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BMJ Clin Evid. 2008; 2008: 1125.
Published online 2008 September 26.
PMCID: PMC2907943

Raynaud's phenomenon (secondary)

Abstract

Introduction

Raynaud’s phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes. It presents as episodic colour changes of the digits, usually in response to cold exposure or stress. The classic triphasic colour change is white (ischaemia), then blue (deoxygenation), then red (reperfusion). Raynaud’s phenomenon can be primary (idiopathic) or secondary to several different conditions and causes. This review deals with secondary Raynaud’s phenomenon.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of self-help measures for secondary Raynaud’s phenomenon? What are the effects of drug treatments for secondary Raynaud’s phenomenon? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alpha-blockers; angiotensin-converting enzyme (ACE) inhibitors; angiotensin II receptor antagonists; antithrombotics/inhibitors of platelet aggregation; biofeedback; calcium channel blockers; endothelin-1 receptor antagonists; glyceryl trinitrate (transdermal); hand exercises; inositol nicotinate; moxisylyte; naftidrofuryl oxylate; phosphodiesterase inhibitors; prostaglandins (oral, intravenous); relaxation therapy; serotonin reuptake inhibitors (SRIs); smoking cessation; and warming hands and feet.

Key Points

Raynaud’s phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes.

It presents as episodic colour changes of the digits, usually in response to cold exposure or stress. The classic change is white (ischaemia), then blue (deoxygenation), then red (reperfusion).

Raynaud’s phenomenon can be primary (idiopathic) or secondary to several different conditions and causes. This review deals with secondary Raynaud’s phenomenon.

Most trials we found were in people with Raynaud's phenomenon secondary to systemic sclerosis.

We don't know whether biofeedback, hand exercises, relaxation therapy, smoking cessation, or warming hands and feet or keeping warm work, as we found no evidence.

  • Although we found no evidence, given the adverse effects of smoking on the vasculature, it is reasonable to encourage people with secondary Raynaud's to stop smoking.
  • Similarly, although we found no evidence, given that many people report exacerbation of symptoms in the cold, it is reasonable to avoid cold exposure and to keep the hands and feet warm if an attack develops.

Intravenous iloprost (a prostaglandin) reduces the frequency and severity of attacks compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis.

  • Intravenous prostaglandins other than iloprost have been less well studied.

Calcium channel blockers (mainly nifedipine) may decrease the frequency and severity of vasospastic attacks over 2 weeks compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis. However, evidence is limited.

Bosentan (a dual endothelin-1 receptor antagonist) may reduce new digital ulcer formation compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis and with previous digital ulcers in the last 12 months. However, we found no evidence on bosentan in people with secondary Raynaud's without previous digital ulceration, so the results are not generalisable to all people with secondary Raynaud's.

We don't know whether naftidrofuryl oxalate, alpha-blockers, angiotensin II receptor antagonists, ACE inhibitors, antithrombotics/inhibitors of platelet aggregation, glyceryl trinitrate (transdermal), inositol nicotinate, moxisylyte, phosphodiesterase inhibitors, or SRIs work, as we found no evidence.

Oral prostaglandins are unlikely to be beneficial in people with secondary Raynaud's phenomenon.

About this condition

Definition

Raynaud's phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes. It presents as episodic colour changes of the digits, usually in response to cold exposure or stress. The classic triphasic colour change is white (ischaemia), then blue (deoxygenation), then red (reperfusion). Raynaud's phenomenon can be primary (idiopathic) or secondary to several different conditions or causes, including connective tissue diseases such as systemic sclerosis, extrinsic vascular obstruction (e.g., in thoracic outlet syndrome), certain drugs/chemicals (e.g., ergotamine, vinyl chloride), vibration exposure (hand-arm vibration syndrome), and hyperviscosity states. This review excludes primary (idiopathic) Raynaud's phenomenon, and concerns the management of secondary Raynaud’s phenomenon. Most of the evidence we found on secondary Raynaud's phenomenon was in people with systemic sclerosis.

Incidence/ Prevalence

See Raynaud's phenomenon (primary). The prevalence of secondary Raynaud's depends on the associated disease or condition. For example, the prevalence of Raynaud's phenomenon in people with systemic sclerosis is almost 100%.

Aetiology/ Risk factors

Many different conditions can be associated with secondary Raynaud’s phenomenon, and the pathogenesis and pathophysiology of Raynaud’s phenomenon vary depending upon these underlying conditions. Abnormalities of the blood vessel wall, of the neural control of vascular tone, and intravascular factors may all have a role. Other factors have also been implicated, including smoking (in people with systemic sclerosis, smoking is associated with severity of digital ischaemia), hormonal factors (Raynaud's is more common in women than in men), and genetic factors.

Prognosis

Secondary Raynaud’s phenomenon can be severe, and may progress to ulceration, scarring, and sometimes gangrene necessitating amputation. Therefore, prognosis depends, at least to some extent, on the underlying cause of Raynaud’s phenomenon. Prognosis has been studied best in people with systemic sclerosis who develop underlying structural vascular abnormalities affecting both the microcirculation and the digital arteries. One study found that, of 1168 people with systemic sclerosis, 203 people (17.4%) had severe digital vasculopathy (Raynaud's phenomenon complicated by digital ulceration, critical digital ischaemia, gangrene, or requiring digital sympathectomy).

Aims of intervention

To relieve or reduce the frequency and severity of Raynaud′s attacks, prevent tissue damage, preserve hand function, and improve quality of life, with minimal adverse effects of treatment.

Outcomes

Raynaud's attacks: frequency and duration of symptoms as assessed by patient diary; severity of symptoms assessed by patient diary or by visual analogue scales, Likert scales, or the Raynaud's Condition Score; Digital ulceration: rates, size and healing of digital ulceration; Hand function; Quality of life; and Adverse effects of treatment.

Methods

Clinical Evidence search and appraisal May 2007. The following databases were used to identify studies for this systematic review: Medline 1987 to May 2007 for systematic reviews and 1987 to July 2007 for RCTs and cohort studies, Embase 1987 to May 2007 for systematic reviews and 1987 to July 2007 for RCTs and cohort studies, and The Cochrane Database of Systematic Reviews Issue 2, 2007 and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 2. Additional searches used these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the reviews. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, at least single blinded for drug interventions but including open studies for non-drug interventions, and containing 20 or more people, of whom more than 65% were followed up. In addition, we searched for prospective cohort studies for non-drug interventions. We included studies of people with primary Raynaud's if a subset of people with secondary Raynaud's could be separately identified and outcomes independently assessed, or if over 75% of people in the RCT had secondary Raynaud's. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. Most studies we found of treatment for secondary Raynaud's phenomenon were in people with systemic sclerosis. Difficulties in undertaking and interpreting clinical trials in people with Raynaud's phenomenon include the need to account for other extrinsic factors (e.g., symptoms may be worse over winter) and the need for an adequate comparison group (due to high rates of placebo response and the fluctuating nature of the disease). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table
GRADE Evaluation of interventions for Raynaud's phenomenon (secondary).

