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Efficacy and tolerability of transdermal 17 beta-estradiol in patients with climacteric symptoms: dose titration according to individual choice
CURRENT THERAPEUTIC RESEARCH” VOL. 57, NO. 7, JULY 1996
EFFICACY AND TOLERABILITY OF TRANSDERMAL 17 BETA-ESTRADIOL IN PATIENTS WITH CLIMACTERIC SYMPTOMS: DOSE TITRATION ACCORDING TO INDIVIDUAL CHOICE DAVID SEFATY’ ‘Department
of Gynecology,
AND FRANCINE
CAULIN’
Hdpital Saint Louis, Paris and ‘RhBne-Poulenc International, Antony, France
Rarer
ABSTRACT
The aim of this open-label, multicenter study was to determine the efficacy and tolerability of four doses of transdermal 17 beta-estradiol (25, 50, 75, and 100 pg/d) in postmenopausal women and to evaluate the effectiveness of individually and pragmatically adjusted doses, following up and down titration of the initial dose. After a 2-week washout period, women began the first cycle of treatment with transdermal 17 beta-estradiol50 pg/d. After 1 month, women could choose to continue, decrease, or increase that dose, according to their perception of effectiveness and tolerance. After cycle 2, women had another opportunity to alter their dose. A total of 77% (176 of 228) of patients completed all three treatment cycles, and 199 were considered suitable for evaluation on a per-protocol basis. After 1 month, a total of 47% of women chose to stay on a fixed 50-Kg/d dose, 23% increased to 75 pgld, and only 1 chose to increase to 100 pgld; 18% decreased to 25 pg/d; and ll%, after initial modification, returned to the initial 50-pgld dose. The climacteric symptom of hot flushes was the main indicator of effectiveness. At baseline, all women had a similar daily number of hot flushes, which was significantly reduced from 6.9 f 5.0 at baseline to 1.1 + 3.6 at the end of cycle 3. By titration group, patients who chose to maintain their treatment on a fixed dose or to decrease had a significantly greater reduction in hot flushes at cycles 1 and 2 compared with the other groups. Nevertheless, when mean scores on a loo-mm visual analog scale for hot flushes and nocturnal sweating were combined, results showed that at the end of cycle 3, the therapeutic effect was similar for all titration groups. Mild or minor adverse events were reported by 56% (128 of 228) of patients; in 79% of patients (101 of 128), these events were considered related to the study drug. Breast sensitivity (29%; 65 of 228) and skin reactions (20%; 46 of 228) were the most commonly reported side effects. An increased number of adverse effects were reported by patients who increased their dose. These results suggest that women are able to adapt hormone replacement therapy dose themselves, according to their initial (1 month) individual response to treatment in terms of effectiveness and tolerance, with no significant loss of therapeutic benefit.
Address correspondence to: F. C&in, 20 Avenue Raymond Arm, 92165 Antony, Cedex, France. Received for publication on March 18,1996. Printed in the U.S.A. Reproduction in whole or part is not permitted.
506
0011-393X/96/$3.50
D. SEFATY
AND F. CAULlN
INTRODUCTION
It is well established that hormone replacement therapy (HRT), typically administered on a short-term basis, can reduce climacteric symptoms such as hot flushes and night sweating.’ Quality of life can also improve with both short- and long-term treatment.2,3 Furthermore, HRT has been shown to be effective in reducing bone 10ss*,~both immediately and later on after menopause. Epidemiologic studies also suggest that long-term HRT reduces the incidence of bone fractures and is associated with a reduction in cardiovascular disease. 6*7However, the number of postmenopausal women who use HRT remains smal1.s After HRT is prescribed, noncompliance with treatment is very common: 40% to 60% of women stop treatment within 1 year, and only 5% to 34% comply with HRT during the first 5 years.g The reasons most commonly reported for discontinuation of therapy are reoccurrence of bleedingl’ and symptoms of premenstrual syndrome (PM@, especially breast tenderness. This latter symptom often triggers a fear of breast cancer, although studies have shown that HRT does not increase this risk in shortterm users* but does so in long-term users (~5 years).” Estrogen plasma levels of approximately 30 to 50 pg/mLi2 have been shown to be sufficient for the alleviation of climacteric symptoms.‘3 However, effectiveness and tolerance may vary among women for the same dose administered. It is possible that compliance could be improved if dosage was individualized. The objectives of this study were to determine the efficacy and safety of four doses of transdermal 17 beta-estradiol* in postmenopausal women and to evaluate the effectiveness of individually preferred doses, following up and down titration of the initial dose. The classic climacteric symptom of hot flushes was chosen as the main indicator of effectiveness because its occurrence can be assessed easily in a 3-month period. PATIENTS
AND METHODS
This open-label, multicenter study included ambulatory, postmenopausal women aged 40 to 65 years with climacteric symptoms. The study duration was 3.5 months, with assessments performed on inclusion, after a 2-week washout period, and after 1, 2, and 3 months of treatment. Women were eligible for the study if (1) their last menstrual period was at least 3 months before enrollment; or (2) if they were having monthly withdrawal bleeding related to sequential estrogen therapy and had a plasma estradiol level of ~10 pg/mL or ~30 pg/mL if the follicle *Trademark: Menorest@ (RhBne-Poulenc Rarer, Antony, France).
