Calcium channel blockers for primary and secondary Raynaud's phenomenon

Fadumo Rirash; Paul C Tingey; Sarah E Harding; Lara J Maxwell; Elizabeth Tanjong Ghogomu; George A Wells; Peter Tugwell; Janet Pope

doi:10.1002/14651858.CD000467.pub2

Inhibiteurs des canaux calciques pour le phénomène de Raynaud primitif et secondaire

Appendices

Appendix 1. Appendix 1: search methods

Appendix 1: search methods

Raynaud's phenomenon
Database and coverage	Search date	Number of references retrieved	With duplicates removed
The Cochrane Library Cochrane Reviews Issue 12 of 12, December 2015 Other Reviews (DARE) Issue 2 of 4, April 2014 CENTRAL Methods studies Issue 3 of 4, July 2012 Technology assessments Issue 2 of 4, April 2014 Economic evaluation	December 2, 2015	14 26 1011 5 2 3	8 26 358 2 3 3
Ovid MEDLINE(R) 1946‐present		1027	1005
Ovid Embase Classic + Embase 1947‐present		1251	884
Clinicaltrials.gov		50	48
WHO portal (who.int/trialsearch, all years)		0	0
	Totals	3389	2337

Cochrane Library – Issue 6, 2014
Search name: Raynaud's
Last saved: 02/12/2015 13:58:12.787
Description:

ID search:

#1 MeSH descriptor: [Raynaud Disease] explode all trees

#2 raynaud*:ti,ab,kw

#3 vasospasm:ti,ab,kw

#4 #1 or #2 or #3

Database: Ovid MEDLINE(R) In‐Process & Other Non‐Indexed Citations and Ovid MEDLINE(R) <1946 to present>

Search strategy:

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

1 Raynaud Disease/ (5811)

2 Vasospasm.ti,ab. (9022)

3 raynaud$.tiw. (5879)

4 or/1‐3 (16735)

5 randomized controlled trial.pt. (376269)

6 controlled clinical trial.pt. (88551)

7 randomized.ab. (296657)

8 placebo.ab. (154994)

9 clinical trials as topic.sh. (170411)

10 randomly.ab. (214652)

11 trial.ti. (127683)

12 or/5‐11 (909747)

13 exp animals/ not humans.sh. (3951755)

14 12 not 13 (839533)

15 4 and 14 (1027)

Database: Embase Classic + Embase <1947 to June 20, 2014>

Search strategy:

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

1 Raynaud phenomenon/ (11646)

2 vasospasm/ (7831)

3 raynaud$.tiw. (8895)

4 or/1‐3 (20897)

5 random$.tiw. (900126)

6 factorial$.tiw. (23754)

7 crossover$.tiw. (50156)

8 cross over.tw. (22510)

9 cross‐over.tw. (22510)

10 placebo$.tiw. (207490)

11 (doubl$ adj blind$).tiw. (150810)

12 (singl$ adj blind$).tiw. (14649)

13 assign$.tiw. (244100)

14 allocate$.tiw. (85325)

15 volunteer$.tiw. (186103)

16 crossover procedure/ (39529)

17 double blind procedure/ (118455)

18 randomized controlled trial/ (346367)

19 single blind procedure/ (18431)

20 or/5‐19 (1457107)

21 4 and 20 (1251)

Clinicaltrials.gov
Advanced search screen

Condition=raynaud

Updated search performed on May 19, 2017

Raynaud's phenomenon
Database and coverage	Search date	Number of references retrieved	With duplicates removed
EBM Reviews ‐ CENTRAL (via OVID)	May 19, 2017	101
Ovid Medline(R) 1946‐present	May 19, 2017	50
Ovid Embase Classic + Embase 1947‐present	May 19, 2017	104


	Totals	255

CENTRAL
Search name: Raynaud's
Last saved: May 19, 2017
Description:

ID search:

C1 ‐ Database: EBM Reviews ‐ Cochrane Central Register of Controlled Trials <April 2017>

Search Strategy:

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

1 Raynaud Disease/ (267)

2 Vasospasm.ti,ab. (570)

3 raynaud$.tiw. (524)

4 or/1‐3 (1084)

5 limit 4 to yr="2015 ‐Current" (101)

C1 ‐ Database: Ovid MEDLINE(R) In‐Process & Other Non‐Indexed Citations and Ovid MEDLINE(R) <1946 to present>

Search strategy:

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

1 Raynaud Disease/ (6394)

2 Vasospasm.ti,ab. (10215)

3 raynaud$.tiw. (6728)

4 or/1‐3 (18859)

5 randomized controlled trial.pt. (462560)

6 controlled clinical trial.pt. (94063)

7 randomized.ab. (395329)

8 placebo.ab. (186432)

9 clinical trials as topic.sh. (185904)

10 randomly.ab. (275397)

11 trial.ti. (177271)

12 or/5‐11 (1120634)

13 exp animals/ not humans.sh. (4399234)

14 12 not 13 (1032602)

15 4 and 14 (1163)

16 limit 15 to ed=20151202‐20170519 (50)

C1 ‐ Database: Embase <1974 to May 18, 2017>

Search strategy:

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

1 Raynaud phenomenon/ (11924)

2 vasospasm/ (7993)

3 raynaud$.tiw. (9084)

4 or/1‐3 (21611)

5 random$.tiw. (1188308)

6 factorial$.tiw. (30059)

7 crossover$.tiw. (61652)

8 cross over.tw. (27084)

9 cross‐over.tw. (27084)

10 placebo$.tiw. (254043)

11 (doubl$ adj blind$).tiw. (177952)

12 (singl$ adj blind$).tiw. (19292)

13 assign$.tiw. (311284)

14 allocate$.tiw. (115199)

15 volunteer$.tiw. (219603)

16 crossover procedure/ (51208)

17 double blind procedure/ (138220)

18 randomized controlled trial/ (449401)

19 single blind procedure/ (26863)

20 or/5‐19 (1850737)

21 4 and 20 (1495)

22 Raynaud phenomenon/ (11924)

23 vasospasm/ (7993)

24 raynaud$.tiw. (9084)

25 or/22‐24 (21611)

26 random$.tiw. (1188308)

27 factorial$.tiw. (30059)

28 crossover$.tiw. (61652)

29 cross over.tw. (27084)

30 cross‐over.tw. (27084)

31 placebo$.tiw. (254043)

32 (doubl$ adj blind$).tiw. (177952)

33 (singl$ adj blind$).tiw. (19292)

34 assign$.tiw. (311284)

35 allocate$.tiw. (115199)

36 volunteer$.tiw. (219603)

37 crossover procedure/ (51208)

38 double blind procedure/ (138220)

39 randomized controlled trial/ (449401)

40 single blind procedure/ (26863)

41 or/26‐40 (1850737)

42 25 and 41 (1495)

43 limit 42 to dd=20151202‐20170519 (104)

Appendix 2. Appendix 2: dosage guidelines

Dosage guidelines*

Calcium channel blocker	Low dose (daily dose)	Medium dose (daily dose)	High dose (daily dose)
Amlodipine	2.5 mg	5 mg	10 mg
Isradipine	5 mg	10 mg	‐
Nicardipine	60 mg	90 mg	120 mg
Nifedipine	< or = 30 mg	>30 mg	90 mg
Nisoldipine	20 mg	30 mg	60 mg
Diltiazem	180 mg	240 mg	360 mg
Verapamil	180 mg	240 mg	360 mg

*Dosage based on Greater Rochester Independent Practice Association (GRIPA) guidelines.

Appendix 3. Appendix 3: Dichotomous outcomes from cross‐over trials

Study	General improvement				Treatment preference				Side effects				Withdrawals
	Treatment		Placebo		Treatment		Placebo		Treatment		Placebo		Treatment		Placebo
	Events	Total	Events	Total	Events	Total	Events	Total	Events	Total	Events	Total	Events	Total	Events	Total
Aldoori 1986									10	13	4	13
Bravard 1983	5	5	3	5
Challenor 1989									16	24	5	24	2	24	0	24
Corbin 1986					15	22	2	22	14	23	2	23	3	22	0	22
Ettinger 1984	15	19	12	19					12	22	1	22
Ferri 1992									2	21	0	21
French Co‐op 1991									19	69	7	69	2	69	5	69
Gjorup 1986a					12	19	4	19	5	19	0	19
Gjorup 1986b					19	21	0	21	16	21	0	21	4	26	0	26
Hawkins 1985									19	57	6	57	7	57	1	57
Kahan 1985a	12	15	1	15					6	15	2	15
Kahan 1985b	9	16	3	16					6	16	2	16
Kahan 1985c									9	30	3	30
Kahan 1987									7	20	2	20	7	20	2	20
Kallenberg 1987	14	15	0	15
Kinney 1982									3	14	10	14
Kirch 1987	8	10	2	10					2	10	2	10
La Civita 1997									11	20	0	20
Leppert 1989									5	10	3	10
Meyrick Thomas 1987									1	9	2	9	1	10	0	10
Nilsson 1987									20	28	8	28	1	28	0	28
Rhedda 1985									2	19	1	19
Rodeheffer 1983	9	15	2	15	15	27	11	27	12	15	3	15
Rupp 1987									15	27	9	27
Smith 1982									15	17	1	17
Taixeira Da Costa 1987	4	14	6	14
Waller 1986									26	29	5	29
Wigley 1987									12	25	7	25	12	25	7	25
White 1982	9	11	1	11
Wollersheim 1991													2	25	1	25
Total	76	109	29	109	61	89	17	89	265	573	85	573	39	281	15	281

