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Calcium channel blockers for primary Raynaud's phenomenon - PubMed

  • ️Fri Jan 01 2016

Review

Calcium channel blockers for primary Raynaud's phenomenon

Holly Ennis et al. Cochrane Database Syst Rev. 2016.

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.

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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.

Figures

1
1

Study flow diagram.

2
2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

3
3

Comparison 1 Calcium channel blockers versus placebo, Outcome: 1 Number of attacks.

4
4

Comparison: 1 Calcium channel blockers versus placebo, Outcome: 1.5 Number of attacks ‐ without RTS 2000 (sensitivity analysis).

5
5

Comparison 1: Calcium channel blockers versus placebo, Outcome: 1.2 Number of attacks ‐ Nifedipine trials only.

6
6

Comparison 1: Calcium channel blockers versus placebo, Outcome: 1.3 Number of attacks ‐ Nicardipine trials only.

1.1
1.1. Analysis

Comparison 1 Calcium channel blockers versus placebo, Outcome 1 Number of attacks ‐ Primary.

1.2
1.2. Analysis

Comparison 1 Calcium channel blockers versus placebo, Outcome 2 Number of attacks ‐ without Ettinger (sensitivity analysis).

1.3
1.3. Analysis

Comparison 1 Calcium channel blockers versus placebo, Outcome 3 Number of attacks ‐ without RTS 2000 (sensitivity analysis).

1.4
1.4. Analysis

Comparison 1 Calcium channel blockers versus placebo, Outcome 4 Number of attacks ‐ Nifedipine trials only.

1.5
1.5. Analysis

Comparison 1 Calcium channel blockers versus placebo, Outcome 5 Number of attacks ‐ Nifedipine trials only (random‐effects).

1.6
1.6. Analysis

Comparison 1 Calcium channel blockers versus placebo, Outcome 6 Number of attacks ‐ Nicardipine trials only.

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References

References to studies included in this review

Ettinger 1984 {published data only}
    1. Ettinger WH, Wise RA, Schaffhauser D, Wigley FM. Controlled double‐blind trial of dazoxiben and nifedipine in the treatment of Raynaud's phenomenon. American Journal of Medicine 1984;77(3):451‐6. - PubMed
    1. Malamet R, Wise RA, Ettinger EH, Wigley FM. Nifedipine in the treatment of Raynaud's phenomenon. Evidence for inhibition of platelet activation. American Journal of Medicine 1985;78(4):602‐8. - PubMed
    1. Wigley FM, Malamet R, Wise RA. Reproducibility of cold provocation in patients with Raynaud's phenomenon. Journal of Rheumatology 1987;14(4):751‐5. - PubMed
Kahan 1987 {published data only}
    1. Kahan A, Amor B, Menkes CJ. Nicardipine in the treatment of Raynaud's phenomenon. Revue du Rhumatisme et des Maladies Osteo‐Articulaires 1987;54(6):487‐90. - PubMed
    1. Kahan A, Amor B, Menkes CJ, Weber S, Guerin F, Degeorges M. Nicardipine in the treatment of Raynaud's phenomenon: A randomized double‐blind trial. Angiology 1987;38(4):333‐7. - PubMed
Rodeheffer 1983 {published data only}
    1. Rodeheffer RJ, Rommer JA, Wigley F, Smith CR. Controlled double‐blind trial of nifedipine in the treatment of Raynaud's phenomenon. New England Journal of Medicine 1983;308(15):880‐3. - PubMed
RTS 2000 {published data only}
    1. Maricq HR, Jennings JR, Valter I, Frederick M, Thompson B, Smith EA, et al. Evaluation of treatment efficacy of Raynaud phenomenon by digital blood pressure response to cooling. Raynaud's Treatment Study Investigators. Vascular Medicine 2000;5(3):135‐40. - PubMed
    1. Middaugh SJ, Haythornthwaite JA, Thompson B, Hill R, Brown KM, Freedman RR, et al. The Raynaud's Treatment Study: biofeedback protocols and acquisition of temperature biofeedback skills. Applied Psychophysiology and Biofeedback 2001;26(4):251‐78. - PubMed
    1. Raynaud's Treatment Study Investigators. Comparison of sustained‐release nifedipine and temperature biofeedback for treatment of primary Raynaud phenomenon. Results from a randomized clinical trial with 1‐year follow‐up. Archives of Internal Medicine 2000;160(8):1101‐8. - PubMed
    1. Thompson B, Geller NL, Hunsberger S, Frederick M, Hill R, Jacob RG, et al. Behavioral and pharmacologic interventions: the Raynaud's Treatment Study. Controlled Clinical Trials 1999;20(1):52‐63. - PubMed
Sarkozi 1986 {published data only}
    1. Sarkozi J, Bookman AA, Mahon W, Ramsay C, Detsky AS, Keystone EC. Nifedipine in the treatment of idiopathic Raynaud's syndrome. Journal of Rheumatology 1986;13(2):331‐6. - PubMed
Vayssairat 1991 {published data only}
    1. Vayssairat M, Boccalon H, Ginestet MC, Priollet P, Franco A, Carpentier P, et al. Controlled multicenter double‐blind trial of nicardipine in the treatment of primary Raynaud phenomenon. American Heart Journal 1991;122(1 Suppl 2):352‐5. - PubMed
Wollersheim 1991 {published data only}
    1. Wollersheim H, Thien T. Double‐blind placebo‐controlled crossover study of oral nicardipine in the treatment of Raynaud's phenomenon. Journal of Cardiovascular Pharmacology 1991;18(6):813‐8. - PubMed

