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(Circulation. 2005;112:2980-2985.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Sildenafil in the Treatment of Raynaud’s Phenomenon Resistant to Vasodilatory Therapy

Roland Fries, MD; Kaveh Shariat, MD; Hubertus von Wilmowsky, MD; Michael Böhm, MD

From Klinik für Innere Medizin III (Kardiologie, Angiologie, Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Homburg/Saar (R.F., K.S., M.B.), and Klinik für Rheumatologie, Knappschaftskrankenhaus, Püttlingen (H.v.W.), Germany.

Correspondence to Priv-Doz Dr Roland Fries, Gotthard-Schettler-Klinik, Prof-Kurt-Sauer Str 4, 76669 Bad Schönborn, Germany. (E-mail r.fries{at}gotthard-schettler-klinik.de), or to Prof Dr M. Böhm, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany (E-mail michael.boehm@uniklinikum-saarland.de).

Received November 23, 2004; revision received June 14, 2005; accepted July 12, 2005.

	Abstract

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Background— Vasodilatory therapy of Raynaud’s phenomenon represents a difficult clinical problem because treatment often remains inefficient and may be not tolerated because of side effects.

Methods and Results— To investigate the effects of sildenafil on symptoms and capillary perfusion in patients with Raynaud’s phenomenon, we performed a double-blinded, placebo-controlled, fixed-dose, crossover study in 16 patients with symptomatic secondary Raynaud’s phenomenon resistant to vasodilatory therapy. Patients were treated with 50 mg sildenafil or placebo twice daily for 4 weeks. Symptoms were assessed by diary cards including a 10-point Raynaud’s Condition Score. Capillary flow velocity was measured in digital nailfold capillaries by means of a laser Doppler anemometer. While taking sildenafil, the mean frequency of Raynaud attacks was significantly lower (35±14 versus 52±18, P=0.0064), the cumulative attack duration was significantly shorter (581±133 versus 1046±245 minutes, P=0.0038), and the mean Raynaud’s Condition Score was significantly lower (2.2±0.4 versus 3.0±0.5, P=0.0386). Capillary blood flow velocity increased in each individual patient, and the mean capillary flow velocity of all patients more than quadrupled after treatment with sildenafil (0.53±0.09 versus 0.13±0.02 mm/s, P=0.0004). Two patients reported side effects leading to discontinuation of the study drug.

Conclusions— Sildenafil is an effective and well-tolerated treatment in patients with Raynaud’s phenomenon.

Key Words: microcirculation • capillaries • drugs • blood flow • nitric oxide

	Introduction

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Raynaud’s phenomenon describes temperature-sensitive, digital vasospasms leading to pale and consecutively cyanotic skin mostly limited to the digits, occurring in 3% to 5% in the general population.^1,2 Besides the uncomplicated primary Raynaud’s phenomenon, the secondary form occurring in connective tissue disease presents more severely, with potentially disabling ulceration or tissue necrosis.³ Nonpharmacological therapy includes avoidance of cold temperatures, emotional stress, and smoking. Pharmacological therapy with vasodilators such as calcium channel blockers, ₁-adrenergic receptor blockers, or angiotensin II receptor antagonists and other agents has been used.³ Effects of treatments, however, are often disappointing and inefficient. Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase type 5. Besides its established effect in erectile dysfunction,^4,5 sildenafil provides cGMP-dependent microvascular and macrovascular dilation. Consistently, sildenafil has been successfully used in nonerectile indications such as primary⁶ and secondary pulmonary hypertension.^7–10 We performed a placebo-controlled, double-blinded, crossover evaluation of the efficacy of sildenafil on capillary blood flow velocity and vasospastic symptoms in patients with therapy-resistant Raynaud’s phenomenon.

