Prasugrel: Indications of an additional benefit for some patients, but also of greater harm, study finds

This is the result of a final report presented by IQWiG on 5 September 2011.

ASA and prasugrel should complement each other in their effect

Prasugrel has been available on the German market since 2009 under the trade name "Efient®" and in some patients can be used as an alternative to the drug clopidogrel, which was already assessed by IQWiG in 2009.

Like clopidogrel, prasugrel is an anti-platelet drug ("platelet aggregation inhibitor") that is used in a similar way to ASA. It inhibits parts of the blood-clotting system, leading to a reduction in platelet clotting (aggregation) and of the subsequent formation of blood clots (thrombi). Prasugrel is thus supposed to reduce the risk of heart attacks and strokes, for example. However, the risk of bleeding may increase. As the manner in which prasugrel and ASA act on blood clotting differs, it is assumed that the 2 drugs complement each other and that the overall inhibitory effect on the formation of blood clots increases. Prasugrel differs mainly from clopidogrel through its faster onset of action, and is intended to be used if a rapid treatment effect is required.

Different approval status for clopidogrel and prasugrel

Prasugrel is approved in Germany solely in combination with ASA for patients with acute coronary syndrome (ACS), i.e. with acute stenosis of the coronary vessels, who are to undergo surgery in the form of a PCI to dilate their vessels. These patients have either unstable angina pectoris or have suffered an acute heart attack.

In contrast to prasugrel, clopidogrel is not approved in patients who experienced a "severe" heart attack (i.e. an "ST-segment-elevation myocardial infarction," STEMI) and therefore undergo a PCI. However, in practice, clopidogrel is still also commonly used in these patients, but it has not yet been sufficiently investigated in studies whether they benefit from this. Following the requirements of the contracting agency, the Federal Joint Committee (G-BA), the benefit assessment of prasugrel was to be conducted within the approval status valid in Germany. Accordingly, in patients with STEMI, IQWiG only compared prasugrel plus ASA combination therapy versus ASA monotherapy, but not versus clopidogrel plus ASA combination therapy.

Two studies included in the assessment

IQWiG included 2 studies in the assessment: in one long-term study (TRITON), patients were followed between 6 and 15 months, and in one short-term study (JUMBO) up to 35 days. TRITON and JUMBO were randomized controlled trials, and both compared the combination therapies prasugrel plus ASA versus clopidogrel plus ASA.

In both studies, large groups of participants were treated differently than envisaged in the German approval conditions for prasugrel and clopidogrel. IQWiG could therefore use the results only for the subgroups of participants receiving approval-compliant treatment. In this context, IQWiG's conclusions are primarily based on the TRITON study, as, with several thousand patients, considerably more patients received approval-compliant treatment than in the JUMBO study (less than 200 patients).

Studies comparing prasugrel plus ASA with ASA monotherapy were not available, which is why the final report cannot draw any conclusions on advantages and disadvantages of prasugrel in patients with STEMI.

No proof, but indication of a benefit

In patients with a "minor" heart attack or unstable angina, i.e. patients with a "non-ST-segment-elevation myocardial infarction" (UA/NSTEMI), IQWiG found indications of a potential advantage of prasugrel plus ASA versus clopidogrel plus ASA. In the TRITON study, patients taking prasugrel suffered fewer (renewed) non-fatal heart attacks or strokes, or required fewer interventions with a balloon catheter for dilatation of the coronary vessels.

IQWiG does not interpret these results as proof, but only as an indication of an advantage of prasugrel, as the study participants only received the medications some time after the occurrence of heart attack symptoms. As prasugrel generally has a more rapid onset of effect, clopidogrel was presumably systematically disadvantaged by the study design. "The rules for a fair comparison were broken here," says Thomas Kaiser, Head of IQWiG's Drug Assessment Department, "We cannot exclude the possibility that the result would have been different if both drugs had been given earlier."

Moreover, regarding the prevention of a stroke, the indication of an additional benefit of prasugrel only applies to certain patients, as such indications were only found in the studies in patients without a known history of vascular disease.

Also indication of harm

At the same time, IQWiG also found indications of greater harm, as major bleeding events occurred more often with prasugrel plus ASA than with clopidogrel plus ASA. This included, for example, bleeding events that required a blood transfusion.

Neoplasia (benign and malignant tumours) were also diagnosed more often in patients treated with prasugrel. However, due to the more common occurrence of bleeding, patients treated with prasugrel were also closely examined more often. It is therefore possible that additional tumours not detected in patients taking clopidogrel were detected by chance in such examinations. As the results of the TRITON study cannot be interpreted with certainty, IQWiG only sees a "hint" (i.e. no indication or proof) of greater harm.

Whereas in the preliminary report a number of questions concerning the benefit and harm of prasugrel remained open as information on the TRITON study was lacking, these gaps in knowledge could be partly filled in the final report, because the manufacturer and study sponsor (the Eli Lilly company) provided missing information during the course of the commenting procedure. This particularly applies to the results for non-fatal heart attacks and bleeding events.

Procedure of report production

IQWiG published the preliminary results in the form of the preliminary report in March 2011 and interested parties were invited to submit comments. When the comments stage ended, the preliminary report was revised and sent as a final report to the contracting agency, the Federal Joint Committee, in July 2011. The written comments were published in a separate document at the same time as the final report. The report was produced in collaboration with external experts.