Br. J. clin. Pharmac. (1991), 31, 477-480
ADONIS 030652519100090 K
Subjective and objective assessment of enalapril in primary Raynaud's phenomenon V. F. CHALLENOR', D. G. WALLER', R. A. HAYWARD2, M. J. GRIFFIN2 & 0. S. ROATH3 'Clinical Pharmacology Group, 2Institute of Sound and Vibration Research and 3University Haematology, Southampton General Hospital and University of Southampton, Southampton
1 The efficacy and acceptability of enalapril were assessed in a double-blind, randomised, placebo controlled cross-over study in 21 patients with primary Raynaud's phenomenon. 2 Skin temperature was assessed by thermocouples in response to a 15° C cold water challenge as an index of digital blood flow. 3 Following enalapril there were no significant changes in the number and severity of Raynaud's attacks, and no subjective benefit from treatment as measured by visual analogue scales, 5 point rating scales, and skin temperature response to cold challenge when compared with placebo. 4 Enalapril in a dose of 20 mg daily is ineffective in the management of primary Raynaud's phenomenon.
Keywords
enalapril
Raynaud's phenomenon
cold challenge
Introduction
Methods
Raynaud's phenomenon is a condition characterized by reversible digital vasospasm commonly in response to cold (Raynaud, 1862). Although patients often respond to simple physical measures for maintaining or increasing local skin temperature, the severity of symptoms may require drug treatment. Compounds with arteriatvasodilator properties are often advocated, but few have been the subject of well-controlled studies on adequate numbers of patients. Nevertheless, encouraging results have been obtained with vasodilators such as naftidrofuryl, tetranicotinoyl fructose, the a-adrenoceptor antagonists thymoxamine and prazosin and the calcium antagonist nifedipine (Waller, 1989). Benefit is usually recorded in up to two thirds of patients with primary Raynaud's phenomenon but there is considerable interindividual variation in responses and acceptability may be limited by unwanted effects. Angiotensin-converting enzyme (ACE) inhibitors have been the subject of small studies in Raynaud's phenomenon, but their role remains controversial. Controlled observations have been encouraging but inconclusive (Janini et al., 1988; Miyazaki et al., 1982) but captopril has also been reported to precipitate digital vasospasm (Havalka et al., 1982; Studer et al., 1981). The aims of the current study were firstly to assess the efficacy and acceptability of the long-acting ACE inhibitor enalapril in patients with primary Raynaud's phenomenon. Secondly, the effect of enalapril on hand rewarming after a cold challenge was measured as an objective index of improvement.
Patient selection Twenty-one patients with primary Raynaud's phenomenon, diagnosed on typical clinical history (Blunt & Porter, 1981) entered the study, which was conducted between January and May 1988. Secondary causes of Raynaud's phenomenon were excluded by history, examination and appropriate blood tests. Nineteen patients were female and two male with a mean age of 38.6 years (range 21-59) and a mean duration of Raynaud's of 22 years (range 2-50 years). Three were smokers. Concurrent treatment was continued unchanged in 11 patients and consisted of an oral contraceptive (3), frusemide (1), mebhydrolin (1), carbimazole (1), timolol eye drops (1), Vitamin B12 injections (1), co-dydramol (1), premarin (1) and vitamin capsules (1). The study was approved by the ethics sub-committee of the Southampton and SouthWest Hampshire Health Authority and all patients gave written informed consent.
Study design The study was undertaken in a double-blind placebo controlled randomised cross-over design with two 4 week study periods. Patients were randomised to receive either 20 mg of enalapril or matching placebo. A 3 day dose titration (5, 10, 20 mg enalapril) was used to minimise the risk of hypotension (Abrams et al., 1984).
