Platelet inhibition has been considered as a possible therapeutic option in sickle cell disease (SCD) for many years. Initial interest understandably focused on aspirin, which in addition to inhibiting platelets, also acetylates hemoglobin and increases oxygen affinity. This was not found to be a clinically useful effect,1 but interest moved on to the potential prevention of vaso-occlusion from platelet inhibition. Dr. Hugh Chaplin studied three patients with SCD treated with aspirin and dipyridamole during a two-year period and found improved laboratory markers of disease activity and modest prophylactic benefit against acute painful episodes.2 Further small studies followed, including a trial of aspirin in 49 children with SCD3 and an additional study in 29 children and adults,4 both of which gave negative results. Interest in aspirin and antiplatelet agents in SCD understandably waned for about 20 years.
In the past decade, interest in antiplatelet agents in SCD has re-emerged, driven by increasing evidence of the role of platelet activation in pathophysiology,5 the emergence of new platelet inhibitors with clear benefit in cardiovascular disease, and incentives to perform clinical trials of repurposed drugs in orphan diseases such as SCD. A large randomized controlled trial of prasugrel, a P2Y12 receptor antagonist, achieved 25 percent platelet inhibition and showed a nonsignificant trend toward decreasing vaso-occlusive events in children.6 Phase II studies of ticagrelor, a different P2Y12 inhibitor, showed encouraging results in SCD.7 In their article, Dr. Matthew Heeney and colleagues describe the phase III study of ticagrelor, in which they used the agent to try to achieve a greater degree of platelet inhibition, with the primary aim of producing a significant reduction in vaso-occlusive episodes. The authors randomized 101 children to ticagrelor and 92 to placebo, and the desired level of platelet inhibition was achieved in the ticagrelor group (median, 34.9% inhibition predose). The drug was well tolerated, but there was no evidence of clinical benefit, with a nonsignificant increase in vaso-occlusive events in the ticagrelor arm. There were also no positive results amongst the secondary end points and post-hoc analyses. The trial was stopped four months early, following recommendations by the independent data and safety monitoring committee because of lack of therapeutic benefit.
In Brief
And so, two large, multinational, placebo-controlled trials of platelet inhibition have now shown no evidence of clinical benefit in SCD, despite abnormal platelet activation being an established feature of the condition. It is possible that a greater degree of platelet inhibition might yet yield clinical benefit, but this would be difficult to achieve safely. Although both prasugrel and ticagrelor were statistically safe in these trials, two patients taking P2Y12 antagonists, one in each study, died of intracranial bleeding, which is a rare cause of death in children with SCD. These studies suggest that platelet inhibition is unlikely to be a useful therapeutic strategy to prevent vaso-occlusion in SCD, which in turn suggests that abnormal platelet activation in SCD is more of a downstream epiphenomenon than a central pathological process. It remains possible that platelet inhibition may have a role in managing cerebrovascular disease in SCD given the equivalent benefits in the non-SCD population.8 However, it is difficult to see how appropriate clinical trials could be performed in this rare complication, which is currently managed with transfusions, hydroxyurea, and stem cell treatments. Given the emergence of other novel treatments, it seems likely that this is the end of the road for platelet inhibition in SCD.
Competing Interests
Dr. Rees has been an advisor to AstraZeneca and an investigator on the DOVE trial of prasugrel, and indicated no other relevant conflicts of interest.