Glossary

Low-quality evidence
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.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Notes

Raynaud's phenomenon (primary)

References

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7. Thompson AE, Shea B, Welch V, et al. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum 2001;44:1841–1847. [PubMed]
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9. Rodeheffer RJ, Rommer JA, Wigley F, et al. Controlled double-blind trial of nifedipine in the treatment of Raynaud's phenomenon. N Engl J Med 1983;14;308:880–883. [PubMed]
10. Ettinger WH, Wise RA, Schaffhauser D, et al. Controlled double-blind trial of dazoxiben and nifedipine in the treatment of Raynauds phenomenon. Am J Med 1984;77:451–456. [PubMed]
11. Kahan A, Foult JM, Weber S, et al. Nifedipine and alpha 1-adrenergic blockade in Raynauds phenomenon. Eur Heart J 1985;6:702–705. [PubMed]
12. Kahan A, Weber S, Amor B, et al. Calcium entry blocking agents in digital vasospasm (Raynaud′s phenomenon). Eur Heart J 1983;4(Suppl C):123–129. [PubMed]
13. Scorza R, Caronni M, Mascagni B, et al. Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon. A randomized, controlled study. Clin Exp Rheumatol 2001;19:503–508. [PubMed]
14. Rademaker M, Cooke ED, Almond NE, et al. Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study. BMJ 1989;298:561–564. [PMC free article] [PubMed]
15. Wood HM, Ernst ME, Heidi M. Renin-angiotensin system mediators and Raynaud's phenomenon. Ann Pharmacother 2006;40:1998–2002. [PubMed]
16. Dziadzio M, Denton CP, Smith R, et al. Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 1999;42:2646–2655. [PubMed]
17. Coleiro B, Marshall SE, Denton CP, et al. Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology 2001;40:1038–1043. [PubMed]
18. Pope J, Fenlon D, Thompson, A, et al. Prazosin for Raynaud′s phenomenon in progressive systemic sclerosis. In: The Cochrane Library, Issue 2, 2007. Chichester, UK: John Wiley & Sons, Ltd. Search date 1999.
19. Korn JH, Mayes M, Matucci, Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004;50:3985–3993. [PubMed]
20. Levien TL. Phosphodiesterase inhibitors in Raynaud's phenomenon. Ann Pharmacother 2006;40:1388–1393. [PubMed]
21. Rajagopalan S, Pfenninger D, Somers E, et al. Effects of cilostazol in patients with Raynaud's syndrome. Am J Cardiol 2003;92:1310–1315. [PubMed]
22. Pope J, Fenlon D, Thompson A, et al. Iloprost and cisaprost for Raynauds phenomenon in progressive systemic sclerosis. In: The Cochrane Library, Issue 2 2007. Chichester, UK: John Wiley & Sons, Ltd. Search date 1999.
23. Wigley FM, Korn JH, Csuka ME, et al. Oral iloprost treatment in patients with Raynaud′s phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study. Arthritis Rheum 1998;41:670–677. [PubMed]
24. Black CM, Halkier-Sorensen L, Belch JJ, et al. Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study. Br J Rheumatol 1998;37:952–960. [PubMed]
25. Vayssairat M. French Microcirculation Society Multicenter Group for the Study of Vascular Acrosyndromes. Preventive effect of an oral prostacyclin analog, beraprost sodium, on digital necrosis in systemic sclerosis. J Rheumatol 1999;26:2173–2178. [PubMed]
26. Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with Raynaud's phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Inter Med 1994;120:199–206. [PubMed]
2008; 2008: 1125.
Published online 2008 September 26.

Warming hands and feet or keeping warm

Summary

We don't know whether warming hands and feet or keeping warm work, as we found no evidence.

Although we found no evidence, given that many people report exacerbation of symptoms in the cold, it is reasonable to avoid cold exposure and to keep the hands and feet warm if an attack develops.

Benefits and harms

Warming hands and feet or keeping warm versus no treatment:

We found no systematic reviews, RCTs, or cohort studies.

Warming hands and feet or keeping warm versus other self-help interventions covered in this review:

We found no systematic reviews, RCTs, or cohort studies.

Further information on studies

Comment

Clinical guide:

Although there have been no clinical trials of warming of the hands and feet in people with secondary Raynaud's phenomenon, people almost invariably report exacerbation of their symptoms in the cold, and so it seems sensible to, firstly, avoid cold exposure whenever possible and, secondly, to keep the hands and feet warm and if an attack does develop, to rewarm them as soon as possible to expedite reperfusion.

Substantive changes

Warming hands and feet or keeping warm New option. No systematic reviews, RCTs, or cohort studies identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Relaxation therapy

Summary

We don't know whether relaxation therapy works as we found no evidence.

Benefits and harms

Relaxation therapy versus no treatment:

We found one systematic review (search date 1999), which identified one RCT that did not meet Clinical Evidence reporting criteria.

Relaxation therapy versus other self-help interventions covered in this review:

We found no systematic reviews, RCTs, or cohort studies.

Further information on studies

Comment

Clinical guide:

Relaxation therapy has been little studied in people with secondary Raynaud's phenomenon. However, many people report that stress exacerbates their symptoms, and so avoiding stress through relaxation therapy may confer benefit in some people.

Substantive changes

Relaxation therapy New option. No systematic reviews, RCTs, or cohort studies identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Biofeedback

Summary

We don't know whether biofeedback works, as we found no evidence.

Benefits and harms

Biofeedback versus no treatment:

We found no systematic reviews, RCTs, or cohort studies.

Biofeedback versus other self-help interventions covered in this review:

We found no systematic reviews, RCTs, or cohort studies.

Further information on studies

Comment

Clinical guide:

Temperature biofeedback has been more studied in primary than in secondary Raynaud's phenomenon. One controlled trial in 2000 did not demonstrate any efficacy of temperature biofeedback in primary Raynaud's, and this treatment is not widely recommended for either primary or secondary Raynaud's phenomenon.

Substantive changes

Biofeedback New option. No systematic reviews, RCTs, or cohort studies identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Smoking cessation

Summary

We don't know whether smoking cessation works as we found no evidence.

Although we found no evidence, given the adverse effects of smoking on the vasculature, it is reasonable to encourage people with secondary Raynaud's to stop smoking.

Benefits and harms

Smoking cessation versus no treatment:

We found no systematic reviews, RCTs, or cohort studies.

Smoking cessation versus other self-help interventions covered in this review:

We found no systematic reviews, RCTs, or cohort studies.

Further information on studies

None.

Comment

Clinical guide:

Although smoking cessation has not been studied in secondary Raynaud's phenomenon, the adverse effects of smoking on the vasculature suggest that it is appropriate for clinicians to encourage people to stop smoking.

Substantive changes

Smoking cessation New option. No systematic reviews, RCTs, or cohort studies identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Hand exercises

Summary

We don't know whether hand exercises work, as we found no evidence.

Benefits and harms

Hand exercises versus no treatment:

We found no systematic reviews, RCTs, or cohort studies.

Hand exercises versus other self-help interventions covered in this review:

We found no systematic reviews, RCTs, or cohort studies.

