DACAB: Ticagrelor Plus Aspirin Improves CABG Graft Patency

Susan Jeffrey

November 12, 2017

ANAHEIM, CA — A new trial shows the combination of aspirin plus ticagrelor (Brilinta, AstraZeneca) resulted in significant improvement in saphenous vein graft (SVG) patency at 12 months compared with aspirin alone in patients undergoing CABG[1].

Patency was better with ticagrelor plus aspirin compared with either agent alone, although the results were only statistically significant for dual therapy vs aspirin.

Dr Qiang Zhao

"Ticagrelor plus aspirin combination therapy significantly improves SVG patency 1 year after CABG when compared with aspirin monotherapy, and the risk of major bleeding was minimal," lead author Dr Qiang Zhao (Ruijin Hospital, Jiaolong University School of Medicine, Shanghai, China) concluded.

Results of the Efficacy of Different Antiplatelet Therapy Strategy after Coronary Artery Bypass Grafting (DACAB) trial were presented here at the American Heart Association (AHA) 2017 Scientific Sessions.

The saphenous vein graft is the still the most commonly used graft for CABG, the authors note. Failure rates for this graft, though, are estimated at between 10% and 25% after the first year and 50% by 10 years postprocedure.

Dual antiplatelet therapy has been shown to reduce major adverse cardiovascular events (MACE) in patients with acute coronary syndromes who undergo bypass surgery, they add, but data on the effect of therapy on the patency of SVG grafts are limited. A small pilot study looking at the combination of ticagrelor and aspirin on graft patency was terminated early due to low recruitment, the researchers note.

In DACAB, investigators undertook to assess the efficacy and safety of a dual antiplatelet strategy of aspirin plus ticagrelor vs ticagrelor alone and aspirin alone 1 year after elective CABG surgery.

The trial was an open-label study with 500 patients from six Chinese hospitals, randomized to one of three arms: ticagrelor 90 mg twice daily plus aspirin 100 mg daily (n=168); ticagrelor 90 mg twice daily (n=166); or aspirin 100 mg daily (n=166).

Eligible patients were between 18 and 88 years of age with an indication for CABG. Exclusion criteria included hemodynamic instability, a prior need for dual antiplatelet therapy or a vitamin K antagonist, a high risk for serious bleeding due to a history of intracerebral hemorrhage, for example, and any contraindication to study medication.

The primary outcome was SVG patency assessed using CT scan and coronary angiography at 1 year using intention-to-treat analysis. Scans were evaluated by an independent committee blinded to treatment assignment, Zhao said.

Secondary outcomes included SVG patency at 7 days, MACE or recurrence of angina within a year, atrial fibrillation at 7 days, and bleeding events using TIMI criteria within the 1 year follow-up.

At 1 year, the number of patients in each group available for a primary outcome scan was 94.1% in the combined-therapy group, 94.0% among those receiving only ticagrelor, and 92.2% among those on aspirin alone. The most common reason for missing the follow-up assessment was patient decision for eight, 10, and 10 patients for each group respectively; no patient was lost to follow-up. Two patients in the combination group and three patients on aspirin alone died during follow-up and did not receive the primary outcome scan.

Baseline characteristics showed the mean age of patients was about 64 years old, with a high rate of hypertension and hyperlipidemia; upwards of 40% had diabetes. "Most of these patients had a moderate to high SYNTAX score and a low to moderate EuroSCORE, which was matched to the coronary bypass surgery indication," Zhao said.

The mean number of SVGs used per case in each group was identical at 2.9.

For the primary outcome, they found that "combination therapy with ticagrelor and aspirin had a better outcome than aspirin monotherapy," he told a press conference here. "The overall vein graft patency for dual therapy at 1 year is 88.7%, and in the aspirin group was 76.5%. The difference is 12.2%, which is statistically significant (P=0.0006).

The comparison between ticagrelor monotherapy and aspirin alone showed a trend to reduction with ticagrelor (6.3%) that did not reach statistical significance (P=0.0962).

DACAB: SVG Outcomes at 1 Year (Intention to Treat)
End Point Ticagrelor + Aspirin (%) Ticagrelor (%) Aspirin (%)
Patency (Fitzgibbon A) 88.7 82.8 76.5
Nonocclusion (Fitzgibbon A + B) 89.9 86.1 80.6

The per-protocol analysis showed similar results, with a significant difference between dual therapy and aspirin (10;4%, P=0.0004) and a nonsignificant difference between the ticagrelor and aspirin monotherapy groups (4.3%, P=0.1719).

DACAB: SVG Outcomes at 1 Year (Per Protocol)
End Point Ticagrelor + Aspirin (%) Ticagrelor (%) Aspirin (%)
Patency (Fitzgibbon A) 93.7 87.6 83.3
Nonocclusion (Fitzgibbon A + B) 95.0 91.0 87.6

Overall MACE events were low, he said, but were highest in the aspirin monotherapy and lowest with combination therapy.

