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Observational study of compliance and continuance rates of raloxifene in the prevention and treatment of osteoporosis
~URRENT THERAPEUTIC RESEARCH ~ VOLUME 65, No. 6, NOVEMBER/DEcEMBER2004
Observational Study of Compliance and Continuance Rates of Raloxifene in the Prevention and Treatment of Osteoporosis Jos~ R. Zanchetta, MD, Carina Hakim, MD, and Carola Lombas, MD Metabolic Research Institute, University of El Salvador School of Medicine, Buenos Aires, Argentina
ABSTRACT Background: Medical practitioners face t h e challenge of n o n c o m p l i a n c e with prescriptions, particularly in chronic, asymptomatic, diseases such as osteoporosis. Objective: The aim of this study was to assess t h e raloxifene compliance and continuance rates and a d v e r s e effects o v e r 24 m o n t h s in clinical practice. Methods: Using a retrospective study of clinical histories obtained from a d a t a b a s e at t h e Metabolic Research Institute, University of El Salvador School of Medicine, Buenos Aires, Argentina, as well as telephone interviews, we assessed compliance and continuance with raloxifene t h e r a p y in postm e n o p a u s a l patients who had received prescriptions for raloxifene to p r e v e n t or treat osteoporosis. Patients were contacted by telephone 24 m o n t h s after t h e y had received a prescription for raloxifene. Compliance and continuance rates were calculated based on the data provided by t h e patients. Results: Data from 419 patients ( m e a n [SD] age, 61.4 [7.4] y e a r s [range, 42-90 y e a r s ] ) w e r e included in t h e study. At t h e t i m e of t h e t e l e p h o n e interview, 225 (53.7%) w e r e still receiving raloxifene, 105 (25.1%) had s t o p p e d t r e a t m e n t at t h e i r own discretion, 59 (14.1%) had not s t a r t e d t r e a t m e n t , and 30 (7.2%) had discontinued t r e a t m e n t as a result of a d v i c e from a physician. The r e a s o n s for not starting t r e a t m e n t w e r e fear of t h r o m b o l y t i c e v e n t s (21 patients [35.6%]); lack of interest in starting t r e a t m e n t (12 [20.3%]); o t h e r physician's a d v i c e (11 [18.6%]); family p r o b l e m s (3 [5.1%]); dissatisfaction with t h e p r e s c r i b i n g physician, t r e a t m e n t cost, health p r o b l e m s u n r e l a t e d to osteoporosis, and m i s t r u s t in t h e p r e s c r i p t i o n (each, 2 [3.4%]); and a d v i c e from family/friends, fear of b r e a s t cancer, belief that raloxifene is h o r m o n a l , and that t h e patient was a l r e a d y p o l y m e d i c a t e d (each, 1 [1.7%]). Eleven of t h e 59 patients (18.6%) who had not s t a r t e d t h e r a p y w e r e a d v i s e d by a physician o t h e r t h a n t h e p r e s c r i b i n g physician not to s t a r t t r e a t m e n t and w e r e excluded from t h e c o m p l i a n c e analysis. Thus, t h e c o m p l i a n c e analysis included 408 patients. The 2 m o s t c o m m o n reasons for discontinuing t r e a t m e n t at the patient's own discretion were health p r o b l e m s unrelated to osteoporosis Accepted fol publir ation November 9, 2004. Reproduction in whole or part is not permitted. 470
doi:l 0.10161j.cu rtheres.2005.01.003 0011 393X/04/$19.00 Copyright © 2004 Excerpta Medica, Inc.
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(25 [23.8%]) and d i g e s t i v e p r o b l e m s n o t c o n s i d e r e d t r e a t m e n t related (16 [15.2%]). T h e c o m p l i a n c e r a t e s w e r e 75.0%, 71.1%, 65.0%, 57.1%, and 52.0% at 3, 6, 12, 18, a n d 24 m o n t h s , respectively. In p a t i e n t s w h o s t a r t e d raloxifene t r e a t m e n t , t h e c o n t i n u a n c e r a t e s w e r e 85.0%, 80.6%, 73.6%, 64.7%, a n d 58.9% at 3, 6, 12, 18, a n d 24 m o n t h s , respectively. Sixty-two of t h e 135 p a t i e n t s w h o d i s c o n t i n u e d t r e a t m e n t did so within 3 m o n t h s of r e c e i v i n g t h e p r e s c r i p t i o n , a c c o u n t i n g for 45.9% of all d i s c o n t i n u a t i o n s . Conclusions: In t h e p r e s e n t s t u d y of raloxifene c o m p l i a n c e and c o n t i n u a n c e in clinical practice, t h e c o m p l i a n c e rate a p p e a r e d to be relatively high comp a r e d with t h o s e of h o r m o n e - r e p l a c e m e n t t h e r a p y (HRT) and o t h e r non-HRT t r e a t m e n t s . Almost half of patients w h o discontinued t r e a t m e n t did s o in t h e first 3 months. (Curr Ther Res Clin Exp. 2004;65:470-480) Copyright © 2004 Excerpta Medica, Inc. Key words: compliance, adherence, raloxifene.
INTRODUCTION In p a t i e n t s with chronic, a s y m p t o m a t i c d i s e a s e s , t h e r a t e of c o m p l i a n c e with t h e r a p y is -50%. 1 In 1979, H a y n e s et al 2 d e f i n e d compliance as t h e d e g r e e to w h i c h a p a t i e n t ' s b e h a v i o r c o i n c i d e s with t h e p h y s i c i a n ' s p r e s c r i p t i o n o r advice. F o r g e t f u l n e s s and t h e m e d i c a t i o n b e i n g p e r c e i v e d as u n n e c e s s a r y are t h e m o s t f r e q u e n t r e a s o n s for n o n c o m p l i a n c e . 3 In t h e s e c a s e s , p a t i e n t s refuse to b u y t h e m e d i c a t i o n , forget to t a k e it regularly, o r d i s c o n t i n u e it completely. O s t e o p o r o s i s is a c h r o n i c and often a s y m p t o m a t i c disease; therefore, ens u r i n g c o m p l i a n c e c a n b e difficult. Continuance, defined as r e c e i v i n g m e d ication for a d u r a t i o n long e n o u g h to a c h i e v e t h e d e s i r e d effect, 4 s h o u l d also b e a d d r e s s e d . In o s t e o p o r o s i s , t h e c h r o n i c n a t u r e of t h e d i s e a s e n e c e s s i t a t e s y e a r s r a t h e r t h a n m o n t h s of therapy. Consequently, t r e a t m e n t c o m p l i a n c e and c o n t i n u a n c e are e s s e n t i a l for s u c c e s s f u l t r e a t m e n t . O s t e o p o r o s i s h a s b e e n m a n a g e d with h o r m o n e - r e p l a c e m e n t t h e r a p y (HRT). However, e n c o u r a g i n g c o m p l i a n t b e h a v i o r is difficult with HRT d u e to a d v e r s e effects (AEs) and fear of a potential i n c r e a s e in c a n c e r risk. Raloxifene, a selective e s t r o g e n r e c e p t o r modulator, h a s been a p p r o v e d for t h e p r e v e n t i o n and t r e a t m e n t of p o s t m e n o p a u s a l o s t e o p o r o s i s . Clinical trials 5,6 h a v e s h o w n it to b e effective in m a i n t a i n i n g b o n e m a s s a n d r e d u c i n g t h e i n c i d e n c e of v e r t e b r a l f r a c t u r e s . However, in t h e clinical trial setting, t h e high a d h e r e n c e rate (>80%) 5 to t h e raloxifene t r e a t m e n t r e g i m e n is n o t n e c e s s a r i l y reflective of t h e s i t u a t i o n in clinical practice. T h e aim of t h i s s t u d y w a s to a s s e s s t h e r a t e s of c o m p l i a n c e a n d continua n c e o v e r 24 m o n t h s a f t e r t h e p r e s c r i p t i o n of raloxifene for t h e p r e v e n t i o n o r t r e a t m e n t of o s t e o p o r o s i s . 471