Editorial p 2894

	Methods

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Study Patients
We initially recruited 20 patients with Raynaud’s phenomenon resistant to vasodilatory therapy and studied 18 of them after 2 patients discontinued use of the study medication because of side effects. Sixteen patients had a secondary Raynaud’s phenomenon and 2 patients had a primary Raynaud’s phenomenon. Inclusion criteria were (1) regular occurrence of painful Raynaud attacks and (2) resistance to conventional vasodilatory treatment with at least 2 agents. All patients provided written informed consent, and the study protocol was approved by the institutional ethics committee at the University of Saarland. Clinical characteristics of the patients are shown in the Table. Patients had been recruited during the 6 preceding months, and underlying disease was diagnosed by the referring rheumatologists following standard criteria. Six patients with secondary Raynaud’s phenomenon had chronic digital ulcerations.

View this table: [in this window] [in a new window]   Clinical Characteristics of Patients With Raynaud’s Phenomenon Treated With Sildenafil and Placebo

Study Protocol
In this double-blinded, placebo-controlled, fixed-dose, crossover study, patients were randomly assigned to take placebo or 50 mg of sildenafil twice daily for 4 weeks. According to the half-life of sildenafil (about 4 hours), we choose a washout period of 1 week, after which patients were switched to the other therapy (Figure 1). We planed a priori to include 20 patients. All other vasodilatory agents were stopped before the trial, and concomitant medication for treatment of rheumatic disease remained unchanged during the whole study. The primary outcome variables were frequency and duration of Raynaud attacks, capillary flow velocity detected by nailfold capillary microscopy using a laser Doppler anemometer, and evolution of trophic digital lesions. Doctor’s samples of sildenafil provided by Pfizer, Inc, to individual physicians at our institution were collected, and the hospital’s pharmacist performed blinding and encapsulation of the tablets. Study started in June, 2003, and was finished in September, 2003.

View larger version (15K): [in this window] [in a new window]   Figure 1. Study design. R indicates randomization; NCM, nailfold capillary microscopy.

Clinical Evaluation
Symptoms of Raynaud’s phenomenon were assessed by diary cards. When an attack occurred, patients immediately recorded the event and its duration in the diary. At the end of each day, patients gave an overall estimation of the last 24 hours, using a 10-point Raynaud’s Condition Score (0 points = subject felt not handicapped by Raynaud attacks; 10 points = subject felt extremely handicapped) validated as described elsewhere.¹¹

Microvascular Function
Before the treatment and at the end of each 4-week treatment interval, nailfold capillary microscopy was performed and capillary flow velocity was detected with the use of a laser Doppler anemometer (CAM 1 Laser Anemometer, KK-Technology, Bridleways). This system uses a 1.5-mW, 780-nm laser diode focused to an elliptical spot of 5x10 µm. Under control of a Charge Coupled Device (CCD) camera (Model ST-50CE, Sony) the laser beam can be positioned on a single capillary. The laser radiation is reflected with a Doppler shift generating an electrical current in a photodetector. Amplification and processing of the current results in detection of the actual Doppler shift frequency that allows calculation of blood cell velocity. An acoustic control of the Doppler shift provides exact positioning of the laser beam during the whole measurement. The method is described in detail elsewhere.¹² It contrast to other methods for evaluation of microvascular flow velocity, this technique provides precisely localized measurements in defined vessels and was therefore chosen to be used in this study.

In each patient, 3 capillaries suitable for flow measurements were identified. All flow measurements were performed after 30 minutes of acclimatization in a quiet, air-conditioned room (comfortably tempered at 22°C) at the same time of day (4 PM to 6 PM), with the patient in sitting position. Under control of an infrared thermometer, the skin of the tested hand was heated to a constant level of 37°C by means of an infrared lamp and a controllable heating pad. This procedure was chosen to increase capillary flow velocity and to minimize episodes of physiological capillary blood stasis, which may occur frequently and last long in patients with Raynaud’s phenomenon. Blood cell velocity was measured continuously for 7 minutes in the same 3 capillaries in each patient at any one time. Normal capillaries of comparable width were chosen (10 to 15 µm), and individual capillaries were relocated, following their characteristic form and environment by comparing photographs taken during the first measurement. The CAM-1 Laser anemometer system computes mean maximum, minimum, and average flow velocity in Doppler flow recordings of up to 20 minutes. Incorrect positioning of the laser beam caused by accidental patient movements were indicated by a fading sound of the Doppler shift and were marked on the recording. The beginning and end of the corresponding time intervals were later precisely assigned offline and were not considered in the calculation of flow velocity. The mean capillary blood cell velocity was assessed as the average of the mean flow velocities in the 3 measured capillaries.

