Ticagrelor’s Dominance Over Clopidogrel Again Questioned

Ticagrelor (Brilinta; AstraZeneca) doesn’t lessen risks of MI or death and may increase bleeding relative to clopidogrel, according to the results of a study in a real-world ACS population.

Across five hospitals in northwest England, there were no significant differences in rates of major bleeding or adverse clinical outcomes between patients treated with ticagrelor and those treated with the older P2Y12 inhibitor, researchers led by Liam Mullen, MBBS (Liverpool Heart and Chest Hospital, England), report.

Ticagrelor had established itself as the go-to P2Y12 inhibitor for the treatment of ACS based on the results of the PLATO trial, which showed that it reduced ischemic events without increasing major bleeding compared with clopidogrel. Ticagrelor did, however, carry a higher risk of non-CABG-related major bleeding according to PLATO criteria (4.5% vs 3.8%; P = 0.03).

But, as the authors of the current analysis point out, PLATO included a relatively young population and low percentages of patients who were female or had chronic renal disease. Older age, female sex, and renal dysfunction—established risk factors for bleeding—are all more common in real-world ACS populations, they note.

“For these reasons, it is conceivable that the net clinical benefit of ticagrelor compared with clopidogrel seen in PLATO may be less marked in real-world populations,” Mullen et al write.

In their study, the vast majority of patients (87%) did not undergo CABG, and in this group, ticagrelor was associated with greater risks of BARC type 3 to 5 bleeding and PLATO major bleeding; still, there were no differences between treatment groups in terms of adverse clinical outcomes.

Senior author Aleem Khand, MD (Liverpool Heart and Chest Hospital), acknowledged that observational studies—regardless of methodological rigor—have limitations when it comes to drawing firm conclusions. But, he told TCTMD, “we did our statistical analysis in a number of ways and we couldn’t find any signal at all that supported use of ticagrelor in terms of MI reduction. And so I think there is value to this study, and it should be taken along with a number of other studies that actually indicate that the apparent benefit of ticagrelor demonstrated in the clinical trial population [of PLATO] may not be observed in the broader population.”

That includes studies like CHANGE DAPT and a Canadian registry analysis.

Khand stressed, however, that “we’re not saying that there is no place for the potent antiplatelets. I think there is. . . . But to give everyone this is probably unwise, and I think you’ll see a shift in practice [away from a strategy of] universal potent antiplatelets for all to one that is a bit more nuanced to the bleeding-thrombotic balance.”

The findings, some of which were previously presented at EuroPCR 2019, were published recently online in the Journal of the American Heart Association.

From Trials to Everyday Practice

To explore PLATO’s real-world applicability, the investigators examined data on 5,116 patients (median age 68 years; 34% women) treated at five centers in England between 2011 and 2015, a span during which ticagrelor displaced clopidogrel as the P2Y12 inhibitor of choice. The analysis includes 2,491 patients treated clopidogrel and 2,625 treated with ticagrelor. Overall, nearly half of patients were medically treated, with 39% undergoing PCI and 13% CABG.

In general, patients treated during the clopidogrel era were higher risk, with an older average age and a heavier burden of comorbidities, and Mullen et al adjusted for those differences using a Cox proportional hazards model.

In the overall cohort, there were no differences between the ticagrelor and clopidogrel groups in BARC type 3 to 5 bleeding (3.7% vs 3.7%; adjusted HR 1.23; 95% CI 0.90-1.68) or PLATO major bleeding (4.5% vs 4.2%; adjusted HR 1.30; 95% CI 0.98-1.74). After excluding patients who underwent CABG, though, ticagrelor was associated with significantly higher rates of both BARC type 3 to 5 bleeding (adjusted HR 1.52; 95% CI 1.06-2.18) and PLATO major bleeding (adjusted HR 1.56; 95% CI 1.11-2.18).

There were no signs that ticagrelor resulted in lower rates of adverse clinical outcomes, including MI, stroke, and all-cause mortality. The unadjusted rate of confirmed type 1 or 2 MI was 3.8% in the ticagrelor group and 3.7% in the clopidogrel group (adjusted HR 1.20; 95% CI 0.87-1.64). The lack of a significant difference was consistent in revascularized and medically treated patients, although there was a nonsignificant trend suggesting a greater risk in the ticagrelor group (adjusted HR 1.53; 95% CI 1.00-2.34).

In an unadjusted analysis, mortality was lower in the ticagrelor group (16.3% vs 9.5%), but that difference disappeared after statistical adjustment (adjusted HR 0.90; 95% CI 0.76-1.10). A similar pattern was seen for stroke, and all of these findings were confirmed in a propensity-matched population.

Khand said that slight changes in practice over time could influence the findings. But, he noted, there was slightly greater use radial versus femoral access, slightly more use of off-pump surgery, and less use of glycoprotein IIb/IIIa inhibitors toward the end of the study period, which would presumably lessen the risk of bleeding during a time when ticagrelor was predominant.

“Everything in terms of the trends for bleeding favors ticagrelor, yet the results still bear out that especially in the medically treated population, ticagrelor was associated with significantly more bleeding and there was no hint of a reduction in MI,” Khand said.

Taking Another Look at Clopidogrel?

Based on this study and others published in recent years indicating perhaps a blunting of the benefits of more-potent P2Y12 inhibitors in contemporary, real-world practice, hospitals in Khand’s region in northwest England are moving back to clopidogrel as first-line therapy, particularly for medically treated ACS, with ticagrelor reserved for use when it is not an option. For patients who undergo PCI, said Khand, they’re moving to prasugrel based on the results of the ISAR-REACT 5 trial.

Khand advocated for a more-individualized approach to giving P2Y12 inhibitors in patients with an ACS. “We have to look at this bleeding-thrombotic balance and then make judgments,” he said, noting that there are a number of tools to help clinicians do that. “But for medically treated patients, I think clopidogrel should be the way to go.”

Michael Savage, MD (Thomas Jefferson University Hospital, Philadelphia), however, provided a more-cautious interpretation of the data, pointing out that the study was retrospective and included a patient population smaller than the PLATO population.

“I personally haven’t seen any compelling data to make me doubt that clopidogrel is inferior to ticagrelor for higher-risk ACS patients,” Savage commented to TCTMD. He acknowledged that with more-potent P2Y12 inhibition, “there’s no free lunch. . . .  Any drug that has a reduction in ischemic events by reducing thrombotic events is going to pay a penalty of more bleeding.”

Nonetheless, ticagrelor should remain the preferred choice for ACS, Savage said. “We’re always trying to manage the decisions on the two-edged sword of ischemic risk and thrombosis risk versus bleeding risk, so I think that’s why these studies continue to be of interest.”

For him, the more-interesting issue when it comes to discussing P2Y12 inhibition in ACS is whether ticagrelor or prasugrel is better, an issue that came to the forefront after the ISAR-REACT 5 results were released. Savage, who edited a book entitled “Clopidogrel and the Newer P2Y12 Antiplatelet Agents” with David Fischman, MD, and Mamas Mamas, BMBCh, DPhil, said he believes both agents more effectively reduce ischemic and thrombotic events compared with clopidogrel.