DACAB: Major Adverse Cardiac Events
End Point Ticagrelor + Aspirin, n (%) Ticagrelor, n (%) Aspirin, n (%)
All 3 (1.8) 4 (2.4) 9 (5.4)
CV death 1 (0.6) 0 (0) 2 (1.2)
MI 2 (1.2) 2 (1.2) 3 (1.8)
Stroke 0 (0) 2 (1.2) 4 (2.4)

Bleeding rates were also generally low, including major bleeding, but non–CABG-related bleeding and minimal bleeding events were higher with the dual therapy.

DACAB: Bleeding Events
Bleeding Event Ticagrelor + Aspirin, n (%) Ticagrelor, n (%) Aspirin, n (%)
CABG-related 1 (0.6) 1 (0.6) 0
Non–CABG-related 51 (30.4) 20 (12.1) 15 (9.0)
Major bleeding 2 (1.2) 1 (0.6) 0
Minor bleeding 2 (1.2) 0 2 (1.2)
Minimal bleeding 48 (28.6) 19 (11.4) 13 (7.8)
CABG-related plus non–CABG-related major bleeding 3 (1.8) 2 (1.2) 0

"Compelling" but Insufficient to Change Practice

Invited discussant for the DACAB trial John H Alexander (Duke Clinical Research Institute, Duke Health, Durham, North Carolina) was not yet entirely convinced by these results.

"The conclusions I would take away from this are that the DACAB trial established an effect of ticagrelor on saphenous vein graft patency, and their findings are compelling, but they will be insufficient to drive changes in practice," Alexander said. "And that's because the effects on major adverse cardiac events and the bleeding trade-off for this vein graft patency have not been adequately assessed in this study."

Clinical trials of dual antiplatelet therapy with clinical outcomes are needed, Alexander added, "because the relationship between saphenous vein graft patency and subsequent clinical outcomes is not entirely clear."

He pointed to a paper his group published in 2012 using data from the PREVENT 4 trial[2] showing that graft SVG patency at 1 year "really doesn't correlate with death or myocardial infarction out to 4 years later.

"It's intuitive, I think, that for patients undergoing CABG surgery having patent vein grafts is desirable," he elaborated later. "However, many of these vein grafts fail over a year without having a clinical consequence, so if we're only keeping open vein grafts that aren't important, that doesn't provide a benefit to patients.

"Ultimately, the effect on clinical outcomes, including major adverse cardiac events and bleeding, is what's important, and I think the results of the DACAB trial are intriguing, and even the small numbers of events go in the right direction on major adverse clinical events and in the expected wrong direction on bleeding," he said.

"Fortunately, such trials are coming," Alexander noted. Two "modest" sized trials, one in the Netherlands (700 patients) and one in the US and Canada (300 patients), are studying ticagrelor with vein graft failure as an outcome. Another larger trial of almost 4000 patients looking at ticagrelor in the same population with MACE as an outcome is being conducted in Germany, and then other trials are being planned looking at other agents, notably one in Brazil of prasugrel with a target of 4000 patients.  

Cardiac surgeon Dr Timothy Gardner (Christiana Care Center for Heart & Vascular Health, Christiana Care Value Institute, Newark, DE), a former president of the American Heart Association, who was not involved in the research, agreed with Alexander's assessment of the potential impact of this finding.

"I think we have been concerned about early vein graft failure, thrombosis, and this does demonstrate that dual antiplatelet therapy does provide for better 1-year graft patency," Gardner told theheart.org  | Medscape Cardiology. "I think all of us have been wondering about whether patients will do better with dual antiplatelet therapy—but the bleeding concern remains."

He said he felt Alexander gave a "very thoughtful answer to that: there probably isn't enough evidence yet of clear clinical benefit using dual antiplatelet therapy, especially since there is this increased risk of bleeding, so I think this will continue to inhibit many surgeons from adopting this, and they will continue to use aspirin."

The DACAB trial was sponsored by Ruijin Hospital. Zhao reports that he has served as a speaker for AstraZeneca, Medtronic, and Johnson & Johnson, and has been an investigator on clinical trials sponsored by AstraZeneca, Novartis, Sanofi, and Bayer. Alexander reports research support from AstraZeneca (2016), Boehringer Ingelheim, Bristol-Myers Squibb, CryoLife, CSL Behring, Pfizer, Sanofi, Tenax Therapeutics, US FDA, US National Institutes of Health, Volumetrix, and having been a consultant for AstraZeneca, Bristol-Myers Squibb, Cempra, CryoLife, CSL Behring, Merck, Pfizer, Portola, US Veterans Administration, VasoPrep, and Zafgen.

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