Abstract
Introduction
Raynaud’s phenomenon is an episodic, reversible vasospasm of the peripheral arteries (usually digital). It causes pallor, followed by cyanosis and/or redness, often with pain and, at times, paraesthesia. On rare occasions, it can lead to ulceration of the fingers and toes (and, in some cases, of the ears or nose). This review focuses on primary (idiopathic) Raynaud's phenomenon, occurring in the absence of an underlying disease. The prevalence of primary Raynaud's phenomenon varies by sex, country, and exposure to workplace vibration.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of drug treatments for primary Raynaud’s phenomenon? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2013 (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 9 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: amlodipine, diltiazem, nicardipine, and nifedipine.
Key Points
Raynaud's phenomenon is an episodic, reversible vasospasm of the peripheral arteries (usually digital). It causes pallor, followed by cyanosis and/or redness, often with pain and, at times, paraesthesia. On rare occasions, it can lead to ulceration of the fingers and toes (and, in some cases, of the ears or nose). This review focuses on primary (idiopathic) Raynaud's phenomenon occurring in the absence of an underlying disease.
Prevalence, which varies by sex and country, is around 3% to 5% in most population studies, 80% to 90% of which is primary Raynaud's phenomenon; it is slightly higher in women than in men.
Attacks may last from several minutes to a few hours, and long-term sufferers of initially idiopathic Raynaud's phenomenon can later go on to display features of underlying disorders such as systemic sclerosis.
Nifedipine seems to reduce the frequency and severity of Raynaud's attacks, although it is associated with high rates of adverse effects such as tachycardia, headache, and flushing.
We found no evidence of sufficient quality to judge the effectiveness of amlodipine or diltiazem in treating primary Raynaud's phenomenon.
Nicardipine may successfully treat primary Raynaud's phenomenon, but we found no studies large enough to enable us to draw firm conclusions.
Clinical context
General background
Raynaud’s phenomenon (RP) occurs in 3 to 5% of the population. It is reversible vasospasm of arteries; especially of the digits with pallor and either redness and/or cyanosis RP is divided into primary (no associated underlying cause, i.e. idiopathic, also known as Raynaud’s disease) or secondary RP (associated with an underlying cause such as connective tissue disease). Primary RP often does not need treatment with medication but keeping warm and smoking cessation are recommended despite lack of RCT data. If these measures do not work, drug therapy, such as calcium channel blockers, is considered.
Focus of the review
Calcium channel blockers (mostly of the dihydropyridine type: nifedipine, nicardipine, amlodipine, and less often diltiazem) on an as-needed basis are the mainstay of medical management for primary RP. Other vasodilator classes are rarely used in primary RP. Decision-making regarding which calcium channel blocker to prescribe depends on need for a medication and tolerability and efficacy, where nifedipine is usually the first-line drug treatment. This review looks at the evidence for calcium channel blockers in primary RP.
Comments on evidence
Within the calcium channel blockers group, nifedipine has the largest body of evidence to support its efficacy. The benefit of RP treatment are greater in primary RP (idiopathic) compared to secondary RP as the latter is more difficult to treat due to blood vessel abnormalities that may not be reversible superimposed on vasospasm.
Search and appraisal summary
The update literature search for this review was carried out from the date of the last search, May 2010, to August 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 18 studies. After de-duplication and removal of conference abstracts, 6 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of all 6 studies so none were added at this update.
Additional information
Topical nitrates may be used to treat primary RP, especially if there are side effects related to calcium channel blocker use such as symptomatic hypotension. Topical nitrates are applied to the web spaces between fingers (as prevention or treatment) in a small amount in order to avoid side effects such as hypotension, flushing and headaches. If RP has complications such as digital ulcers or severe ischemia, then secondary causes of RP should be sought. In these rare cases, data from secondary RP trials may be considered although not tested in primary RP such as phosphodiesterase 5 inhibitors and intravenous prostacyclin (iloprost).
About this condition
Definition
Raynaud's phenomenon is an episodic, reversible vasospasm of the peripheral arteries (usually digital). It causes pallor, followed by cyanosis and/or erythema, which can cause pain and, at times, paraesthesia. On rare occasions, it can lead to ulceration of the fingers and toes (and, in some cases, of the ears or nose). Primary or idiopathic Raynaud's phenomenon (Raynaud's disease) occurs without an underlying disease. Secondary Raynaud's phenomenon (Raynaud's syndrome) occurs in association with an underlying disease — usually connective tissue disorders, such as systemic sclerosis (SSc; scleroderma), systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, or polymyositis. This review excludes secondary Raynaud's phenomenon. Diagnosis: The diagnosis of Raynaud's phenomenon is by a history of clearly demarcated pallor of digit(s), followed by at least one other colour change (cyanosis, erythema), which is usually precipitated by cold. A good history, physical examination, and laboratory results can help rule out secondary Raynaud's phenomenon. Review of symptoms or signs for connective tissue disease should be done. Laboratory testing may include full blood count (FBC), ESR, and ANA with pattern if connective tissue diseases are suspected. Magnification of the nail-beds to observe abnormal capillaries is also important in order to rule out Raynaud's phenomenon associated with connective tissue diseases.