Further information on studies

None.

Comment

Clinical guide:

The effects of hand exercises have not been studied in secondary Raynaud's phenomenon. Where the Raynaud's phenomenon is associated with reduced finger movements — for example, in systemic sclerosis — then it seems sensible to recommend exercises to retain as great a range of mobility as possible.

Substantive changes

Hand exercises New option. No systematic reviews, RCTs, or cohort studies identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Glyceryl trinitrate (transdermal)

Summary

We don’t know whether glyceryl trinitrate (transdermal) works.

Transdermal glyceryl trinitrate has been associated with headaches, which limits its use in people with Raynaud's phenomenon.

Benefits and harms

Glyceryl trinitrate (transdermal) versus placebo:

We found one crossover RCT.

Raynaud's attacks

Transdermal glyceryl trinitrate compared with placebo Transdermal glyceryl trinitrate may be more effective at reducing the mean number and severity of Raynaud's attacks over 7 days (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Frequency of attack

RCT
Crossover design
21 people with Raynaud's phenomenon secondary to systemic sclerosis
Subgroup analysis
Mean difference of frequency of attacks (post-crossover) 7 days
with transdermal glyceryl trinitrate (0.2 mg/hour for 12 hours/day)
with placebo
Absolute results not reported

P = 0.046
Result is of borderline significance
Result should be interpreted with caution; see further information on studies for full details
Effect size not calculatedtransdermal glyceryl trinitrate
Severity of attack

RCT
Crossover design
21 people with Raynaud's phenomenon secondary to systemic sclerosis
Subgroup analysis
Mean difference in overall severity score (post-crossover) 7 days
with transdermal glyceryl trinitrate (0.2 mg/hour for 12 hours/day)
with placebo
Absolute results not reported

P = 0.036
Result should be interpreted with caution; see further information on studies for full details
Effect size not calculatedtransdermal glyceryl trinitrate

RCT
Crossover design
21 people with Raynaud's phenomenon secondary to systemic sclerosis
Subgroup analysis
Mean difference in numbness score (post-crossover) 7 days
with transdermal glyceryl trinitrate (0.2 mg/hour for 12 hours/day)
with placebo
Absolute results not reported

P = 0.009
Result should be interpreted with caution; see further information on studies for full details
Effect size not calculatedtransdermal glyceryl trinitrate

RCT
Crossover design
21 people with Raynaud's phenomenon secondary to systemic sclerosis
Subgroup analysis
Mean difference in pain score (post-crossover) 7 days
with transdermal glyceryl trinitrate (0.2 mg/hour for 12 hours/day)
with placebo
Absolute results not reported

P = 0.034
Result should be interpreted with caution; see further information on studies for full details
Effect size not calculatedtransdermal glyceryl trinitrate

Digital ulceration

No data from the following reference on this outcome.

Hand function

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache

RCT
Crossover design
42 people with primary (17 people) and secondary (15 people) Raynaud's phenomenon Headache
26/32 (81%) with glyceryl trinitrate
10/32 (31%) with placebo

P <0.001
Result should be interpreted with caution; see further information on studies for full details
Effect size not calculatedplacebo
Withdrawals

RCT
Crossover design
42 people with primary (17 people) and secondary (15 people) Raynaud's phenomenon Withdrawals
with glyceryl trinitrate
with placebo

Significance not assessed

Glyceryl trinitrate (transdermal) versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

The RCT did not include a washout period and did not report pre-crossover results or methods of randomisation. Results based on 15/21 (71%) people with secondary Raynaud's who completed the trial.

Comment

Clinical guide:

Although topical glyceryl trinitrate, a nitric oxide donor, administered by "patch", has been shown in one small study to be effective in systemic sclerosis-related Raynaud's phenomenon, this is at the expense of adverse effects (mainly headaches) due to its systemic absorption. Therefore, local delivery systems (applying glyceryl trinitrate directly to the fingers) are being researched with the aim of achieving local but not systemic increases in blood flow.

Substantive changes

Glyceryl trinitrate (transdermal) New option. One small crossover RCT (42 people in total, of whom 21 people had secondary Raynaud's phenomenon) included, which compares transdermal glyceryl trinitrate versus placebo. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Calcium channel blockers

Summary

Calcium channel blockers (mainly nifedipine) may decrease the frequency and severity of vasospastic attacks over 2 weeks compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis. However, evidence is limited.

Benefits and harms

Calcium channel blockers versus placebo:

We found two systematic reviews (search date 2000, 8 RCTs, 187 people, 109 with Raynaud's phenomenon secondary to systemic sclerosis) and (search date 2005), comparing calcium channel blockers versus placebo. The first review identified seven RCTs assessing nifedipine and one RCT assessing nicardipine. The second systematic review was narrative in character, and did not meta-analyse data or identify any further RCTs not identified by the first review.

Raynaud's attacks

Calcium channel blockers compared with placebo Calcium channel blockers (mainly nifedipine) may be more effective at reducing the frequency and severity of vasospastic attacks at 2 weeks in people with Raynaud's secondary to systemic sclerosis (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Frequency of attack

Systematic review
59 people with Raynaud's phenomenon secondary to systemic sclerosis
6 RCTs in this analysis
Mean reduction in frequency of attack 2 weeks
with calcium channel blockers
with placebo
Absolute results not reported

WMD –8.31 attacks
95% CI –15.71 attacks to –0.91 attacks
P = 0.03
Methodological limitations; see further information on studies for full details
Effect size not calculatedcalcium channel blockers

Systematic review
44 people with Raynaud's phenomenon secondary to systemic sclerosis
5 RCTs in this analysis
Mean reduction in frequency of attack 2 to 12 weeks
with nifedipine (10–20 mg three times daily)
with placebo

WMD –10.21 attacks
95% CI –20.09 attacks to –0.34 attacks
P = 0.04
Methodological limitations; see further information on studies for full details
Effect size not calculatednifedipine
Severity of attack

Systematic review
31 people with Raynaud's phenomenon secondary to systemic sclerosis
3 RCTs in this analysis
Severity of attack 2 weeks
with calcium channel blockers
with placebo

SMD –0.69
95% CI –1.21 to –0.17
P = 0.01
Methodological limitations; see further information on studies for full details
Effect size not calculatedcalcium channel blockers

Digital ulceration

No data from the following reference on this outcome.