References to studies excluded from this review

Agnelli 1984 {published data only}
    1. Agnelli G, Parise P, Colangeli C. Pilot evaluation of flunarizine in Raynaud's disease: A placebo‐ controlled, double blind cross‐over study. Acta Therapeutica 1984;10(2):153‐62.
Aldoori 1986 {published data only}
    1. Aldoori M, Campbell WB, Dieppe PA. Nifedipine in the treatment of Raynaud's syndrome. Cardiovascular Research 1986;20(6):466‐70. - PubMed
Baadsgaard 1983 {published data only}
    1. Baadsgaard O, Schmidt JF, Ironmann L. The effect of nifedipin (adalat) on Raynaud's phenomenon. Ugeskrift for Laeger 1983;145(49):3814‐6. - PubMed
Brotzu 1989 {published data only}
    1. Brotzu G, Falchi S, Mannu B, Montisci R, Petruzzo P, Staico R. The importance of presynaptic beta receptors in Raynaud's disease. Journal of Vascular Surgery 1989;9(6):767‐71. - PubMed
Caglayan 2012 {published data only}
    1. Caglayan E, Axmann S, Hellmich M, Moinzadeh P, Rosenkranz S. Vardenafil for the treatment of Raynaud phenomenon: A randomized, double‐blind, placebo‐controlled crossover study. Archives of Internal Medicine 2012;172(15):1182‐4. - PubMed
Challenor 1987 {published data only}
    1. Challenor VF, Waller DG, Francis DA, Francis JL, Mani R, Roath S. Nisoldipine in primary Raynaud's phenomenon. European Journal of Clinical Pharmacology 1987;33(1):27‐30. - PubMed
    1. Francis JL, Roath OS, Challenor VF, Waller DG. The effect of nisoldipine on whole blood platelet aggregation in patients with Raynaud's phenomenon. British Journal of Clinical Pharmacology 1988;25(6):751‐4. - PMC - PubMed
Challenor 1989 {published data only}
    1. Challenor VF, Waller DG, Hayward RA, Griffin MJ, Roath OS. Vibrotactile sensation and response to nifedipine dose titration in primary Raynaud's phenomenon. Angiology 1989;40(2):122‐8. - PubMed
Choi 2009 {published data only}
    1. Choi WS, Choi CJ, Kim KS, Lee JH, Song CH, Chung JH, et al. To compare the efficacy and safety of nifedipine sustained release with Ginkgo biloba extract to treat patients with primary Raynaud's phenomenon in South Korea; Korean Raynaud study (KOARA study). Clinical Rheumatology 2009;28(5):553‐9. - PubMed
Codella 1989 {published data only}
    1. Codella O, Caramaschi P, Olivieri O, Perbellini L, Perbellini A, Bambara LM, et al. Controlled comparison of ketanserin and nifedipine in Raynaud's phenomenon. Angiology 1989;40(2):114‐21. - PubMed
Coleiro 2001 {published data only}
    1. Coleiro B, Marshall SE, Denton CP, Howell K, Blann A, Welsh KI, et al. Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology 2001;40(9):1038‐43. - PubMed
Corbin 1986 {published data only}
    1. Corbin DO, Wood DA, Macintyre CC, Housley E. A randomized double blind cross‐over trial of nifedipine in the treatment of primary Raynaud's phenomenon. European Heart Journal 1986;7(2):165‐70. - PubMed
    1. Corbin DOC, Wood DA, Macintyre CCA, Housley El. A randomised double blind cross‐over trial of nifedipine in the treatment of primary Raynaud's phenomenon [abstract]. Clinical Science 1985; Vol. 69, issue Suppl 12:21P. - PubMed
Costantini 1987 {published data only}
    1. Costantini A, Martelli E, Bavera P, Agus GB. Slow release nifedipine in the treatment of Raynaud's phenomenon. International Angiology 1987;6(4):359‐63. - PubMed
Creager 1984 {published data only}
    1. Creager MA, Pariser KM, Winston EM, Rasmussen HM, Miller KB, Coffman JD. Nifedipine‐induced fingertip vasodilation in patients with Raynaud's phenomenon. American Heart Journal 1984;108(2):370‐3. - PubMed
