Pharmacodynamics of Adjunctive Vorapaxar With DAPT in Type 2 Diabetes

Platelet-mediated thrombogenicity is reduced when vorapaxar is added to dual antiplatelet therapy (DAPT) without affecting clot kinetics in patients with and without type 2 diabetes (T2D), according to recent study results published in JACC: Basic to Translational Science.

The clinical trial was designed to investigate potential differential pharmacodynamic (PD) effects of adjunctive treatment with vorapaxar in patients with and without T2D. The primary endpoint was to assess global thrombogenicity as measured by a combination of collagen-related peptide (2 μg/mL), adenosine diphosphate (5 μM), and thrombin receptor-activating peptide (15 μM) (CAT) and maximum platelet aggregation using light transmittance aggregometry after triple therapy (vorapaxar in combination with DAPT) and dual therapy (vorapaxar + clopidogrel) in patients with and without T2D.

In this prospective, open-label, parallel-design investigation, researchers divided patients with prior myocardial infarction or peripheral arterial disease who were also receiving DAPT (aspirin [81 mg] in combination with clopidogrel [75 mg]) into groups according to concomitant diagnosis of T2D. They then added vorapaxar to each study arm and collected blood samples to measure PD effects at baseline and at 30±5 days after starting triple therapy. Both groups then discontinued aspirin but maintained dual therapy with vorapaxar and clopidogrel for another 30±5 days, at which time investigators collected blood samples to measure PD effects again. 

From March 2016 until October 2018, a total of 64 patients participated in the study (with T2D, n=30; without T2D, n=34). Study investigators reported statistical significance for therapy with vorapaxar on global thrombogenicity, noting that “adding vorapaxar to DAPT reduced CAT-induced aggregation” for both groups (with T2D, mean difference 15; 95% CI, 7-23; P <.001; without T2D, mean difference 20; 95% CI, 15-25; P <.001).

Discontinuing aspirin was associated with increased CAT-induced aggregation in both groups, thus “not meeting the primary [endpoint] of noninferiority.” 

The study was limited by not assessing clinical outcomes and was conducted in patients receiving aspirin and clopidogrel, although many patients with a history of MI are now treated with more potent medications.

Study investigators concluded that “platelet-mediated thrombogenicity is increased after aspirin withdrawal” for patients with T2D. The investigators also noted no “potential clinical advantage of dual therapy with vorapaxar and clopidogrel compared with standard of care DAPT with aspirin and clopidogrel”; however, they also noted that the relationship between the “[pharmacodynamic] findings and clinical outcomes in patients with vascular disease manifestations treated with strategies modulating the effects of thrombin warrant further investigation.” 

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Franchi F, Rollini F, Kairouz V, et al. Pharmacodynamic effects of vorapaxar in patients with and without diabetes mellitus treated with dual antiplatelet therapy: results of the OPTIMUS-5 (Optimizing Anti-Platelet Therapy in Diabetes Mellitus-5) study [published online September 1, 2019]. JACC Basic Transl Sci. doi:10.1016/j.jacbts.2019.07.011