Calcium channel blockers for primary Raynaud's phenomenon

Holly Ennis, Michael Hughes, Marina E Anderson, Jack Wilkinson, Ariane L Herrick, Holly Ennis, Michael Hughes, Marina E Anderson, Jack Wilkinson, Ariane L Herrick

Abstract

Background: Calcium channel blockers are the most commonly prescribed drugs for people with primary Raynaud's phenomenon. Primary Raynaud's phenomenon is a common condition characterised by an exaggerated vasospastic response to cold or emotion: classically the digits (fingers and toes) turn white, then blue, then red. This is an update of the review first published in 2014.

Objectives: To assess the effects of different calcium channel blockers for primary Raynaud's phenomenon as determined by attack rates, severity scores, participant-preference scores and physiological measurements.

Search methods: For this update the Cochrane Vascular Trial Search Co-ordinator searched the Specialised Register (last searched January 2016) and the Cochrane Register of Studies (CENTRAL) (2015, Issue 12). In addition the TSC searched clinical trials databases.

Selection criteria: Randomised controlled trials evaluating the effects of oral calcium channel blockers for the treatment of primary Raynaud's phenomenon.

Data collection and analysis: Three review authors independently assessed the trials for inclusion and their quality, and extracted the data. Data extraction included adverse events. We contacted trial authors for missing data.

Main results: We included seven randomised trials with 296 participants. Four trials examined nifedipine and the remainder nicardipine. Comparisons were with placebo in six trials and with both dazoxiben and placebo in one trial (only the nifedipine versus placebo data were used within this review). Treatment with oral calcium channel blockers was minimally effective in primary Raynaud's phenomenon at decreasing the frequency of attacks (standardised mean difference of 0.23; 95% confidence interval (CI) 0.08 to 0.38, P = 0.003). This translates to 1.72 (95% CI 0.60 to 2.84) fewer attacks per week on calcium channel blockers compared to placebo. One trial provided details on duration of attacks reporting no statistically significant difference between the nicardipine and placebo groups (no P value reported). Only two trials provided any detail of statistical comparisons of (unvalidated) severity scores between treatment groups: one of these trials (60 participants) reported a mean severity score of 1.55 on placebo and 1.36 on nicardipine, difference 0.2 (95% CI of difference 0 to 0.4, no P value reported) and the other trial (three participants only with primary Raynaud's phenomenon) reported a median severity score of 2 on both nicardipine and placebo treatment (P > 0.999) suggesting little effect on severity. Participant-preference scores were included in four trials, but in only two were results specific to participants with primary Raynaud's phenomenon, and scoring systems differed between trials: scores differed between treatments in only one trial, in which 33% of participants on placebo and 73% on nifedipine reported improvement in symptoms (P < 0.001). Physiological measurements were included as outcome measures in five trials (different methodologies were used in each): none of these trials found any statistically significant between-treatment group differences. Treatment with calcium channel blockers appeared to be associated with a number of adverse reactions, including headaches, flushing and oedema (swelling). Overall, the trials were classed as being at low or unclear risk of bias; and the quality of the evidence presented was moderate for number of attacks, very low for duration of attacks, high for severity scores and low for patient preference scores.

Authors' conclusions: The randomised controlled trials included in this review provide moderate quality evidence that oral calcium channel blockers are minimally effective in the treatment of primary Raynaud's phenomenon as measured by the frequency of attacks and high-quality evidence that they have little effect on severity. We are unable to comment on duration of attacks or on patient preference due to the very low and low quality of evidence as a result of small sample sizes in the included studies and the variable data quality of outcome measures.

Conflict of interest statement

HE: declares that she is currently employed by the University of Edinburgh with no known conflicts. MH: none known. MA: has received honoraria and financial support to attend educational national and international meetings from Actelion Pharmaceuticals and Bristol‐Meyers Squibb. These included Coronary artery hypertension meeting and Consensus best practice for digital ulcer management meeting presentations (Actelion Pharmaceuticals) and national presentations (Bristol‐Meyers Squibb). MA received support to attend Advisory board and consensus best practice for digital ulcer management meeting organised and supported by Actelion Pharmaceutical. MA's institution receives National Digital Ulcer Registry participation payments (supported by Actelion Pharmaceuticals). AH: declares that she has undertaken consultancy work for Actelion and Apricus (Data Safety Monitoring Board). AH's institution has received research grant funding from Actelion and she has spoken at meetings sponsored by Actelion. AH has been a PI on a study sponsored by Orion (this study was on systemic sclerosis‐related Raynaud's phenomenon), and is a PI on studies sponsored by Actelion (these studies are on systemic sclerosis‐related Raynaud's phenomenon). JW: none known.