Csiki 2011 {published data only}
    1. Csiki Z, Garai I, Shemirani AH, Papp G, Zsori KS, Andras C, et al. The effect of metoprolol alone and combined metoprolol‐felodipin on the digital microcirculation of patients with primary Raynaud's syndrome. Microvascular Research 2011;82(1):84‐7. - PubMed
Da Costa 1987 {published data only}
    1. Costa J, Gomes JA, Espirito Santo J, Queiros M. Inefficacy of diltiazem in the treatment of Raynaud's Phenomenon with associated connective tissue disease: a double blind placebo controlled study. Journal of Rheumatology 1987;14(4):858‐9. - PubMed
Denton 1999 {published data only}
    1. Denton CP, Bunce TD, Dorado MB, Roberts Z, Wilson H, Howell K, et al. Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud's phenomenon. Rheumatology 1999;38(4):309‐15. - PubMed
Dompeling 1992 {published data only}
    1. Dompeling EC, Smit AJ. Assessment of pinacidil in patients with primary Raynaud's phenomenon. Vasa Supplementum 1992;34:34‐7. - PubMed
Dziadzio 1999a {published data only}
    1. Dziadzio M, Denton CP, Smith R, Howell K, Blann A, Bowers E, et al. Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen‐week, randomized, parallel‐group, controlled trial. Arthritis and Rheumatism 1999;42(12):2646‐55. - PubMed
Ferri 1992 {published data only}
    1. Ferri C, Cecchetti R, Cini G, Gambini I, Civita L, Bernini L, et al. Slow‐releasing nicardipine in the treatment of Raynaud's phenomena without underlying diseases. Clinical Rheumatology 1992;11(1):76‐80. - PubMed
Finch 1986 {published data only}
    1. Finch MB, Johnston GD, Dawson J. The peripheral vascular effects of nifedipine in Raynaud's disease. British Journal of Clinical Pharmacology 1985; Vol. 21:100P‐1P.
    1. Finch MB, Johnston GD, Dawson J. The peripheral vascular effects of nifedipine in Raynaud's disease associated with scleroderma: a double blind crossover study. Clinical Rheumatology 1986; Vol. 5, issue 4:493‐8. - PubMed
Finch 1988 {published data only}
    1. Finch MB, Copeland S, Passmore AP, Johnston GD. A double‐blind cross‐over study of nifedipine retard in patients with Raynaud's phenomenon. Clinical Rheumatology 1988;7(3):359‐65. - PubMed
Fontenelle 2008 {published data only}
    1. Fontenelle SM, Kayser C, Pucinelli ML, Andrade LE. Cold stimulus fingertip lacticemy test ‐ an effective method to monitor acute therapeutic intervention on primary Raynaud's phenomenon and systemic sclerosis. Rheumatology (Oxford, England) 2008;47(1):80‐3. - PubMed
Gjorup 1986a {published data only}
    1. Gjorup T, Kelbaek H, Hartling OJ, Nielsen SL. Controlled double‐blind trial of the clinical effect of nifedipine in the treatment of idiopathic Raynaud's phenomenon. American Heart Journal 1986;111(4):742‐5. - PubMed
Gjorup 1986b {published data only}
    1. Gjorup T, Hartling OJ, Kelbaek H, Nielsen SL. Controlled double blind trial of nisoldipine in the treatment of idiopathic Raynaud's phenomenon. European Journal of Clinical Pharmacology 1986;31(4):387‐9. - PubMed
Gush 1987 {published data only}
    1. Gush RJ, Taylor LJ, Jayson MI. Acute effects of sublingual nifedipine in patients with Raynaud's phenomenon. Journal of Cardiovascular Pharmacology 1987;9(5):628‐31. - PubMed
Hawkins 1986 {published data only}
    1. Hawkins SJ, Black CM, Hall ND, McGregor A, Ring EF, Maddison PJ. Clinical and laboratory effects of nifedipine in Raynaud's phenomenon. Rheumatology International 1986;6(2):85‐8. - PubMed
Kahan 1981 {published data only}
