Oestrogen improves exercise-induced myocardial ischaemia in women

RESEARCH LETTERS

Oestrogen improves exerciseinduced myocardial ischaemia in women Carolyn M Webb, Giuseppe M C Rosano, Peter Collins

Decreased plasma oestrogen concentrations associated with the menopause appear to be a risk factor for coronary heart disease in women. Oestrogen replacement therapy has beneficial effects on plasma lipids, haemostatic factors, and peripheral and coronary arterial reactivity, suggesting a possible therapeutic effect of oestrogen therapy. Acute1,2 and chronic3 oestrogen administration attenuates or reverses acetylcholine-induced coronary-artery vasoconstriction at physiological concentrations. Acute oestrogen administration favourably affects pacing-induced and exercise-induced myocardial ischaemia in postmenopausal women with coronary artery disease.4,5 However the efficacy of long-term oestrogen therapy on the treatment of angina in the presence of coronary artery disease is unknown. We evaluated the effect of chronic 17␤-oestradiol therapy on exercise-induced myocardial ischaemia in 12 postmenopausal women (mean age 65 [SE 1] years) with atherosclerotic coronary heart disease. Patients carried out, off antianginal and hormone therapy, two screening treadmill exercise tests (Marquette CASE-15) with a modified Bruce protocol. They were then randomised in a double-blind fashion to a 50 ␮g 17␤g-oestradiol patch (Evorel, Janssen-Cilag, Saunderton, UK) or identical placebo for 4 weeks, followed by an increase to 100 ␮g oestradiol (2⫻50 ␮g patches) or identical placebo for a further 4 weeks. Patients then crossed over and repeated the study protocol on the opposite treatment regimen. Exercise testing was done after 4 and 8 weeks on each treatment. Total exercise time, time to 1 mm ST-segment depression, heart rate and blood pressure at the onset of 1 mm ST-segment depression and peak exercise, maximal ST-segment depression and time to development of angina during exercise were recorded.

Double product was calculated as the product of heart rate and systolic blood pressure. Exercise electrocardiograms (ECG) were analysed by an experienced independent investigator who was unaware of the clinical data. The lead showing the greatest ST-segment depression in the screening exercise tests was selected for analysis. A blood sample for radioimmunoassay measurement of plasma 17␤-oestradiol levels (Abbott IMX System, Abbott Diagnostics Division, Berkshire, UK)) was taken immediately before the first screening exercise test and before each test after randomisation; number of episodes of angina was noted for each treatment phase from an angina diary. Plasma 17␤-oestradiol levels were significantly increased after 17␤-oestradiol at 4 and 8 weeks compared with placebo (geometric mean 201 [95% CI 124–325] and 238 [147–385] vs 46 [29–75] and 73[45–118] pmol/L, oestradiol 50 ␮g and 100 ␮g vs placebo 1 patch and 2 patches respectively; p⬍0·001) (table). At 4 and 8 weeks there was a significant increase in exercise time to 1 mm ST-segment depression by oestradiol with a mean increase of 89 (11–168; p=0·028) seconds after 4 weeks’ treatment and 117 (38–195; p=0·006) after 8 weeks of treatment compared with placebo. Oestradiol increased double product at 1 mm ST-segment depression by 8% after 4 weeks (p=0·011) and 9% after 8 weeks (p=0·003). Heart rate and double product at peak exercise were significantly decreased after 8 weeks of oestrogen treatment (p=0·005 and 0·015 respectively). There was no difference in maximal ST-segment depression, total exercise time, or time to angina between oestrogen and placebo. There was no difference in number of episodes of angina experienced by patients when taking either oestradiol or placebo at 4 weeks (4·3 [2·1–6·4] vs 4·6 [2·5–6·7] angina attacks/week; p=0·72; oestradiol vs placebo) or after 8 weeks (5·0 [2·9–7·2] vs 5·2 [3·0–7·3] angina attacks/week; p=0·87; oestradiol vs placebo). No carry-over effect was detected, except for systolic blood pressure at peak exercise (p=0·018) Chronic 17␤-oestradiol increased time to onset of exerciseinduced myocardial ischaemia,4,5 but contrary to the findings of the acute study by Rosano et al5 we found no effect of