Hand function

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
15 people in total, 9 with systemic sclerosis
In review
headache
80% with nifedipine
20% with placebo
Absolute numbers not reported

P = 0.003
Effect size not calculatedplacebo

RCT
15 people in total, 9 with systemic sclerosis
In review
Lightheadedness
33% with nifedipine
7% with placebo
Absolute numbers not reported

P = 0.17
Not significant

RCT
22 people in total, 8 with systemic sclerosis
In review
Adverse effects
12/22 (55%) with nifedipine
2/22 (9%) with placebo

P <0.005
Effect size not calculatedplacebo

RCT
15 people in total, 7 people with systemic sclerosis
In review
Adverse effects
6/15 (40%) with nifedipine
2/15 (13%) with placebo

Significance not assessed

RCT
30 people in total, 10 people with systemic sclerosis
In review
Headache
4 people with nifedipine
0 people with placebo

Significance not assessed

RCT
30 people in total, 10 people with systemic sclerosis
In review
Nausea
5 people with nifedipine
2 people with placebo

Significance not assessed

RCT
30 people in total, 10 people with systemic sclerosis
In review
Ankle oedema
7 people with nifedipine
0 people with placebo

Significance not assessed

RCT
30 people in total, 10 people with systemic sclerosis
In review
Facial flushing
5 people with nifedipine
0 people with placebo

Significance not assessed

RCT
30 people in total, 10 people with systemic sclerosis
In review
Faintness
0 people with nifedipine
1 person with placebo

Significance not assessed

RCT
30 people in total, 10 people with systemic sclerosis
In review
Palpitations
0 people with nifedipine
1 person with placebo

Significance not assessed

Calcium channel blockers versus intravenous prostaglandins:

We found two systematic reviews (search date 2000 and search date 2005), and one subsequent RCT. The first systematic review identified one RCT, comparing oral nifedipine versus intravenous iloprost. The RCT reported only baseline changes for the number, duration, or severity of attacks, and did not report a direct statistical comparison between nifedipine and iloprost for these outcomes, so we have not reported data on our outcomes of interest. We have reported general adverse effects from this RCT. The second systematic review (search date 2005) reported the findings of the first systematic review, but did not pool data or identify any further RCTs. The subsequent RCT compared oral nifedipine versus intravenous iloprost for 12 months. However, the RCT reported only baseline changes for severity of attacks, and did not report a direct statistical comparison between nifedipine and iloprost for this outcomes, so we have not reported data on our outcomes of interest. We have reported general adverse effects from this RCT.

Raynaud's attacks

No data from the following reference on this outcome.

Digital ulceration

No data from the following reference on this outcome.

Hand function

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
23 people with Raynaud's phenomenon and systemic sclerosis
In review
Withdrawals
with oral nifedipine
with intravenous iloprost

RCT
46 people with Raynaud's phenomenon and systemic sclerosis Headache
100% with intravenous iloprost (given initially by infusion over 8 hours on 5 consecutive days plus one 8-hour infusion every 6 weeks)
18% with oral nifedipine (twice daily)
Absolute numbers not reported

Significance not assessed

RCT
46 people with Raynaud's phenomenon and systemic sclerosis Hypotension
14% with intravenous iloprost (given initially by infusion over 8 hours on 5 consecutive days plus one 8-hour infusion every 6 weeks)
29% with oral nifedipine (twice daily)
Absolute numbers not reported

Significance not assessed

RCT
46 people with Raynaud's phenomenon and systemic sclerosis Withdrawals
6 people with (given initially by infusion over 8 hours on 5 consecutive days plus one 8-hour infusion every 6 weeks)
5 people with oral nifedipine (twice daily)

Significance not assessed

Calcium channel blockers versus angiotensin II receptor antagonists:

We found three systematic reviews. The first and third systematic review (search date 2000, and search date 2006) identified one RCT comparing slow-release nifedipine versus losartan. The RCT did not satisfy Clinical Evidence inclusion criteria as it is an open study, and is therefore not discussed further. The second systematic review (search date 2005) reported the findings of the first systematic review, but identified no additional RCTs.

Calcium channel blockers versus SRIs:

We found one crossover RCT (53 people, 27 with secondary Raynaud's phenomenon) comparing oral nifedipine versus fluoxetine for 6 weeks. The RCT did not meet Clinical Evidence reporting criteria as it is an open study, and is therefore not discussed further.

Calcium channel blockers versus glyceryl trinitrate (transdermal), alpha-blockers, naftidrofuryl oxylate, moxisylyte, inositol nicotinate, ACE inhibitors, endothelin-1 receptor antagonists, phosphodiesterase inhibitors, antithrombotics/inhibitors of platelet aggregation, or prostaglandins (oral):

We found no systematic review or RCTs.

Further information on studies

Of the eight RCTs included in the review, seven RCTs were of crossover design. The review noted that results prior to crossover were not reported in many studies, which may have led to a smaller than expected treatment effect. It noted that, because many of the studies included people with primary and secondary Raynaud's phenomenon, the subgroup analysis could be biased if randomisation was not stratified within the groups of people with secondary Raynaud's. The review also noted that treatment duration was often short, and the eight RCTs had small sample sizes (109 people in total with systemic sclerosis).

Additional adverse effects reported with iloprost included nausea/vomiting (83%), jaw pain (69%), myalgia (34%), diarrhoea (28%), and chills (17%). Additional adverse effects reported with nifedipine included tachycardia (6%).

Comment

Clinical guide:

Many clinicians believe that calcium channel blockers should be used as first-line drug treatment for secondary Raynaud's phenomenon, although not all people benefit, and a large proportion of people have adverse effects, including headache, flushing, hypotension, peripheral oedema, and nausea.

Substantive changes

Calcium channel blockers New option. Three systematic reviews and two RCTs identified. One systematic review, which included eight RCTs (109 people with secondary Raynaud's phenomenon [secondary to systemic sclerosis]), pooled data and compared calcium channel blockers versus placebo, and also nifedipine alone versus placebo. Categorised as Likely to be beneficial.

2008; 2008: 1125.
Published online 2008 September 26.

Alpha-blockers (oral)

Summary

We don’t know whether alpha-blockers work.

Benefits and harms

Alpha-blockers versus placebo:

We found two systematic reviews (search date 1996 and search date 2005). The first review (2 RCTs, 26 people with Raynaud's phenomenon and systemic sclerosis) compared alpha-blockers versus placebo in people with Raynaud's and systemic sclerosis. The review included RCTs of people with primary Raynaud's phenomenon and Raynaud's phenomenon secondary to systemic sclerosis if results from people with scleroderma could be separately identified and their outcome independently assessed. The analysis of the second RCT in the review included less than 20 people — which does not meet Clinical Evidence reporting criteria, and so is not reported further. The second systematic review identified the same RCTs as the first systematic review, but did not pool data or identify any further RCTs.

Raynaud's attacks

Alpha-blockers compared with placebo The alpha-blocker prazosin may be more effective at reducing the frequency of vasospastic attacks at 12 weeks in people with Raynaud's phenomenon secondary to systemic sclerosis (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Frequency of attack

Systematic review
20 people with Raynaud's phenomenon and systemic sclerosis
Data from 1 RCT
Frequency of vasospastic attack 12 weeks
with oral prazosin (3–9 mg/day)
with placebo
Absolute results not reported

WMD –3.50 attacks
95% CI –5.85 attacks to –1.15 attacks
P = 0.003
Effect size not calculatedoral prazosin

Digital ulceration

No data from the following reference on this outcome.

