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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2023;148:e9–e119. DOI: 10.1161/CIR.0000000000001168 August 29, 2023

Virani et al 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Chronic Coronary Disease Guideline

randomized 26 449 patients with history of MI, ischemic stroke, or peripheral artery disease to either 2.5 mg of vorapaxar daily or placebo on a background of aspirin therapy. At a mean follow up of 3 years, patients who received vorapaxar experienced an ischemic event less often or died from cardiovascular causes; however, they had more major and intracranial bleeding.15 In a prespecified subgroup analysis of 17 779 patients who had previous MI, there was a reduced incidence of cardiovascular death, MI, or stroke in the vorapaxar group compared with placebo; however, moderate or severe bleeding was increased.16 In a prespecified analysis of 16 897 patients with previous MI without a history of stroke or TIA and on thienopyridine therapy, vorapaxar reduced the composite of cardiovascular death, MI, or stroke compared with thienopyridine use; however, GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate or severe bleeding was increased. Three-year rates of fatal bleeding were 0.2% versus 0.1% in patients receiving vorapaxar versus thienopyridine. Intracranial hemorrhage rates were 0.5% versus 0.4% in that cohort. Vorapaxar had net clinical benefit with a combined risk of all-cause death, MI, stroke, or GUSTO severe bleeding decreased by 13% compared with placebo. Of note, thienopyridine use was not randomized in this study; therefore, formal comparison is limited. The thienopyridine used was clopidogrel therefore extrapolation to more potent P2Y12 agents is not possible.17

6 In a systematic review and meta-analysis of

observational and RCTs (N=20 315 patients) comparing DAPT with SAPT after urgent or elective CABG,18 investigators performed a pooled sensitivity analysis of studies with stable ischemic heart disease–predominant patients (>50% of study population), and found no difference between SAPT and DAPT after CABG in overall mortality (odds ratio, 0.83 [95% CI, 0.63–1.10]; P=0.20), cardiovascular mortality (odds ratio, 0.66 [95% CI, 0.34–1.29]; P=0.23), MI (odds ratio, 1.15 [95% CI, 0.66–1.99]; P=0.63), stroke (odds ratio, 0.58 [95% CI, 0.32–1.06]; P=0.08), combined incidence of cardiovascular death, MI, and stroke (odds ratio, 0.81 [95% CI, 0.57–1.16]; P=0.25), and arterial graft occlusions (odds ratio, 1.13 [95% CI, 0.73–1.73]; P=0.59). In the studies that had predominantly stable patients with CAD, the rate of saphenous vein graft occlusion was lower among those receiving DAPT (odds ratio, 0.74 [95% CI, 0.60–0.90]; P<0.01). 7.	 Clopidogrel plus aspirin is not more effective than

aspirin alone in reducing the rate of MI, stroke, or death from cardiovascular causes in patients at high risk for atherothrombotic events.19

8 In the TRAP 2P–TIMI 50 trial, after 2 years the

data and safety monitoring board recommended discontinuation of study treatment in patients with a history of stroke because of the risk of intracranial hemorrhage. Significant reduction in cardiovascular death, MI, stroke, or recurrent ischemia leading to revascularization was observed; however, the primary driver of benefit was in lower risk of MI, at a cost of increased moderate to severe bleeding along with increased intracranial bleeding.15,57 Vorapaxar is FDA approved for use in patients with previous MI for the reduction in cardiovascular death, MI, stroke, or recurrent ischemia leading to revascularization; however, it carries a 55% increase in moderate or severe bleeding and is contraindicated with a history of stroke, TIA, or intracranial hemorrhage. 9.	 In the TRITON-TIMI 38 (Therapeutic Outcomes

by Optimizing Platelet Inhibition With Prasugrel– Thrombolysis In Myocardial Infarction 38) trial, patients with previous TIA or stroke had increased risk of intracranial hemorrhage leading to an FDA warning: Prasugrel can cause significant, sometimes fatal, bleeding and should not be used in patients with active pathological bleeding or with a history of TIA or stroke. Patients ≥75 years of age and weighing <60 kg had less clinical efficacy with prasugrel use.21,58

10 Investigators have assessed the vascular and gas-

trointestinal side effects in patients with vascular disease and have found major vascular events were increased by about a third by a coxib (relative risk, 1.37 [95% CI, 1.14–1.66]; P=0.0009) or diclofenac (relative risk, 1.41 [95% CI, 1.12– 1.78]; P=0.0036), because of an increase in major coronary events (coxibs relative risk, 1.76 [95% CI, 1.31–2.37]; P=0.0001; diclofenac relative risk, 1.70 [95% CI, 1.19–2.41]; P=0.0032). Ibuprofen also significantly increased major coronary events (relative risk, 2.22 [95% CI, 1.10– 4.48]; P=0.0253). Vascular death was increased significantly by coxibs (relative risk, 1.58 [99% CI, 1.00–2.49]; P=0.0103) and diclofenac (relative risk, 1.65 [95% CI, 0.95–2.85], P=0.0187). HF risk was doubled by all nonsteroidal antiinflammatory drugs.22 However, at moderate doses, celecoxib was found to be noninferior to naproxen or ibuprofen regarding increased cardiovascular risk in patients with arthritis who were considered high cardiovascular risk (stable angina, history of MI, unstable angina, status post CABG or PCI, TIA, or cerebrovascular accident within 3 months, >50% stenosis, carotid disease, peripheral artery disease, diabetes, age

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