After acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) is the standard of care for both invasive management with percutaneous intervention and noninvasive (medical) management. Conversely, studies using dual antiplatelet in the population of patients presenting with ACS who undergo coronary artery bypass grafting (CABG) are conflicting. The appropriate antiplatelet regimen after CABG remains an area of controversy. Plaque stability, prevention of graft closure, and secondary thrombosis form the basis for using a second antiplatelet drug, whereas the additional risk of bleeding and lack of conclusive evidence should also be considered. After an extensive literature search, 12 clinical trials with efficacy outcomes were identified. Most of the studies are retrospective, nonrandomized single-center trials. A few large patient populations have been examined using database information. To date, there is only 1 prospective, multicenter, randomized trial published. Recommendations from national guidelines differ, proposing single antiplatelet therapy with aspirin or DAPT with the combination of aspirin and clopidogrel. The purpose of this report is to review the available clinical trial data and provide guidance to practitioners when caring for this patient population. In conclusion, there is no clear consensus regarding the use of DAPT in patients after CABG. If not contraindicated, it is reasonable to use DAPT, starting in the postoperative period, in patients presenting with ACS. Large, multicenter, randomized clinical trials are needed to definitively investigate the role of DAPT in patients with ACS after CABG.
Coronary artery disease is a health care issue of epidemic proportions and has a profound impact on resource utilization. Platelet aggregation is a crucial component in the development of acute ischemic syndromes. For decades, aspirin (ASA) has been one of the mainstays of treatment for patients with acute coronary syndrome (ACS) irrespective of management strategy. In recent guidelines, dual antiplatelet therapy (DAPT) with ASA and a P2Y 12 antagonist is recommended for all patients with ACS for at least 12 months. Despite great advancements in the availability and efficacy of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) remains the best management strategy for certain patients with severe multivessel coronary artery disease. After ACS, DAPT is the standard of care for both invasive management with PCI and noninvasive (medical) management. However, studies examining DAPT in the population of patients who undergo CABG are conflicting. The purpose of this report is to review the available clinical trial data and provide guidance to practitioners when caring for this patient population.
Importance of antiplatelet therapy after CABG
Rupture of an atherosclerotic plaque is the usual initiating event in ACS. Plaque rupture often leads to thrombus formation and persistent thrombotic occlusion results in acute myocardial infarction (MI). Platelet activation and vein graft thrombosis after CABG are thought to be early steps in the process of stenosis and occlusion and form the rationale for using antiplatelet therapy postoperatively. During the first 12 months after CABG, intimal hyperplasia is the most common cause of saphenous vein graft closure, thought to be because of platelet adhesion to the intimal surface. After adhering to the intima, platelets release mitogenic proteins, stimulating smooth muscle cell migration and resulting in intimal proliferation and hyperplasia. Considering the mechanism of early graft failure, it seems logical that potent platelet inhibition may improve graft patency.
The Antithrombotic Trialists’ Collaboration reviewed the effect of antiplatelet therapy, mostly ASA in nearly 200,000 patients. Antiplatelet therapy produced a significant 46% reduction in the combined end point of subsequent nonfatal MI, nonfatal stroke, or vascular death (8% vs 13%) in patients with unstable angina and a 30% reduction in patients with acute MI (10% vs 14%). With respect to efficacy in patients who underwent CABG, they also concluded that antiplatelet therapy, particularly if given early, was associated with improved graft patency at an average of 1 year after surgery (pooled odds reduction for graft closure of 44%). Although ASA had been the cornerstone of treatment for many years, there are some notable concerns. Aspirin resistance is prevalent, in addition to that on-pump surgery can induce inflammation, causing platelet reactivity and enhancing resistance, which may be responsible for early graft closures.
