Antithrombotic Therapy in Patients with Coronary Artery Disease and Prior Stroke
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Journal of Clinical Medicine Review Antithrombotic Therapy in Patients with Coronary Artery Disease and Prior Stroke Elisa Bellettini and Leonardo De Luca * Department of Cardiosciences, U.O.C. of Cardiology, Azienda Ospedaliera San Camillo-Forlanini, 00152 Roma, Italy; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +39-06-58704419; Fax: +39-06-5870-4361 Abstract: Patients with coronary artery disease (CAD) and prior cerebrovascular events (CVE) are frequently faced in clinical practice and present a high rate of both ischemic and bleeding events. For these reasons, the antithrombotic management is particularly challenging in this subgroup of patients. Recent trials suggest that, although a potent antiplatelet strategy is safe in the acute phases of myocardial ischemia for these patients, the risk of major bleeding complications, including intracranial hemorrhage, is extremely high when the antithrombotic therapy is prolonged for a long period of time. Therefore, especially in patients with chronic CAD and history of CVE, the antithrombotic management should be carefully balanced between ischemic and bleeding risks. The present review is aimed at critically evaluating the available evidence to help make these crucial clinical decisions regarding the better antithrombotic therapy to use in this high-risk subgroup Citation: Bellettini, E.; De Luca, L. of patients. Antithrombotic Therapy in Patients with Coronary Artery Disease and Prior Stroke. J. Clin. Med. 2021, 10, Keywords: antithrombotic therapy; clopidogrel; ticagrelor; prasugrel; aspirin; rivaroxaban; acute 1923. https://doi.org/10.3390/ coronary syndromes; prior stroke jcm10091923 Academic Editors: Wolfgang Dichtl and Andrzej Surdacki 1. Introduction Patients with ischemic stroke present a 4-fold increased risk for coronary artery disease Received: 28 February 2021 (CAD) compared to patients without cerebrovascular diseases (CVD) [1]. Patients with Accepted: 27 April 2021 both CAD and CVD present a 3 times higher risk for stroke and intracranial bleeding Published: 29 April 2021 compared with patients without history of CVD [1–5]. For these reasons, literature agrees in identifying this group of patients as particularly challenging to manage, especially when Publisher’s Note: MDPI stays neutral the right balance between safety and efficacy of antithrombotic treatment needs to be find. with regard to jurisdictional claims in published maps and institutional affil- 2. Prevalence of Stroke in Patients with CAD iations. Patients affected by CAD rarely report a history of stroke or transient ischaemic attack (TIA). In the Global Registry of Acute Coronary Events (GRACE) Registry, 8% of the overall population with acute coronary syndromes (ACS) enrolled reported a prior CVD [2]. Similar rates of CVD have been detected in recent nationwide registries on consecutive Copyright: © 2021 by the authors. ACS patients and in contemporary clinical trials including patients with ACS or stable Licensee MDPI, Basel, Switzerland. CAD [3–5] (Tables1 and2). Likewise, in a cohort of more than 26.000 patients with CAD This article is an open access article included in the REACH (REduction of Atherothrombosis for Continued Health) registry, distributed under the terms and the prevalence of previous CVD was approximately 17% [6]. conditions of the Creative Commons Patients with CAD and CVD are generally older, more likely to have history of Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ angina, myocardial infarction (MI), heart failure, coronary artery bypass surgery, diabetes, 4.0/). hypertension, dyslipidaemia, and atrial fibrillation [2,3,6]. J. Clin. Med. 2021, 10, 1923. https://doi.org/10.3390/jcm10091923 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 1923 2 of 12 Table 1. Major trials on antithrombotic therapies in ACS. Efficacy End Point in Safety end Point in Year Trial Population (n) Prior CVE (%) Drug Efficacy End Point Safety End Point Stroke Subgroup Stroke Subgroup Clopidogrel Reduced Increased VS Placebo MACE: 9.3% vs. 2001 CURE 12.562 4 Major bleeding: 3.7% vs. added to 11.4%, p < 0.001, HR 2.7%; RR 1.38; p = 0.001) ASA 0.80, 95% CI 0.72–0.90 Increased Increased Prasugrel Reduced TIMI