A Comprehensive Update on Aspirin Management During Noncardiac Surgery

Neal S. Gerstein, MD, FASE; Cory L. Albrechtsen, BS; Nestor Mercado, MD, PhD; Joaquin E. Cigarroa, MD; Peter M. Schulman, MD


Anesth Analg. 2020;131(4):1111-1123. 

In This Article

Future Directions

The body of literature examining antiplatelet agent efficacy in CV disease continues to expand, with much research focused on the use of nonaspirin antiplatelet agents (ie, P2Y12 inhibitors) as monotherapy in certain CV disease contexts, varying time courses of DAPT, and potential ways to better optimize antithrombotic regimens to mitigate against bleeding risks.

Shortening the Duration of DAPT

Derived from an initial trial of almost 16,000 patients with stable and unstable CAD undergoing PCI with a DES, Franzone et al[53] reported the GLOBAL LEADERS Adjudication Substudy (GLASSY), a follow-up prespecified ancillary study of A Clinical Study Comparing Two Forms of Antiplatelet Therapy After Stent Implantation trial ("GLOBAL LEADERS").[54] The GLASSY study was an international open-label randomized trial examining the impact of low-dose aspirin (75–100 mg) plus ticagrelor for 1 month followed by 23 months of ticagrelor monotherapy (n = 3794) versus 1 of 2 DAPT regimens, which were considered controls: aspirin and clopidogrel if stable CAD or aspirin and ticagrelor if recent ACS for 12 months, followed by aspirin monotherapy for 12 months (n = 3791).[53] The GLASSY study used 2 independent coprimary end points for both safety (Bleeding Academic Research Consortium type 3 or 5 bleeding) and efficacy (composite of all-cause mortality, nonfatal MI, nonfatal stroke, or urgent target vessel revascularization) of the experimental intervention using both noninferior and superiority methodology for both end points. After 2 years, as compared to the control group, the coprimary efficacy end point occurred less in the experimental group (7.14% vs 8.41%, rate ratio = 0.85, 95% CI, 0.72–0.99; P for noninferiority <.001), but did not achieve superiority (P = .0465, α of 2.5%). For the safety end point related to bleeding, there were identical rates between groups (2.48% for both; rate ratio = 1.00, 95% CI, 0.75–1.33; P for superiority = .99). However, in a follow-up post hoc study to the initial GLOBAL LEADERS trial, no difference was found in the risk of the primary end point between single-vessel and multivessel PCI patients, but there was a significant relationship favoring the experimental arm in the multivessel PCI subgroup to reduce death or recurrent MI.[54,55] The interpretation of these findings should be tempered due to the inherent problems of subgroup analyses. However, in contrast to current standard antiplatelet regimens, patients undergoing multivessel PCI may benefit from long-term ticagrelor monotherapy after completion of 4 weeks of DAPT.[56]