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PATIENTS A N D METHODS We r e t r o s p e c t i v e l y r e v i e w e d t h e d a t a b a s e at t h e Metabolic R e s e a r c h Institute, U n i v e r s i t y of El S a l v a d o r School of Medicine, B u e n o s Aires, Argentina, to identify all p o s t m e n o p a u s a l p a t i e n t s p r e s c r i b e d raloxifene from March 1998 t h r o u g h O c t o b e r 2000. From a m o n g t h e s e patients, we i n c l u d e d t h o s e w h o could b e c o n t a c t e d b y t e l e p h o n e . All of t h e p a t i e n t s included h a d und e r g o n e b o n e m i n e r a l d e n s i t y m e a s u r e m e n t , h a d r e c e i v e d a p r e s c r i p t i o n for raloxifene 60 m g / d for t h e p r e v e n t i o n o r t r e a t m e n t of o s t e o p o r o s i s , and w e r e enrolled in a h e a l t h i n s u r a n c e plan. T h e s c r i p t u s e d in t h e t e l e p h o n e i n t e r v i e w s w a s a p p r o v e d b y t h e i n s t i t u t i o n a l r e v i e w b o a r d at t h e M e t a b o l i c R e s e a r c h I n s t i t u t e , a n d p a t i e n t s w e r e r e q u i r e d to p r o v i d e v e r b a l i n f o r m e d c o n s e n t f o r t h e interview. Two p e o p l e c o n d u c t e d t h e t e l e p h o n e i n t e r v i e w s , w h i c h c o n s i s t e d of 2 s e c t i o n s - - o p e n and c l o s e d q u e s t i o n s - - t o a s s e s s c o m p l i a n c e , c o n t i n u a n c e , and AEs a s s o c i a t e d with raloxifene t r e a t m e n t . Closed q u e s t i o n s included multiple-choice and y e s / n o q u e s t i o n s (eg, "Did y o u e x p e r i e n c e a n y a d v e r s e e v e n t s after s t a r t i n g t r e a t m e n t with raloxifene?"). If a p a t i e n t found it difficult to r e m e m b e r c e r t a i n data, s h e w a s a s k e d , "Do y o u r e m e m b e r h a v i n g h o t f l a s h e s a f t e r s t a r t i n g t r e a t m e n t with raloxifene?" Following d a t a collection, p a t i e n t b e h a v i o r w a s classified a c c o r d i n g to c o m p l i a n c e . P a t i e n t s w e r e c o n s i d e r e d c o m p l i a n t if t h e y m e t a n y of t h e following criteria: (1) t h e y w e r e still t a k i n g raloxifene at t h e t i m e of t h e interview; (2) t h e y h a d d i s c o n t i n u e d raloxifene t r e a t m e n t as a result of a d v i c e from t h e p h y s i c i a n w h o p r e s c r i b e d raloxifene o r a n o t h e r physician; (3) t h e y h a d t e m p o r a r i l y i n t e r r u p t e d t r e a t m e n t as a result of a d v i c e from a physician d u e to a t r a n s i t o r y c o n d i t i o n (eg, p r o l o n g e d rest); o r (4) t h e y h a d n o t s t a r t e d t r e a t m e n t as a r e s u l t of r e c e i v i n g an a l t e r n a t i v e p r e s c r i p t i o n from t h e p r e s c r i b i n g p h y s i c i a n o r as a result of a d v i c e from a n o t h e r physician. In addition, p a t i e n t s w h o h a d t e m p o r a r i l y i n t e r r u p t e d raloxifene treatm e n t for <5% of t h e total t i m e of t r e a t m e n t w e r e c o n s i d e r e d partially compliant and w e r e i n c l u d e d in t h e c o m p l i a n t group. N o n c o m p l i a n t p a t i e n t s w e r e t h o s e who, at t h e i r o w n discretion, h a d not s t a r t e d t r e a t m e n t o r h a d d i s c o n t i n u e d it. T h e r a t e of c o n t i n u a n c e w a s calculated as t h e n u m b e r of c o m p l i a n t p a t i e n t s a m o n g t h o s e w h o h a d s t a r t e d therapy. C o m p l i a n c e and c o n t i n u a n c e w e r e a s s e s s e d at 3, 6, 12, 18, and 24 m o n t h s after t h e p r e s c r i p t i o n w a s given.
Statistical Analysis T i m e to d i s c o n t i n u a t i o n w a s analyzed u s i n g t h e Kaplan-Meier m e t h o d of s u r v i v a l analysis. To d e t e r m i n e a relationship b e t w e e n s o m e of t h e v a r i a b l e s and c o m p l i a n c e , w e a t t e m p t e d to p e r f o r m an a n a l y s i s of logistic r e g r e s s i o n . Statistical analysis w a s p e r f o r m e d u s i n g Statistix v e r s i o n 7.0 (Analytical Software, Tallahassee, Florida). 472
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RESULTS T h e d a t a b a s e identified 455 eligible p o s t m e n o p a u s a l p a t i e n t s w h o h a d b e e n p r e s c r i b e d raloxifene. Of t h e s e , 419 p a t i e n t s could b e c o n t a c t e d b y telep h o n e a n d w e r e included in t h e a n a l y s i s ( m e a n [SD] age, 61.4 [7.4] y e a r s [range, 42-90 y e a r s ] ) . T h e b a s e l i n e c h a r a c t e r i s t i c s of t h e s t u d y p a t i e n t s a r e s h o w n in T a b l e I. Of t h e 419 p a t i e n t s included in t h e analysis, 360 (85.9%) h a d s t a r t e d treatm e n t at t h e t i m e of t h e t e l e p h o n e interview. Two h u n d r e d twenty-five pat i e n t s (53.7%) w e r e still t a k i n g raloxifene (24 m o n t h s a f t e r p r e s c r i p t i o n ) at t h e t i m e of t h e interview, 105 (25.1%) h a d d i s c o n t i n u e d t h e r a p y at t h e i r o w n discretion, a n d 30 (7.2%) h a d d i s c o n t i n u e d t r e a t m e n t d u e to a p h y s i c i a n ' s advice. T h e 59 r e m a i n i n g p a t i e n t s (14.1%) h a d not s t a r t e d t h e r a p y , t h e reas o n s for which are s h o w n in T a b l e II. Eleven of t h e s e 59 p a t i e n t s (18.6%) w e r e c o n s i d e r e d c o m p l i a n t b e c a u s e t h e y h a d followed t h e a d v i c e of a n o t h e r Table I. Baseline demographic and clinical characteristics of the study patients (N -- 419). Characteristic
Value
Age, y Mean (SD) Range
61.4 (7.4) 42 90
Age gl~up, y, no. (%)
17 190 1 68 39
~80 Years since rnenopause Mean (SD) Range Concomitant medications, mean (range) BMD classification, *t no. (%) Normal Mild osteopenia Moderate osteopenia Severe osteopenia Osteoporosis
(4.1) (45.3) (40.1) (9.3)
S (1.2) 14 (7.8) 1 42 2.91 (0 11) 14 26 52 119 208
(3.3) (6.2) (12.4) (28.4) (49.6)
BMD bone mineral density. *Measured by %score (the number of SDs above or below the average BMD value for young, healthy, white women). Scale: ~ 1.0 normal; < 1.0 to > 1.5 mild osteopenia; ~ 1.5 to > 2.0 moderate osteopenia; ~ 2.0 to > 2.5 severeosteopenia; ~ 2.5 osteoporosis. fPercentages do not total 100 due to rounding. 473
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Table II. Reasons for not starting raloxifene treatment (n = 59). Reason Fear of thrombolytic events after reading the package insert Lack of interest in starting treatment Advice from a physician other than the prescribing physician* Family problems Dissatisfaction with prescribing physician Treatment cost Health problems unrelated to osteopomsis Mistrust in the prescription Advice from family/friends Fear of breast cancer Belief that raloxifene is a hormonal treatment Patient was already polymedicated
No. (%)
21 (35.6) 12 (20.3) 11 (18.6) 3 (s.1) 2 (3.4) 2 (3.4) 2 (3.4) 2 (3.4) 1 (1.7) 1 (1.7) 1 (1.7) 1 (1.7)
*These patientswere considered to be compliant.
physician (general practitioner [6 patients], cardiologist [2], gynecologist [2], and hematologist [1]). The reasons t h e s e physicians advised the patients against raloxifene t h e r a p y were not recorded. Of 30 patients who discontinued treatment as a result of advice from a physician (compliant patients), the physician who initially prescribed raloxifene subsequently prescribed another drug due to lack of raloxifene efficacy (12 patients), or a physician (mainly gynecologists) o t h e r than t h e prescribing physician advised the patient to discontinue raloxifene, believing that there were better drugs for t h e prevention and t r e a t m e n t of osteoporosis (18). In the 105 patients who discontinued t r e a t m e n t at their own discretion (noncompliant patients), t h e 2 most c o m m o n reasons were health problems unrelated to osteoporosis (25 [23.8%]) and digestive p r o b l e m s not considered t r e a t m e n t related (16 [15.2%]) (Table III). The 25 patients who discontinued t r e a t m e n t due to health problems unrelated to osteoporosis reported that t h e y considered their o t h e r health problems m o r e serious or troubling than osteoporosis. These health conditions included arthralgia (12), cardiac p r o b l e m s (12), and tiredness (1). Of the 135 discontinuers, 62 discontinued within 3 months of receiving the prescription, accounting for 45.9% of all discontinuers. Of these, 52 patients (38.5%) did so at their own discretion, and 10 (7.4%) as a result of advice from a physician. An additional 42 patients (31.1%) discontinued treatment within 12 m o n t h s of receiving the prescription, 30 (22.2%) at their own discretion, and 12 (8.9%) as a result of advice from a physician. Twenty-seven more patients (20.0%) discontinued treatment within 24 months of receiving the prescription, 20 (14.8%) at their own discretion, and 7 (5.2%) as a result of advice from a physician. 474
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Table III. Reasons for discontinuing raloxifene treatment (n -- 105).* Reason
No. (%)
Health pl~blems unrelated to osteopol~sis
25 (23.8)
Digestive problems not considered treatment related
16 (15.2)
Lack of interest in starting treatment
12 (11.4)
Treatment cost
12 (11.4)
Vasodilation
12 (11.4)
Fear of thrombolytic events after reading the package insert
7 (6.7)
Lower limb discomfort
S (4.8)
Patient was already polymedicated
S (4.8)
Leg cramps
4 (3.8)
Family problems
3 (2.9)
Lower limb edema
3 (2.9)
Belief that raloxifene is not necessalT
1 (1.0)
*Pementagesdo not total 100 due to rounding.
