent P2Y12 inhibitors in different bleeding/thrombotic risk subsets.[107] Further external validation required. |
Consensus definition of HBR in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing PCI |
Combination of major and minor risk factors; see [Fig. 1] |
No AUC in primary publication/consensus document |
Eight independent predictors of MI and/or ST, 8 predictors for risk of BARC types 3 to 5 bleeding; both risk models showed moderate discrimination; AUC = 0.69 for predicting MI and/or ST and 0.68 for predicting BARC types 3 to 5 bleeding.[21] |
Recommended in current guidelines,[7] [31] reproducible validation in external cohorts, high sensitivity, limited specifity[108] [109] |
|
BleeMACS (range: 0–80)[25] |
Patients with ACS undergoing PCI (ASA + clopidogrel (91%), + ticagrelor (4%), + prasugrel (5%)) |
Age (categories), Hypertension, vascular disease, history of bleeding, Malignancy, creatinine (categories) hemoglobin |
AUC: 0.71 for 1-year major bleeding in derivation cohort (0.72 internal validation) AUC: 0.65 (ACS + PCI); AUC: 0.63 (ACS) |
Not validated |
Acceptable performance in elderly ACS patients[110]; further validation required |
Abbreviations: ACS, acute coronary syndrome; ASA, acetyl salicylic acid; AUC, area under the curve; BARC, Bleeding Academic Research Consortium; CHF, congestive heart failure; DAPT, dual antiplatelet therapy; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.
a Age, sex, diabetes, hypertension, hyperlipidemia, peripheral artery disease, estimated glomerular filtration rate (EGFR; using the Modification of Diet in Renal Disease study formula), previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass graft, previous stroke, previous bleeding, malignancy, STEMI at presentation, hemoglobin, and left ventricular ejection fraction [LVEF].
b Treatment with β blockers, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, statins, oral anticoagulation, and proton-pump inhibitors.
c Multivessel disease and complete revascularization.
d Vascular access and percutaneous coronary intervention with drug-eluting stent.
#
Evaluation before Resumption of Antiplatelet Therapy
Has the Bleeding Stopped?
Determining whether a major bleeding event has stopped depends on the source and severity of the bleeding and may require multidisciplinary evaluation. Repeated diagnostic assessment might be required to determine cessation of a bleeding event, including close measurements (daily or even hourly depending on urgency of bleeding) to document hemoglobin drops. Repeated computed tomography (CT) scans can help to determine the time point of cessation of ICH and complications of the bleeding potentially requiring neurosurgical intervention (e.g., hydrocephalus). In addition, CT angiography and post-contrast CT may aid in identifying patients at high risk of hematoma expansion according to the presence of contrast within the bleed, defined as “spot signs,” or brain vascular malformation.[26] Scores that included further information on number of spot signs, dimension, and attenuation have been shown to be predictive for mortality and poor outcome.[27] Evaluation of spot sign dynamics on CT perfusion source images might yield even better prognostic information with regard to hematoma expansion.[28]
In case of GIB, repeated endoscopy may provide information about the localization and cause of the bleeding. The use of endoscopy can effectively contribute to treatment of the bleeding lesion, e.g., by epinephrine injection, cauterization, variceal band ligation, and metal clip placement. Endovascular angiography[29] and medical options such as octreotide infusions may also be considered for bleeding from angioectasia,[30] when endoscopic therapies fail or when bleeding originates from less accessible locations such as the small bowel. Thus, in many situations, GIB can be effectively controlled to allow a timely resumption of APT if indicated.
#
Is Antiplatelet Therapy Still Needed?
The question whether APT is still needed after a bleeding event and, if so, at what potency and duration is subject to individual risk–benefit assessment. In many cases, antithrombotic therapy can be shortened according to recent guideline recommendations.[31] Individualized strategies to reduce the bleeding risk by mitigating APT should include the type of intervention and the initial drug strategy. Thus, use of an abbreviated DAPT duration with ultrathin stents has been shown to reduce bleeding risk in HBR patients without substantially increasing ischemic risk, including stent thrombosis.[32] Recently, recommendations to guide the design of clinical trials of devices and drugs in HBR patients undergoing percutaneous coronary intervention (PCI) have been proposed.[33]
#
ASA Used for Primary Prevention in Individuals with Low or Moderate Risk for Ischemic Events
ASA may be considered for primary prevention in high- and very high-risk individuals according to the SCORE2 and SCORE2-OP risk classifications[34] given its unfavorable net benefit versus placebo in moderate risk or diabetic patients.[35] [36] Resumption of ASA used for primary prevention after a bleeding event should therefore be avoided in low-risk patients and discussed on a case-by-case approach in high- and very high-risk patients given its accumulating benefit over time.[37]
#
SAPT for Secondary Prevention
The most common single antiplatelet therapy (SAPT) for secondary prevention in cardio-, cerebrovascular, and peripheral artery disease is aspirin. However, there are cumulative data demonstrating clopidogrel monotherapy to be as effective and safer than aspirin for chronic maintenance monotherapy.[38] [39]
#
Dual Antiplatelet Therapy
Duration of DAPT can be reduced down to 1 month in patients undergoing elective PCI with modern stents and to 1 to 3 months after acute coronary syndrome (ACS) in high and very high bleeding risk patients according to recent guidelines.[31] [32] [40] De-escalation to less potent P2Y12 inhibitors or early switching to P2Y12 inhibitor monotherapy has been established as effective strategies to prevent bleeding in HBR patients and in patients in whom the trade-off prevails on the bleeding risk side ([Table 3]).[41] [42] [43] [44] [45] [46]
#
What Caused the Bleeding?
Risk factors for bleeding can be classified into reversible and irreversible factors ([Table 4]). The question of what caused the bleeding is closely linked to the question of which modifiable factors may have contributed to the bleed and whether definitive treatment of these factors has been achieved. Identification of reversible/modifiable and irreversible factors as well as the risk for recurrence is important to provide an individual strategy to resume APT.
Reversible causes of bleeding |
Irreversible causes of bleeding |
---|---|
General factors |
|
Arterial hypertension Alcohol abuse Drug abuse |
Older age (≥75 years) History of major spontaneous bleeding Malignancy Genetic factors Cirrhotic liver disease Uncontrollable arterial hypertension Hematologic abnormalities (e.g., low platelet count <50.000 per µL) Dialysis-dependent kidney disease or renal transplantation[111] |
Specific factors |
|
GI bleeding |
|
Small bleeding ulcer that can be treated by endoscopic therapy Bleeding from gastric ulcer associated with Helicobacter disease |
Bleeding from sources that cannot be sufficiently treated by surgery or endoscopic procedures e.g., colonic tumor, angiodysplasia |
Intracranial bleeding |
|
Traumatic cause of ICH Poor INR control, overdosing of antithrombotic therapies |
Cerebral amyloid angiopathy Vascular abnormalities that cannot be treated by surgical or interventional procedures. Spontaneous ICH without identifiable risk factors (e.g., poor INR control) |
Abbreviations: ICH, intracranial hemorrhage; INR, international normalized ratio.
#
Recurrence of Bleeding after Resumption of Antiplatelet Therapy
The dilemma of weighing the benefit against the harm of resumption of antithrombotic therapy warrants interdisciplinary discussion for defining both severity of bleeding and risks of bleeding recurrence and thromboembolic events. [Table 4] summarizes risk factors for bleeding recurrence after ICH and major GIB. In addition, bleeding event history and comorbidities add to the bleeding risk recurrence and should be carefully included in the risk assessment, especially if risk factors cannot be controlled. Additional bleeding risk factors include those listed in the ARC-HBR classification scheme ([Fig. 1]).[1] The use of biomarkers like growth differentiation factor-15 has been investigated to determine recurrent bleeding risk and recurrent events in post-hoc analyses of large clinical trials.[47] However, its use in clinical routine is still limited.
