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Compliance and satisfaction with raloxifene versus alendronate for the treatment of postmenopausal osteoporosis in clinical practice: An open-label, prospective, nonrandomized, observational study
CLINICAL THERAPEUTICS® / VOL. 26, NO. 2, 2004
Compliance and Satisfaction with Raloxifene Versus Alendronate for the Treatment of Postmenopausal Osteoporosis in Clinical Practice: An Open-Label, Prospective, Nonrandomized, Observational Study Carmen Turbí, MD,1 Gabriel Herrero-Beaumont, MD,2 Juan Carlos Acebes, MD, PhD,2 Antonio Torrijos, MD,3 Jenaro Graña, MD, PhD,4 Roberto Miguélez, MD, PhD,5 José Antonio Sacristán, MD,1 and Fernando Marín, MD, PhD6 1Department of Medical Research, Lilly S.A., Madrid, 2Rheumatology Service, Fundación Jiménez Díaz, Madrid, 3Rheumatology Service, Hospital La Paz, Madrid, 4Rheumatology Service, Hospital Juan Canalejo, La Coruña, 5Rheumatology Service, Hospital de Móstoles, Madrid, Spain, and 6Department of Medical Research, Lilly European
Operations, Windlesham, United Kingdom
ABSTRACT
Background: The treatment of osteoporosis among postmenopausal women represents a major public health challenge because long-term therapy is needed to prevent fractures and chronic disability. Low patient compliance with prescribed osteoporosis treatments can severely distort the validity of controlled clinical trials. Raloxifene and alendronate have been shown to reduce the incidence of osteoporotic fracture in postmenopausal women in well-conducted randomized trials, but few data are available on the rate of adherence to these treatments in routine clinical practice. Objective: The primary aim of this study was to assess the compliance of postmenopausal women at risk for osteoporotic fractures who were treated with raloxifene hydrochloride (RLX) versus alendronate sodium (ALN) during a 12-month observational period in a routine clinical setting. Secondary objectives were the assessment of factors that might contribute to noncompliance and patient satisfaction. Methods: This open-label, prospective, multicenter, nonrandomized, observational, comparative study was conducted at 154 centers across Spain. Assignment to either RLX or ALN treatment was determined by the physician and was based on each patient’s clinical profile. Compliance with RLX (60-mg tablet once daily) versus ALN (10-mg tablet once daily) was assessed using 3 different compliance assessment tools: the MoriskyGreen test, the Autocompliance test, and the Compliance Questionnaire. A logistic regression model was used to assess different factors affecting compliance. Patient satisfaction was also assessed using a questionnaire. Adverse events (AEs) were collected as reasons for discontinuation in the Compliance Questionnaire and at the discontinuation visit. Results: A total of 902 women (RLX group, n = 476; ALN group, n = 426) were included in the study (mean age, 64.4 [6.9] years). Overall, patients in the RLX group reported significantly better compliance than patients in the ALN group, as collected either by the Morisky-Green test (68.7% vs 54.0%; P < 0.001) or the Autocompliance test (94.7% vs 90.6%; P = 0.033). More patients discontinued treatment prematurely in the ALN group compared with the RLX group (25.8% vs 16.4%; P < 0.001). The age-adjusted relative risk for discontinuation was 1.4-fold higher for women treated with ALN than for those treated with RLX (95% CI, 1.21–1.61). The main reason for premature discontinuation was due to AEs (RLX 4.8% vs ALN 11.0%; P < 0.001). The proportion of patients with gastrointestinal AEs was 9.9% in the ALN group and 3.4% in the RLX Accepted for publication December 8, 2003. Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2004 Excerpta Medica, Inc.
0149-2918/04/$19.00
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group (P < 0.001). Only treatment and type of physician were independent covariates of treatment compliance. After 12 months of observation, significantly more patients in the RLX group were satisfied or very satisfied with their treatment than patients in the ALN group (P < 0.001). Conclusions: In this study of postmenopausal women at risk for osteoporotic fractures, compliance with 12-month treatment with daily RLX was higher than with daily ALN in a clinical setting. RLX showed significant benefits compared with ALN in terms of compliance assessed by means of the Morisky-Green and Autocompliance tests and the patient’s selfreported satisfaction (Clin Ther. 2004;26:245–256) © 2004 Excerpta Medica, Inc. Key words: compliance, osteoporosis, raloxifene, alendronate, clinical practice, postmenopausal.
INTRODUCTION
The selective estrogen receptor modulator raloxifene hydrochloride (RLX) and the bisphosphonate alendronate sodium (ALN) have been shown to reduce the incidence of osteoporotic fracture in postmenopausal women in randomized trials.1–4 However, according to a MEDLINE search (key terms, postmenopausal osteoporosis, compliance, adherence, discontinuation, alendronate, and raloxifene; years, 1985–2003), few data are available on the rate of adherence to these treatments in routine clinical practice,5–7 where compliance is likely to be different than in clinical trials. In fact, double-blind, randomized clinical trials tend to underestimate the likelihood of treatment discontinuation in routine clinical practice because patients participating in clinical trials are probably healthier and better counseled than patients in clinical practice.8 Because nonadherence limits the effectiveness of therapies for osteoporosis when used in clinical practice, it is important to assess treatment compliance in a clinical setting. Compliance with RLX or ALN therapy may be different from that in randomized trials. Few studies allow comparisons of the rate of adherence and patient satisfaction with these treatments in routine clinical practice.9 The aims of this study were to assess compliance (primary objective) and factors that might contribute to noncompliance with, as well as satisfaction of, RLX 246
or ALN (secondary objectives) in postmenopausal women at risk for osteoporotic fractures during a 12month period in a routine clinical setting. PATIENTS AND METHODS Study Design
This open-label, prospective, multicenter, nonrandomized, observational, comparative study was conducted at 154 centers across Spain. The protocol was approved by an independent review board. Patients
Postmenopausal women aged ≥55 years and at risk for osteoporotic fractures (according to the attending physician) were eligible for inclusion in the study. Patients had to comply with all the recommendations stated in the summaries of drug characteristics10,11 and to provide written informed consent. Exclusion criteria were use of antiresorptive treatment (except for calcium and vitamin D) within the 3 months before the study, contraindications as stated in the summaries of product characteristics for the use of RLX or ALN therapy, inability to adhere to the requirements of the study, and participation in another observational or experimental study. Methods Study Visits
Study visits occurred as follows: 1 visit at baseline, 1 visit at any time in the first 3 months (period 1), 1 visit at any time in the next 3 to 6 months (period 2), and a final visit at 12 months. At the baseline visit, several variables that might affect compliance were recorded, including patient demographic characteristics, type of physician, practice situation, number of previous diseases, number of concomitant medications, reason for using RLX or ALN treatment, and level of disease knowledge. Level of disease knowledge was assessed using a 3-item questionnaire that had been validated in a Spanish population.12 The questions were as follows: (1) “Is osteoporosis a disease that you will have for the rest of your life?” (2) “Can you prevent osteoporosis by changing your lifestyle or using medicines?” and (3) “State a complication of this disease.” This test was used to differentiate between 3 levels of knowledge: (1) acceptable knowledge (patient knows osteoporosis is a chronic, treatable condition and knows a complication); (2) unacceptable knowledge (patient does not
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know any complication of osteoporosis); and (3) moderately acceptable knowledge (any other combination of answers to the 3 questions). Also at the baseline visit, patients were assigned to self-administered oral treatment with RLX 60-mg tablet once daily or ALN 10-mg tablet once daily for 12 months. Treatment assignment to either RLX or ALN was determined by the physician based on the patient’s clinical profile. In cases of premature withdrawal from the study, questionnaires for compliance assessment and treatment satisfaction were to be administered.
Table I.
The Morisky-Green test.*13
1. “Do you ever forget to take your medicine?” 2. “Did you take your medicine at the indicated hour?” 3. “When you feel better, do you sometimes stop taking your medicine?” 4. “If you feel worse when you take the medicine, do you sometimes stop taking it?” *Scale: 0
= no, 1 = yes. In the second question of the Morisky-Green test,13 an affirmative answer adds 0 points and a negative answer adds 1 point to the total score. 0 = high Morisky-Green score, indicating maximum compliance; 1 or 2 = moderate score; 3 or 4 = low score. A score of 0–2 is considered good compliance.