The discontinuation rates a m o n g patients who started t r e a t m e n t (n 360) were 17.2% (62 patients), 11.7% (42), and 7.5% (27) at 3, 12, and 24 months, respectively. A m o n g all 419 patients, this overall rate was 105 (25.1%). Eleven of 419 patients analyzed (2.6%) were advised by a physician o t h e r than t h e prescribing physician not to start t r e a t m e n t and were excluded from t h e compliance analysis. The compliance rate in the remaining 408 patients was 75.0% (306 patients) at 3 months, 71.1% (290) at 6 months, 65.0% (265) at 12 months, 57.1% (233) at 18 months, and 52.0% (212) at 24 months. Once patients had started t r e a t m e n t (360 patients), the rates of continuance were 85.0%, 80.6%, 73.6%, 64.7%, and 58.9% at 3, 6, 12, 18, and 24 months, respectively (Figure). T h e logistic regression analysis s h o w e d that c o m p l i a n c e did not s e e m to be affected by age, n u m b e r of concomitant medications, lumbar T-score, femoral neck T-score, or k n o w l e d g e of t h e p r e s e n c e of v e r t e b r a l and n o n v e r t e b r a l fractures.
DISCUSSION
Well-designed clinical trials s,7 d e m o n s t r a t e d that t h e efficacy of t h e various osteoporosis therapies in increasing bone m a s s o r reducing fracture risk is pivotal for clinical success. However, t h e success of a t r e a t m e n t is also heavily d e p e n d e n t on a patient's compliance with that treatment. In o t h e r words, it is t h e combination of efficacy and compliance that determines t h e effectiveness 475
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Follow-Up ( m o ) Figure. C o m p l i a n c e and c o n t i n u a n c e rates o v e r t i m e (analysis excludes 11 patients w h o w e r e advised by a physician o t h e r t h a n t h e prescribing physician n o t t o start t r e a t m e n t ) .
of t r e a t m e n t in t h e clinical setting. Studies d e s i g n e d to a s s e s s c o m p l i a n c e with HRT h a v e r e p o r t e d low rates of compliance. ~1° For example, one s t u d y found that nearly half of w o m e n w h o s t a r t e d HRT w e r e r e p o r t e d to h a v e discontinued t h e r a p y after a m e a n of 9 months. 11 T h e i n v e s t i g a t o r s s u g g e s t e d this could h a v e b e e n d u e in part to t h e fear of t h e risk for b r e a s t a n d / o r endometrial c a n c e r a s s o c i a t e d with HRT. 11 Thus, d e s p i t e t h e extraskeletal benefits of HRT (eg, i m p r o v e d lipid levels and v a s o m o t o r s y m p t o m s ) , m a n y w o m e n are reluctant to accept this therapeutic option. Vaginal bleeding is another c o m m o n reason that w o m e n discontinue HRT. 12 Using results from population-based studies and clinical trials, H a m m o n d 13 a s s e s s e d patients' c o m p l i a n c e with HRT. He d e t e r m i n e d that < 20% of p o s t m e n o p a u s a l w o m e n in t h e United States h a v e been p r e s c r i b e d t r e a t m e n t with HRT on at least 1 occasion, and of t h o s e w h o s t a r t e d treatment, <40% continued it after 1 year. A n o t h e r s t u d y b y Ettinger et a112 s h o w e d differe n c e s in t h e r e a s o n s for s t a r t i n g and a b a n d o n i n g HRT in y o u n g e r w o m e n (aged 50-55 y e a r s ) and older w o m e n (aged ->65 years): older w o m e n s t a r t e d HRT to treat osteoporosis, w h e r e a s t h e y o u n g e r w o m e n did so to e a s e v a s o m o t o r s y m p t o m s . The HRT discontinuation rate was h i g h e r in t h e older group t h a n in t h e y o u n g e r group. In a third, r e t r o s p e c t i v e study, Ettinger et a114 a s s e s s e d c o m p l i a n c e with a l e n d r o n a t e t h e r a p y u s i n g t e l e p h o n e i n t e r v i e w s with 812 w o m e n ( m e a n age, 68.7 y e a r s ) . Overall, 28.5% of w o m e n r e p o r t e d d i s c o n t i n u a t i o n of a l e n d r o n a t e within 8 m o n t h s of initiating therapy. Based on a r e v i e w of p r e s c r i p t i o n data, 34.9% of t h e s e w o m e n had d i s c o n t i n u e d b y 6 m o n t h s , m o s t often b e c a u s e of g a s t r o i n t e s t i n a l AEs. A n o t h e r s t u d y d e s i g n e d to d e t e r m i n e c o m p l i a n c e with 476
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a l e n d r o n a t e r e p o r t e d t h a t s o m e p a t i e n t s did not n e c e s s a r i l y follow d o s i n g i n s t r u c t i o n s (eg, patients reported lying d o w n o r eating within 30 m i n u t e s of receiving alendronate). 15 K a y s e r et a116 r e p o r t e d d i f f e r e n c e s in c o m p l i a n c e b e t w e e n w o m e n receiving raloxifene and t h o s e receiving e s t r o g e n - c o n t a i n i n g t h e r a p i e s . Both g r o u p s w e r e s i m i l a r in a g e ( m e a n age, 69 y e a r s ) , b u t raloxifene w a s m o r e c o m m o n ly p r e s c r i b e d b y i n t e r n i s t s t h a n b y g y n e c o l o g i s t s . Overall, 19% of p a t i e n t s r e c e i v i n g raloxifene a n d 31% r e c e i v i n g e s t r o g e n - c o n t a i n i n g t h e r a p y did not h a v e t h e p r e s c r i p t i o n refilled. At 12 a n d 24 m o n t h s , d i s c o n t i n u a t i o n w a s r e p o r t e d in 50% a n d 56%, respectively, of p a t i e n t s r e c e i v i n g raloxifene thera p y c o m p a r e d with 63% a n d 72%, respectively, of t h o s e r e c e i v i n g e s t r o g e n c o n t a i n i n g t h e r a p y . W o m e n of a s i m i l a r a g e r e c e i v i n g raloxifene w e r e 25% less likely to discontinue medication t h a n t h o s e receiving estrogen-containing therapy. In t h e p r e s e n t study, t h e m o s t c o m m o n r e a s o n for not s t a r t i n g raloxifene t h e r a p y w a s t h e fear of t h r o m b o l y t i c e v e n t s a f t e r r e a d i n g t h e p a c k a g e insert, w h i c h lists it as a p o s s i b l e AE. In c o n t r a s t , 2 large s u r v e y s t u d i e s 17,18 reported t h a t up to 20% of p a t i e n t s did not h a v e t h e i r p r e s c r i p t i o n s filled, m o s t freq u e n t l y b e c a u s e t h e y b e l i e v e d t h e y did not n e e d t h e m e d i c a t i o n p r e s c r i b e d . A n o t h e r s t u d y found t h a t a m o n g p a t i e n t s w h o did h a v e t h e p r e s c r i p t i o n filled, t h e 2 m o s t f r e q u e n t r e a s o n s for n o n c o m p l i a n c e w e r e d o s e o m i s s i o n a n d d r u g i n g e s t i o n at an i n c o r r e c t t i m e point. 19 T h e s e n o n c o m p l i a n t b e h a v iors are also c o m m o n in patients with o t h e r chronic conditions, s u c h as hypert e n s i o n , h y p e r c h o l e s t e r o l e m i a , a n d epilepsy. 2° 23 R u d d et a118 i n t r o d u c e d t h e t e r m partial compliance to refer to t h e b e h a v ior of p a t i e n t s w h o d o not d i s c o n t i n u e t h e i r m e d i c a t i o n e n t i r e l y b u t interr u p t it for a p e r i o d of time. In t h e elderly, t h i s t y p e of n o n c o m p l i a n c e is o f t e n unintentional. 3 An i m p o r t a n t finding in t h e p r e s e n t s t u d y w a s t h e lack of s h o r t - t e r m c o m p l i a n c e : 45.9% of t h e d i s c o n t i n u a t i o n s o c c u r r e d in t h e first 3 m o n t h s , 83.9% of w h i c h w e r e at p a t i e n t s ' o w n d i s c r e t i o n . D r u g d i s c o n t i n u a t i o n w a s m a i n l y a s s o c i a t e d with p e r s o n a l c i r c u m s t a n c e s o r c h o i c e s . For e x a m p l e , 4.8% of d i s c o n t i n u e r s c o n s i d e r e d it i n c o n v e n i e n t to a d d a n o t h e r d r u g to t h e i r usual r e g i m e n ( p o l y m e d i c a t e d ) , a n d f a m i l y p r o b l e m s p r e v e n t e d 2.9% of d i s c o n t i n u e r s from t a k i n g c a r e of t h e i r o w n health. T h e r e c o g n i z e d AEs of raloxifene (eg, v a s o d i l a t i o n , leg c r a m p s ) w e r e not a s s o c i a t e d with i n c r e a s e d d i s c o n t i n u a t i o n , w h i c h s u p p o r t s t h e s a f e t y a n d tolerability of t h e drug. No c a s e s of d e e p v e n o u s t h r o m b o s i s o r p u l m o n a r y t h r o m b o e m b o l i s m w e r e reported. In t h e p r e s e n t study, p a t i e n t s w h o d i s c o n t i n u e d t r e a t m e n t at t h e r e c o m m e n d a t i o n of a p h y s i c i a n w e r e c o n s i d e r e d compliant. In t h e s e patients, interr u p t i o n of t r e a t m e n t w a s r e c o m m e n d e d e i t h e r b y t h e p h y s i c i a n w h o initially w r o t e t h e p r e s c r i p t i o n for raloxifene a n d t h e n p r e s c r i b e d a n o t h e r d r u g d u e to lack of efficacy, o r b y a n o t h e r p h y s i c i a n w h o a d v i s e d t h e p a t i e n t to s t o p 477