Benefit of DAPT in ACS
The first study to establish the benefit of DAPT in an ACS population consisting of unstable angina and non–ST-segment elevation was the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial, which compared ASA alone with the combination of ASA and clopidogrel (DAPT). At an average follow-up of 9 months, DAPT led to a significant reduction in the combined primary end point of cardiovascular death, nonfatal MI, or stroke (9.3% vs 11%, relative risk [RR] 0.80, 95% confidence interval [CI] 0.72 to 0.90, p <0.001), which was largely because of a significant reduction in nonfatal MI (5.2% vs 6.7%, RR 0.77, 95% CI 0.67 to 0.89, p not provided). Major bleeding was significantly higher in the DAPT arm (3.7% vs 2.7%, RR 1.38, 95% CI 1.13 to 1.67, p = 0.001), although life-threatening bleeding did not differ. In addition, both the COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) and CLARITY (CLopidogrel as Adjunctive ReperfusIon TherapY) trials found significant benefit from DAPT in reducing vascular events in the ST-segment elevation population with no increased risk of bleeding.
Prasugrel, a second-generation thienopyridine was studied in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI [TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel] 38). In this study, 2 DAPT regimens, ASA plus clopidogrel and ASA plus prasugrel, were compared in 13,608 patients with ACS who underwent PCI. The primary efficacy end point composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke occurred at significantly lower rate with prasugrel (10%) than clopidogrel (12%) (hazard ratio [HR] 0.81, 95% CI 0.73 to 0.90; p <0.001). Not surprising, there was a significantly higher rate of major bleeding, including spontaneous and fatal bleeding in the prasugrel group. CABG-related TIMI major bleeding was fourfold greater in the prasugrel group; therefore, administration is not recommended before angiography and should be held for 7 days before CABG surgery.
The newest P2Y 12 agent, ticagrelor, was studied in an ACS population in the Platelet Inhibition and Patient Outcomes (PLATO) trial. In this study, ticagrelor was compared with clopidogrel in 18,624 patients managed by medical and invasive strategies. All patients received a DAPT regimen including ASA. The composite of death from vascular causes, MI, or stroke occurred at a rate of 10% in the ticagrelor arm and 12% in the clopidogrel arm (HR 0.84, 95% CI 0.77 to 0.92, p <0.001). Rates of major bleeding were similar, although the rate of non–CABG-related major bleeding was significantly higher in the ticagrelor arm (4.5% vs 3.8%, p = 0.03). Of the 1,261 patients who underwent CABG, the composite efficacy end point did not differ between the 2 groups (ticagrelor 13% vs clopidogrel 11%, HR 0.84, 95% CI 0.60 to 1.16, p = 0.29), and there was no difference in bleeding.
Benefit of DAPT in ACS
The first study to establish the benefit of DAPT in an ACS population consisting of unstable angina and non–ST-segment elevation was the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial, which compared ASA alone with the combination of ASA and clopidogrel (DAPT). At an average follow-up of 9 months, DAPT led to a significant reduction in the combined primary end point of cardiovascular death, nonfatal MI, or stroke (9.3% vs 11%, relative risk [RR] 0.80, 95% confidence interval [CI] 0.72 to 0.90, p <0.001), which was largely because of a significant reduction in nonfatal MI (5.2% vs 6.7%, RR 0.77, 95% CI 0.67 to 0.89, p not provided). Major bleeding was significantly higher in the DAPT arm (3.7% vs 2.7%, RR 1.38, 95% CI 1.13 to 1.67, p = 0.001), although life-threatening bleeding did not differ. In addition, both the COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) and CLARITY (CLopidogrel as Adjunctive ReperfusIon TherapY) trials found significant benefit from DAPT in reducing vascular events in the ST-segment elevation population with no increased risk of bleeding.
Prasugrel, a second-generation thienopyridine was studied in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI [TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel] 38). In this study, 2 DAPT regimens, ASA plus clopidogrel and ASA plus prasugrel, were compared in 13,608 patients with ACS who underwent PCI. The primary efficacy end point composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke occurred at significantly lower rate with prasugrel (10%) than clopidogrel (12%) (hazard ratio [HR] 0.81, 95% CI 0.73 to 0.90; p <0.001). Not surprising, there was a significantly higher rate of major bleeding, including spontaneous and fatal bleeding in the prasugrel group. CABG-related TIMI major bleeding was fourfold greater in the prasugrel group; therefore, administration is not recommended before angiography and should be held for 7 days before CABG surgery.
