Raynaud’s Phenomenon: Pathophysiologic Features and Treatment with Calcium-Channel Blockers

CRAIG R. SMITH, MD, and RICHARD J. RODEHEFFER, MD

Raynaud’s phenomenon may be associated with severe pain, functional disability and digital infarc- tion, particularly in patients with underlying vascular disease. The pathophysiologic features of Raynaud’s phenomenon are complex although vasospasm contributes to the production of digital ischemia in most cases. Calcium-channel blockers have been shown to produce arteriolar vasodilation and an increase in peripheral blood flow. They have been used to treat patients with Raynaud’s phenomenon in several prospective, randomized, double-blind, placebo-controlled trials. Low doses of verapamil

were ineffective but both diltiarem and nifedipine produced subjective improvement in 60 to 90% of cases. Objective measures of digital blood flow were not improved. Patients without underlying vascular disease responded more readily to therapy than patients with scleroderma. Adverse effects were uncommon and seldom necessitated discontinuation of therapy. These data suggest that nifedipine and diltiazem provide effective short-term improvement in symptoms for most patients with Raynaud’s phenomenon.

(Am J Cardiol 1965;55:1548-1578)

Raynaud’s phenomenon is characterized by the abrupt development of digital pallor or cyanosis in response to cold exposure or stress.lt2 Ischemic symptoms such as parathesias and numbness often accompany the pallor, last as long as the stimulus is present and are followed by hyperemia, pain and throbbing of the digits. The color changes are usually sharply circumscribed, involve 1 or more fingers and may be asymmetrical. The con- dition may produce functional disability, digital atro- phy, ulceration or gangrene, particularly in patients with underlying vascular disease. Raynaud’s phenom- enon may also be part of a generalized process involving the feet, ear lobes and visceral vessels of the lung, kidney or heart.

Pathophysiologic Features The pathophysiologic features of Raynaud’s phe-

nomenon are complex (Fig. l).s From Poiseuille’s law it can be deduced that there are 3 mechanisms that may decrease digital blood flow: decreased perfusion pres- sure, increased blood viscosity or decreased luminal area of the digital artery. 4,5 Each of these mechanisms may occur individually or in combination and each may be caused by specific anatomic or functional abnormalities. Decreased perfusion pressure may be caused by sys-

From the Divisions of Internal Medicine and Clinical Pharmacology, the Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Address for reprints: Craig R. Smith, MD, Harvey 402, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland.

temic hypotension or proximal vascular occlusion. In- creased blood viscosity may be caused by increased plasma fibrinogen, increased platelet adhesion or de- creased red cell deformability.s-9 Most often decreased flow is induced by a decrease in the luminal area of the digital artery. Decreased luminal area is caused either by anatomic vascular occlusion, vasospasm or both. Anatomic luminal occlusion is the hallmark of patients with scleroderma. These patients have intimal and advential fibrosis, but they may also have diffuse small fibrin thrombi that further impair digital flow.‘O Pa- tients with systemic lupus erythematosis, rheumatoid arthritis and polyarteritis nodosa also have luminal obstruction due to focal vasculitis or thrombosis.

Arterial and arteriolar vasospasm is a normal re- sponse to cold exposure or stress. Vasospasm may be caused by a central adrenergic response or to changes in local mediators that control vascular smooth muscle tone. Recent data suggest that cold increases the ar-ad- renergic responsiveness of the digital vessels by in- creasing release of norepinephrine, decreasing norepi- nephrine degradation and possibly increasing receptor sensitivity.” An increase in adrenergic vasomotor tone has long been thought to be a factor in Raynaud’s phe- nomenon. Perhaps patients with Raynaud’s phenom- enon have a more aggregated response making them more likely to have spasm or severe spasm.

Local mediator abnormalities including diminished prostacyclin or increased thromboxane production have also been suggested as causes for vasospasm in Ray- naud’s, but conclusive evidence for these abnormalities

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January 25, 1995 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 55 1558

TABLE I Double-Blind Clinical Trials of Calcium-Channel Blockers in Raynaud’s Phenomenon

Attack Patients Ihe Duration Frequency Subjective Objective

Report (n) Drug (mg) (weeks) Decreased Improvement Improvement

Kinney et alI6 Vayssairat et ali7 :i

Verapamil Diltiazem

;;;;O qid %

No No No Yes Yes l .

Kahan et a121 30 Nifedioine 20 tid 2 Yes Yes l . . .

Smith and McKendry22 Rodeheffer et al23

17 Nifedipine 10 qid 15 Nifedipine 20 tid

Yes Yes

Yes No Yes No

+ Not measured. qid = 4 times daily; tid = 3 times daily.

is lacking.i2 In fact, a preliminary report suggests that subjective evaluation of overall effectiveness and digital thromboxane is not of pathogenic importance in Ray- systolic pressures. There was no significant difference naud’s phenomenon. l3 Serotonin responsiveness has between placebo- and verapamil-treated patients in the also been studied in an in vitro system. Cutaneous number or severity of attacks, the subjective evaluation vascular smooth muscle strips from patients with scle- of effectiveness or the mean digital systolic pressure roderma had an increased contractile response to sero- during cold exposure. In this study, small doses of tonin compared with vascular smooth muscle strips verapamil were used and most patients had underlying from normal subjects. On the basis of these data, further vascular disease. Further study is necessary to deter- studies of the influence of serotonin and the re- mine if larger doses would be more effective and to de- sponsiveness of the vasculature to serotonin seem termine if patients without underlying vascular disease indicated. would be more responsive.