Statistical Analysis
The symptom variables (number and cumulative duration of Raynaud attacks, Raynaud’s Condition Score), capillary flow velocity measurements, blood pressure, and heart rate measurements are shown as mean±SEM values. Values recorded during sildenafil treatment were compared with those during placebo by Wilcoxon signed rank test. Differences were considered significant when probability values were less than 0.05. The treatment effect of patients who received sildenafil first and then placebo was compared with the treatment effect of those who received placebo first by a Mann-Whitney U test.

	Results

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Sildenafil Effect on Symptoms
Seventeen patients (94%) correctly completed their diary cards. One patient reported only daily Raynaud’s Condition Scores. Figure 2 shows the mean number and cumulative duration of Raynaud attacks in each 4-week treatment period and the mean daily Raynaud’s Condition Score during treatment with placebo and sildenafil in the 16 patients with secondary Raynaud’s phenomenon. The frequency of Raynaud attacks was significantly lower (35±14 versus 52±18, P=0.0064) and the cumulative attack duration significantly shorter (581±133 versus 1046±245 minutes, P=0.0038) while patients were taking sildenafil. Accordingly, the Raynaud’s Condition Score during placebo treatment was significantly higher (3.0±0.5 versus 2.2±0.4, P=0.0386) (Figure 2). Treatment effect on clinical symptoms was comparable in patients who received sildenafil first and in those who received placebo first (P=0.2 for the mean frequency of Raynaud attacks, P=0.16 for the cumulative attack duration, and P=0.19 for the percentage of change in Raynaud’s Condition Score).

View larger version (32K): [in this window] [in a new window]   Figure 2. Symptoms of the 16 study patients with secondary Raynaud’s phenomenon while taking sildenafil and placebo.

In all 6 patients with secondary Raynaud’s phenomenon who had chronic digital ulcerations, trophic lesions began to clearly visibly heal during treatment with sildenafil (Figure 3). In 2 patients, ulcerations completely disappeared. Ulcerations reappeared or progressed again after treatment with sildenafil was stopped. By contrast, healing of ulceration did not occur during treatment with placebo.

View larger version (75K): [in this window] [in a new window]   Figure 3. Example of ulcerations before (left) and after 4 weeks of treatment with sildenafil (right).

Clinical symptoms improved as well in the 2 patients with primary Raynaud’s phenomenon: Mean frequency of Raynaud attacks was 5±0.5 (sildenafil) versus 19±18 (placebo), cumulative attack duration was 125±15 (sildenafil) versus 848±833 (placebo), and Raynaud’s Condition Score was 0.4±0.2 (sildenafil) versus 0.8±0.8 (placebo).

