NIHR DC Discover

NIHR Signal Calcium channel blockers are useful in managing Raynaud’s phenomenon

Published on 20 February 2018

doi: 10.3310/signal-000556

Calcium channel blockers, such as nifedipine, are confirmed as useful in reducing the frequency, duration, severity of attacks, pain and disability associated with Raynaud’s phenomenon. People had two to six fewer attacks per week on average with treatment, and 13 without. Raynaud’s is a disorder which reduces blood flow to the fingers and toes as a result of the blood vessels tightening and going into spasm in the cold.

This updated review suggested that calcium channel blockers may be more effective in higher doses than lower doses and help primary symptoms rather than the secondary form of Raynaud’s that is due to underlying disease. Most research has been into nifedipine. Although no serious adverse events while using calcium channel blockers were reported, more people withdrew from trials as a result of minor side effects.

Previous studies have also shown that calcium channel blockers were effective, but this review expands the research for this indication and might inform future guidelines.

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Why was this study needed?

Between three and five in every 100 people have Raynaud's, and no underlying disease is identified for 80 to 90% of cases. Conservative and older treatments for Raynaud’s such as alpha blockers have been replaced by a variety of drugs considered to have fewer side effects. Calcium channel blockers are one such drug group. They have shown some benefits for some individuals.

There is still some uncertainty regarding the most effective treatment for Raynaud’s. No previous meta-analyses have yet picked apart the effects of dose, type of calcium channel blockers or subtype of Raynaud’s.

This review is the first of its kind to analyse the effectiveness of these medications in primary compared with secondary Raynaud’s and by channel blocker type and dose.

What did this study do?

This systematic review of 38 randomised controlled trials aimed to assess the benefits and harms of calcium channel blockers versus placebo for treatment of individuals with Raynaud’s.

The trials lasted about seven weeks and included 982 participants aged 18 and over. Nine trials identified patients with primary Raynaud’s and five studies identified patients with secondary Raynaud’s. The rest examined a mixture of patients with both primary and secondary from of the disease.

Major outcomes considered included frequency and severity of attacks, pain, quality of life, withdrawals and serious adverse events. The researchers assessed the risk of bias and concluded that most of the trials were considered at moderate to low risk.

What did it find?

  • From 23 trials (528 participants), considering both primary and secondary Raynaud’s, treatment reduced attacks, from about 13.7 per week in the placebo group to 6.13 per week with treatment (mean difference -6.07, 95% confidence interval -6.53 to -5.61). The difference was only two attacks when a trial from the 1980s was excluded from the analysis.
  • Pain was reduced by 1.5 points on a 0 to 10 scale (15% absolute reduction, with a lower score meaning less pain) compared with placebo.
  • Subgroup analyses by Raynaud’s type, drug class, and drug dose suggest that higher doses of nifedipine may be more effective for primary Raynaud’s than for secondary Raynaud’s, and are likely have a greater effect in primary than in secondary Raynaud’s. However, differences were small and were not found for all outcomes.

What does current guidance say on this issue?

NICE (2014) states there is currently no good evidence recommending the use of drugs other than calcium channel blockers for secondary Raynaud’s. Bosentan, an alternative type of drug, may reduce new digital ulcer formation compared with placebo, secondary to systemic sclerosis, but should only be used under specialist supervision.

Other options include surgical interventions such as digital sympathectomy, removing affected tissue, stellate ganglion blocks, lumbar sympathetic blocks and lifestyle measures such as avoiding temperature drops which stimulate attacks.

For primary Raynaud’s, trialling nifedipine (one type of calcium channel blocker) is suggested but based on limited evidence. For day to day management, wearing gloves and warm footwear, avoiding stress and exercising regularly are recommended.

What are the implications?

This review also suggests that calcium channel blockers in higher doses may be beneficial for the managing the frequency and severity of primary Raynaud’s compared to lower doses but differences were small and not found for all outcomes.

It was not possible to ascertain the long-term treatment effects as the trials did not exceed 20 weeks. Adverse effects were more common with Calcium channel blockers compared to placebo, but none were considered serious.

