Phosphodiesterase 5 inhibitors (PDE5i) for the treatment of Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon is a vasodilatory phenomenon characterised by digital pallor, cyanosis, and pain of the extremities. Primary Raynaud's phenomenon has no underlying disease associated with it, while secondary Raynaud's phenomenon is associated with connective tissue disorders such as systemic sclerosis. Systemic sclerosis causes fibrosis and commonly affects the skin and internal organs such as the gastrointestinal tract, lungs, kidney, and heart. Phosphodiesterase 5 inhibitors (PDE5i) are a class of drugs that increases blood flow to the extremities and may be beneficial in the treatment of Raynaud's phenomenon. OBJECTIVES: To assess the benefits and harms of PDE5i compared to placebo for the treatment of Raynaud's phenomenon. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial registries up to June 2022. We did not apply any language restrictions. We searched the bibliographies of retrieved articles and contacted key experts in the field for additional and unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing PDE5i to placebo in people with primary and secondary Raynaud's phenomenon. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: This review included nine RCTs which ranged in duration from four to eight weeks and included a total of 411 participants. The majority had Raynaud's phenomenon secondary to systemic sclerosis. Tadalafil was assessed in four studies, sildenafil in three studies, vardenafil in one study, and a new PDE5 inhibitor known as "PF-00489791" in one study. Three studies were parallel design and six studies were cross-over. The frequency of attacks per week was 24 with placebo and PDE5i reduced the frequency of attacks by an average of three attacks per week (mean difference (MD) -3.07, 95% confidence interval (CI) -5.15 to -1.00; 8 studies; low-certainty evidence). The duration of attacks per day was 55 minutes with placebo and PDE5i reduced the duration of attacks by an average of five minutes (MD -5.31, 95% CI -8.90 to -1.71; 8 studies; low-certainty evidence). Very low-certainty evidence from one study with eight participants showed severity of Raynaud's attacks (assessed on a 10 cm visual analogue scale with lower scores indicating less severity) was 20% lower with a PDE5i (3.7 with placebo compared to 1.6 with treatment; MD -2.1, 95% CI -2.7 to 1.4; very low-certainty evidence). Pain and patient global assessment were assessed on a 10 cm visual analogue scale with lower scores indicating improvement. Low-certainty evidence showed that the use of PDE5i may result in little to no difference compared to placebo in reducing the average pain of Raynaud's attacks (3 to 2.9; MD -0.10, 95% CI -0.78 to 0.57; 4 studies). Global scores were 36% lower with the use of a PDE5i compared to placebo (9.2 to 5.6; MD -3.59, 95% CI -4.45 to -2.73; 1 study, 24 participants; low-certainty evidence). The rate of withdrawals during treatment with PDE5i ranged from 4% to 20% compared with 2% in the placebo group in five studies. Four studies reported no withdrawals due to adverse events. Seven studies reported no serious adverse events. The rate of serious adverse events reported in two studies ranged from 2% during treatment to 4% with placebo. The majority of the studies were judged as low or unclear risk of bias for selection, performance, and detection bias. Almost half were judged at high risk of attrition bias and unclear risk for selective reporting bias. We downgraded frequency of attacks, duration of attacks, pain intensity, and patient global assessment for small sample sizes and concerns about inconsistency and graded each as low certainty of evidence. We downgraded severity of attacks to very low certainty due to serious concerns about imprecision and publication bias. We downgraded withdrawals due to adverse events and serious adverse events to moderate certainty of evidence due to a low number of reported events. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, PDE5i may reduce the frequency of attacks of Raynaud's phenomenon by a small amount per week, result in a small reduction in the duration of attack, improve patients' global assessment of their disease, and result in little to no difference in pain. PDE5i probably result in little or no difference in serious adverse events but slightly increase the likelihood of withdrawing from treatment due to an adverse event.