Compliance Assessment
Compliance was assessed at the observational periods using 3 questionnaires (the Morisky-Green test, the Autocompliance test, and the Compliance Questionnaire), administered by the patient’s physician. The Morisky-Green test is a closed questionnaire with 4 questions about disease treatment (Table I).13 This questionnaire has been validated in the Spanish population.14 The Autocompliance test was used to estimate the number of tablets not taken during the previous month, following the methodology of Haynes et al,15 as well as difficulty taking the medication, and consists of 2 open questions: (1) “Do you have difficulty in taking the tablets?” and (2) “How many tablets have you missed in the last month?” Compliance was determined by calculating the number of tablets remaining, using the following formula:
Compliance =
30 – no. of missed tablets during the previous month
× 100
30 A patient was considered a complier if she declared she had missed ≤20% of the total number of tablets prescribed. Finally, the Compliance Questionnaire asked 2 questions: (1) “Is the patient going to continue on the initially assigned osteoporosis treatment?” and (2) “If not, please specify the reason and time of discontinuation.” Satisfaction Assessment
Patient satisfaction was assessed using a specific questionnaire with 1 question: “How satisfied are you
with the treatment you took during your participation in this study?” This questionnaire evaluates the patient’s satisfaction with the treatment by a 4-ordinal categorical scale (very dissatisfied, dissatisfied, satisfied, and very satisfied). All participating physicians were instructed to make their assessments as consistent as possible and not to influence patients’ assessments of treatment satisfaction and self-reported compliance. Tolerability Assessment
Information on adverse effects (AEs) was based on data from the Compliance Questionnaire and the discontinuation visit. Statistical Analysis
The compliance analysis included consideration of each compliance measurement, each compliance question, and each study visit. The sample size of 900 patients was calculated to detect a ≥10% difference in self-reported compliance between the 2 treatments, assuming 80% power and a 2-sided α error of 0.05. Adjusted patient age was used as a covariate in all the analyses (Cochran-Mantel-Haenszel test and analysis of covariance). The variables included in the logistic regression analysis were compliance according to the Morisky-Green test throughout the study (dependent variable) and patient demographic characteristics, type of physician, practice situation, number of previous diseases, number of concomitant medications, reason for using antiresorptive treatment, and level of disease knowledge (independent variables). These independent variables were selected according to their clinical or statistical significance. 247
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Treatment days were measured as the interval between starting treatment and the time of treatment discontinuation or the date of the final visit, whichever occurred first. A Cox proportional hazards model was used to determine the hazard ratio for discontinuation (adjusted for treatment and age). SAS software version 8.1 (SAS Institute Inc., Cary, North Carolina) was used in the statistical analyses. RESULTS Study Population
A total of 926 postmenopausal women were screened for this study between October 2000 and April 2001. Twenty-four patients were excluded because they did not meet eligibility criteria. The analyzed population consisted of 902 patients (mean [SD] age, 64.4 [6.9] years), of whom 476 (52.8%) were treated with RLX and 426 (47.2%) with ALN. Table II shows the baseline characteristics of the study population, as well as the factors that may affect compliance. In both groups, the primary reason for initiating treatment was osteoporosis (P = NS). However, significantly more patients in the RLX group than the ALN group were treated for osteopenia (P < 0.001), and significantly more patients in the ALN group were treated for established osteoporosis (P = 0.003). A total of 628 (69.6%) patients had not received any antiresorptive treatment prior to inclusion in the study (RLX, 68.1% vs ALN, 71.4%; P = NS). Overall, 90.9% of the patients attended ≥1 visit after period 1, 708 (78.5%) patients attended the visit after period 2, and 665 (73.7%) patients attended the final visit.
(P = 0.018) (Figure 2). The proportion of patients who took all of the tablets during the 30 days before each study visit was statistically higher in the RLX group (70.0%) than in the ALN group (54.3%) (all P < 0.001). The Autocompliance test also showed that the proportion of compliers throughout the study was statistically higher in the RLX group (94.7%) than in the ALN group (90.6%) (P = 0.033). As measured using the Compliance Questionnaire, in the first 3 months, the proportion of patients who did not continue the initially assigned treatment was statistically significantly higher in the ALN group (13.0%) than in the RLX group (4.9%) (P < 0.001). No significant difference was found with regard to treatment compliance between the 2 groups after the first 3 months of follow-up. The proportion of patients who withdrew from the study prematurely was statistically higher in the ALN group (25.8%) than in the RLX group (16.4%) (P < 0.001). Among 188 patients discontinuing prematurely (both treatment groups), 139 (74%) discontinued during the first 3 months of observation. Factors Contributing to Compliance
Table IV shows the results of the logistic regression analysis. Treatment and type of physician were the only variables found to be related to treatment compliance. None of the other variables included in the model (age, marital status, educational level, employment status, practice situation, reason for using antiresorptive treatment, number of previous diagnoses, number of concomitant medications, and disease knowledge level) showed a predictive power for compliance.
Compliance Results
Satisfaction Results
The proportion of patients with a high MoriskyGreen test score (0 points), indicating maximum compliance throughout the study, was statistically higher in the RLX group (68.7%) than in the ALN group (54.0%) (P < 0.001) (Figure 1). The proportion of patients considered good compliers (0–2 points) throughout the study was similar between the 2 groups. The Morisky-Green test scores for each study period are shown in Table III. Based on the Autocompliance test, the ALN group showed a statistically higher proportion of patients who experienced difficulty taking the medication compared with the RLX group throughout the study
The proportion of patients reporting that they were satisfied or very satisfied with the treatment was statistically higher in the RLX group (95.7%) than in the ALN group (85.4%) (P < 0.001).
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Tolerability Results
AEs were significantly less frequently the reason for RLX discontinuation compared with the ALN group (4.8% vs 11.0%; P < 0.001). The estimated relative risk was 1.4 (adjusted by age), indicating a 1.4-fold higher risk for discontinuation in the ALN group (95% CI, 1.21–1.61). The crude relative risk was 1.42 (95% CI, 1.22–1.64).
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Table II. Baseline demographic and clinical characteristics of the study patients (N = 902). (Values are expressed as no. [%] of patients unless otherwise noted.) Characteristic
Raloxifene* (n = 476)
Alendronate* (n = 426)
Age, mean (SD), y
63.5 (6.3)
65.4 (7.3)
Age group 55– ≤64 y 65– ≤75 y >75 y NR
289 165 20 2
(60.7) (34.7) (4.2) (0.4)
212 167 43 4
(49.8) (39.2) (10.1) (0.9)
Marital status Married Widowed Single Separated/divorced NR
348 78 35 15 0
(73.1) (16.4) (7.4) (3.2) (0.0)
277 96 42 9 2
(65.0) (22.5) (9.9) (2.1) (0.5)
Educational level Certificate of primary education Certificate of secondary education University No formal education NR
277 128 43 25 3
(58.2) (26.9) (9.0) (5.3) (0.6)
278 85 30 28 5
(65.3) (20.0) (7.0) (6.6) (1.2)
Employment status Homemaker Retired Full-time work Part-time work NR
292 96 49 27 12
(61.3) (20.2) (10.3) (5.7) (2.5)
276 90 35 10 15
(64.8) (21.1) (8.2) (2.3) (3.5)
P <0.001, ANOVA <0.001, CMH
0.024, Χ2
0.043, Χ2
0.086, Χ2
0.929, Χ2
Menopause type Natural Surgical NR
397 (83.4) 66 (13.9) 13 (2.7)
355 (83.3) 58 (13.6) 13 (3.1)
Age at menopause, mean (SD), y
48.3 (5.0)
48.3 (4.9)
0.815, ANOVA 0.349, Χ2
Type of physician Orthopedic surgeon Rheumatologist Rehabilitation NR
240 226 8 2
(50.4) (47.5) (1.7) (0.4)
195 221 9 1
(45.8) (51.9) (2.1) (0.2)
Practice situation Public Private Mixed NR
252 197 25 2
(52.9) (41.4) (5.3) (0.4)
254 150 22 0
(59.6) (35.2) (5.2) (0.0)
Reason for using RLX or ALN Osteoporosis Osteopenia Established osteoporosis Osteoporotic fracture risk factors Other NR
215 102 95 56 8 0
(45.2) (21.4) (20.0) (11.8) (1.7) (0.0)
198 52 120 47 7 2
(46.5) (12.2) (28.2) (11.0) (1.6) (0.5)
0.135, Χ2
0.646, Χ2 <0.001, Χ2 0.003, Χ2 0.749, Χ2
(continued)
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Table II. (Continued) Characteristic
Raloxifene* (n = 476)
Alendronate* (n = 426)
No. of previous diagnoses 0 1 2 ≥3 NR
273 126 47 30 0
(57.4) (26.5) (9.9) (6.3) (0.0)
228 126 47 25 0
(53.5) (29.6) (11.0) (5.9) (0.0)
No. of concomitant medications 0 1 2 3 ≥4 NR
268 109 46 24 29 0
(56.3) (22.9) (9.7) (5.0) (6.1) (0.0)
223 107 47 23 26 0
(52.3) (25.1) (11.0) (5.4) (6.1) (0.0)
Disease knowledge level Acceptable† Unacceptable‡ Moderate§ Not assessed
228 159 68 21
(47.9) (33.4) (14.3) (4.4)
200 158 56 12
(46.9) (37.1) (13.1) (2.8)
P 0.631, CMH
0.814, CMH
0.588, CMH
ANOVA = analysis of variance; CMH = Cochran-Mantel-Haenszel; NR = not reported; Χ2 = chi-square; RLX = raloxifene; ALN = alendronate. *Percentages may not add to 100 due to rounding. †Patient knows osteoporosis is a chronic, preventable, treatable condition and knows a complication. ‡Patient does not know any complication of osteoporosis. §Any combination of the 3 questions.