Any serious adverse side effects reported were rare and did not differ from placebo.

Citation and Funding

Rirash F, Tingey PC, Harding SE, et al. Calcium channel blockers for primary and secondary Raynaud's phenomenon. Cochrane Database Syst Rev. 2017;12:CD000467.

Cochrane UK and the Cochrane Musculoskeletal Group are supported by NIHR infrastructure funding.

Bibliography

Arthritis Research UK. Raynaud’s Phenomenon. Chesterfield: Arthritis Research UK; 2017.

ASSH. The Cold Hand. Washington: American Society for Surgery of the Hand; 2012.

Menon R, Swanepoel A. Sympathetic Blocks. Continuing Education in Anaesthesia Critical Care & Pain. 2010;10(3):88-92.

NICE. Raynaud’s phenomenon. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2014.

RCA. Stellate Ganglion Block for the treatment of pain. London: Royal College of Anaesthetists; 2017.

Scleroderma & Raynaud’s UK. What is Raynaud’s? London: Scleroderma & Raynaud’s UK; 2016.

Why was this study needed?

Between three and five in every 100 people have Raynaud's, and no underlying disease is identified for 80 to 90% of cases. Conservative and older treatments for Raynaud’s such as alpha blockers have been replaced by a variety of drugs considered to have fewer side effects. Calcium channel blockers are one such drug group. They have shown some benefits for some individuals.

There is still some uncertainty regarding the most effective treatment for Raynaud’s. No previous meta-analyses have yet picked apart the effects of dose, type of calcium channel blockers or subtype of Raynaud’s.

This review is the first of its kind to analyse the effectiveness of these medications in primary compared with secondary Raynaud’s and by channel blocker type and dose.

What did this study do?

This systematic review of 38 randomised controlled trials aimed to assess the benefits and harms of calcium channel blockers versus placebo for treatment of individuals with Raynaud’s.

The trials lasted about seven weeks and included 982 participants aged 18 and over. Nine trials identified patients with primary Raynaud’s and five studies identified patients with secondary Raynaud’s. The rest examined a mixture of patients with both primary and secondary from of the disease.

Major outcomes considered included frequency and severity of attacks, pain, quality of life, withdrawals and serious adverse events. The researchers assessed the risk of bias and concluded that most of the trials were considered at moderate to low risk.

What did it find?

  • From 23 trials (528 participants), considering both primary and secondary Raynaud’s, treatment reduced attacks, from about 13.7 per week in the placebo group to 6.13 per week with treatment (mean difference -6.07, 95% confidence interval -6.53 to -5.61). The difference was only two attacks when a trial from the 1980s was excluded from the analysis.
  • Pain was reduced by 1.5 points on a 0 to 10 scale (15% absolute reduction, with a lower score meaning less pain) compared with placebo.
  • Subgroup analyses by Raynaud’s type, drug class, and drug dose suggest that higher doses of nifedipine may be more effective for primary Raynaud’s than for secondary Raynaud’s, and are likely have a greater effect in primary than in secondary Raynaud’s. However, differences were small and were not found for all outcomes.

What does current guidance say on this issue?

NICE (2014) states there is currently no good evidence recommending the use of drugs other than calcium channel blockers for secondary Raynaud’s. Bosentan, an alternative type of drug, may reduce new digital ulcer formation compared with placebo, secondary to systemic sclerosis, but should only be used under specialist supervision.

Other options include surgical interventions such as digital sympathectomy, removing affected tissue, stellate ganglion blocks, lumbar sympathetic blocks and lifestyle measures such as avoiding temperature drops which stimulate attacks.

For primary Raynaud’s, trialling nifedipine (one type of calcium channel blocker) is suggested but based on limited evidence. For day to day management, wearing gloves and warm footwear, avoiding stress and exercising regularly are recommended.

What are the implications?

This review also suggests that calcium channel blockers in higher doses may be beneficial for the managing the frequency and severity of primary Raynaud’s compared to lower doses but differences were small and not found for all outcomes.

