Adherence and persistence: Impact on outcomes and health care resources

Bone 38 (2006) S18 – S21 www.elsevier.com/locate/bone

Adherence and persistence: Impact on outcomes and health care resources Jean-Yves Reginster ⁎ World Health Organisation Collaborating Center for Public Health Aspects of Rheumatic Diseases, University of Liège, 45 Quai Godefroid Kurth (+9), 4020 Liège, Belgium Received 20 September 2005; accepted 10 November 2005 Available online 27 January 2006

Abstract Non-adherence to and poor persistence with antiresorptive medication are significant problems in preventing adverse consequences of osteoporosis. Adherence rates for oral bisphosphonate therapy drop off dramatically during the first year of treatment and continue to decline thereafter. Inadequate adherence is associated with smaller decreases in rate of bone turnover, smaller bone mineral density (BMD) gains, and greater risk of fracture. Measures to improve patient adherence include improved physician/patient communication, close monitoring, and early intervention in declining adherence. Another approach is strengthening of patient commitment through reinforcement of the connection between treatment response and quality of life benefits. Use of biochemical markers of response or BMD measurements to illustrate response to patients may be useful in this regard. Simplification of treatment regimens would also be of considerable value in improving adherence and persistence. © 2005 Elsevier Inc. All rights reserved. Keywords: Osteoporosis; Adherence; Persistence; Bisphosphonates

Introduction

Adherence and outcomes in antiresorptive therapy

Non-adherence to and poor persistence with medical therapy are widespread public health problems. It is estimated that only half of patients comply with long-term therapy [1,2] and that up to one in five patients do not even redeem prescriptions [3]. Poor adherence to treatment is common in osteopenia and osteoporosis [4,5]. Overcoming non-adherence presents particular challenges in presymptomatic bone resorption disease and other chronic, asymptomatic conditions [6]; in such settings, the level of perceived threat to health does not motivate the patient to adhere to therapy; in addition, risk of non-adherence with any therapy increases with increased duration of treatment [7]. Poor adherence to medication has an adverse effect on outcome in osteoporosis/osteopenia, with non-adherent patients exhibiting smaller decreases in rate of bone turnover [8], smaller bone mineral density (BMD) gains [8,9], and a significantly greater risk of fracture [10].

Bisphosphonates are the most commonly used prescription medication for osteoporosis. As shown in Fig. 1, rates of adherence to bisphosphonate treatment given daily on an intermittent basis drop off dramatically after 1 year of treatment and decrease further after 2 years [11]. Fig. 1 also shows that decrease in adherence is evident within the first few months of treatment and is continuous throughout the first year [12]. Tosteson and colleagues found that one in five patients discontinued established osteoporosis medications—consisting of hormone replacement therapy, bisphosphonates (which were being taken once weekly in 77% of patients), within 6 to 7 months of starting treatment (Fig. 2) [13]. In an observational study of 247 postmenopausal women, Bandeira and colleagues found that 18% of alendronate patients and 17% of raloxifene patients abandoned therapy at 6 months [14]. The impact of suboptimal adherence has been examined in a number of recent studies. Yood et al. [4] found that the percentage increase in spine (P b 0.0056) and hip (P b 0.004) BMD was significantly greater among patients with ≥66% compliance with estrogen or bisphosphonate therapy compared with lower compliance in 176 patients with osteoporosis followed for a mean of 590 days (Fig. 3). Analysis of outcomes

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J.-Y. Reginster / Bone 38 (2006) S18–S21

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Fig. 3. Mean annual changes in BMD among 91 patients receiving estrogen replacement therapy or bisphosphonate treatment according to degree of compliance (compliance b66%, n = 35; compliance ≥66%, n = 56). Data are from Yood et al. [4].

Fig. 1. Top: Proportions of patients continuing treatment with cyclical etidronate or alendronate over time. Data are from General Practitioners Research Database, UK [11]. Bottom: Probability of continuing alendronate treatment among 401 women in an osteoporosis clinic. Discontinuation increases dramatically over the course of 1 year. Data are from Lombas et al. [12].

among 11,249 women with osteoporosis in the Saskatchewan health data files showed that adherence to osteoporosis medication of b80% was associated with a significantly increased risk of fracture (hazard ratio = 1.16, P = 0.005) on multivariate analysis (Fig. 4) [10]. Sebaldt and colleagues [15] assessed the impact of inconsistent use of bisphosphonates, defined as early discontinuation or self-reported use less than 80% of the time, on change in lumbar BMD among 4405 patients with initial T scores of b − 2.5 receiving bisphosphonate treatment between 1990 and 2002; it was found that consistent use was associated with significantly greater increase in BMD at 1, 2, and 3 years of follow-up (Fig. 5). Tankó et al. [16] measured changes in the serum concentration of the C-

terminal telopeptide of collagen type I (CTX) associated with various regimens of suboptimal dosing of oral ibandronate. Healthy women (N = 200) 50–70 years old (mean, 63.1 years) with a lumbar spine BMD T score of −1 to − 5 were randomly allocated to oral ibandronate according to one of eight dosing regimens (regimens 3 through 7 were designed to mimic various patterns of non-adherence): (1) 2.5 mg/day for 84 days for a cumulative dose of 210 mg (positive control); (2) 20 mg/week for 84 days; (3) 2.5 mg/day for 28 days + no treatment for 56 days; (4) 2.5 mg/day for 28 days + 2.5 mg/week for 56 days; (5) 2.5 mg/day for 28 days + 2.5 mg 3×/week for 56 days; (6) 2.5 mg/day for 14 days + 2.5 mg 3×/week for 56 days; (7) 2.5 mg 3×/week for 84 days; (8) no treatment for 168 days (negative control). Fig. 6 illustrates the results for the suboptimal treatment groups. Effect of adherence on health care systems Poor adherence has a profound negative effect on health care systems, including increased amounts of unused prescriptions, increased visits to health care providers, unnecessary treatment costs (e.g., for changes in prescribed agents), and admission to care because of associated treatment failure; in the latter regard, it is estimated that such treatment failure accounts for 10% of hospital admissions and 20% of admissions to nursing homes [17–20]. Estimates for 1986 indicate that non-adherence to medication resulted in an annual $8.5 billion in expenditures for hospitalization and an additional $17 to $25 billion in indirect costs (e.g., loss of productivity, morbidity, mortality) in the United States [18], an amount roughly equivalent to the annual cost to society of traffic accidents in that country. Improving patient adherence

