Thromb Haemost 2019; 119(09): 1527-1538
DOI: 10.1055/s-0039-1692441
Atherosclerosis and Ischaemic Disease
Georg Thieme Verlag KG Stuttgart · New York

Gender and Outcomes following Guided De-Escalation of Antiplatelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Gender Substudy

Lisa Gross*
1   Department of Cardiology, LMU München, Munich, Germany
,
Danny Kupka*
1   Department of Cardiology, LMU München, Munich, Germany
,
Dietmar Trenk
2   University Heart Center Freiburg-Bad Krozingen, Bad Krozingen, Germany
,
Tobias Geisler
3   Department of Cardiology, University Hospital of Tuebingen, Tübingen, Germany
,
Martin Hadamitzky
4   Department of Radiology, German Heart Center of Munich, Munich, Germany
,
Anja Löw
1   Department of Cardiology, LMU München, Munich, Germany
,
Martin Orban
1   Department of Cardiology, LMU München, Munich, Germany
,
Kurt Huber
5   Wilhelminen Hospital, 3rd Medical Department for Cardiology and Emergency Medicine, and Sigmund Freud University, Medical School, Vienna, Austria
,
Robert Gabor Kiss
6   Department of Cardiology, Military Hospital, Budapest, Hungary
,
Bela Merkely
7   Heart and Vascular Centre, Semmelweis University, Budapest, Hungary
,
Zenon Huczek
8   1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
,
Bo Eric Beuthner
9   Department of Cardiology and Pneumology, University Medical Center Göttingen (UMG), Göttingen, Germany
,
Ralph Hein-Rothweiler
1   Department of Cardiology, LMU München, Munich, Germany
,
Monika Baylacher
1   Department of Cardiology, LMU München, Munich, Germany
,
Konstantinos Rizas
1   Department of Cardiology, LMU München, Munich, Germany
,
Steffen Massberg
1   Department of Cardiology, LMU München, Munich, Germany
10   DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
,
Daniel Aradi
11   Heart Centre Balatonfüred and Heart and Vascular Centre, Semmelweis University, Budapest, Hungary
,
Dirk Sibbing*
1   Department of Cardiology, LMU München, Munich, Germany
10   DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
,
Claudius Jacobshagen*
9   Department of Cardiology and Pneumology, University Medical Center Göttingen (UMG), Göttingen, Germany
› Author Affiliations
Funding TROPICAL-ACS is an independent, investigator-initiated trial with an academic sponsor (Klinikum der Universität München). The trial was financially supported by a research grant from Roche Diagnostics (Rotkreuz, Switzerland) and a research grant from the German Centre for Cardiovascular Research (DZHK). Prasugrel purchase, drug delivery, and related logistics were kindly supported by Eli Lilly and Company and Daiichi Sankyo Company. Funders of this study had no role in study design, collection of data and data analysis, or writing of the manuscript.
Further Information

Publication History

03 March 2019

21 April 2019

Publication Date:
21 June 2019 (online)

Abstract

Objectives This prespecified analysis of the TROPICAL-ACS trial aimed to assess the impact of gender on clinical outcomes and platelet reactivity (PR) following guided de-escalation of dual antiplatelet treatment (DAPT) in acute coronary syndrome (ACS) patients.

Background Guided de-escalation of DAPT was recently identified as an effective alternative treatment strategy in ACS.

Methods We used Cox proportional hazards models and linear regression analysis to assess the interaction of gender with clinical endpoints and PR.

Results In both male (n = 2,052) and female (n = 558) patients, the 1-year incidence of the primary endpoint did not differ in guided de-escalation versus control group patients (male: 7.0% vs. 9.0%; hazard ratio [HR], 0.78, 95% confidence interval [CI], 0.57–1.06, p = 0.11; female: 8.4% vs. 9.2%; HR, 0.92, 95% CI, 0.53–1.62, p = 0.76, p int = 0.60). The 1-year incidence of combined ischemic events (male: 2.5% vs. 3.3%; HR, 0.76, 95% CI, 0.46–1.26, p = 0.29; female: 2.2% vs. 2.8%; HR, 0.78,95% CI, 0.27–2.25, p = 0.65, p int = 0.96) as well as Bleeding Academic Research Consortium ≥ 2 bleeding (male: 4.6% vs. 6.0%; HR, 0.77, 95% CI, 0.52–1.12, p = 0.17; female: 6.2% vs. 6.4%; HR, 0.99, 95% CI, 0.51–1.92, p = 0.97, p int = 0.51) was similar in the guided de-escalation versus control group for both male and female patients. Interaction testing revealed no significant impact of gender on PR levels (prasugrel or clopidogrel) across treatment groups (p int = 0.72).