Major bleeding Increased TIMI major non CABG VS Clopi- MACE: 9.9% vs. non-related to CABG 2.4% MACE: 19.1% VS 14.4%, TRITON-TIMI related bleeding: 5.0% vs. 2007 13.608 4 dogre, 12.1%, HR 0.81, 95% VS 1.8% HR 1.32; 95% CI p = 0.15, HR 1.37, 95% CI 38 2.9%, HR 2.46, 95% CI added to CI: 0.73–0.90; 1.03–1.68; p = 0.03. Fatal 0.89–2.13; interaction 0.94–6.42; p for ASA p < 0.001; bleeding (0.4% vs. 0.1%; p = 0.02 interaction = 0–22 p = 0.002) No interaction: MACE: Reduced No interaction: PLATO 19.0% vs. 20.8% (HR 0.87; Ticagrelor MACE 9.8% vs. 11.7% major bleeding: 14.6% vs. No significant increased 95% CI 0.66–1.13; vs. Clopi- (HR 0.84; 95% CI 14.9% (HR 0.99; 95% CI PLATO-major bleeding interaction p = 0.84) 2009 PLATO 18.624 6 dogre, 0.77–0.92; p < 0.001) 0.71–1.37) ICH 0.9% vs. 11.6% vs. 11.2%, HR 1.04, All-cause Death: 7.9% vs. added to CV Death 4.0% vs. 0.7%, HR 1, 95% CI 95% CI 0.95–1.13; p = 0.43 13.0% (HR 0.62; 95% CI ASA 5.1% (HR 0.79, 95% CI 0.25–3-99; interaction 0.42–0.91; interaction 0.69–0.91; p = 0.001) p = 0.38 p = 0.49) Not reduced MACE: Increased TIMI major Apixaban 5 Trend toward worse 7.5% vs. 7.9% (HR bleeding: 1.3% vs. 0.5% (HR 2011 APPRAISE-2 7.392 10 mg VS outcome (p for No interaction (p = 0.31) 0.95; 95% CI 0.80–1.11; 2.59; 95% CI 1.50–4.46; Placebo interaction = 0.08) p = 0.51) p = 0.001) Not reduced MACE, Increased moderate and No significant interaction: Vorapaxar recurrent ischemia, severe bleeding: 7.2% VS MACE, recurrent No significant interaction: VS Placebo, urgent coronary 5.2% HR 1.35; 95% CI 1.16 ischemia, urgent coronary Moderate and severe 2012 TRACER 12.944 4 added to revascularization: to 1.58; p < 0.001). ICH 1.1% revascularization: HR bleeding: 1.48 (0.77, 2.83) standard 18.5% vs. 19.9%; HR vs. 0.2%, HR 3.39; 95% CI 0.88 (0.63, 1.22), interaction p = 0.771) therapy 0.92; 95% CI 0.85–1.01; 1.78–6.45; p < 0.001 Interaction p = 0.795 p = 0.07 J. Clin. Med. 2021, 10, 1923 3 of 12 Table 1. Cont. Efficacy End Point in Safety end Point in Year Trial Population (n) Prior CVE (%) Drug Efficacy End Point Safety End Point Stroke Subgroup Stroke Subgroup Reduced Increased Rivaroxaban MACE: 8.9% vs. 10.7% TIMI major bleeding not No significant reduction Four events in 2.5 VS (HR 0.84; 95% CI ATLAS ACS related to CABG: 2.1% vs. MACE: HR 1.57, 95% CI rivaroxaban group; none 2012 15.526 3 Rivariaban 0.74–0.96; p = 0.008), -TIMI 51 0.6%, p < 0.001; HR 3.96, 0.75–3.31; p in placebo group (p for 5 mg VS CV death: 3.3% vs. 95% CI 2.46–6.38). ICH: interaction = 0.1 interaction not possible) placebo 4.1%, p = 0.04 (HR 0.6% vs. 0.2%, p = 0.009 0.80, 95% CI 0.65–0.99) Reduced primary end point Cangrelor (death from any cause, Not increased severe VS Clopi- CHAMPION MI, ischemia-driven GUSTO bleeding: 0.16% vs. No interaction No interaction 2013 11.145 5 dogrel, PHOENIX revascularization, 0.11% (OR 1.50; 95% CI 0.53 p = 0.97 p = 0.5 added to stent thrombosis) 4.7% to 4.22; p = 0.44) ASA vs. 5.9% (OR 0.78; 95% CI 0.6–0.93; p = 0.005) Table 2. Major trials on antithrombotic therapies in secondary prevention. Efficacy End Point Safety End Point in Year Trial Population (n) Setting Prior CVE (%) Drug Efficacy End Point Safety End Point in Stroke Subgroup Stroke Subgroup Not increased documented Reduced bleedings: 9.27% vs. RR reduction 14.9% CVD (prior MI, Clopidogrel vs. RR reduction 8.7%, 1996 CAPRIE 19.185 9.28%, p > 0.05; ICH (95% CI, 0.3–27.3; Not increased prior stroke, Aspirin 95% CI 0·3–16·5; 0·33% vs. 0·47%, p = 0.045) PAD) p = 0·043 p = 0.23 Reduced Clopidogrel vs. Not increased major RR reduction 27%, 2002 CREDO 2116 elective PCI 6 Placebo, added to bleeding (8.8% vs. Not reported Not reported 95% CI 3.9–44.4%; Aspirin 6.7%; p = 0.07) p = 0.02 J. Clin. Med. 2021, 10, 1923 4 of 12 Table 2. Cont. Efficacy End Point Safety End Point in Year Trial Population (n) Setting Prior CVE (%) Drug Efficacy End Point Safety End Point in Stroke Subgroup Stroke Subgroup Not significantly increased severe bleeding 1.7% vs. multiple CV risk Not increased 6.8% 1.3%; RR 1.25; 95% Reduced 7.3% versus Not increased 1.7% Clopidogrel vs. factors or vs. 7.3%, RR 0.93; CI 0.97–1.61 percent; 8.8%, p = 0.01; HR versus 1.5%, 2006 CHARISMA 21.6 3.245 Placebo, added to documented 95% CI 0.83–1.05; p = 0.09. Moderate 0.829, 95% CI p = 0.50; HR 1.114, Aspirin CVD p = 0.22 bleeding 2.1% vs.