Correspondence: Dr V. F. Challenor, Clinical Pharmacology Group, CF104 Centre Block, Southampton General Hospital, Southampton S09 4XY
477
478
V. F. Challenor et al.
Mean daily temperature estimations were obtained for the City of Southampton from the Meteorological Office. These temperatures were also assumed to be applicable for the two patients who came from nearby surrounding areas. Compliance with the tablet regimen was assessed by tablet count. From the percentage of tablets that should have been taken, compliance during active treatment was assessed as good (> 80%), moderate (50-80%) or poor (< 50%).
Statistical analysis Results are expressed as mean ± s.e. mean. Clinical data were analysed by the method of paired differences (Hills & Armitage, 1979) in order to assess independently for treatment and order effects during both treatment and placebo periods. The relative numbers of patients experiencing more attacks on either enalapril or placebo were compared by means of the F test. Cold challenge data were analysed by the paired Student's t-test.
Measurements
a) Record diary: Patients were requested to keep a daily record of episodes of Raynaud's phenomenon noting the number of attacks, their duration and their severity graded as mild (1), moderate (2) or severe (3). In addition, the approximate numbers of visits out of doors per day was recorded. Unwanted effects which might have been related to treatment were also recorded, and elicited by open enquiry.
Results
One patient withdrew from the study for personal reasons unrelated to treatment and was not included in the analysis. There were no withdrawals related to treatment. No order effects or treatment-order interactions were found. Clinical response
b) Subjective assessments of improvement using both a 5 point rating scale and a 10 cm visual analogue scale were undertaken at the end of each treatment period as previously described (Waller et al., 1986). c) Skin temperature as an index of digital blood flow was recorded at rest, as well as during and after a cold water challenge. Type K thermocouples were taped on each separate segment of all eight fingers and the palms of both hands and connected to a multi-channel box (CIL Electronics, Sussex). The patients were then acclimatised for at least 30 min in a room in which the temperature was maintained between 210 C and 250 C. The left hand was placed inside a thin plastic bag (Disposaglove, Surgikos) to ensure dryness, and immersed in a cooled water bath (W38.CZ1 Grant Instruments, Cambridge) at 15° C for 5 min. The hand was then removed from the water bath and the subject remained seated until temperatures had returned to the pre-immersion level, or at least 45 min had elapsed since the end of the cold provocation. The hands were positioned at the level of the heart and the position remained unaltered throughout the acclimatisation, challenge and recovery periods. The temperature at each thermocouple was scanned every 5 s during baseline, cooling and recovery and stored by microcomputer (Commodore 4032-32N). Rewarming curves were calculated for all eight digits. Measurements of the initial slope and the time for finger temperature to rise 60 C from the lowest temperature achieved were recorded, as these had previously been shown to be the most discriminant features of the rewarming curve comparing subjects with and without Raynaud's phenomenon (unpublished data).
d) Blood was obtained for enalaprilat concentrations approximately 2 to 4 h after the last dose to coincide with expected peak plasma concentrations after enalapril. Plasma was stored at -20° C until analysed, as previously described (Hitchens et al., 1981).
Mean ambient temperatures were 3.6 ± 0.40 C during active treatment and 3.7 ± 0.3° C during the equivalent placebo phase. During treatment with enalapril 20 mg daily the mean numbers of attacks of Raynaud's per week were 7.0 ± 1.1 compared with 5.9 ± 1.2 on placebo (P = NS). The mean difference in the number of attacks during active treatment as compared with placebo was 0.8 with 95 % confidence intervals +0.4 to + 1.2. There were no patients free of attacks during either the active or placebo phases, and thirteen patients experienced more attacks during active treatment than with placebo (P < 0.01). The mean severity rating of attacks was similar at 48.4 ± 11.6 on placebo compared with 49.8 + 10.8 on enalapril. Overall efficacy of enalapril was rated higher than placebo by four patients (19%) while placebo was rated higher by seven patients (33%) (P = NS). There was a small non-significant mean deterioration in the visual analogue scale score on enalapril at 5.1 ± 0.4 compared with 4.0 ± 0.4 on placebo. Unwanted effects were reported by nine patients on enalapril and eight patients on placebo. Dizziness was the commonest unwanted effect during active treatment (five patients, one with placebo) but all effects during active treatment were transient. Tablet counts for the 18 patients who completed the trial and returned unused drugs revealed that compliance was good in 17 and moderate in one during the active treatment phase. The mean plasma enalaprilat concentration measured 2-4 h post dosing was 109.3 ± 24.3 ng ml-1 (range 9.1 to > 200 ng ml-). Cold challenge
Resting finger temperatures were not significantly altered following 4 weeks treatment with enalapril. Following cold challenge there was no significant improvement in the initial slope of the rewarming curve (0.0064 + 0.0015 c.f. 0.0058 ± 0.0012 °C s-1) or the time to recover 6° C from the lowest temperature (1723 ± 485 c.f. 1787 ± 483 s) when enalapril was compared with placebo.