    1. Kahan A, Weber S, Amor B, Saporta L, Hodara M, Degoerges M. Nifedipine and Raynaud's phenomenon. Annals of Internal Medicine 1981;94(41):546. - PubMed
Kahan 1983a {published data only}
    1. Kahan A, Weber S, Amor B, Menkes CJ, Hodara M, Degeorges M. Nifedipine and Raynaud's phenomenon associated with connective tissue diseases. International Angiology 1985;4(2):221‐3. - PubMed
    1. Kahan A, Weber S, Amor B, Menkes CJ, Saporta L, Hodara M, et al. Calcium entry blocking agents in digital vasospasm (Raynaud's phenomenon). European Heart Journal 1983;4(Suppl C):123‐9. - PubMed
    1. Kahan A, Weber S, Amor B, Saporta L, Hodara M, Degeorges M. Controlled study of nifedipine in the treatment of Raynaud's phenomenon. Revue du Rhumatisme et des Maladies Osteo‐Articulaires 1982;49(5):337‐43. - PubMed
Kahan 1983b {published data only}
    1. Kahan A, Weber S, Amor B, Guerin F, Degeorges M. Nifedipine in the treatment of migraine in patients with Raynaud's phenomenon. New England Journal of Medicine 1983;308(18):1102‐3. - PubMed
Kahan 1985a {published data only}
    1. Kahan A, Amor B, Menkes CJ. A randomised double‐blind trial of diltiazem in the treatment of Raynaud's phenomenon. Annals of the Rheumatic Diseases 1985;44(1):30‐3. - PMC - PubMed
Kahan 1985b {published data only}
    1. Kahan A, Foult JM, Weber S, Amor B, Menkes CJ, Degeorges M. Nifedipine and alpha1‐adrenergic blockade in Raynaud's phenomenon. European Heart Journal 1985;6(8):702‐5. - PubMed
Kahan 1986 {published data only}
    1. Kahan A, Amor B, Menkes CJ, Weber S, Guerin F, Degeorges M. Controlled double‐blind trial of nicardipine in the treatment of Raynaud's phenomenon. International Journal of Clinical Pharmacology and Therapeutics 1986; Vol. 39, issue 2:202.
Kallenberg 1987 {published data only}
    1. Kallenberg CG, Wouda AA, Kuitert JJ, Tijssen J, Wesseling H. Nifedipine in Raynaud's phenomenon: Relationship between immediate, short term and longterm effects. Journal of Rheumatology 1987;14(2):284‐90. - PubMed
    1. Kallenberg CG, Wouda AA, Kuitert JJ, Tijssen J, Wesseling H. Treatment of Raynaud's phenomenon with nifedipine short‐term and long‐term effects. Vasa Supplementum 1987;18:68‐70. - PubMed
La Civita 1993 {published data only}
    1. Civita L, Pitaro N, Rossi M, Gambini I, Giuggioli D, Cini G, et al. Amlodipine in the treatment of Raynaud's phenomenon. British Journal of Rheumatology 1993;32(6):524‐5. - PubMed
    1. Civita L, Pitaro N, Rossi M, Giuggioli D, Gambini I, Cini G, et al. Amlodipine in the treatment of Raynaud's phenomenon. A double‐blind placebo‐controlled crossover study. Clinical Drug Investigation 1997;13(Suppl 1):126‐31.
La Civita 1996 {published data only}
    1. Civita L, Giuggioli D, Chicca MG, Longombardo G, Pasero G, Ferri C. Effect of isradipine on endothelin‐1 plasma concentrations in patients with Raynaud's phenomenon [letter]. Annals of the Rheumatic Diseases 1996;55(5):331‐2. - PMC - PubMed
Lee 2014 {published data only}
    1. Lee EY, Park JK, Lee W, Kim YK, Park CS‐Y, Giles JT, et al. Head‐to‐head comparison of udenafil vs amlodipine in the treatment of secondary raynaud's phenomenon: A double‐blind, randomized, cross‐over study. Rheumatology (Oxford, England) 2014;53(4):658‐64. - PubMed
Leppert 1989 {published data only}
    1. Leppert J, Jonasson T, Nilsson H, Ringqvist I. The effect of isradipine, a new calcium‐channel antagonist, in patients with primary Raynaud's phenomenon: A single‐blind dose‐response study. Cardiovascular Drugs Therapy 1989;3(3):397‐401. - PubMed