Resting

P1

E1

Heart rate (bpm)

88 (83, 92) 144 (135, 152) 83 (80, 87)

87 (83, 91) 141 (132, 149) 89 (81, 88)

0·85

127 (120, 133) 174 (163, 183) 21475 (19734, 23216) 490 (383, 596)

131 (124, 138) 171 (161, 180) 23265 (21524, 25006) 579 (472, 685)

0·18

134 (128, 141) 177 (171, 183) 23839 (2290, 25388) 671 (602, 740)

138 (132, 144) 174 (168, 181) 24142 (22593, 25691) 652 (584, 722)

476 (374, 606) 2·2 (1·7, 2·7)

483 (380, 616) 2·2 (1·7, 2·8)

Systolic blood pressure (mm Hg) Double product (mm Hg⫻bpm) 1mm ST-segment depression Heart rate (bpm) Systolic blood pressure (mm Hg) Double product (mm Hg⫻bpm) Time(s) Peak exercise Heart rate (bpm) Systolic blood pressure (mm Hg) Double product (mm Hg⫻bpm) Time(s) Time to angina* (s) Maximum ST-segment depression (mm)

p

0·60 0·69

0·55 0·011 0·028

0·22 0·55 0·73 0·35 0·87 0·91

P2

E2

p

89 (85, 93) 136 (128, 145) 81 (78, 85)

86 (82, 90) 144 (135, 152) 84 (80, 88)

0·27

125 (119, 132) 165 (156, 175) 20272 (18531, 22013) 497 (390, 603)

130 (124, 137) 172 (163, 182) 22389 (20648, 24130) 613 (507, 720)

0·17

140 (133, 146) 178 (171, 184) 25041 (23492, 26590) 668 (599, 737)

131 (124, 137) 273 (163, 182) 22813 (21264, 24362) 656 (587, 725)

537 (422, 684) 2·5 (2·0, 3·0)

464 (364, 591) 2·4 (1·9, 3·0)

0·17 0·38

0·14 0·003 0·006

0·005 0·25 0·015 0·53 0·15 0·58

P1= patch placebo; P2=2 patches placebo; E1 50 ␮g oestradiol; E2 100 ␮g patch oestradiol; bpm, beats per minute. Values are mean (95% CI), * values are geometric mean (95% CI).

Effects of 17␤-oestradiol at rest and during exercise

1556

THE LANCET • Vol 351 • May 23, 1998

RESEARCH LETTERS

MPA trough plasma concentration (␮g/mL)

chronic 17␤-oestradiol on total exercise time. This disparity may be related to the high plasma concentrations in the acute study, compared with the replacement concentrations achieved in the present study, or to possible mechanistic differences associated with acute versus chronic oestrogen exposure. Studies of conventional antianginal therapy such as verapamil have also shown no effect on total exercise time but an increase in time to 1 mm ST-segment depression. The decrease in heart rate and double product induced after 8 weeks of oestrogen treatment may indicate an effect of oestrogen on sympathetic neurotransmission. Chronic oestrogen treatment may be decreasing heart rate and myocardial work at peak exercise via this mechanism. A direct vasodilatory effect on the coronary arteries, possibly via an endothelium-dependent mechanism, may also account for this effect. Further chronic studies are required to establish whether different hormone therapy regimens have different potencies in the treatment of stable angina in women, or may be used as an adjunct to existing antianginal therapy. Supported by the British Heart Foundation and Janssen-Cilag Ltd. 1

2

3

4

5

Gilligan DM, Quyyumi AA, Cannon RO, III. Effects of physiological levels of oestrogen on coronary vasomotor function in postmenopausal women. Circulation 1994; 89: 2545–51. Collins P, Rosano GMC, Sarrel PM, et al. Estradiol-17␤ attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation 1995; 92: 24–30. Herrington DM, Braden GA, Williams JK, Morgan TM. Endothelialdependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy. Am J Cardiol 1994; 73: 951–52. Rosano GMC, Caixeta AM, Chierchia SL, et al. Acute anti-ischemic effect of estradiol-17␤ in postmenopausal women with coronary heart disease. Circulation 1997; 96: 2837–41. Rosano GMC, Sarrel PM, Poole-Wilson PA, Collins P. Beneficial effect of oestrogen on exercise-induced myocardial ischaemia in women with coronary heart disease. Lancet 1993; 342: 133–36.