Hand function

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
20 people with Raynaud's phenomenon and systemic sclerosis
Data from 1 RCT
Adverse effects
2/11 people (18%) with prazosin
0/9 people (0%) with placebo

OR 6.82
95% CI 0.39 to 119.26
P = 0.2
Not significant

Alpha-blockers versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

There is weak evidence supporting the use of alpha-blockers in secondary Raynaud's. Further RCTs are necessary to establish the role of alpha-blockers for secondary Raynaud's phenomenon.

Substantive changes

Alpha-blockers (oral) New option. Two systematic reviews identified, both of which identified one RCT of sufficient quality comparing oral prazosin versus placebo. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Naftidrofuryl oxylate

Summary

We don’t know whether naftidrofuryl oxylate works as we found no evidence.

Benefits and harms

Naftidrofuryl oxylate versus placebo:

We found no systematic review or RCTs.

Naftidrofuryl oxylate versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

Although naftidrofuryl oxalate is occasionally prescribed for people with secondary Raynaud's phenomenon, at present there is no evidence to support its use. RCTs are needed to establish whether naftidrofuryl oxalate is of benefit for people with Raynaud's phenomenon.

Substantive changes

Naftidrofuryl oxylate New option. No systematic reviews or RCTs identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Moxisylyte

Summary

We don’t know whether moxisylyte works as we found no evidence.

Benefits and harms

Moxisylyte versus placebo:

We found systematic review or RCTs.

Moxisylyte versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

Although moxisylyte is occasionally prescribed for people with secondary Raynaud's phenomenon, at present there is no evidence to support its use. RCTs are needed to establish whether moxisylyte is of benefit for people with Raynaud's phenomenon.

Substantive changes

Moxisylyte New option. No systematic reviews or RCTs identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Inositol nicotinate

Summary

We don’t know whether inositol nicotinate works as we found no evidence.

Benefits and harms

Inositol nicotinate versus placebo:

We found no systematic review or RCTs.

Inositol nicotinate versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

Although inositol nicotinate is occasionally prescribed for people with secondary Raynaud's phenomenon, at present there is no evidence to support its use. RCTs are required to establish whether inositol nicotinate is of benefit for people with Raynaud's phenomenon.

Substantive changes

Inositol nicotinate New option. No systematic reviews or RCTs identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

ACE inhibitors

Summary

We don’t know whether ACE inhibitors work as we found no evidence.

Benefits and harms

ACE inhibitors versus placebo:

We found one systematic review (search date 2006), which identified no RCTs that met Clinical Evidence reporting criteria. The searches in the review were restricted to English language studies. We found no subsequent RCTs.

ACE inhibitors versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

There is no good evidence in favour of ACE inhibitors for the treatment of secondary Raynaud's phenomenon. Further RCTs are required to establish the role of ACE inhibitors for secondary Raynaud's phenomenon.

Substantive changes

ACE inhibitors New option. One systematic review identified, which identified no RCTs that satisfy Clinical Evidence inclusion criteria, and no subsequent RCTs identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Angiotensin II receptor antagonists (oral)

Summary

We don’t know whether angiotensin II receptor antagonists work as we found no evidence.

Benefits and harms

Angiotensin II receptor antagonists versus placebo:

We found no systematic review or RCTs.

Angiotensin II receptor antagonists versus calcium channel blockers:

See option on calcium channel blockers.

Angiotensin II receptor antagonists versus glyceryl trinitrate (transdermal), alpha-blockers, naftidrofuryl oxylate, moxisylyte, inositol nicotinate, ACE inhibitors, SRIs, endothelin-1 receptor antagonists, phosphodiesterase inhibitors, antithrombotics/inhibitors of platelet aggregation, prostaglandins (oral), or prostaglandins (intravenous):

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

Some clinicians prescribe angiotensin II receptor antagonists for people with secondary Raynaud's phenomenon, although at present there is only weak evidence for this from an open study comparing losartan to nifedipine. Further RCTs are needed to establish the role of angiotensin II receptor antagonists for secondary Raynaud's phenomenon.

Substantive changes

Angiotensin II receptor antagonists (oral) New option. Three systematic reviews identified, which found no RCTs that satisfied Clinical Evidence inclusion criteria. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

SRIs (SEROTONIN REUPTAKE INHIBITORS)

Summary

We don’t know whether SRIs work as we found no evidence.

Benefits and harms

SRI versus placebo:

We found no systematic review or RCTs.

SRI versus calcium channel blockers:

See option on calcium channel blockers.

SRI versus glyceryl trinitrate (transdermal), alpha-blockers, naftidrofuryl oxylate, moxisylyte, inositol nicotinate, ACE inhibitors, angiotensin II receptor antagonists, endothelin-1 receptor antagonists, phosphodiesterase inhibitors, antithrombotics/inhibitors of platelet aggregation, prostaglandins (oral), or prostaglandins (intravenous):

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

Some clinicians prescribe SRIs for people with secondary Raynaud's phenomenon, although at present there is only weak evidence for this from an open study comparing fluoxetine versus nifedipine. Further RCTs are required to establish the role of SRIs for secondary Raynaud's phenomenon.

Substantive changes

SRIs New option. No systematic reviews or RCTs that satisfied Clinical Evidence inclusion criteria identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Endothelin-1 receptor antagonists

Summary

Bosentan (a dual endothelin-1 receptor antagonist) may reduce new digital ulcer formation compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis and with previous digital ulcers in the last 12 months. However, we found no evidence on bosentan in people with secondary Raynaud's without previous digital ulceration, so the results are not generalisable to all people with secondary Raynaud's.

Bosentan has been associated with abnormal liver function tests.

Benefits and harms

Bosentan versus placebo:

We found one RCT comparing oral bosentan versus placebo for 16 weeks.

Digital ulceration

Bosentan compared with placebo Bosentan (a dual endothelin-1 receptor antagonist) may be more effective at reducing the number of new digital ulcers in people with systemic sclerosis and a history of digital ulceration in the previous 12 months, but not at improving ulcer healing rates. We found no evidence in people with secondary Raynaud's without previous digital ulceration (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Development of digital ulcers

RCT
122 people with systemic sclerosis and a history of a documented digital ulcer within the previous 12 months Mean number of new digital ulcers 16 weeks
1.4 with bosentan (125 mg twice daily)
2.7 with placebo

P = 0.0083
Effect size not calculatedbosentan

RCT
76 people with existing digital ulcers at baseline
Subgroup analysis
Mean number of new digital ulcers 16 weeks
1.8 with bosentan (125 mg twice daily)
3.6 with placebo

P = 0.0075
Effect size not calculatedbosentan
Time to ulcer healing

RCT
122 people with systemic sclerosis and a history of a documented digital ulcer within the previous 12 months Time to complete or partial ulcer healing 16 weeks
with bosentan (125 mg twice daily)
with placebo
Absolute results reported graphically

Reported as not significant
P value not reported
Not significant

Hand function

Bosentan compared with placebo Bosentan may be more effective at improving hand function (as measured by modified Scleroderma Health Assessment Questionnaire [SHAQ]) at 16 weeks (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Hand function

RCT
122 people with systemic sclerosis and a history of a documented digital ulcer within the previous 12 months Hand function (measured by modified Scleroderma Health Assessment Questionnaire [SHAQ]) 6 weeks
with bosentan (125 mg twice daily)
with placebo
Absolute results reported graphically

P <0.005
Effect size not calculatedbosentan

Raynaud's attacks

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
122 people with systemic sclerosis and a history of a documented digital ulcer within the previous 12 months Serious adverse effects
2/79 (3%) with bosentan (125 mg twice daily)
3/43 (7%) with placebo

Significance not assessed

Endothelin-1 receptor antagonists other than bosentan versus placebo:

We found no systematic review or RCTs.

