PDE5 Inhibition: New Drug for Raynaud Disease?

Abstract & Commentary

By Allan J. Wilke, MD, Residency Program Director, Associate Professor of Family Medicine, University of Alabama at Birmingham School of Medicine—Huntsville Regional Medical Campus. Dr. Wilke reports no financial relationship to this field of study.

Synopsis: Add vardenafil to the list of phosphodiesterase type 5 inhibitors with promise in the treatment of Raynaud disease.

Source: Caglayan E, et al. Phosphodiesterase type 5 inhibition is a novel therapeutic option in Raynaud disease. Arch Intern Med. 2006;166:231-233.

In an open-label pilot study, 40 patients (37 women) with Raynaud disease (RD) took vardenafil (Levitra®) 10 mg twice daily for 2 weeks. Their average age was 49 years. Twelve of them smoked cigarettes, but all abstained from smoking for at least 12 hours before testing. Seven had primary RD (no history or signs of a connective tissue disease, normal nail fold capillaries, and no autoantibodies). All calcium channel blockers, nitrates, and any other vasodilators were discontinued for at least one week before inclusion into the study. Primary outcomes were: blood flow in the index finger at 24°C and at 4°C ("cold exposure test" [CET]) one hour after taking the first dose and repeated after 2 weeks of treatment; nail fold capillary microscopy; the Raynaud condition score (RCS) that measures frequency, total daily duration, and severity of RD attacks; and the patient's daily impression of difficulty with RD on a 0 (no difficulty) to 10 (very severe) scale.

Statistically significant blood flow improvement was demonstrated at 1 hour and at 2 weeks at both temperatures. The most dramatic improvement was noted during the CET. There was no change in capillary microscopy, as expected. At baseline the average RCS was 5.05; at 2 weeks it had dropped to 3.54, which was also statistically significant. Patients experienced a modest reduction in blood pressure, but no serious adverse events were noted. Side effects commonly associated with phosphodiesterase type 5 (DPE5) inhibitors (headache, flushing, dyspepsia, rhinorrhea, and visual abnormalities) occurred in a minority of patients.

Commentary

Raynaud disease (also termed Raynaud's phenomenon) has a prevalence of 3 to 5% (up to 30% in young women). It is primary when there are no signs or symptoms of a systemic connective tissue disease, such as scleroderma or lupus erythematosus. Classically, it appears as discoloration of the fingers or toes in the white, then blue, then red pattern over time, accompanied by pain or numbness. One patient in eight with primary RD will eventually develop an inflammatory rheumatic disease.1 Women are 3 to 5 times more frequently affected than men. Management involves avoidance of cold temperatures, tobacco smoke, and vasoconstrictors, and use of calcium channel blockers (eg, nifedipine) and sympathetic nervous system inhibitors (eg, prazosin). Angiotensin II, serotonin, and thromboxane A2 have been implicated in some cases of RD, and losarten,2 fluoxetine,3 and low-dose aspirin have also been studied and prescribed. Cyclic intravenous iloprost (another vasodilator) was efficacious in the treatment of Raynaud's phenomenon in patients with systemic sclerosis and led to a marked improvement in the quality of life.4

We've all seen the movie where the classically trained pianist journeys to the big city to seek fame and fortune, only to be disappointed and ending up playing honky tonks. Then, one night, the impresario wanders in, listens as the pianist plays Chopin's Polonaise in A-flat Major, Op. 53, and exclaims, "Hey, this kid's got talent!" He plays Carnegie Hall and the rest is history. This is the storyline of the phosphodiesterase type 5 inhibitors. Originally developed as a treatment for hypertension and angina, sildenafil (Viagra®) was marketed as a treatment for erectile dysfunction. Subsequently, it has been shown to be useful in the treatment of pulmonary hypertension5 and is marketed for same under the trade name Revatio®. Now is appears that we can add RD to list of diseases that respond to DPE5 inhibitors. Sildenafil was shown to be effective and well-tolerated in a small double-blinded, placebo-controlled study of patients with Raynaud's phenomenon.6 A patient who had RD and had failed sildenafil did respond to tadalafil (Cialis®).7

Am I ready to begin using vardenafil in the treatment of RD? Not based on this study. Because of its design (open-labeled, not randomized, not placebo-controlled, only 2 weeks long, undefined patient selection, inclusion, and exclusion criteria), the best that can be said, and echoed by its authors, is that the results are intriguing and a proper study is warranted.

References

1. Spencer-Green G. Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med. 1998;158:595-600.

2. Dziadzio M, et al. Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum. 1999;42: 2646-2655.

3. Coleiro B, et al. Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxford). 2001;40:1038-1043.

4. Milio G, et al. Iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis and the quality of life: a new therapeutic protocol. Rheumatology (Oxford). 2006 Feb 16; [Epub ahead of print]

5. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet. 2003;361:1533-1544.

6. Fries R, et al. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation. 2005;112:2980-2985.

7. Baumhaekel M, et al. Use of tadalafil in a patient with a secondary Raynaud's phenomenon not responding to sildenafil. Microvasc Res. 2005;69:178-179.