#
Risk of Recurrence of Gastrointestinal Bleeding
Predictors of recurrent GIB risk and bleeding fatality depend on the cause of bleeding. Thus, worse outcomes are associated with chronic alcoholism and active cancer.[22] Risk scoring systems have been evaluated to predict the risk of mortality and rebleeding after GIB. The Rockall scoring system[48] and the Glasgow–Blatchford Scale[49] are scoring systems that include clinical, laboratory, and/or endoscopic findings. These risk scores are used to predict the mortality associated with GIB, the urgency of endoscopy, and likelihood of endoscopic intervention, but they have not been validated for guidance regarding resumption of APT. The endoscopic appearances of a peptic ulcer, as described by the Forrest classification,[50] may be used to predict the risk of rebleeding in the period soon after an endoscopy. Patients with actively bleeding ulcers or ulcers with a visible blood vessel have a much greater risk of rebleeding than ulcers with a clean base.[51] It is important to evaluate whether the GIB occurred during proton-pump inhibitor (PPI) treatment or not. If the upper GIB happens under effective PPI treatment, this might be an indicator to stop or reduce APT on an individual basis if there are no other reversible factors (Helicobacter pylori [HP], nonsteroidal anti-inflammatory drug, endoscopic therapy). Initiation of effective gastroprotection is a way to prevent recurrent bleeding. A randomized placebo-controlled trial showed that high-dose intravenous PPI treatment (omeprazole 80 mg bolus then 8 mg/h infusion for 72 hours after endoscopic therapy)[52] in patients who had undergone endoscopic treatment of peptic ulcers effectively reduced the risk of rebleeding compared with endoscopy and placebo. Recent meta-analyses support the use of PPI therapy to promote healing of peptic ulcers thus reducing bleeding and mortality in patients at risk for upper GIB.[53] [54] There is no randomized controlled trial (RCT) that has evaluated the use of different PPI regimens and durations in patients that require resumption of antithrombotic therapy after major GIB. The common-sense view of the authors is that PPI therapy should be continued indefinitely at standard dose in patients with major upper GIB unless there are clear contraindications. Active HP infection is frequent with a reported prevalence of 20% in acute MI patients and still is an underestimated risk factor for GIB in patients treated with DAPT.[55] [56] [57] Therefore, HP screening, eradication, and gastroprotective measures are important to minimize recurrent GIB risk.[57] [58] [59]
#
Risk of Recurrence after Intracranial Bleeding
The REstart or STop Antithrombotics Randomized Trial (RESTART) evaluated the efficacy and safety of restarting APT after ICH. APT could be restarted in the interventional arm by using either one or a combination of ASA, dipyridamole, or clopidogrel at any time beyond 24 hours (median: 76 days) after randomization. In the comparator arm, no APT was allowed. However, it was permitted to start or discontinue APT or anticoagulant therapy if clinically indicated during follow-up, regardless of initial treatment allocation. Interestingly, RESTART demonstrated a reduced risk of both thromboembolic events and hemorrhagic strokes in patients restarting APT.[60] [61] These observations were recently confirmed in an extended follow-up at a median of 3.0 years.[62] Given the variable time points of restarting APT in RESTART, the optimal time interval from ICH is still uncertain.
Arterial hypertension is a major cause underlying ICH, and consensus exists that blood pressure should be well controlled after ICH.[63] Also, other modifiable risk factors promoting continued stress to the already fragile vessel wall, or progressive endothelial damage such as in diabetes, should be treated before re-initiating any kind of antithrombotic regimen after ICH.[64] [65] Risk of ICH recurrence is higher in patients with lobar intracerebral bleeds compared with those with hemorrhage in deep subcortical brain structures; nonetheless, resumption of APT seems beneficial with regard to mortality and functional outcome even in patients who suffered from a lobar bleed.[60] Superficial hemosiderosis and microbleeds are not visible on CT but their presence, number, and location can be visualized on magnetic resonance imaging (MRI) and have been linked to the risk of ICH,[61] [66] A nearly fivefold increased ICH risk has been observed in patients with five or more microbleeds.[67] However, even in patients with more than 20 microbleeds, the rate of ischemic stroke exceeded that of ICH.[67] Whereas microbleeds in the white matter or basal ganglia result from small vessel disease due to long-lasting arterial hypertension or diabetes, i.e., treatable conditions, cortical microbleeds are found in patients with (untreatable) cerebral amyloid angiopathy and are regarded as a precursor of atypical lobar bleeds. MRI might thus be superior to CT when it comes to selection of ICH candidates for restarting antithrombotic therapy ([Fig. 3]).[68]
![](https://www.thieme-connect.de/media/10.1055-s-00035024/202302/thumbnails/10-1055-s-0042-1750419-i220100-3.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
#
#
Strategies to Resume Antiplatelet Therapy
What Are the Patients' Overall Goals of Care?
The main goal of restarting APT is to prevent ischemic events without increasing bleeding events and to reduce mortality and disability caused by recurrent stroke. For most patients, APT, if indicated, should be restarted after most bleeding events, considering that, for most of the therapies, fatal bleeding during APT is rare ([Table 1]) and so the risk–benefit assessment does not favor permanent discontinuation of therapy. The mortality risk associated with major adverse events, e.g., MI or stroke, outweighs the risk of dying from minor or moderate bleeding events (e.g., BARC 2 and 3a bleeding).[19] Interruption and resumption of APT should be individually tailored according to bleeding severity/location, indication for antithrombotic therapy, risk for bleeding recurrence, and thrombotic risk. APT should only be interrupted in case of major/severe bleeding. In clinically relevant but not major bleeding events, therapy in patients with clear indication for APT can be safely continued in most cases after short interruption. There is no need for interruption of APT in patients with minor/trivial bleeding events.