507
PATIENT
DOSE TITRATION
OF 17 BETA-ESTRADIOL
stimulating hormone level was >40 mIU/mL (or above the normal premenopausal laboratory range). Women with menopause secondary to oophorectomy performed >l month previously were also included. All patients had an average of three hot flushes per day or at least 21 hot flushes during the week before inclusion. A mammography and Papanicolaou smear in nonhysterectomized women were obtained, unless these tests had been performed within the last 12 months, to confirm the lack of contraindications to estrogen therapy. Patients were ineligible for the study if they had a history or presence of any dermatologic condition interfering with the application of patches; known skin contact allergy diseases; estrogen implants; malignant tumors of the breast, endometrium, uterus, cervix, or ovaries; a history of intolerance to estrogen and progestogen therapy; previous severe side effects with oral contraceptives; or specific contraindications to estrogen and progestogen therapy. Eligible women had to give written informed consent and be willing to discontinue any previous HRT for 2 weeks. Additional sex hormone therapy and concomitant medication were not permitted during the study. After the 2-week washout period, patients began the first 25-day cycle of treatment with transdermal 17 beta-estradiol 50 p_g/d,followed by 4 2 1 days without treatment. Nonhysterectomized patients received concomitant progestogen therapy, as determined by their physician, for at least the last 12 days of estrogen treatment, typically starting by day 14 and continuing until day 25. Using daily diary cards, patients recorded the dates of each new patch application and patch removal, intensity and number of hot flushes, occurrence of spotting and/or bleeding, timing of progestogen treatment, and any problems associated with patch adherence. At the end of the first follow-up visit, patients were given the opportunity to maintain their treatment dose or to increase or decrease to the next consecutive dose for cycle 2, according to their personal tolerance and efficacy of the medication. Four patch sizes were available, delivering the drug at rates of 25, 50, 75, and 100 kg/d. Likewise, treatment for cycle 3 was given according to the patient’s preferred dose. At each follow-up visit, the patient assessed the intensity of hot flushes, nocturnal sweating, and sleep disturbances according to a lOO-mm visual analog scale (VAS) with ratings from none to severe and graded PMS symptoms such as breast tenderness, migraine/headache, and swollen legs also on a VAS; vaginal dryness was evaluated separately. Treatment compliance was assessed from unused medications returned to the investigator and diary card data. The physician also performed a topical skin evaluation and adverse-event assessment (open questions). Treatment interruptions, other than between cycles, were reported on 508
D.SEFATYANDF.CAULIN
the case report form, and patients were excluded if the number of days of patch application fell below 75% of the prescribed amount.
Statistical Analp& Daily numbers of hot flushes were assessed for the total per-protocol population and dose titration groups; the results were presented descriptively with 95% confidence intervals. Differences in hot flushes relative to baseline were compared using Wilcoxon’s signed rank test. Differences between titration groups were compared using the Kruskal-Wallis test. Safety was analyzed on an intent-to-treat basis. All probabilities reported were two tailed, interpreted at the 5% significance level. RESULTS A total of 228 women from seven European countries were included in the study. Of these, 77% (176 of 228) completed all three treatment cycles, 14% (32 of 228) completed two cycles, and 9% (20 of 228) completed only the first cycle. Twenty-nine patients were excluded because of protocol violations, leaving 199 patients who were considered suitable to evaluate on a perprotocol basis. Baseline symptoms for these patients are shown in Tables I and II.
Dose Titration Ninety-four (47%) patients chose to maintain their dose of estrogen at 50 pg/d during the entire study period, and 63 (32%) chose to increase to 75 p.g/d after the first month of treatment. Within this group, 47 (75%) patients maintained this dose after the second month, one chose to increase the dose to 100 kg/d, and 15 patients (24%) chose to return to the initial 50 pg/d dose (identified as switchers). Fourty-two (21%) patients opted to decrease their dose to 25 pg/d after the first month of treatment. Of this Table I. Baseline symptoms for total per-protocol population.
