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Review
. 2023 Nov 6;11(11):CD014089.
doi: 10.1002/14651858.CD014089.

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

Nancy Maltez  1 , Lara J Maxwell  2 , Fadumo Rirash  3 , Elizabeth Tanjong Ghogomu  4 , Sarah E Harding  5 , Paul C Tingey  3 , George A Wells  6 , Peter Tugwell  7 , Janet Pope  8
Affiliations
Review

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

Nancy Maltez et al. Cochrane Database Syst Rev. .

Abstract

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 We searched the bibliographies of retrieved articles and contacted key experts in the field for additional and unpublished data.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 2% to 20% compared with 2% to 4% 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 ranFged 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.

Trial registration: ClinicalTrials.gov NCT01117298 NCT01347008 NCT00822354 NCT02050360.

PubMed Disclaimer

Conflict of interest statement

PT: Independent Contractor/Consultant for Data And Safety Monitoring Board, Reformulary Group, Outcome Measures in Rheumatology (OMERACT).

GAW: University of Ottawa (Employment)

JP, NM, LJM, EG, SEH, PCT, FR: none known

Figures

1
1
PRISMA study flow diagram; CT=clinicaltrials.gov; ICTRP=International Clinical Trials Registry Platform
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: PDE5i vs placebo, Outcome 1: Frequency of attacks (average per week)
1.2
1.2. Analysis
Comparison 1: PDE5i vs placebo, Outcome 2: Duration of attacks (average attack duration, minutes)
1.3
1.3. Analysis
Comparison 1: PDE5i vs placebo, Outcome 3: Severity of attacks (0 to 10 VAS)
1.4
1.4. Analysis
Comparison 1: PDE5i vs placebo, Outcome 4: Pain (0 to 10 VAS)
1.5
1.5. Analysis
Comparison 1: PDE5i vs placebo, Outcome 5: Patient global assessment
1.6
1.6. Analysis
Comparison 1: PDE5i vs placebo, Outcome 6: Function
1.7
1.7. Analysis
Comparison 1: PDE5i vs placebo, Outcome 7: Raynaud's Condition Score
1.8
1.8. Analysis
Comparison 1: PDE5i vs placebo, Outcome 8: Physician global assessment
1.9
1.9. Analysis
Comparison 1: PDE5i vs placebo, Outcome 9: Number of people with healed digital ulcers
1.10
1.10. Analysis
Comparison 1: PDE5i vs placebo, Outcome 10: Number of people with new digital ulcers
1.11
1.11. Analysis
Comparison 1: PDE5i vs placebo, Outcome 11: Adverse effects
2.1
2.1. Analysis
Comparison 2: Subgroup: primary and secondary Raynaud's phenomenon, Outcome 1: Frequency of attacks (average per week)
2.2
2.2. Analysis
Comparison 2: Subgroup: primary and secondary Raynaud's phenomenon, Outcome 2: Duration of attacks (average attack duration, minutes)
3.1
3.1. Analysis
Comparison 3: Subgroup: PDE5i inhibitor type, Outcome 1: Frequency of attacks (average per week)
3.2
3.2. Analysis
Comparison 3: Subgroup: PDE5i inhibitor type, Outcome 2: Duration of attacks (minutes)
4.1
4.1. Analysis
Comparison 4: Subgroup: sildenafil dosing regimen, Outcome 1: Frequency of attacks (average per week)
4.2
4.2. Analysis
Comparison 4: Subgroup: sildenafil dosing regimen, Outcome 2: Duration of attacks (average attack duration, minutes)
5.1
5.1. Analysis
Comparison 5: Subgroup: trial design, Outcome 1: Frequency of attacks (average per week)
5.2
5.2. Analysis
Comparison 5: Subgroup: trial design, Outcome 2: Duration of attacks (average attack duration, minutes)
6.1
6.1. Analysis
Comparison 6: Sensitivity analysis: PDE5i vs placebo (major outcomes), Outcome 1: Frequency of attacks (average per week)
6.2
6.2. Analysis
Comparison 6: Sensitivity analysis: PDE5i vs placebo (major outcomes), Outcome 2: Duration of attacks (average attack duration, minutes)
6.3
6.3. Analysis
Comparison 6: Sensitivity analysis: PDE5i vs placebo (major outcomes), Outcome 3: Severity of attacks (0 to 10 VAS)
6.4
6.4. Analysis
Comparison 6: Sensitivity analysis: PDE5i vs placebo (major outcomes), Outcome 4: Pain (0 to 10 VAS)
6.5
6.5. Analysis
Comparison 6: Sensitivity analysis: PDE5i vs placebo (major outcomes), Outcome 5: Patient global assessment
See this image and copyright information in PMC

References

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References to other published versions of this review

Rirash 2021
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