Conclusion Guided de-escalation of DAPT appears to be equally safe and effective in women and men. Especially in patients with increased bleeding risk and independent from gender, a guided DAPT de-escalation strategy may be used as an alternative treatment strategy.

Clinical Trial Registration URL: https//www.clinicaltrials.gov. Unique Identifier: NCT: 01959451.

* Both first authors and both senior authors contributed equally to this work.


 
  • References

  • 1 Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol 2016; 13 (01) 11-27
  • 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. J Am Coll Cardiol 2016; 68 (10) 1082-1115
  • 3 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 (02) 87-165
  • 4 Kim ES, Carrigan TP, Menon V. Enrollment of women in National Heart, Lung, and Blood Institute-funded cardiovascular randomized controlled trials fails to meet current federal mandates for inclusion. J Am Coll Cardiol 2008; 52 (08) 672-673
  • 5 Lau ES, Braunwald E, Murphy SA. , et al. Potent P2Y12 inhibitors in men versus women: a collaborative meta-analysis of randomized trials. J Am Coll Cardiol 2017; 69 (12) 1549-1559
  • 6 Berger JS, Bhatt DL, Cannon CP. , et al. The relative efficacy and safety of clopidogrel in women and men a sex-specific collaborative meta-analysis. J Am Coll Cardiol 2009; 54 (21) 1935-1945
  • 7 Husted S, James SK, Bach RG. , et al; PLATO study group. The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2014; 35 (23) 1541-1550
  • 8 Xian Y, Wang TY, McCoy LA. , et al. Association of discharge aspirin dose with outcomes after acute myocardial infarction: insights from the treatment with ADP receptor inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) Study. Circulation 2015; 132 (03) 174-181
  • 9 Motovska Z, Hlinomaz O, Kala P. , et al; PRAGUE-18 Study Group. 1-year outcomes of patients undergoing primary angioplasty for myocardial infarction treated with prasugrel versus ticagrelor. J Am Coll Cardiol 2018; 71 (04) 371-381
  • 10 Sibbing D, Aradi D, Jacobshagen C. , et al; TROPICAL-ACS Investigators. A randomised trial on platelet function-guided de-escalation of antiplatelet treatment in ACS patients undergoing PCI. Rationale and design of the Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Trial. Thromb Haemost 2017; 117 (01) 188-195
  • 11 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
  • 12 Zettler ME, Peterson ED, McCoy LA. , et al; TRANSLATE-ACS Investigators. Switching of adenosine diphosphate receptor inhibitor after hospital discharge among myocardial infarction patients: insights from the Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) observational study. Am Heart J 2017; 183: 62-68
  • 13 Amsterdam EA, Wenger NK, Brindis RG. , et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 64 (24) e139-e228
  • 14 Ibanez B, James S, Agewall S. , et al; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018; 39 (02) 119-177
  • 15 Tantry US, Bonello L, Aradi D. , et al; Working Group on On-Treatment Platelet Reactivity. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013; 62 (24) 2261-2273
  • 16 Aradi D, Kirtane A, Bonello L. , et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015; 36 (27) 1762-1771
  • 17 Thygesen K, Alpert JS, Jaffe AS. , et al; Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction; Authors/Task Force Members Chairpersons; Biomarker Subcommittee; ECG Subcommittee; Imaging Subcommittee; Classification Subcommittee; Intervention Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; ESC Committee for Practice Guidelines (CPG); Document Reviewers. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60 (16) 1581-1598
  • 18 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
  • 19 De Luca L, D'Ascenzo F, Musumeci G. , et al. Incidence and outcome of switching of oral platelet P2Y12 receptor inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention: the SCOPE registry. EuroIntervention 2017; 13 (04) 459-466
  • 20 Breet NJ, Sluman MA, van Berkel MA. , et al. Effect of gender difference on platelet reactivity. Neth Heart J 2011; 19 (11) 451-457