Enalapril in Raynaud's phenomenon Discussion Previous reports suggesting symptomatic benefit in Raynaud's phenomenon following treatment with either captopril or enalapril did not use placebo comparisons. Truebstein et al. (1984) in an open study of patients with primary and secondary Raynaud's phenomenon demonstrated symptomatic improvement following captopril 25 mg three times a day in 14 out of 20 patients. A similar study by Tosi et al. (1987) reported improvement in symptoms in patients with primary Raynaud's phenomenon following the same dose of captopril but no response in Raynaud's phenomenon secondary to scleroderma. Two-thirds of their patients reported a greater than 50% improvement in both frequency and severity of vasospastic attack measured over a 3 month treatment period. By contrast, Madsen & Hvidt (1984) and Rustin et al. (1984) carried out randomised double-blind cross-over studies comparing captopril 25 mg thrice daily with placebo in patients with both primary and secondary Raynaud's phenomenon (Madsen & Hvidt, 1984) or primary Raynaud's only (Rustin et al., 1987) in the latter, and found no significant difference in frequency of attacks. Janini et al. (1988) found that enalapril at a dose of 20 mg daily led to at least a 20% reduction in the number of attacks of Raynaud's in 9 of 17 patients with either primary or secondary Raynaud's although these results did not achieve statistical significance. In the present study, which included only patients with primary Raynaud's phenomenon, there were no significant differences in either the numbers or severity of attacks when enalapril was compared with placebo over a 4 week period. Indeed, in contrast to the study of Janini et al. (1988) a significantly greater number of patients experienced more attacks during treatment with enalapril. Several hormonal effects of ACE inhibitors may contribute to their vasodilator effects including suppression of angiotensin II formation, or increased levels of kinins or prostaglandins. The current results suggest that neither increased local generation of angiotensin II or enhanced sensitivity to its vasoconstrictor effects, play a prominent part in the pathogenesis of primary Raynaud's phenomenon. It is less certain whether reduced generation of kinins or prostaglandins could be involved since ACE inhibitors without a sulphydryl group (such
479
as enalapril) may have a lesser effect on these substances than captopril (Zusman, 1987). Consistent with the lack of clinical benefit, we were also unable to demonstrate any objective improvement in digital rewarming times following enalapril in the present study. Using this method we have demonstrated an improvement in rewarming times in patients with primary Raynaud's phenomenon after a single dose of nifedipine (unpublished data). Interestingly, Janini etal. (1988) found no alteration in finger systolic pressure after cooling following enalapril despite a trend suggesting useful clinical responses. However, their study involved patients with both primary Raynaud's phenomenon and secondary Raynaud's phenomenon associated with scleroderma. In the latter group, alterations in vasomotor tone may have a minor role in the pathogenesis of the disorder. Tosi et al. (1987) were able to demonstrate an improvement in digital blood flow using strain gauge plethysmography in patients with primary Raynaud's phenomenon after treatment with captopril. Those with secondary Raynaud's phenomenon due to scleroderma showed no improvement in digital blood flow following cold challenge although resting blood flow did appear to be enhanced. Rustin et al. (1987) have also demonstrated in patients with primary Raynaud's phenomenon a significant improvement in cutaneous blood flow after captopril assessed by both laser Doppler flowmetry and photoplethysmography following cold stress. This was not, however, accompanied by any improvement in symptoms. The disparity between subjective and objective observations reported in some studies can only be resolved by properly controlled studies using adequate numbers of patients. The importance of separately grouping patients who have primary or secondary Raynaud's phenomenon cannot be over-emphasised. We conclude that enalapril in a dose of 20 mg daily given for 4 weeks is ineffective in the management of Raynaud's phenomenon, and may in some individuals lead to a deterioration in symptoms. However, this study cannot determine whether there is a dose-dependent response to ACE inhibitors in Raynaud's phenomenon. We are indebted to Dianne Wilson for typing the manuscript and to Merck Sharp and Dohme Limited for their financial support of the study.
