No Differences in Gastrointestinal Bleeding Risk among Clopidogrel-, Ticagrelor-, or Prasugrel-Based Dual Antiplatelet Therapy
Abstract
:1. Introduction
2. Material and Methods
Statistical Analysis
3. Results
3.1. Baseline Characteristics
3.2. Gastrointestinal Events During Follow-up
3.3. Global Events During Follow-up
3.4. PPI Therapy and DAPT after a Major Gastrointestinal Event
3.5. Causes of Death
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
Total n = 114 |
Clopidogrel-DAPT n = 56 |
New Antiplatelet-DAPT n = 58 | |
---|---|---|---|
Epistaxis, n (%) | 38 (33.3) | 19 (33.9) | 19 (32.8) |
Hematuria, n (%) | 29 (25.4) | 15 (26.8) | 14 (24.1) |
Hematoma, n (%) | 25 (21.9) | 12 (21.4) | 13 (22.4) |
Intracranial bleeding, n (%) | 6 (5.3) | 4 (7.1) | 2 (3.4) |
Other, n (%) | 16 (14.0) | 6 (10.7) | 10 (17.2) |
Total n = 131 |
Clopidogrel-DAPT n = 82 |
New Antiplatelet-DAPT n = 49 | |
---|---|---|---|
Angina, n (%) | 71 (54.2) | 44 (53.7) | 27 (55.1) |
Non-ST elevation acute coronary syndrome, n (%) | 30 (22.9) | 19 (23.2) | 11 (22.4) |
ST elevation acute coronary syndrome, n (%) | 9 (6.9) | 7 (8.5) | 2 (4.1) |
Stroke, n (%) | 9 (6.9) | 3 (3.7) | 6 (12.2) |
Other, * n (%) | 12 (9.2) | 9 (11) | 3 (6.1) |
References
- Design, S.; Patients, S. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. N. Engl. J. Med. 2001, 345, 494–502. [Google Scholar]
- CAPRIE Steering Committee. A randomized blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996, 348, 1329–1339. [Google Scholar] [CrossRef]
- Klein, M.D.; Williams, A.K.; Lee, C.R.; Stouffer, G.A. Clinical Utility of CYP2C19 Genotyping to Guide Antiplatelet Therapy in Patients with an Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention. Arterioscler. Thromb. Vasc. Biol. 2019, 39, 647–652. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Angiolillo, D.J.; Ueno, M. Optimizing platelet inhibition in clopidogrel poor metabolizers: Therapeutic options and practical considerations. JACC Cardiovasc. Interv. 2011, 4, 411–414. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lin, C.-C.; Hu, H.-Y.; Luo, J.-C.; Peng, Y.-L.; Hou, M.-C.; Lin, H.-C.; Lee, F.Y. Risk factors of gastrointestinal bleeding in clopidogrel users: A nationwide population-based study. Aliment. Pharmacol. Ther. 2013, 38, 1119–1128. [Google Scholar] [CrossRef]
- Lanas, Á.; Carrera-Lasfuentes, P.; Arguedas, Y.; García, S.; Bujanda, L.; Calvet, X.; Ponce, J.; Perez-Aísa, A.; Castro, M.; Muñoz, M.; et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin. Gastroenterol. Hepatol. 2015, 13, 906–912. [Google Scholar] [CrossRef]
- Hallas, J.; Dall, M.; Andries, A.; Andersen, B.S.; Aalykke, C.; Hansen, J.M.; Andersen, M.; Lassen, A.T. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: Population based case-control study. BMJ 2006, 333, 726. [Google Scholar] [CrossRef] [Green Version]
- Casado Arroyo, R.; Polo-Tomas, M.; Roncales, M.P.; Scheiman, J.; Lanas, A. Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: Long-term follow-up of a cohort of patients commonly using PPI co-therapy. Heart 2012, 98, 718–723. [Google Scholar] [CrossRef]