Mean + SD
No. (%) Hot flushes Daily number VAS Sleep disturbances (VAS) Nocturnal sweating (VAS) Mean VAS score for hot flushes and sweating Vaginal dryness
6.9 64.3 51.6 55.1 59.7 1.1
Cl = confidence interval; VAS = visual analog scale. 509
-c 2 k * t 5
5.02 22.41 29.28 29.85 22.45 0.98
95% Cl 6.2-7.6 61.2-67.4 47.5-55.6 GEE 0.9-l .2
PATIENT
DOSE TITRATION
OF 17 BETA-ESTRADIOL
group 35 (83%) patients remained with the low dose until the end of treatment and 16% decided to return to the 50qg/d dose (switchers). The reasons for dose reduction were mainly side effects, 63% (of which breast tenderness accounted for 33%); complete remission of symptoms, (20%) was the second largest reason for decreasing the dose. Increases in dose were prompted mainly by the desire to further reduce climacteric symptoms (87% of patients). Efficacy The main effectiveness criterion was a decrease in the daily number of hot flushes. Overall, the number of hot flushes decreased from 6.9 + 5.0 daily at baseline to 1.1 * 3.6 daily at the end of cycle 3 (Wilcoxon’s signed rank test, P = 0.0001). Compared with baseline, the mean difference in number of daily hot flushes during cycles 1,2, and 3 were - 3.4 + 4.5, - 5.6 ? 4.7, and -5.8 2 6.0, respectively. The fixed-dose and dose-decrease groups achieved a greater reduction in hot flushes during cycles 1 and 2 compared with the other groups (Kruskal-Wallis test, cycle 1, P = 0.0001; cycle 2, P = 0.0626). Interestingly, there was no increase in the daily number of hot flushes during the off-treatment period (days 25 to 29). A statistically significant improvement in VAS scores for hot flushes was seen at each cycle compared with baseline (Wilcoxon’s signed rank test, P = 0.0001). VAS scores decreased from 64.3 + 22.4 mm at baseline to 9.3 t 15.6 mm by the end of cycle 3. Likewise, a statistically significant improvement as treatment progressed was observed for sleep disturbances and nocturnal sweating (Wilcoxon’s signed rank test, P = 0.0001). Hot flushes and nocturnal sweating are considered closely related. These two variables were combined, and the results also show a consistent reduction of the mean score over time, from 59.7 + 22.4 mm at baseline to 9 + 15.3 mm after cycle 3 (mean difference from baseline, -50.7 -+ 7.1 mm). Furthermore, the results by titration group show that the doseincrease and dose-decrease groups experienced a similar reduction in these symptoms by the end of cycle 3, with the fixed dose being slightly more effective (Figure 1). A statistically significant improvement relative to baseline was observed for vaginal dryness at each of the cycles (Wilcoxon’s signed rank test, P = 0.0001). The global PMS score at baseline was 2.1 + 2.2. It improved progressively at each treatment cycle, reaching 1.2 ? 1.5 by the end of cycle 3. The mean differences relative to baseline were -0.4 2 1.9, -0.5 ? 2.2, and - 0.8 ? 2.2 for cycles 1,2, and 3, respectively. Within each titration group, the incidence of patients with a global PMS score <4 did not change substantially over time. At the end of cycle 3,85% of women in the fixed-dose
510
D. SEFATY AND F. CAULIN
80
I
I
I
I
Baeellne
Cycle 1
Cycle 2
Cycle 3
Dose decrease Dow incrcHse DoseswItch ____ ____. FIxeddoss
______
Figure 1. Scores (mean 2 SE) at each cycle on a loo-mm visual analog scale for hot flushes and sleep disturbances by titration group. Dose switch refers to patients who increased or decreased the dose but returned to initial dose.
group had a global PMS score <4 compared with 71% in the dose-increase group (Table III). At baseline, only nine patients (5%) experienced spotting and/or bleeding. After the first cycle, the mean number of days for which the patient reported spotting and/or bleeding was 1.4 + 2.3, which rose to 3.3 1 3.9 after cycle 2; a minimal change was noted during the third cycle (3.2 + 3.9). By titration group, these results were similar except for cycle 3, during which women decreasing the dose had a mean of 1.8 k 2.2 days with
511
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Table II. Baseline symptoms and global score for premenstrual per-protocol population.
syndrome
(PMS) for total
No. (%) PM;o;;mptoms Light/mild Moderate Heavy/severe Missing data Total PMSqglobal score*
1;; (f
Zal
199 I 100)
* Four-point scale (0 = none; 0.5 = mild; 1 = moderate; 1.5 = severe).
spotting and/or bleeding compared with a mean of 3 to 4 days in the other groups (Figure 2). Safety
Adverse events, excluding spotting, bleeding, and PMS symptoms, were analyzed for the overall population. Overall, 56% of patients (128 of 228) reported a total of 226 adverse events during the study. The most commonly reported adverse reactions were breast sensitivity in 29% of patients (65 of 228) and skin reactions such as erythema, pruritus, and irritation in 20% of patients (46 of 228). When comparing the titration groups for the study population, 48% of patients (45 of 94) remaining on a fixed dose reported side effects. The proportions were higher for women who opted for a dose change: 56% (27 of 48) of dose increasers, 77% (27 of 35) of dose decreasers, and 86% (19 of 22) of dose switchers (those who returned to original dose). Adverse events were considered severe in 8% of patients (10 of 128) Table III. Premenstrual syndrome evaluation: per titration group.
Percentage
of patients with a global score
<4
Titration Group Fixed Dose (%)
Dose Decrease (%)
512
Dose Increase (%)
Dose Switch (%)
D. SEFATY AND F. CAULIN
5.0 -
3.5 -
3.0 cn % P ‘ii
2.5-
s 2.0 -
1.5-
1.0I 0.5 -
I cycle 1
I cyc* 2
I cycle 3
l-l Dowdecmwe
_
DoseIncrease Doseswitch
_ __ _____ __
Fixeddose
______
Figure 2. Menstrual record (number [mean 2 SE1 of days with spotting and/or bleeding) by titration group. Dose switch refers to patients who increased or decreased the dose but returned to the initial dose.
and related to the study drug in 79% of patients (101 of 128). Adverse events were considered serious in only three patients: one patient was withdrawn after erythema, pruritus, and irritation were observed at the site of a 17 beta-estradiol 25 *g/d patch; one patient continued after erythema, originally considered as “serious,” was then rated as mild by the investigator; and one patient had a migraine and nausea due to a car accident, for which she was hospitalized for 1 day. Some women reported episodic lack of adhesiveness of the patch, which did not impair effectiveness.
