Ticagrelor Loading Dose May be Unnecessary for ACS Patients Previously on Clopidogrel

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Switching from clopidogrel to ticagrelor without use of a loading dose does not adversely affect platelet inhibition in patients with acute coronary syndromes (ACS), reports a pharmacodynamic study published online January 21, 2014, ahead of print in Circulation: Cardiovascular Interventions.

For the SHIFT-OVER study, Ciro Indolfi, MD, of Consiglio Nazionale delle Ricerche (Catanzaro, Italy), and colleagues enrolled 50 ACS patients receiving aspirin and clopidogrel, randomizing them to ticagrelor at a starting dose of 90 mg or 180 mg. In both groups, patients continued on a twice daily maintenance dose of 90 mg.

Platelet aggregation was measured using point-of-care multiple electrode aggregometry (MEA; Dynabyte Medical, Munich, Germany) just prior to the first ticagrelor administration and at 2, 6, 24, and 72 hours thereafter. Results were confirmed using light transmission aggregometry (LTA; Helena Laboratories, Beaumont, TX).

Platelet Aggregation, Clinical Outcomes Similar

Residual platelet aggregation was similar between the 2 study arms when patients were receiving clopidogrel at baseline. Ticagrelor administration—with or without loading—reduced levels of aggregation compared with clopidogrel (P < 0.001 for both), and there was no difference between the 2 dosing strategies at 2 hours (primary endpoint; table 1).

Table 1. Platelet Aggregation by MEA

Use of a loading dose continued to have no influence on platelet aggregation by MEA through 72 hours, and LTA again showed no difference by loading strategy.

By 30 days, there were no instances of death, MI, stroke, or major bleeding and interruptions or modifications of dual antiplatelet therapy. Patients who received a loading dose were more likely to be hospitalized during that time frame (8.3% vs 0; P < 0.001) and showed a trend toward fewer minor bleeding events (8.3% vs 29%; P = 0.064) compared with those who proceeded straight to the ticagrelor maintenance dose.

Multivariate analysis was performed to assess influences on ticagrelor response at 72 hours. Among age, sex, BMI, diabetes status, hypertension, smoking status, creatinine levels, and ticagrelor loading dose, only hypertension independently predicted response (P = 0.002).

A Way to Reduce Bleeding?

“[A]t present, a loading dose of ticagrelor is administered at most centers because all patients enrolled in the large PLATO trial received a loading dose of the new drug, regardless of the previous antiplatelet regimen,” Dr. Indolfi and colleagues write, noting that there is no direct evidence to support this strategy.

Indeed, there could be advantages to eliminating loading, they argue. “These findings generate the intriguing hypothesis that avoiding the loading dose of ticagrelor when switching the P2Y12 antiplatelet agent in clopidogrel-treated patients could be associated with a reduction in the incidence of bleeding complications, without affecting the efficacy profile of ticagrelor,” the authors assert, “If confirmed in future studies using clinical end points, this novel therapeutic schema would improve patient safety while maintaining the significant efficacy of ticagrelor for reduction of cardiovascular events.”

Several Red Flags

In a telephone interview with TCTMD, however, Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), said that several aspects of the current study raise concerns.

Though the paper lists resistance to clopidogrel as an exclusion criterion, the authors do not define what constitutes ‘resistance,’ nor did they measure pre-clopidogrel platelet reactivity. In addition, the values reported for maximal aggregation during clopidogrel therapy were unusually low at approximately 30%, suggesting that the patients may be hyper-responders, Dr. Gurbel said; he reported that his own research has found an average maximal aggregation of 50% from 20 micromolar ADP in clopidogrel responders.

“If you start out with very low platelet reactivity on clopidogrel, it is more difficult to determine if there is even more reduction in platelet reactivity from a load of ticagrelor.  This is one of the many limitations of the study,” he commented.

Moreover, Dr. Gurbel questioned the assertion that eliminating ticagrelor loading would reduce bleeding. With the equivalent results seen here for platelet function between the loaded and non-loaded groups, he explained, it does not make sense that avoidance of a loading dose would reduce bleeding.

Clinicians “should not change what they do based on this study, which is at variance with what’s published in the literature in much larger numbers of patients,” Dr. Gurbel said, referencing the 18,000-patient PLATO trial. “We know the clinical outcomes associated with this strategy. In contrast, there are no rigorous clinical outcome data associated with the absence of a loading dose.”

Omission of loading “in a truly clopidogrel resistant patient may have serious clinical consequences,” he stressed. “At this time, the use of ticagrelor without a load cannot be advised.”

Strategy Irrelevant for Most Patients But Not All

Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), said he saw little need for the study in the first place, as PLATO uncovered no increase in bleeding with ticagrelor vs clopidogrel. “The impetus for such a study is small to nonexistent,” Dr. Brener said in an interview with TCTMD.

While there is no need to pursue a no-loading strategy across the board, it may still be useful for high-risk subgroups, Dr. Brener noted. “The fact that both [study arms] were very well inhibited means that certainly in patients in whom you’re worried about bleeding, you can skip the loading dose.”

More interesting, he added, is the rapid improvement in inhibition when switching from clopidogrel to ticagrelor, which is evident after just 1 dose. “It’s profound,” Dr. Brener said.

 

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Source:
Caiazzo G, De Rosa S, Torella D, et al. Administration of a loading dose has no additive effect on platelet aggregation during the switch from ongoing clopidogrel treatment to ticagrelor in patients with acute coronary syndrome. Circ Cardiovasc Interv. 2014;Epub ahead of print.

 

 

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