Sildenafil Effect on Capillary Perfusion
Figure 4 shows nailfold capillaries in a patient with mixed connective tissue disease (Figure 4A) and a typical original recording of laser Doppler detected flow velocity after treatment with placebo (Figure 4B) and sildenafil (Figure 4C) in the same capillary. Figure 5 shows mean capillary flow velocity in the 16 patients with secondary Raynaud’s phenomenon. Capillary blood flow velocity was significantly higher after treatment with sildenafil in each individual patient independent of the randomization order, and mean capillary flow velocity increased significantly after treatment with sildenafil but not with placebo (Figure 5A and 5B). In patients treated with placebo first, mean capillary flow velocity did not increase while treated with placebo (0.14±0.03 versus 0.21±0.05 mm/s) but did increase significantly after administration of sildenafil (0.60±0.13 P=0.0077) (Figure 5A). In patients treated with sildenafil first, mean capillary flow velocity increased from 0.13±0.03 to 0.44±0.10 mm/s (P=0.018) and declined to the baseline level again (0.12±0.03 P=0.018) after administration of placebo (Figure 5B). Altogether, mean capillary blood flow velocity increased by more than 400% during sildenafil treatment, from 0.13±0.02 mm/s to 0.53±0.09 mm/s (P=0.0004; Figure 5C). Treatment effect on mean capillary flow velocity was comparable in patients who received sildenafil first and in those who received placebo first (P=0.37). In the 2 patients with primary Raynaud’s phenomenon, mean capillary flow velocity improved from 0.2±0.1 mm/s (placebo) to 0.9±0.4 mm/s (sildenafil).

View larger version (94K): [in this window] [in a new window]   Figure 4. Nailfold capillaries in 250-fold magnification. A, + indicates focus of laser Doppler beside a greatly enlarged capillary. Laser Doppler flow velocity after treatment with placebo (B) and sildenafil (C) measured in a capillary of normal shape and width (not shown) in the same patient.

View larger version (26K): [in this window] [in a new window]   Figure 5. Individual laser Doppler flow velocity (average of mean flow velocity in 3 capillaries during 7 minutes in each patient) at baseline, after 4 weeks of treatment with placebo, and sildenafil in patients with secondary Raynaud’s phenomenon treated with placebo first (A) or sildenafil first (B) and mean capillary flow velocity in all 16 patients with secondary Raynaud’s phenomenon (C).

All patients reported that they were certain whether they were receiving sildenafil or placebo. After breaking the code, it was noticed that all patients had been right. At the end of the study, 16 patients (89%) asked for continuation of the sildenafil treatment on the basis of an off-label prescription.

Adverse Effects
One of 20 patients initially included in the study stopped taking sildenafil because of treatment-related headache. Another patient discontinued treatment because of muscle pain in the legs. Later, this patient asked for open-label treatment with sildenafil because of symptom relapse and reported no more adverse effects. Because of the small sample size, both patients were not considered in the analysis of symptoms and capillary flow velocity as an intention to treat. One patient reported transient swelling of the nasal mucosa, 3 patients reported mild, transient headache, 3 patients reported transient facial sensation of heat, 2 patients reported mild nausea after taking the first capsules of sildenafil, and another patient reported transient dizziness. During placebo treatment, no side effects occurred. There was no significant effect of sildenafil on blood pressure and heart rate (Figure 6).

View larger version (29K): [in this window] [in a new window]   Figure 6. Blood pressure (BP) and heart rate during treatment with placebo and sildenafil in the study patients (n=18). bpm indicates beats per minute.

	Discussion

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This study demonstrates that sildenafil significantly improves microcirculation in patients with Raynaud’s phenomenon resistant to therapy with vasodilators. After administration of 50 mg sildenafil twice daily during 4 weeks, mean capillary blood cell velocity more than quadrupled in patients with secondary Raynaud’s phenomenon. Corresponding to this, occurrence and duration of symptoms of Raynaud’s phenomenon decreased considerably, thus leading to significantly better well-being of the patients. These results confirm recent case reports on successful occasional use of sildenafil in patients with Raynaud’s phenomenon.^10,13