513
PATIENT
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DISCUSSION
OF 17 BETA-ESTRADIOL
AND CONCLUSIONS
All women suffered from approximately the same daily number of hot flushes at the start of the study. Women who chose to decrease their HRT dose, however, achieved nearly the same reduction in daily number of hot flushes as women who remained on a fixed dose. Moreover, the combined mean VAS scores for hot flushes and night sweating showed that whether women chose to increase or decrease their dose, or remain on a fixed dose, the therapeutic effect after three cycles of HRT was similar. In total, 63% of women who opted for a dose reduction did so because of side effects and 87% of dose-increasers made that decision to further reduce climacteric symptoms. Once these women started taking a higher dose, they experienced a further degree of hot flush reduction; only one woman chose to increase the dose to 100 pg/d. The incidence of PMS symptoms, however, did not change substantially over time within each titration group and by the end of cycle 3, 71% of women in the dose-increase group had a global PMS score ~4 compared with 85% in the fixed-dose group. On the other hand, women who increased their dose experienced an increase of withdrawal bleeding. There was no reoccurrence of hot flushes during the off-period, confirming a maintenance of effectiveness after decreased estrogen blood levels.” This point is important to consider when estrogens are prescribed for therapeutic effectiveness other than postmenopausal symptoms. Finally, it is often thought that women given sequential HRT treatment will experience bleeding only during the off-treatment days, but our results do not support this hypothesis. When the incidences of patients with spotting and/or bleeding on days with treatment versus days offtreatment were compared over all three treatment cycles, they were similar (80% vs 78%). Within cycles, the incidence was different only for the first cycle (23% vs 63%). These results suggest that women are able to adapt HRT dose themselves, according to their individual response to treatment, with no significant loss of therapeutic effect. Furthermore, slightly more than 50% of women in this study chose to alter their dose, demonstrating the variable effectiveness among individuals of a given dose of estradiol. Allowing women to control their dose could therefore play an important part in compliance. In conclusion, if women are given the opportunity to adapt the HRT dose themselves according to their individual response to treatment, compliance may be improved and the overall effectiveness in terms of lowering climacteric symptoms can be increased. Dialogue between women and their physicians and physicians advice will be the keys for improved patient benefit. 514
D. SEFATY
AND F. CAULIN
Acknowledgments The authors wish to acknowledge the following investigators and coordinators who worked on the trials discussed in this paper. Investigators: France: Dr. Aubeny, Dr. Buvat-Herbaux, Dr. Dreyfus, Dr. Homasson, Dr. Langlade, Dr. Lefebvre, Dr. Levrier, Dr. Missey-Kolb, Dr. Raab-Rosner, Dr. Rossin-Amar, and Dr. Serfaty; Belgium: Prof. Schwers, Prof. Thomas, Dr. Gerris, Dr. Rozenberg, and Dr. Vanderick; The Netherlands: Mrs. Beijers-De Bie, Dr. Beekhuis, Dr. Ras, Dr. Van Soest, and Dr. Ypma; Germany: Prof. Petersen; the Czech Republic: Prof. Presl; Hungary: Prof. Papp. Study Coordinators: Mrs. Weisenberger, Dr. Nauert, Dr. van der Schaaf, Dr. Krygier, Dr. Deslandes, and Mr. Desmedt. This study was supported by a grant from Rhone-Poulenc Rorer International, Antony, France. References: 1. Lauritxen C. Clinical use of oestrogens or progestogens. Maturitos. 1990;12:199-214. 2. Wiklund I, Holst J, Karlberg J, et al. Long-term effect of transdermal hormonal therapy on aspects of quality of life in postmenopausal women. Muturitus. 1992;14:225-236. 3. Wiklund I, Berg G, Hammar M, et al. A new methodological approach to the evaluation of quality of life in postmenopausal women. Maturitas. 1992;14:211-224. 4. The Writing Group for PEPI trial. Effect of estrogen or estrogen/progestin regimen on heart disease risk factors in postmenopausal women. JAMA. 1995;273:199-206. 5. Whiteroft SIJ, Stevenson JC. Hormone replacement therapy: Risks and benefits. Clin Endocrinol. 1992;36:15-20. 6. Grady D, Rubin SM, Pettiti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Zntern Med. 1992;117:1016-1037. 7. Stampfer MJ, Cold& GA. Estrogen replacement therapy and coronary artery disease: A quantitative review of epidemiologic evidence. Preu Med. 1991;20:47-63. 8. Lauritzen C, ed. Hormone Replacement Therapy: Practical Guidelines for General Pmctitioners. Amsterdam: Excerpta Medica; 1995. 9. Speroff T, Dawson NV, Speroff L, Haber RI. A risk-benefit analysis of elective bilateral oophorectomy: Effect of changes in compliance with estrogen therapy on outcome. Am J Obstet Gynecol. 1991;164:165-174. 10. Ravniker VA. Compliance with hormone therapy. Am J Obstet Gynecol. 1987;156:13321334. 11. Cold& GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. NEJM. 1995;332:1589-1593. 12. Lobe RA, March CM, Goebelsmann U, et al. Subepidermal estradiol pellets following hysterectomy and oophorectomy. Am J Obstet Gynecol. 1980;138:714-719. 13. Lomax P, Schonbaum E. Postmenopausal hot flushes and their management. Pharmacol Ther. 1993;57:347-358.
