Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Artery Bypass Graft Surgery: A Systematic Review and Meta-analysis

Abstract

Importance: The role of ticagrelor with or without aspirin after coronary artery bypass graft surgery remains unclear.

Objective: To compare the risks of vein graft failure and bleeding associated with ticagrelor dual antiplatelet therapy (DAPT) or ticagrelor monotherapy vs aspirin among patients undergoing coronary artery bypass graft surgery.

Data sources: MEDLINE, Embase, and Cochrane Library databases from inception to June 1, 2022, without language restriction.

Study selection: Randomized clinical trials (RCTs) comparing the effects of ticagrelor DAPT or ticagrelor monotherapy vs aspirin on saphenous vein graft failure.

Data extraction and synthesis: Individual patient data provided by each trial were synthesized into a combined data set for independent analysis. Multilevel logistic regression models were used.

Main outcomes and measures: The primary analysis assessed the incidence of saphenous vein graft failure per graft (primary outcome) in RCTs comparing ticagrelor DAPT with aspirin. Secondary outcomes were saphenous vein graft failure per patient and Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding events. A supplementary analysis included RCTs comparing ticagrelor monotherapy with aspirin.

Results: A total of 4 RCTs were included in the meta-analysis, involving 1316 patients and 1668 saphenous vein grafts. Of the 871 patients in the primary analysis, 435 received ticagrelor DAPT (median age, 67 years [IQR, 60-72 years]; 65 women [14.9%]; 370 men [85.1%]) and 436 received aspirin (median age, 66 years [IQR, 61-73 years]; 63 women [14.5%]; 373 men [85.5%]). Ticagrelor DAPT was associated with a significantly lower incidence of saphenous vein graft failure (11.2%) per graft than was aspirin (20%; difference, -8.7% [95% CI, -13.5% to -3.9%]; OR, 0.51 [95% CI, 0.35 to 0.74]; P < .001) and was associated with a significantly lower incidence of saphenous vein graft failure per patient (13.2% vs 23.0%, difference, -9.7% [95% CI, -14.9% to -4.4%]; OR, 0.51 [95% CI, 0.35 to 0.74]; P < .001). Ticagrelor DAPT (22.1%) was associated with a significantly higher incidence of BARC type 2, 3, or 5 bleeding events than was aspirin (8.7%; difference, 13.3% [95% CI, 8.6% to 18.0%]; OR, 2.98 [95% CI, 1.99 to 4.47]; P < .001), but not BARC type 3 or 5 bleeding events (1.8% vs 1.8%, difference, 0% [95% CI, -1.8% to 1.8%]; OR, 1.00 [95% CI, 0.37 to 2.69]; P = .99). Compared with aspirin, ticagrelor monotherapy was not significantly associated with saphenous vein graft failure (19.3% vs 21.7%, difference, -2.6% [95% CI, -9.1% to 3.9%]; OR, 0.86 [95% CI, 0.58 to 1.27]; P = .44) or BARC type 2, 3, or 5 bleeding events (8.9% vs 7.3%, difference, 1.7% [95% CI, -2.8% to 6.1%]; OR, 1.25 [95% CI, 0.69 to 2.29]; P = .46).