The newest P2Y 12 agent, ticagrelor, was studied in an ACS population in the Platelet Inhibition and Patient Outcomes (PLATO) trial. In this study, ticagrelor was compared with clopidogrel in 18,624 patients managed by medical and invasive strategies. All patients received a DAPT regimen including ASA. The composite of death from vascular causes, MI, or stroke occurred at a rate of 10% in the ticagrelor arm and 12% in the clopidogrel arm (HR 0.84, 95% CI 0.77 to 0.92, p <0.001). Rates of major bleeding were similar, although the rate of non–CABG-related major bleeding was significantly higher in the ticagrelor arm (4.5% vs 3.8%, p = 0.03). Of the 1,261 patients who underwent CABG, the composite efficacy end point did not differ between the 2 groups (ticagrelor 13% vs clopidogrel 11%, HR 0.84, 95% CI 0.60 to 1.16, p = 0.29), and there was no difference in bleeding.
Literature review of DAPT after CABG
Despite the clear benefit of DAPT in patients with ACS, few patients in the landmark clinical trials were managed with a surgical strategy. An extensive literature search was conducted using the terms aspirin, clopidogrel, DAPT, and coronary artery bypass surgery. Additional studies were discovered during bibliographic reviews. A total of 12 studies including efficacy end points were identified on this subject with varying results. In general, the studies conducted to date include small patient populations with surrogate end points. Three meta-analyses have been conducted evaluating DAPT after CABG.
Studies with significant benefit of DAPT
Of the 12 clinical trials identified, 5 found significant benefit from DAPT in the CABG population. A summary of the trial findings can be found in Table 1 . The first positive study was published by Gurbuz et al and conducted in 591 off-pump patients who underwent CABG at a single center. In the DAPT group, therapy was administered short term (30 days) or long term (mean of 33.6 + 12 months). The DAPT group had significant reduction in the rates of recurrent angina (DAPT 1.8% vs ASA 8.6%, p = 0.0001), MI (DAPT 0% vs ASA 3.4%, p = 0.001), re-intervention (DAPT 0.6% vs ASA 6.8%, p = 0.0001), and death (DAPT 2.2% vs ASA 8.3%, p = 0.0001). There was no difference in the event rate between short-and long-term administrations. Interestingly, the rate of major bleeding was lower in the DAPT group, although there was no statistical significance of this finding.
| Study | Subjects | Type(s) of CABG | Agents Comparison | Study Duration | Outcomes | Results n (%) | p value | |
|---|---|---|---|---|---|---|---|---|
| ASA | DAPT | |||||||
| Gurbuz et al. (2006) | 591 | Off pump | ASA 325 mg daily ASA 325 mg daily + CLO 75 mg daily | 30 days or longer ∗ | Recurrent angina Death | 23 (8.6%) 22 (8.3%) | 6 (1.8%) 7 (2.2%) | 0.001 0.0001 |
| Kim et al. (2009) | 15,067 | On and Off pump | ASA † ASA + CLO † | Not provided | In hospital mortality | 210 (1.78%) | 31 (0.95%) | 0.048 |
| Gao et al. (2010) | 249 | On and Off pump | ASA 100 mg daily ASA 100 mg daily + CLO 75 mg daily | 3 months | SVG patency at 3 months | 198 (86%) | 219 (92%) | 0.043 |
| Sorensen et al. (2011) | 3,545 | Not provided | No clopidogrel (86.1 % ASA users) † Clopidogrel (87.9% ASA users) † | Mean follow up 452 ± 151 days | Recurrent MI Death from any cause | 25 (2.7%) 36 (3.8%) | 23 (2.4%) 14 (1.5%) | 0.78 <0.002 |
| CRYSSA (2012) | 300 | Off pump | ASA 100 mg daily ASA 100 mg daily + CLO 75 mg daily | 12 months | Total graft occlusion ‡ SVG occlusion ‡ | 39 (27%) 35 (13%) | 22 (15%) 19 (7.4%) | 0.02 0.04 |
∗ Short term vs long term (duration not defined; mean 33.6 ± 12 months).