515
EFFICACY AND TOLERABILITY OF TRANSDERMAL 17 BETA-ESTRADIOL IN PATIENTS WITH CLIMACTERIC SYMPTOMS: DOSE TITRATION ACCORDING TO INDIVIDUAL CHOICE DAVID SEFATY’ ‘Department
of Gynecology,
AND FRANCINE
CAULIN’
Hdpital Saint Louis, Paris and ‘RhBne-Poulenc International, Antony, France
Rarer
ABSTRACT
The aim of this open-label, multicenter study was to determine the efficacy and tolerability of four doses of transdermal 17 beta-estradiol (25, 50, 75, and 100 pg/d) in postmenopausal women and to evaluate the effectiveness of individually and pragmatically adjusted doses, following up and down titration of the initial dose. After a 2-week washout period, women began the first cycle of treatment with transdermal 17 beta-estradiol50 pg/d. After 1 month, women could choose to continue, decrease, or increase that dose, according to their perception of effectiveness and tolerance. After cycle 2, women had another opportunity to alter their dose. A total of 77% (176 of 228) of patients completed all three treatment cycles, and 199 were considered suitable for evaluation on a per-protocol basis. After 1 month, a total of 47% of women chose to stay on a fixed 50-Kg/d dose, 23% increased to 75 pgld, and only 1 chose to increase to 100 pgld; 18% decreased to 25 pg/d; and ll%, after initial modification, returned to the initial 50-pgld dose. The climacteric symptom of hot flushes was the main indicator of effectiveness. At baseline, all women had a similar daily number of hot flushes, which was significantly reduced from 6.9 f 5.0 at baseline to 1.1 + 3.6 at the end of cycle 3. By titration group, patients who chose to maintain their treatment on a fixed dose or to decrease had a significantly greater reduction in hot flushes at cycles 1 and 2 compared with the other groups. Nevertheless, when mean scores on a loo-mm visual analog scale for hot flushes and nocturnal sweating were combined, results showed that at the end of cycle 3, the therapeutic effect was similar for all titration groups. Mild or minor adverse events were reported by 56% (128 of 228) of patients; in 79% of patients (101 of 128), these events were considered related to the study drug. Breast sensitivity (29%; 65 of 228) and skin reactions (20%; 46 of 228) were the most commonly reported side effects. An increased number of adverse effects were reported by patients who increased their dose. These results suggest that women are able to adapt hormone replacement therapy dose themselves, according to their initial (1 month) individual response to treatment in terms of effectiveness and tolerance, with no significant loss of therapeutic benefit.
Address correspondence to: F. C&in, 20 Avenue Raymond Arm, 92165 Antony, Cedex, France. Received for publication on March 18,1996. Printed in the U.S.A. Reproduction in whole or part is not permitted.
506
0011-393X/96/$3.50
D. SEFATY
AND F. CAULlN
INTRODUCTION
It is well established that hormone replacement therapy (HRT), typically administered on a short-term basis, can reduce climacteric symptoms such as hot flushes and night sweating.’ Quality of life can also improve with both short- and long-term treatment.2,3 Furthermore, HRT has been shown to be effective in reducing bone 10ss*,~both immediately and later on after menopause. Epidemiologic studies also suggest that long-term HRT reduces the incidence of bone fractures and is associated with a reduction in cardiovascular disease. 6*7However, the number of postmenopausal women who use HRT remains smal1.s After HRT is prescribed, noncompliance with treatment is very common: 40% to 60% of women stop treatment within 1 year, and only 5% to 34% comply with HRT during the first 5 years.g The reasons most commonly reported for discontinuation of therapy are reoccurrence of bleedingl’ and symptoms of premenstrual syndrome (PM@, especially breast tenderness. This latter symptom often triggers a fear of breast cancer, although studies have shown that HRT does not increase this risk in shortterm users* but does so in long-term users (~5 years).” Estrogen plasma levels of approximately 30 to 50 pg/mLi2 have been shown to be sufficient for the alleviation of climacteric symptoms.‘3 However, effectiveness and tolerance may vary among women for the same dose administered. It is possible that compliance could be improved if dosage was individualized. The objectives of this study were to determine the efficacy and safety of four doses of transdermal 17 beta-estradiol* in postmenopausal women and to evaluate the effectiveness of individually preferred doses, following up and down titration of the initial dose. The classic climacteric symptom of hot flushes was chosen as the main indicator of effectiveness because its occurrence can be assessed easily in a 3-month period. PATIENTS
AND METHODS
This open-label, multicenter study included ambulatory, postmenopausal women aged 40 to 65 years with climacteric symptoms. The study duration was 3.5 months, with assessments performed on inclusion, after a 2-week washout period, and after 1, 2, and 3 months of treatment. Women were eligible for the study if (1) their last menstrual period was at least 3 months before enrollment; or (2) if they were having monthly withdrawal bleeding related to sequential estrogen therapy and had a plasma estradiol level of ~10 pg/mL or ~30 pg/mL if the follicle *Trademark: Menorest@ (RhBne-Poulenc Rarer, Antony, France).