Figure 1

Flow diagram of study.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

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

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Figure 4

Funnel plot of comparison: 1 CCBs vs placebo (generic inverse variance method), outcome: 1.1 Frequency of attacks (average/week).

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Figure 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).

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Analysis 1.1

Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 1 Frequency of attacks (average/week).

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Analysis 1.2

Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 2 Frequency of attacks (average/week).

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Analysis 1.3

Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 3 Duration of attacks (minutes).

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Analysis 1.4

Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 4 Severity of attacks (average, on a 10‐cm VAS).

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Analysis 1.5

Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 5 Pain (10‐cm visual analogue scale).

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Analysis 1.6

Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 6 Patient global.

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Analysis 1.7

Comparison 1 CCBs vs placebo (generic inverse variance method), Outcome 7 Number of withdrawals (due to treatment).

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Analysis 2.1

Comparison 2 Subgroup analysis by RP type, Outcome 1 Frequency of attacks (average/week).

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Analysis 2.2

Comparison 2 Subgroup analysis by RP type, Outcome 2 Severity of attacks (average, on a 10‐cm VAS).

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Analysis 3.1

Comparison 3 Subgroup analysis: nifedipine versus placebo by RP type, Outcome 1 Frequency of attacks: nifedipine vs placebo by RP type.

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Analysis 3.2

Comparison 3 Subgroup analysis: nifedipine versus placebo by RP type, Outcome 2 Severity of attacks: nifedipine vs placebo by RP type.

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Analysis 4.1

Comparison 4 Subgroup analysis by CCB class, Outcome 1 Frequency of attacks (average/week).

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Analysis 4.2

Comparison 4 Subgroup analysis by CCB class, Outcome 2 Frequency of attacks (average/week).

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Analysis 4.3

Comparison 4 Subgroup analysis by CCB class, Outcome 3 Severity of attacks (average, on a 10‐cm VAS).

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Analysis 4.4

Comparison 4 Subgroup analysis by CCB class, Outcome 4 Severity of attacks (average, on a 10‐cm VAS).

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Analysis 5.1

Comparison 5 Subgroup analysis by CCB dose, Outcome 1 Frequency of attacks (average/week).

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Analysis 5.2

Comparison 5 Subgroup analysis by CCB dose, Outcome 2 Duration of attacks (minutes).

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Analysis 5.3

Comparison 5 Subgroup analysis by CCB dose, Outcome 3 Severity of attacks (average, on a 10‐cm VAS).

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Analysis 5.4

Comparison 5 Subgroup analysis by CCB dose, Outcome 4 Pain (10‐cm visual analogue scale).

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Analysis 5.5

Comparison 5 Subgroup analysis by CCB dose, Outcome 5 Patient global.

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Analysis 6.1

Comparison 6 Minor outcomes, Outcome 1 Number of participants with improvement.

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Analysis 6.2

Comparison 6 Minor outcomes, Outcome 2 Side effects.