Raloxifene (n = 447) Alendronate (n = 402)
100 90 80
% of Patients
70
*
60 50 40 30 20 10 0 Maximum Compliance (High Morisky-Green Score)
Good Compliance (High/Moderate Morisky-Green Score)
Figure 1. Compliance according to Morisky-Green score13 throughout the study. *P < 0.001 versus alendronate. 250
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Table III. Morisky-Green scores (no. [%] of patients) (N = 820). Time Point
Raloxifene
Alendronate
P
Period 1 (0–3 mo) High Moderate Low NR
(n = 427) 305 (71.4) 110 (25.8) 6 (1.4) 6 (1.4)
(n = 393) 236 (60.1) 136 (34.6) 17 (4.3) 4 (1.0)
<0.001
Period 2 (3–6 mo) High Moderate Low NR
(n = 393) 304 (77.4) 80 (20.4) 6 (1.5) 3 (0.8)
(n = 315) 210 (66.7) 90 (28.6) 10 (3.2) 5 (1.6)
0.004
Final visit (12 mo) High Moderate Low NR
(n = 364) 254 (69.8) 99 (27.2) 8 (2.2) 3 (0.8)
(n = 301) 195 (64.8) 84 (27.9) 17 (5.6) 5 (1.7)
0.036
NR = not reported.
Raloxifene Alendronate
12
% of Patients
10 8 6 4
* *
†
2 0 n=
427
393
Period 1 (0–3 mo)
393
315
Period 2 (3–6 mo)
364
301
Final Visit (12 mo)
Figure 2. Patients with difficulties taking the medication. *P < 0.001 versus alendronate; †P = 0.018 versus alendronate. 251
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Table IV. Multivariate logistic regression analysis to assess factors affecting compliance. Odds Ratios Effect Treatment (raloxifene vs alendronate) Physician type (rheumatologist vs orthopedic surgeon)
Wald Χ2
P > Χ2
Point Estimate
Wald 95% CI
13.17 7.41
<0.001 <0.007
1.76 1.53
1.29–2.38 1.13–2.07
Χ2 = chi-square.
The most common AEs that caused withdrawal were gastrointestinal disorders (RLX group, 3.4%; ALN group, 9.9%; P < 0.001). Dyspepsia, upper abdominal pain, and abdominal discomfort were the AEs reported most frequently by the study population, and all of these AEs were reported significantly more frequently in the ALN group than in the RLX group (P < 0.05). Two serious AEs were recorded during treatment with ALN and were considered relevant clinical AEs (moderate pyrosis and gastralgia in 1 patient and moderate epigastric pain in 1 patient). No venous thromboembolic events were recorded in the RLX group throughout the study. Mean (SD) treatment duration was 323.6 (111.7) days in the RLX group and 291.1 (136.6) days in the ALN group; the difference was statistically significant (P < 0.001). The hazard ratio was adjusted for treatment group and patient age. The overall likelihood of discontinuation was not significantly different between treatment groups (hazard ratio, 1.061). DISCUSSION
According to our MEDLINE search, the present study was the first prospective, direct comparison between RLX and ALN with regard to treatment compliance in clinical practice. In this observational study, patients treated for osteopenia or osteoporosis reported significantly better compliance with daily RLX compared with daily ALN during 12 months of treatment in a clinical setting. The results showed a relatively high consistency between the compliance rates based on the MoriskyGreen and the Autocompliance tests (differences in the absolute percentage of compliance of <5% between the 2 tests) and a lower correlation of these 2 tests with the Compliance Questionnaire (differences in compliance of 10%–16%), with lowest compliance reported on the latest Compliance Questionnaire taken. 252
Compliance with prescribed postmenopausal osteoporosis treatment is important for clinical effectiveness. Low patient compliance with prescribed treatments for chronic diseases is a common problem in clinical care, with reported 50% noncompliance in 1 review,16 and represents a relevant problem in chronic diseases such as osteoporosis.9,17 In 2 clinical trials,1,2 daily ALN was shown to be well tolerated; the discontinuation rates ranged from 8% to 13% after 3 years, and the overall incidence of upper gastrointestinal side effects was 1%. Compliance with ALN outside of the controlled trial setting is lower due to its tolerability profile and complex procedures for taking the drug.5,18 The discontinuation rate in clinical practice is much higher, with 30% discontinuation at 6 months5 and 46% at 1 year of treatment, mostly because of upper gastrointestinal AEs.18,19 In 2 clinical trials, the discontinuation rates for RLX due to AEs through 3 and 4 years were 10.3%3 and 12.8%,4 respectively. Few data on compliance with RLX and ALN therapy in routine clinical practice are available. In 1 study9 using structured telephone interviews (with a mean of 7 months after treatment initiation) to assess discontinuation rates, the proportion of women discontinuing differed by treatment and was 26% for hormone replacement therapy versus 19% for RLX (P = 0.03) and 19% for ALN (P = 0.02 vs hormone replacement therapy). Approximately two thirds of the women cited AEs as the reason for discontinuing treatment. In the present study, we used indirect methods to assess compliance. Direct methods (eg, measurement of serum or urine drug levels or observation of the patient taking the medication) are more objective but are complicated and expensive and therefore not feasible for routine clinical practice.20 Indirect measures of compliance may not be considered the most accu-
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rate and reliable methods to determine compliance, but 2 studies21,22 in a routine clinical setting found significant associations between indirect methods and other compliance measurements. The advantages of the methods in this study include simplicity, speed, and feasibility for routine clinical practice. Furthermore, a combination of different methods, such as those we used in our study, is more accurate in determining compliance than using only 1 method.20 The Morisky-Green test, with a sensitivity of 81% (the proportion of compliant patients correctly identified as compliant) and a specificity of 44% (the proportion of noncompliant patients correctly identified as noncompliant),13 has been used in several studies23–26 to assess treatment compliance in clinical practice. In the present study, the proportion of patients with a high compliance index score (indicating maximum compliance) throughout the study was statistically higher in the RLX group than in the ALN group (Figure 1). More good compliers were found in the RLX group, although the difference was borderline statistically nonsignificant (Figure 1). The proportion of compliant patients throughout the study, as determined by the Autocompliance test, was statistically higher in the RLX group than in the ALN group. Nevertheless, compliance was very high for both treatments, with a self-reported compliance of >90% in both groups. However, as previously described, it should be noted that patients tend to overreport adherence with self-reported measurements.20,26 Moreover, significantly more patients reported difficulty taking ALN compared with RLX throughout the study. These results are notably different from a report27 that used a prescription-claims database to assess compliance, where ALN showed a 12-month compliance probability of 15.6%, when obtaining <75% of the prescribed medication was considered as noncompliance. Regarding factors affecting compliance, only treatment and type of physician were variables related to treatment compliance. Surprisingly, other demographic variables (age, marital status, educational level, employment status, practice situation, reason for using antiresorptive treatment, number of previous diagnoses, number of concomitant medications, and disease knowledge level) were not related to treatment compliance.
