Avatrombopag (Doptelet®) and eltrombopag (Promacta®/Revolade®) are both thrombopoietin receptor agonists (TPO-RAs), a class of drugs that stimulate the body to produce new platelets. This clinical trial aimed to directly compare the impact on platelet count, the number of bleeding events, and other safety profiles of these medications.
Ten healthcare sites enrolled a total of 23 patients; 12 received avatrombopag and 11 received eltrombopag. The average platelet counts at baseline were similar between avatrombopag (8,500) and eltrombopag (15,000). At week six of the clinical trial, average platelet counts were 117,000 for those receiving avatrombopag and 48,000 for the eltrombopag group.
At day eight, the average platelet count for the avatrombopag group was 40,000, and 25,000 for the eltrombopag group. The proportion of participants that achieved a platelet count greater than 50,000 at day seven or eight was 5/11 (45%) in the avatrombopag group and 4/11 (36%) in the eltrombopag group.
Adverse events were experienced by 9/12 and 8/11 in the avatrombopag and eltrombopag groups respectively. These were considered treatment-emergent adverse events, meaning they occurred after initiating treatment, not that they were necessarily caused by the treatment. Researchers in this paper commented on the likelihood that these adverse events were due to the treatment.
Grade 3 or 4 adverse events (severe bleeding) occurred in 3/12 participants in the avatrombopag group and 3/11 in the eltrombopag group. Among those receiving avatrombopag, nausea (probably related) and vomiting (probably related) occurred in one patient; flare-up of chronic obstructive pulmonary disorder (unrelated) and a lung collapse (unrelated) occurred in one patient; and a blood clot formation (possibly related) and inflammation of a vein due to infection (possibly related) occurred in one patient. In the eltrombopag group, general discomfort (probably related), low levels of phosphate in the blood (unrelated), and physical weakness/lack of energy (unrelated) occurred in one patient each.
Grade 1 or 2 bleeding events (mild-moderate bleeding) occurred in 46% of participants in the avatrombopag group and 82% in the eltrombopag group.
Comments from PDSA Medical Advisors
This phase 3 clinical trial was developed several years ago to compare avatrombopag and eltrombopag. Approximately 248 patients were intended to be enrolled. However preclinical studies in rats with avatrombopag suggested potential for gastric toxicity. Therefore, the FDA requested for endoscopy to be added to the clinical trial to assess whether this occurred in humans (ultimately, it was determined that gastric toxicity was not an issue). However, in patients with ITP, endoscopy with biopsy is not simple if the platelet count is low. For this reason, very few patients were enrolled in the clinical trial, and it was closed for poor accrual and thus finished with very few patients. This remains the only comparative study of two TPO agents. The very limited results suggest that avatrombopag is not inferior to eltrombopag.
This study aimed to investigate the patterns of ITP incidence and prevalence in Denmark over time from 1980 to 2016. Prevalence refers to the number of people with ITP compared to the general population, whereas incidence refers to the number of new cases of ITP compared to the general population each year. A previous study showed that the life expectancy of individuals with chronic ITP has improved with time, therefore, the purpose of this study was to understand how the incidence and prevalence of ITP may be changing.
Researchers used the records of 5,443 ITP patients over 18 years of age in Denmark between 1980 and 2016. The researchers found that both the incidence and prevalence of primary ITP increased from 1980 to 2016. The incidence of primary ITP increased from 1.01 to 5.71 per 100,000 people. Throughout this time period, the rates of primary ITP for individuals over 60 years old were at least double that of those under 60 years old. They also found that the prevalence of primary ITP seemed to increase more steeply after 1994. In terms of gender differences, the incidence of ITP from 1980 to2016 appeared similar for men and women, but there was a slightly higher prevalence of ITP in women than men.
Comments from PDSA Medical Advisors
The authors report an increase in the incidence (new cases) and prevalence (accumulation of cases over time) of primary ITP based on review of Danish nationwide health registers from 1980-2016. It seems unlikely that there has been a dramatic reduction in mortality in patients with ITP, which was and remains low, to explain the increase in prevalence. Nor is it clear why there would be an increase in new cases of ITP to explain changes in incidence although this cannot be excluded as diseases change over time. There have been some changes in predisposing causes of ITP during the observation period of this study. For example, ITP has been reported after vaccinations against SARS-CoV-2, in patients given immunosuppressants such as alemtuzimab, or with immunoadjuvants such as checkpoint inhibitors to treat cancer. However, the cumulative impact of these new predisposing conditions on the overall incidence of ITP is likely low based on population-based studies. The authors suggest the increase in the incidence of ITP is due to an increase in the elderly population, as noted by several investigators, and consistent with an increased lifespan in many countries and the finding of an increased incidence of ITP in the elderly. At the same time, it is worth noting that the data come from medical coding to which there are regular updates and changes. It is possible that improved recognition of milder cases might have influenced incidence and prevalence figures.
Nevertheless, improvements in health care leading to an increase in a more elderly population susceptible to developing ITP is worthy of continued study. This is especially important because several studies have suggested that management strategies may require modification in this population which has increased vulnerabilities to side effects and possibly different treatment responses as well.