A large, retrospective, database analysis of 15,067 on- and off-pump patients who underwent CABG was conducted to evaluate efficacy and safety of DAPT compared with ASA alone. The use of DAPT was associated with a significant inhospital mortality reduction (DAPT 0.95% vs ASA 1.78%, OR 0.50, 95% CI 0.25 to 0.99, p = 0.048). There was no difference in the rate of ischemic or thrombotic events. Like the previous study, there was a reduction in bleeding events with DAPT (4.19%) compared with ASA (5.17%, OR 0.70, 95% CI 0.51 to 0.97, p = 0.029), which could be related to selection bias by the surgeon when prescribing DAPT.
In a single-center randomized trial in China, Gao et al evaluated vein graft patency 3 months after elective CABG using 64-slice multislice computerized tomography angiography. The primary end point of saphenous vein graft patency occurred at a rate of 92% (219 of 239) in the DAPT group versus 86% (198 of 231) in the ASA group (RR 1.707, 95% CI 1.010 to 2.886, p = 0.043). In a multivariate analysis, combined antiplatelet therapy independently increased venous graft patency (p = 0.045). The rate of bleeding was not reported.
A Danish observational study evaluated the efficacy of DAPT in the only complete CABG ACS population studied to date. Of the population of 3,545 patients who underwent CABG within 180 days of MI, 27% filled clopidogrel prescriptions after discharge (DAPT group). The rate of all-cause mortality matched by propensity score was significantly lower in the DAPT arm compared with the ASA arm (1.5% vs 3.8%, p <0.002). The rate of recurrent MI and the composite of all-cause mortality and recurrent MI did not differ between the groups. Bleeding rates were similar in both groups.
Finally, Mannacio et al evaluated optimal platelet inhibition after CABG (Prevention of Coronary Artery Bypass Occlusion After Off-pump Procedures [CRYSSA] trial) and concluded that addition of clopidogrel to ASA not only overcomes single therapy antiplatelet resistance but also improves venous graft patency without an increased risk of bleeding. In their study of 300 off-pump patients, combined therapy was associated with a reduced vein graft occlusion rate by computed tomography angiography (DAPT 7.4% vs ASA 13%, p = 0.04) but no difference in the rate of arterial graft occlusion. Synergistic ASA and clopidogrel activity was a strong predictor of vein graft patency (RR 5.1, 95% CI 1.4 to 16.3, p <0.01).
There are some notable characteristics of these studies. Three of the 5 studies were conducted at a single center, and 2 of these were observational in nature. The remaining 2 studies are database analyses. Importantly, 3 of these studies used clinical end points and found reductions in cardiovascular events and mortality. Two studies used surrogate end points of saphenous vein graft (SVG) patency, where DAPT was found to be superior to ASA. Fortunately, none of the studies found an increased risk of bleeding, although only 3 studies reported bleeding events, and in some cases, bleeding rates were higher in the ASA-only group. This higher rate of bleeding in the ASA-only group was found in the observational studies and may be because of selection bias, whereby patients with perceived bleeding risks were prescribed ASA alone.
Studies with neutral findings
The remaining 7 studies found no difference in outcomes with DAPT compared with ASA and are summarized in Table 2 . In 2004, subgroups of patients who underwent CABG from the CURE and CREDO (Clopidogrel for the Reduction of Events During Observation trial) trials were published. As described previously, the overall results from the CURE trial found a significant benefit of DAPT in an ACS population of unstable angina and patients with non–ST-segment elevation MI. In the 2,072 patients who underwent CABG, the use of DAPT did not result in a significant reduction in the primary end point of cardiovascular death, nonfatal MI, or nonfatal stroke compared with ASA alone (DAPT 14% vs ASA 16%, RR 0.89, 95% CI 0.71 to 1.11, p value not provided). The rate of major bleeding was similar, although there was a numerically higher rate of life-threatening bleeding events in the DAPT group. Similarly, the subgroup of 83 patients who underwent CABG from the CREDO trial failed to show a significant benefit of long-term DAPT on the composite of death, MI, or stroke (28 days DAPT 12% vs 1 year DAPT 14%, RR reduction 17%, p = 0.78). Of note, this subgroup was underpowered to detect differences between the 2 groups.