#
Restarting/De-escalating Antiplatelet Therapy
The need for continuation of APT should be carefully assessed by weighing thrombotic versus bleeding risk. The impact of early resumption (immediately after endoscopic therapy) of low-dose ASA therapy was investigated in a small placebo-controlled trial in 156 patients presenting with bleeding from peptic ulcer during ASA treatment. Within 30 days, the incidence of recurrent ulcer bleeding was 10.3% of patients who continued ASA treatment versus 5.4% in patients receiving placebo (p = 0.25). All-cause mortality was markedly lower in the ASA group compared with the placebo group (1.3 vs. 12.9%, p = 0.005). The low statistical power does not allow definite conclusions to be drawn from this trial.[69] A recent meta-analysis including this RCT and observational studies reports inconsistent evidence for a protective effect of aspirin resumption soon after nonvariceal upper GIB.[70] Current guidelines recommend resumption of aspirin for secondary prevention within 3 to 7 days after upper GIB cessation.[71] [72] The European Society of Gastrointestinal Endoscopy recently recommended determining the time point of ASA re-initiation based on endoscopic classification of peptic ulcer classification. In patients with low-risk endoscopic stigmata identified by Forrest classification IIc or III, ASA should be restarted immediately. In patients with high-risk stigmata (Forrest Ia, Ib, IIa, IIb), ASA should be restarted at day 3, given that adequate hemostasis could be achieved.[73] Extrapolating data from patients undergoing polypectomy show a similar bleeding risk between patients discontinuing and those continuing ASA.[74] The American College of Gastroenterology (ACG) recommends not to discontinue ASA for secondary prophylaxis in patients with established cardiovascular disease in the setting of lower GIB.[75]
In some situations, permanent cessation or de-escalation of DAPT may be considered. In patients with major bleeding, the duration of DAPT can be shortened to 1 month after elective PCI and to 6 months or less after ACS according to recent guidelines.[7] [31] [40] There are accumulating data from trials indicating safety of 1 month DAPT in high-bleeding-risk patients treated with modern drug-eluting stents.[32] [44] [76] [77] [78] In patients with ACS undergoing PCI, the highest risk for recurrent cardiovascular event lies within the first 3 months and cessation of DAPT within the first month is associated with high risk of MACE and stent thrombosis.[9] Therefore, longer periods of discontinuation of DAPT (i.e., ≥5 days) should be avoided in this vulnerable phase. Of note, the bleeding event itself can trigger a prothrombotic condition by inflammatory processes, but also by the administration of blood products, coagulation factors, and antidotes. Therefore, in patients with temporary enhanced bleeding risk and high thrombotic risk requiring DAPT (e.g., patients with a recent major bleeding and acute MI), antiplatelet compounds with short offset of action, i.e., cangrelor might be a temporary option. However, there is only limited experience with regard to safety and efficacy profile in bleeding situations. According to the product labels, the use of cangrelor, eptifibatide, and tirofiban is off-label in bleeding situations. Based on previous consensus documents, it is advisable to restart DAPT within 3 days after moderate GIB.[9] [73] DAPT should be interrupted for a longer period after major GIB and may be resumed after 7 to 15 days in patients with low/moderate risk of recurrence.[73] [79] There is no clear consensus if early re-initiation of a P2Y12 inhibitor and omission of ASA is associated with a favorable risk–benefit profile early after major GIB. The ACG guideline recommends that, in patients on DAPT or SAPT with clopidogrel, non-ASA-based APT should be resumed as soon as possible and at least within 7 days based on multidisciplinary assessment of cardiovascular and gastrointestinal risk. A second endoscopic examination may help to evaluate the further risk after initiation of DAPT. DAPT should not be discontinued in patients with an ACS within the past 90 days or coronary stenting within the past 30 days (strong recommendation, low-quality evidence).[75] SAPT should be maintained if possible in most instances. Concomitant long-term therapy with PPIs should be implemented if not already started.[73] [80] In addition, de-escalation therapy to DAPT with clopidogrel in post-ACS patients after a short period of DAPT with prasugrel or ticagrelor might be applicable to HBR patients, which has shown to be beneficial regarding reduction of bleeding in recent trials.[42] [46] [81] This includes de-escalation guided by platelet function or genetic testing, which has demonstrated favorable effects in a recent meta-analysis[46] and could be particularly useful in patients with both high bleeding and ischemic risk. Early switching to monotherapy after 1 to 3 months of DAPT to ticagrelor[41] [45] [82] or clopidogrel[44] monotherapy represents alternative strategies to reduce future bleeding events without losing efficacy in selected patients. Availability of the specific antidote (i.e., antibody-based antidote bentracimab [PB2452] for ticagrelor) may be relevant when choosing the oral P2Y12 inhibitor for long-term treatment in HBR patients. However, there are limited data on efficacy and safety in acute bleeding situations and the antidote is not yet available.[83]
#
Restarting Combination Therapy (Anticoagulation + APT)
Triple therapy should be avoided in patients with atrial fibrillation (AFIB) undergoing PCI who experienced a prior major bleeding event. The better safety of dual antithrombotic therapy consisting of non-vitamin-K-antagonist oral anticoagulants (NOACs) plus a P2Y12 receptor inhibitor compared with triple therapy[2] [84] is established and highly recommended.[31] [85] In HBR patients, switching from triple therapy (NOAC + DAPT) to dual therapy (NOAC + P2Y12 inhibitor) and from vitamin-K antagonists to NOAC are possible strategies to reduce the bleeding risk. In case bleeding occurred under dual antithrombotic therapy (NOAC + SAPT), dose reduction of NOAC to the lowest effective dose should be considered.[7] Although the preferred dosing for patients with AFIB undergoing PCI in general should be the highest approved NOAC dose, if indicated, the current guidelines recommend lowering the dose in HBR patients.[85] If risk for recurrent bleeding remains high even under a reduced NOAC dose, left atrial appendage occlusion may be considered in patients to get along with APT only for long-term treatment.
#
#
#
Conclusion
Growing use of antithrombotic drugs in the elderly and frail patients leads to more bleeding events and challenging situations with respect to resuming therapies. The clinician often faces the dilemma of whether and when to restart APT after a bleeding event. Risk estimation requires a multidisciplinary team discussion to adequately determine the risk for thrombosis and bleeding recurrence. Guidance on the optimal time point to resume APT is based on retrospective registry data analysis and expert consensus. The presented review and algorithm ([Fig. 4]) provide guidance based on an individual dynamic risk assessment and advocate for enrollment of patients in one of the ongoing trials ([Table 5]). Potential strategies to reduce future bleeding risk by modification of antithrombotic therapy are summarized in [Table 6].
![](https://www.thieme-connect.de/media/10.1055-s-00035024/202302/thumbnails/10-1055-s-0042-1750419-i220100-4.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
Abbreviations: ACS, acute coronary syndrome; ASA, acetyl salicylic acid; DAPT, dual antiplatelet therapy; ICH, intracranial hemorrhage.
Abbreviations: ACS, acute coronary syndrome; ASA, acetyl salicylic acid; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; LAA, left atrial appendage; NOAC, non-vitamin-K-antagonist oral anticoagulant; SAPT, single antiplatelet therapy.
#
#
Conflict of Interest
T.G. reports personal fees from Astra Zeneca, Boehringer Ingelheim, Pfizer, Boston Scientific, and Abbott; grants and personal fees from Bayer Healthcare, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, and Medtronic outside of the submitted work. T.G. was supported by the German Research Foundation (DFG) KFO-274—Project number 190538538, by the German Research Foundation (DFG)—Project number 374031971-TRR 240, and funded by the German Research Foundation (DFG)—Project number 335549539-GRK2381. S.P. reports research grants from Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, the European Union (EU), and the Federal Joint Committee Innovation Fund (GB-A Innovationsfonds), and speakers' honoraria and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, and Werfen outside of the submitted work. K.H. reports lecture fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, Portola, and Sanofi Aventis outside of the submitted work. D.R. has no conflicts to report. P.A. has no conflicts to report. S.D.K. has no conflicts to report. R.F.S. reports research grants and personal fees from AstraZeneca, Cytosorbents, GlyCardial Diagnostics and Thromboserin, and personal fees from Alnylam, Bayer, Bristol Myers Squibb/Pfizer, Chiesi, CSL Behring, HengRui, Idorsia, Intas Pharmaceuticals, Medscape, Novartis, PhaseBio, Portola, and Sanofi Aventis outside of the submitted work. A.B. has no conflicts of interest. J.P.C. reports personal fees and honoraria from AstraZeneca, Bristol-Myers Squibb, Lead-Up, Medtronic, and WebMD, and research grant to the institution from Medtronic and Boston Scientific. J.T.B. reports speaker and consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, Accu-Metrics, Boehringer Ingelheim, BMS, Pfizer, Bayer, and Ferrer, and grants from ZonMw and AstraZeneca outside of the submitted work.
Acknowledgment
We thank Prof. Dr. Ulrike Ernemann, University Hospital Tübingen, Germany for radiological expertise and MR images.
* Contributed equally, shared first authorship.
-
References
- 1 Urban P, Mehran R, Colleran R. et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation 2019; 140 (03) 240-261
- 2 Lopes RD, Hong H, Harskamp RE. et al. Safety and efficacy of antithrombotic strategies in patients with atrial fibrillation undergoing percutaneous coronary intervention: a network meta-analysis of randomized controlled trials. JAMA Cardiol 2019; 4 (08) 747-755
- 3 Kikkert WJ, Delewi R, Ouweneel DM. et al. Prognostic value of access site and nonaccess site bleeding after percutaneous coronary intervention: a cohort study in ST-segment elevation myocardial infarction and comprehensive meta-analysis. JACC Cardiovasc Interv 2014; 7 (06) 622-630
- 4 Ducrocq G, Schulte PJ, Becker RC. et al. Association of spontaneous and procedure-related bleeds with short- and long-term mortality after acute coronary syndromes: an analysis from the PLATO trial. EuroIntervention 2015; 11 (07) 737-745
- 5 Held C, Hylek EM, Alexander JH. et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J 2015; 36 (20) 1264-1272
- 6 Steg PG, Huber K, Andreotti F. et al. Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2011; 32 (15) 1854-1864
- 7 Valgimigli M, Bueno H, Byrne RA. et al; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
- 8 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 (9906): 1714-1722
- 9 Halvorsen S, Storey RF, Rocca B. et al; ESC Working Group on Thrombosis. Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2017; 38 (19) 1455-1462
- 10 Turgeon RD, Koshman SL, Dong Y. et al. P2Y12 inhibitor adherence trajectories in patients with acute coronary syndrome undergoing percutaneous coronary intervention: prognostic implications. Eur Heart J 2022; DOI: 10.1093/eurheartj/ehac116.
