Aspirin at the Intersection of Antiplatelet and Anticoagulant Therapy An Act of Commission?

Aspirin at the Intersection of Antiplatelet and Anticoagulant Therapy An Act of Commission? Ty J. Gluckman, MD, FACC, FAHA Medical Director, Center for Cardiovascular Analytics, Research and Data Science (CARDS) Providence St. Joseph Health Heart Institute Portland, Oregon

An Amazing Journey With a Storied Past Salicylate-rich plants belonging to the Spiraea genus noted in ancient Egypt Hippocrates noted willow leaves and bark relieved pain and fevers Felix Hoffmann re-synthesized ASA and in 1899 Bayer branded it as Aspirin Alexei Romanov, a hemophiliac, had increased bleeding with Aspirin Dr. Lawrence Craven wrote of Aspirin s ability to prevent heart attacks and strokes

Aspirin s Effect in Higher Risk Individuals When Used Alone Antithrombotic Trialists Collaboration Antithrombotic Trialists Collaboration. BMJ 2002;324:71-86

Aspirin s Effect in Higher Risk Individuals When Used Alone Stroke Prevention in Atrial Fibrillation (SPAF) Study 1,330 patients with atrial fibrillation randomized to aspirin (325 mg/day), warfarin, or placebo for a mean of 1.3 years Ischemic stroke or systemic embolism (%) Aspirin (n=552) Placebo (n=568) HR=0.56, p=0.02 Stroke Prevention in Atrial Fibrillation Investigators. Circulation 1991;84:527-539 Days

Questions We Should Be Asking Stable ASCVD Mechanical Valve Atrial Fibrillation Aspirin VKA OAC Is an OAC a preferred alternative? If yes, should aspirin be added? Should aspirin be added? Should aspirin be added in those with SIHD (excluding those with recent ACS and/or PCI)?

Aspirin, an Oral Anticoagulant, or Both in ASCVD Reduction of Atherothrombosis Disease (REACH) Registry Observational registry of 25,686 US outpatients with established atherothrombosis* or >3 atherothrombotic risk factors enrolled from December 2003 to June 2004 *Coronary, cerebrovascular, or peripheral artery disease Cannon CP et al. Am J Cardiol 2010;105:105:445-452

Aspirin, an Oral Anticoagulant, or Both in SIHD Intervention CV death, MI, or stroke Major bleeding Moderate intensity OAC (INR 2-3) vs. control OR=0.86 (p=0.20) OR=7.7 (p<0.0001) High intensity OAC (INR >2.8) vs. control OR=0.57 (p<0.0001) OR=4.5 (p<0.00001) Moderate-high intensity OAC vs. aspirin OR=0.79 (p=0.008) OR=2.1 (p<0.00001) Moderate-high intensity OAC + aspirin vs. aspirin OR=0.88 (p=0.01)* OR=1.12 (p>0.01)** Moderate-high intensity OAC + aspirin vs. OAC OR=0.86 (p=0.15) OR=0.95 (p=0.80) *7 trials enrolling 12,333 patients **10 trials enrolling 6,655 patients Anand SS, Yusuf S. JACC 2003;41:62S-69S

Aspirin, an Oral Anticoagulant, or Both in ASCVD Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial 27,395 patients with stable ASCVD randomized to rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg/day), rivaroxaban (5 mg twice daily), or aspirin (100 mg/day) for a mean of 23 months Outcome R + A R A R + A vs. A R + A vs. R R vs A CV death, MI, or stroke 4.1% 4.9% 5.4% HR=0.76, p<0.001 HR=0.90, p=0.12 CV death 1.7% 2.1% 2.2% HR=0.78, p=0.02 HR=0.96, p=0.69 All cause death 3.4% 4.0% 4.1% HR=0.82, p=0.01 HR=0.97, p=0.67 MI 1.9% 2.0% 2.2% HR=0.86, p=0.14 HR=0.89, p=0.24 Stroke 0.9% 1.3% 1.6% HR=0.58, p<0.001 HR=0.82, p=0.12 Major bleeding 3.1% 2.8% 1.9% HR=1.70, p<0.001 HR=1.51, p<0.001 Fatal bleeding 0.2% 0.2% 0.1% HR=1.49, p=0.32 HR-1.40, HR=0.41 GI bleeding 1.5% 1.0% 0.7% HR=2.15, p<0.001 HR=1.40, p=0.04 A=Aspirin, R=Rivaroxaban Eikelboom JW et al. NEJM 2017;377:1319-1330

Questions We Should Be Asking Stable Ischemic Heart Disease Mechanical Valve Atrial Fibrillation Aspirin VKA OAC Is an OAC a preferred alternative? If yes, should aspirin be added? Should aspirin be added? Should aspirin be added in those with SIHD (excluding those with recent ACS and/or PCI)?