Endothelin-1 receptor antagonists versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

Serious adverse effects Serious adverse effects in the bosentan group were palpitations (1/79 [1.3%]), and dyspnoea (1/79 [1.3%]). Serious adverse effects in the placebo group were dyspnoea (1/43 [2.3%]), oesophagitis and vomiting (1/43 [2.3%]), and digital ischaemia (1/43 [2.3%]) Liver function tests: In total, 11/89 (14%) people given bosentan developed abnormal liver function tests, specifically elevated transaminases. Abnormalities of liver function tests led to five people discontinuing bosentan. In all people who stopped treatment, transaminase values returned to normal.

Comment

Clinical guide:

There is some evidence to support the use of bosentan in people with systemic sclerosis-related digital ulceration, particularly those with multiple or recurrent ulcers. Liver function must be closely monitored, because a significant proportion of people develop raised transaminases.

Substantive changes

Endothelin-1 receptor antagonists New option. One RCT (122 people with systemic sclerosis and a history of a documented digital ulcer within the previous 12 months) added comparing oral bosentan versus placebo. "Bosentan (an endothelin-1 receptor antagonist) (reduced new digital ulcers compared with placebo in people with systemic sclerosis and previous digital ulceration in the last 12 months; however, no evidence in people with secondary Raynaud's without previous digital ulceration)" categorised as Likely to be beneficial.

2008; 2008: 1125.
Published online 2008 September 26.

Phosphodiesterase inhibitors

Summary

We don’t know whether phosphodiesterase inhibitors work.

Benefits and harms

Phosphodiesterase inhibitors versus placebo:

We found one systematic review (search date 2006), which identified one RCT that did not meet Clinical Evidence reporting criteria. The searches in the review were restricted to English language studies. We found one additional RCT.

Raynaud's attacks

Phosphodiesterase inhibitors compared with placebo Phosphodiesterase type III inhibitors (oral cilostazol) may be no more effective at reducing the frequency and severity of vasospastic attacks at 6 weeks (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Frequency of attack

RCT
21 people with Raynaud's phenomenon (secondary to connective tissue disorder)
Subgroup analysis
mean number of vasospastic attacks 6 weeks
46 with oral cilostazol (100 mg twice daily)
45 with placebo

P = 0.96
Method of randomisation not clear
Not significant

RCT
21 people with Raynaud's phenomenon (secondary to connective tissue disorder)
Subgroup analysis
mean attack incidence number of attacks/day
1 with oral cilostazol (100 mg twice daily)
1 with placebo

P = 0.99
Method of randomisation unclear
Not significant
Severity of attack

RCT
21 people with Raynaud's phenomenon (secondary to connective tissue disorder)
Subgroup analysis
mean severity score [scale of 0–9] 6 weeks
3.0 with oral cilostazol (100 mg twice daily)
2.6 with placebo

P = 0.64
Method of randomisation unclear
Not significant

Digital ulceration

No data from the following reference on this outcome.

Hand function

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Headache

RCT
21 people with Raynaud's phenomenon (secondary to connective tissue disorder)
Subgroup analysis
Headache
35% with oral cilostazol (100 mg twice daily)
0% with placebo
Absolute numbers not reported

Significance not assessed
Method of randomisation unclear
Palpitations

RCT
21 people with Raynaud's phenomenon (secondary to connective tissue disorder) Palpitations
2 people with oral cilostazol (100 mg twice daily)
0 people with placebo

Significance not assessed
Method of randomisation unclear

Phosphodiesterase inhibitors versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

At present, there is no good evidence for using phosphodiesterase inhibitors for secondary Raynaud's phenomenon — although there is anecdotal evidence for benefit in some people, and a good therapeutic rationale for their use. Some clinicians prescribe these drugs in people refractory to other treatments. Further RCTs are needed to establish the role of phosphodiesterase inhibitors for secondary Raynaud's phenomenon.

Substantive changes

Phosphodiesterase inhibitors New option. One systematic review identified, which found no RCTs that met Clinical Evidence inclusion criteria. One small additional RCT (43 people in total, of whom 21 people has secondary Raynaud's) added, comparing cilostazol versus placebo. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Antithrombotics/inhibitors of platelet aggregation

Summary

We don’t know whether antithrombotics/inhibitors of platelet aggregation work as we found no evidence.

Benefits and harms

Antithrombotics/inhibitors of platelet aggregation versus placebo:

We found no systematic review or RCTs.

Antithrombotics/inhibitors of platelet aggregation versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

Although there is a therapeutic rationale for using antithrombotics and inhibitors of platelet aggregation in some people with secondary Raynaud′s phenomenon — for example in people with systemic sclerosis, a disorder in which platelet activation is well recognised — at present there is no good evidence base for this approach. Further RCTs are needed to establish the role of these drugs for secondary Raynaud's phenomenon.

Substantive changes

Antithrombotics/inhibitors of platelet aggregation New option. No systematic reviews or RCTs identified. Categorised as Unknown effectiveness.

2008; 2008: 1125.
Published online 2008 September 26.

Prostaglandins (oral)

Summary

Oral prostaglandins are unlikely to be beneficial in people with secondary Raynaud's phenomenon.

Benefits and harms

Oral prostaglandins versus placebo:

We found one systematic review (search date 1996, 2 RCTs, 112 people with Raynaud's phenomenon and systemic sclerosis) comparing oral prostaglandins versus placebo. The review included RCTs of people with primary and secondary Raynaud's phenomenon if results from people with secondary Raynaud's phenomenon were reported separately, or if at least 80% of people in the RCT had systemic sclerosis. We found three subsequent RCTs.