- Wiviott, S.D.; Braunwald, E.; McCabe, C.H.; Montalescot, G.; Ruzyllo, W.; Gottlieb, S.; Neumann, F.J.; Ardissino, D.; De Servi, S.; Murphy, S.A.; et al. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. N. Engl. J. Med. 2007, 357, 2001–2015. [Google Scholar] [CrossRef] [Green Version]
- Wallentin, L.; Becker, R.C.; Budaj, A.; Cannon, C.P.; Emanuelsson, H.; Held, C.; Horrow, J.; Husted, S.; James, S.; Katus, H.; et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N. Engl. J. Med. 2009, 361, 1045–1057. [Google Scholar] [CrossRef]
- Chen, H.-B.; Zhang, X.-L.; Liang, H.-B.; Liu, X.-W.; Zhang, X.-Y.; Huang, B.-Y.; Xiu, J. Meta-Analysis of Randomized Controlled Trials Comparing Risk of Major Adverse Cardiac Events and Bleeding in Patients With Prasugrel Versus Clopidogrel. Am. J. Cardiol. 2015, 116, 384–392. [Google Scholar] [CrossRef] [PubMed]
- Bavishi, C.; Panwar, S.; Messerli, F.H.; Bangalore, S. Meta-Analysis of Comparison of the Newer Oral P2Y12 Inhibitors (Prasugrel or Ticagrelor) to Clopidogrel in Patients with Non-ST-Elevation Acute Coronary Syndrome. Am. J. Cardiol. 2015, 116, 809–817. [Google Scholar] [CrossRef] [PubMed]
- Serebruany, V.L.; Dinicolantonio, J.J.; Can, M.M.; Pershukov, I.V.; Kuliczkowski, W. Gastrointestinal adverse events after dual antiplatelet therapy: Clopidogrel is safer than ticagrelor, but prasugrel data are lacking or inconclusive. Cardiology 2013, 126, 35–40. [Google Scholar] [CrossRef] [PubMed]
- Sahlén, A.; Varenhorst, C.; Lagerqvist, B.; Renlund, H.; Omerovic, E.; Erlinge, D.; Wallentin, L.; James, S.K.; Jernberg, T. Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: Experiences from SWEDEHEART registry. Eur. Heart J. 2016, 37, 3335–3342. [Google Scholar]
- Guo, C.-G.; Chen, L.; Chan, E.W.; Cheung, K.S.; Isshiki, T.; Wong, I.C.K.; Leung, W.K. Systematic review with meta-analysis: The risk of gastrointestinal bleeding in patients taking third-generation P2Y 12 inhibitors compared with clopidogrel. Aliment. Pharmacol. Ther. 2019, 49, 7–19. [Google Scholar] [CrossRef] [PubMed]
- Lee, C.-H.; Cheng, C.-L.; Kao Yang, Y.-H.; Chao, T.-H.; Chen, J.-Y.; Li, Y.-H. Cardiovascular and Bleeding Risks in Acute Myocardial Infarction Newly Treated With Ticagrelor vs. Clopidogrel in Taiwan. Circ. J. 2017, 82, 747–756. [Google Scholar] [CrossRef] [Green Version]
- Hiatt, W.R.; Fowkes, F.G.R.; Heizer, G.; Berger, J.S.; Baumgartner, I.; Held, P.; Katona, B.G.; Mahaffey, K.W.; Norgren, L.; Jones, W.S.; et al. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. N. Engl. J. Med. 2017, 376, 32–40. [Google Scholar] [CrossRef] [Green Version]
- Roe, M.T.; Armstrong, P.W.; Fox, K.A.A.; White, H.D.; Prabhakaran, D.; Goodman, S.G.; Cornel, J.H.; Bhatt, D.L.; Clemmensen, P.; Martinez, F.; et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N. Engl. J. Med. 2012, 367, 1297–1309. [Google Scholar] [CrossRef] [Green Version]