507
PATIENT
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OF 17 BETA-ESTRADIOL
stimulating hormone level was >40 mIU/mL (or above the normal premenopausal laboratory range). Women with menopause secondary to oophorectomy performed >l month previously were also included. All patients had an average of three hot flushes per day or at least 21 hot flushes during the week before inclusion. A mammography and Papanicolaou smear in nonhysterectomized women were obtained, unless these tests had been performed within the last 12 months, to confirm the lack of contraindications to estrogen therapy. Patients were ineligible for the study if they had a history or presence of any dermatologic condition interfering with the application of patches; known skin contact allergy diseases; estrogen implants; malignant tumors of the breast, endometrium, uterus, cervix, or ovaries; a history of intolerance to estrogen and progestogen therapy; previous severe side effects with oral contraceptives; or specific contraindications to estrogen and progestogen therapy. Eligible women had to give written informed consent and be willing to discontinue any previous HRT for 2 weeks. Additional sex hormone therapy and concomitant medication were not permitted during the study. After the 2-week washout period, patients began the first 25-day cycle of treatment with transdermal 17 beta-estradiol 50 p_g/d,followed by 4 2 1 days without treatment. Nonhysterectomized patients received concomitant progestogen therapy, as determined by their physician, for at least the last 12 days of estrogen treatment, typically starting by day 14 and continuing until day 25. Using daily diary cards, patients recorded the dates of each new patch application and patch removal, intensity and number of hot flushes, occurrence of spotting and/or bleeding, timing of progestogen treatment, and any problems associated with patch adherence. At the end of the first follow-up visit, patients were given the opportunity to maintain their treatment dose or to increase or decrease to the next consecutive dose for cycle 2, according to their personal tolerance and efficacy of the medication. Four patch sizes were available, delivering the drug at rates of 25, 50, 75, and 100 kg/d. Likewise, treatment for cycle 3 was given according to the patient’s preferred dose. At each follow-up visit, the patient assessed the intensity of hot flushes, nocturnal sweating, and sleep disturbances according to a lOO-mm visual analog scale (VAS) with ratings from none to severe and graded PMS symptoms such as breast tenderness, migraine/headache, and swollen legs also on a VAS; vaginal dryness was evaluated separately. Treatment compliance was assessed from unused medications returned to the investigator and diary card data. The physician also performed a topical skin evaluation and adverse-event assessment (open questions). Treatment interruptions, other than between cycles, were reported on 508
D.SEFATYANDF.CAULIN
the case report form, and patients were excluded if the number of days of patch application fell below 75% of the prescribed amount.
Statistical Analp& Daily numbers of hot flushes were assessed for the total per-protocol population and dose titration groups; the results were presented descriptively with 95% confidence intervals. Differences in hot flushes relative to baseline were compared using Wilcoxon’s signed rank test. Differences between titration groups were compared using the Kruskal-Wallis test. Safety was analyzed on an intent-to-treat basis. All probabilities reported were two tailed, interpreted at the 5% significance level. RESULTS A total of 228 women from seven European countries were included in the study. Of these, 77% (176 of 228) completed all three treatment cycles, 14% (32 of 228) completed two cycles, and 9% (20 of 228) completed only the first cycle. Twenty-nine patients were excluded because of protocol violations, leaving 199 patients who were considered suitable to evaluate on a perprotocol basis. Baseline symptoms for these patients are shown in Tables I and II.
Dose Titration Ninety-four (47%) patients chose to maintain their dose of estrogen at 50 pg/d during the entire study period, and 63 (32%) chose to increase to 75 p.g/d after the first month of treatment. Within this group, 47 (75%) patients maintained this dose after the second month, one chose to increase the dose to 100 kg/d, and 15 patients (24%) chose to return to the initial 50 pg/d dose (identified as switchers). Fourty-two (21%) patients opted to decrease their dose to 25 pg/d after the first month of treatment. Of this Table I. Baseline symptoms for total per-protocol population.