References Abrams, W. B., Davies, R. 0. & Gomez, H. J. (1984). Clinical pharmacology of enalapril. J. Hypertension, 2 (Suppl. 2), 31-36. Blunt, R. J. & Porter, J. M. (1981). Raynaud's syndrome. Semin. Arthritis Rheum., 10, 282-308. Havalka, J., Boerlin, H. J. & Studer, A. (1982). Long-term experience with captopril in severe hypertension. Br. J. clin. Pharmac., 14 (Suppl. 2), 71S-76S. Hills, M. & Armitage, P. (1979). The two period cross-over clinical trial. Br. J. clin. Pharmac., 8, 7-20. Hichens, M., Hand, E. L. & Mycahy, W. S. (1981). Radioimmunoassay for angiotension converting enzyme inhibitors. Ligand Quarterly, 4, 43. Janini, S. D. N., Scott, D. G. I., Coppock, J. S., Bacon, P. A.
& Kendall, M. J. (1988). Enalapril in Raynaud's phenomenon. J. clin. Phamac. Ther., 13, 145-150. Madsen, J. L. & Hvidt, S. (1984). A randomised double-blind cross-over investigation of treatment of Raynaud's disease with captopril. Ugeshr Laeger, 146, 2695-2697. Miyazaki, S., Muira, K., Kasai, Y., Abe, K. & Yoshinaga, K. (1982). Relief from digital vasospasm by treatment with captopril and its complete inhibition by serine proteinase inhibitors in Raynaud's phenomenon. Br. med. J., 284, 310. Raynaud, M. (1862). De l'asphyxie locale et de la gangrene sym6trique des extremites. Thesis, Leclerc, L., LibraireEditeur, University of Paris. Rustin, M. H. A., Almond, N. E., Beacham, J. A., Brooks,
480
V. F. Challenor et al.
R. J., Jones, D. P., Cooke, E. D. & Dowd, P. M. (1987). The effect of captopril on cutaneous blood flow in patients with primary Raynaud's phenomenon. Br. J. Dermatol., 117, 751-758. Studer, A., Luscher, T., Siegenthaler, W. & Vetter, W. (1981). Captopril in various forms of severe therapy-resistant hypertension. Klin. Wochenschr., 59, 59-67. Tosi, S., Marchesoni, A., Messina, K., Bellintani, C., Sironi, G. & Faravelli, C. (1987). Treatment of Raynaud's phenomenon with captopril. Drugs exp. clin. Res., 13, 37-42. Truebstein, G., Wigger, E., Truebstein, R., Ludwig, M., Wilgalis, M. & Stumpe, K. 0. (1984). Behandlung des Raynaud-Symptoms mit Captopril. Dtsch. med. Wochenschr., 109, 857-860. Waller, D. G. (1989). Drug treatment of Raynaud's Phe-
nomenon. In Raynaud's: A guide for health professionals, ed. Roath, 0. S., pp. 83-105. London, New York: Chapman & Hall. Waller, D. G., Challenor, V. F., Francis, D. A. & Roath, 0. S. (1986). Clinical and rheological effects of nifedipine in Raynaud's phenomenon. Br. J. clin. Pharmac., 22, 449-454. Zusman, R. M. (1987). Effects of converting-enzyme inhibitors on the renin-angiotensin-aldosterone, bradykinin and arachidonic acid-prostaglandin systems: correlation of chemical structure and biological activity. Am. J. Kid. Dis., 10 (Suppl. 1), 13-23.
