Background/Purpose: There is evidence of enhanced platelet activation in Raynaud’s phenomenon (RP), particularly in systemic sclerosis (SSc). Upon activation, platelets release vasoconstrictive mediators (e.g. thromboxane and serotonin) which may contribute to microvascular compromise. Platelet activation can be inhibited using aspirin (ASA) and dipyridamole (DIP). Pleiotropic effects of DIP include vasodilation and direct antioxidant effects. We investigated the effects of combination ASA and DIP on digital vascular function, platelet function and oxidative stress in primary RP and SSc.

Methods: This was an investigator-led single-centre exploratory open-label phase IIB study. Patients with primary RP and SSc received combination ASA (25mg) and DIP (200mg), given as a single capsule twice daily for 2 weeks. The primary endpoints were the individual components of the Raynaud’s Condition Score (RCS) diary. Secondary endpoints included objective assessment of digital vascular response to local cold challenge assessed using infrared thermography (IRT) and laser speckle contrast imaging (LSCI). Platelet function was assessed using light transmission aggregometry (LTA) to adenosine diphosphate (ADP) and arachidonic acid (AA). Plasma levels of p-selectin, soluble CD40 ligand and TGF-beta were measured using ELISA. Urinary levels of 11-dehydro-TxB₂ (metabolite of thromboxane), 2,3-dinor-6-keto-PGF_1a (metabolite of prostacyclin) and F₂-isoprostanes (biomarker of oxidative stress) were measured using gas chromatography mass spectrometry.

Results: Nineteen patients were recruited to the study (n=11 SSc). Four patients withdrew due to adverse drug reactions (ADR, headache n=3 and possible allergic reaction n=1). Fifteen patients completed the study (n= 9 SSc). There was significant improvement in the RCS score (median 2.29 [2.27] vs.1.11 [1.52], p=0.006) and the daily frequency of RP attacks (median 2.04 [2.67] vs. 1.32 [2.66], p=0.039). There was no improvement in mean daily duration of RP attacks. There was no improvemnt in objective assessment of digital microvascular responses to cold challenge using IRT or LSCI. There were significant reductions in aggregation to both ADP and AA (p<0.005 for all comparisons vs. baseline). The significant reduction in urinary 11-dehydro-TxB₂ levels (398 [198] vs. 157 [170] pg/mg, p=0.001) was lower than expected. There was also a significant reduction in urinary 2,3-dinor-6-keto-PGF_1a (147 [93] vs. 135 [130] pg/mg, p=0.017) but no significant change in urinary F₂-isoprostane levels or plasma levels of p-selectin, soluble CD40 ligand and TGF-beta. The commonest ADR was headache, reported in 16/19 (84.2%).

Conclusion: The apparent improvement of RP severity following combination ASA/DIP therapy in patients with primary RP and SSc is likely to be related to placebo effect although the high prevalence of headaches suggests a vasodilatory effect. We did not identify any beneficial effect of treatment on objective assessment of basal digital microvascular perfusion or recovery following local cold challenge. The results of this exploratory study do not support the initiation of larger controlled studies of combination ASA/DIP for peripheral vascular disease in RP or SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluating-the-effects-of-combination-aspirin-and-dipyridamole-asasantin-retard-on-platelet-function-oxidative-stress-and-peripheral-vascular-function-in-primary-raynauds-phenomenon-and-sy/