Raynaud's attacks

Oral prostaglandins compared with placebo Oral prostaglandins may be no more effective at reducing the severity, duration, and pain of Raynaud's attacks at 6 to 12 months (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptom severity

Systematic review
63 people with Raynaud's phenomenon and systemic sclerosis
Data from 1 RCT
Proportion of people who improved
20/32 (63%) with iloprost (50–150 micrograms twice daily for 10 days)
12/31 (31%) with placebo

OR 2.55
95% CI 0.96 to 6.80
P = 0.06
Not significant

Systematic review
49 people with Raynaud's phenomenon and systemic sclerosis
Data from 1 RCT
Proportion of people who improved
8/16 (50%) with cisaprost (2.5 or 5.0 micrograms three times daily for 10 days)
7/16 (44%) with placebo

OR 1.28
95% CI 0.33 to 5.00
P = 0.7
Not significant

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Proportion of people with >50% improvement in frequency of attacks 5 to 6 weeks
24.8% with iloprost (50 micrograms twice daily)
24.5% with placebo
Absolute numbers not reported

Reported as not significant
P value not reported
Not significant

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Reduction in Raynaud's condition score from baseline
1.32 with iloprost (50 micrograms twice daily)
1.00 with placebo

adjusted mean difference: –0.24
P = 0.323
Not significant

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Proportion of people with >50% reduction in the Raynaud's score 5 to 6 weeks
35% with iloprost (50 micrograms twice daily)
25% with placebo
Absolute numbers not reported

P = 0.043
Effect size not calculatediloprost

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Duration of Raynaud's attacks 5 to 6 weeks
with iloprost (50 micrograms twice daily)
with placebo
Absolute results not reported

Adjusted mean difference: 5.74 mins
P = 0.569
Not significant

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Proportion of people with >50% improvement in duration of attacks
46% with oral iloprost (50 micrograms twice daily)
42% with placebo
Absolute numbers not reported

Reported as not significant
P value not reported
Not significant

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Proportion of people who improved (physician global assessment) 6 weeks
57% with iloprost (50 micrograms twice daily)
64% with iloprost (100 micrograms twice daily)
44% with placebo
Absolute numbers not reported

Reported as not significant
P value not reported
Not significant

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Proportion of people who improved (physician global assessment) 12 weeks
50% with iloprost (100 micrograms twice daily)
50% with iloprost (50 micrograms twice daily)
50% with placebo
Absolute numbers not reported

Significance not assessed

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Patient-assessed Raynaud's condition mean score 5 to 6 weeks
3.0 with iloprost (50 micrograms twice daily)
2.6 with iloprost (100 micrograms twice daily)
3.9 with placebo

Significance not assessed

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Patient-assessed Raynaud's condition % change from baseline 5 to 6 weeks
–29% with iloprost (50 micrograms twice daily)
–47% with iloprost (100 micrograms twice daily)
–14% with placebo

P = 0.07 for among-group difference
Not significant

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Patient-assessed Raynaud's mean condition score 11 to 12 weeks
2.8 with iloprost (50 micrograms twice daily)
1.8 with iloprost (100 micrograms twice daily)
3.7 with placebo

Significance not assessed

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Patient-assessed Raynaud's condition score; % change from baseline 11 to 12 weeks
–38% with iloprost (50 micrograms twice daily)
–60% with iloprost (100 micrograms twice daily)
–15% with placebo

P = 0.007 for among-group difference

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Mean frequency of daily Raynaud's attacks 5 to 6 weeks
2.5 with iloprost (50 micrograms twice daily)
2.9 with iloprost (100 micrograms twice daily)
3 with placebo

Significance not assessed

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Frequency of daily Raynaud's attacks; % change from baseline 5 to 6 weeks
–31% with iloprost (50 micrograms twice daily)
–34% with iloprost (100 micrograms twice daily)
–13% with placebo

P = 0.37 for among-group difference
Not significant

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Mean frequency of daily Raynaud's attacks 11 to 12 weeks
2.1 with iloprost (50 micrograms twice daily)
2.3 with iloprost (100 micrograms twice daily)
3 with placebo

Significance not assessed

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Mean frequency of daily Raynaud's attacks; % change from baseline 11 to 12 weeks
–46% with iloprost (50 micrograms twice daily)
–50% with iloprost (100 micrograms twice daily)
–15% with placebo

P = 0.07 for among-group difference
Not significant

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Mean change in duration of Raynaud's attacks (from baseline) 5 to 6 weeks
From 83 mins to 46 minutes with iloprost (50 micrograms twice daily)
From 95 minutes to 51 minutes with iloprost (100 micrograms twice daily)
From 69 minutes to 81 minutes with placebo

Significance not assessed

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Mean duration of Raynaud's attacks; % change from baseline 5 to 6 weeks
–40% with iloprost (50 micrograms twice daily)
–35% with iloprost (100 micrograms twice daily)
+10% with placebo

P = 0.03 for among-group difference

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Mean change in duration of Raynaud's attacks (from baseline) 11 to 12 weeks
From 83 minutes to 32 minutes with iloprost (50 micrograms twice daily)
From 95 minutes to 27 minutes with iloprost (100 micrograms twice daily)
From 69 minutes to 70 minutes with placebo

Significance not assessed

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Mean duration of Raynaud's attacks; % change from baseline 11 to 12 weeks
–60% with iloprost (50 micrograms twice daily)
–60% with iloprost (100 micrograms twice daily)
–9% with placebo

P = 0.001 for among-group difference

Digital ulceration

Oral prostaglandins compared with placebo Oral prostaglandins seem no more effective at reducing the proportion of people with new digital ulcerations at 5 weeks to 12 months, or the mean time to appearance of digital ulceration (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Digital ulcer status

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Frequency of Raynaud's attacks (digital ulcer status) 5 to 6 weeks
with iloprost (50 micrograms twice daily)
with placebo
Absolute results not reported

Adjusted mean difference: –0.15
P = 0.459
Not significant

RCT
107 people with a history of previous healed digital ulceration New digital ulceration 6 to 12 months
25/52 (48%) with beraprost sodium (60 micrograms three times daily)
30/51 (59%) with placebo

OR 0.65
95% CI 0.3 to 1.4
P = 0.33
Not significant

RCT
107 people with a history of previous healed digital ulceration Mean time to appearance of digital ulceration
160 days with beraprost sodium (60 micrograms three times daily)
105 days with placebo

P = 0.23
Not significant

No data from the following reference on this outcome.

Hand function

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
63 people with Raynaud's phenomenon and systemic sclerosis
Data from 1 RCT
Adverse effects
31/32 (97%) with iloprost (50–150 micrograms twice daily for 10 days)
19/31 (61%) with placebo

OR 8.49
95% CI 2.53 to 28.48
Large effect sizeplacebo

Systematic review
49 people with Raynaud's phenomenon and systemic sclerosis
Data from 1 RCT
Adverse effects
12/16 (75%) with cisaprost (2.5 or 5.0 micrograms three times daily for 10 days)
10/16 (63%) with placebo

OR 1.76
95% CI 0.40 to 7.65
P = 0.5
Not significant

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Headache
67% with iloprost (50 micrograms twice daily)
29% with placebo
Absolute numbers not reported

P <0.0001
Effect size not calculatedplacebo

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Flushing
31% with iloprost (50 micrograms twice daily)
6% with placebo
Absolute numbers not reported

P <0.0001
Effect size not calculatedplacebo

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Nausea
22% with iloprost (50 micrograms twice daily)
11% with placebo
Absolute numbers not reported

P = 0.009
Effect size not calculatedplacebo

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Dizziness
19% with iloprost (50 micrograms twice daily)
9% with placebo
Absolute numbers not reported

P = 0.019
Effect size not calculatedplacebo

RCT
308 people with Raynaud's phenomenon and systemic sclerosis Discontinued treatment
9% with iloprost (50 micrograms twice daily)
5% with placebo
Absolute numbers not reported