Calcium-Channel Blockers Both in vitro and in vivo experiments have demon-

strated that calcium-channel blockers decrease vascular smooth muscle tone and relieve arterial vasospasm. Drug-induced vasodilation causes a decrease in pe- ripheral vascular resistance and an increase in periph- eral blood flow.14 Moreover, calcium-channel blockers inhibit, in vitro, norepinephrine-induced vasospasm of rabbit and human peripheral arteries and veins.15 Be- cause of these unique properties, several investigators have studied the effectiveness of calcium-channel blockers in patients with Raynaud’s phenomenon (Table I).

Vayssairat et all7 studied diltiazem in 26 patients with Raynaud’s phenomenon. Diltiazem, 60 mg, was given 3 times a day for 2 weeks in a double-blind, pla- cebo-controlled prospective trial. This study demon- strated an improvement in patients’ subjective assess- ment of disability and in the frequency of attacks. Symptoms decreased 17% during placebo treatment compared with 51% during diltiazem treatment and the number of vasospastic attacks decreased by 6.5 and 64%, respectively (p <0.05). No objective evidence of im- provement in digital blood flow was demonstrable. The investigators concluded that diltiazem was effective therapy for patients with Raynaud’s phenomenon.

Kinney et all6 conducted a double-blind, prospective, crossover trial in 17 patients given verapamil40 to 80 mg 4 times a day for 2 weeks. They measured thera- peutic efficacy by diary tabulation of attack frequency,

Matoba et aP have also investigated diltiazem. They conducted an open-label trial in 17 men with vibra- tion-induced Raynaud’s. Diltiazem, 30 mg, was given 3 times a day for 6 weeks. Effectiveness was assessed by subjective patient reports, skin temperature recovery

Decreased Digital Blood Flow

Decreased Decreased Increased Pressure

FIGURE 1. Pathophysiologic features of Raynaud’s phenomenon.

Pro~im~~~~~~~~~lity

Enhanced Anatomic Local Alpha Adrenergic Luminal Mediator

Response Occlusion Abnormality

I I Increased Mediator lntimal Fibrosis

I

Decreased Mediator Decreased PGE, PGll

Adventitial Fibrosis Degradation

Increased TXA2 Thrombosis

Receptor Abnormality

156B A SYMPOSIUM: CALCIUM-CHANNEL BLOCKERS

TABLE II Patient Assessment of Therapeutic Efficacy

Nifedipine Placebo Subjective Assessment n(%) n (%)

Moderated or marked improvement

Minimal improvement, no change or worse

9 (60)” 2 (13)

8 (40) 13 (87)

+ p = 0.02, Fisher’s exact test.

times and digital sensory tests. Matoba observed sig- nificant (p <0.05) improvement in skin temperature recovery times and sensory tests. Most notably, 69.6% of the patients judged diltiazem “effective” and no ad- verse effects were reported. Matoba concluded that diltiazem was effective in the long-term management of vibration-induced Raynaud’s phenomenon.

Most recently, a randomized, prospective, double- blind trial of diltiazem has been reported by Kahan et al.lg They studied 16 patients with scleroderma, rheu- matoid arthritis, systemic lupus erythematosis and id- iopathic Raynaud’s phenomenon. Symptom severity was measured using a 10 point scale. When all 16 pa- tients were evaluated, mean attack frequency decreased from 18.9 per 2-week period with placebo to a 12.6 with diltiazem (p <0.05). Attack severity was rated 6.2 with placebo and 4.2 with diltiazem (p <0.05). Patients with idiopathic disease appeared to respond more dra- matically than those with an underlying systemic disease.

Three studies have assessed the effects of nifedipine in patients with Raynaud’s phenomenon. Kahan et also reported the preliminary results of a controlled, pro- spective trial in 16 patients. Nifedipine, 20 mg, was given as a single oral dose on 2 consecutive days. Vaso- spasm was induced by hand immersion in cold water before and at the first and sixth hour after nifedipine and placebo administration. Nifedipine delayed the onset of digital vasospasm in 14 of the 16 patients compared with placebo. A long-term, open-label study of the effectiveness of nifedipine, 20 mg 3 times daily, was then conducted with 10 patients. There was a de- crease in the mean number of digital vasospastic attacks per week from 29.5 to 4.3 and 4 of the 10 patients were entirely free from attacks. Kahan et aP1 subsequently published the results of a randomized, prospective, placebo-controlled, double-blind, crossover trial in 30 patients treated with nifedipine, 20 mg 3 times daily for 2 weeks. The number of vasospastic episodes de- creased 90.1% for patients with idiopathic Raynaud’s phenomenon, 78.6% for patients with systemic lupus erythematosis and 64% for patients with scleroderma. These differences were statistically significant com- pared with placebo, suggesting that nifedipine was ef- fective therapy for most patients with digital vasospasm, but more so in those with idiopathic Raynaud’s phenomenon.