In the present study, the overall withdrawal rate was 20.8%, and 73.9% of these withdrawals occurred during the first 3 months of treatment. The proportion of patients who withdrew from the study prematurely was statistically higher in the ALN group than in the RLX group. On the basis of self-reporting, most patients who discontinued ALN therapy did so because of treatment-related AEs.5,6,9 Although in clinical trials with daily ALN, gastrointestinal AEs were as common in women receiving placebo as among those taking the active drug,1,2 some reports5,9,28 have shown that as many as 20% to 30% of patients develop upper gastrointestinal tract AEs while taking ALN therapy and that a substantial proportion of these AEs are assumed to be the direct result of ALN. The withdrawal rate that we observed with ALN was similar to the 26% rate described by Kelly and Taggart29 and the 19% rate with risedronate.30 The higher withdrawal rates in those studies compared with the reported rates for ALN in controlled clinical trials1,2 support the assumption of a higher rate in routine clinical practice. The lower withdrawal rate found with RLX compared with ALN is in accordance with the results of trials6,7 comparing RLX with other preventive therapies, such as hormone replacement therapy, in a clinical setting. One study7 found a 25% lower probability of treatment discontinuation with RLX compared with systemic estrogens at 24 months. Similarly, the higher rate of withdrawal with ALN in our study might be due in part to AEs, namely, gastrointestinal disorders, which were significantly more common with ALN. The most commonly reported gastrointestinal AEs that caused premature withdrawal were dyspepsia and upper abdominal pain, with a statistically higher incidence of both in the ALN group. This finding might have contributed to the higher level of treatment satisfaction in patients in the RLX group because tolerability might be 1 important factor in discontinuations. This study has several limitations. Given the openlabel, nonrandomized allocation of the study treatments, a certain degree of biased information and selection cannot be ruled out. Caution should be used when interpreting the results because 2 of the 3 measures used to assess compliance were self-reported and, thus, subjective. Also, in this study, it was not possible to confirm the prescription file information with other data sources (eg, pill count). Although pill 253
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counts may provide more definitive measures of compliance in clinical trials, they are not feasible in most clinical settings and are characterized by many methodologic difficulties. To effectively prevent osteoporotic fractures through enhanced long-term treatment compliance, it is crucial to identify the most tolerable treatment. However, being aware of the reasons for discontinuation allows physicians to look carefully into them to improve patients’ compliance. CONCLUSIONS
In this study of postmenopausal women at risk for osteoporotic fractures, compliance with 12-month treatment with daily RLX was higher than with daily ALN in a clinical setting. RLX showed significant benefits compared with ALN in terms of compliance assessed by means of the Morisky-Green and Autocompliance tests, and the patient’s self-reported satisfaction. ACKNOWLEDGMENTS
This study was supported by an unrestricted grant from Eli Lilly & Company, Madrid, Spain. The following investigators participated in the Spanish Compliance Osteoporosis Study (PROCUOS): Julio Acal González, Juan Carlos Acebes Cachafeiro, Musa Ahmad Sabah, Juan Almansa Buades, Vicente Alonso Mendieta, Alberto Alonso Ruiz, Luis María Altuzarra Corral, Encarnación Amigo Díaz, José María Aparicio Gómez, Jaime Asín Ungría, Antonio Atanes Sandoval, Fernando Barandiaran Luca de Tena, Santiago Bartrons Casas, Miguel Angel Belmonte Serrano, Joaquín Belzumegui Otano, Edgar Benalcázar Cueva, Miguel Bernard Pineda, Mario Bernard Sánchez, Xavier Biarnes Margalef, Manuel Brito Suarez, Juan Luis Calatayud Carretero, Jaime Calderón Rodríguez, José Manuel Camacho Núñez, Estrella Cánovas Cánovas, Antonio Cardenal Escarcena, Miguel Carrión Gil, Inmaculada Carvajal Méndez, Montserrat Centellas Portella, Josep María Climent Barberá, Antonio Conca Roig, Juan Antonio Copano Abad, Monserrat Corteguera Coro, Belén Criado Portero, Juan Cruz Martínez, Juan Ramón Daza Mesas, Manuel De Haro Liger, Marcial De la Hera Martinez, Francisco Javier de Toro Santos, Juvenal de Vega Jiménez, Máximo Del Castillo Arbeloa, Esther del Rincón Padilla, César Díaz López, 254
Alberto Díaz Oca, Elvira Díez Álvarez, José Antonio Diez Jorro, José Manuel Docampo Riva, Francisco Domínguez Somoza, Celia Erausquin Arruabarrena, Carlos Fenollosa Costa, Jaime Fernández Campillo, José Luis Fernández Espejo, José Emilio Fernández García, Antonio Fernández Nebro, José Ferrero Boronat, Mercedes Freire González, Maria Ángeles Gantes Mora, Julio García Feito, Celia García Gimenez, Sergio García Pérez, Rosa García Portales, Florencio García Velazco, Emilio García-Mancha Arévalo, Saul Mario Gelman Aizen, Manuel Giner Pascual, Balbina González Álvarez, Teresa González Hernández, Julio Gracia Estévez, Jenaro Graña Gil, José Luis Guerra Vazquez, Antonio Gutierrez Rubio, José Francisco Hermida Seoane, José Luis Hernández Gómez, José Hernández Pomada, Susana Holgado Pérez, Talal Issa Mufti, José Ivorra Cortés, José María Jolonch Palau, Florencio Larramendi Pérez, Manuel Alejo Leal Muro, Alvaro Lesta Arnal, Isabel Linares Fernández, Xavier Llaurado Barenys, Carlos Lobato Kropnick, Hector López Artacho, Luis Maraver López del Valle, Juan Manuel López Gollonet, Antonio López Meseguer, Javier López Torroba, Antonio Luque Galán, Fernando Macías Olmeda, Javier Mareque Abad, Esperanza Martín Forero, Silvia Martínez Pardo, Fernando Martínez Pintor, Miguel Ángel Martínez Villar, Pedro Martínez Vitorio, Zouhair Massri Zeituni, Marta Medrano San Ildefonso, Francisco Mesa Ramos, Roberto Miguelez Sánchez, José Minguet Baixauli, Alvaro Minuesa Asensio, María Mira Molero, Carlos Miranda de Larra y de Onis, Arturo Molina López-Navas, José María Moreno Martínez, Francisco Mulet Clos, Cristobal Núnez-Cornejo Piquer, Carlos Ossorio Castellanos, Andrés Pámpano Pérez, Alberto Pascual Codeso, Carlos Pascual Martín, Isidoro Pascual Molina, Gilberto Pastor Zatarain, Encarnación Pérez López, Jaime Pérez Núñez, Fernando Pérez Ruiz, Trinidad Pérez Sandoval, Josep Oriol Pérez Serra, Juan Manuel Piedra Priego, Vicente Pomares Boix, Francisco Prats Maeso, Josep Pujol Costa, Javier Reparaz Padros, Félix Rico Navarro, Maria Porfiria Rodríguez del Hoyo, Ramón Rodríguez Franco, Antonio Rodríguez González, Jesus Rodríguez Moreno, Joaquín Rodríguez Soler, Juan Roig Juliá, Daniel Roig Vilaseca, Pascual Rosser Marín, Ivan Joaquín Sagarra Miró, Luis Sainz de los Terreros, Juan Saldaña Cuchillos, Ana Isabel Sánchez Atrio, Ginés Sánchez
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Nievas, José Manuel Sarabia Conde, Antonio Scarpellini Vera, Carlos Simortee Moreno, José Félix Solano Fernández, José María Subirana Conde, Santiago Toca Ximenez, José Luis Toribio Madrazo, Maria Carmen Torres Martín, Antonio Torrijos Eslava, Manuel Utrilla Utrilla, Vicente Vila Fayos, Mercedes Yagüe Asensio, and Manuel Zabala Gamarra. REFERENCES 1. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348: 1535–1541. 2. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk fracture in women with low bone density but without vertebral fractures: Results from the Fracture Intervention Trial. JAMA. 1998;280: 2077–2082. 3. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators [published correction appears in JAMA. 1999;282:2124]. JAMA. 1999;282:637–645. 4. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: Four-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2002;87:3609–3617. 5. Ettinger B, Pressman A, Schein J, et al. Alendronate use among 812 women: Prevalence of gastrointestinal complaints, noncompliance with patient instructions and discontinuation. J Manag Care Pharm. 1998;4: 488–492. 6. Ettinger B, Tosteson AN, Grove M, et al. Side effect severity and discontinuation rate among women initiating hormone replacement therapy, raloxifene, or alendronate following BMD testing. Bone. 2001;28:S76. 7. Kayser J, Ettinger B, Pressman A. Postmenopausal hormonal support: Discontinuation of raloxifene versus estrogen. Menopause. 2001;8:328–332. 8. Fawcett J. Compliance: Definitions and key issues. J Clin Psychiatry. 1995;56(Suppl 1):4–8. 9. Tosteson AN, Grove MR, Hammond CS, et al. Early discontinuation of treatment for osteoporosis. Am J Med. 2003;115:209–216.
