The hallmark and most common manifestation of sickle cell disease (SCD) is debilitating, severe acute vaso-occlusive pain often resulting in intravenous morphine given continuously for days to weeks. In more than 50 years, there has been no evidence-based strategy for maximizing the management of acute vaso-occlusive pain events in children and adults with SCD. For multiple decades, clinicians have offered nonsteroidal anti-inflammatory therapy, typically ibuprofen, to augment acute pain management without evidence that such treatment attenuates current or future pain events. Platelets have been indirectly implicated in vaso-occlusive events based on their activation markers, including, but not limited to, CD63, P-selectin (CD62), and activated glycoprotein (GP)IIb/IIIa. Thus, with the evidence that platelets are activated and mitigate vascular occlusion, the authors postulated that an antiplatelet agent that inhibits adenosine- diphosphate (ADP) release from activated platelets would decrease the incidence of vaso-occlusive events. Based on a strong biological basis and prior promising results demonstrating a decrease in platelet activation biomarkers, as well as a trend toward decreased pain in a multicenter phase II study of prasugrel (a thienopyridine that inhibits ADP-mediated platelet activation),1 the investigators pursued a phase III trial.
Dr. Matthew Heeney and colleagues from 51 sites and 13 countries are to be congratulated in completing one of the few international SCD trials that includes participants from the United Kingdom, Africa, Europe, Brazil, and North America. In this phase III double-blind placebo-controlled, parallel-group multinational clinical trial—The Determining Effect of Platelet Inhibition on Vaso-occlusive Events (DOVE) trial—the investigative team tested the hypothesis that prasugrel is effective in reducing the rate of vaso-occlusive events (pain or acute chest syndrome) in children and adolescents with SCD. Each participant was expected to receive either placebo or prasugrel for at least nine months or a maximum of 24 months. There was a 1:1 random assignment of placebo versus prasugrel (initial dose, 0.08 mg/kg; range, 0.04 mg/kg - 0.12 mg/kg titrated to a predetermined level of platelet reactivity). The trial had several unique components, including assessment of platelet reactivity with an assay describing the ADP-induced platelet aggregation and the percentage of inhibition. Another novel component was the use of a handheld, mobile electronic patient-reporting device to remind participants and family members to record secondary outcomes, including a diary to document the rate and intensity of pain.
In 27 months, a total of 341 participants were enrolled, exceeding the target enrollment of 220 participants. The trial had a power of 85 percent to detect a 35 percent lower incidence of vaso-occlusive events in the treatment group compared with the placebo group. The primary outcome was that vaso-occlusive events occurred in 2.30 events per person-year and 2.77 events per person-year (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; p=0.12) in the treatment group and placebo group, respectively. Similarly, the secondary endpoints did not reveal any evidence that prasugrel was superior to placebo, including assessments for rates of hospitalization, vaso-occlusive events, transfusions, analgesic use, school absenteeism, and intensity of pain. A major concern in any negative therapeutic trial is that the adherence rate was too low; however, the adherence rates were exceptionally high in both groups, 78.2 percent and 81.2 percent in the prasugrel and placebo groups, respectively.
In Brief
What lessons did we learn from this multinational, randomized, controlled trial for an antiplatelet agent showing no benefit for the primary endpoint and multiple secondary endpoints? Perhaps the most important lesson is that the international community of families and investigators are eager to participate in a clinical trial attenuating the severity and frequency of pain. Despite being the largest phase III trial ever completed in children and adolescents with SCD, the recruitment goal was reached in 27 months. Another important take-home message is the ability to support adherence to study protocol with an electronic device that prompts family participation. Despite the clear evidence that hydroxyurea therapy decreases vaso-occlusive pain events, only 45 percent of the study population was on hydroxyurea at the time of enrollment. Clearly families of children and adolescents, clinicians, or both, are not enamored with taking hydroxyurea. A better understanding of the barriers for hydroxyurea therapy is needed, as are effective alternatives for this vulnerable population. With the successful completion of the DOVE trial, the SCD community can be optimistic about future phase III trials designed to decrease the frequency and intensity of acute vaso-occlusive events.
References
Competing Interests
Dr. DeBaun indicated no relevant conflicts of interest.