- 11 Valgimigli M, Cao D, Angiolillo DJ. et al; XIENCE 90 and XIENCE 28 Investigators. Duration of dual antiplatelet therapy for patients at high bleeding risk undergoing PCI. J Am Coll Cardiol 2021; 78 (21) 2060-2072
- 12 Bonaca MP, Storey RF, Theroux P. et al. Efficacy and safety of ticagrelor over time in patients with prior MI in PEGASUS-TIMI 54. J Am Coll Cardiol 2017; 70 (11) 1368-1375
- 13 Généreux P, Giustino G, Witzenbichler B. et al. Incidence, predictors, and impact of post-discharge bleeding after percutaneous coronary intervention. J Am Coll Cardiol 2015; 66 (09) 1036-1045
- 14 Butala NM, Faridi KF, Tamez H. et al. Estimation of DAPT study treatment effects in contemporary clinical practice: findings from the EXTEND-DAPT study. Circulation 2022; 145 (02) 97-106
- 15 Becker RC, Bassand JP, Budaj A. et al. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2011; 32 (23) 2933-2944
- 16 Antman EM, Wiviott SD, Murphy SA. et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol 2008; 51 (21) 2028-2033
- 17 Bonaca MP, Bhatt DL, Cohen M. et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372 (19) 1791-1800
- 18 Secemsky EA, Yeh RW, Kereiakes DJ. et al; Dual Antiplatelet Therapy (DAPT) Study Investigators. Mortality following cardiovascular and bleeding events occurring beyond 1 year after coronary stenting: a secondary analysis of the dual antiplatelet therapy (DAPT) study. JAMA Cardiol 2017; 2 (05) 478-487
- 19 Valgimigli M, Costa F, Lokhnygina Y. et al. Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial. Eur Heart J 2017; 38 (11) 804-810
- 20 Costa F, van Klaveren D, James S. et al; PRECISE-DAPT Study Investigators. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017; 389 (10073): 1025-1034
- 21 Urban P, Gregson J, Owen R. et al. Assessing the risks of bleeding vs thrombotic events in patients at high bleeding risk after coronary stent implantation: the ARC-high bleeding risk trade-off model. JAMA Cardiol 2021; 6 (04) 410-419
- 22 Yeh RW, Secemsky EA, Kereiakes DJ. et al; DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016; 315 (16) 1735-1749
- 23 Baber U, Mehran R, Giustino G. et al. Coronary thrombosis and major bleeding after PCI with drug-eluting stents: risk scores from PARIS. J Am Coll Cardiol 2016; 67 (19) 2224-2234
- 24 D'Ascenzo F, De Filippo O, Gallone G. et al; PRAISE study group. Machine learning-based prediction of adverse events following an acute coronary syndrome (PRAISE): a modelling study of pooled datasets. Lancet 2021; 397 (10270): 199-207
- 25 Raposeiras-Roubín S, Faxén J, Íñiguez-Romo A. et al. Development and external validation of a post-discharge bleeding risk score in patients with acute coronary syndrome: the BleeMACS score. Int J Cardiol 2018; 254: 10-15
- 26 Wada R, Aviv RI, Fox AJ. et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke 2007; 38 (04) 1257-1262
- 27 Delgado Almandoz JE, Yoo AJ, Stone MJ. et al. The spot sign score in primary intracerebral hemorrhage identifies patients at highest risk of in-hospital mortality and poor outcome among survivors. Stroke 2010; 41 (01) 54-60
- 28 Sun S-J, Gao P-Y, Sui B-B. et al. “Dynamic spot sign” on CT perfusion source images predicts haematoma expansion in acute intracerebral haemorrhage. Eur Radiol 2013; 23 (07) 1846-1854
- 29 Ramaswamy RS, Choi HW, Mouser HC. et al. Role of interventional radiology in the management of acute gastrointestinal bleeding. World J Radiol 2014; 6 (04) 82-92
- 30 Junquera F, Saperas E, Videla S. et al. Long-term efficacy of octreotide in the prevention of recurrent bleeding from gastrointestinal angiodysplasia. Am J Gastroenterol 2007; 102 (02) 254-260
- 31 Collet J-P, Thiele H, Barbato E. et al. ESC Scientific Document Group. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021; 42 (14) 1289-1367
- 32 Valgimigli M, Frigoli E, Heg D. et al; MASTER DAPT Investigators. Dual antiplatelet therapy after PCI in patients at high bleeding risk. N Engl J Med 2021; 385 (18) 1643-1655
- 33 Capodanno D, Morice M-C, Angiolillo DJ. et al. Trial design principles for patients at high bleeding risk undergoing PCI: JACC Scientific Expert Panel. J Am Coll Cardiol 2020; 76 (12) 1468-1483
- 34 Visseren FLJ, Mach F, Smulders YM. et al; ESC National Cardiac Societies; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021; 42 (34) 3227-3337
- 35 Bowman L, Mafham M, Wallendszus K. et al; ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018; 379 (16) 1529-1539
- 36 McNeil JJ, Wolfe R, Woods RL. et al; ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018; 379 (16) 1509-1518
- 37 Seidu S, Kunutsor SK, Sesso HD. et al. Aspirin has potential benefits for primary prevention of cardiovascular outcomes in diabetes: updated literature-based and individual participant data meta-analyses of randomized controlled trials. Cardiovasc Diabetol 2019; 18 (01) 70
- 38 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348 (9038): 1329-1339
- 39 Koo B-K, Kang J, Park KW. et al; HOST-EXAM investigators. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial. Lancet 2021; 397 (10293): 2487-2496
- 40 Neumann F-J, Sousa-Uva M, Ahlsson A. et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019; 40 (02) 87-165
- 41 Mehran R, Baber U, Sharma SK. et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med 2019; 381 (21) 2032-2042
- 42 Sibbing D, Aradi D, Jacobshagen C. et al; TROPICAL-ACS Investigators. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017; 390 (10104): 1747-1757
- 43 Hahn J-Y, Song YB, Oh J-H. et al; SMART-CHOICE Investigators. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA 2019; 321 (24) 2428-2437
- 44 Watanabe H, Domei T, Morimoto T. et al; STOPDAPT-2 Investigators. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial. JAMA 2019; 321 (24) 2414-2427
- 45 Vranckx P, Valgimigli M, Jüni P. et al; GLOBAL LEADERS Investigators. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet 2018; 392 (10151): 940-949
- 46 Galli M, Benenati S, Capodanno D. et al. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Lancet 2021; 397 (10283): 1470-1483
- 47 Hagström E, James SK, Bertilsson M. et al; PLATO Investigators. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. Eur Heart J 2016; 37 (16) 1325-1333
- 48 Rockall TA, Logan RF, Devlin HB, Northfield TC. National Audit of Acute Upper Gastrointestinal Haemorrhage. Selection of patients for early discharge or outpatient care after acute upper gastrointestinal haemorrhage. Lancet 1996; 347 (9009): 1138-1140
- 49 Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper-gastrointestinal haemorrhage. Lancet 2000; 356 (9238): 1318-1321
- 50 Forrest JA, Finlayson ND, Shearman DJ. Endoscopy in gastrointestinal bleeding. Lancet 1974; 2 (7877): 394-397
- 51 Guglielmi A, Ruzzenente A, Sandri M. et al. Risk assessment and prediction of rebleeding in bleeding gastroduodenal ulcer. Endoscopy 2002; 34 (10) 778-786
- 52 Lau JYW, Sung JJY, Lee KKC. et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000; 343 (05) 310-316
- 53 Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor therapy for peptic ulcer bleeding: Cochrane collaboration meta-analysis of randomized controlled trials. Mayo Clin Proc 2007; 82 (03) 286-296
- 54 Scally B, Emberson JR, Spata E. et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. Lancet Gastroenterol Hepatol 2018; 3 (04) 231-241
