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Meta-Analysis
. 2017 Dec 13;12(12):CD000467.
doi: 10.1002/14651858.CD000467.pub2.

Calcium channel blockers for primary and secondary Raynaud's phenomenon

Fadumo Rirash  1 , Paul C Tingey, Sarah E Harding, Lara J Maxwell, Elizabeth Tanjong Ghogomu, George A Wells, Peter Tugwell, Janet Pope
Affiliations
Meta-Analysis

Calcium channel blockers for primary and secondary Raynaud's phenomenon

Fadumo Rirash et al. Cochrane Database Syst Rev. .

Abstract

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 We also searched bibliographies of retrieved articles and contacted key experts for additional and unpublished data.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; I² = 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; I² = 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.

PubMed Disclaimer

Conflict of interest statement

JP: has consulted for Actelion, Mediquest, Pfizer, and United Therapeutics in the area of Raynaud's phenomenon and/or digital ulcers.

PTu: grants/honoraria from Bristol Myers and UCB.

FR: none known.

PTi: none known.

SH: none known.

LM: none known.

EG: none known.

GW: none known.

Figures

1
1
Flow diagram of study.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot of comparison: 1 CCBs vs placebo (generic inverse variance method), outcome: 1.1 Frequency of attacks (average/week).
5
5
Funnel plot of comparison: 11 CCBs vs placebo (generic inverse variance method), outcome: 11.4 Severity of attacks (average, on a 10‐cm VAS).
1.1
1.1. Analysis
Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 1 Frequency of attacks (average/week).
1.2
1.2. Analysis
Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 2 Frequency of attacks (average/week).
1.3
1.3. Analysis
Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 3 Duration of attacks (minutes).
1.4
1.4. Analysis
Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 4 Severity of attacks (average, on a 10‐cm VAS).
1.5
1.5. Analysis
Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 5 Pain (10‐cm visual analogue scale).
1.6
1.6. Analysis
Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 6 Patient global.
1.7
1.7. Analysis
Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 7 Number of withdrawals (due to treatment).
2.1
2.1. Analysis
Comparison 2 Subgroup analysis by RP type, Outcome 1 Frequency of attacks (average/week).
2.2
2.2. Analysis
Comparison 2 Subgroup analysis by RP type, Outcome 2 Severity of attacks (average, on a 10‐cm VAS).
3.1
3.1. Analysis
Comparison 3 Subgroup analysis: nifedipine versus placebo by RP type, Outcome 1 Frequency of attacks: nifedipine vs placebo by RP type.
3.2
3.2. Analysis
Comparison 3 Subgroup analysis: nifedipine versus placebo by RP type, Outcome 2 Severity of attacks: nifedipine vs placebo by RP type.
4.1
4.1. Analysis
Comparison 4 Subgroup analysis by CCB class, Outcome 1 Frequency of attacks (average/week).
4.2
4.2. Analysis
Comparison 4 Subgroup analysis by CCB class, Outcome 2 Frequency of attacks (average/week).
4.3
4.3. Analysis
Comparison 4 Subgroup analysis by CCB class, Outcome 3 Severity of attacks (average, on a 10‐cm VAS).
4.4
4.4. Analysis
Comparison 4 Subgroup analysis by CCB class, Outcome 4 Severity of attacks (average, on a 10‐cm VAS).
5.1
5.1. Analysis
Comparison 5 Subgroup analysis by CCB dose, Outcome 1 Frequency of attacks (average/week).
5.2
5.2. Analysis
Comparison 5 Subgroup analysis by CCB dose, Outcome 2 Duration of attacks (minutes).
5.3
5.3. Analysis
Comparison 5 Subgroup analysis by CCB dose, Outcome 3 Severity of attacks (average, on a 10‐cm VAS).
5.4
5.4. Analysis
Comparison 5 Subgroup analysis by CCB dose, Outcome 4 Pain (10‐cm visual analogue scale).
5.5
5.5. Analysis
Comparison 5 Subgroup analysis by CCB dose, Outcome 5 Patient global.
6.1
6.1. Analysis
Comparison 6 Minor outcomes, Outcome 1 Number of participants with improvement.
6.2
6.2. Analysis
Comparison 6 Minor outcomes, Outcome 2 Side effects.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD000467

References

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    1. Wu YJ, Luo SF, Yang SH, Chen JY, Yu KH, See LC. Vascular response of Raynaud's phenomenon to nifedipine or herbal (Duhuo‐Tisheng Tang with Danggui‐Sini Tang): a preliminary study. Chan Gung Medicine Journal 2008;31(5):492‐501. - PubMed

References to studies awaiting assessment

Kahan 1982 {published data only}
    1. Kahan A, Weber S, Amor B, Saporta L, Hodara M, Degeorges M. Controlled study of nifedipine in the treatment of Raynaud's phenomenon [Etude controllee de la nifedipine dans le traitement du phenomene de Raynaud]. Revue du Rhumatism 1982;49(5):337‐43. - PubMed
Redondo 1986 {published data only}
    1. Redondo FR, Noguerado A, Asensio JP, Bote L, Alvaro‐Gracia JL, Castellanos M. Nifedipine treatment of Raynaud's phenomenon: a double blind controlled clinical study. Revista Espanola de Reumatologia 1986;13:121‐3.
Wasir 1983 {published data only}
    1. Wasir HS, Singh G, Kaul R, Sachdeva, Kahan WA, Chhina GS, et al. A comparative study of trifluoperazine a calmodulin inhibitor, nifedipine, dipyridamole and intraarterial reserpine in the treatment of raynaud's phenomenon: a double blind randomised controlled trial [abstract]. Indian Heart Journal 1983;35(5):306.
Wise 1987 {published data only}
    1. Wise RA, Malamet R, Wigley FM. Acute effects of nifedipine on digital blood flow in human subjects with Raynaud's phenomenon: a double blind placebo controlled trial. Journal of Rheumatology 1987;14(2):278‐83. - PubMed

References to ongoing studies

Nazarinia 2016 {published data only}
    1. Nazarinia MA. Assessing and Comparing the Effect of Diltiazem Gel Versus Nitroglycerin Ointment in Healing Process of Scleroderma Digital Ulcers. Clinicaltrials.gov 2017.
Vera‐Kellet 2017 {published data only (unpublished sought but not used)}
    1. Vera‐Kellet C. Color Doppler Ultrasound Comparison of Topical 10% Nifedipine Versus 5% Sildenafil in Secondary Raynaud: A Randomized, Double‐blind, Placebo‐controlled Pilot Study. Clinicaltrials.gov 2017.

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