- Sun, J.; Xiang, Q.; Li, C.; Wang, Z.; Hu, K.; Xie, Q.; Cui, Y. Efficacy and Safety of Novel Oral P2Y12 Receptor Inhibitors in Patients With ST-Segment Elevation Myocardial Infarction Undergoing PCI. J. Cardiovasc. Pharmacol. 2017, 69, 215–227. [Google Scholar] [CrossRef] [Green Version]
- Vercellino, M.; Sànchez, F.A.; Boasi, V.; Perri, D.; Tacchi, C.; Secco, G.G.; Cattunar, S.; Pistis, G.; Mascelli, G. Ticagrelor versus clopidogrel in real-world patients with ST elevation myocardial infarction: 1-year results by propensity score analysis. BMC Cardiovasc. Disord. 2017, 17, 97. [Google Scholar] [CrossRef] [Green Version]
- Parodi, G.; Bellandi, B.; Venditti, F.; Carrabba, N.; Valenti, R.; Migliorini, A.; Grassellini, S.; Ramazzotti, E.; Antoniucci, D. Residual platelet reactivity, bleedings, and adherence to treatment in patients having coronary stent implantation treated with prasugrel. Am. J. Cardiol. 2012, 109, 214–218. [Google Scholar] [CrossRef] [PubMed]
- Kheiri, B.; Osman, M.; Abdalla, A.; Haykal, T.; Barbarawi, M.; Zayed, Y.; Hicks, M.; Ahmed, S.; Bachuwa, G.; Hassan, M.; et al. Ticagrelor versus clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: A systematic review and meta-analysis of randomized clinical trials. J. Thromb. Thrombolysis 2018, 46, 299–303. [Google Scholar] [CrossRef] [PubMed]
- Danchin, N.; Lettino, M.; Zeymer, U.; Widimsky, P.; Bardaji, A.; Barrabes, J.A.; Cequier, A.; Claeys, M.J.; De Luca, L.; Dörler, J.; et al. Use, patient selection and outcomes of P2Y12 receptor inhibitor treatment in patients with STEMI based on contemporary European registries. Eur. Heart J. Cardiovasc. Pharmacother. 2016, 2, 152–167. [Google Scholar] [CrossRef] [PubMed]
- Mehran, R.; Rao, S.V.; Bhatt, D.L.; Gibson, C.M.; Caixeta, A.; Eikelboom, J.; Kaul, S.; Wiviott, S.D.; Menon, V.; Nikolsky, E.; et al. Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the bleeding academic research consortium. Circulation 2011, 123, 2736–2747. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Quinlan, D.J.; Eikelboom, J.W.; Goodman, S.G.; Welsh, R.C.; Fitchett, D.H.; Throux, P.; Mehta, S.R. Implications of variability in definition and reporting of major bleeding in randomized trials of oral P2Y 12 inhibitors for acute coronary syndromes. Eur. Heart J. 2011, 32, 2256–2265. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Beigel, R.; Iakobishvili, Z.; Shlomo, N.; Segev, A.; Witberg, G.; Zahger, D.; Atar, S.; Alcalai, R.; Kapeliovich, M.; Gottlieb, S.; et al. Real-World Use of Novel P2Y12 Inhibitors in Patients with Acute Myocardial Infarction: A Treatment Paradox. Cardioly 2017, 136, 21–28. [Google Scholar] [CrossRef]
- Flores-Blanco, P.J.; Cambronero-Sánchez, F.; Raposeiras-Roubin, S.; Abu-Assi, E.; Leithold, G.; Cobas-Paz, R.; Rodriguez Serrano, A.I.; Calvo-Iglesias, F.; Valdés, M.; Januzzi, J.L.; et al. Association Between Ischemic and Bleeding Risk Scores and the Use of New P2Y 12 Inhibitors in Patients With Acute Coronary Syndrome. Rev. Española Cardiol. 2018, 71, 538–544. [Google Scholar] [CrossRef]