Lewis 1987 {published data only}
    1. Lewis P, Psaila JV, Morgan RH, Davies WT, Woodcock JP. Nifedipine in patients with Raynaud's syndrome ‐ effects on radial artery flow. European Heart Journal 1987;8(Suppl K):83‐6. - PubMed
Martinez 1999 {published data only}
    1. Martinez S, Lozano P, Pallares L, Julia J, Artigues I, Plaza A, et al. Usefulness of photoplethysmography and indexes of digital pressure in Raynaud phenomenon. Medicina Clinica 1999;113(9):327‐30. - PubMed
Mascagni 1994 {published data only}
    1. Mascagni B, Sardina M, Alvino S, Berruti V, Bazzi S, Scorza R. Effects of iloprost in comparison to nifedipine in patients with Raynaud's phenomenon secondary to progressive systemic sclerosis. International Angiology 1994; Vol. 13, issue Suppl 1:81.
Morgan 1987 {published data only}
    1. Morgan RH, Psaila JV, Davies WT, Carolan G, Woodcock JP. Digital and radial artery blood flow in patients with Raynaud's phenomenon in response to nifedipine. European Journal of Vascular Surgery 1987;1(6):403‐8. - PubMed
Moriau 1993 {published data only}
    1. Moriau M, Lavenne‐Pardonge E, Crasborn L, Frenckell R, Col‐Debeys C. Treatment of Raynaud's phenomenon with piracetam. Arzneimittel‐Forschung 1993;43(5):526‐35. - PubMed
Müller‐Bühl 1983 {published data only}
    1. Diehm C, Müller‐Bühl U, Mörl H, Schettler G. Calcium antagonists in Raynaud's phenomenon [Calciumantagonistum beim Raynaud‐phanomen]. Zeitschrift fur Kardiologie 1982; Vol. 71, issue 9:Abstract 86.
    1. Müller‐Bühl U, Diehm C, Scheuermann W, Mörl H. Calcium antagonists for the treatment of Raynaud's phenomenon. Deutsche Medizinische Wochenschrift 1983;108(47):1795‐7. - PubMed
Nilsson 1987 {published data only}
    1. Nilsson H, Jonason T, Leppert J, Ringqvist I. The effect of the calcium‐entry blocker nifedipine on cold‐induced digital vasospasm. A double‐blind crossover study versus placebo. Acta Medica Scandinavica 1987;221(1):53‐60. - PubMed
Pisenti 1984 {published data only}
    1. Pisenti L, Hart LL. DIAS Rounds. Nifedipine and prazosin in Raynaud's phenomenon. Drug Intelligence and Clinical Pharmacy 1984;18(3):213‐4. - PubMed
Redondo 1986 {published data only}
    1. Rivera Redondo J, Noguerado Asensio A, López Bote JP, Alvaro‐Gracia Alvaro JM, Ossorio Castellanos C. Nifedipine treatment of Raynaud's phenomenon: a double blind controlled clinical study. Revista Espanola de Reumatologia 1986;13:121‐3.
Rhedda 1985 {published data only}
    1. Rhedda A, McCans J, Willan AR, Ford PM. A double blind placebo controlled crossover randomized trial of diltiazem in Raynaud's phenomenon. Journal of Rheumatology 1985;12(4):724‐7. - PubMed
Rupp 1987 {published data only}
    1. Rupp PA, Mellinger S, Kohler J, Dorsey JK, Furst DE. Nicardipine for the treatment of Raynaud's phenomena: A double blind crossover trial of a new calcium entry blocker. Journal of Rheumatology 1987;14(4):745‐50. - PubMed
Sauza 1984 {published data only}
    1. Sauza J, Kraus A, González‐Amaro R, Alarcón‐Segovia D. Effect of the calcium channel blocker nifedipine on Raynaud's Phenomenon. A controlled double blind trial. Journal of Rheumatology 1984;11(3):362‐4. - PubMed
Schmidt 1989 {published data only}
    1. Schmidt JF, Valentin N, Nielsen SL. The clinical effect of felodipine and nifedipine in Raynaud's phenomenon. European Journal of Clinical Pharmacology 1989;37(2):191‐2. - PubMed
Scorza 2001 {published data only}