P2Y12 Inhibitor Monotherapy

The use of P2Y12 inhibitor monotherapy in lieu of aspirin in the context of CAD and CVD has been described as far back as 1996.[57–59] The Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy Versus Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents (SMART-CHOICE) comprising almost 3000 patients from 33 different sites in Korea compared P2Y12 inhibitor monotherapy (clopidogrel, prasugrel, or ticagrelor) after 3 months of DAPT post-PCI versus a conventional 12 months of DAPT. The primary outcome included major adverse cardiac and cerebrovascular events, to include a composite of all-cause death, MI, or stroke at 12 months after the index PCI procedure. P2Y12 inhibitor monotherapy was found noninferior to DAPT for the primary outcome (2.9% vs 2.5%; 1-sided 95% CI, −∞ to 1.3; P = .007). No intergroup differences were found in any of the following: the cumulative rates of the primary end point components at 12 months (all-cause death, MI, and stroke), the risk of stent thrombosis, or the per-protocol analysis versus the intention-to-treat analyses. Moreover, the rate of bleeding was significantly lower in the P2Y12 inhibitor monotherapy group compared to the DAPT group (HR = 0.58, 2.0% vs 3.4%, 95% CI, 0.34–0.97; P = .4).[60] In a second recent study, the Short and Optimal Duration of Dual Antiplatelet Therapy After Evirolimus-Eluting Cobalt-Chromium Stent (STOPDAPT-2) trial, 3045 patients received either 1 month of DAPT followed by clopidogrel monotherapy or 12 months of DAPT with aspirin and clopidogrel.[61] Similar to the SMART-CHOICE trial, 1-month's duration of DAPT followed by clopidogrel was found to be both noninferior and superior to 12-month DAPT for the primary end point of CV death, MI, stroke, stent thrombosis, or major or minor bleeding at 12 months, occurring in 2.36% of 1 month DAPT versus 3.70% of 12-month DAPT (HR = 0.64, 95% CI, 0.42–0.98; noninferiority [P < .001] and superiority [P = .04]). The secondary bleeding end point was found also superior in the 1-month group (0.41% 1-month DAPT versus 1.54% with 12-month DAPT; HR = 0.26, 95% CI, 0.11–0.64; P = .004).[61]

In both the STOPDAPT-2 and SMART-CHOICE trials, DAPT cessation followed by P2Y12 inhibitor monotherapy as a post-PCI strategy had previously not been intensely studied aside from 1 trial, the aforementioned GLOBAL LEADERS trial. Nonetheless, P2Y12 monotherapy after DAPT is supported by the known pharmacodynamic effects of greater intense platelet inhibition by P2Y12 inhibitors as compared to aspirin.[62,63] In addition, a number of factors impacting the generalizability of both the STOPDAPT-2 and SMART-CHOICE trials, which were conducted in East Asian populations, need to be considered. A large percentage of PCI procedures performed in Japan (STOPDAPT-2) and South Korea (SMART-CHOICE) use intravascular imaging intraprocedurally in contrast to minimal use in the United States or Europe.[62] P2Y12 inhibitors are impacted by body mass index (BMI), whereby higher BMIs are associated with lower drug responses and poor inhibition of platelet reactivity.[64,65] The average BMI in both trials was 24–25, which is lower than the average US BMI of 30 reported in similar trials.[66] Finally, cytochrome P2C19 (CYP2C19), the principal hepatic enzyme involved in converting clopidogrel to its active metabolite, has over 25 alleles with major phenotypes ranging from ultrarapid metabolizer to poor metabolizers.[67] The most important loss-of-function allele for the CYP2C19 enzyme is (*2), leading to poor metabolism, and is found in higher percentages of East Asians (29%–35%) as compared to Caucasians (12%–15%).[68] Appreciation of these aforementioned issues is warranted as clinicians factor how to modify current clinical practice.

Finally, the Ticagrelor With or Without Aspirin in High-Risk Patients After PCI (TWILIGHT) trial examined the safety and efficacy of a shorter-duration (3 months) DAPT with ticagrelor and aspirin followed by ticagrelor monotherapy versus conventional 12 months DAPT (ticagrelor and aspirin) in 7119 patients receiving PCI with a DES and with ≥1 high-risk bleeding or ischemia characteristic. TWILIGHT investigators found that short-duration DAPT followed by ticagrelor monotherapy for 12 months resulted in less bleeding compared with the conventional 12 months longer-duration DAPT among study patients (4.0% vs 7.1%; HR = 0.56; 95% CI, 0.45–0.68, P < .001). Moreover, there was noninferiority for ischemic rates (all-cause mortality, stroke, and MI) between both groups (3.9% for both; difference, −0.06% points; 95% CI, 0.97–0.84; HR = 0.99; 95% CI, 0.78–1.25, P < .001 for noninferiority).[69] See Supplemental Digital Content, Table 1, http://links.lww.com/AA/D140, for study details.