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t r e a t m e n t , with no f u r t h e r e x p l a n a t i o n from t h e p h y s i c i a n . In t h e l a t t e r group, t h e p a t i e n t s did n o t k n o w t h e r e a s o n for t h e r e g i m e n c h a n g e . It is p o s s i b l e t h a t conflicting a d v i c e from p r e s c r i b e r s m a y c o n t r i b u t e to confus i o n a m o n g p a t i e n t s . A n o t h e r p o s s i b i l i t y m a y b e i n e f f e c t i v e p r o v i d e r comm u n i c a t i o n (eg, insufficient i n f o r m a t i o n p r o v i d e d b y t h e p h y s i c i a n , inadeq u a t e r e s p o n s e to a p a t i e n t ' s individual n e e d s ) . N o n c o m p l i a n c e as a c o n s e q u e n c e of d r u g c o s t m a y also b e a significant p r o b l e m . In t h e p r e s e n t study, 3.3% (14/419) of p a t i e n t s s t a t e d t h e y could not afford t h e m e d i c a t i o n . In a s u r v e y of elderly p a t i e n t s , 3 c o s t w a s g i v e n as t h e r e a s o n for n o n c o m p l i a n c e b y 10% of p a t i e n t s . Clinical e x p e r i e n c e sugg e s t s t h a t e l d e r l y p a t i e n t s with fixed i n c o m e s s o m e t i m e s m a k e s t r a t e g i c d e c i s i o n s a b o u t w h i c h m e d i c a t i o n s t h e y c a n afford. 23 R e g a r d i n g t h e logistic r e g r e s s i o n analysis, g i v e n t h e small s a m p l e size, t h e r e w a s not sufficient p o w e r to d r a w a c o n c l u s i o n . M o s t of t h e p a t i e n t s w h o c o m e to t h e Metabolic R e s e a r c h Institute a r e enrolled in p r i v a t e l y o w n e d h e a l t h i n s u r a n c e p l a n s t h a t allow t h e m to visit p h y s i c i a n s w h o s p e c i a l i z e in o s t e o p o r o s i s w i t h o u t b e i n g referred b y a prim a r y c a r e physician. T h i s could r e p r e s e n t a potential s e l e c t i o n bias. A n o t h e r limitation of t h e s t u d y c o n c e r n e d t h e s e n s i t i v i t y of t h e s u r v e y i n s t r u m e n t s , w h i c h m a y not h a v e b e e n a c c u r a t e in v e r i f y i n g t h a t a p a r t i c i p a n t actually r e c e i v e d raloxifene as r e p o r t e d . We m e a s u r e d a d h e r e n c e to raloxifene treatm e n t t h r o u g h p a t i e n t r e p o r t s b y t e l e p h o n e a n d r e v i e w of clinical histories. Both of t h e s e m e a s u r e s a r e indirect a n d t h u s h a v e s o m e limitations. Telep h o n e i n t e r v i e w s m a y h a v e led to significant recall bias. Moreover, it is not c l e a r w h e t h e r t h e results of t h e p r e s e n t s t u d y c a n b e applied to o t h e r clinics, and f u r t h e r s t u d i e s would b e r e q u i r e d to clarify this. O u r r e s e a r c h p r o v i d e s a b a s i s for t h e s t u d y of raloxifene c o m p l i a n c e and c a n b e u s e d to d e v e l o p w a y s of p r o m o t i n g it. T h e r e s u l t s s u g g e s t a n e e d for a c o l l a b o r a t i v e p h y s i c i a n - p a t i e n t r e l a t i o n s h i p a n d for t a i l o r i n g c a r e to individual p a t i e n t s , with a t t e n t i o n to t h e i r social c o n t e x t (eg, social n o r m s a n d h e a l t h r i s k s in o l d e r [age, >65 y e a r s ] p a t i e n t s ) . M a n y o l d e r p a t i e n t s a r e u n a b l e to u n d e r s t a n d t h e i r d i s e a s e s a n d t r e a t m e n t goals, and insufficient i n f o r m a t i o n p r o v i d e d b y t h e p h y s i c i a n o r i n a d e q u a t e a t t e n t i o n to an individual p a t i e n t ' s n e e d s m a y lead to p o o r c o m p l i a n c e . S o m e p a t i e n t s , part i c u l a r l y o l d e r ones, m a y r e m e m b e r only p a r t o r n o n e of t h e d o s i n g i n s t r u c tions. A p h y s i c i a n ' s e n t h u s i a s m a n d u s e of s e v e r a l m e t h o d s of c o m m u n i c a t i o n (eg, c h a r t s , i n s t r u c t i o n s w r i t t e n in large l e t t e r s ) c a n help p a t i e n t s r e m e m b e r t h e i n s t r u c t i o n s . P h y s i c i a n s s h o u l d also highlight t h e b e n e f i t s of c o m p l i a n c e and explain t h e r i s k s of n o n c o m p l i a n c e (ie, f r a c t u r e s ) . O n e s t u d y s h o w e d t h a t s p e n d i n g 15 m i n u t e s c o u n s e l i n g o l d e r a d u l t s a b o u t t h e i r m e d i c a t i o n s i n c r e a s e d t h e i r u n d e r s t a n d i n g of t h e n e e d for t r e a t m e n t c o m p l i a n c e . 24 Finally, t h e h i g h d i s c o n t i n u a t i o n r a t e d u r i n g t h e first 3 m o n t h s could h a v e b e e n t h e result of r o u t i n e clinical p r a c t i c e at o u r c e n t e r : t h e first m e d i c a t i o n follow-up v i s i t is s c h e d u l e d for 6 m o n t h s a f t e r t h e p r e s c r i b 478
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ing visit. We s u g g e s t t h a t m o r e f r e q u e n t follow-up v i s i t s (eg, at t h e first and t h i r d m o n t h s following p r e s c r i p t i o n of t h e d r u g ) also c o u l d h e l p i m p r o v e adherence.
CONCLUSIONS In t h e present s t u d y of raloxifene compliance and continuance in postm e n o p a u s a l patients, t h e compliance rate appeared to be relatively high compared with t h o s e of HRT and o t h e r non-HRT treatments. Almost half of patients who d i s c o n t i n u e d t r e a t m e n t did so in the first 3 months. We suggest attention to individual patients' needs, effective communication, and more frequent followup visits would i m p r o v e adherence with o s t e o p o r o s i s t r e a t m e n t modalities.
ACKNOWLEDGMENT Sherie Dowsett, PhD (Eli Lilly and Company, Indianapolis, Indiana) provided editorial review and comments.
REFERENCES 1. Eraker SA, Kirscht JR Becker MH. Understanding and improving patient compliance. Ann Intern Ned. 1984;100:258-268. 2. Haynes RB, Taylor DW, Sakert DL, et al. Compliance in Health Care. Baltimore, Md: The Johns Hopkins University Press; 1979. 3. Col N, Fanale JE, Kronholm R The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderl~ Arch Intern Ned. 1990;150:841-845. 4. Achieving long-term continuance of menopausal ERT/HRT: Consensus opinion of the North America Menopause Societ~ Nenopause. 1998;5:69-76. 5. Ettinger B, Black DM, Mitlak BH, et al, for the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial [published correction appears in JAMA. 1999;282:2124]. JAMA. 1999;282:637-645. 6. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol, concentration, and uterine endometrium in postmenopausal women. NEngl JNed. 1997;337:1641-1647. 7. Black DM, Cummings SR, Karpf DB, et al, for the Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on the risk of fracture in women with existing vertebral fracture. Lancet. 1996;348:1535-1541. 8. Jones MM, Francis RM, Nordin BE. Five year follow-up of oestrogen therapy in 94 women. Naturitas. 1982;4:123-130. 9. Ravnikar VA. Compliance with hormone therap~ Am J Obstet Gynecol. 1987;156: 1332-1334. 10. Wallace WA, Price VH, Elliot CA, et al. Hormone replacement therapy acceptability to Nottingham post-menopausal women with a risk factor for osteoporosis. J R 5bc Ned. 1990;83:699-701. 479
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11. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. NEngl JMed. 1975;293:1167-1170. 12. Ettinger B, Pressman A, Silver R Effect of age on reasons for initiation and discontinuation of hormone replacement therapy [published correction appears in Menopause. 2000;7:135]. Menopause. 1999;6:282-289. 13. Hammond CB. Women's concerns with hormone replacement therapy--compliance issues. FertiISteril. 1994;62(Suppl 2):157S-160S. 14. Ettinger B, Pressman A, Schein J, et al. Use of alendronate in 812 women: Prevalence of gastrointestinal disturbances, lack of instructions, compliance and discontinuation. J Manag Care Pharm. 1998:488-492. 15. Mersfelder T, Armitstead JA, Ivey MF, et al. A medication use evaluation of alendronate: Compliance with administration guidelines. Pharm Pract Manag Q. 1999; 18:50-58. 16. Kayser J, Ettinger B, Pressman A. Postmenopausal hormonal support: Discontinuation of raloxifene versus estrogen. Menopause. 2001;8:323-332. 17. Survey by Applied Research Techniques Conducted for the American Association of Retired Persons. Washington, DC: American Association of Retired Persons; 1984. 18. National Prescription Buyers survey. Kalamazoo, Mich: Upjohn; 1985. 19. Rudd R Clinicians and patients with hypertension: Unsettled issues about compliance. Am Heart ~ 1995;130:572-579. 20. Rudd P, Ahmed S, Zachary V, et al. Compliance with medication timing: Implications from a medication trial for drug development and clinical practice. J Clin Res Pharmacoepidemiol. 1992;6:15-27. 21. Kruse WH. Compliance with treatment of hyperlipoproteinemia in medical practice and clinical trials. In: Cramer JA, Spilker B, eds. Patients Compliance in Medical Practice and Clinical Trials. New York, NY: Raven Press; 1991:175-186. 22. Cramer JA, Mattson RH. Monitoring compliance with antiepileptic drug therapy. In: Cramer JA, Spilker B, eds. Patients Compliance in Medical Practice and Clinical Trials. New York, NY: Raven Press; 1991:123-137. 23. Salzman C. Medication compliance in the elderly. J Clin Psychiatry. 1995;56(Suppl 1): 18-22. 24. Johnston M, Clarke A, Mundy K, et al. Facilitating comprehension of discharge medication in elderly patients. Age Ageing. 1986;15:304-306.