It was not possible to ascertain the long-term treatment effects as the trials did not exceed 20 weeks. Adverse effects were more common with Calcium channel blockers compared to placebo, but none were considered serious.

Any serious adverse side effects reported were rare and did not differ from placebo.

Citation and Funding

Rirash F, Tingey PC, Harding SE, et al. Calcium channel blockers for primary and secondary Raynaud's phenomenon. Cochrane Database Syst Rev. 2017;12:CD000467.

Cochrane UK and the Cochrane Musculoskeletal Group are supported by NIHR infrastructure funding.

Bibliography

Arthritis Research UK. Raynaud’s Phenomenon. Chesterfield: Arthritis Research UK; 2017.

ASSH. The Cold Hand. Washington: American Society for Surgery of the Hand; 2012.

Menon R, Swanepoel A. Sympathetic Blocks. Continuing Education in Anaesthesia Critical Care & Pain. 2010;10(3):88-92.

NICE. Raynaud’s phenomenon. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2014.

RCA. Stellate Ganglion Block for the treatment of pain. London: Royal College of Anaesthetists; 2017.

Scleroderma & Raynaud’s UK. What is Raynaud’s? London: Scleroderma & Raynaud’s UK; 2016.

Calcium channel blockers for primary and secondary Raynaud's phenomenon

Published on 14 December 2017

Rirash, F.,Tingey, P. C.,Harding, S. E.,Maxwell, L. J.,Tanjong Ghogomu, E.,Wells, G. A.,Tugwell, P.,Pope, J.