(Received 11 April 1990, accepted 14 November 1990)
ADONIS 030652519100090 K
Subjective and objective assessment of enalapril in primary Raynaud's phenomenon V. F. CHALLENOR', D. G. WALLER', R. A. HAYWARD2, M. J. GRIFFIN2 & 0. S. ROATH3 'Clinical Pharmacology Group, 2Institute of Sound and Vibration Research and 3University Haematology, Southampton General Hospital and University of Southampton, Southampton
1 The efficacy and acceptability of enalapril were assessed in a double-blind, randomised, placebo controlled cross-over study in 21 patients with primary Raynaud's phenomenon. 2 Skin temperature was assessed by thermocouples in response to a 15° C cold water challenge as an index of digital blood flow. 3 Following enalapril there were no significant changes in the number and severity of Raynaud's attacks, and no subjective benefit from treatment as measured by visual analogue scales, 5 point rating scales, and skin temperature response to cold challenge when compared with placebo. 4 Enalapril in a dose of 20 mg daily is ineffective in the management of primary Raynaud's phenomenon.
Keywords
enalapril
Raynaud's phenomenon
cold challenge
Introduction
Methods
Raynaud's phenomenon is a condition characterized by reversible digital vasospasm commonly in response to cold (Raynaud, 1862). Although patients often respond to simple physical measures for maintaining or increasing local skin temperature, the severity of symptoms may require drug treatment. Compounds with arteriatvasodilator properties are often advocated, but few have been the subject of well-controlled studies on adequate numbers of patients. Nevertheless, encouraging results have been obtained with vasodilators such as naftidrofuryl, tetranicotinoyl fructose, the a-adrenoceptor antagonists thymoxamine and prazosin and the calcium antagonist nifedipine (Waller, 1989). Benefit is usually recorded in up to two thirds of patients with primary Raynaud's phenomenon but there is considerable interindividual variation in responses and acceptability may be limited by unwanted effects. Angiotensin-converting enzyme (ACE) inhibitors have been the subject of small studies in Raynaud's phenomenon, but their role remains controversial. Controlled observations have been encouraging but inconclusive (Janini et al., 1988; Miyazaki et al., 1982) but captopril has also been reported to precipitate digital vasospasm (Havalka et al., 1982; Studer et al., 1981). The aims of the current study were firstly to assess the efficacy and acceptability of the long-acting ACE inhibitor enalapril in patients with primary Raynaud's phenomenon. Secondly, the effect of enalapril on hand rewarming after a cold challenge was measured as an objective index of improvement.
Patient selection Twenty-one patients with primary Raynaud's phenomenon, diagnosed on typical clinical history (Blunt & Porter, 1981) entered the study, which was conducted between January and May 1988. Secondary causes of Raynaud's phenomenon were excluded by history, examination and appropriate blood tests. Nineteen patients were female and two male with a mean age of 38.6 years (range 21-59) and a mean duration of Raynaud's of 22 years (range 2-50 years). Three were smokers. Concurrent treatment was continued unchanged in 11 patients and consisted of an oral contraceptive (3), frusemide (1), mebhydrolin (1), carbimazole (1), timolol eye drops (1), Vitamin B12 injections (1), co-dydramol (1), premarin (1) and vitamin capsules (1). The study was approved by the ethics sub-committee of the Southampton and SouthWest Hampshire Health Authority and all patients gave written informed consent.
Study design The study was undertaken in a double-blind placebo controlled randomised cross-over design with two 4 week study periods. Patients were randomised to receive either 20 mg of enalapril or matching placebo. A 3 day dose titration (5, 10, 20 mg enalapril) was used to minimise the risk of hypotension (Abrams et al., 1984).