Address correspondence to: Jos6 R. Zanchetta, MD, lnstituto de lnvestigaciones Metab61icas (IDIM), USAL University, School of Medicine, Libertad 8:36, 1st Floor, Buenos Aires C1012AAR, Argentina. E-mail: [email protected] 480
Observational Study of Compliance and Continuance Rates of Raloxifene in the Prevention and Treatment of Osteoporosis Jos~ R. Zanchetta, MD, Carina Hakim, MD, and Carola Lombas, MD Metabolic Research Institute, University of El Salvador School of Medicine, Buenos Aires, Argentina
ABSTRACT Background: Medical practitioners face t h e challenge of n o n c o m p l i a n c e with prescriptions, particularly in chronic, asymptomatic, diseases such as osteoporosis. Objective: The aim of this study was to assess t h e raloxifene compliance and continuance rates and a d v e r s e effects o v e r 24 m o n t h s in clinical practice. Methods: Using a retrospective study of clinical histories obtained from a d a t a b a s e at t h e Metabolic Research Institute, University of El Salvador School of Medicine, Buenos Aires, Argentina, as well as telephone interviews, we assessed compliance and continuance with raloxifene t h e r a p y in postm e n o p a u s a l patients who had received prescriptions for raloxifene to p r e v e n t or treat osteoporosis. Patients were contacted by telephone 24 m o n t h s after t h e y had received a prescription for raloxifene. Compliance and continuance rates were calculated based on the data provided by t h e patients. Results: Data from 419 patients ( m e a n [SD] age, 61.4 [7.4] y e a r s [range, 42-90 y e a r s ] ) w e r e included in t h e study. At t h e t i m e of t h e t e l e p h o n e interview, 225 (53.7%) w e r e still receiving raloxifene, 105 (25.1%) had s t o p p e d t r e a t m e n t at t h e i r own discretion, 59 (14.1%) had not s t a r t e d t r e a t m e n t , and 30 (7.2%) had discontinued t r e a t m e n t as a result of a d v i c e from a physician. The r e a s o n s for not starting t r e a t m e n t w e r e fear of t h r o m b o l y t i c e v e n t s (21 patients [35.6%]); lack of interest in starting t r e a t m e n t (12 [20.3%]); o t h e r physician's a d v i c e (11 [18.6%]); family p r o b l e m s (3 [5.1%]); dissatisfaction with t h e p r e s c r i b i n g physician, t r e a t m e n t cost, health p r o b l e m s u n r e l a t e d to osteoporosis, and m i s t r u s t in t h e p r e s c r i p t i o n (each, 2 [3.4%]); and a d v i c e from family/friends, fear of b r e a s t cancer, belief that raloxifene is h o r m o n a l , and that t h e patient was a l r e a d y p o l y m e d i c a t e d (each, 1 [1.7%]). Eleven of t h e 59 patients (18.6%) who had not s t a r t e d t h e r a p y w e r e a d v i s e d by a physician o t h e r t h a n t h e p r e s c r i b i n g physician not to s t a r t t r e a t m e n t and w e r e excluded from t h e c o m p l i a n c e analysis. Thus, t h e c o m p l i a n c e analysis included 408 patients. The 2 m o s t c o m m o n reasons for discontinuing t r e a t m e n t at the patient's own discretion were health p r o b l e m s unrelated to osteoporosis Accepted fol publir ation November 9, 2004. Reproduction in whole or part is not permitted. 470
doi:l 0.10161j.cu rtheres.2005.01.003 0011 393X/04/$19.00 Copyright © 2004 Excerpta Medica, Inc.
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(25 [23.8%]) and d i g e s t i v e p r o b l e m s n o t c o n s i d e r e d t r e a t m e n t related (16 [15.2%]). T h e c o m p l i a n c e r a t e s w e r e 75.0%, 71.1%, 65.0%, 57.1%, and 52.0% at 3, 6, 12, 18, a n d 24 m o n t h s , respectively. In p a t i e n t s w h o s t a r t e d raloxifene t r e a t m e n t , t h e c o n t i n u a n c e r a t e s w e r e 85.0%, 80.6%, 73.6%, 64.7%, a n d 58.9% at 3, 6, 12, 18, a n d 24 m o n t h s , respectively. Sixty-two of t h e 135 p a t i e n t s w h o d i s c o n t i n u e d t r e a t m e n t did so within 3 m o n t h s of r e c e i v i n g t h e p r e s c r i p t i o n , a c c o u n t i n g for 45.9% of all d i s c o n t i n u a t i o n s . Conclusions: In t h e p r e s e n t s t u d y of raloxifene c o m p l i a n c e and c o n t i n u a n c e in clinical practice, t h e c o m p l i a n c e rate a p p e a r e d to be relatively high comp a r e d with t h o s e of h o r m o n e - r e p l a c e m e n t t h e r a p y (HRT) and o t h e r non-HRT t r e a t m e n t s . Almost half of patients w h o discontinued t r e a t m e n t did s o in t h e first 3 months. (Curr Ther Res Clin Exp. 2004;65:470-480) Copyright © 2004 Excerpta Medica, Inc. Key words: compliance, adherence, raloxifene.
