Raynaud's phenomenon (RP) is a condition affecting the small blood vessels in the extremities, usually in the fingers but also in the toes and other body parts. It is caused by temporary narrowing of the blood vessels, which leads to color changes with associated numbness, tingling, and pain. Various triggers for this condition are known, such as stress, cold, and use of vibrational hand tools. Conservative measures to control this condition include stopping smoking and maintaining both peripheral and ambient warmth. Medications that dilate the blood vessels such as calcium channel blockers (CCBs) may be used but can have side effects. This review aims to investigate the effectiveness and safety of drugs that dilate the blood vessels other than CCBs.
Study characteristics and key results
We found seven new studies for this update, bringing the total to 15 (search was good to November 16, 2020). This update now includes other routes of administration such as through the veins (intravenous) and the skin (topical), in contrast to previous reviews, which focused on oral forms of treatment. The studies were published between 1989 and 2013 and involved a total of 635 participants randomly assigned to receive treatment or placebo control. Many studies did not describe various aspects of study methods such as randomization, allocation concealment, and blinding. Treatment duration varied between two weeks and six months.
Angiotensin-converting enzyme (ACE) inhibitors as a drug class, specifically enalapril and captopril in this review, in general increased the frequency of Raynaud's attacks per week but did not affect the severity of the attacks. Enalapril worsened subjective assessment of improvement, and captopril did not improve subjective outcomes or digital blood flow. Buflomedil showed a small reduction in the frequency and severity of attacks with increased side effects. Beraprost and dazoxiben did not demonstrate any change in frequency or severity of attacks nor in disability score and were associated with increased side effects. Ketanserin did not demonstrate improvement in frequency or duration of attacks nor in digital blood flow but did demonstrate improvement in severity scoring of RP. In a small study, moxisylyte was shown to reduce the frequency and severity of attacks to a small degree but with increased side effects. Topical glyceryl trinitrate did not show any effect on reducing the frequency of attacks per week. One study reported subjective improvement in Raynaud Condition Score (RCS). One small study reported improvements in frequency and severity of attacks as subjective changes. Headaches were the most significant and common side effect of treatment. Phosphodiesterase inhibitors did not cause a reduction in frequency, severity, or duration of attacks and did not improve RCS. One study reported in favor of vardenafil alone to reduce RCS but found that the effect is likely small. One study reported that cilostazol increased the frequency and severity of attacks; more research is needed to confirm this finding. Risk of headache as a side effect of treatment was increased with cilostazol use. PF-00489791 at a dose of 20 mg was found to slightly improve all subjective outcome measures and RCS.
Reliability of the evidence
We have very low to moderate confidence in these results, so we cannot make any firm conclusions about the benefit of these drugs for improving symptoms of primary RP. We cannot be confident because of the small numbers of participants involved in studies, issues with how studies were designed, and differences in how they measured whether or not treatments were effective. Therefore, the clinical importance of these results is difficult to assess, especially when placebo response is high. It is also pertinent that the results for each drug class and for individual drugs within each drug class must be interpreted in the context that they may have varying pharmacologic effects in addition to vasodilation. This must be taken into consideration when any conclusions are made about the overall effects of each drug class and/or individual drug.
The included studies investigated several different vasodilators (topical and oral) for treatment of primary Raynaud's phenomenon. Small sample sizes, limited data, and variability in outcome reporting yielded evidence of very low to moderate certainty. Evidence is insufficient to support the use of vasodilators and suggests that vasodilator use may even worsen disease.
Numerous agents have been suggested for the symptomatic treatment of primary Raynaud's phenomenon. Apart from calcium channel blockers, which are considered to be the drugs of choice, evidence of the effects of alternative pharmacological treatments is limited. This is an update of a review first published in 2008.
To assess the effects of drugs with vasodilator effects on primary Raynaud's phenomenon as determined by frequency, severity, and duration of vasospastic attacks; quality of life; adverse events; and Raynauds Condition Score.
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases, and the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov trial register to November 16, 2020.
We included randomized controlled trials evaluating effects of oral, intravenous, and topical formulations of any drug with vasodilator effects on subjective symptoms, severity scores, and radiological outcomes in primary Raynaud's phenomenon. Treatment with calcium channel blockers was not assessed in this review, nor were these agents compared.
Two review authors independently selected studies for inclusion, assessed studies using the Cochrane "Risk of bias" tool, and extracted study data. Outcomes of interest included frequency, severity, and duration of attacks; quality of life (QoL); adverse events (AEs); and the Raynaud Condition Score (RCS). We assessed the certainty of the evidence using GRADE.