- 55 Wärme J, Sundqvist M, Mars K. et al. Helicobacter pylori screening in clinical routine during hospitalization for acute myocardial infarction. Am Heart J 2021; 231: 105-109
- 56 Venerito M, Schneider C, Costanzo R, Breja R, Röhl FW, Malfertheiner P. Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors. Aliment Pharmacol Ther 2018; 47 (11) 1464-1471
- 57 Chan FKL, Ching JYL, Suen BY, Tse YK, Wu JC, Sung JJ. Effects of Helicobacter pylori infection on long-term risk of peptic ulcer bleeding in low-dose aspirin users. Gastroenterology 2013; 144 (03) 528-535
- 58 Malfertheiner P, Megraud F, O'Morain CA. et al; European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 2017; 66 (01) 6-30
- 59 Chan FKL, Chung SCS, Suen BY. et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001; 344 (13) 967-973
- 60 Al-Shahi Salman R, Dennis M, Sandercock P. et al; RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet 2019; 393 (10191): 2613-2623
- 61 Al-Shahi Salman R, Minks DP, Mitra D. et al; RESTART Collaboration. Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial. Lancet Neurol 2019; 18 (07) 643-652
- 62 Al-Shahi Salman R, Dennis MS, Sandercock PAG. et al; RESTART Collaboration. Effects of antiplatelet therapy after stroke caused by intracerebral hemorrhage: extended follow-up of the RESTART randomized clinical trial. JAMA Neurol 2021; 78 (10) 1179-1186
- 63 Biffi A, Anderson CD, Battey TWK. et al. Association between blood pressure control and risk of recurrent intracerebral hemorrhage. JAMA 2015; 314 (09) 904-912
- 64 Boulanger M, Poon MTC, Wild SH, Al-Shahi Salman R. Association between diabetes mellitus and the occurrence and outcome of intracerebral hemorrhage. Neurology 2016; 87 (09) 870-878
- 65 Saliba W, Barnett-Griness O, Gronich N. et al. Association of diabetes and glycated hemoglobin with the risk of intracerebral hemorrhage: a population-based cohort study. Diabetes Care 2019; 42 (04) 682-688
- 66 Charidimou A, Boulouis G, Roongpiboonsopit D. et al. Cortical superficial siderosis multifocality in cerebral amyloid angiopathy: a prospective study. Neurology 2017; 89 (21) 2128-2135
- 67 Wilson D, Ambler G, Lee K-J. et al; Microbleeds International Collaborative Network. Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies. Lancet Neurol 2019; 18 (07) 653-665
- 68 Rodrigues MA, Samarasekera N, Lerpiniere C. et al. The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study. Lancet Neurol 2018; 17 (03) 232-240
- 69 Sung JJY, Lau JY, Ching JY. et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med 2010; 152 (01) 1-9
- 70 Hashash JG, Aoun R, El-Majzoub N. et al. Resuming aspirin in patients with non-variceal upper gastrointestinal bleeding: a systematic review and meta-analysis. Ann Gastroenterol 2021; 34 (03) 344-353
- 71 Abraham NS, Hlatky MA, Antman EM. et al; ACCF/ACG/AHA. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol 2010; 105 (12) 2533-2549
- 72 Acosta RD, Abraham NS, Chandrasekhara V. et al; ASGE Standards of Practice Committee. The management of antithrombotic agents for patients undergoing GI endoscopy. Gastrointest Endosc 2016; 83 (01) 3-16
- 73 Gralnek IM, Dumonceau J-M, Kuipers EJ. et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2015; 47 (10) a1-a46
- 74 Manocha D, Singh M, Mehta N, Murthy UK. Bleeding risk after invasive procedures in aspirin/NSAID users: polypectomy study in veterans. Am J Med 2012; 125 (12) 1222-1227
- 75 Strate LL, Gralnek IM. ACG clinical guideline: management of patients with acute lower gastrointestinal bleeding. Am J Gastroenterol 2016; 111 (04) 459-474
- 76 Ariotti S, Adamo M, Costa F. et al; ZEUS Investigators. Is bare-metal stent implantation still justifiable in high bleeding risk patients undergoing percutaneous coronary intervention?: a pre-specified analysis from the ZEUS trial. JACC Cardiovasc Interv 2016; 9 (05) 426-436
- 77 Varenne O, Cook S, Sideris G. et al; SENIOR investigators. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. Lancet 2018; 391 (10115): 41-50
- 78 Kedhi E, Latib A, Abizaid A. et al. Rationale and design of the Onyx ONE global randomized trial: a randomized controlled trial of high-bleeding risk patients after stent placement with 1 month of dual antiplatelet therapy. Am Heart J 2019; 214: 134-141
- 79 Qureshi W, Mittal C, Patsias I. et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol 2014; 113 (04) 662-668
- 80 Ray WA, Chung CP, Murray KT. et al. Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding. Gastroenterology 2016; 151 (06) 1105-1112.e10
- 81 Cuisset T, Deharo P, Quilici J. et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J 2017; 38 (41) 3070-3078
- 82 Escaned J, Cao D, Baber U. et al. Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HBR. Eur Heart J 2021; 42 (45) 4624-4634
- 83 Bhatt DL, Pollack CV, Mazer CD. et al. Bentracimab for ticagrelor reversal in patients undergoing urgent surgery. NEJM Evid 2021; 1 (03) EVIDoa2100047
- 84 Gargiulo G, Goette A, Tijssen J. et al. Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials. Eur Heart J 2019; 40 (46) 3757-3767
- 85 Knuuti J, Wijns W, Saraste A. et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020; 41 (03) 407-477
- 86 Zheng SL, Roddick AJ. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis. JAMA 2019; 321 (03) 277-287
- 87 Huang W-Y, Saver JL, Wu Y-L, Lin CJ, Lee M, Ovbiagele B. Frequency of intracranial hemorrhage with low-dose aspirin in individuals without symptomatic cardiovascular disease: a systematic review and meta-analysis. JAMA Neurol 2019; 76 (08) 906-914
- 88 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
- 89 Collaboration AT. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324 (7329): 71-86
- 90 Whitlock EP, Burda BU, Williams SB, Guirguis-Blake JM, Evans CV. Bleeding risks with aspirin use for primary prevention in adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2016; 164 (12) 826-835
- 91 García Rodríguez LA, Lanas A, Soriano-Gabarró M, Cea Soriano L. Low-dose aspirin and risk of upper/lower gastrointestinal bleeding by bleed severity: a cohort study with nested case-control analysis using primary care electronic health records from the United Kingdom. Ann Med 2019; 51 (02) 182-192
- 92 Spencer FA, Prasad M, Vandvik PO, Chetan D, Zhou Q, Guyatt G. Longer- versus shorter-duration dual-antiplatelet therapy after drug-eluting stent placement: a systematic review and meta-analysis. Ann Intern Med 2015; 163 (02) 118-126
- 93 Bhatt DL, Fox KAA, Hacke W. et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354 (16) 1706-1717
- 94 Mauri L, Kereiakes DJ, Yeh RW. et al; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371 (23) 2155-2166
- 95 Wiviott SD, Braunwald E, McCabe CH. et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20) 2001-2015
- 96 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
- 97 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
- 98 Mehran R, Rao SV, Bhatt DL. et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
- 99 Chichareon P, Modolo R, Kawashima H. et al. DAPT score and the impact of ticagrelor monotherapy during the second year after PCI. JACC Cardiovasc Interv 2020; 13 (05) 634-646