- Zeymer, U.; Widimsky, P.; Danchin, N.; Lettino, M.; Bardaji, A.; Barrabes, J.A.; Cequier, A.; Claeys, M.J.; De Luca, L.; Dörler, J.; et al. P2Y12 receptor inhibitors in patients with non-ST-elevation acute coronary syndrome in the real world: Use, patient selection, and outcomes from contemporary European registries. Eur. Heart J. Cardiovasc. Pharmacother. 2016, 2, 229–243. [Google Scholar] [CrossRef] [Green Version]
- Sostres, C.; Marcén, B.; Laredo, V.; Alfaro, E.; Ruiz, L.; Camo, P.; Carrera-Lasfuentes, P.; Lanas, A. Risk of rebleeding, vascular events and death after gastrointestinal bleeding in anticoagulant and/or antiplatelet users. Aliment. Pharmacol. Ther. 2019, 50, 919–929. [Google Scholar] [CrossRef] [Green Version]
- Von Elm, E.; Altman, D.G.; Egger, M.; Pocock, S.J.; Gøtzsche, P.C.; Vandenbroucke, J.P.; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. J. Clin. Epidemiol. 2008, 61, 344–349. [Google Scholar] [CrossRef] [Green Version]
- Schmucker, J.; Fach, A.; Mata Marin, L.A.; Retzlaff, T.; Osteresch, R.; Kollhorst, B.; Hambrecht, R.; Pohlabeln, H.; Wienbergen, H. Efficacy and Safety of Ticagrelor in Comparison to Clopidogrel in Elderly Patients With ST-Segment-Elevation Myocardial Infarctions. J. Am. Heart Assoc. 2019, 8, e012530. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sánchez-Martínez, M.; Manzano-Fernández, S.; Valdés, M.; Marín, F. Why do we take into account the risk of both bleeding and ischemia in acute coronary syndrome? Rev Española Cardiol Supl. 2014, 14, 10–17. [Google Scholar]
- Lanas, A.; García-Rodríguez, L.A.; Polo-Tomás, M.; Ponce, M.; Alonso-Abreu, I.; Perez-Aisa, M.A.; Perez-Gisbert, J.; Bujanda, L.; Castro, M.; Muñoz, M.; et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am. J. Gastroenterol. 2009, 104, 1633–1641. [Google Scholar] [CrossRef] [PubMed]
- Valgimigli, M.; Bueno, H.; Byrne, R.A.; Collet, J.P.; Costa, F.; Jeppsson, A.; Jüni, P.; Kastrati, A.; Kolh, P.; Mauri, L.; et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur. J. Cardio Thorac. Surg. 2018, 53, 34–78. [Google Scholar] [CrossRef] [Green Version]
- Sehested, T.S.G.; Carlson, N.; Hansen, P.W.; Gerds, T.A.; Charlot, M.G.; Torp-Pedersen, C.; Kober, L.; Gislason, G.H.; Hlatky, M.A.; Fosbol, E.L. Reduced risk of gastrointestinal bleeding associated with proton pump inhibitor therapy in patients treated with dual antiplatelet therapy after myocardial infarction. Eur. Heart J. 2019, 40, 1963–1970. [Google Scholar] [CrossRef]
- Bhatt, D.L.; Scheiman, J.; Abraham, N.S.; Antman, E.M.; Chan, F.K.L.; Furberg, C.D.; Johnson, D.A.; Mahaffey, K.W.; Quigley, E.M.; Harrington, R.A.; et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am. J. Gastroenterol. 2008, 103, 2890–2907. [Google Scholar] [CrossRef]
- Lanas, A. We Are Using Too Many PPIs, and We Need to Stop: A European Perspective. Am. J. Gastroenterol. 2016, 111, 1085–1086. [Google Scholar] [CrossRef]
Total (N = 1327) |
ASA + Clopidogrel (n = 717) |
ASA + New Antiplatelets (n = 610) | p Value | |
---|---|---|---|---|