Smith and McKendryss conducted a prospective, double-blind, crossover trial comparing placebo with nifedipine, 10 mg 4 times daily for 2 weeks, in 17 women with idiopathic Raynaud’s phenomenon, scle-

roderma and systemic lupus erythematosis. Effective- ness was assessed by diaries, subjective evaluation and skin temperature recovery times after cold exposure. Severity and global effectiveness were measured with 10 cm visual analogue scales in which a score of 10 in- dicated the greatest severity or effectiveness. The fre- quency of attacks decreased from 2.5 f 0.4lday with placebo to 1.3 f 0.3/day with nifedipine. The severity of attacks decreased from 5.8 f 0.6 with placebo to 3.4 f 0.5 for nifedipine, and effectiveness improved from 1.3 f 0.6 to 5.3 f 0.8. No improvement was measurable in skin temperature recovery times.

Finally, Rodeheffer et a123 conducted a placebo- controlled, double-blind trial of nifedipine in the treatment of patients with Raynaud’s phenomenon. Patients with digital vasospasm caused by thoracic outlet syndrome, vibratory trauma, large vessel ath- erosclerosis, thromboangiitis obliterans and polyarte- ritis nodosa were excluded from the trial. The trial consisted of 4 study periods: a placebo run-in period lasting 2 weeks followed by 2 treatment periods of 2 weeks duration each, separated by a l-week washout period. During the treatment periods, patients received either nifedipine, 20 mg 3 times a day, or placebo. Sev- eral measurements were taken to determine the drug effectiveness. These included the patient’s global as- sessment of drug effectiveness on a 5 point scale, diaries in which the patients tabulated the frequency and se- verity of their vasospastic episodes on a daily basis and digital artery systolic pressures, taken while patients were lying on a thermal blanket at 30 and 15OC. The trial was conducted during cold weather months.

The frequency of Raynaud’s attacks per 2 weeks de- creased from 14.7 episodes with placebo to 10.8 episodes with nifedipine (p <0.05); This response was more pronounced in patients with idiopathic Raynaud’s phenomenon. The patients’ overall assessment of the effectiveness of nifedipine versus placebo therapy was also significantly different. Moderate or marked sub- jective improvement occurred in 60% of the patients with nifedipine and in only 13% with placebo, p = 0.02 (Table II). Despite improvement in the number of vasospastic episodes and marked improvement in the patients’ global assessment of therapy, no changes could be detected in digital perfusion pressures when nifedi- pine and placebo were compared.

The results of these clinical trials indicate that during nifedipine treatment many patients have a decrease in the frequency of vasospastic attacks and a moderate or marked alleviation in their symptoms. However, there was variability in the response to therapy, with some patients having no response at all. Patients without underlying vascular disease appeared to respond better whereas patients with scleroderma appeared to do less well. The reason for the difference in individual re- sponses to nifedipine cannot be determined from the data, but may be due to variation in the severity of vasospasm, variation in extent of fixed anatomic nar- rowing of the digital arteries, presence of active vascu- litis or other as yet uncharacterized variables associated with the presence of an underlying systemic disease.

January 25. 1965 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 55 1570

In these studies, calcium-channel blockers were conveniently administered and well tolerated. The most common adverse effects were flushing, mild headache, a sensation of light-headedness and ankle edema. Be- cause these symptoms were usually mild and transient, they should not limit the clinical utility of these drugs in patients with Raynaud’s phenomenon.

The lack of correlation between subjective alleviation of symptoms and objective evidence of improvement in digital blood flow was a consistent finding in these studies. The methods used to measure digital flow in- cluded digital sphygomomanometry, venous occlusion plethysmography and skin temperature recovery times. The reason for the failure of these methods to detect improvement is not clear. It may be that blood flow was improved during the tests but the methods were not sensitive enough to detect it, or that blood flow was not improved during the application of the tests. In each study blood flow measurements were performed after a cold challenge; in 2 studies the hands were placed in ice cold water for 20 seconds2c*21 and in 1 study patients were asked to lie on a cooling blanket at 15OC for 20 minutes.23 These stimuli provoked digital vasospasm in most patients. Although it is possible that the blood flow measurement techniques used were insensitive, it is also possible that the magnitude of the stimuli used during the objective tests was too great to be reversed by nifedipine or diltiazem. Because the magnitude of the stimuli used during the tests was probably far in excess of the magnitude of the stimuli these patients were exposed to in daily living, it may be that calcium- channel blockers were effective in blocking the vasos- pastic response to mild or moderate stimuli but not to severe stimuli.

In summary, 5 independent, double-blind, controlled clinical trials have shown that short-term treatment with nifedipine or diltiazem provides symptomatic relief in many patients with Raynaud’s phenomenon. Further clinical studies are needed to determine the site of drug action, the dose-response relation, the effectiveness

of long-term therapy and the predictors of clinical responsiveness.

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