10. Raloxifene Hydrochloride (Evista®). Summary of product characteristics. Madrid, Spain: Eli Lilly and Company; 2000. 11. Alendronate Sodium (Fosamax®). Summary of product characteristics. Madrid, Spain: Merck, Sharp & Dohme; 2000. 12. Batalla C, Blanquer A, Ciurana R, et al. Compliance with drug therapy in hypertensive patients [in Spanish]. Aten Primaria. 1984;1:185–191. 13. Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care. 1986;24:67–74. 14. Val Jimenez A, Amoros Ballestero G, Martinez Visa P, et al. Descriptive study of patient compliance in pharmacologic antihypertensive treatment and validation of the Morisky and Green test [in Spanish]. Aten Primaria. 1992;10:767–770. 15. Haynes RB, Sackett DL, Gibson ES, et al. Improvement of medication compliance in uncontrolled hypertension. Lancet. 1976;1:1265–1268. 16. Miller NH. Compliance with treatment regimens in chronic asymptomatic diseases. Am J Med. 1997;102:43–49. 17. Sclar DA. Improving medication compliance: A review of selected issues. Clin Ther. 1991;13:436–440. 18. Ettinger B, Shein JR, Pressman A. Upper gastrointestinal symptoms and noncompliance with dosing instructions associated with alendronate for osteoporosis in a large HMO. Bone. 1998;23:S311. 19. Nattrass S, Silverman S, Drinkwater B. Effectiveness of education and/or NTx results as a means of encouraging compliance to alendronate. Osteoporos Int. 2000;11:S164. 20. Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. Clin Ther. 1999;21:1074–1090. 21. McCombs JS, Cody M, Besinque K, et al. Measuring the impact of patient counseling in the outpatient pharmacy setting: The research design of the Kaiser Permanente/USC patient consultation study. Clin Ther. 1995;17:1188–1206. 22. Melnikow J, Kiefe C. Patient compliance and medical research: Issues in methodology. J Gen Intern Med. 1994;9:96–105. 23. Gil V, Pineda M, Martínez JL, et al. Validity of 6 indirect methods to assess treatment compliance in arterial hypertension [in Spanish]. Med Care (Barc). 1994;102:532–536. 24. George CF, Peveler RC, Heiliger S, Thompson C. Compliance with tricyclic antidepressants: The value 255
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of four different methods of assessment. Br J Clin Pharmacol. 2000;50:166–171. 25. Gao X, Nau DP. Congruence of three self-report measures of medication adherence among HIV patients. Ann Pharmacother. 2000;34:1117–1122. 26. Waterhouse DM, Calzone KA, Mele C, Brenner DE. Adherence to oral tamoxifen: A comparison of patient self-report, pill counts, and microelectronic monitoring. J Clin Oncol. 1993;11:1189–1197. 27. Faulkner DL, Lucy LM, Heath H, et al. A claims data assessment of patient compliance with alendronate. Osteoporos Int. 1998;8(Suppl 3):21.
28. Ettinger B, Pressman A, Schein J. Clinic visits and hospital admissions for care of acid-related upper gastrointestinal disorders in women using alendronate for osteoporosis. Am J Manag Care. 1998;4:1377– 1382. 29. Kelly R, Taggart H. Incidence of gastrointestinal side effects due to alendronate is high in clinical practice. BMJ. 1997;315:1235. 30. Hamilton B, McCoy K, Taggart H. Tolerability and compliance with risedronate in clinical practice. Osteoporos Int. 2003;14:259–262.
Address correspondence to: Carmen Turbí, MD, Av. de la Industria 30, Alcobendas, 28108 Madrid, Spain. E-mail: [email protected] 256
Compliance and Satisfaction with Raloxifene Versus Alendronate for the Treatment of Postmenopausal Osteoporosis in Clinical Practice: An Open-Label, Prospective, Nonrandomized, Observational Study Carmen Turbí, MD,1 Gabriel Herrero-Beaumont, MD,2 Juan Carlos Acebes, MD, PhD,2 Antonio Torrijos, MD,3 Jenaro Graña, MD, PhD,4 Roberto Miguélez, MD, PhD,5 José Antonio Sacristán, MD,1 and Fernando Marín, MD, PhD6 1Department of Medical Research, Lilly S.A., Madrid, 2Rheumatology Service, Fundación Jiménez Díaz, Madrid, 3Rheumatology Service, Hospital La Paz, Madrid, 4Rheumatology Service, Hospital Juan Canalejo, La Coruña, 5Rheumatology Service, Hospital de Móstoles, Madrid, Spain, and 6Department of Medical Research, Lilly European
Operations, Windlesham, United Kingdom
ABSTRACT
Background: The treatment of osteoporosis among postmenopausal women represents a major public health challenge because long-term therapy is needed to prevent fractures and chronic disability. Low patient compliance with prescribed osteoporosis treatments can severely distort the validity of controlled clinical trials. Raloxifene and alendronate have been shown to reduce the incidence of osteoporotic fracture in postmenopausal women in well-conducted randomized trials, but few data are available on the rate of adherence to these treatments in routine clinical practice. Objective: The primary aim of this study was to assess the compliance of postmenopausal women at risk for osteoporotic fractures who were treated with raloxifene hydrochloride (RLX) versus alendronate sodium (ALN) during a 12-month observational period in a routine clinical setting. Secondary objectives were the assessment of factors that might contribute to noncompliance and patient satisfaction. Methods: This open-label, prospective, multicenter, nonrandomized, observational, comparative study was conducted at 154 centers across Spain. Assignment to either RLX or ALN treatment was determined by the physician and was based on each patient’s clinical profile. Compliance with RLX (60-mg tablet once daily) versus ALN (10-mg tablet once daily) was assessed using 3 different compliance assessment tools: the MoriskyGreen test, the Autocompliance test, and the Compliance Questionnaire. A logistic regression model was used to assess different factors affecting compliance. Patient satisfaction was also assessed using a questionnaire. Adverse events (AEs) were collected as reasons for discontinuation in the Compliance Questionnaire and at the discontinuation visit. Results: A total of 902 women (RLX group, n = 476; ALN group, n = 426) were included in the study (mean age, 64.4 [6.9] years). Overall, patients in the RLX group reported significantly better compliance than patients in the ALN group, as collected either by the Morisky-Green test (68.7% vs 54.0%; P < 0.001) or the Autocompliance test (94.7% vs 90.6%; P = 0.033). More patients discontinued treatment prematurely in the ALN group compared with the RLX group (25.8% vs 16.4%; P < 0.001). The age-adjusted relative risk for discontinuation was 1.4-fold higher for women treated with ALN than for those treated with RLX (95% CI, 1.21–1.61). The main reason for premature discontinuation was due to AEs (RLX 4.8% vs ALN 11.0%; P < 0.001). The proportion of patients with gastrointestinal AEs was 9.9% in the ALN group and 3.4% in the RLX Accepted for publication December 8, 2003. Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2004 Excerpta Medica, Inc.
0149-2918/04/$19.00
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group (P < 0.001). Only treatment and type of physician were independent covariates of treatment compliance. After 12 months of observation, significantly more patients in the RLX group were satisfied or very satisfied with their treatment than patients in the ALN group (P < 0.001). Conclusions: In this study of postmenopausal women at risk for osteoporotic fractures, compliance with 12-month treatment with daily RLX was higher than with daily ALN in a clinical setting. RLX showed significant benefits compared with ALN in terms of compliance assessed by means of the Morisky-Green and Autocompliance tests and the patient’s selfreported satisfaction (Clin Ther. 2004;26:245–256) © 2004 Excerpta Medica, Inc. Key words: compliance, osteoporosis, raloxifene, alendronate, clinical practice, postmenopausal.
INTRODUCTION
The selective estrogen receptor modulator raloxifene hydrochloride (RLX) and the bisphosphonate alendronate sodium (ALN) have been shown to reduce the incidence of osteoporotic fracture in postmenopausal women in randomized trials.1–4 However, according to a MEDLINE search (key terms, postmenopausal osteoporosis, compliance, adherence, discontinuation, alendronate, and raloxifene; years, 1985–2003), few data are available on the rate of adherence to these treatments in routine clinical practice,5–7 where compliance is likely to be different than in clinical trials. In fact, double-blind, randomized clinical trials tend to underestimate the likelihood of treatment discontinuation in routine clinical practice because patients participating in clinical trials are probably healthier and better counseled than patients in clinical practice.8 Because nonadherence limits the effectiveness of therapies for osteoporosis when used in clinical practice, it is important to assess treatment compliance in a clinical setting. Compliance with RLX or ALN therapy may be different from that in randomized trials. Few studies allow comparisons of the rate of adherence and patient satisfaction with these treatments in routine clinical practice.9 The aims of this study were to assess compliance (primary objective) and factors that might contribute to noncompliance with, as well as satisfaction of, RLX 246
or ALN (secondary objectives) in postmenopausal women at risk for osteoporotic fractures during a 12month period in a routine clinical setting. PATIENTS AND METHODS Study Design
This open-label, prospective, multicenter, nonrandomized, observational, comparative study was conducted at 154 centers across Spain. The protocol was approved by an independent review board. Patients
Postmenopausal women aged ≥55 years and at risk for osteoporotic fractures (according to the attending physician) were eligible for inclusion in the study. Patients had to comply with all the recommendations stated in the summaries of drug characteristics10,11 and to provide written informed consent. Exclusion criteria were use of antiresorptive treatment (except for calcium and vitamin D) within the 3 months before the study, contraindications as stated in the summaries of product characteristics for the use of RLX or ALN therapy, inability to adhere to the requirements of the study, and participation in another observational or experimental study. Methods Study Visits
Study visits occurred as follows: 1 visit at baseline, 1 visit at any time in the first 3 months (period 1), 1 visit at any time in the next 3 to 6 months (period 2), and a final visit at 12 months. At the baseline visit, several variables that might affect compliance were recorded, including patient demographic characteristics, type of physician, practice situation, number of previous diseases, number of concomitant medications, reason for using RLX or ALN treatment, and level of disease knowledge. Level of disease knowledge was assessed using a 3-item questionnaire that had been validated in a Spanish population.12 The questions were as follows: (1) “Is osteoporosis a disease that you will have for the rest of your life?” (2) “Can you prevent osteoporosis by changing your lifestyle or using medicines?” and (3) “State a complication of this disease.” This test was used to differentiate between 3 levels of knowledge: (1) acceptable knowledge (patient knows osteoporosis is a chronic, treatable condition and knows a complication); (2) unacceptable knowledge (patient does not
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know any complication of osteoporosis); and (3) moderately acceptable knowledge (any other combination of answers to the 3 questions). Also at the baseline visit, patients were assigned to self-administered oral treatment with RLX 60-mg tablet once daily or ALN 10-mg tablet once daily for 12 months. Treatment assignment to either RLX or ALN was determined by the physician based on the patient’s clinical profile. In cases of premature withdrawal from the study, questionnaires for compliance assessment and treatment satisfaction were to be administered.