Conclusions and relevance: Among patients undergoing coronary artery bypass graft surgery, adding ticagrelor to aspirin was associated with a significantly decreased risk of vein graft failure. However, this was accompanied by a significantly increased risk of clinically important bleeding.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Sandner reported receiving institutional research grants from Vascular Grafts Solutions outside the submitted work. Dr Angiolillo reported receiving consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and research grants to his institution from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr Janssen reported receiving grants from AstraZeneca funding for the POPular CABG trial during the conduct of the study. Dr Kulik reported receiving grants from AstraZeneca during the conduct of the study. Dr Mehran reported receiving research grants from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Applied Therapeutics, Arena, AstraZeneca, Bayer, Beth Israel Deaconess, Biosensors, Biotronik, Bristol Myers Squibb, Boston Scientific Research, CardiaWave Research, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, Daiichi Sankyo Inc, Duke University, Humacyte, Idorsa Pharmaceuticals, Insel Gruppe AG, Janssen, Medtronic, Novartis, OrbusNeich, Philips, Vivasure, and Zoll, all to her institution; serving as a consultant to the California Institute for Regenerative Medicine; serving on the scientific advisory board of the American Medical Association; serving on the advisory boards of CERC (Biosnsors), Abbott, Arena, Biotronik, CardiaWave, Chiesi, Concept Medical, Humacyte, Magenta, Novartis, and Philips, all to her institution; serving on the board of the American College of Cardiology, and as a committee member of the Women in Innovations of the Society for Cardiovascular Angiography, all to her institution; serving as an unpaid faculty of the Cardiovascular Research Foundation; receiving personal fees from Cine-Med, Janssen, and WebMD; receiving less than 1% of equity in Applied Therapeutics Equity, Elixir Medical, Stel, and ControlRad Equity (spouse) outside the submitted work; and having other financial or nonfinancial interests in Boston Scientific Corp and divested final stock options of less than 1% in Claret Medical. Dr Saw reported receiving grants from AstraZeneca outside the submitted work and serving as the principal investigator for the TAP-CABG study. Dr ten Berg reported receiving speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, and Celecor and institutional research grants from AstraZeneca and ZonMw. Dr Willemsen reported receiving grants from AstraZeneca funding of the POPular CABG trial during the conduct of the study. Dr Zhao reported receiving grants from AstraZeneca during the conduct of the study and from Chugai Pharma China outside the submitted work. Dr Zhu reported receiving personal fees from Chugai Pharma China outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Individual and Pooled Estimates for Saphenous Vein Graft Failure

aAdjusted by trial. DAPT indicates dual antiplatelet therapy; SVG, saphenous vein graft.

Figure 2.. Pooled Estimates for Bleeding Events and Cardiovascular Events

aType 0 indicates no bleeding; type 1, bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment; type 2, any overt, actionable sign of hemorrhage (eg, bleeding that does not fit type 3, 4, or 5 criteria but meets at least 1 of the following: [1] requires nonsurgical medical intervention, [2] leads to hospitalization or increased level of care, or [3] prompts evaluation); type 3a, overt bleeding plus hemoglobin drop of 3 to 5 g/dL (provided hemoglobin drop is related to the bleeding event) or any transfusion with overt bleeding; 3b, overt bleeding plus hemoglobin drop of 5 g/dL (provided hemoglobin drop is related to the bleeding event), cardiac tamponade, bleeding requiring surgical intervention for control (excluding dental, nasal, skin, or hemorrhoid), and bleeding requiring intravenous vasoactive agents; 3c, intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal), subcategories confirmed by autopsy or imaging or lumbar puncture, intraocular bleed compromising vision; type 4, coronary artery bypass graft surgery–related bleeding; and type 5, fatal bleeding. bAdjusted by trial. cPost hoc outcomes. dSecondary outcome. eDefined as the composite of all-cause death, myocardial infarction, stroke, or revascularization. fAdditional outcomes. gDefined as the composite of cardiovascular death, myocardial infarction, or stroke. Includes patients from the TAP-CABG, DACAB, and POPular CABG trials. See the Methods section for the full names of the studies. CV indicates cardiovascular; DAPT, dual antiplatelet therapy; HR, hazard ratio; MACCE, major adverse cardiac and cerebrovascular event; MACE, major adverse cardiovascular event; OR, odds ratio; SVG, saphenous vein graft.

Figure 3.. Saphenous Vein Graft Failure in Subgroups

Subgroup analyses for harvesting technique and target vessel territory could not be performed due to the limited number of events in the endoscopic-harvesting group and left anterior descending coronary artery territory group. Treatment duration varied in 1 trial only. aAdjusted by trial. bSelf-reported diagnosis, elevated hemoglobin A1c levels, or active therapy. Definitions varied by trial. cIncludes ST-segment elevation myocardial infarction, non–ST-segment elevation ACS, or unstable angina. Definitions varied by trial. dDefined as saphenous vein grafts with more than 1 anastomosis. Includes patients from the TAP-CABG, DACAB, and POPular CABG trials. See the Methods section for the full names of the studies. ACS indicates acute coronary syndrome; CPB, cardiopulmonary bypass; DAPT, dual antiplatelet therapy; SVG, saphenous vein graft.