  • 21 Yu J, Mehran R, Baber U. , et al. Sex differences in the clinical impact of high platelet reactivity after percutaneous coronary intervention with drug-eluting stents: results from the ADAPT-DES Study (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents). Circ Cardiovasc Interv 2017; 10 (02) 10
  • 22 Jastrzebska M, Marcinowska Z, Oledzki S. , et al. Variable gender-dependent platelet responses to combined antiplatelet therapy in patients with stable coronary-artery disease. J Physiol Pharmacol 2018; 69 (04) 69
  • 23 Choi SY, Kim MH. Comparison of factors affecting platelet reactivity in various platelet function tests. Platelets 2018; 1-6
  • 24 Faraday N, Goldschmidt-Clermont PJ, Bray PF. Gender differences in platelet GPIIb-IIIa activation. Thromb Haemost 1997; 77 (04) 748-754
  • 25 Wang TY, Angiolillo DJ, Cushman M. , et al. Platelet biology and response to antiplatelet therapy in women: implications for the development and use of antiplatelet pharmacotherapies for cardiovascular disease. J Am Coll Cardiol 2012; 59 (10) 891-900
  • 26 Verdoia M, Pergolini P, Nardin M. , et al. Prevalence and predictors of high-on treatment platelet reactivity during prasugrel treatment in patients with acute coronary syndrome undergoing stent implantation. J Cardiol 2019; 73 (03) 198-203
  • 27 Verdoia M, Pergolini P, Rolla R. , et al; Novara Atherosclerosis Study Group (NAS). Gender differences in platelet reactivity in patients receiving dual antiplatelet therapy. Cardiovasc Drugs Ther 2016; 30 (02) 143-150
  • 28 Small DS, Farid NA, Payne CD. , et al. Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmacodynamics of prasugrel. Clin Pharmacokinet 2010; 49 (12) 777-798
  • 29 Wrishko RE, Ernest II CS, Small DS. , et al. Population pharmacokinetic analyses to evaluate the influence of intrinsic and extrinsic factors on exposure of prasugrel active metabolite in TRITON-TIMI 38. J Clin Pharmacol 2009; 49 (08) 984-998
  • 30 Clemmensen P, Roe MT, Hochman JS. , et al; TRILOGY ACS Investigators. Long-term outcomes for women versus men with unstable angina/non-ST-segment elevation myocardial infarction managed medically without revascularization: insights from the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes trial. Am Heart J 2015; 170 (04) 695-705.e5
  • 31 Hochholzer W, Wiviott SD, Antman EM. , et al. Predictors of bleeding and time dependence of association of bleeding with mortality: insights from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel--Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). Circulation 2011; 123 (23) 2681-2689
  • 32 Bhatt DL, Fox KA, 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
  • 33 Steinhubl SR, Berger PB, Mann III JT. , et al; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288 (19) 2411-2420
  • 34 Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. ; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345 (07) 494-502
  • 35 Price MJ, Berger PB, Teirstein PS. , et al; GRAVITAS Investigators. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011; 305 (11) 1097-1105
  • 36 Collet JP, Cuisset T, Rangé G. , et al; ARCTIC Investigators. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367 (22) 2100-2109
  • 37 Trenk D, Stone GW, Gawaz M. , et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012; 59 (24) 2159-2164
  • 38 Cayla G, Cuisset T, Silvain J. , et al; ANTARCTIC investigators. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016; 388 (10055): 2015-2022
  • 39 Motovska Z, Hlinomaz O, Miklik R. , et al; PRAGUE-18 Study Group. Prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: multicenter randomized PRAGUE-18 study. Circulation 2016; 134 (21) 1603-1612
  • 40 Déry JP, Mehta SR, Fisher HN. , et al; Canadian Observational AntiPlatelet sTudy (COAPT) Investigators. Baseline characteristics, adenosine diphosphate receptor inhibitor treatment patterns, and in-hospital outcomes of myocardial infarction patients undergoing percutaneous coronary intervention in the prospective Canadian Observational AntiPlatelet sTudy (COAPT). Am Heart J 2016; 181: 26-34
  • 41 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
  • 42 Pagidipati NJ, Peterson ED. Acute coronary syndromes in women and men. Nat Rev Cardiol 2016; 13 (08) 471-480