We identified seven new studies for this update. In total, we included 15 studies involving 635 participants. These studies compared different vasodilators to placebo. Individual studies used different methods and measures to report different outcomes.
Angiotensin-converting enzyme (ACE) inhibitors
Combining data from three studies revealed a possible small increase in the frequency of attacks per week after treatment (captopril or enalapril) compared to placebo (mean difference [MD] 0.79, 95% confidence interval [CI] 0.43 to 1.17; low-certainty evidence). There was no evidence of a difference between groups in severity of attacks (MD -0.17, 95% CI -4.66 to 4.31; 34 participants, 2 studies; low-certainty evidence); duration of attacks (MD 0.54, 95% CI -2.42 to 1.34; 14 participants, 1 study; low-certainty evidence); or AEs (risk ratio [RR] 1.35, 95% CI 0.67 to 2.73; 46 participants, 3 studies; low-certainty evidence). QoL and RCS were not reported.
Two studies used alpha blockers (buflomedil or moxisylyte). We were unable to combine data due to the way results were presented. Buflomedil probably reduced the frequency of attacks compared to placebo (MD -8.82, 95% CI -11.04 to -6.60; 31 participants, 1 study; moderate-certainty evidence) and may improve severity scores (MD -0.41, 95% CI -0.62 to -0.30; moderate-certainty evidence). With moxisylyte, investigators reported fewer attacks (P < 0.02), less severe symptoms (P < 0.01), and shorter duration of attacks, but the clinical relevance of these results is unclear. No evidence of a difference in AEs between buflomedil and placebo groups was noted (RR 1.41, 95% CI 0.27 to 7.28; 31 participants, 1 study; moderate-certainty evidence). More AEs were observed in participants in the moxisylyte group than in the placebo group.
One study compared beraprost versus placebo. There was no evidence of benefit for frequency (MD 2.00, 95% CI -0.35 to 4.35; 118 participants, low-certainty evidence) or severity (MD -0.06, 95% CI -0.34 to 0.22; 118 participants, low-certainty evidence) of attacks. Overall, more AEs were noted in the beraprost group (RR 1.59, 95% CI 1.05 to 2.42; 125 participants; low-certainty evidence). This study did not report on duration of attacks, QoL, or RCS.
Thromboxane synthase inhibitors
One study compared a thromboxane synthase inhibitor (dazoxiben) versus placebo. There was no evidence of benefit for frequency of attacks (MD 0.8, 95% CI -1.81 to 3.41; 6 participants; very low-certainty evidence). Adverse events were not reported in subgroup analyses of participants with primary Raynaud's phenomenon, and the study did not report on duration of attacks, severity of symptoms, QoL, or RCS.
Selective serotonin reuptake inhibitors
One study compared ketanserin with placebo. There may be a slight reduction in the number of attacks per week with ketanserin compared to placebo (MD -14.0, 95% CI -27.72 to -0.28; 41 participants; very low-certainty evidence) and reduced severity score (MD -133.00, 95% CI -162.40 to -103.60; 41 participants; very low-certainty evidence). There was no evidence that ketanserin reduced the duration of attacks (MD -4.00, 95% CI -14.82 to 6.82; 41 participants; very low-certainty evidence), or that AEs were increased in either group (RR 1.54, 95% CI 0.89 to 2.65; 41 participants; very low-certainty evidence). This study did not report on QoL or RCS.
Four studies compared topical treatments of nitroglycerin or glyceryl trinitrate versus placebo, each reporting on limited outcomes. Meta-analysis demonstrated no evidence of effect on frequency of attacks per week (MD -1.57, 95% CI -4.31 to 1.17; 86 participants, 2 studies; very low-certainty evidence). We were unable to pool any data for the remaining outcomes.
Three studies compared phosphodiesterase inhibitors (vardenafil, cilostazol or PF-00489791) to an equivalent placebo. Results showed no evidence of a difference in frequency of attacks (standardized MD [SMD] -0.05, 95% CI -6.71 to 6.61; 111 participants, 2 studies; low-certainty evidence), severity of attacks (MD -0.03, 95% CI -1.04 to 0.97; 111 participants, 2 studies; very low-certainty evidence), duration of attacks (MD -1.60, 95% CI -7.51 to 4.31; 73 participants, 1 study; low-certainty evidence), or RCS (SMD -0.8, 95% CI -1.74 to 0.13; 79 participants, 2 studies; low-certainty evidence). Study authors reported that 35% of participants on cilostazol complained of headaches, which were not reported in the placebo group. PF-00489791 caused 34 of 54 participants to experience AEs versus 43 of 102 participants receiving placebo (RR 1.49). Headache was most common, affecting 14 participants (PF-00489791) versus nine participants (placebo).