    1. Scorza R, Caronni M, Mascagni B, Berruti V, Bazzi S, Micallef E, et al. Effects of long‐term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon. A randomized, controlled study. Clinical and Experimental Rheumatology 2001;19(5):503‐8. - PubMed
Shcherbakov 1987 {published data only}
    1. Shcherbakov AB, Guseva NG, Mach ES. Treatment of Raynaud's syndrome with calcium entry blockers. Terapevticheskii Arkhiv 1987;59(4):89‐92. - PubMed
Smith 1982 {published data only}
    1. Smith CD, McKendry RJ. Controlled trial of nifedipine in the treatment of Raynaud's phenomenon. Lancet 1982;2(8311):1299‐301. - PubMed
    1. Smith D, McKendry R. Treatment of Raynaud's phenomenon with nifedipine. Annals of the Royal College of Physicians and Surgeons of Canada 1982;15(4):Abstract 282.
Stefenelli 1986 {published data only}
    1. Stefenelli T, Silberbauer K, Glogar D. Pentoxifylline/placebo/nifedipine in patients with Raynaud's phenomenon: influence on frequency of attacks and rewarming time. Klinische Wochenschrift 1986;64:1155‐6.
Van Heereveld 1988 {published data only}
    1. Heereveld H, Wollersheim H, Gough K, Thien T. Intravenous nicardipine in Raynaud's phenomenon: A controlled trial. Journal of Cardiovascular Pharmacology 1988;11(1):68‐74. - PubMed
Varela‐Aguilar 1997 {published data only}
    1. Varela‐Aguilar JM, Sanchez‐Roman J, Talegon Melendez A, Castillo Palma MJ. [Comparative study of misoprostol and nifedipine in the treatment of Raynaud's phenomenon secondary to systemic diseases. Hemodynamic assessment with Doppler duplex]. Revista Clinica Espanola 1997;197(2):77‐83. - PubMed
Waller 1986 {published data only}
    1. Francis DA, Waller DG, Challenor VF, Roath OS. Red cell deformability in patients with Raynaud's phenomenon treated with nifedipine. Clinical Hemorheology 1985; Vol. 5, issue 5:742.
    1. Waller DG, Challenor VF, Francis DA, Roath OS. Clinical and rheological effects of nifedipine in Raynaud's phenomenon. British Journal of Clinical Pharmacology 1986;22(4):449‐54. - PMC - PubMed
Wasir 1983 {published data only}
    1. Wasir HS, Singh G, Kaul R, Sachdeva U, Khan 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. Indian Heart Journal 1983; Vol. 35, issue 5:306.
Weber 1990 {published data only}
    1. Weber A, Bounameaux H. Effects of low‐dose nifedipine on a cold provocation test in patients with Raynaud's disease. Journal of Cardiovascular Pharmacology 1990;15(5):853‐5. - PubMed
White 1986 {published data only}
    1. White CJ, Phillips WA, Abrahams LA, Watson TD, Singleton PT Jr. Objective benefit of nifedipine in the treatment of Raynaud's phenomenon. American Journal of Medicine 1986;80(4):623‐5. - PubMed
Wigley 1987a {published data only}
    1. Wigley FM, Wise RA, Malamet R, Scott TE. Nicardipine in the treatment of Raynaud's phenomenon. Dissociation of platelet activation from vasospasm. Arthritis and Rheumatism 1987;30(3):281‐6. - PubMed
Winston 1983 {published data only}
    1. Winston EL, Pariser KM, Miller KB, Salem DN, Creager MA. Nifedipine as a therapeutic modality for Raynaud's phenomenon. Arthritis and Rheumatism 1983;26(10):1177‐80. - PubMed
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
Wollersheim 1987 {published data only}
    1. Wollersheim H, Thien T, Van't Laar A. Acute and chronic effects of nifedipine in Raynaud's phenomenon. European Journal of Clinical Investigation 1986;16(Suppl):A16.
    1. Wollersheim H, Thien T, Van't Laar A. Nifedipine in primary Raynaud's phenomenon and in scleroderma: oral versus sublingual hemodynamic effects. Journal of Clinical Pharmacology 1987;27(11):907‐13. - PubMed