Correspondence: Dr V. F. Challenor, Clinical Pharmacology Group, CF104 Centre Block, Southampton General Hospital, Southampton S09 4XY
477
478
V. F. Challenor et al.
Mean daily temperature estimations were obtained for the City of Southampton from the Meteorological Office. These temperatures were also assumed to be applicable for the two patients who came from nearby surrounding areas. Compliance with the tablet regimen was assessed by tablet count. From the percentage of tablets that should have been taken, compliance during active treatment was assessed as good (> 80%), moderate (50-80%) or poor (< 50%).
Statistical analysis Results are expressed as mean ± s.e. mean. Clinical data were analysed by the method of paired differences (Hills & Armitage, 1979) in order to assess independently for treatment and order effects during both treatment and placebo periods. The relative numbers of patients experiencing more attacks on either enalapril or placebo were compared by means of the F test. Cold challenge data were analysed by the paired Student's t-test.
Measurements
a) Record diary: Patients were requested to keep a daily record of episodes of Raynaud's phenomenon noting the number of attacks, their duration and their severity graded as mild (1), moderate (2) or severe (3). In addition, the approximate numbers of visits out of doors per day was recorded. Unwanted effects which might have been related to treatment were also recorded, and elicited by open enquiry.
Results
One patient withdrew from the study for personal reasons unrelated to treatment and was not included in the analysis. There were no withdrawals related to treatment. No order effects or treatment-order interactions were found. Clinical response
b) Subjective assessments of improvement using both a 5 point rating scale and a 10 cm visual analogue scale were undertaken at the end of each treatment period as previously described (Waller et al., 1986). c) Skin temperature as an index of digital blood flow was recorded at rest, as well as during and after a cold water challenge. Type K thermocouples were taped on each separate segment of all eight fingers and the palms of both hands and connected to a multi-channel box (CIL Electronics, Sussex). The patients were then acclimatised for at least 30 min in a room in which the temperature was maintained between 210 C and 250 C. The left hand was placed inside a thin plastic bag (Disposaglove, Surgikos) to ensure dryness, and immersed in a cooled water bath (W38.CZ1 Grant Instruments, Cambridge) at 15° C for 5 min. The hand was then removed from the water bath and the subject remained seated until temperatures had returned to the pre-immersion level, or at least 45 min had elapsed since the end of the cold provocation. The hands were positioned at the level of the heart and the position remained unaltered throughout the acclimatisation, challenge and recovery periods. The temperature at each thermocouple was scanned every 5 s during baseline, cooling and recovery and stored by microcomputer (Commodore 4032-32N). Rewarming curves were calculated for all eight digits. Measurements of the initial slope and the time for finger temperature to rise 60 C from the lowest temperature achieved were recorded, as these had previously been shown to be the most discriminant features of the rewarming curve comparing subjects with and without Raynaud's phenomenon (unpublished data).
d) Blood was obtained for enalaprilat concentrations approximately 2 to 4 h after the last dose to coincide with expected peak plasma concentrations after enalapril. Plasma was stored at -20° C until analysed, as previously described (Hitchens et al., 1981).
