A Randomized Controlled Trial of Prasugrel for Prevention of Early Saphenous Vein Graft Thrombosis

Abstract: Objectives. To test whether administration of prasugrel after coronary artery bypass grafting (CABG) reduces saphenous vein graft (SVG) thrombosis. Use of aspirin after CABG improves graft patency, but administration of other antiplatelet agents has yielded equivocal results. Methods. We performed a double-blind trial randomizing patients to prasugrel or placebo after CABG at four United States centers. Almost all patients were receiving aspirin. Follow-up angiography, optical coherence tomography (OCT), intravascular ultrasound (IVUS), and near-infrared spectroscopy (NIRS) were performed at 12 months. The primary efficacy endpoint was prevalence of OCT-detected SVG thrombus. The primary safety endpoint was incidence of Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) severe bleeding. Results. The study was stopped early due to slow enrollment after randomizing 84 patients. Mean age was 64 ± 6 years; 98% of the patients were men. Follow-up angiography was performed in 59 patients. IVUS was performed in 52 patients, OCT in 53 patients, and NIRS in 33 patients. Thrombus was identified by OCT in 56% vs 50% of patients in the prasugrel vs placebo groups, respectively (P=.78). Angiographic SVG failure occurred in 24% of patients in the prasugrel arm vs 40% in the placebo arm (P=.19). The 1-year incidence of major adverse cardiovascular events was 14.3% vs 2.4% in the prasugrel and placebo groups, respectively (P=.20), without significant differences in GUSTO severe bleeding (P=.32). Conclusion. Early SVG failure occurred in approximately one-third of patients. Prasugrel did not decrease prevalence of SVG thrombus 12 months after CABG.   

J INVASIVE CARDIOL 2020;32(12):E305-E312. Epub 2020 September 22. 

Key words: CABG, coronary artery bypass grafting, saphenous vein graft, thrombus

Coronary artery bypass graft (CABG) surgery is effective in treating advanced coronary artery disease,^1,2 and is among the most frequently performed surgical procedures. However, patency of saphenous vein grafts (SVGs) dramatically declines in the years following CABG. Early SVG failure is common,^3-5 has been associated with increased morbidity and mortality, and can be challenging to treat.^6-8 Thrombus formation is postulated to play an important role in early SVG failure, through graft thrombosis, platelet-mediated intimal hyperplasia, and development of atherosclerotic plaque.⁹ Early initiation of aspirin has been shown to reduce rates of SVG failure,¹⁰ and is currently used in nearly all patients undergoing CABG. The addition of clopidogrel, a thienopyridine that inhibits the platelet P₂Y₁₂ adenosine diphosphate receptor, to aspirin has yielded conflicting results in maintaining SVG patency in small, randomized studies.^11-14 Prasugrel is another thienopyridine that results in more rapid, consistent, and potent platelet inhibition than clopidogrel. We performed a randomized-controlled trial to examine whether early administration of prasugrel after CABG reduces thrombus formation in SVGs during the first postoperative year, as well as fewer clinical events without increasing the risk of severe bleeding. 

Methods 

We performed a double-blind, randomized, controlled trial at 4 Veterans Affairs medical centers from December 2012 to June 2018 (Prasugrel for Prevention of Early Saphenous Vein Graft Thrombosis; NCT01560780). Patients undergoing clinically indicated CABG were randomized to 12 months of 10 mg prasugrel daily or placebo, which was initiated at the time of discharge from the hospital. Eligibility criteria are listed in Table 1. The institutional review boards of each participating center approved the study protocol. All patients who participated in the study provided informed consent prior to enrollment in the study. At 12 months, patients underwent SVG angiography, optical coherence tomography (OCT), intravascular ultrasound (IVUS), and near-infrared spectroscopy (NIRS). Patients were treated according to current guidelines, which included the use of aspirin, lipid-lowering agents, and beta-blockers as tolerated. Randomization was stratified by center. All patients, investigators, and study personnel were blinded to the treatment assignment, except for 1 study coordinator who generated the randomization sequence. 

SVG angiography and intravascular imaging. Intravascular imaging was performed in 1 SVG per patient, selected by the operator as the longest and least angulated graft amenable to intravascular imaging. After intragraft administration of 200 µg of nitroglycerin, a DragonFly OCT catheter (St. Jude Medical) was advanced 40-50 mm distal to the proximal SVG anastomosis and pulled back using a motorized system at a speed of 20 mm/s. Subsequently, a  3.2 Fr Revolution (R) 45 MHz rotational IVUS catheter (Volcano Therapeutics) was advanced as distal as possible within the SVG, and was pulled back to the SVG aortic ostium using a motorized system at a speed of 0.5 mm/s. Gray-scale IVUS was recorded at a rate of 30 frames/s. A 3.2 Fr NIRS Lipiscan IVUS catheter (InfraReDx) was advanced into the target SVG and positioned to the same location where the IVUS catheter was previously placed, if feasible. The catheter was then pulled back to the aortic ostium using a motorized system at a speed of 0.5 mm/s, resulting in a chemogram of the SVG wall. 