Table I.
The Morisky-Green test.*13
1. “Do you ever forget to take your medicine?” 2. “Did you take your medicine at the indicated hour?” 3. “When you feel better, do you sometimes stop taking your medicine?” 4. “If you feel worse when you take the medicine, do you sometimes stop taking it?” *Scale: 0
= no, 1 = yes. In the second question of the Morisky-Green test,13 an affirmative answer adds 0 points and a negative answer adds 1 point to the total score. 0 = high Morisky-Green score, indicating maximum compliance; 1 or 2 = moderate score; 3 or 4 = low score. A score of 0–2 is considered good compliance.
Compliance Assessment
Compliance was assessed at the observational periods using 3 questionnaires (the Morisky-Green test, the Autocompliance test, and the Compliance Questionnaire), administered by the patient’s physician. The Morisky-Green test is a closed questionnaire with 4 questions about disease treatment (Table I).13 This questionnaire has been validated in the Spanish population.14 The Autocompliance test was used to estimate the number of tablets not taken during the previous month, following the methodology of Haynes et al,15 as well as difficulty taking the medication, and consists of 2 open questions: (1) “Do you have difficulty in taking the tablets?” and (2) “How many tablets have you missed in the last month?” Compliance was determined by calculating the number of tablets remaining, using the following formula:
Compliance =
30 – no. of missed tablets during the previous month
× 100
30 A patient was considered a complier if she declared she had missed ≤20% of the total number of tablets prescribed. Finally, the Compliance Questionnaire asked 2 questions: (1) “Is the patient going to continue on the initially assigned osteoporosis treatment?” and (2) “If not, please specify the reason and time of discontinuation.” Satisfaction Assessment
Patient satisfaction was assessed using a specific questionnaire with 1 question: “How satisfied are you
with the treatment you took during your participation in this study?” This questionnaire evaluates the patient’s satisfaction with the treatment by a 4-ordinal categorical scale (very dissatisfied, dissatisfied, satisfied, and very satisfied). All participating physicians were instructed to make their assessments as consistent as possible and not to influence patients’ assessments of treatment satisfaction and self-reported compliance. Tolerability Assessment
Information on adverse effects (AEs) was based on data from the Compliance Questionnaire and the discontinuation visit. Statistical Analysis
The compliance analysis included consideration of each compliance measurement, each compliance question, and each study visit. The sample size of 900 patients was calculated to detect a ≥10% difference in self-reported compliance between the 2 treatments, assuming 80% power and a 2-sided α error of 0.05. Adjusted patient age was used as a covariate in all the analyses (Cochran-Mantel-Haenszel test and analysis of covariance). The variables included in the logistic regression analysis were compliance according to the Morisky-Green test throughout the study (dependent variable) and patient demographic characteristics, type of physician, practice situation, number of previous diseases, number of concomitant medications, reason for using antiresorptive treatment, and level of disease knowledge (independent variables). These independent variables were selected according to their clinical or statistical significance. 247
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Treatment days were measured as the interval between starting treatment and the time of treatment discontinuation or the date of the final visit, whichever occurred first. A Cox proportional hazards model was used to determine the hazard ratio for discontinuation (adjusted for treatment and age). SAS software version 8.1 (SAS Institute Inc., Cary, North Carolina) was used in the statistical analyses. RESULTS Study Population
A total of 926 postmenopausal women were screened for this study between October 2000 and April 2001. Twenty-four patients were excluded because they did not meet eligibility criteria. The analyzed population consisted of 902 patients (mean [SD] age, 64.4 [6.9] years), of whom 476 (52.8%) were treated with RLX and 426 (47.2%) with ALN. Table II shows the baseline characteristics of the study population, as well as the factors that may affect compliance. In both groups, the primary reason for initiating treatment was osteoporosis (P = NS). However, significantly more patients in the RLX group than the ALN group were treated for osteopenia (P < 0.001), and significantly more patients in the ALN group were treated for established osteoporosis (P = 0.003). A total of 628 (69.6%) patients had not received any antiresorptive treatment prior to inclusion in the study (RLX, 68.1% vs ALN, 71.4%; P = NS). Overall, 90.9% of the patients attended ≥1 visit after period 1, 708 (78.5%) patients attended the visit after period 2, and 665 (73.7%) patients attended the final visit.
(P = 0.018) (Figure 2). The proportion of patients who took all of the tablets during the 30 days before each study visit was statistically higher in the RLX group (70.0%) than in the ALN group (54.3%) (all P < 0.001). The Autocompliance test also showed that the proportion of compliers throughout the study was statistically higher in the RLX group (94.7%) than in the ALN group (90.6%) (P = 0.033). As measured using the Compliance Questionnaire, in the first 3 months, the proportion of patients who did not continue the initially assigned treatment was statistically significantly higher in the ALN group (13.0%) than in the RLX group (4.9%) (P < 0.001). No significant difference was found with regard to treatment compliance between the 2 groups after the first 3 months of follow-up. The proportion of patients who withdrew from the study prematurely was statistically higher in the ALN group (25.8%) than in the RLX group (16.4%) (P < 0.001). Among 188 patients discontinuing prematurely (both treatment groups), 139 (74%) discontinued during the first 3 months of observation. Factors Contributing to Compliance
Table IV shows the results of the logistic regression analysis. Treatment and type of physician were the only variables found to be related to treatment compliance. None of the other variables included in the model (age, marital status, educational level, employment status, practice situation, reason for using antiresorptive treatment, number of previous diagnoses, number of concomitant medications, and disease knowledge level) showed a predictive power for compliance.
Compliance Results
Satisfaction Results
The proportion of patients with a high MoriskyGreen test score (0 points), indicating maximum compliance throughout the study, was statistically higher in the RLX group (68.7%) than in the ALN group (54.0%) (P < 0.001) (Figure 1). The proportion of patients considered good compliers (0–2 points) throughout the study was similar between the 2 groups. The Morisky-Green test scores for each study period are shown in Table III. Based on the Autocompliance test, the ALN group showed a statistically higher proportion of patients who experienced difficulty taking the medication compared with the RLX group throughout the study
The proportion of patients reporting that they were satisfied or very satisfied with the treatment was statistically higher in the RLX group (95.7%) than in the ALN group (85.4%) (P < 0.001).
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Tolerability Results
AEs were significantly less frequently the reason for RLX discontinuation compared with the ALN group (4.8% vs 11.0%; P < 0.001). The estimated relative risk was 1.4 (adjusted by age), indicating a 1.4-fold higher risk for discontinuation in the ALN group (95% CI, 1.21–1.61). The crude relative risk was 1.42 (95% CI, 1.22–1.64).