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Summary of findings for the main comparison. Calcium channel blockers compared with placebo for treatment of Raynaud's phenomenon

Calcium channel blockers (CCBs) compared with placebo for treatment of Raynaud's phenomenon
Patient or population: patients with Raynaud's phenomenon Settings: outpatient settings Intervention: calcium channel blockers (CCBs) (all) Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	CCBs (all)
Frequency of attacks Average number of attacks/week Follow‐up: 4 to 20 weeks	Mean frequency of attacks in control groups: 13.7 attacks^a	Mean frequency of attacks in intervention groups: 6.13 lower (6.60 to 5.67 lower)^b		528 (23 studies)	⊕⊕⊕⊝ moderate^c	Note: Excluding a study with a very large reduction in frequency of attacks changed the mean difference to ‐2.93 per week (95% CI ‐3.44 to ‐2.43). NNTB: N/A^d Absolute risk difference: N/A^d Relative percent change: ‐44% (95% CI ‐48% to ‐41%)
Duration of attacks Average duration per attack measured in minutes Follow‐up: 2 to 20 weeks	Mean duration of attacks in control groups: 18.8 minutes^a	Mean duration of attacks in intervention groups: 1.67 fewer minutes (‐3.29 to 0)		69 (6 studies)	⊕⊕⊝⊝ low^c,e	NNTB: N/A^d Absolute risk difference: N/A^d Relative percent change: ‐9% (95% CI ‐18% to 0%)
Severity of attacks Average severity per attack assessed on a 10‐cm visual analogue scale (0 = no symptoms, 10 = maximal severity) Follow‐up: 2 to 12 weeks	Mean severity of attacks in control groups: 6.7 cm^a	Mean severity of attacks in intervention groups: 0.62 lower (0.72 to 0.51 lower)		415 (18 studies)	⊕⊕⊕⊝ moderate^c	NNTB: N/A^d Absolute risk difference: ‐6% (95% CI ‐7% to ‐5%) Relative percent change: ‐9% (95% CI ‐11% to ‐8%)
Pain Average pain per attack, measured on a 10‐cm visual analogue scale (0 = no pain, 10 = maximal pain) Follow‐up: 2 to 10 weeks	Mean pain in control groups: 3.13 cm^a	Mean pain in intervention groups: 1.47 lower (2.21 to 0.74 lower)		62 (4 studies)	⊕⊕⊝⊝ low^c,e	N/A^d Absolute risk difference: ‐15% (95% CI ‐22% to ‐7%) Relative percent change: ‐47% (95% CI ‐71% to ‐24%)
Patient global Disability due to Raynaud's assessed on a 10‐cm visual analogue scale (0 = no disability, 10 = maximal disability) Follow‐up: 5 weeks	Mean patient global in control group: 3.9 cm^a	Mean patient global in intervention groups: 0.37 lower (0.73 lower to 0)		92 (2)	⊕⊕⊕⊝ moderate^e	NNTB: N/A^f Absolute risk difference: ‐4% (95% CI ‐7% to 0%) Relative percent change: ‐9% (95% CI ‐19% to 0%)
Number of withdrawals due to adverse events Number of participants who dropped out of studies owing to adverse treatment effects Follow‐up: 2 to 20 weeks	194 per 1000	252 per 1000 (99 to 645)	RR 1.30 (0.51 to 3.33)	63 (2 studies)	⊕⊕⊝⊝ low^e,g	NNTH: N/A^f Absolute risk reduction: 6% (95% CI ‐14% to 26%) Relative percent change: 30% (95% CI ‐49% to 233%)
Serious adverse events Number of participants who died or withdrew and were hospitalized as a result of adverse effects of treatment	See comment.	See comment.	Not estimable	0 (0)	See comment.	No serious adverse events reported
The basis for the assumed risk* (eg, median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CCB: calcium channel blocker; CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aFinal value: weighted mean of scores in placebo group across studies in the meta‐analysis. ^bWith exclusion of Kahan 1985c, CCBs leading to reduced frequency of attacks per week by 2.93 (95% CI ‐3.44 to ‐2.43). ^cDowngraded 1 level for significant statistical heterogeneity (I² > 50%). ^dN/A value not calculated. ^eDowngraded 1 level for imprecision (total population size < 400 for continuous outcomes; total number of events < 300 for dichotomous outcomes). ^fNNTB (number needed to benefit) and NNTH (number needed to harm) calculated only for statistically significant outcomes. ^gDowngraded 1 level for inclusion of studies with high risk of bias due to attrition.