INTRODUCTION In p a t i e n t s with chronic, a s y m p t o m a t i c d i s e a s e s , t h e r a t e of c o m p l i a n c e with t h e r a p y is -50%. 1 In 1979, H a y n e s et al 2 d e f i n e d compliance as t h e d e g r e e to w h i c h a p a t i e n t ' s b e h a v i o r c o i n c i d e s with t h e p h y s i c i a n ' s p r e s c r i p t i o n o r advice. F o r g e t f u l n e s s and t h e m e d i c a t i o n b e i n g p e r c e i v e d as u n n e c e s s a r y are t h e m o s t f r e q u e n t r e a s o n s for n o n c o m p l i a n c e . 3 In t h e s e c a s e s , p a t i e n t s refuse to b u y t h e m e d i c a t i o n , forget to t a k e it regularly, o r d i s c o n t i n u e it completely. O s t e o p o r o s i s is a c h r o n i c and often a s y m p t o m a t i c disease; therefore, ens u r i n g c o m p l i a n c e c a n b e difficult. Continuance, defined as r e c e i v i n g m e d ication for a d u r a t i o n long e n o u g h to a c h i e v e t h e d e s i r e d effect, 4 s h o u l d also b e a d d r e s s e d . In o s t e o p o r o s i s , t h e c h r o n i c n a t u r e of t h e d i s e a s e n e c e s s i t a t e s y e a r s r a t h e r t h a n m o n t h s of therapy. Consequently, t r e a t m e n t c o m p l i a n c e and c o n t i n u a n c e are e s s e n t i a l for s u c c e s s f u l t r e a t m e n t . O s t e o p o r o s i s h a s b e e n m a n a g e d with h o r m o n e - r e p l a c e m e n t t h e r a p y (HRT). However, e n c o u r a g i n g c o m p l i a n t b e h a v i o r is difficult with HRT d u e to a d v e r s e effects (AEs) and fear of a potential i n c r e a s e in c a n c e r risk. Raloxifene, a selective e s t r o g e n r e c e p t o r modulator, h a s been a p p r o v e d for t h e p r e v e n t i o n and t r e a t m e n t of p o s t m e n o p a u s a l o s t e o p o r o s i s . Clinical trials 5,6 h a v e s h o w n it to b e effective in m a i n t a i n i n g b o n e m a s s a n d r e d u c i n g t h e i n c i d e n c e of v e r t e b r a l f r a c t u r e s . However, in t h e clinical trial setting, t h e high a d h e r e n c e rate (>80%) 5 to t h e raloxifene t r e a t m e n t r e g i m e n is n o t n e c e s s a r i l y reflective of t h e s i t u a t i o n in clinical practice. T h e aim of t h i s s t u d y w a s to a s s e s s t h e r a t e s of c o m p l i a n c e a n d continua n c e o v e r 24 m o n t h s a f t e r t h e p r e s c r i p t i o n of raloxifene for t h e p r e v e n t i o n o r t r e a t m e n t of o s t e o p o r o s i s . 471
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PATIENTS A N D METHODS We r e t r o s p e c t i v e l y r e v i e w e d t h e d a t a b a s e at t h e Metabolic R e s e a r c h Institute, U n i v e r s i t y of El S a l v a d o r School of Medicine, B u e n o s Aires, Argentina, to identify all p o s t m e n o p a u s a l p a t i e n t s p r e s c r i b e d raloxifene from March 1998 t h r o u g h O c t o b e r 2000. From a m o n g t h e s e patients, we i n c l u d e d t h o s e w h o could b e c o n t a c t e d b y t e l e p h o n e . All of t h e p a t i e n t s included h a d und e r g o n e b o n e m i n e r a l d e n s i t y m e a s u r e m e n t , h a d r e c e i v e d a p r e s c r i p t i o n for raloxifene 60 m g / d for t h e p r e v e n t i o n o r t r e a t m e n t of o s t e o p o r o s i s , and w e r e enrolled in a h e a l t h i n s u r a n c e plan. T h e s c r i p t u s e d in t h e t e l e p h o n e i n t e r v i e w s w a s a p p r o v e d b y t h e i n s t i t u t i o n a l r e v i e w b o a r d at t h e M e t a b o l i c R e s e a r c h I n s t i t u t e , a n d p a t i e n t s w e r e r e q u i r e d to p r o v i d e v e r b a l i n f o r m e d c o n s e n t f o r t h e interview. Two p e o p l e c o n d u c t e d t h e t e l e p h o n e i n t e r v i e w s , w h i c h c o n s i s t e d of 2 s e c t i o n s - - o p e n and c l o s e d q u e s t i o n s - - t o a s s e s s c o m p l i a n c e , c o n t i n u a n c e , and AEs a s s o c i a t e d with raloxifene t r e a t m e n t . Closed q u e s t i o n s included multiple-choice and y e s / n o q u e s t i o n s (eg, "Did y o u e x p e r i e n c e a n y a d v e r s e e v e n t s after s t a r t i n g t r e a t m e n t with raloxifene?"). If a p a t i e n t found it difficult to r e m e m b e r c e r t a i n data, s h e w a s a s k e d , "Do y o u r e m e m b e r h a v i n g h o t f l a s h e s a f t e r s t a r t i n g t r e a t m e n t with raloxifene?" Following d a t a collection, p a t i e n t b e h a v i o r w a s classified a c c o r d i n g to c o m p l i a n c e . P a t i e n t s w e r e c o n s i d e r e d c o m p l i a n t if t h e y m e t a n y of t h e following criteria: (1) t h e y w e r e still t a k i n g raloxifene at t h e t i m e of t h e interview; (2) t h e y h a d d i s c o n t i n u e d raloxifene t r e a t m e n t as a result of a d v i c e from t h e p h y s i c i a n w h o p r e s c r i b e d raloxifene o r a n o t h e r physician; (3) t h e y h a d t e m p o r a r i l y i n t e r r u p t e d t r e a t m e n t as a result of a d v i c e from a physician d u e to a t r a n s i t o r y c o n d i t i o n (eg, p r o l o n g e d rest); o r (4) t h e y h a d n o t s t a r t e d t r e a t m e n t as a r e s u l t of r e c e i v i n g an a l t e r n a t i v e p r e s c r i p t i o n from t h e p r e s c r i b i n g p h y s i c i a n o r as a result of a d v i c e from a n o t h e r physician. In addition, p a t i e n t s w h o h a d t e m p o r a r i l y i n t e r r u p t e d raloxifene treatm e n t for <5% of t h e total t i m e of t r e a t m e n t w e r e c o n s i d e r e d partially compliant and w e r e i n c l u d e d in t h e c o m p l i a n t group. N o n c o m p l i a n t p a t i e n t s w e r e t h o s e who, at t h e i r o w n discretion, h a d not s t a r t e d t r e a t m e n t o r h a d d i s c o n t i n u e d it. T h e r a t e of c o n t i n u a n c e w a s calculated as t h e n u m b e r of c o m p l i a n t p a t i e n t s a m o n g t h o s e w h o h a d s t a r t e d therapy. C o m p l i a n c e and c o n t i n u a n c e w e r e a s s e s s e d at 3, 6, 12, 18, and 24 m o n t h s after t h e p r e s c r i p t i o n w a s given.
Statistical Analysis T i m e to d i s c o n t i n u a t i o n w a s analyzed u s i n g t h e Kaplan-Meier m e t h o d of s u r v i v a l analysis. To d e t e r m i n e a relationship b e t w e e n s o m e of t h e v a r i a b l e s and c o m p l i a n c e , w e a t t e m p t e d to p e r f o r m an a n a l y s i s of logistic r e g r e s s i o n . Statistical analysis w a s p e r f o r m e d u s i n g Statistix v e r s i o n 7.0 (Analytical Software, Tallahassee, Florida). 472
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RESULTS T h e d a t a b a s e identified 455 eligible p o s t m e n o p a u s a l p a t i e n t s w h o h a d b e e n p r e s c r i b e d raloxifene. Of t h e s e , 419 p a t i e n t s could b e c o n t a c t e d b y telep h o n e a n d w e r e included in t h e a n a l y s i s ( m e a n [SD] age, 61.4 [7.4] y e a r s [range, 42-90 y e a r s ] ) . T h e b a s e l i n e c h a r a c t e r i s t i c s of t h e s t u d y p a t i e n t s a r e s h o w n in T a b l e I. Of t h e 419 p a t i e n t s included in t h e analysis, 360 (85.9%) h a d s t a r t e d treatm e n t at t h e t i m e of t h e t e l e p h o n e interview. Two h u n d r e d twenty-five pat i e n t s (53.7%) w e r e still t a k i n g raloxifene (24 m o n t h s a f t e r p r e s c r i p t i o n ) at t h e t i m e of t h e interview, 105 (25.1%) h a d d i s c o n t i n u e d t h e r a p y at t h e i r o w n discretion, a n d 30 (7.2%) h a d d i s c o n t i n u e d t r e a t m e n t d u e to a p h y s i c i a n ' s advice. T h e 59 r e m a i n i n g p a t i e n t s (14.1%) h a d not s t a r t e d t h e r a p y , t h e reas o n s for which are s h o w n in T a b l e II. Eleven of t h e s e 59 p a t i e n t s (18.6%) w e r e c o n s i d e r e d c o m p l i a n t b e c a u s e t h e y h a d followed t h e a d v i c e of a n o t h e r Table I. Baseline demographic and clinical characteristics of the study patients (N -- 419). Characteristic
Value
Age, y Mean (SD) Range
61.4 (7.4) 42 90
Age gl~up, y, no. (%)
17 190 1 68 39
~80 Years since rnenopause Mean (SD) Range Concomitant medications, mean (range) BMD classification, *t no. (%) Normal Mild osteopenia Moderate osteopenia Severe osteopenia Osteoporosis
(4.1) (45.3) (40.1) (9.3)
S (1.2) 14 (7.8) 1 42 2.91 (0 11) 14 26 52 119 208
(3.3) (6.2) (12.4) (28.4) (49.6)
BMD bone mineral density. *Measured by %score (the number of SDs above or below the average BMD value for young, healthy, white women). Scale: ~ 1.0 normal; < 1.0 to > 1.5 mild osteopenia; ~ 1.5 to > 2.0 moderate osteopenia; ~ 2.0 to > 2.5 severeosteopenia; ~ 2.5 osteoporosis. fPercentages do not total 100 due to rounding. 473
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Table II. Reasons for not starting raloxifene treatment (n = 59). Reason Fear of thrombolytic events after reading the package insert Lack of interest in starting treatment Advice from a physician other than the prescribing physician* Family problems Dissatisfaction with prescribing physician Treatment cost Health problems unrelated to osteopomsis Mistrust in the prescription Advice from family/friends Fear of breast cancer Belief that raloxifene is a hormonal treatment Patient was already polymedicated
No. (%)
21 (35.6) 12 (20.3) 11 (18.6) 3 (s.1) 2 (3.4) 2 (3.4) 2 (3.4) 2 (3.4) 1 (1.7) 1 (1.7) 1 (1.7) 1 (1.7)
*These patientswere considered to be compliant.