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Table II. Baseline demographic and clinical characteristics of the study patients (N = 902). (Values are expressed as no. [%] of patients unless otherwise noted.) Characteristic
Raloxifene* (n = 476)
Alendronate* (n = 426)
Age, mean (SD), y
63.5 (6.3)
65.4 (7.3)
Age group 55– ≤64 y 65– ≤75 y >75 y NR
289 165 20 2
(60.7) (34.7) (4.2) (0.4)
212 167 43 4
(49.8) (39.2) (10.1) (0.9)
Marital status Married Widowed Single Separated/divorced NR
348 78 35 15 0
(73.1) (16.4) (7.4) (3.2) (0.0)
277 96 42 9 2
(65.0) (22.5) (9.9) (2.1) (0.5)
Educational level Certificate of primary education Certificate of secondary education University No formal education NR
277 128 43 25 3
(58.2) (26.9) (9.0) (5.3) (0.6)
278 85 30 28 5
(65.3) (20.0) (7.0) (6.6) (1.2)
Employment status Homemaker Retired Full-time work Part-time work NR
292 96 49 27 12
(61.3) (20.2) (10.3) (5.7) (2.5)
276 90 35 10 15
(64.8) (21.1) (8.2) (2.3) (3.5)
P <0.001, ANOVA <0.001, CMH
0.024, Χ2
0.043, Χ2
0.086, Χ2
0.929, Χ2
Menopause type Natural Surgical NR
397 (83.4) 66 (13.9) 13 (2.7)
355 (83.3) 58 (13.6) 13 (3.1)
Age at menopause, mean (SD), y
48.3 (5.0)
48.3 (4.9)
0.815, ANOVA 0.349, Χ2
Type of physician Orthopedic surgeon Rheumatologist Rehabilitation NR
240 226 8 2
(50.4) (47.5) (1.7) (0.4)
195 221 9 1
(45.8) (51.9) (2.1) (0.2)
Practice situation Public Private Mixed NR
252 197 25 2
(52.9) (41.4) (5.3) (0.4)
254 150 22 0
(59.6) (35.2) (5.2) (0.0)
Reason for using RLX or ALN Osteoporosis Osteopenia Established osteoporosis Osteoporotic fracture risk factors Other NR
215 102 95 56 8 0
(45.2) (21.4) (20.0) (11.8) (1.7) (0.0)
198 52 120 47 7 2
(46.5) (12.2) (28.2) (11.0) (1.6) (0.5)
0.135, Χ2
0.646, Χ2 <0.001, Χ2 0.003, Χ2 0.749, Χ2
(continued)
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Table II. (Continued) Characteristic
Raloxifene* (n = 476)
Alendronate* (n = 426)
No. of previous diagnoses 0 1 2 ≥3 NR
273 126 47 30 0
(57.4) (26.5) (9.9) (6.3) (0.0)
228 126 47 25 0
(53.5) (29.6) (11.0) (5.9) (0.0)
No. of concomitant medications 0 1 2 3 ≥4 NR
268 109 46 24 29 0
(56.3) (22.9) (9.7) (5.0) (6.1) (0.0)
223 107 47 23 26 0
(52.3) (25.1) (11.0) (5.4) (6.1) (0.0)
Disease knowledge level Acceptable† Unacceptable‡ Moderate§ Not assessed
228 159 68 21
(47.9) (33.4) (14.3) (4.4)
200 158 56 12
(46.9) (37.1) (13.1) (2.8)
P 0.631, CMH
0.814, CMH
0.588, CMH
ANOVA = analysis of variance; CMH = Cochran-Mantel-Haenszel; NR = not reported; Χ2 = chi-square; RLX = raloxifene; ALN = alendronate. *Percentages may not add to 100 due to rounding. †Patient knows osteoporosis is a chronic, preventable, treatable condition and knows a complication. ‡Patient does not know any complication of osteoporosis. §Any combination of the 3 questions.
Raloxifene (n = 447) Alendronate (n = 402)
100 90 80
% of Patients
70
*
60 50 40 30 20 10 0 Maximum Compliance (High Morisky-Green Score)
Good Compliance (High/Moderate Morisky-Green Score)
Figure 1. Compliance according to Morisky-Green score13 throughout the study. *P < 0.001 versus alendronate. 250
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Table III. Morisky-Green scores (no. [%] of patients) (N = 820). Time Point
Raloxifene
Alendronate
P
Period 1 (0–3 mo) High Moderate Low NR
(n = 427) 305 (71.4) 110 (25.8) 6 (1.4) 6 (1.4)
(n = 393) 236 (60.1) 136 (34.6) 17 (4.3) 4 (1.0)
<0.001
Period 2 (3–6 mo) High Moderate Low NR
(n = 393) 304 (77.4) 80 (20.4) 6 (1.5) 3 (0.8)
(n = 315) 210 (66.7) 90 (28.6) 10 (3.2) 5 (1.6)
0.004
Final visit (12 mo) High Moderate Low NR
(n = 364) 254 (69.8) 99 (27.2) 8 (2.2) 3 (0.8)
(n = 301) 195 (64.8) 84 (27.9) 17 (5.6) 5 (1.7)
0.036
NR = not reported.
Raloxifene Alendronate
12
% of Patients
10 8 6 4
* *
†
2 0 n=
427
393
Period 1 (0–3 mo)
393
315
Period 2 (3–6 mo)
364
301
Final Visit (12 mo)
Figure 2. Patients with difficulties taking the medication. *P < 0.001 versus alendronate; †P = 0.018 versus alendronate. 251
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Table IV. Multivariate logistic regression analysis to assess factors affecting compliance. Odds Ratios Effect Treatment (raloxifene vs alendronate) Physician type (rheumatologist vs orthopedic surgeon)
Wald Χ2
P > Χ2
Point Estimate
Wald 95% CI
13.17 7.41
<0.001 <0.007
1.76 1.53
1.29–2.38 1.13–2.07
Χ2 = chi-square.
The most common AEs that caused withdrawal were gastrointestinal disorders (RLX group, 3.4%; ALN group, 9.9%; P < 0.001). Dyspepsia, upper abdominal pain, and abdominal discomfort were the AEs reported most frequently by the study population, and all of these AEs were reported significantly more frequently in the ALN group than in the RLX group (P < 0.05). Two serious AEs were recorded during treatment with ALN and were considered relevant clinical AEs (moderate pyrosis and gastralgia in 1 patient and moderate epigastric pain in 1 patient). No venous thromboembolic events were recorded in the RLX group throughout the study. Mean (SD) treatment duration was 323.6 (111.7) days in the RLX group and 291.1 (136.6) days in the ALN group; the difference was statistically significant (P < 0.001). The hazard ratio was adjusted for treatment group and patient age. The overall likelihood of discontinuation was not significantly different between treatment groups (hazard ratio, 1.061). DISCUSSION
According to our MEDLINE search, the present study was the first prospective, direct comparison between RLX and ALN with regard to treatment compliance in clinical practice. In this observational study, patients treated for osteopenia or osteoporosis reported significantly better compliance with daily RLX compared with daily ALN during 12 months of treatment in a clinical setting. The results showed a relatively high consistency between the compliance rates based on the MoriskyGreen and the Autocompliance tests (differences in the absolute percentage of compliance of <5% between the 2 tests) and a lower correlation of these 2 tests with the Compliance Questionnaire (differences in compliance of 10%–16%), with lowest compliance reported on the latest Compliance Questionnaire taken. 252
Compliance with prescribed postmenopausal osteoporosis treatment is important for clinical effectiveness. Low patient compliance with prescribed treatments for chronic diseases is a common problem in clinical care, with reported 50% noncompliance in 1 review,16 and represents a relevant problem in chronic diseases such as osteoporosis.9,17 In 2 clinical trials,1,2 daily ALN was shown to be well tolerated; the discontinuation rates ranged from 8% to 13% after 3 years, and the overall incidence of upper gastrointestinal side effects was 1%. Compliance with ALN outside of the controlled trial setting is lower due to its tolerability profile and complex procedures for taking the drug.5,18 The discontinuation rate in clinical practice is much higher, with 30% discontinuation at 6 months5 and 46% at 1 year of treatment, mostly because of upper gastrointestinal AEs.18,19 In 2 clinical trials, the discontinuation rates for RLX due to AEs through 3 and 4 years were 10.3%3 and 12.8%,4 respectively. Few data on compliance with RLX and ALN therapy in routine clinical practice are available. In 1 study9 using structured telephone interviews (with a mean of 7 months after treatment initiation) to assess discontinuation rates, the proportion of women discontinuing differed by treatment and was 26% for hormone replacement therapy versus 19% for RLX (P = 0.03) and 19% for ALN (P = 0.02 vs hormone replacement therapy). Approximately two thirds of the women cited AEs as the reason for discontinuing treatment. In the present study, we used indirect methods to assess compliance. Direct methods (eg, measurement of serum or urine drug levels or observation of the patient taking the medication) are more objective but are complicated and expensive and therefore not feasible for routine clinical practice.20 Indirect measures of compliance may not be considered the most accu-
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rate and reliable methods to determine compliance, but 2 studies21,22 in a routine clinical setting found significant associations between indirect methods and other compliance measurements. The advantages of the methods in this study include simplicity, speed, and feasibility for routine clinical practice. Furthermore, a combination of different methods, such as those we used in our study, is more accurate in determining compliance than using only 1 method.20 The Morisky-Green test, with a sensitivity of 81% (the proportion of compliant patients correctly identified as compliant) and a specificity of 44% (the proportion of noncompliant patients correctly identified as noncompliant),13 has been used in several studies23–26 to assess treatment compliance in clinical practice. In the present study, the proportion of patients with a high compliance index score (indicating maximum compliance) throughout the study was statistically higher in the RLX group than in the ALN group (Figure 1). More good compliers were found in the RLX group, although the difference was borderline statistically nonsignificant (Figure 1). The proportion of compliant patients throughout the study, as determined by the Autocompliance test, was statistically higher in the RLX group than in the ALN group. Nevertheless, compliance was very high for both treatments, with a self-reported compliance of >90% in both groups. However, as previously described, it should be noted that patients tend to overreport adherence with self-reported measurements.20,26 Moreover, significantly more patients reported difficulty taking ALN compared with RLX throughout the study. These results are notably different from a report27 that used a prescription-claims database to assess compliance, where ALN showed a 12-month compliance probability of 15.6%, when obtaining <75% of the prescribed medication was considered as noncompliance. Regarding factors affecting compliance, only treatment and type of physician were variables related to treatment compliance. Surprisingly, other demographic variables (age, marital status, educational level, employment status, practice situation, reason for using antiresorptive treatment, number of previous diagnoses, number of concomitant medications, and disease knowledge level) were not related to treatment compliance.