Incidence/ Prevalence
The prevalence of primary Raynaud's phenomenon varies by sex, country, and workplace exposure to vibration. One large US cohort study (4182 people) found symptoms in 9.6% of women and 8.1% of men, of whom 81% had primary Raynaud's phenomenon. Smaller cohort studies in Spain have estimated the prevalence of Raynaud's phenomenon to be 3.7% to 4.0%, of which 90% is primary Raynaud's phenomenon. One study in Japan (332 men, 731 women) found symptoms of primary Raynaud's phenomenon in 3.4% of women and 3.0% of men. A study of 12,907 people in the UK reported that 4.6% of people had demarcated finger blanching with cold exposure.
Aetiology/ Risk factors
The cause of primary Raynaud's phenomenon is unknown. There is evidence for genetic predisposition, usually in those with early-onset Raynaud's phenomenon (aged under 40 years). One prospective observational study (424 people with Raynaud's phenomenon) found that 73% of sufferers first developed symptoms before the age of 40 years. Women are at higher risk than men (OR 3.0, 95% CI 1.2 to 7.8, in one US case control study of 235 people). The other known risk factor is occupational exposure to vibration from tools (symptoms developed in about 8% with exposure v 2.7% with no exposure in 2 cohorts from Japan). People who are obese may be at lower risk. Exposure to cold or heightened emotion can worsen symptoms.
Prognosis
Attacks may last from several minutes to a few hours. One systematic review (search date 1996, 10 prospective observational studies, 639 people with primary Raynaud's phenomenon) found that 13% of long-term sufferers later manifested an underlying disorder, such as systemic sclerosis. In a large cohort of patients diagnosed with Raynaud's phenomenon without a known connective tissue disease who were seen in a specialist rheumatology clinic, 13% developed systemic sclerosis over time. Those who progressed to systemic sclerosis had both abnormal dilated capillaries at the nail folds and systemic-sclerosis-specific antibodies. Complications of Raynaud's phenomenon, such as digital ulceration or severe ischaemia, may indicate a secondary cause. In general, complications of primary Raynaud’s phenomenon do not occur. However, some patients without a known underlying cause have complications. They may over time manifest as secondary Raynaud’s phenomenon but are not yet able to be diagnosed. For instance, a small proportion (1%–2%) of people with primary Raynaud’s phenomenon may transition to secondary Raynaud’s phenomenon annually. The latter are likely the patients who have complications of Raynaud’s phenomenon.
Aims of intervention
To reduce the number and severity of attacks; to prevent tissue damage; to minimise adverse effects of treatment.
Outcomes
Raynaud's attacks: including frequency, severity, impact, and duration of symptoms (as assessed by patient diary); severity assessed by visual analogue scales, Likert scales, or the Raynaud's Condition Score; and digital ulceration, including rates, size, and healing. Adverse effects of treatment.
Methods
Clinical Evidence search and appraisal August 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to August 2013, Embase 1980 to August 2013, and The Cochrane Database of Systematic Reviews 2013, issue 2 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against pre-defined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against pre-defined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single-blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required for included studies. We searched for any RCTs comparing included options in the review versus placebo, or versus each other, in people with primary Raynaud's. Many RCTs included people with both primary and secondary Raynaud's phenomenon. We excluded RCTs in which less than 50% of people had primary Raynaud's phenomenon or where the type of Raynaud's was unclear. We also excluded RCTs in which attacks were experimentally induced (e.g., by dipping the hands in cold water) or those that did not assess clinical outcomes. Some RCTs compared changes in symptoms from baseline within each treatment group, rather than directly comparing outcomes between treatment groups. These have been described in the comment sections. We included systematic reviews of RCTs and RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). 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 (primary).
| Important outcomes | Digital ulceration, Raynaud's attacks | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of drug treatments for primary Raynaud's phenomenon? | |||||||||
| 12 (unclear) | Raynaud's attacks | Nifedipine versus placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results, poor crossover methodology, and poor follow-up. Directness point deducted for RCTs that included people with other conditions |
| 2 (94) | Raynaud's attacks | Nicardipine versus placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and poor crossover methodology. Directness point deducted for broad inclusion criteria |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Very low-quality evidence
Any estimate of effect is very uncertain.
Raynaud's phenomenon (secondary)
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.
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