Topical 10 % Nifedipine Versus 5% Sildenafil in Secondary Raynaud
Condition: Raynaud Phenomenon Due to Trauma; Raynaud Disease; System; Sclerosis; Lupus Erythematosus, Systemic; Dermatomyositis; Ultrasound Therapy; Complications
MeSH terms: Dermatomyositis; Raynaud Disease; Lupus Erythematosus, Systemic; Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Objective: To compare the efficacy of topical 10% nifedipine versus 5% sildenafil in patients
      with secondary Raynaud's phenomenon (RP).

      Methods: A randomized, double-blind, placebo-controlled pilot study took place in 10 patients
      with secondary RP. Topical 10% nifedipine on one hand and 5% sildenafil on the other hand
      were applied. The thumbs didn't receive any cream and served as a control group. The primary
      outcome was the improvement of blood flow and vessel diameter of the digital arteries
      measured by high frequency color Doppler ultrasound before and 1 hour after treatment.
    

Detailed description: 
      Raynaud's phenomenon (RP) is an exaggerated vascular response characterized by at least
      biphasic change (pallor and cyanosis) in the skin color of the digits, induced by cold
      temperature or emotional stress, The prevalence varies from 3 to 5%. In primary RP, there is
      no evidence of a secondary cause and patients have a younger age at onset (between 15 and 30
      years), whereas in secondary RP, patients are older and have a connective tissue diseases
      (CTD), such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), dermatomyositis
      (DM), Sjögren's syndrome and rheumatoid arthritis. In secondary RP there are endothelial
      dysfunction and intimal fibrosis that compromise capillary blood flow. The treatment includes
      maintaining warmth of the whole body, smoking cessation and avoiding cold exposure,
      sympathomimetic medications and emotional stress. When these measures fail, the first line
      drugs are calcium-channel blockers (CCBs), eg. nifedipine. If CCBs are ineffective or not
      tolerated, a phosphodiesterase type 5 inhibitor (PDE-5), eg. sildenafil, or a topical nitrate
      should be used alone or in combination with CCBs. Other drugs includes serotonin reuptake
      inhibitors, angiotensin receptor blockers and prostaglandins. Unfortunately, secondary RP in
      patients with CTD most often is refractory to standard therapies, becoming a therapeutic
      challenge for clinicians. Based on the pathophysiology, topical vasodilators may act as an
      adjuvant therapy. Several randomized trials have demonstrated the benefit of various forms of
      topical nitrates (eg. nitroglycerin). In relation to other topical agents, solid evidence is
      lacking. Color Doppler ultrasound is a noninvasive imaging method that allows observation
      with good definition of skin and deep planes, including vascularization in real time.

      The aim of this study is to compare the efficacy of topical 10% nifedipine versus 5%
      sildenafil in patients with secondary RP using high-frequency color Doppler ultrasound
      Patients The inclusion criteria considered patients with secondary RP associated with a CTD
      diagnosed and under follow-up in the Department of Dermatology. Diagnosis of CTD was made
      according to the ACR classification criteria for SSc, the Mixed Connective Tissue Disease
      criteria proposed by Kasukawa et al, the Bohan and Peter DM criteria and the SLICC SLE
      criteria. The exclusion criteria were primary RP patients; concurrent infection of any digit;
      allergic reaction and current use of any CCB or PDE-5 inhibitor;, , pregnancy, hypo and
      hypertension, history of myocardial infarction, stroke, or life-threatening arrhythmia. All
      patients signed a written informed consent. The Ethics Committee of Pontificia Universidad
      Católica de Chile approved the study protocol.

      Study design This prospective study was conducted in August 2016 (winter). After screening,
      patients who were being treated with a vasodilator were required to discontinue it for at
      least 24 hours before randomization. All patients were receiving immunosuppressive treatment
      for their underlying disease. Patient hands (right versus left) were randomized to treatment
      with topical sildenafil or nifedipine cream. The thumbs of both hands didn't receive any
      cream so that each subject served as her own control. Subjects were instructed to apply 5
      grams of 10% nifedipine cream in one hand and 5 grams of 5% sildenafil cream to the opposite
      hand. Vinyl gloves were supplied to improve the absorption of the cream into the hand,
      leaving the thumb of both hands out of the glove without any cream.

      Clinical assessments The temperature of the examination room was set at 19ºC (66ºF) for ≥ 30
      min and all patients underwent a high-frequency color Doppler ultrasound examination before
      and 1 hour after the topical treatments. The same radiologist with extensive experience in
      dermatologic ultrasound, performed all sonographic examinations. The radiologist was blinded
      to the clinical data of the study and the senior dermatologist in charge of the supervision
      of the application of the topical treatments was blinded to the color Doppler ultrasound
      results. The ultrasound equipment was a Logic E9 XD Clear working with a high frequency
      (upper range 18 MHz) compact linear probe (General Electric Health Systems, Waukesha, WI).
      The ultrasound protocol included grey scale, color Doppler and spectral curve analysis of the
      arterial flow using the settings of the machine for studying skin and superficial structures.
      The ultrasound device automatically provided the values. The primary outcome was the
      improvement of blood flow in the digital arteries. For Doppler sonography, peak systolic
      velocity (PSV, cm/sec) and diameter (mm) were measured at the palmar proper digital (PPD)
      arteries (proximal phalanx level) of radial aspect of the index, middle and thumb fingers of
      both hands. Also, PSV and diameter were measured at the dorsal (PD) arterial arch of the
      proximal nail fold of the index, middle and thumb fingers of both hands. Immediate and late
      adverse effects were monitored in all patients until 3 months after the study.

      Statistical analysis PSV of the PPD artery and PD arterial arch of the index and middle
      fingers were added for a total PSV. The diameter of the PPD artery and PD arterial arch of
      the index and middle fingers were added for a total diameter. Due to the low velocity ranges,
      the values of peak systolic velocities in cm/sec were transformed into mm/sec. Treatment
      efficacy was assessed by using the differences in digital artery blood flows (total PSV) and
      diameters (total diameter) at baseline (time [t] = 0) and after 60 minutes (t = 60).
      Difference in digital artery blood flow and the digital artery diameter was defined as (t =
      0) minus (t = 60); thus, the efficacy of the treatment was reflected by a negative
      difference. In all cases, mean differences less than zero indicates that the study drug cream
      was effective; mean differences greater than or equal to zero indicates that the study drug
      cream was ineffective. The Wilcoxon signed-rank tests and paired t-tests were used to assess
      the changes in outcomes within the group before and after treatment as appropriate. All tests
      were performed using two-tailed probabilities and p ≤ 0.05 was considered statistically
      significant.
    

Intervention name(s): 10% nifedipine cream; 5% sildenafil cream
Intervention type(s): Drug; Drug
Intervention description(s): Topical treatment for Raynaud; Topical treatment for Raynaud
Other intervention name(s): Topical treatment for Raynaud; Topical treatment for Raynaud
Intervention MeSH terms: Nifedipine; Sildenafil Citrate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Raynaud Phenomena; System; Sclerosis; Lupus Erythematosus, Systemic; Ultrasound; sildenafil; Nifedipine