Additional references

Allen 1932
    1. Allen EV, Brown GE. Raynaud's disease: a critical review of minimal requisites for diagnosis. American Journal of Medical Science 1932;183(2):187‐200.
ATC classification
    1. ATC 2013. Anatomical Therapeutical Chemical Classification. WHO. http://www.whocc.no/atcddd (accessed 21 February 2013).
Block 2001
    1. Block JA, Sequeira W. Raynaud's phenomenon. Lancet 2001;357(9273):2042‐8. - PubMed
Dziadzio 1999
    1. Dziadzio M, Denton CP, Smith R, Howell K, Blann A, Bowers E, et al. Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen‐week, randomized, parallel‐group, controlled trial. Arthritis and Rheumatism 1999;42(12):2646‐55. - PubMed
Elbourne 2002
    1. Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta‐analyses involving cross‐over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140–9. - PubMed
GRADE Working Group 2004
    1. GRADE Working Group. Grading quality of evidence and strength of recommendations. British Medical Journal 2004;328:1490‐4. - PMC - PubMed
Guyatt 2008a
    1. Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck‐Ytter Y, Schunemann HJ, GRADE Working Group. What is 'quality of evidence' and why is it so important to clinicians?. British Medical Journal 2008;336(7651):995‐8. - PMC - PubMed
Guyatt 2008b
    1. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck‐Ytter Y, Alonso‐Coello P, et al. GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. British Medical Journal 2008;336(7650):924‐6. - PMC - PubMed
Harding 1998
    1. Harding SE, Tingey PC, Pope J, Fenlon D, Furst D, Shea B, et al. Prazosin for Raynaud's phenomenon in progressive systemic sclerosis. Cochrane Database of Systematic Reviews 1998, Issue 2. [DOI: 10.1002/14651858.CD000956] - DOI - PMC - PubMed
Herrick 2005
    1. Herrick AL. Pathogenesis of Raynaud's phenomenon. Rheumatology 2005;44(5):587‐96. - PubMed
Higgins 2003
    1. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. British Medical Journal 2003;327(7414):557‐60. - PMC - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Hirschl 2006
    1. Hirschl M, Hirschl K, Lenz M, Katzenschlager R, Hutter HP, Kundi M. Transition from primary Raynaud's phenomenon to secondary Raynaud's phenomenon identified by diagnosis of an associated disease; results of ten years of prospective surveillance. Arthritis and Rheumatism 2006;54(6):1974‐81. - PubMed
Hughes 2015
    1. Hughes M, Snapir A, Wilkinson J, Snapir D, Wigley FM, Herrick AL. Prediction and impact of attacks of Raynaud's phenomenon, as judged by patient perception. Rheumatology (Oxford, England) 2015;54(8):1443‐7. [10.1093/rheumatology/kev002. Epub 2015 Mar 9] - PubMed
Koenig 2008