Mean + SD
No. (%) Hot flushes Daily number VAS Sleep disturbances (VAS) Nocturnal sweating (VAS) Mean VAS score for hot flushes and sweating Vaginal dryness
6.9 64.3 51.6 55.1 59.7 1.1
Cl = confidence interval; VAS = visual analog scale. 509
-c 2 k * t 5
5.02 22.41 29.28 29.85 22.45 0.98
95% Cl 6.2-7.6 61.2-67.4 47.5-55.6 GEE 0.9-l .2
PATIENT
DOSE TITRATION
OF 17 BETA-ESTRADIOL
group 35 (83%) patients remained with the low dose until the end of treatment and 16% decided to return to the 50qg/d dose (switchers). The reasons for dose reduction were mainly side effects, 63% (of which breast tenderness accounted for 33%); complete remission of symptoms, (20%) was the second largest reason for decreasing the dose. Increases in dose were prompted mainly by the desire to further reduce climacteric symptoms (87% of patients). Efficacy The main effectiveness criterion was a decrease in the daily number of hot flushes. Overall, the number of hot flushes decreased from 6.9 + 5.0 daily at baseline to 1.1 * 3.6 daily at the end of cycle 3 (Wilcoxon’s signed rank test, P = 0.0001). Compared with baseline, the mean difference in number of daily hot flushes during cycles 1,2, and 3 were - 3.4 + 4.5, - 5.6 ? 4.7, and -5.8 2 6.0, respectively. The fixed-dose and dose-decrease groups achieved a greater reduction in hot flushes during cycles 1 and 2 compared with the other groups (Kruskal-Wallis test, cycle 1, P = 0.0001; cycle 2, P = 0.0626). Interestingly, there was no increase in the daily number of hot flushes during the off-treatment period (days 25 to 29). A statistically significant improvement in VAS scores for hot flushes was seen at each cycle compared with baseline (Wilcoxon’s signed rank test, P = 0.0001). VAS scores decreased from 64.3 + 22.4 mm at baseline to 9.3 t 15.6 mm by the end of cycle 3. Likewise, a statistically significant improvement as treatment progressed was observed for sleep disturbances and nocturnal sweating (Wilcoxon’s signed rank test, P = 0.0001). Hot flushes and nocturnal sweating are considered closely related. These two variables were combined, and the results also show a consistent reduction of the mean score over time, from 59.7 + 22.4 mm at baseline to 9 + 15.3 mm after cycle 3 (mean difference from baseline, -50.7 -+ 7.1 mm). Furthermore, the results by titration group show that the doseincrease and dose-decrease groups experienced a similar reduction in these symptoms by the end of cycle 3, with the fixed dose being slightly more effective (Figure 1). A statistically significant improvement relative to baseline was observed for vaginal dryness at each of the cycles (Wilcoxon’s signed rank test, P = 0.0001). The global PMS score at baseline was 2.1 + 2.2. It improved progressively at each treatment cycle, reaching 1.2 ? 1.5 by the end of cycle 3. The mean differences relative to baseline were -0.4 2 1.9, -0.5 ? 2.2, and - 0.8 ? 2.2 for cycles 1,2, and 3, respectively. Within each titration group, the incidence of patients with a global PMS score <4 did not change substantially over time. At the end of cycle 3,85% of women in the fixed-dose
510
D. SEFATY AND F. CAULIN
80
I
I
I
I
Baeellne
Cycle 1
Cycle 2
Cycle 3
Dose decrease Dow incrcHse DoseswItch ____ ____. FIxeddoss
______
Figure 1. Scores (mean 2 SE) at each cycle on a loo-mm visual analog scale for hot flushes and sleep disturbances by titration group. Dose switch refers to patients who increased or decreased the dose but returned to initial dose.
group had a global PMS score <4 compared with 71% in the dose-increase group (Table III). At baseline, only nine patients (5%) experienced spotting and/or bleeding. After the first cycle, the mean number of days for which the patient reported spotting and/or bleeding was 1.4 + 2.3, which rose to 3.3 1 3.9 after cycle 2; a minimal change was noted during the third cycle (3.2 + 3.9). By titration group, these results were similar except for cycle 3, during which women decreasing the dose had a mean of 1.8 k 2.2 days with
511
PATIENT
DOSE TITRATION
OF 17 BETA-ESTRADIOL
Table II. Baseline symptoms and global score for premenstrual per-protocol population.
syndrome
(PMS) for total
No. (%) PM;o;;mptoms Light/mild Moderate Heavy/severe Missing data Total PMSqglobal score*
1;; (f
Zal
199 I 100)
* Four-point scale (0 = none; 0.5 = mild; 1 = moderate; 1.5 = severe).
spotting and/or bleeding compared with a mean of 3 to 4 days in the other groups (Figure 2). Safety
Adverse events, excluding spotting, bleeding, and PMS symptoms, were analyzed for the overall population. Overall, 56% of patients (128 of 228) reported a total of 226 adverse events during the study. The most commonly reported adverse reactions were breast sensitivity in 29% of patients (65 of 228) and skin reactions such as erythema, pruritus, and irritation in 20% of patients (46 of 228). When comparing the titration groups for the study population, 48% of patients (45 of 94) remaining on a fixed dose reported side effects. The proportions were higher for women who opted for a dose change: 56% (27 of 48) of dose increasers, 77% (27 of 35) of dose decreasers, and 86% (19 of 22) of dose switchers (those who returned to original dose). Adverse events were considered severe in 8% of patients (10 of 128) Table III. Premenstrual syndrome evaluation: per titration group.
Percentage
of patients with a global score
<4
Titration Group Fixed Dose (%)
Dose Decrease (%)
512
Dose Increase (%)
Dose Switch (%)
D. SEFATY AND F. CAULIN
5.0 -
3.5 -
3.0 cn % P ‘ii
2.5-
s 2.0 -
1.5-
1.0I 0.5 -
I cycle 1
I cyc* 2
I cycle 3
l-l Dowdecmwe
_
DoseIncrease Doseswitch
_ __ _____ __
Fixeddose
______
Figure 2. Menstrual record (number [mean 2 SE1 of days with spotting and/or bleeding) by titration group. Dose switch refers to patients who increased or decreased the dose but returned to the initial dose.
and related to the study drug in 79% of patients (101 of 128). Adverse events were considered serious in only three patients: one patient was withdrawn after erythema, pruritus, and irritation were observed at the site of a 17 beta-estradiol 25 *g/d patch; one patient continued after erythema, originally considered as “serious,” was then rated as mild by the investigator; and one patient had a migraine and nausea due to a car accident, for which she was hospitalized for 1 day. Some women reported episodic lack of adhesiveness of the patch, which did not impair effectiveness.