In the present study, the overall withdrawal rate was 20.8%, and 73.9% of these withdrawals occurred during the first 3 months of treatment. The proportion of patients who withdrew from the study prematurely was statistically higher in the ALN group than in the RLX group. On the basis of self-reporting, most patients who discontinued ALN therapy did so because of treatment-related AEs.5,6,9 Although in clinical trials with daily ALN, gastrointestinal AEs were as common in women receiving placebo as among those taking the active drug,1,2 some reports5,9,28 have shown that as many as 20% to 30% of patients develop upper gastrointestinal tract AEs while taking ALN therapy and that a substantial proportion of these AEs are assumed to be the direct result of ALN. The withdrawal rate that we observed with ALN was similar to the 26% rate described by Kelly and Taggart29 and the 19% rate with risedronate.30 The higher withdrawal rates in those studies compared with the reported rates for ALN in controlled clinical trials1,2 support the assumption of a higher rate in routine clinical practice. The lower withdrawal rate found with RLX compared with ALN is in accordance with the results of trials6,7 comparing RLX with other preventive therapies, such as hormone replacement therapy, in a clinical setting. One study7 found a 25% lower probability of treatment discontinuation with RLX compared with systemic estrogens at 24 months. Similarly, the higher rate of withdrawal with ALN in our study might be due in part to AEs, namely, gastrointestinal disorders, which were significantly more common with ALN. The most commonly reported gastrointestinal AEs that caused premature withdrawal were dyspepsia and upper abdominal pain, with a statistically higher incidence of both in the ALN group. This finding might have contributed to the higher level of treatment satisfaction in patients in the RLX group because tolerability might be 1 important factor in discontinuations. This study has several limitations. Given the openlabel, nonrandomized allocation of the study treatments, a certain degree of biased information and selection cannot be ruled out. Caution should be used when interpreting the results because 2 of the 3 measures used to assess compliance were self-reported and, thus, subjective. Also, in this study, it was not possible to confirm the prescription file information with other data sources (eg, pill count). Although pill 253
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counts may provide more definitive measures of compliance in clinical trials, they are not feasible in most clinical settings and are characterized by many methodologic difficulties. To effectively prevent osteoporotic fractures through enhanced long-term treatment compliance, it is crucial to identify the most tolerable treatment. However, being aware of the reasons for discontinuation allows physicians to look carefully into them to improve patients’ compliance. CONCLUSIONS
In this study of postmenopausal women at risk for osteoporotic fractures, compliance with 12-month treatment with daily RLX was higher than with daily ALN in a clinical setting. RLX showed significant benefits compared with ALN in terms of compliance assessed by means of the Morisky-Green and Autocompliance tests, and the patient’s self-reported satisfaction. ACKNOWLEDGMENTS
This study was supported by an unrestricted grant from Eli Lilly & Company, Madrid, Spain. The following investigators participated in the Spanish Compliance Osteoporosis Study (PROCUOS): Julio Acal González, Juan Carlos Acebes Cachafeiro, Musa Ahmad Sabah, Juan Almansa Buades, Vicente Alonso Mendieta, Alberto Alonso Ruiz, Luis María Altuzarra Corral, Encarnación Amigo Díaz, José María Aparicio Gómez, Jaime Asín Ungría, Antonio Atanes Sandoval, Fernando Barandiaran Luca de Tena, Santiago Bartrons Casas, Miguel Angel Belmonte Serrano, Joaquín Belzumegui Otano, Edgar Benalcázar Cueva, Miguel Bernard Pineda, Mario Bernard Sánchez, Xavier Biarnes Margalef, Manuel Brito Suarez, Juan Luis Calatayud Carretero, Jaime Calderón Rodríguez, José Manuel Camacho Núñez, Estrella Cánovas Cánovas, Antonio Cardenal Escarcena, Miguel Carrión Gil, Inmaculada Carvajal Méndez, Montserrat Centellas Portella, Josep María Climent Barberá, Antonio Conca Roig, Juan Antonio Copano Abad, Monserrat Corteguera Coro, Belén Criado Portero, Juan Cruz Martínez, Juan Ramón Daza Mesas, Manuel De Haro Liger, Marcial De la Hera Martinez, Francisco Javier de Toro Santos, Juvenal de Vega Jiménez, Máximo Del Castillo Arbeloa, Esther del Rincón Padilla, César Díaz López, 254
Alberto Díaz Oca, Elvira Díez Álvarez, José Antonio Diez Jorro, José Manuel Docampo Riva, Francisco Domínguez Somoza, Celia Erausquin Arruabarrena, Carlos Fenollosa Costa, Jaime Fernández Campillo, José Luis Fernández Espejo, José Emilio Fernández García, Antonio Fernández Nebro, José Ferrero Boronat, Mercedes Freire González, Maria Ángeles Gantes Mora, Julio García Feito, Celia García Gimenez, Sergio García Pérez, Rosa García Portales, Florencio García Velazco, Emilio García-Mancha Arévalo, Saul Mario Gelman Aizen, Manuel Giner Pascual, Balbina González Álvarez, Teresa González Hernández, Julio Gracia Estévez, Jenaro Graña Gil, José Luis Guerra Vazquez, Antonio Gutierrez Rubio, José Francisco Hermida Seoane, José Luis Hernández Gómez, José Hernández Pomada, Susana Holgado Pérez, Talal Issa Mufti, José Ivorra Cortés, José María Jolonch Palau, Florencio Larramendi Pérez, Manuel Alejo Leal Muro, Alvaro Lesta Arnal, Isabel Linares Fernández, Xavier Llaurado Barenys, Carlos Lobato Kropnick, Hector López Artacho, Luis Maraver López del Valle, Juan Manuel López Gollonet, Antonio López Meseguer, Javier López Torroba, Antonio Luque Galán, Fernando Macías Olmeda, Javier Mareque Abad, Esperanza Martín Forero, Silvia Martínez Pardo, Fernando Martínez Pintor, Miguel Ángel Martínez Villar, Pedro Martínez Vitorio, Zouhair Massri Zeituni, Marta Medrano San Ildefonso, Francisco Mesa Ramos, Roberto Miguelez Sánchez, José Minguet Baixauli, Alvaro Minuesa Asensio, María Mira Molero, Carlos Miranda de Larra y de Onis, Arturo Molina López-Navas, José María Moreno Martínez, Francisco Mulet Clos, Cristobal Núnez-Cornejo Piquer, Carlos Ossorio Castellanos, Andrés Pámpano Pérez, Alberto Pascual Codeso, Carlos Pascual Martín, Isidoro Pascual Molina, Gilberto Pastor Zatarain, Encarnación Pérez López, Jaime Pérez Núñez, Fernando Pérez Ruiz, Trinidad Pérez Sandoval, Josep Oriol Pérez Serra, Juan Manuel Piedra Priego, Vicente Pomares Boix, Francisco Prats Maeso, Josep Pujol Costa, Javier Reparaz Padros, Félix Rico Navarro, Maria Porfiria Rodríguez del Hoyo, Ramón Rodríguez Franco, Antonio Rodríguez González, Jesus Rodríguez Moreno, Joaquín Rodríguez Soler, Juan Roig Juliá, Daniel Roig Vilaseca, Pascual Rosser Marín, Ivan Joaquín Sagarra Miró, Luis Sainz de los Terreros, Juan Saldaña Cuchillos, Ana Isabel Sánchez Atrio, Ginés Sánchez
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Address correspondence to: Carmen Turbí, MD, Av. de la Industria 30, Alcobendas, 28108 Madrid, Spain. E-mail: [email protected] 256