Summary of findings for the main comparison. Calcium channel blockers compared with placebo for treatment of Raynaud's phenomenon

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Comparison 1. CCBs vs placebo (generic inverse variance method)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Frequency of attacks (average/week) Show forest plot	23	1024	Mean Difference (Fixed, 95% CI)	‐6.07 [‐6.53, ‐5.61]

2 Frequency of attacks (average/week) Show forest plot	22		Mean Difference (Fixed, 95% CI)	‐2.93 [‐3.44, ‐2.43]

3 Duration of attacks (minutes) Show forest plot	6	138	Mean Difference (Fixed, 95% CI)	‐1.67 [‐3.29, ‐0.04]

4 Severity of attacks (average, on a 10‐cm VAS) Show forest plot	16	748	Risk Difference (Fixed, 95% CI)	‐0.62 [‐0.72, ‐0.51]

5 Pain (10‐cm visual analogue scale) Show forest plot	4	124	Std. Mean Difference (Fixed, 95% CI)	‐1.47 [‐2.21, ‐0.74]

6 Patient global Show forest plot	2	192	Std. Mean Difference (Fixed, 95% CI)	‐0.37 [‐0.73, ‐0.02]

7 Number of withdrawals (due to treatment) Show forest plot	2	63	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [0.51, 3.33]

Comparison 1. CCBs vs placebo (generic inverse variance method)

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Comparison 2. Subgroup analysis by RP type

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Frequency of attacks (average/week) Show forest plot	15	624	Mean Difference (Fixed, 95% CI)	‐3.15 [‐3.67, ‐2.63]

1.1 CCBs vs placebo for primary RP	12	420	Mean Difference (Fixed, 95% CI)	‐3.02 [‐3.65, ‐2.38]
1.2 CCBs vs placebo for secondary RP	9	204	Mean Difference (Fixed, 95% CI)	‐3.42 [‐4.33, ‐2.51]
2 Severity of attacks (average, on a 10‐cm VAS) Show forest plot	10	506	Mean Difference (Fixed, 95% CI)	‐0.67 [‐0.77, ‐0.57]

2.1 Primary RP: CCBs vs placebo	8	368	Mean Difference (Fixed, 95% CI)	‐0.95 [‐1.11, ‐0.79]
2.2 Secondary RP: CCBs vs placebo	6	138	Mean Difference (Fixed, 95% CI)	‐0.48 [‐0.61, ‐0.35]

Comparison 2. Subgroup analysis by RP type

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Comparison 3. Subgroup analysis: nifedipine versus placebo by RP type

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Frequency of attacks: nifedipine vs placebo by RP type Show forest plot	9	268	Mean Difference (Fixed, 95% CI)	‐4.34 [‐5.09, ‐3.59]

1.1 Nifedipine vs placebo for primary RP	6	148	Mean Difference (Fixed, 95% CI)	‐4.42 [‐5.35, ‐3.50]
1.2 Nifedipine vs placebo for secondary RP	6	120	Mean Difference (Fixed, 95% CI)	‐4.19 [‐5.47, ‐2.91]
2 Severity of attacks: nifedipine vs placebo by RP type Show forest plot	4	108	Mean Difference (Fixed, 95% CI)	‐0.82 [‐1.07, ‐0.58]

2.1 Primary RP	2	54	Mean Difference (Fixed, 95% CI)	‐1.74 [‐2.09, ‐1.39]
2.2 Secondary RP	3	54	Mean Difference (Fixed, 95% CI)	0.01 [‐0.32, 0.34]

Comparison 3. Subgroup analysis: nifedipine versus placebo by RP type

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Comparison 4. Subgroup analysis by CCB class

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Frequency of attacks (average/week) Show forest plot	23		Mean Difference (Fixed, 95% CI)	‐6.07 [‐6.53, ‐5.61]

1.1 Dihydropyridines vs placebo	22		Mean Difference (Fixed, 95% CI)	‐6.13 [‐6.60, ‐5.67]
1.2 Non‐dihydropyridines vs placebo	1		Mean Difference (Fixed, 95% CI)	‐3.15 [‐6.33, 0.03]
2 Frequency of attacks (average/week) Show forest plot	21	960	Mean Difference (Fixed, 95% CI)	‐6.27 [‐6.73, ‐5.80]

2.1 Nifedipine vs placebo	15	582	Mean Difference (Fixed, 95% CI)	‐8.62 [‐9.20, ‐8.03]
2.2 Nicardipine vs placebo	5	300	Mean Difference (Fixed, 95% CI)	‐1.92 [‐2.80, ‐1.04]
2.3 Nisoldipine vs placebo	2	78	Mean Difference (Fixed, 95% CI)	‐1.00 [‐4.57, ‐1.43]
3 Severity of attacks (average, on a 10‐cm VAS) Show forest plot	16	748	Mean Difference (Fixed, 95% CI)	‐0.62 [‐0.72, ‐0.51]