513
PATIENT
DOSE TITRATION
DISCUSSION
OF 17 BETA-ESTRADIOL
AND CONCLUSIONS
All women suffered from approximately the same daily number of hot flushes at the start of the study. Women who chose to decrease their HRT dose, however, achieved nearly the same reduction in daily number of hot flushes as women who remained on a fixed dose. Moreover, the combined mean VAS scores for hot flushes and night sweating showed that whether women chose to increase or decrease their dose, or remain on a fixed dose, the therapeutic effect after three cycles of HRT was similar. In total, 63% of women who opted for a dose reduction did so because of side effects and 87% of dose-increasers made that decision to further reduce climacteric symptoms. Once these women started taking a higher dose, they experienced a further degree of hot flush reduction; only one woman chose to increase the dose to 100 pg/d. The incidence of PMS symptoms, however, did not change substantially over time within each titration group and by the end of cycle 3, 71% of women in the dose-increase group had a global PMS score ~4 compared with 85% in the fixed-dose group. On the other hand, women who increased their dose experienced an increase of withdrawal bleeding. There was no reoccurrence of hot flushes during the off-period, confirming a maintenance of effectiveness after decreased estrogen blood levels.” This point is important to consider when estrogens are prescribed for therapeutic effectiveness other than postmenopausal symptoms. Finally, it is often thought that women given sequential HRT treatment will experience bleeding only during the off-treatment days, but our results do not support this hypothesis. When the incidences of patients with spotting and/or bleeding on days with treatment versus days offtreatment were compared over all three treatment cycles, they were similar (80% vs 78%). Within cycles, the incidence was different only for the first cycle (23% vs 63%). These results suggest that women are able to adapt HRT dose themselves, according to their individual response to treatment, with no significant loss of therapeutic effect. Furthermore, slightly more than 50% of women in this study chose to alter their dose, demonstrating the variable effectiveness among individuals of a given dose of estradiol. Allowing women to control their dose could therefore play an important part in compliance. In conclusion, if women are given the opportunity to adapt the HRT dose themselves according to their individual response to treatment, compliance may be improved and the overall effectiveness in terms of lowering climacteric symptoms can be increased. Dialogue between women and their physicians and physicians advice will be the keys for improved patient benefit. 514
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AND F. CAULIN
Acknowledgments The authors wish to acknowledge the following investigators and coordinators who worked on the trials discussed in this paper. Investigators: France: Dr. Aubeny, Dr. Buvat-Herbaux, Dr. Dreyfus, Dr. Homasson, Dr. Langlade, Dr. Lefebvre, Dr. Levrier, Dr. Missey-Kolb, Dr. Raab-Rosner, Dr. Rossin-Amar, and Dr. Serfaty; Belgium: Prof. Schwers, Prof. Thomas, Dr. Gerris, Dr. Rozenberg, and Dr. Vanderick; The Netherlands: Mrs. Beijers-De Bie, Dr. Beekhuis, Dr. Ras, Dr. Van Soest, and Dr. Ypma; Germany: Prof. Petersen; the Czech Republic: Prof. Presl; Hungary: Prof. Papp. Study Coordinators: Mrs. Weisenberger, Dr. Nauert, Dr. van der Schaaf, Dr. Krygier, Dr. Deslandes, and Mr. Desmedt. This study was supported by a grant from Rhone-Poulenc Rorer International, Antony, France. References: 1. Lauritxen C. Clinical use of oestrogens or progestogens. Maturitos. 1990;12:199-214. 2. Wiklund I, Holst J, Karlberg J, et al. Long-term effect of transdermal hormonal therapy on aspects of quality of life in postmenopausal women. Muturitus. 1992;14:225-236. 3. Wiklund I, Berg G, Hammar M, et al. A new methodological approach to the evaluation of quality of life in postmenopausal women. Maturitas. 1992;14:211-224. 4. The Writing Group for PEPI trial. Effect of estrogen or estrogen/progestin regimen on heart disease risk factors in postmenopausal women. JAMA. 1995;273:199-206. 5. Whiteroft SIJ, Stevenson JC. Hormone replacement therapy: Risks and benefits. Clin Endocrinol. 1992;36:15-20. 6. Grady D, Rubin SM, Pettiti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Zntern Med. 1992;117:1016-1037. 7. Stampfer MJ, Cold& GA. Estrogen replacement therapy and coronary artery disease: A quantitative review of epidemiologic evidence. Preu Med. 1991;20:47-63. 8. Lauritzen C, ed. Hormone Replacement Therapy: Practical Guidelines for General Pmctitioners. Amsterdam: Excerpta Medica; 1995. 9. Speroff T, Dawson NV, Speroff L, Haber RI. A risk-benefit analysis of elective bilateral oophorectomy: Effect of changes in compliance with estrogen therapy on outcome. Am J Obstet Gynecol. 1991;164:165-174. 10. Ravniker VA. Compliance with hormone therapy. Am J Obstet Gynecol. 1987;156:13321334. 11. Cold& GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. NEJM. 1995;332:1589-1593. 12. Lobe RA, March CM, Goebelsmann U, et al. Subepidermal estradiol pellets following hysterectomy and oophorectomy. Am J Obstet Gynecol. 1980;138:714-719. 13. Lomax P, Schonbaum E. Postmenopausal hot flushes and their management. Pharmacol Ther. 1993;57:347-358.
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