Imaging analysis. Quantitative assessments of SVG patency were performed by CAAS quantitative coronary angiography (Pie Medical Imaging) to obtain minimal lumen diameter, reference lumen diameter, and percent diameter stenosis. Angiographic SVG failure was defined as SVG luminal stenosis ≥75% in at least 1 SVG per patient. Each target SVG was evaluated for the presence or absence of SVG thrombus on OCT by 2 investigators (BD, KA). Discrepancies between the 2 readers were resolved by a third reader (ESB). SVG thrombus was defined as a mass protruding into the vessel lumen from the surface of the vessel wall, discontinuous from the surface of the vessel wall. Thrombus was semiquantified as the number of quadrants involved on the cross-sectional OCT image. IVUS pullbacks of the longest possible length of each target SVG were analyzed at 1-mm intervals. Manual planimetry was used to trace the leading edges of the lumen and external elastic membrane, and calculate the following areas in accordance with the standards of the American College of Cardiology: percent atheroma volume, total atheroma volume, normalized total atheroma volume, and mean intimal area.¹⁵ 

Chemograms were generated using the NIRS LipiScan Coronary Imaging System, which has been previously described.¹⁶ Chemograms were analyzed using EchoPlaque software (INDEC Medical Systems) to measure the lipid core burden index. All imaging analyses were performed blinded to treatment assignment. 

Outcomes. The primary efficacy endpoint was defined as the prevalence of OCT-detected SVG thrombus. The primary safety endpoint was the incidence of Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) severe bleeding, defined as intracranial hemorrhage, or bleeding that causes hemodynamic compromise and requires intervention.¹⁷ Secondary endpoints included: incidence of angiographic failure, defined as ≥75% SVG diameter stenosis in at least 1 SVG; total and normalized SVG atheroma volume within at least 40 mm of the target SVG, as assessed by IVUS; lipid core burden index of target SVG, as assessed by intravascular NIRS; incidence of major adverse cardiac events (composite of percutaneous coronary intervention, acute coronary syndrome, death); and incidence of GUSTO moderate bleeding, defined as bleeding that requires blood transfusion but does not result in hemodynamic compromise.¹⁷ The incidence of bleeding according to the Bleeding Academic Research Consortium (BARC) definition was also assessed.¹⁸ All endpoints were adjudicated blinded to the treatment assignment. 

Statistical analyses. The prevalence of thrombus within the target SVG at 12-month OCT imaging was compared between the 2 groups using Fisher’s exact test. Multivariable logistic regression was performed to adjust for potential differences in the baseline characteristics. These prespecified adjustment variables included patient age, prior myocardial infarction, total cholesterol and high-density lipoprotein cholesterol levels, mean arterial pressure, left ventricular ejection fraction, male gender, serum creatinine, diabetes, and current smoking. 

Kaplan-Meier survival curves were constructed for the probability of severe GUSTO bleeding (defined using the GUSTO study criteria)¹⁷ and time-to-event was compared using the log-rank test. Differences in angiographic SVG failure were compared using Fisher’s exact test. A logistic regression model was developed to evaluate the treatment effect on this outcome, adjusting for the same variables as above. Total and normalized SVG atheroma volume and lipid core burden index were compared using Student’s t-test. Kaplan-Meier survival curves were constructed for the probability of major adverse cardiovascular events at 12 months and time-to-event in the 2 groups was compared using the log-rank test. All other variables were compared using the Chi-squared test or Student’s t-test, as appropriate. All tests were 2-sided, with an alpha level of 0.05. All endpoints were analyzed using an intention-to-treat approach. The sample size of the study was determined assuming that the prevalence of SVG thrombus in asymptomatic patients within 3 years after CABG is 25%.¹⁹ Given the potent antiplatelet effect of prasugrel, an 80% reduction in the prevalence of thrombus was anticipated. To achieve 80% power and a 2-sided alpha level of 0.05, a total of 48 patients would be required in each group; this was increased to 60 patients to allow for 20% dropout. 

