EMBARGO : 31 August 2015 at 14:30 BST
“Coronary artery disease and acute coronary syndromes are the cause of death and disability in many patients,” said Dr Raban Jeger, interventional cardiologist and head of the structural heart disease programme at the University Hospital Basel, Switzerland. “In these patients prasugrel, by inhibition of platelet aggregation, prevents recurrent ischaemic events but also may cause bleedings.”
He added: “Although prasugrel is more effective than other drugs, it is only approved for patients with acute coronary syndromes. In patients with stable coronary artery disease, however, until now it was unknown whether prasugrel had a similar safety as in acute coronary syndromes or caused side effects without benefit.”
To assess the safety of prasugrel in patients with stable coronary artery disease, the investigators performed a prespecified secondary analysis of the BASKET-PROVE (BAsel Kosten Effektivitäts Trial – PROspective Validation Examination) II trial.
BASKET-PROVE II was a European multicentre randomised controlled trial that tested the efficacy and safety of two different drug-eluting stents (DES), a biolimus-eluting stent with a bioresorbable polymer and an everolimus-eluting stent with a durable polymer against a bare metal stent between 2010 and 2014. All 2 291 patients enrolled in the trial were treated with aspirin and prasugrel for 12 months irrespective of the indication, i.e., acute coronary syndrome or stable coronary disease. Patients were followed up for two years for major bleeding, defined as a class ≥3 within the Bleeding Academic Research Consorium (BARC) classification.
The main results showed that the bioresorbable polymer DES was noninferior to the durable polymer DES and more effective than the bare metal stent. But there was no evidence for better safety or lower rates of very late stent thrombosis beyond one year.2
For this analysis, 845 patients with stable coronary artery disease on prasugrel (new indication) were compared with 1 446 patients with acute coronary syndrome on prasugrel (established indication) and - as a historical control group – 822 patients with stable coronary artery disease on clopidogrel (established indication). For the latter comparison, a precursor trial with similar inclusion and exclusion criteria but a comparison with other stents and a clopidogrel-based dual antiplatelet therapy served as a historical control group (BASKET-PROVE).
The investigators found that in patients with stable coronary artery disease, prasugrel had a similar safety profile as in patients with acute coronary syndrome, where prasugrel is an approved indication (Figure 1; p=0.167). However, during the treatment period, there was a trend to more major bleedings on prasugrel, which was pronounced in patients at increased bleeding risk (Figure 2; p=0.021 for the period with dual antiplatelet therapy, i.e., the first 12 months, left, and p=0.968 for the period with aspirin only, right).
Dr Jeger said: “Of note, in these high-bleeding-risk patients, defined as patients >75 years of age and <60 kg of body weight, the prescribed dose was reduced from 10 mg to 5 mg. Therefore, there were significantly more major bleedings in elderly and low-weight patients despite a reduced dose.” (Figure 2)
Dr Jeger concluded: “These findings have relevant implications for the daily use of prasugrel in patients with stable coronary artery disease, and raise a concern regarding the safety of current label prescriptions in patients at high risk of bleeding.”
Figure 1: Overall major bleeding events (BARC 3/5) in patients on prasugrel with acute coronary syndromes (blue curve) and stable coronary artery disease (red curve; p=0.167).
Figure 2: Bleeding risk in patients on prasugrel 5 mg (high risk patients, i.e., >75 years of age and/or <60 kg of weight; yellow curve) vs. 10 mg (pink curve). Landmark analysis for the time on dual antiplatelet therapy (first 12 months; p=0.021) vs. time on aspirin only (second 12 months; p=0.968).