- 100 Ueda P, Jernberg T, James S. et al. External validation of the DAPT score in a nationwide population. J Am Coll Cardiol 2018; 72 (10) 1069-1078
- 101 Harada Y, Michel J, Lohaus R. et al. Validation of the DAPT score in patients randomized to 6 or 12 months clopidogrel after predominantly second-generation drug-eluting stents. Thromb Haemost 2017; 117 (10) 1989-1999
- 102 Brener SJ, Kirtane AJ, Rinaldi MJ. et al. Prediction of ischemic and bleeding events using the dual antiplatelet therapy score in an unrestricted percutaneous coronary intervention population. Circ Cardiovasc Interv 2018; 11 (10) e006853
- 103 Bianco M, D'ascenzo F, Raposeiras Roubin S. et al. Comparative external validation of the PRECISE-DAPT and PARIS risk scores in 4424 acute coronary syndrome patients treated with prasugrel or ticagrelor. Int J Cardiol 2020; 301: 200-206
- 104 Costa F, van Klaveren D, Colombo A. et al; PRECISE-DAPT Study Investigators. A 4-item PRECISE-DAPT score for dual antiplatelet therapy duration decision-making. Am Heart J 2020; 223: 44-47
- 105 Choi SY, Kim MH, Cho Y-R. et al. Performance of PRECISE-DAPT score for predicting bleeding complication during dual antiplatelet therapy. Circ Cardiovasc Interv 2018; 11 (12) e006837
- 106 Wester A, Mohammad MA, Olivecrona G, Holmqvist J, Yndigegn T, Koul S. Validation of the 4-item PRECISE-DAPT score: a SWEDEHEART study. J Am Heart Assoc 2021; 10 (20) e020974
- 107 Patti G, D'Ascenzo F, De Filippo O. et al. Safety and efficacy of different P2Y12 inhibitors in patients with acute coronary syndromes stratified by the PRAISE risk score: a multi-center study. Eur Heart J Qual Care Clin Outcomes 2022; DOI: 10.1093/ehjqcco/qcac002.
- 108 Cao D, Mehran R, Dangas G. et al. Validation of the academic research consortium high bleeding risk definition in contemporary PCI patients. J Am Coll Cardiol 2020; 75 (21) 2711-2722
- 109 Ueki Y, Bär S, Losdat S. et al. Validation of the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria in patients undergoing percutaneous coronary intervention and comparison with contemporary bleeding risk scores. EuroIntervention 2020; 16 (05) 371-379
- 110 Garay A, Ariza-Solé A, Formiga F. et al. Prediction of post-discharge bleeding in elderly patients with acute coronary syndromes: insights from the BleeMACS registry. Thromb Haemost 2018; 118 (05) 929-938
- 111 Sood MM, Garg AX, Bota SE. et al. Risk of major hemorrhage after kidney transplantation. Am J Nephrol 2015; 41 (01) 73-80
Address for correspondence
Publication History
Received: 01 March 2022
Accepted: 26 April 2022
Article published online:
04 July 2022
© 2022. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Urban P, Mehran R, Colleran R. et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation 2019; 140 (03) 240-261
- 2 Lopes RD, Hong H, Harskamp RE. et al. Safety and efficacy of antithrombotic strategies in patients with atrial fibrillation undergoing percutaneous coronary intervention: a network meta-analysis of randomized controlled trials. JAMA Cardiol 2019; 4 (08) 747-755
- 3 Kikkert WJ, Delewi R, Ouweneel DM. et al. Prognostic value of access site and nonaccess site bleeding after percutaneous coronary intervention: a cohort study in ST-segment elevation myocardial infarction and comprehensive meta-analysis. JACC Cardiovasc Interv 2014; 7 (06) 622-630
- 4 Ducrocq G, Schulte PJ, Becker RC. et al. Association of spontaneous and procedure-related bleeds with short- and long-term mortality after acute coronary syndromes: an analysis from the PLATO trial. EuroIntervention 2015; 11 (07) 737-745
- 5 Held C, Hylek EM, Alexander JH. et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J 2015; 36 (20) 1264-1272
- 6 Steg PG, Huber K, Andreotti F. et al. Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2011; 32 (15) 1854-1864
- 7 Valgimigli M, Bueno H, Byrne RA. et al; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
- 8 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 (9906): 1714-1722
- 9 Halvorsen S, Storey RF, Rocca B. et al; ESC Working Group on Thrombosis. Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2017; 38 (19) 1455-1462
- 10 Turgeon RD, Koshman SL, Dong Y. et al. P2Y12 inhibitor adherence trajectories in patients with acute coronary syndrome undergoing percutaneous coronary intervention: prognostic implications. Eur Heart J 2022; DOI: 10.1093/eurheartj/ehac116.
- 11 Valgimigli M, Cao D, Angiolillo DJ. et al; XIENCE 90 and XIENCE 28 Investigators. Duration of dual antiplatelet therapy for patients at high bleeding risk undergoing PCI. J Am Coll Cardiol 2021; 78 (21) 2060-2072
- 12 Bonaca MP, Storey RF, Theroux P. et al. Efficacy and safety of ticagrelor over time in patients with prior MI in PEGASUS-TIMI 54. J Am Coll Cardiol 2017; 70 (11) 1368-1375
- 13 Généreux P, Giustino G, Witzenbichler B. et al. Incidence, predictors, and impact of post-discharge bleeding after percutaneous coronary intervention. J Am Coll Cardiol 2015; 66 (09) 1036-1045
- 14 Butala NM, Faridi KF, Tamez H. et al. Estimation of DAPT study treatment effects in contemporary clinical practice: findings from the EXTEND-DAPT study. Circulation 2022; 145 (02) 97-106
- 15 Becker RC, Bassand JP, Budaj A. et al. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2011; 32 (23) 2933-2944
- 16 Antman EM, Wiviott SD, Murphy SA. et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol 2008; 51 (21) 2028-2033
- 17 Bonaca MP, Bhatt DL, Cohen M. et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372 (19) 1791-1800
- 18 Secemsky EA, Yeh RW, Kereiakes DJ. et al; Dual Antiplatelet Therapy (DAPT) Study Investigators. Mortality following cardiovascular and bleeding events occurring beyond 1 year after coronary stenting: a secondary analysis of the dual antiplatelet therapy (DAPT) study. JAMA Cardiol 2017; 2 (05) 478-487
- 19 Valgimigli M, Costa F, Lokhnygina Y. et al. Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial. Eur Heart J 2017; 38 (11) 804-810
- 20 Costa F, van Klaveren D, James S. et al; PRECISE-DAPT Study Investigators. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017; 389 (10073): 1025-1034
- 21 Urban P, Gregson J, Owen R. et al. Assessing the risks of bleeding vs thrombotic events in patients at high bleeding risk after coronary stent implantation: the ARC-high bleeding risk trade-off model. JAMA Cardiol 2021; 6 (04) 410-419
- 22 Yeh RW, Secemsky EA, Kereiakes DJ. et al; DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016; 315 (16) 1735-1749
- 23 Baber U, Mehran R, Giustino G. et al. Coronary thrombosis and major bleeding after PCI with drug-eluting stents: risk scores from PARIS. J Am Coll Cardiol 2016; 67 (19) 2224-2234
- 24 D'Ascenzo F, De Filippo O, Gallone G. et al; PRAISE study group. Machine learning-based prediction of adverse events following an acute coronary syndrome (PRAISE): a modelling study of pooled datasets. Lancet 2021; 397 (10270): 199-207
- 25 Raposeiras-Roubín S, Faxén J, Íñiguez-Romo A. et al. Development and external validation of a post-discharge bleeding risk score in patients with acute coronary syndrome: the BleeMACS score. Int J Cardiol 2018; 254: 10-15
- 26 Wada R, Aviv RI, Fox AJ. et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke 2007; 38 (04) 1257-1262