3.1 Dihydropyridines vs placebo	15	716	Mean Difference (Fixed, 95% CI)	‐0.60 [‐0.71, ‐0.50]
3.2 Non‐dihydropyridines vs placebo	1	32	Mean Difference (Fixed, 95% CI)	‐2.0 [‐3.16, ‐0.84]
4 Severity of attacks (average, on a 10‐cm VAS) Show forest plot	15	716	Mean Difference (Fixed, 95% CI)	‐0.60 [‐0.71, ‐0.50]

4.1 Nifedipine vs placebo	9	378	Mean Difference (Fixed, 95% CI)	‐0.79 [‐0.96, ‐0.61]
4.2 Nicardipine vs placebo	5	300	Mean Difference (Fixed, 95% CI)	‐0.47 [‐0.61, ‐0.33]
4.3 Nisoldipine vs placebo	1	38	Mean Difference (Fixed, 95% CI)	‐0.79 [‐1.36, ‐0.22]

Comparison 4. Subgroup analysis by CCB class

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Comparison 5. Subgroup analysis by CCB dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Frequency of attacks (average/week) Show forest plot	23	1024	Mean Difference (Fixed, 95% CI)	‐6.07 [‐6.53, ‐5.61]

1.1 Low‐dose CCBs vs placebo	14	620	Mean Difference (Fixed, 95% CI)	‐1.00 [‐3.63, ‐2.37]
1.2 Medium/high‐dose CCBs vs placebo	9	404	Mean Difference (Fixed, 95% CI)	‐9.50 [‐10.17, ‐8.83]
2 Duration of attacks (minutes) Show forest plot	6	138	Mean Difference (Fixed, 95% CI)	‐1.67 [‐3.29, ‐0.04]

2.1 Low‐dose CCBs vs placebo	3	56	Mean Difference (Fixed, 95% CI)	2.24 [‐0.24, 4.73]
2.2 Medium‐dose CCBs vs placebo	3	82	Mean Difference (Fixed, 95% CI)	‐4.60 [‐6.76, ‐2.45]
3 Severity of attacks (average, on a 10‐cm VAS) Show forest plot	16	748	Mean Difference (Fixed, 95% CI)	‐0.62 [‐0.72, ‐0.51]

3.1 Low‐dose CCBs vs placebo	9	434	Mean Difference (Fixed, 95% CI)	‐0.56 [‐0.68, ‐0.45]
3.2 Medium/high‐dose CCBs vs placebo	7	314	Mean Difference (Fixed, 95% CI)	‐0.91 [‐1.18, ‐0.64]
4 Pain (10‐cm visual analogue scale) Show forest plot	4	124	Mean Difference (Fixed, 95% CI)	‐1.47 [‐2.21, ‐0.74]

4.1 Low‐dose CCBs vs placebo	2	72	Mean Difference (Fixed, 95% CI)	‐3.04 [‐4.34, ‐1.75]
4.2 Medium‐dose CCBs vs placebo	2	52	Mean Difference (Fixed, 95% CI)	‐0.73 [‐1.62, 0.16]
5 Patient global Show forest plot	2	192	Mean Difference (Fixed, 95% CI)	‐0.37 [‐0.73, ‐0.02]

5.1 Low‐dose CCBs vs placebo	1	72	Mean Difference (Fixed, 95% CI)	‐0.2 [‐0.63, 0.23]
5.2 High‐dose CCBs vs placebo	1	120	Mean Difference (Fixed, 95% CI)	‐0.74 [‐1.37, ‐0.11]

Comparison 5. Subgroup analysis by CCB dose

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Comparison 6. Minor outcomes

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants with improvement Show forest plot	3	59	Risk Ratio (M‐H, Fixed, 95% CI)	2.38 [1.35, 4.20]

2 Side effects Show forest plot	3	78	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.87, 1.45]

Comparison 6. Minor outcomes

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Appendices

Appendix 1. Appendix 1: search methods

Appendix 2. Appendix 2: dosage guidelines

Appendix 3. Appendix 3: Dichotomous outcomes from cross‐over trials

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Appendices

Appendix 1. Appendix 1: search methods

Appendix 2. Appendix 2: dosage guidelines

Appendix 3. Appendix 3: Dichotomous outcomes from cross‐over trials

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