    1. Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis and Rheumatism 2008;58(12):3902‐12. - PubMed
LeRoy 1992
    1. LeRoy EC, Medsger TA Jr. Raynaud's phenomenon: a proposal for classification. Clinical and Experimental Rheumatology 1992;10(5):458‐8. - PubMed
Maricq 1988
    1. Maricq HR, Weinrich MC. Diagnosis of Raynaud's phenomenon assisted by colour charts. Journal of Rheumatology 1988;15(3):454‐9. - PubMed
Maricq 1997
    1. Maricq HR, Carpentier PH, Weinrich MC, Keil JE, Palesch Y, Biro C, et al. Geographic variation in the prevalence of Raynaud's phenomenon: a 5 region comparison. Journal of Rheumatology 1997;24(5):879‐89. - PubMed
Merkel 2002
    1. Merkel PA, Herlyn K, Martin RW, Anderson JJ, Mayes MD, Bell P, et al. Scleroderma Clinical Trials Consortium. Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon. Arthritis and Rheumatism 2002;46(9):2410‐20. - PubMed
Priollet 1987
    1. Priollet P, Vayssairat M, Housset E. How to classify Raynaud's phenomenon. Long‐term follow up study of 73 cases. American Journal of Medicine 1987;83(3):494‐8. - PubMed
R Development Core Team 2012
    1. R Development Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing, 2012.
RevMan 2012 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Schunemann 2006
    1. Schunemann HJ, Jaeschke R, Cook DJ, Bria WF, El‐Solh AA, Ernst A, et al. ATS Documents Development and Implementation Committee. An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. American Journal of Respiratory and Critical Care Medicine 2006;174(5):605‐14. - PubMed
Silman 1990
    1. Silman A, Holligan S, Brennan P, Maddison P. Prevalence of symptoms of Raynaud's phenomenon in general practice. British Medical Journal 1990;301(6752):590‐2. - PMC - PubMed
Sturgill 1998
    1. Sturgill MG, Seibold JR. Rational use of calcium‐channel antagonists in Raynaud's phenomenon. Current Opinion in Rheumatology 1998;10(6):584‐8. - PubMed
Suter 2005
    1. Suter LG, Murabito JM, Felson DT, Fraenkel L. The incidence and natural history of Raynaud's phenomenon in the community. Arthritis and Rheumatism 2005;52(4):1259‐63. - PubMed
Thompson 2005
    1. Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud's phenomenon: a meta‐analysis. Rheumatology 2005;44(2):145‐50. - PubMed
Wigley 2002
    1. Wigley FM. Raynaud's phenomenon. Clinical practice Raynaud's phenomenon. New England Journal of Medicine 2002;347(13):1001‐8. - PubMed

References to other published versions of this review

Ennis 2014
    1. Ennis H, Anderson ME, Wilkinson J, Herrick AL. Calcium channel blockers for primary Raynaud's phenomenon. Cochrane Database of Systematic Reviews 2014, Issue 1. [DOI: 10.1002/14651858.CD002069.pub4] - DOI - PubMed

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