- 27 Delgado Almandoz JE, Yoo AJ, Stone MJ. et al. The spot sign score in primary intracerebral hemorrhage identifies patients at highest risk of in-hospital mortality and poor outcome among survivors. Stroke 2010; 41 (01) 54-60
- 28 Sun S-J, Gao P-Y, Sui B-B. et al. “Dynamic spot sign” on CT perfusion source images predicts haematoma expansion in acute intracerebral haemorrhage. Eur Radiol 2013; 23 (07) 1846-1854
- 29 Ramaswamy RS, Choi HW, Mouser HC. et al. Role of interventional radiology in the management of acute gastrointestinal bleeding. World J Radiol 2014; 6 (04) 82-92
- 30 Junquera F, Saperas E, Videla S. et al. Long-term efficacy of octreotide in the prevention of recurrent bleeding from gastrointestinal angiodysplasia. Am J Gastroenterol 2007; 102 (02) 254-260
- 31 Collet J-P, Thiele H, Barbato E. et al. ESC Scientific Document Group. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021; 42 (14) 1289-1367
- 32 Valgimigli M, Frigoli E, Heg D. et al; MASTER DAPT Investigators. Dual antiplatelet therapy after PCI in patients at high bleeding risk. N Engl J Med 2021; 385 (18) 1643-1655
- 33 Capodanno D, Morice M-C, Angiolillo DJ. et al. Trial design principles for patients at high bleeding risk undergoing PCI: JACC Scientific Expert Panel. J Am Coll Cardiol 2020; 76 (12) 1468-1483
- 34 Visseren FLJ, Mach F, Smulders YM. et al; ESC National Cardiac Societies; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021; 42 (34) 3227-3337
- 35 Bowman L, Mafham M, Wallendszus K. et al; ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018; 379 (16) 1529-1539
- 36 McNeil JJ, Wolfe R, Woods RL. et al; ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018; 379 (16) 1509-1518
- 37 Seidu S, Kunutsor SK, Sesso HD. et al. Aspirin has potential benefits for primary prevention of cardiovascular outcomes in diabetes: updated literature-based and individual participant data meta-analyses of randomized controlled trials. Cardiovasc Diabetol 2019; 18 (01) 70
- 38 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348 (9038): 1329-1339
- 39 Koo B-K, Kang J, Park KW. et al; HOST-EXAM investigators. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial. Lancet 2021; 397 (10293): 2487-2496
- 40 Neumann F-J, Sousa-Uva M, Ahlsson A. et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019; 40 (02) 87-165
- 41 Mehran R, Baber U, Sharma SK. et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med 2019; 381 (21) 2032-2042
- 42 Sibbing D, Aradi D, Jacobshagen C. et al; TROPICAL-ACS Investigators. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017; 390 (10104): 1747-1757
- 43 Hahn J-Y, Song YB, Oh J-H. et al; SMART-CHOICE Investigators. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA 2019; 321 (24) 2428-2437
- 44 Watanabe H, Domei T, Morimoto T. et al; STOPDAPT-2 Investigators. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial. JAMA 2019; 321 (24) 2414-2427
- 45 Vranckx P, Valgimigli M, Jüni P. et al; GLOBAL LEADERS Investigators. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet 2018; 392 (10151): 940-949
- 46 Galli M, Benenati S, Capodanno D. et al. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Lancet 2021; 397 (10283): 1470-1483
- 47 Hagström E, James SK, Bertilsson M. et al; PLATO Investigators. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. Eur Heart J 2016; 37 (16) 1325-1333
- 48 Rockall TA, Logan RF, Devlin HB, Northfield TC. National Audit of Acute Upper Gastrointestinal Haemorrhage. Selection of patients for early discharge or outpatient care after acute upper gastrointestinal haemorrhage. Lancet 1996; 347 (9009): 1138-1140
- 49 Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper-gastrointestinal haemorrhage. Lancet 2000; 356 (9238): 1318-1321
- 50 Forrest JA, Finlayson ND, Shearman DJ. Endoscopy in gastrointestinal bleeding. Lancet 1974; 2 (7877): 394-397
- 51 Guglielmi A, Ruzzenente A, Sandri M. et al. Risk assessment and prediction of rebleeding in bleeding gastroduodenal ulcer. Endoscopy 2002; 34 (10) 778-786
- 52 Lau JYW, Sung JJY, Lee KKC. et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000; 343 (05) 310-316
- 53 Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor therapy for peptic ulcer bleeding: Cochrane collaboration meta-analysis of randomized controlled trials. Mayo Clin Proc 2007; 82 (03) 286-296
- 54 Scally B, Emberson JR, Spata E. et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. Lancet Gastroenterol Hepatol 2018; 3 (04) 231-241
- 55 Wärme J, Sundqvist M, Mars K. et al. Helicobacter pylori screening in clinical routine during hospitalization for acute myocardial infarction. Am Heart J 2021; 231: 105-109
- 56 Venerito M, Schneider C, Costanzo R, Breja R, Röhl FW, Malfertheiner P. Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors. Aliment Pharmacol Ther 2018; 47 (11) 1464-1471
- 57 Chan FKL, Ching JYL, Suen BY, Tse YK, Wu JC, Sung JJ. Effects of Helicobacter pylori infection on long-term risk of peptic ulcer bleeding in low-dose aspirin users. Gastroenterology 2013; 144 (03) 528-535
- 58 Malfertheiner P, Megraud F, O'Morain CA. et al; European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 2017; 66 (01) 6-30
- 59 Chan FKL, Chung SCS, Suen BY. et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001; 344 (13) 967-973
- 60 Al-Shahi Salman R, Dennis M, Sandercock P. et al; RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet 2019; 393 (10191): 2613-2623
- 61 Al-Shahi Salman R, Minks DP, Mitra D. et al; RESTART Collaboration. Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial. Lancet Neurol 2019; 18 (07) 643-652
- 62 Al-Shahi Salman R, Dennis MS, Sandercock PAG. et al; RESTART Collaboration. Effects of antiplatelet therapy after stroke caused by intracerebral hemorrhage: extended follow-up of the RESTART randomized clinical trial. JAMA Neurol 2021; 78 (10) 1179-1186
- 63 Biffi A, Anderson CD, Battey TWK. et al. Association between blood pressure control and risk of recurrent intracerebral hemorrhage. JAMA 2015; 314 (09) 904-912
- 64 Boulanger M, Poon MTC, Wild SH, Al-Shahi Salman R. Association between diabetes mellitus and the occurrence and outcome of intracerebral hemorrhage. Neurology 2016; 87 (09) 870-878
- 65 Saliba W, Barnett-Griness O, Gronich N. et al. Association of diabetes and glycated hemoglobin with the risk of intracerebral hemorrhage: a population-based cohort study. Diabetes Care 2019; 42 (04) 682-688
- 66 Charidimou A, Boulouis G, Roongpiboonsopit D. et al. Cortical superficial siderosis multifocality in cerebral amyloid angiopathy: a prospective study. Neurology 2017; 89 (21) 2128-2135
- 67 Wilson D, Ambler G, Lee K-J. et al; Microbleeds International Collaborative Network. Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies. Lancet Neurol 2019; 18 (07) 653-665
- 68 Rodrigues MA, Samarasekera N, Lerpiniere C. et al. The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study. Lancet Neurol 2018; 17 (03) 232-240
- 69 Sung JJY, Lau JY, Ching JY. et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med 2010; 152 (01) 1-9
- 70 Hashash JG, Aoun R, El-Majzoub N. et al. Resuming aspirin in patients with non-variceal upper gastrointestinal bleeding: a systematic review and meta-analysis. Ann Gastroenterol 2021; 34 (03) 344-353
- 71 Abraham NS, Hlatky MA, Antman EM. et al; ACCF/ACG/AHA. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol 2010; 105 (12) 2533-2549