Sex (male), n (%) | 1019 (76.8) | 527 (73.5) | 492 (80.7) | 0.002 |
Age (mean ± SD) | 66.9 ± 12.6 | 71.4 ± 11.6 | 61.5 ± 11.7 | <0.001 |
Charlson comorbidity index (mean ± SD) | 3.2 ± 2.5 | 4.2 ± 2.5 | 1.9 ± 1.9 | <0.001 |
Anticoagulant treatment, n (%) | 173 (13.0) | 148 (20.6) | 25 (4.1) | <0.001 |
PPI therapy, n (%) | 1238 (93.3) | 661 (92.2) | 577 (94.6) | 0.098 |
Previous GI risk, * n (%) | 261 (19.7) | 168 (23.4) | 93 (15.2) | <0.001 |
ASA + Clopidogrel (n = 717) |
ASA + New Antiplatelets (n = 610) |
HR (95% CI) | p Value | Adjusted HR (95% CI) | p Value | |
---|---|---|---|---|---|---|
Any GI event, n (%) | 252 (35.1) | 140 (23.0) | 0.572 (0.465–0.704) | <0.001 | 0.935 (0.735–1.188) | 0.581 |
Major GI event, n (%) | 25 (3.5) | 20 (3.3) | 0.877 (0.487–1.579) | 0.662 | 0.996 (0.497–1.996) | 0.991 |
All minor GI events, n (%) | 227 (31.7) | 120 (19.7) | 0.546 (0.437–0.681) | <0.001 | 0.920 (0.712–1.189) | 0.524 |
Minor GI event, anemia, n (%) | 201 (28.0) | 96 (15.7) | 0.495 (0.388–0.632) | <0.001 | 0.876 (0.663–1.157) | 0.351 |
Minor GI event,iron deficiency, n (%) | 26 (3.6) | 24 (3.9) | 1.014 (0.582–1.767) | 0.960 | 1.110 (0.581–2.124) | 0.751 |
Location | Cause | n (%) |
---|---|---|
Upper | Mallory–Weiss syndrome Gastric ulcer Gastric cancer Vascular gastric lesions Gastroduodenal erosions Vascular duodenal lesions Other | 12 (26.67) 1 2 1 2 3 2 1 |
Lower | Hemorrhoidal bleeding Large bowel diverticulosis Ischemic colitis Colorectal cancer Angiodysplasia Other * Unknown | 30 (66.67) 6 4 4 4 4 6 2 |
Obscure | 3 (6.67%) |
Total (N = 1327) |
ASA + Clopidogrel (n = 717) |
ASA + New Antiplatelets (n = 610) | p Value | |
---|---|---|---|---|
Major gastrointestinal event, n (%) | 45 (3.4) | 25 (3.5) | 20 (3.3) | 0.880 |
All minor gastrointestinal events, n (%) | 347 (26.1) | 227 (31.7) | 120 (19.7) | <0.001 |
Non-gastrointestinal bleeding events, * n (%) | 114 (8.6) | 56 (7.8) | 58 (9.5) | 0.281 |
Ischemic or cardiovascular events, ** n (%) | 131 (9.9) | 82 (11.4) | 49 (8.0) | 0.042 |
Death | 23 (1.7) | 21 (2.9) | 2 (0.3) | <0.001 |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Laredo, V.; Sostres, C.; García, S.; Carrera-Lasfuentes, P.; Revilla-Marti, P.; Lanas, Á. No Differences in Gastrointestinal Bleeding Risk among Clopidogrel-, Ticagrelor-, or Prasugrel-Based Dual Antiplatelet Therapy. J. Clin. Med. 2020, 9, 1526. https://doi.org/10.3390/jcm9051526
Laredo V, Sostres C, García S, Carrera-Lasfuentes P, Revilla-Marti P, Lanas Á. No Differences in Gastrointestinal Bleeding Risk among Clopidogrel-, Ticagrelor-, or Prasugrel-Based Dual Antiplatelet Therapy. Journal of Clinical Medicine. 2020; 9(5):1526. https://doi.org/10.3390/jcm9051526
Chicago/Turabian StyleLaredo, Viviana, Carlos Sostres, Sandra García, Patricia Carrera-Lasfuentes, Pablo Revilla-Marti, and Ángel Lanas. 2020. "No Differences in Gastrointestinal Bleeding Risk among Clopidogrel-, Ticagrelor-, or Prasugrel-Based Dual Antiplatelet Therapy" Journal of Clinical Medicine 9, no. 5: 1526. https://doi.org/10.3390/jcm9051526