Ticagrelor may be superior to clopidogrel in poor metabolizers

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– In patients who had experienced a minor stroke or a transient ischemic attack with a moderate to high risk of stroke, the combination of ticagrelor and aspirin reduced the 90-day incidence of high on-treatment platelet reactivity, according to results from the PRINCE trial.

Although the combination outperformed clopidogrel (Plavix) plus aspirin, ticagrelor (Brilinta) was associated with higher bleeding risk.

The researchers also saw a trend toward a reduction in strokes that did not reach statistical significance, but the trial was halted following an interim analysis showing that the high on-treatment platelet reactivity (HOPR) endpoint, defined as P2Y12 reaction unit (PRU) greater than 208, showed a statistically significant difference. “To prove the clinical benefit, we will need a larger sample size,” study first author and presenter Yilong Wang, MD, PhD, of Beijing Tiantan Hospital, Capital Medical University, said in an interview at the International Stroke Conference, sponsored by the American Heart Association.

Dr. Yilong Wang of Beijing Tiantan Hospital Michele G. Sullivan/Frontline Medical News

Dr. Yilong Wang

A genetic subanalysis revealed a similar benefit in patients with loss-of-function alleles in the CYP2C19 gene. In previous clinical trials, these patients did not benefit from clopidogrel combined with aspirin, compared with aspirin alone. As a result, the Food and Drug Administration has included a boxed warning on clopidogrel’s labeling that advises alternative strategies in patients with these loss-of-function alleles, which prevent them from efficiently metabolizing the drug to its active form.

Previously, the SOCRATES trial found no advantage to treatment with ticagrelor over aspirin, but a prespecified exploratory analysis focusing on Asian patients (Stroke. 2017;48:167-73) found a trend toward reducing vascular events in the ticagrelor group, compared with patients taking aspirin.

In the Platelet Reactivity in Acute Stroke or Transient Ischemic Attack (PRINCE) trial, the researchers sought to examine the safety and efficacy of ticagrelor when compared with clopidogrel in 675 Asian patients (mean age 61 years, one-quarter of whom were female) from 26 centers in China and randomized them to ticagrelor plus aspirin (Tica) or clopidogrel plus aspirin (Clop). Within 24 hours of symptom onset, patients received 180 mg ticagrelor or 300 mg clopidogrel plus 100-300 mg aspirin. During days 1-21, they received 90 mg ticagrelor twice per day or 75 mg clopidogrel once per day. Both groups received 100 mg aspirin once per day. From day 21 to day 90, they received 90 mg ticagrelor twice per day or 75 mg clopidogrel once per day, with no aspirin.


At 90 days, the mean PRU value was 175.44 in the Clop group, compared with 69.24 in the Tica group. Overall, 27.7% of the Clop group experienced HOPR in the first 7 days, compared with 3.9% of the Tica group. At 90 days, 29.7% of the Clop group had experienced HOPR, compared with 12.5% of the Tica group (odds ratio, 0.33; 95% confidence interval, 0.21-0.51; P less than .001).

Ticagrelor was associated with greater benefit among those with impaired ability to metabolize clopidogrel. Among poor metabolizers, HOPR occurred in 10.5% in the Tica group and 42.4% of the Clop group (OR, 0.16; 95% CI, 0.05-0.56; P = .004). A similar favorable effect was seen in intermediate metabolizers in the Tica group (OR, 0.24; 95% CI, 0.12-0.49; P less than .001).

The 90-day stroke rate was no different between the Tica and Clop groups (6.3% vs. 8.8%, respectively; P = .20).

Minimal bleeding was higher in the Tica group (19.0% vs. 10.6%; hazard ratio, 1.86; P = .003), as was any bleeding (22.3% vs. 14.2%; HR, 1.65; P = .007). There were three deaths in the Tica group and two in the Clop group.

Dyspnea was the most common cause of drug discontinuation, and occurred in 4.2% of patients taking ticagrelor but none of the patients taking clopidogrel (P = .0001).

The researchers hope to demonstrate the clinical benefits of the combination in the upcoming PRINCE 2 trial. The results will have an important impact because CYP2C19 loss of function alleles are more common in Asian population. “It’s a very big problem for us,” Dr. Wang said.

The study was funded by the National Natural Science Foundation of China, the Beijing Institute for Brain, and the Beijing Municipal Science & Technology Commission of Cerebral Vascular Disease. AstraZeneca provided study drugs. Dr. Wang reported having no financial disclosures.

SOURCE: Wang Y et al. ISC 2018, abstract LB8

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