Mean ambient temperatures were 3.6 ± 0.40 C during active treatment and 3.7 ± 0.3° C during the equivalent placebo phase. During treatment with enalapril 20 mg daily the mean numbers of attacks of Raynaud's per week were 7.0 ± 1.1 compared with 5.9 ± 1.2 on placebo (P = NS). The mean difference in the number of attacks during active treatment as compared with placebo was 0.8 with 95 % confidence intervals +0.4 to + 1.2. There were no patients free of attacks during either the active or placebo phases, and thirteen patients experienced more attacks during active treatment than with placebo (P < 0.01). The mean severity rating of attacks was similar at 48.4 ± 11.6 on placebo compared with 49.8 + 10.8 on enalapril. Overall efficacy of enalapril was rated higher than placebo by four patients (19%) while placebo was rated higher by seven patients (33%) (P = NS). There was a small non-significant mean deterioration in the visual analogue scale score on enalapril at 5.1 ± 0.4 compared with 4.0 ± 0.4 on placebo. Unwanted effects were reported by nine patients on enalapril and eight patients on placebo. Dizziness was the commonest unwanted effect during active treatment (five patients, one with placebo) but all effects during active treatment were transient. Tablet counts for the 18 patients who completed the trial and returned unused drugs revealed that compliance was good in 17 and moderate in one during the active treatment phase. The mean plasma enalaprilat concentration measured 2-4 h post dosing was 109.3 ± 24.3 ng ml-1 (range 9.1 to > 200 ng ml-). Cold challenge
Resting finger temperatures were not significantly altered following 4 weeks treatment with enalapril. Following cold challenge there was no significant improvement in the initial slope of the rewarming curve (0.0064 + 0.0015 c.f. 0.0058 ± 0.0012 °C s-1) or the time to recover 6° C from the lowest temperature (1723 ± 485 c.f. 1787 ± 483 s) when enalapril was compared with placebo.
Enalapril in Raynaud's phenomenon Discussion Previous reports suggesting symptomatic benefit in Raynaud's phenomenon following treatment with either captopril or enalapril did not use placebo comparisons. Truebstein et al. (1984) in an open study of patients with primary and secondary Raynaud's phenomenon demonstrated symptomatic improvement following captopril 25 mg three times a day in 14 out of 20 patients. A similar study by Tosi et al. (1987) reported improvement in symptoms in patients with primary Raynaud's phenomenon following the same dose of captopril but no response in Raynaud's phenomenon secondary to scleroderma. Two-thirds of their patients reported a greater than 50% improvement in both frequency and severity of vasospastic attack measured over a 3 month treatment period. By contrast, Madsen & Hvidt (1984) and Rustin et al. (1984) carried out randomised double-blind cross-over studies comparing captopril 25 mg thrice daily with placebo in patients with both primary and secondary Raynaud's phenomenon (Madsen & Hvidt, 1984) or primary Raynaud's only (Rustin et al., 1987) in the latter, and found no significant difference in frequency of attacks. Janini et al. (1988) found that enalapril at a dose of 20 mg daily led to at least a 20% reduction in the number of attacks of Raynaud's in 9 of 17 patients with either primary or secondary Raynaud's although these results did not achieve statistical significance. In the present study, which included only patients with primary Raynaud's phenomenon, there were no significant differences in either the numbers or severity of attacks when enalapril was compared with placebo over a 4 week period. Indeed, in contrast to the study of Janini et al. (1988) a significantly greater number of patients experienced more attacks during treatment with enalapril. Several hormonal effects of ACE inhibitors may contribute to their vasodilator effects including suppression of angiotensin II formation, or increased levels of kinins or prostaglandins. The current results suggest that neither increased local generation of angiotensin II or enhanced sensitivity to its vasoconstrictor effects, play a prominent part in the pathogenesis of primary Raynaud's phenomenon. It is less certain whether reduced generation of kinins or prostaglandins could be involved since ACE inhibitors without a sulphydryl group (such
479
as enalapril) may have a lesser effect on these substances than captopril (Zusman, 1987). Consistent with the lack of clinical benefit, we were also unable to demonstrate any objective improvement in digital rewarming times following enalapril in the present study. Using this method we have demonstrated an improvement in rewarming times in patients with primary Raynaud's phenomenon after a single dose of nifedipine (unpublished data). Interestingly, Janini etal. (1988) found no alteration in finger systolic pressure after cooling following enalapril despite a trend suggesting useful clinical responses. However, their study involved patients with both primary Raynaud's phenomenon and secondary Raynaud's phenomenon associated with scleroderma. In the latter group, alterations in vasomotor tone may have a minor role in the pathogenesis of the disorder. Tosi et al. (1987) were able to demonstrate an improvement in digital blood flow using strain gauge plethysmography in patients with primary Raynaud's phenomenon after treatment with captopril. Those with secondary Raynaud's phenomenon due to scleroderma showed no improvement in digital blood flow following cold challenge although resting blood flow did appear to be enhanced. Rustin et al. (1987) have also demonstrated in patients with primary Raynaud's phenomenon a significant improvement in cutaneous blood flow after captopril assessed by both laser Doppler flowmetry and photoplethysmography following cold stress. This was not, however, accompanied by any improvement in symptoms. The disparity between subjective and objective observations reported in some studies can only be resolved by properly controlled studies using adequate numbers of patients. The importance of separately grouping patients who have primary or secondary Raynaud's phenomenon cannot be over-emphasised. We conclude that enalapril in a dose of 20 mg daily given for 4 weeks is ineffective in the management of Raynaud's phenomenon, and may in some individuals lead to a deterioration in symptoms. However, this study cannot determine whether there is a dose-dependent response to ACE inhibitors in Raynaud's phenomenon. We are indebted to Dianne Wilson for typing the manuscript and to Merck Sharp and Dohme Limited for their financial support of the study.