Results

Eighty-four patients were randomly assigned to receive either prasugrel or placebo (Figure 1). The study was stopped early due to slow enrollment. Baseline characteristics are summarized in Table 2. 

Follow-up imaging. Figure 1 demonstrates the study enrollment and follow-up. Imaging characteristics at 12-month follow-up are summarized in Table 3. Prevalence of thrombus on OCT at 12 months was 56% in the prasugrel group vs 50% in the placebo group (P=.78). The adjusted odds ratio for prevalence of thrombus on OCT for patients in the prasugrel group vs the placebo group was 0.61 (95% confidence interval [CI], 0.13-2.80; P=.53). Figure 2 demonstrates several OCT frames containing thrombus from patients in both study groups. The secondary endpoints of angiographic SVG failure, total and normalized SVG atheroma volume, and lipid core burden index were similar in the 2 groups. The adjusted odds ratio for SVG failure in the prasugrel group was 0.17 (95% CI, 0.03-1.04; P=.06). 

Clinical outcomes. The 12-month Kaplan-Meier probability estimate of major adverse cardiovascular events was 14.3% in the prasugrel group vs 2.4% in the placebo group (log-rank P=.20) (Figure 3). Clinical events are summarized in Table 4. The 12-month Kaplan-Meier probability estimate of severe GUSTO bleeding was 2.4% in the prasugrel group vs 0% in the placebo group (log-rank P=.32). There were no instances of moderate GUSTO bleeding. The incidence of BARC bleeding is summarized in Table 5. As-treated and per-protocol analyses are summarized in Table 6. There was a numerically lower incidence of angiographic SVG failure among patients who received 12 months of prasugrel vs those who did not (18% vs 41%, respectively; P=.09) in the as-treated analysis. 

Discussion

The main finding of our study is that early administration of prasugrel does not prevent the development of SVG thrombus during the first year after CABG. Early graft failure, SVG atheroma burden, SVG lipid deposition, and major adverse cardiovascular events were also not significantly reduced. Administration of prasugrel was not associated with significantly greater risk of severe or moderate bleeding; however, our findings were limited by early termination of the trial. The prevalence of SVG thrombus by OCT was greater than expected at approximately 50%, and was possibly attributable to OCT’s high spatial resolution (mean largest thrombus area was <1 mm²) and is similar to another smaller OCT study. There was no significant difference in the mean thrombus area or the number of quadrants containing thrombus in the prasugrel vs control groups. Although the prevalence of thrombus did not appear to be reduced by prasugrel administration, the clinical significance of small thrombi is uncertain. There was no significant difference in measurements of intimal hyperplasia and atheroma burden between the groups, suggesting that administration of prasugrel did not prevent development of early atherosclerotic plaque. These results are concordant with those of the CASCADE (Clopidogrel After Surgery for Coronary Artery DiseasE) trial,¹⁴ which demonstrated no significant difference in vein intimal area in patients receiving clopidogrel and aspirin vs aspirin alone. In our cohort, as-treated analyses comparing patients who received <11 months of prasugrel with those who received 12 months of treatment did not demonstrate any significant difference in the primary or secondary endpoints, indicating that the lack of difference in the endpoints was not likely due to discontinuation of prasugrel. These findings may be due to cohort size, or may reflect a delayed impact on SVG wall thickening by antiplatelet agents that is not apparent at 1 year. SVG-NIRS imaging demonstrated no difference in lipid core burden index between the 2 groups, suggesting that prasugrel administration does not prevent early atherosclerotic plaque development. The lipid core burden index in vein grafts in our cohort was low, suggesting minimal lipid deposition during the first postoperative year, which is not surprising since lipid deposition is associated with SVG age, and there was nearly universal statin use in this study.^20,21 

The overall rate of graft failure at 1 year was high, but similar to the 20%-40% range that is reported in other studies. In our cohort, there was a numerically lower incidence of SVG failure in the prasugrel group vs the placebo group (24% vs 40%, respectively; P=.19), and was more pronounced in the as-treated analysis (18% vs 41%, respectively; P=.09). This may be a signal of benefit with prasugrel administration and is consistent with the results of the DACAB (Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery) trial (NCT02201771), which showed that dual-antiplatelet therapy with ticagrelor and aspirin resulted in improved graft patency at 1 year compared with aspirin or ticagrelor alone. A certain thrombus burden threshold may be reached before graft failure occurs, and prasugrel may modulate the rate at which significant thrombus burden develops. 

