Ischemic events after stenting have decreased considerably in recent years thanks to the introduction of newer-generation drug-eluting stents (DESs) and progressive refinement of pharmaco-interventional techniques. However, due to more potent and prolonged platelet inhibition, the incidence of bleeding complications has increased, especially in patients with high bleeding risk (HBR).

To reduce bleeding complications after percutaneous coronary intervention (PCI) in HBR patients, optimal discrimination of HBR patients is needed before taking practical measures, namely pharmacological and interventional approaches. Pharmacological approaches include a shorter duration of dual antiplatelet therapy (DAPT), and de-escalation and dose adjustment of a P2Y12 inhibitor. Interventional approaches include simpler strategies and less thrombogenic devices, which may help reduce thrombotic events without requiring a longer DAPT duration. These practices may be used alone or in combination.

The European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend DAPT duration according to the clinical status and risks of bleeding and ischemia.1,2 Several bleeding risk scores established from large-scale studies are used in clinical practice. The ESC guidelines use the PRECISE-DAPT score to discriminate HBR patients.3 For HBR patients with a PRECISE-DAPT score ≥ 25, a suitable DAPT duration depends on the coronary status: 3 months for those with stable coronary artery disease and 6 months for those with acute coronary syndrome (ACS). The ACC/AHA guidelines reference the DAPT score to quantify risk for ischemia and bleeding; a score ≥ 2 correlates with a favorable risk/benefit ratio for prolonged DAPT, whereas a score < 2 has an unfavorable risk/benefit profile for prolonged DAPT.4 The 2016 ACC/AHA guidelines gave a class I, level A recommendation for a minimum mandatory DAPT duration of 6 months for patients with stable ischemic heart disease being treated with a newer-generation DES, a reduction from the former ACC/AHA recommendation of 12 months. Additionally, they gave a class IIb, level C-LD recommendation for discontinuation of P2Y12 inhibitor after 3 months for those who develop a high risk of bleeding or are at high risk for severe bleeding complications. For patients with ACS being treated with BMS or DES, the recommendation for at least 12 months of DAPT remained.2 Other well-known scores include the PARIS score5 and CREDO-Kyoto risk score.6 The contributing factors of these scores are quite different from one another (Table 1). Using them to discriminate HBR patients in real-world settings needs careful attention to the differences in patient populations, as will be described in this article.


De-escalation of P2Y12 inhibitor treatment (eg, switching from prasugrel or ticagrelor to clopidogrel) guided by platelet function testing may be considered as an alternative DAPT strategy,7 especially for patients with ACS who are deemed unsuitable for 12-month potent platelet inhibition in the ESC/ESCTA guidelines. A widely used dose of prasugrel in Japan, however, is different from the global standard. The efficacy of this strategy cannot be easily applied to practice in Japan because of the difference in physique. The ACC/AHA guidelines do not recommend the use of platelet function testing, as no randomized controlled trial has demonstrated an improvement in outcomes when used to guide P2Y12 inhibitor treatment; similarly, no randomized data are available on the long-term safety of efficacy of switching patients to a different P2Y12 inhibitor.2

The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction) showed that in ACS patients with scheduled PCI, prasugrel therapy with a loading dose of 60 mg and a maintenance dose of 10 mg was associated with reduced ischemic events, but was also associated with increased bleeding events, in comparison with clopidogrel therapy.8 On the basis of the report that East Asians have a higher bleeding risk and a lower ischemic event risk than Westerners (known as “East Asian Paradox”),9 the PRASFIT-ACS (Prasugrel Compared with Clopidogrel for Japanese Patients with ACS Undergoing PCI) determined an appropriate dose of prasugrel (loading dose of 20 mg and maintenance dose of 3.75 mg) and confirmed its safety and efficacy in Japanese ACS patients; therefore, an adjusted dose of prasugrel is more commonly used in Japan instead of clopidogrel for both ACS and stable coronary artery disease patients.10 Furthermore, efficacy of a maintenance dose of prasugrel 2.5 mg was demonstrated as an option for HBR-ACS patients with low body weight (≤ 50 kg), advanced age (≥ 75 years), or renal insufficiency (estimated glomerular filtration rate ≤ 30 mL/min/1.73 m2).11 Further dose adjustment of prasugrel may be an option for HBR patients in Japan.