Fig. 2. Proportions of 956 women abandoning treatment over 6–7 months after starting. Reproduced from Tosteson AN, et al. Early discontinuation of treatment for osteoporosis. Am J Med 2003; 115: 209–16, with permission from Excerpta Medica, Inc.

Improving patient adherence with osteoporosis therapy requires effective patient/provider communication and close patient monitoring for early identification of declining adherence [7,21]. Patients' belief in a medication contributes to better adherence [22] and can be improved by firmly associating

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Fig. 4. Hazard ratios and confidence intervals for fracture according to risk factor among 11,249 women who received osteoporosis medication. Data are from Caro et al. [10].

monitoring or monitoring involving graphing of urinary Ntelopeptide of type I collagen response to treatment compared with patients receiving no monitoring [23]. Another primary component of improving adherence is to use simplified or user-friendly treatment programs. It has been found across a range of therapeutic areas that adherence with medications is inversely related to frequency of dosing [24]. It should be remembered that inadequate adherence can also take Serum CTX

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Fig. 5. Difference in lumbar BMD (lBMD) over time between consistent users (n = 920) and inconsistent users (n = 121) of bisphosphonate treatment among 1041 patients with initial T scores b − 2.5. “Inconsistent” was defined as early discontinuation or self-reported use less than 80% of the time. Data are from Sebaldt et al. [15].

treatment with expected benefits such as reduced risk of fracture and improved quality of life. Patients may often be encouraged to maintain adherence when presented with measurements of chemical markers of bone turnover or their BMD measurements with an explanation of how these measures relate to risk reduction. One study reported a 57% improvement in adherence to antiresorptive therapy at 1 year in patients receiving nurse

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Fig. 6. Changes in the serum concentration of the C-terminal telopeptide of collagen type I (CTX) to various regimens of suboptimal dosing of oral ibandronate. Top panel: ▿, 2.5 mg/day for 28 days followed by no treatment (cumulative dose 70 mg); □, 2.5 mg/day for 28 days followed by 2.5 mg once weekly (cumulative dose 90 mg); ⋄, 2.5 mg/day for 28 days followed by 2.5 mg 3×/week (cumulative dose 130 mg); ○, placebo (0 mg). Bottom panel: ▾, 2.5 mg/day for 14 days followed by 2.5 mg 3×/week (cumulative dose 110 mg); ■, 2.5 mg 3×/week (cumulative dose 90 mg); ●, placebo (0 mg). Since error bars (± SEM) were virtually of the same size throughout the study, they are only given for the last data point per group. *P b 0.05 compared to placebo. Reprinted with permission from Tankó LB, et al. Oral ibandronate: changes in markers of bone turnover during adequately dosed continuous and weekly therapy and during different suboptimally dosed treatment regimens. Bone 2003; 32: 687–93.

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the form of improper drug administration even when doses are not missed. Hamilton et al. [25] have reported that one in four patients taking oral daily bisphosphonates did not follow dosing instructions properly, with 15% using too little water, 7% not fasting long enough, and 3% not staying upright long enough; such non-adherence poses the potential problems of decreased drug absorption and increased risk for adverse effects. Conclusion Poor adherence to and lack of persistence in antiresorptive medication regimens are widespread problems that can negatively affect patient outcomes. Rates of adherence to bisphosphonate therapy drop substantially over time. Adherence can be strengthened by improved patient monitoring, improved patient motivation through linkage of treatment response to quality of life, and simplified treatment programs. References [1] Sung JC, Nichol MB, Venturini F, Bailey KL, McCombs JS, Cody M. Factors affecting patient compliance with antihyperlipidemic medications in an HMO population. Am J Manag Care 1998;4:1421–30. [2] Rizzo JA, Simons WR. Variations in compliance among hypertensive patients by drug class: implications for health care costs. Clin Ther 1997;19:1446–57. [3] Giuffrida A, Torgerson DJ. Should we pay the patient? Review of financial incentives to enhance patient compliance. BMJ 1997;315:703–7. [4] Yood RA, Emani S, Reed JI, Lewis BE, Charpentier M, Lydick E. Compliance with pharmacologic therapy for osteoporosis. Osteoporos Int 2003;14:965–8. [5] McCombs JS, Thiebaud P, McLaughlin-Miley C, Shi J. Compliance with drug therapies for the treatment and prevention of osteoporosis. Maturitas 2004;48:271–87. [6] Miller NH. Compliance with treatment regimens in chronic asymptomatic diseases. Am J Med 1997;102:43–9. [7] Bond WS, Hussar DA. Detection methods and strategies for improving medication compliance. Am J Hosp Pharm 1991;48:1978–88. [8] Eastell R, Gamero P, Vrijens B, van de Langerjit L, Pols HAP, Ringe JD, et al. Influence of patient compliance with risedronate therapy on bone turnover marker and bone mineral density response: the IMPACT study. Calcif Tissue Int 2003;72:297–408. [9] Finigan J, Bainbridge PR, Eastell R. Adherence to osteoporosis therapies. Osteoporos Int 2001;12:S48–9 [Abstract P110].

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