Observational evidence suggests that early SVG failure is associated with higher rates of revascularization, and possibly mortality.^6,7 However, the TICAB (Ticagrelor Compared with Aspirin for Prevention of Vascular Events in Patients Undergoing Coronary Artery Bypass Graft Operation) trial²² did not find a benefit of ticagrelor monotherapy compared with aspirin for prevention of major adverse cardiovascular events in the first post-CABG year. A recent network meta-analysis of trials comparing antithrombotic strategies after CABG demonstrated that dual-antiplatelet therapy with aspirin and either ticagrelor or clopidogrel was more efficacious in preventing SVG failure than aspirin alone.²³ However, there did not appear to be differences in mortality or myocardial infarction among the antithrombotic strategies. While dual-antiplatelet therapy was associated with an increased bleeding risk, the risk did not differ among the dual-antiplatelet strategies.²³ 

Clinically severe bleeding was infrequent in our study, with only 1 event occurring in a patient taking prasugrel. Patients at high risk of bleeding were excluded and prasugrel was initiated at the time of hospital discharge, rather than immediately after bypass surgery, to mitigate bleeding risk.^11,24 

The incidence of major adverse cardiovascular events was numerically higher in the prasugrel group vs the placebo group, and was primarily driven by percutaneous coronary intervention. In contrast, a substudy of TRITON TIMI-38 showed a reduction in risk-adjusted all-cause mortality in non-randomized CABG patients receiving prasugrel vs clopidogrel.²⁵ As the difference in events was not statistically significant, it is likely that the observed difference was due to chance. 

Study limitations. The present study was designed with a surrogate primary efficacy endpoint, rather than a clinical endpoint. However, we performed multimodality SVG imaging to provide a comprehensive evaluation of SVG failure. Our study was terminated prior to full enrollment. However, given the higher than expected rate of thrombus in the control group, with the enrollment and follow-up achieved, the post hoc study power was >90% to detect an 80% relative reduction in thrombus. Thus, it is unlikely that the primary outcome would have been met even if the study had completed enrollment. Selection bias was possible due to incomplete angiographic follow-up. Early SVG thrombosis resulting from endothelial activation during the immediate postoperative period may have occurred prior to initiation of prasugrel. In addition, only 1 SVG was imaged per patient, which presents the possibility of undetected thrombus in non-imaged SVGs. Because the least angulated graft per patient was selected for imaging, non-imaged grafts may have been more likely to occlude due to intimal hyperplasia secondary to shear stress in angulated vessels. Intravascular imaging was performed primarily in SVGs that had not failed, limiting evaluation of the exact mechanisms of graft failure. The study was performed in a predominantly male population, limiting generalizability to women. 

Conclusion

Administration of prasugrel was not associated with lower prevalence of SVG thrombus detected by intravascular OCT 12 months after CABG. Early graft failure occurred in about one-third of patients enrolled in the study. Further investigation is needed to identify strategies that can prevent early SVG failure. 

From the ¹VA North Texas Healthcare System/University of Texas Southwestern, Dallas, Texas; ²San Francisco VA Medical Center/University of California San Francisco, San Francisco, California; ³Jesse Brown VA Medical Center/University of Illinois at Chicago, Chicago, Illinois; ⁴Malcom Randall VA Medical Center/University of Florida, Gainesville, Florida; ⁵Minneapolis Heart Institute, Minneapolis, Minnesota; and ⁶Rutgers University - New Jersey Medical School, Newark, New Jersey.

Funding: This study was funded by the Department of Veterans Affairs Clinical Research and Development Merit Grant #CX000787; Project ID CLIN-002-11F.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Shunk reports research grants from Siemens, Svelte, CSI; consulting fees from Terumo, TransAortic Medical, Medeon Bio. Dr Bavry reports honoraria from the American College of Cardiology; personal fees from CSI. Dr Rangan reports research grants from InfraRedx and Spectranetics. Dr Banerjee reports research grants from Abbott Vascular, Boston Scientific, ARALEZ; speaker’s bureau for Astra Zeneca, Medtronic; Cardiovascular Innovations Foundation (Board of Directors). Dr Brilakis reports consulting/speaker honoraria from Abbott Vascular, American Heart Association (associate editor, Circulation), Boston Scientific, CSI, Elsevier, GE Healthcare, InfraRedx, and Medtronic; research support from Regeneron and Siemens; shareholder in MHI Ventures; Board of Directors for Cardiovascular Innovations Foundation; Board of Trustees for the Society of Cardiovascular Angiography and Interventions. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted June 16, 2020.

Address for correspondence: Shuaib Abdullah, MD, Veterans Affairs North Texas Health Care System, 4500 South Lancaster, 111A, Dallas, TX 75216. Email: shuaib.abdullah@utsouthwestern.edu

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