References Abrams, W. B., Davies, R. 0. & Gomez, H. J. (1984). Clinical pharmacology of enalapril. J. Hypertension, 2 (Suppl. 2), 31-36. Blunt, R. J. & Porter, J. M. (1981). Raynaud's syndrome. Semin. Arthritis Rheum., 10, 282-308. Havalka, J., Boerlin, H. J. & Studer, A. (1982). Long-term experience with captopril in severe hypertension. Br. J. clin. Pharmac., 14 (Suppl. 2), 71S-76S. Hills, M. & Armitage, P. (1979). The two period cross-over clinical trial. Br. J. clin. Pharmac., 8, 7-20. Hichens, M., Hand, E. L. & Mycahy, W. S. (1981). Radioimmunoassay for angiotension converting enzyme inhibitors. Ligand Quarterly, 4, 43. Janini, S. D. N., Scott, D. G. I., Coppock, J. S., Bacon, P. A.
& Kendall, M. J. (1988). Enalapril in Raynaud's phenomenon. J. clin. Phamac. Ther., 13, 145-150. Madsen, J. L. & Hvidt, S. (1984). A randomised double-blind cross-over investigation of treatment of Raynaud's disease with captopril. Ugeshr Laeger, 146, 2695-2697. Miyazaki, S., Muira, K., Kasai, Y., Abe, K. & Yoshinaga, K. (1982). Relief from digital vasospasm by treatment with captopril and its complete inhibition by serine proteinase inhibitors in Raynaud's phenomenon. Br. med. J., 284, 310. Raynaud, M. (1862). De l'asphyxie locale et de la gangrene sym6trique des extremites. Thesis, Leclerc, L., LibraireEditeur, University of Paris. Rustin, M. H. A., Almond, N. E., Beacham, J. A., Brooks,
480
V. F. Challenor et al.
R. J., Jones, D. P., Cooke, E. D. & Dowd, P. M. (1987). The effect of captopril on cutaneous blood flow in patients with primary Raynaud's phenomenon. Br. J. Dermatol., 117, 751-758. Studer, A., Luscher, T., Siegenthaler, W. & Vetter, W. (1981). Captopril in various forms of severe therapy-resistant hypertension. Klin. Wochenschr., 59, 59-67. Tosi, S., Marchesoni, A., Messina, K., Bellintani, C., Sironi, G. & Faravelli, C. (1987). Treatment of Raynaud's phenomenon with captopril. Drugs exp. clin. Res., 13, 37-42. Truebstein, G., Wigger, E., Truebstein, R., Ludwig, M., Wilgalis, M. & Stumpe, K. 0. (1984). Behandlung des Raynaud-Symptoms mit Captopril. Dtsch. med. Wochenschr., 109, 857-860. Waller, D. G. (1989). Drug treatment of Raynaud's Phe-
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(Received 11 April 1990, accepted 14 November 1990)