physician (general practitioner [6 patients], cardiologist [2], gynecologist [2], and hematologist [1]). The reasons t h e s e physicians advised the patients against raloxifene t h e r a p y were not recorded. Of 30 patients who discontinued treatment as a result of advice from a physician (compliant patients), the physician who initially prescribed raloxifene subsequently prescribed another drug due to lack of raloxifene efficacy (12 patients), or a physician (mainly gynecologists) o t h e r than t h e prescribing physician advised the patient to discontinue raloxifene, believing that there were better drugs for t h e prevention and t r e a t m e n t of osteoporosis (18). In the 105 patients who discontinued t r e a t m e n t at their own discretion (noncompliant patients), t h e 2 most c o m m o n reasons were health problems unrelated to osteoporosis (25 [23.8%]) and digestive p r o b l e m s not considered t r e a t m e n t related (16 [15.2%]) (Table III). The 25 patients who discontinued t r e a t m e n t due to health problems unrelated to osteoporosis reported that t h e y considered their o t h e r health problems m o r e serious or troubling than osteoporosis. These health conditions included arthralgia (12), cardiac p r o b l e m s (12), and tiredness (1). Of the 135 discontinuers, 62 discontinued within 3 months of receiving the prescription, accounting for 45.9% of all discontinuers. Of these, 52 patients (38.5%) did so at their own discretion, and 10 (7.4%) as a result of advice from a physician. An additional 42 patients (31.1%) discontinued treatment within 12 m o n t h s of receiving the prescription, 30 (22.2%) at their own discretion, and 12 (8.9%) as a result of advice from a physician. Twenty-seven more patients (20.0%) discontinued treatment within 24 months of receiving the prescription, 20 (14.8%) at their own discretion, and 7 (5.2%) as a result of advice from a physician. 474
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Table III. Reasons for discontinuing raloxifene treatment (n -- 105).* Reason
No. (%)
Health pl~blems unrelated to osteopol~sis
25 (23.8)
Digestive problems not considered treatment related
16 (15.2)
Lack of interest in starting treatment
12 (11.4)
Treatment cost
12 (11.4)
Vasodilation
12 (11.4)
Fear of thrombolytic events after reading the package insert
7 (6.7)
Lower limb discomfort
S (4.8)
Patient was already polymedicated
S (4.8)
Leg cramps
4 (3.8)
Family problems
3 (2.9)
Lower limb edema
3 (2.9)
Belief that raloxifene is not necessalT
1 (1.0)
*Pementagesdo not total 100 due to rounding.
The discontinuation rates a m o n g patients who started t r e a t m e n t (n 360) were 17.2% (62 patients), 11.7% (42), and 7.5% (27) at 3, 12, and 24 months, respectively. A m o n g all 419 patients, this overall rate was 105 (25.1%). Eleven of 419 patients analyzed (2.6%) were advised by a physician o t h e r than t h e prescribing physician not to start t r e a t m e n t and were excluded from t h e compliance analysis. The compliance rate in the remaining 408 patients was 75.0% (306 patients) at 3 months, 71.1% (290) at 6 months, 65.0% (265) at 12 months, 57.1% (233) at 18 months, and 52.0% (212) at 24 months. Once patients had started t r e a t m e n t (360 patients), the rates of continuance were 85.0%, 80.6%, 73.6%, 64.7%, and 58.9% at 3, 6, 12, 18, and 24 months, respectively (Figure). T h e logistic regression analysis s h o w e d that c o m p l i a n c e did not s e e m to be affected by age, n u m b e r of concomitant medications, lumbar T-score, femoral neck T-score, or k n o w l e d g e of t h e p r e s e n c e of v e r t e b r a l and n o n v e r t e b r a l fractures.
DISCUSSION
Well-designed clinical trials s,7 d e m o n s t r a t e d that t h e efficacy of t h e various osteoporosis therapies in increasing bone m a s s o r reducing fracture risk is pivotal for clinical success. However, t h e success of a t r e a t m e n t is also heavily d e p e n d e n t on a patient's compliance with that treatment. In o t h e r words, it is t h e combination of efficacy and compliance that determines t h e effectiveness 475
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Follow-Up ( m o ) Figure. C o m p l i a n c e and c o n t i n u a n c e rates o v e r t i m e (analysis excludes 11 patients w h o w e r e advised by a physician o t h e r t h a n t h e prescribing physician n o t t o start t r e a t m e n t ) .
of t r e a t m e n t in t h e clinical setting. Studies d e s i g n e d to a s s e s s c o m p l i a n c e with HRT h a v e r e p o r t e d low rates of compliance. ~1° For example, one s t u d y found that nearly half of w o m e n w h o s t a r t e d HRT w e r e r e p o r t e d to h a v e discontinued t h e r a p y after a m e a n of 9 months. 11 T h e i n v e s t i g a t o r s s u g g e s t e d this could h a v e b e e n d u e in part to t h e fear of t h e risk for b r e a s t a n d / o r endometrial c a n c e r a s s o c i a t e d with HRT. 11 Thus, d e s p i t e t h e extraskeletal benefits of HRT (eg, i m p r o v e d lipid levels and v a s o m o t o r s y m p t o m s ) , m a n y w o m e n are reluctant to accept this therapeutic option. Vaginal bleeding is another c o m m o n reason that w o m e n discontinue HRT. 12 Using results from population-based studies and clinical trials, H a m m o n d 13 a s s e s s e d patients' c o m p l i a n c e with HRT. He d e t e r m i n e d that < 20% of p o s t m e n o p a u s a l w o m e n in t h e United States h a v e been p r e s c r i b e d t r e a t m e n t with HRT on at least 1 occasion, and of t h o s e w h o s t a r t e d treatment, <40% continued it after 1 year. A n o t h e r s t u d y b y Ettinger et a112 s h o w e d differe n c e s in t h e r e a s o n s for s t a r t i n g and a b a n d o n i n g HRT in y o u n g e r w o m e n (aged 50-55 y e a r s ) and older w o m e n (aged ->65 years): older w o m e n s t a r t e d HRT to treat osteoporosis, w h e r e a s t h e y o u n g e r w o m e n did so to e a s e v a s o m o t o r s y m p t o m s . The HRT discontinuation rate was h i g h e r in t h e older group t h a n in t h e y o u n g e r group. In a third, r e t r o s p e c t i v e study, Ettinger et a114 a s s e s s e d c o m p l i a n c e with a l e n d r o n a t e t h e r a p y u s i n g t e l e p h o n e i n t e r v i e w s with 812 w o m e n ( m e a n age, 68.7 y e a r s ) . Overall, 28.5% of w o m e n r e p o r t e d d i s c o n t i n u a t i o n of a l e n d r o n a t e within 8 m o n t h s of initiating therapy. Based on a r e v i e w of p r e s c r i p t i o n data, 34.9% of t h e s e w o m e n had d i s c o n t i n u e d b y 6 m o n t h s , m o s t often b e c a u s e of g a s t r o i n t e s t i n a l AEs. A n o t h e r s t u d y d e s i g n e d to d e t e r m i n e c o m p l i a n c e with 476
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a l e n d r o n a t e r e p o r t e d t h a t s o m e p a t i e n t s did not n e c e s s a r i l y follow d o s i n g i n s t r u c t i o n s (eg, patients reported lying d o w n o r eating within 30 m i n u t e s of receiving alendronate). 15 K a y s e r et a116 r e p o r t e d d i f f e r e n c e s in c o m p l i a n c e b e t w e e n w o m e n receiving raloxifene and t h o s e receiving e s t r o g e n - c o n t a i n i n g t h e r a p i e s . Both g r o u p s w e r e s i m i l a r in a g e ( m e a n age, 69 y e a r s ) , b u t raloxifene w a s m o r e c o m m o n ly p r e s c r i b e d b y i n t e r n i s t s t h a n b y g y n e c o l o g i s t s . Overall, 19% of p a t i e n t s r e c e i v i n g raloxifene a n d 31% r e c e i v i n g e s t r o g e n - c o n t a i n i n g t h e r a p y did not h a v e t h e p r e s c r i p t i o n refilled. At 12 a n d 24 m o n t h s , d i s c o n t i n u a t i o n w a s r e p o r t e d in 50% a n d 56%, respectively, of p a t i e n t s r e c e i v i n g raloxifene thera p y c o m p a r e d with 63% a n d 72%, respectively, of t h o s e r e c e i v i n g e s t r o g e n c o n t a i n i n g t h e r a p y . W o m e n of a s i m i l a r a g e r e c e i v i n g raloxifene w e r e 25% less likely to discontinue medication t h a n t h o s e receiving estrogen-containing therapy. In t h e p r e s e n t study, t h e m o s t c o m m o n r e a s o n for not s t a r t i n g raloxifene t h e r a p y w a s t h e fear of t h r o m b o l y t i c e v e n t s a f t e r r e a d i n g t h e p a c k a g e insert, w h i c h lists it as a p o s s i b l e AE. In c o n t r a s t , 2 large s u r v e y s t u d i e s 17,18 reported t h a t up to 20% of p a t i e n t s did not h a v e t h e i r p r e s c r i p t i o n s filled, m o s t freq u e n t l y b e c a u s e t h e y b e l i e v e d t h e y did not n e e d t h e m e d i c a t i o n p r e s c r i b e d . A n o t h e r s t u d y found t h a t a m o n g p a t i e n t s w h o did h a v e t h e p r e s c r i p t i o n filled, t h e 2 m o s t f r e q u e n t r e a s o n s for n o n c o m p l i a n c e w e r e d o s e o m i s s i o n a n d d r u g i n g e s t i o n at an i n c o r r e c t t i m e point. 