Significance not assessed

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Headache
26/33 (79%) with iloprost (50 micrograms twice daily)
30/35 (86%) with iloprost (100 micrograms twice daily)
14/35 (40%) with placebo

P <0.001 for among-group difference

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Flushing
9/33 (27%) with iloprost (50 micrograms twice daily)
16/35 (46%) with iloprost (100 micrograms twice daily)
6/35 (17%) with placebo

P = 0.03 for among-group difference

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Nausea
10/33 (30%) with iloprost (50 micrograms twice daily)
13/35 (37%) with iloprost (100 micrograms twice daily)
1/35 (3%) with placebo

P = 0.001 for among-group difference

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Flu syndrome
3/33 (9%) with iloprost (50 micrograms twice daily)
5/35 (14%) with iloprost (100 micrograms twice daily)
11/35 (31%) with placebo

P = 0.02 for among-group difference

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Trismus
2/33 (6%) with iloprost (50 micrograms twice daily)
6/35 (17%) with iloprost (100 micrograms twice daily)
0/35 (0%) with placebo

P = 0.03 for among-group difference

RCT
3-armed trial
103 people with Raynaud's phenomenon and systemic sclerosis Discontinuing treatment
9/33 (27%) with iloprost (50 micrograms twice daily)
18/35 (51%) with iloprost (100 micrograms twice daily)
2/35 (6%) with placebo

P <0.001 for among-group difference

RCT
107 people with a history of previous healed digital ulceration Adverse effects
42/55 (76%) with beraprost sodium
23/52 (44%) with placebo

P = 0.0008
Effect size not calculatedplacebo

RCT
107 people with a history of previous healed digital ulceration Withdrawals
13/55 (24%) with beraprost sodium
16/52 (31%) with placebo

Significance not assessed

Oral prostaglandins versus other drug treatments covered in this review:

We found no systematic review or RCTs.

Further information on studies

None.

Comment

Clinical guide:

Although one RCT suggested some benefit from oral prostanoid therapy, taken together, the results from all RCTs do not show good evidence of efficacy, and people experienced more adverse events with prostanoids than with placebo. Oral prostaglandins/prostanoids are not generally available for prescription in the UK, Europe, and the US.

Substantive changes

Prostaglandins (oral) New option. One systematic review, which includes two RCTs identified, and three subsequent RCTs identified, comparing various oral prostaglandins (including oral iloprost, oral cisaprost, and oral beraprost sodium) versus placebo. Categorised as Unlikely to be beneficial.

2008; 2008: 1125.
Published online 2008 September 26.

Prostaglandins (intravenous)

Summary

Intravenous iloprost (a prostaglandin) reduces the frequency and severity of attacks compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis.

Intravenous prostaglandins other than iloprost have been less well studied.

Benefits and harms

Intravenous prostaglandins versus placebo:

We found one systematic review (search date 1996, 7 RCTs in total [5 RCTs of intravenous iloprost, 1 RCT of oral iloprost, 1 RCT of oral cisaprost], 332 people with Raynaud's phenomenon and systemic sclerosis). The review included RCTs of people with primary and secondary Raynaud's phenomenon if results from people with secondary Raynaud's phenomenon were reported separately, or if at least 80% of people in the RCT had systemic sclerosis.

Raynaud's attacks

Intravenous prostaglandins compared with placebo Intravenous iloprost may be more effective at reducing the frequency and severity of Raynaud's attacks in people with Raynaud's phenomenon (secondary to systemic sclerosis) (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Frequency of attacks

Systematic review
217 people with Raynaud's phenomenon and systemic sclerosis
4 RCTs in this analysis
Reduction in frequency of attacks
with intravenous iloprost
with placebo
Absolute results not reported

WMD –17.6 attacks
95% CI –19.19 attacks to –15.73 attacks
P <0.0001
Significant statistical heterogeneity among the RCTs, and significance was sensitive to the method of analysis used (fixed or random effects)
One RCT (63 people) in the meta-analysis assessed oral rather than intravenous iloprost
See further information on studies for separate reporting of largest RCT included in meta-analysis
Effect size not calculatedintravenous iloprost
Severity scores

Systematic review
238 people with Raynaud's phenomenon and systemic sclerosis
4 RCTs in this analysis
Reduction in severity scores (measured by Likert scale or visual analogue scale)
with intravenous iloprost
with placebo
Absolute results not reported

WMD –0.69 (units not reported)
95% CI –1.12 to –0.26
P = 0.002
Significant statistical heterogeneity among the RCTs, and significance was sensitive to the method of analysis used (fixed or random effects)
One RCT (63 people) in the meta-analysis assessed oral rather than intravenous iloprost
See further information on studies for separate reporting of largest RCT included in meta-analysis
Effect size not calculatedintravenous iloprost

Digital ulceration

No data from the following reference on this outcome.

Hand function

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
166 people
2 RCTs in this analysis
Adverse effects
72/82 (88%) with intravenous iloprost
29/84 (35%) with placebo

OR 9.44
95% CI 5.05 to 17.67
P <0.0001
Large effect sizeplacebo

Intravenous prostaglandins versus calcium channel blockers:

See option on calcium channel blockers.

Prostaglandins (intravenous) versus glyceryl trinitrate (transdermal), alpha-blockers, naftidrofuryl oxylate, moxisylyte, inositol nicotinate, ACE inhibitors, angiotensin II receptor antagonists, SRIs, endothelin-1 receptor antagonists, phosphodiesterase inhibitors, antithrombotics/inhibitors of platelet aggregation, or prostaglandins (oral):

We found no systematic review or RCTs.

Further information on studies

Of the five RCTs comparing intravenous iloprost versus placebo included in the review, the largest and most robust multicentre double-blind RCT (131 people) found that intravenous iloprost significantly increased the proportion of people who improved at 6 and 9 weeks compared with placebo (measured by physician global assessment, % "improved" or "greatly improved": 6 weeks, 32/61 [52%] with intravenous iloprost v 17/62 [27%] with placebo; P = 0.008; 9 weeks, 39/64 [61%] with intravenous iloprost v 18/67 [27%] with placebo; P <0.001). The RCT found that intravenous iloprost significantly reduced the mean weekly number of Raynaud's attacks at 9 weeks compared with placebo (mean decrease in attack frequency weeks 1–9: 39.1% with intravenous iloprost v 22.2% with placebo; P = 0.005). It also found that intravenous iloprost significantly improved disease severity at 9 weeks compared with placebo (mean decrease in severity measured by Raynaud severity score weeks 1–9: 34.8% with intravenous iloprost v 19.7% with placebo; P = 0.01).

Comment

Clinical guide:

There is some evidence that intravenous iloprost is effective in Raynaud's phenomenon (secondary to systemic sclerosis). Other intravenous prostanoids have been less well studied. This treatment requires hospitalisation and has a role in those people not responding to, or intolerant of, oral treatments.

Substantive changes

Prostaglandins (intravenous) New option. One systematic review identified, which includes five RCTs comparing intravenous prostaglandins versus placebo, and which pools data. Categorised as beneficial.


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