Raynaud’s phenomenon occurs as the result of vasoconstriction of the digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts, causing digital ischemia. Nitric oxide (NO) derived from the vascular endothelium plays an important role in the regulation of peripheral vasomotor tone¹⁴ and has been shown to be involved in initiation and maintenance of penile erection.¹⁵ NO activates guanylate cyclase, which results in an increase of cGMP. cGMP is hydrolyzed by phosphodiesterases (PDEs), in particular by the cGMP-specific PDE-5 isoenzyme. Sildenafil is a highly selective and potent inhibitor of PDE-5, that elevates cGMP, resulting in enhanced vasorelaxation. Furthermore, the NO/cGMP pathway resists -mediated vasoconstriction, which may intensify its vasorelaxing properties.¹⁶ Sildenafil has been shown to be effective in the treatment for erectile dysfunction.^4,5 Its effect is not limited to the corpus cavernosum, however, as PDE-5 exists in many other tissues. Therefore, sildenafil acts in various different disorders. It reduces, for example, pulmonary and systemic pressure,^6–10,17 relaxes saphenous veins and pectoral arteries,¹⁸ and increases flow-mediated forearm circulation in patients with chronic heart failure,¹⁹ type 2 diabetes,²⁰ and coronary artery disease.²¹

The effects of sildenafil on microvascular disorders such as Raynaud’s phenomenon have not been subject of controlled studies. In the present study, capillary blood flow was severely impaired and sometimes hardly detectable in patients with Raynaud’s phenomenon. Sildenafil led to a >400% increase of flow velocity. As capillaries have no smooth muscle cells, capillary flow velocity depends mainly on the vasomotor tone in the arterioles. Relaxation of the arterioles results in better capillary filling pressure and higher capillary blood cell velocity. Besides these effects on vascular function, sildenafil-associated inhibition of platelet activation, as reported recently,^21,22 could have contributed to the improvement of microcirculation and symptoms of Raynaud’s phenomenon. Furthermore, central effects, for example, improvement of cardiac output and/or oxygenation, might have played a role.

One might argue the short half-life of sildenafil (about 4 hours) would limit its clinical use. Our data on capillary blood flow velocity, however, as well as the marked reduction of symptoms, are in favor of prolonged functional effects exceeding the plasma half-life of sildenafil. This is supported by recent findings that demonstrate improvement of flow-mediated brachial artery dilation 24 hours after the last dose of sildenafil.²⁰ After statements of our patients, they perceived the impact on digital microcirculation continued about 2 weeks after sildenafil treatment was been stopped. Nevertheless, treatment effect on clinical symptoms and capillary flow velocity was not dependent on randomization order, indicating that the washout period was sufficiently long. The fact that all patients correctly identified if they were on treatment with sildenafil or placebo certainly limited blinding of the study and might have influenced patient statements in their daily questionnaires. This might also be the reason why no side effects were reported during placebo treatment. However, corresponding improvement of capillary flow velocity has been objectified by blood flow measurements and partial healing of digital ulcera.

Although only patients with severe Raynaud’s phenomenon were included in the study, symptoms remained overall relatively low. This is explained by the fact that the study was performed during summer 2003, which was characterized by a stable and extraordinary warm climate in middle Europe. One might object that symptom scores during therapy with sildenafil and placebo may not be comparable without temperature and activity control. However, such control cannot be performed in every day life. Considering the stable meteorologic conditions during the study period, it is very unlikely that significant improvement of Raynaud’s Condition Score was caused by differences in ambient temperature.

One can assume that sildenafil may be well tolerated in most patients with Raynaud’s phenomenon. In this study, only 2 patients interrupted therapy with sildenafil because of treatment-related symptoms, and one of them restarted therapy later without side effects.

Overall, our results demonstrate for the first time in a randomized study the efficacy of treatment with sildenafil on microcirculation and symptoms in patients with therapy-resistant Raynaud’s phenomenon. PDE-5 inhibition appears to be a promising new approach in patients with microcirculatory disorders.

	Acknowledgments

 
The acquisition of the laser Doppler anemometer used in this study was supported by the Saarland-SPORTTOTO GmbH (Saarbrücken, Germany), a state-owned lottery without any involvement in medical affairs.

Disclosure

Dr Böhm served as a consultant for and speaker to Pfizer, Boehringer Ingelheim, Aventis, Astra Zeneca, Servier, and Bayer AG.

	References

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