Calcium channel blockers for primary Raynaud's phenomenon

Background

Raynaud's phenomenon is a disorder whereby blood vessels in the fingers and toes constrict and reduce blood flow, causing pain and discolouration. This is usually in response to cold exposure or emotional stress. In a small number of cases, Raynaud's phenomenon is associated with an underlying disease but, for most people, it is idiopathic (of uncertain cause, or 'primary'). Primary Raynaud's phenomenon is extremely common (especially in women), with one UK study suggesting that over 15% of the population are affected. For people with primary Raynaud's phenomenon who do not respond to conservative measures (e.g. keeping warm), calcium channel blockers represent the first line in drug treatment. Calcium channel blockers (sometimes called calcium antagonists) are drugs that affect the way calcium passes into certain muscle cells and they are the most commonly prescribed medication for primary Raynaud's phenomenon.

Study characteristics and key results

This review examined seven randomised trials which included 296 participants. Although overall all the trials were classed as being at low or unclear risk of bias, the sample size of the included trials was small and there was unclear reporting of outcomes. Two different calcium channel blockers were included: nifedipine and nicardipine. Comparisons in six trials were with placebo and in one trial with both placebo and another type of drug (although only data relating to the calcium channel blocker and placebo were used in this case). Treatment with oral calcium channel blockers was found to be minimally effective in primary Raynaud's phenomenon, reducing the frequency of attacks by around 1.7 attacks per person per week. One trial provided information on duration of attacks reporting no difference between the calcium channel blocker and placebo groups . Oral calcium channel blockers had no effect on severity scores in the two trials in which these were assessed. Only two trials reported preference scores (whereby participants are asked which treatment they prefer) specifically in those with primary Raynaud's phenomenon, and in only one of these was there a between-treatment group difference (participants preferred nifedipine to placebo). Physiological measurements (for example measurement of finger blood flow) were performed in five trials, data could not be combined as the methods were too different, no differences found between calcium channel blocker and placebo treatment were seen in any trial. Treatment with calcium channel blockers was associated with a number of adverse events including headaches, flushing and ankle swelling.

Quality of the evidence

The results of this review were limited by the low number of participants recruited to the studies and by the limitations of currently used outcome measures. This review shows 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 and patient preference due to the very low and low quality of evidence provided by the trials in relation to these outcomes.

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.

Read the full 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 strategy: 

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.

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