  • 43 Xanthopoulou I, Davlouros P, Deftereos S. , et al. Gender-related differences in antiplatelet treatment patterns and outcome: Insights from the GReekAntiPlatElet Registry. Cardiovasc Ther 2017; 35 (04) 35
  • 44 Tan YC, Sinclair H, Ghoorah K, Teoh X, Mehran R, Kunadian V. Gender differences in outcomes in patients with acute coronary syndrome in the current era: a review. Eur Heart J Acute Cardiovasc Care 2016; 5 (07) 51-60
  • 45 Wang WT, James SK, Wang TY. A review of sex-specific benefits and risks of antithrombotic therapy in acute coronary syndrome. Eur Heart J 2017; 38 (03) 165-171
  • 46 Venetsanos D, Sederholm Lawesson S, Alfredsson J. , et al. Association between gender and short-term outcome in patients with ST elevation myocardial infraction participating in the international, prospective, randomised Administration of Ticagrelor in the catheterisation Laboratory or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery (ATLANTIC) trial: a prespecified analysis. BMJ Open 2017; 7 (09) e015241
  • 47 Anand SS, Xie CC, Mehta S. , et al; CURE Investigators. Differences in the management and prognosis of women and men who suffer from acute coronary syndromes. J Am Coll Cardiol 2005; 46 (10) 1845-1851
  • 48 Gutiérrez-Chico JL, Mehilli J. Gender differences in cardiovascular therapy: focus on antithrombotic therapy and percutaneous coronary intervention. Drugs 2013; 73 (17) 1921-1933
  • 49 Berger JS, Elliott L, Gallup D. , et al. Sex differences in mortality following acute coronary syndromes. JAMA 2009; 302 (08) 874-882
  • 50 Hvelplund A, Galatius S, Madsen M. , et al. Women with acute coronary syndrome are less invasively examined and subsequently less treated than men. Eur Heart J 2010; 31 (06) 684-690
  • 51 Bugiardini R, Yan AT, Yan RT. , et al; Canadian Acute Coronary Syndrome Registry I and II Investigators. Factors influencing underutilization of evidence-based therapies in women. Eur Heart J 2011; 32 (11) 1337-1344
  • 52 Gupta A, Wang Y, Spertus JA. , et al. Trends in acute myocardial infarction in young patients and differences by sex and race, 2001 to 2010. J Am Coll Cardiol 2014; 64 (04) 337-345
  • 53 Poon S, Goodman SG, Yan RT. , et al. Bridging the gender gap: insights from a contemporary analysis of sex-related differences in the treatment and outcomes of patients with acute coronary syndromes. Am Heart J 2012; 163 (01) 66-73
  • 54 Kholaif N, Zheng Y, Jagasia P. , et al. Baseline Q waves and time from symptom onset to ST-segment elevation myocardial infarction: insights from PLATO on the influence of sex. Am J Med 2015; 128 (08) 914.e11-914.e19
  • 55 Chiu JH, Bhatt DL, Ziada KM. , et al. Impact of female sex on outcome after percutaneous coronary intervention. Am Heart J 2004; 148 (06) 998-1002
  • 56 Ndrepepa G, Schulz S, Neumann FJ. , et al. Bleeding after percutaneous coronary intervention in women and men matched for age, body mass index, and type of antithrombotic therapy. Am Heart J 2013; 166 (03) 534-540
  • 57 D'Ascenzo F, Grosso A, Abu-Assi E. , et al. Incidence and predictors of bleeding in ACS patients treated with PCI and prasugrel or ticagrelor: an analysis from the RENAMI registry. Int J Cardiol 2018; 273: 29-33
  • 58 Subherwal S, Bach RG, Chen AY. , et al. Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation 2009; 119 (14) 1873-1882
  • 59 Daugherty SL, Thompson LE, Kim S. , et al. Patterns of use and comparative effectiveness of bleeding avoidance strategies in men and women following percutaneous coronary interventions: an observational study from the National Cardiovascular Data Registry. J Am Coll Cardiol 2013; 61 (20) 2070-2078
  • 60 Yu J, Mehran R, Grinfeld L. , et al. Sex-based differences in bleeding and long term adverse events after percutaneous coronary intervention for acute myocardial infarction: three year results from the HORIZONS-AMI trial. Catheter Cardiovasc Interv 2015; 85 (03) 359-368
  • 61 Berger PB, Bhatt DL, Fuster V. , et al; CHARISMA Investigators. Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Circulation 2010; 121 (23) 2575-2583
  • 62 Berger JS, Bhatt DL, Steg PG. , et al. Bleeding, mortality, and antiplatelet therapy: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J 2011; 162 (01) 98-105