- 72 Acosta RD, Abraham NS, Chandrasekhara V. et al; ASGE Standards of Practice Committee. The management of antithrombotic agents for patients undergoing GI endoscopy. Gastrointest Endosc 2016; 83 (01) 3-16
- 73 Gralnek IM, Dumonceau J-M, Kuipers EJ. et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2015; 47 (10) a1-a46
- 74 Manocha D, Singh M, Mehta N, Murthy UK. Bleeding risk after invasive procedures in aspirin/NSAID users: polypectomy study in veterans. Am J Med 2012; 125 (12) 1222-1227
- 75 Strate LL, Gralnek IM. ACG clinical guideline: management of patients with acute lower gastrointestinal bleeding. Am J Gastroenterol 2016; 111 (04) 459-474
- 76 Ariotti S, Adamo M, Costa F. et al; ZEUS Investigators. Is bare-metal stent implantation still justifiable in high bleeding risk patients undergoing percutaneous coronary intervention?: a pre-specified analysis from the ZEUS trial. JACC Cardiovasc Interv 2016; 9 (05) 426-436
- 77 Varenne O, Cook S, Sideris G. et al; SENIOR investigators. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. Lancet 2018; 391 (10115): 41-50
- 78 Kedhi E, Latib A, Abizaid A. et al. Rationale and design of the Onyx ONE global randomized trial: a randomized controlled trial of high-bleeding risk patients after stent placement with 1 month of dual antiplatelet therapy. Am Heart J 2019; 214: 134-141
- 79 Qureshi W, Mittal C, Patsias I. et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol 2014; 113 (04) 662-668
- 80 Ray WA, Chung CP, Murray KT. et al. Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding. Gastroenterology 2016; 151 (06) 1105-1112.e10
- 81 Cuisset T, Deharo P, Quilici J. et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J 2017; 38 (41) 3070-3078
- 82 Escaned J, Cao D, Baber U. et al. Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HBR. Eur Heart J 2021; 42 (45) 4624-4634
- 83 Bhatt DL, Pollack CV, Mazer CD. et al. Bentracimab for ticagrelor reversal in patients undergoing urgent surgery. NEJM Evid 2021; 1 (03) EVIDoa2100047
- 84 Gargiulo G, Goette A, Tijssen J. et al. Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials. Eur Heart J 2019; 40 (46) 3757-3767
- 85 Knuuti J, Wijns W, Saraste A. et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020; 41 (03) 407-477
- 86 Zheng SL, Roddick AJ. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis. JAMA 2019; 321 (03) 277-287
- 87 Huang W-Y, Saver JL, Wu Y-L, Lin CJ, Lee M, Ovbiagele B. Frequency of intracranial hemorrhage with low-dose aspirin in individuals without symptomatic cardiovascular disease: a systematic review and meta-analysis. JAMA Neurol 2019; 76 (08) 906-914
- 88 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
- 89 Collaboration AT. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324 (7329): 71-86
- 90 Whitlock EP, Burda BU, Williams SB, Guirguis-Blake JM, Evans CV. Bleeding risks with aspirin use for primary prevention in adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2016; 164 (12) 826-835
- 91 García Rodríguez LA, Lanas A, Soriano-Gabarró M, Cea Soriano L. Low-dose aspirin and risk of upper/lower gastrointestinal bleeding by bleed severity: a cohort study with nested case-control analysis using primary care electronic health records from the United Kingdom. Ann Med 2019; 51 (02) 182-192
- 92 Spencer FA, Prasad M, Vandvik PO, Chetan D, Zhou Q, Guyatt G. Longer- versus shorter-duration dual-antiplatelet therapy after drug-eluting stent placement: a systematic review and meta-analysis. Ann Intern Med 2015; 163 (02) 118-126
- 93 Bhatt DL, Fox KAA, Hacke W. et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354 (16) 1706-1717
- 94 Mauri L, Kereiakes DJ, Yeh RW. et al; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371 (23) 2155-2166
- 95 Wiviott SD, Braunwald E, McCabe CH. et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20) 2001-2015
- 96 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
- 97 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
- 98 Mehran R, Rao SV, Bhatt DL. et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
- 99 Chichareon P, Modolo R, Kawashima H. et al. DAPT score and the impact of ticagrelor monotherapy during the second year after PCI. JACC Cardiovasc Interv 2020; 13 (05) 634-646
- 100 Ueda P, Jernberg T, James S. et al. External validation of the DAPT score in a nationwide population. J Am Coll Cardiol 2018; 72 (10) 1069-1078
- 101 Harada Y, Michel J, Lohaus R. et al. Validation of the DAPT score in patients randomized to 6 or 12 months clopidogrel after predominantly second-generation drug-eluting stents. Thromb Haemost 2017; 117 (10) 1989-1999
- 102 Brener SJ, Kirtane AJ, Rinaldi MJ. et al. Prediction of ischemic and bleeding events using the dual antiplatelet therapy score in an unrestricted percutaneous coronary intervention population. Circ Cardiovasc Interv 2018; 11 (10) e006853
- 103 Bianco M, D'ascenzo F, Raposeiras Roubin S. et al. Comparative external validation of the PRECISE-DAPT and PARIS risk scores in 4424 acute coronary syndrome patients treated with prasugrel or ticagrelor. Int J Cardiol 2020; 301: 200-206
- 104 Costa F, van Klaveren D, Colombo A. et al; PRECISE-DAPT Study Investigators. A 4-item PRECISE-DAPT score for dual antiplatelet therapy duration decision-making. Am Heart J 2020; 223: 44-47
- 105 Choi SY, Kim MH, Cho Y-R. et al. Performance of PRECISE-DAPT score for predicting bleeding complication during dual antiplatelet therapy. Circ Cardiovasc Interv 2018; 11 (12) e006837
- 106 Wester A, Mohammad MA, Olivecrona G, Holmqvist J, Yndigegn T, Koul S. Validation of the 4-item PRECISE-DAPT score: a SWEDEHEART study. J Am Heart Assoc 2021; 10 (20) e020974
- 107 Patti G, D'Ascenzo F, De Filippo O. et al. Safety and efficacy of different P2Y12 inhibitors in patients with acute coronary syndromes stratified by the PRAISE risk score: a multi-center study. Eur Heart J Qual Care Clin Outcomes 2022; DOI: 10.1093/ehjqcco/qcac002.
- 108 Cao D, Mehran R, Dangas G. et al. Validation of the academic research consortium high bleeding risk definition in contemporary PCI patients. J Am Coll Cardiol 2020; 75 (21) 2711-2722
- 109 Ueki Y, Bär S, Losdat S. et al. Validation of the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria in patients undergoing percutaneous coronary intervention and comparison with contemporary bleeding risk scores. EuroIntervention 2020; 16 (05) 371-379
- 110 Garay A, Ariza-Solé A, Formiga F. et al. Prediction of post-discharge bleeding in elderly patients with acute coronary syndromes: insights from the BleeMACS registry. Thromb Haemost 2018; 118 (05) 929-938
- 111 Sood MM, Garg AX, Bota SE. et al. Risk of major hemorrhage after kidney transplantation. Am J Nephrol 2015; 41 (01) 73-80
![](https://www.thieme-connect.de/media/10.1055-s-00035024/202302/thumbnails/10-1055-s-0042-1750419-i220100-1.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/202302/thumbnails/10-1055-s-0042-1750419-i220100-2.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/202302/thumbnails/10-1055-s-0042-1750419-i220100-3.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/202302/thumbnails/10-1055-s-0042-1750419-i220100-4.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)