Division of Cardiac Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, and Royal Brompton Hospital, London SW3 6LY, UK (P Collins); and Department of Cardiology, Ospedale San Raffaele, Rome, Italy

Trough blood concentrations in long-term treatment with mycophenolate mofetil Sylvia Sanquer, Myriam Breil, Christophe Baron, Djamal Dahmane, Alain Astier, Philippe Lang

Mycophenolate mofetil (MMF) is routinely administered as a fixed regimen. Contrary to the other immunosuppressive drugs, drug monitoring has not been required to optimise its activity or reduce its toxicity.1 The efficacy of MMF in early post-transplant outcomes 2 has led renal transplant physicians to increasingly use this drug for baseline immunosuppression. Despite, however, reduced acute rejection rates, the improvement of 1-year graft survival or incidence of chronic rejection incidence at 3 years has yet to be demonstrated. 3 We looked to see whether timedependent changes in the pharmacokinetics of MMF could contribute to this absence of long-term efficacy. Two groups of stable renal-transplant patients treated with MMF at a dose of 1 g twice daily were enrolled in our study after giving informed consent. The first group was 8 patients who had taken MMF for 2 to 10 months and the second group was 7 patients who had taken MMF for 2–3 years. All patients also received cyclosporin 2·2–3·2 mg/kg/per day and prednisone 0·05–0·35 mg/kg per day. Trough plasma concentration of mycophenolic acid (MPA),

THE LANCET • Vol 351 • May 23, 1998

4

3

* 2

1

0 Short-term

Long-term

MMF

MMF

Mean (SE) trough plasma concentration of MPA in stable renal transplant patients under short-term and long-term MMF therapy. *p=0·0059 long-term MMF therapy versus short-term MMF therapy.

the active metabolite of MMF, was measured with an EMIT assay.4 Values were expressed as mean (SEM) MannWhitney test for independent data was used and a p value below 0·05 was considered significant. Long-term MMF-treated patients had significantly lower trough plasma concentration of MPA compared with patients taking MMF short-term (1·96[0·24] ␮g/mL vs 3·53 [0·45] mg/mL, p=0·0059) (figure). MMF acts through the selective, reversible, and noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH), a pivotal enzyme in the de-novo synthesis of guanosine nucleotides in T and B lymphocytes and IMPDH activity has been shown to parallel MPA concentration in renal transplantation.5 The reduction in the trough plasma concentration of MPA with the length of MMF treatment suggests that pharmacokinetic behaviour of MMF becomes modified and may in turn, lead to alterations in the biological activity of the drug, Adjustment of the regimen of MMF with time seems to be required to maintain effective blood levels with long-term treatment. 1

2

3

4 5

Fulton B, Markham A. Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Drugs 1996; 51: 278–97. European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticoids for prevention of acute rejection. Lancet 1995; 345: 1321–25. The International Mycophenolate Mofetil Study Group. A long-term randomized multicenter study of mycophenolate mofetil (MMF) in cadaveric renal transplantation: results at 3 years. XVIth Annual Meeting of the American Society of Transplant Physicians, Chicago, May 11–14, 1997. Haley CJ, Jaklitsch A, McGowan B. Feasibility of an EMIT assay for mycophenolic acid in plasma. Ther Drug Monit 1995; 17: 431. Langman LJ, LeGatt DG, Halloran PF, Yatscoff RW. Pharmacodynamic assessment of mycophenolic acid-induced immunosuppression in renal transplant recipients. Transplantation 1996; 62: 666–72.

Laboratory of Toxicology-Pharmacology (S Sanquer) and Department of Nephrology, Henri Mondor Hospital, 94010 Crétail, France; and Laboratory of Clinical Pharmacy, School of Pharmacy, Nancy

1557