Cochrane Database Syst Rev Volume 12 , 2017

BACKGROUND: Raynaud's phenomenon is a vasospastic disease characterized by digital pallor, cyanosis, and extremity pain. Primary Raynaud's phenomenon is not associated with underlying disease, but secondary Raynaud's phenomenon is associated with connective tissue disorders such as systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. Calcium channel blockers promote vasodilation and are commonly used when drug treatment for Raynaud's phenomenon is required. OBJECTIVES: To assess the benefits and harms of calcium channel blockers (CCBs) versus placebo for treatment of individuals with Raynaud's phenomenon with respect to Raynaud's type (primary vs secondary) and type and dose of CCBs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (May 19, 2017), MEDLINE (1946 to May 19, 2017), Embase (1947 to May 19, 2017), clinicaltrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Portal. We applied no language restrictions. We also searched bibliographies of retrieved articles and contacted key experts for additional and unpublished data. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing calcium channel blockers versus placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and risk of bias and extracted trial data. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: This review contains 38 RCTs (33 cross-over RCTs) with an average duration of 7.4 weeks and 982 participants; however, not all trials reported all outcomes of interest. Nine of the identified trials studied patients with primary Raynaud's phenomenon (N = 365), five studied patients with secondary Raynaud's phenomenon (N = 63), and the rest examined a mixture of patients with primary and secondary Raynaud's phenomenon (N = 554). The most frequently encountered risk of bias types were incomplete outcome data and poor reporting of randomization and allocation methods.When researchers considered both primary and secondary Raynaud's phenomenon, evidence of moderate quality (downgraded for inconsistency) from 23 trials with 528 participants indicates that calcium channel blockers (CCBs) were superior to placebo in reducing the frequency of attacks. CCBs reduced the average number of attacks per week by six ( weighted mean difference (WMD) -6.13, 95% confidence interval (CI) -6.60 to - 5.67; I(2) = 98%) compared with 13.7 attacks per week with placebo. When review authors excluded Kahan 1985C, a trial showing a very large reduction in the frequency of attacks, data showed that CCBs reduced attack frequency by 2.93 per week (95% CI -3.44 to -2.43; I(2) = 77%).Low-quality evidence (downgraded for imprecision and inconsistency) from six trials with 69 participants suggests that the average duration of attacks did not differ in a statistically significant or clinically meaningful way between CCBs and placebo (WMD -1.67 minutes, 95% CI -3.29 to 0); this is equivalent to a -9% difference (95% CI -18% to 0%).Moderate-quality evidence (downgraded for inconsistency) based on 16 trials and 415 participants showed that CCBs reduced attack severity by 0.62 cm (95% CI -0.72 to - 0.51) on a 10-cm visual analogue scale (lower scores indicate less severity); this was equivalent to absolute and relative percent reductions of 6% (95% CI -11% to -8%) and 9% (95% CI -11% to -8%), respectively, which may not be clinically meaningful.Improvement in Raynaud's pain (low-quality evidence; downgraded for imprecision and inconsistency) and in disability as measured by a patient global assessment (moderate-quality evidence; downgraded for imprecision) favored CCBs (pain: WMD -1.47 cm, 95% CI -2.21 to -0.74; patient global: WMD -0.37 cm, 95% CI -0.73 to 0, when assessed on a 0 to 10 cm visual analogue scale, with lower scores indicating less pain and less disability). However, these effect estimates were likely underpowered, as they were based on limited numbers of participants, respectively, 62 and 92. For pain assessment, absolute and relative percent improvements were 15% (95% -22% to -7%) and 47% (95% CI -71% to -24%), respectively. For patient global assessment, absolute and relative percent improvements were 4% (95% CI -7% to 0%) and 9% (95% CI -19% to 0%), respectively.Subgroup analyses by Raynaud's type, CCB class, and CCB dose suggest that dihydropyridine CCBs in higher doses may be more effective for primary Raynaud's than for secondary Raynaud's, and CCBs likely have a greater effect in primary than in secondary Raynaud's. However, differences were small and were not found for all outcomes. Dihydropyridine CCBs were studied as they are the subgroup of CCBs that are not cardioselective and are traditionally used in RP treatment whereas other CCBs such as verapamil are not routinely used and diltiazem is not used as first line subtype of CCBs. Most trial data pertained to nifedipine.Withdrawals from studies due to adverse effects were inconclusive owing to a wide CI (risk ratio [RR] 1.30, 95% CI 0.51 to 3.33) from two parallel studies with 63 participants (low-quality evidence downgraded owing to imprecision and a high attrition rate); absolute and relative percent differences in withdrawals were 6% (95% CI -14% to 26%) and 30% (95% CI -49% to 233%), respectively. In cross-over trials, although a meta-analysis was not performed, withdrawals were more common with CCBs than with placebo. The most common side effects were headache, dizziness, nausea, palpitations, and ankle edema. However, in all trials, no serious adverse events (death or hospitalization) were reported. AUTHORS' CONCLUSIONS: Randomized controlled trials with evidence of low to moderate quality showed that CCBs (especially the dihydropyridine class) may be useful in reducing the frequency, duration, severity of attacks, pain and disability associated with Raynaud's phenomenon. Higher doses may be more effective than lower doses and these CCBs may be more effective in primary RP. Although there were more withdrawals due to adverse events in the treatment groups, no serious adverse events were reported.

Calcium channel blockers are a group of medicines commonly prescribed to treat conditions of the heart and blood vessels but are also used in the treatment of Raynaud’s  as they promote vasodilation, or the opening of blood cells to allow blood to flow more easily. Digital sympathectomy is a microsurgical technique used to separate the nerves and vessels in the forearm, palm or fingers. A stellate ganglion block is an injection of local anaesthetic in the sympathetic nerve tissue of the neck. A lumbar sympathetic block is an injection of local anaesthetic into or around the sympathetic nerves.

Expert commentary

Raynaud’s phenomenon is common and usually “primary” and so not associated with any serious underlying disease. It causes pain and impacts on everyday hand function.

Calcium channel blockers represent a safe treatment option. Well recognised difficulties of doing trials in Raynaud’s and the relatively short duration of treatment needed to show benefit to make this conclusion meaningful. Cases of “secondary” Raynaud’s  associated with connective tissue disease may benefit less, perhaps reflecting more structurally damaged blood vessels with less capacity to respond to vasodilators. 

On balance, calcium channel blockers provide a standard of care against which new treatments should be compared.

Professor Christopher Denton, UCL Division of Medicine, Royal Free London NHS Foundation Trust