19 T h e s e n o n c o m p l i a n t b e h a v iors are also c o m m o n in patients with o t h e r chronic conditions, s u c h as hypert e n s i o n , h y p e r c h o l e s t e r o l e m i a , a n d epilepsy. 2° 23 R u d d et a118 i n t r o d u c e d t h e t e r m partial compliance to refer to t h e b e h a v ior of p a t i e n t s w h o d o not d i s c o n t i n u e t h e i r m e d i c a t i o n e n t i r e l y b u t interr u p t it for a p e r i o d of time. In t h e elderly, t h i s t y p e of n o n c o m p l i a n c e is o f t e n unintentional. 3 An i m p o r t a n t finding in t h e p r e s e n t s t u d y w a s t h e lack of s h o r t - t e r m c o m p l i a n c e : 45.9% of t h e d i s c o n t i n u a t i o n s o c c u r r e d in t h e first 3 m o n t h s , 83.9% of w h i c h w e r e at p a t i e n t s ' o w n d i s c r e t i o n . D r u g d i s c o n t i n u a t i o n w a s m a i n l y a s s o c i a t e d with p e r s o n a l c i r c u m s t a n c e s o r c h o i c e s . For e x a m p l e , 4.8% of d i s c o n t i n u e r s c o n s i d e r e d it i n c o n v e n i e n t to a d d a n o t h e r d r u g to t h e i r usual r e g i m e n ( p o l y m e d i c a t e d ) , a n d f a m i l y p r o b l e m s p r e v e n t e d 2.9% of d i s c o n t i n u e r s from t a k i n g c a r e of t h e i r o w n health. T h e r e c o g n i z e d AEs of raloxifene (eg, v a s o d i l a t i o n , leg c r a m p s ) w e r e not a s s o c i a t e d with i n c r e a s e d d i s c o n t i n u a t i o n , w h i c h s u p p o r t s t h e s a f e t y a n d tolerability of t h e drug. No c a s e s of d e e p v e n o u s t h r o m b o s i s o r p u l m o n a r y t h r o m b o e m b o l i s m w e r e reported. In t h e p r e s e n t study, p a t i e n t s w h o d i s c o n t i n u e d t r e a t m e n t at t h e r e c o m m e n d a t i o n of a p h y s i c i a n w e r e c o n s i d e r e d compliant. In t h e s e patients, interr u p t i o n of t r e a t m e n t w a s r e c o m m e n d e d e i t h e r b y t h e p h y s i c i a n w h o initially w r o t e t h e p r e s c r i p t i o n for raloxifene a n d t h e n p r e s c r i b e d a n o t h e r d r u g d u e to lack of efficacy, o r b y a n o t h e r p h y s i c i a n w h o a d v i s e d t h e p a t i e n t to s t o p 477
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t r e a t m e n t , with no f u r t h e r e x p l a n a t i o n from t h e p h y s i c i a n . In t h e l a t t e r group, t h e p a t i e n t s did n o t k n o w t h e r e a s o n for t h e r e g i m e n c h a n g e . It is p o s s i b l e t h a t conflicting a d v i c e from p r e s c r i b e r s m a y c o n t r i b u t e to confus i o n a m o n g p a t i e n t s . A n o t h e r p o s s i b i l i t y m a y b e i n e f f e c t i v e p r o v i d e r comm u n i c a t i o n (eg, insufficient i n f o r m a t i o n p r o v i d e d b y t h e p h y s i c i a n , inadeq u a t e r e s p o n s e to a p a t i e n t ' s individual n e e d s ) . N o n c o m p l i a n c e as a c o n s e q u e n c e of d r u g c o s t m a y also b e a significant p r o b l e m . In t h e p r e s e n t study, 3.3% (14/419) of p a t i e n t s s t a t e d t h e y could not afford t h e m e d i c a t i o n . In a s u r v e y of elderly p a t i e n t s , 3 c o s t w a s g i v e n as t h e r e a s o n for n o n c o m p l i a n c e b y 10% of p a t i e n t s . Clinical e x p e r i e n c e sugg e s t s t h a t e l d e r l y p a t i e n t s with fixed i n c o m e s s o m e t i m e s m a k e s t r a t e g i c d e c i s i o n s a b o u t w h i c h m e d i c a t i o n s t h e y c a n afford. 23 R e g a r d i n g t h e logistic r e g r e s s i o n analysis, g i v e n t h e small s a m p l e size, t h e r e w a s not sufficient p o w e r to d r a w a c o n c l u s i o n . M o s t of t h e p a t i e n t s w h o c o m e to t h e Metabolic R e s e a r c h Institute a r e enrolled in p r i v a t e l y o w n e d h e a l t h i n s u r a n c e p l a n s t h a t allow t h e m to visit p h y s i c i a n s w h o s p e c i a l i z e in o s t e o p o r o s i s w i t h o u t b e i n g referred b y a prim a r y c a r e physician. T h i s could r e p r e s e n t a potential s e l e c t i o n bias. A n o t h e r limitation of t h e s t u d y c o n c e r n e d t h e s e n s i t i v i t y of t h e s u r v e y i n s t r u m e n t s , w h i c h m a y not h a v e b e e n a c c u r a t e in v e r i f y i n g t h a t a p a r t i c i p a n t actually r e c e i v e d raloxifene as r e p o r t e d . We m e a s u r e d a d h e r e n c e to raloxifene treatm e n t t h r o u g h p a t i e n t r e p o r t s b y t e l e p h o n e a n d r e v i e w of clinical histories. Both of t h e s e m e a s u r e s a r e indirect a n d t h u s h a v e s o m e limitations. Telep h o n e i n t e r v i e w s m a y h a v e led to significant recall bias. Moreover, it is not c l e a r w h e t h e r t h e results of t h e p r e s e n t s t u d y c a n b e applied to o t h e r clinics, and f u r t h e r s t u d i e s would b e r e q u i r e d to clarify this. O u r r e s e a r c h p r o v i d e s a b a s i s for t h e s t u d y of raloxifene c o m p l i a n c e and c a n b e u s e d to d e v e l o p w a y s of p r o m o t i n g it. T h e r e s u l t s s u g g e s t a n e e d for a c o l l a b o r a t i v e p h y s i c i a n - p a t i e n t r e l a t i o n s h i p a n d for t a i l o r i n g c a r e to individual p a t i e n t s , with a t t e n t i o n to t h e i r social c o n t e x t (eg, social n o r m s a n d h e a l t h r i s k s in o l d e r [age, >65 y e a r s ] p a t i e n t s ) . M a n y o l d e r p a t i e n t s a r e u n a b l e to u n d e r s t a n d t h e i r d i s e a s e s a n d t r e a t m e n t goals, and insufficient i n f o r m a t i o n p r o v i d e d b y t h e p h y s i c i a n o r i n a d e q u a t e a t t e n t i o n to an individual p a t i e n t ' s n e e d s m a y lead to p o o r c o m p l i a n c e . S o m e p a t i e n t s , part i c u l a r l y o l d e r ones, m a y r e m e m b e r only p a r t o r n o n e of t h e d o s i n g i n s t r u c tions. A p h y s i c i a n ' s e n t h u s i a s m a n d u s e of s e v e r a l m e t h o d s of c o m m u n i c a t i o n (eg, c h a r t s , i n s t r u c t i o n s w r i t t e n in large l e t t e r s ) c a n help p a t i e n t s r e m e m b e r t h e i n s t r u c t i o n s . P h y s i c i a n s s h o u l d also highlight t h e b e n e f i t s of c o m p l i a n c e and explain t h e r i s k s of n o n c o m p l i a n c e (ie, f r a c t u r e s ) . O n e s t u d y s h o w e d t h a t s p e n d i n g 15 m i n u t e s c o u n s e l i n g o l d e r a d u l t s a b o u t t h e i r m e d i c a t i o n s i n c r e a s e d t h e i r u n d e r s t a n d i n g of t h e n e e d for t r e a t m e n t c o m p l i a n c e . 24 Finally, t h e h i g h d i s c o n t i n u a t i o n r a t e d u r i n g t h e first 3 m o n t h s could h a v e b e e n t h e result of r o u t i n e clinical p r a c t i c e at o u r c e n t e r : t h e first m e d i c a t i o n follow-up v i s i t is s c h e d u l e d for 6 m o n t h s a f t e r t h e p r e s c r i b 478
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ing visit. We s u g g e s t t h a t m o r e f r e q u e n t follow-up v i s i t s (eg, at t h e first and t h i r d m o n t h s following p r e s c r i p t i o n of t h e d r u g ) also c o u l d h e l p i m p r o v e adherence.
CONCLUSIONS In t h e present s t u d y of raloxifene compliance and continuance in postm e n o p a u s a l patients, t h e compliance rate appeared to be relatively high compared with t h o s e of HRT and o t h e r non-HRT treatments. Almost half of patients who d i s c o n t i n u e d t r e a t m e n t did so in the first 3 months. We suggest attention to individual patients' needs, effective communication, and more frequent followup visits would i m p r o v e adherence with o s t e o p o r o s i s t r e a t m e n t modalities.
ACKNOWLEDGMENT Sherie Dowsett, PhD (Eli Lilly and Company, Indianapolis, Indiana) provided editorial review and comments.
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Address correspondence to: Jos6 R. Zanchetta, MD, lnstituto de lnvestigaciones Metab61icas (IDIM), USAL University, School of Medicine, Libertad 8:36, 1st Floor, Buenos Aires C1012AAR, Argentina. E-mail: [email protected] 480