Calcium channel blockers for primary and secondary Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon is a vasospastic disease characterized by digital pallor, cyanosis, and extremity pain. Primary Raynaud's phenomenon is not associated with underlying disease, but secondary Raynaud's phenomenon is associated with connective tissue disorders such as systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. Calcium channel blockers promote vasodilation and are commonly used when drug treatment for Raynaud's phenomenon is required. OBJECTIVES: To assess the benefits and harms of calcium channel blockers (CCBs) versus placebo for treatment of individuals with Raynaud's phenomenon with respect to Raynaud's type (primary vs secondary) and type and dose of CCBs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (May 19, 2017), MEDLINE (1946 to May 19, 2017), Embase (1947 to May 19, 2017), clinicaltrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Portal. We applied no language restrictions. We also searched bibliographies of retrieved articles and contacted key experts for additional and unpublished data. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing calcium channel blockers versus placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and risk of bias and extracted trial data. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: This review contains 38 RCTs (33 cross-over RCTs) with an average duration of 7.4 weeks and 982 participants; however, not all trials reported all outcomes of interest. Nine of the identified trials studied patients with primary Raynaud's phenomenon (N = 365), five studied patients with secondary Raynaud's phenomenon (N = 63), and the rest examined a mixture of patients with primary and secondary Raynaud's phenomenon (N = 554). The most frequently encountered risk of bias types were incomplete outcome data and poor reporting of randomization and allocation methods.When researchers considered both primary and secondary Raynaud's phenomenon, evidence of moderate quality (downgraded for inconsistency) from 23 trials with 528 participants indicates that calcium channel blockers (CCBs) were superior to placebo in reducing the frequency of attacks. CCBs reduced the average number of attacks per week by six ( weighted mean difference (WMD) -6.13, 95% confidence interval (CI) -6.60 to - 5.67; I² = 98%) compared with 13.7 attacks per week with placebo. When review authors excluded Kahan 1985C, a trial showing a very large reduction in the frequency of attacks, data showed that CCBs reduced attack frequency by 2.93 per week (95% CI -3.44 to -2.43; I² = 77%).Low-quality evidence (downgraded for imprecision and inconsistency) from six trials with 69 participants suggests that the average duration of attacks did not differ in a statistically significant or clinically meaningful way between CCBs and placebo (WMD -1.67 minutes, 95% CI -3.29 to 0); this is equivalent to a -9% difference (95% CI -18% to 0%).Moderate-quality evidence (downgraded for inconsistency) based on 16 trials and 415 participants showed that CCBs reduced attack severity by 0.62 cm (95% CI -0.72 to - 0.51) on a 10-cm visual analogue scale (lower scores indicate less severity); this was equivalent to absolute and relative percent reductions of 6% (95% CI -11% to -8%) and 9% (95% CI -11% to -8%), respectively, which may not be clinically meaningful.Improvement in Raynaud's pain (low-quality evidence; downgraded for imprecision and inconsistency) and in disability as measured by a patient global assessment (moderate-quality evidence; downgraded for imprecision) favored CCBs (pain: WMD -1.47 cm, 95% CI -2.21 to -0.74; patient global: WMD -0.37 cm, 95% CI -0.73 to 0, when assessed on a 0 to 10 cm visual analogue scale, with lower scores indicating less pain and less disability). However, these effect estimates were likely underpowered, as they were based on limited numbers of participants, respectively, 62 and 92. For pain assessment, absolute and relative percent improvements were 15% (95% -22% to -7%) and 47% (95% CI -71% to -24%), respectively. For patient global assessment, absolute and relative percent improvements were 4% (95% CI -7% to 0%) and 9% (95% CI -19% to 0%), respectively.Subgroup analyses by Raynaud's type, CCB class, and CCB dose suggest that dihydropyridine CCBs in higher doses may be more effective for primary Raynaud's than for secondary Raynaud's, and CCBs likely have a greater effect in primary than in secondary Raynaud's. However, differences were small and were not found for all outcomes. Dihydropyridine CCBs were studied as they are the subgroup of CCBs that are not cardioselective and are traditionally used in RP treatment whereas other CCBs such as verapamil are not routinely used and diltiazem is not used as first line subtype of CCBs. Most trial data pertained to nifedipine.Withdrawals from studies due to adverse effects were inconclusive owing to a wide CI (risk ratio [RR] 1.30, 95% CI 0.51 to 3.33) from two parallel studies with 63 participants (low-quality evidence downgraded owing to imprecision and a high attrition rate); absolute and relative percent differences in withdrawals were 6% (95% CI -14% to 26%) and 30% (95% CI -49% to 233%), respectively. In cross-over trials, although a meta-analysis was not performed, withdrawals were more common with CCBs than with placebo. The most common side effects were headache, dizziness, nausea, palpitations, and ankle edema. However, in all trials, no serious adverse events (death or hospitalization) were reported. AUTHORS' CONCLUSIONS: Randomized controlled trials with evidence of low to moderate quality showed that CCBs (especially the dihydropyridine class) may be useful in reducing the frequency, duration, severity of attacks, pain and disability associated with Raynaud's phenomenon. Higher doses may be more effective than lower doses and these CCBs may be more effective in primary RP. Although there were more withdrawals due to adverse events in the treatment groups, no serious adverse events were reported.