ROBOT-ACS: Real-World Data Reiterate Ticagrelor’s Safety

The observational study highlights the mortality difference between ACS patients in trials and those seen in practice.

ROBOT-ACS: Real-World Data Reiterate Ticagrelor’s Safety

PARIS, France—Patients who take ticagrelor after ACS are no more likely to experience a major bleeding event than patients who take clopidogrel, results of the ROBOT-ACS study suggest. The data, presented here last week at EuroPCR 2019, also shed light on the substantial difference in mortality between ACS patients in randomized trials and those in clinical practice.

More than a decade ago, the PLATO trial found ticagrelor (Brilinta; AstraZeneca) to be superior to clopidogrel in reducing ischemic events without any increase in major bleeding and led to a switchover from clopidogrel treatment. However, global data from clinical practice comparing ACS patients treated before and after the switchover are lacking.

“There is concern about the potential hazard of ticagrelor in high-bleeding-risk patients, [who] are often excluded from randomized trials,” noted Liam Mullen (Liverpool Heart and Chest Hospital, England).

ROBOT-ACS set out to compare consecutive patients (n = 2,491) treated with clopidogrel after PLATO but prior to the shift in practice, which they estimated began in mid-2012, versus those treated consecutively with ticagrelor (n = 2,625) from mid-2012 through 2015 at five UK hospitals.

At 12 months, there was no difference between ticagrelor and clopidogrel patients for the primary endpoint of BARC major bleeding (3-5), with an adjusted HR of 1.20 (95% CI 0.87-1.66), or in PLATO major bleeding (HR 1.29; 95% CI 0.96-1.74).

“In a way it's reassuring because there was no major difference in bleeding risk, but it has to be interpreted in the context of a nonrandomized study,” said session co-chair Marco Valgimigli, MD, PhD (Swiss Cardiovascular Center Bern, Switzerland), in an interview with TCTMD. “This is a population that almost never get into randomized studies, [so] to get some insight into the safety of these relatively newer agents in these patients is important.”

Stark Mortality Difference Compared With RCT Patients

Perhaps of greater importance, however, was the difference in mortality when the ROBOT-ACS investigators compared their cohort with that of PLATO. Whereas PLATO patients had a 1-year all-cause mortality rate of 4.9%, the ROBOT-ACS patients were more than twice as likely to die in that same period, with an all-cause mortality rate of 12.6%.

“In reality, outside clinical studies, the vast majority of mortality is coming from noncardiovascular reasons, so I think their results are not that surprising,” Valgimigli noted.

In multivariable analysis, the difference between the ROBOT-ACS and PLATO cohorts for the all-cause mortality endpoint became less striking, with an HR of 1.01 (95% CI 0.85-1.19).

Panelist Dominick Angiolillo, MD, PhD (University of Florida College of Medicine – Jacksonville), questioned whether the study was significantly powered for mortality differences.

Speaking with TCTMD, ROBOT-ACS senior author Aleem Khand, MD (Liverpool Heart and Chest Hospital), said the issue “is not so much the power, it's skepticism that the community might rightly have about the fact that it was nonrandomized and we've used statistics to adjust for the population differences between the clopidogrel- and ticagrelor-treated arms.”

That being said, Khand said he believes the mortality data are real and that they offer a sobering picture of the often very great differences between ACS patients seen in clinical practice and those treated in clinical trials.

Compared with the PLATO cohort, ROBOT-ACS patients were older, with twice as many patients being above age 75, more likely to be female, and less likely to have STEMI. The real-world patients also were much less likely to undergo revascularization, and nearly 50% were managed medically. Mullen said his team is working on analyzing the mortality data to get better insight into individual causes of death.

“What we think is that any improvement in vascular events by ticagrelor may well be swamped by much higher comorbidities and noncardiovascular issues such as cancers, kidney failure, and stroke,” Khand noted to TCTMD. “The implication of the study is that we should have a more nuanced approach to using ticagrelor.

“Just now in the UK, roughly 80% of patients are going onto ticagrelor with aspirin,” he continued. “My argument is that we should try to select patients who should be on ticagrelor to maximize their benefit and to reduce bleeding. These would be young patients who have high plaque burden and low bleeding risk profile. I think in those who have high bleeding risk profiles, whose vascular risk profiles post-MI don't seem to be very high, clopidogrel probably would suffice.”

  • Mullen L. Results of the ROBOT-ACS study. Presented at: EuroPCR 2019. May 23, 2019. Paris, France.

  • Mullen reports speaker fees from Servier Laboratories.
  • Khand reports speaker and expert panel fees from Bayer, Daiichi Sankyo, Astra Zeneca, Menarini, St Jude, and Abbot Vascular; research funding from Bayer; and research contracts from Abbott Diagnostics.