Adding Antiplatelet Therapy to Oral Anticoagulant Therapy Meta-analysis of 4,180 patients from 10 randomized controlled trials comparing aspirin plus oral anticoagulant (OAC) therapy to OAC therapy alone in those with atrial fibrillation (AF), coronary artery disease (CAD), or a mechanical heart valve (MV) Arterial All Major cause thromboembolism bleeding mortality MV MV CAD CAD MV AF MV CAD AF MV Dentali F et al. Arch Intern Med 2007;167:117-124

Questions We Should Be Asking Stable Ischemic Heart Disease Mechanical Valve Atrial Fibrillation Aspirin VKA OAC Is an OAC a preferred alternative? If yes, should aspirin be added? Should aspirin be added? Should aspirin be added in those with SIHD (excluding those with recent ACS and/or PCI)?

How Often is Aspirin Used in Addition to an OAC in AF? Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Observational registry of 10,126 patients from 176 US practices with atrial fibrillation enrolled from June 2010 through August 2011 History OAC Alone OAC + Aspirin Any vascular history 37% 61% Coronary artery disease 20% 47% 35% Previous MI 10% 23% Previous CABG surgery 9% 24% Previous PCI 9% 24% Previous DES 2% 9% Cerebrovascular disease 15% 20% Stroke, nonhemorrhagic 8% 10% TIA 8% 11% Steinberg BA et al. Circulation 2013;128:721-728

Effect of Aspirin Added to an OAC in Atrial Fibrillation Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Observational registry of 10,126 patients from 176 US practices with atrial fibrillation enrolled from June 2010 through August 2011 Event OAC Alone OAC + Aspirin Unadjusted Adjusted Death 1.9% 2.6% HR=1.37, p=0.07 HR=1.26, p=0.08 All cause hospitalization 19% 23% HR=1.17, p=0.008 HR=1.08, HR=0.06 Cardiovascular cause 10.9% 13.3% HR=1.18, p=0.03 HR=1.08, p=0.14 Bleeding cause 1.6% 2.6% HR=1.59, p=0.009 HR=1.52, p=0.002 Other 8.6% 9.6% HR=1.09, p=0.33 HR=0.98, p=0.72 Major bleeding 1.8% 3.0% HR=1.62, p=0.004 HR=1.53, p=0.0006 Nuisance bleeding 10% 11% HR=1.33, p<0.001 HR-1.09, p=0.18 Steinberg BA et al. Circulation 2013;128:721-728

Effect of Aspirin Added to an OAC in Atrial Fibrillation Cohort study of 8,700 patients with atrial fibrillation and stable ischemic heart disease in whom the efficacy and safety of adding antiplatelet therapy to a vitamin K antagonist was assessed Myocardial Thromboembolism infarction Serious Bleeding and coronary death Lamberts M et al. Circulation 2014;129:1577-1585

The Perils of If Some is Good, More Must be Better Cohort study of 82,854 patients from Denmark discharged after a hospitalization for atrial fibrillation on warfarin, aspirin, or clopidogrel either alone or in combination Nonfatal and fatal bleeding Nonfatal and fatal ischemic stroke Hansen ML et al. Arch Intern Med. 2010;170:1433-1441

Takeaways Any ischemic benefit appears to be offset by increased bleeding risk from the addition of a VKA to aspirin in patients with stable ASCVD. Further analysis from the COMPASS trial is needed to understand the benefits/risks associated with rivaroxaban + aspirin compared to rivaroxaban alone. Aspirin (75-100 mg/day) is recommended in addition to a VKA in patients with a mechanical valve prosthesis (Class I, Level A). If there is a compelling indication for anticoagulant therapy (e.g., atrial fibrillation heart valve, left ventricular thrombus, or concomitant venous thromboembolic disease), warfarin should be administered with continuation of low-dose aspirin (Class I, Level A). Current observational data suggests that the addition of aspirin to OAC therapy in atrial fibrillation achieves little ischemic benefit, but significantly increases the risk of bleeding. Nishimura RA et al. JACC 2014;63:e57-e185 Smith Jr. SC et al. JACC 2011;58:2432-2446

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