Combination therapy of oral anticoagulant and antiplatelet therapy, although less known, is an additional risk factor for HBR patients. The ACC/AHA recommendations on DAPT duration are generally not considered applicable to patients treated with oral anticoagulants, as patients on oral anticoagulants were excluded from almost all studies of DAPT duration.2 In the ESC/EACTS guidelines, the use of direct oral anticoagulant (DOAC) is recommended on the basis of some randomized studies demonstrating a comparison of warfarin with DOAC for atrial fibrillation patients with PCI.12 Also, the use of a newer P2Y12 inhibitor, ticagrelor or prasugrel, as a part of a triple therapy regimen is discouraged; however, no comments are made on a dual therapy combining ticagrelor or prasugrel with a DOAC as a possible alternative for a triple therapy with aspirin, clopidogrel, and a DOAC. Using one of these newer P2Y12 inhibitors with a (D)OAC under certain circumstances (eg, perceived high thrombotic risk, ACS, complex PCI, and prior stent thrombosis) may be considered. When using a newer P2Y12 inhibitor in HBR patients with these risk factors, bleeding complications may be prevented with a shorter duration, switching between newer P2Y12 inhibitors, or dose adjustment.


For HBR patients with complex PCI, balancing the risks of bleeding and ischemia is very important and difficult. A recent study demonstrated that patients who had undergone complex PCI had a higher risk of ischemic events, but had no benefit from long-term DAPT.13 For these patients, choosing a simpler PCI strategy may be recommended. Generally, newer-generation DESs are less thrombogenic than first-generation DESs. Newer-generation DESs are coated with permanent polymer or biodegradative polymer, which may lead to less thrombogenicity. Animal studies have suggested that there are differences in antithrombogenicity between newer-generation DESs.14 Choosing a less thrombogenic DES for complex PCI may be considered in the treatment of HBR patients.


In summary, clinical decision-making when treating HBR patients requires balancing the risks of bleeding and ischemia, which should be adjusted to each patient on the basis of guidelines, randomized studies, and clinical experience; patients’ physiological differences in geographic regions (eg, Japanese versus Western) should also be kept in mind when analyzing guidelines.

See Important Safety Information referenced within. ©2019 Abbott. All rights reserved. AP2947511-US Rev. A.

1. Neumann FJ, Sousa-Uva M, Ahlsson A, et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40:87–165.

2. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation. 2016;134:e123-155.

3. Costa F, van Klaveren D, James S, et al. 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;389:1025-1034.

4. Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA. 2016;315:1735-1749.

5. 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;67:2224-2234.

6. Natsuaki M, Morimoto T, Yamaji K, et al. Prediction of thrombotic and bleeding events after percutaneous coronary intervention: CREDO-Kyoto thrombotic and bleeding risk scores. J Am Heart Assoc. 2018;7:e008708.

7. Sibbing D, Aradi D, Jacobshagen C, et al. 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; 390:1747-1757.

8. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.

9. Levine GN, Jeong YH, Goto S, et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol. 2014;11:597-606.

10. Saito S, Isshiki T, Kimura T, et al. Efficacy and safety of adjusted-dose prasugrel compared with clopidogrel in Japanese patients with acute coronary syndrome: the PRASFIT-ACS study. Circ J. 2014;78:1684-1692.

11. Ohya M, Shimada T, Osakada K, et al. In-hospital bleeding and utility of a maintenance dose of prasugrel 2.5mg in high bleeding risk patients with acute coronary syndrome. Circ J. 2018,82:1874-1883.

12. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39:1330-1393.

13. Costa F, Van Klaveren D, Feres F, et al. Dual antiplatelet therapy duration based on ischemic and bleeding risks after coronary stenting. J Am Coll Cardiol. 2019;73:741-754.

14. Otsuka F, Cheng Q, Yahagi K, et al. Acute thrombogenicity of a durable polymer everolimus-eluting stent relative to contemporary drug-eluting stents with biodegradable polymer coatings assessed ex vivo in a swine shunt model. J Am Coll Cardiol Interv. 2015;8:1248-1260.

Kazushige Kadota, MD, PhD
Department of Cardiology
Kurashiki Central Hospital
Okayama, Japan
Disclosures: Abbott, Daiichi Sankyo, Sanofi, Boehringer-Ingelheim.