This randomised, controlled study compared persistence on treatment in postmenopausal women receiving monthly ibandronate (150 mg) plus patient support, or weekly alendronate (70 mg). The study was designed to reflect everyday clinical practice and to avoid falsely elevated persistence rates often reported in the clinical trial setting.
The primary endpoint of the study – persistence on treatment – was significantly greater in patients receiving ibandronate plus patient support compared with patients receiving alendronate. By the end of the study at 6 months, there was an 18% absolute difference between the ibandronate/PSP and alendronate groups in the proportion of patients persisting with treatment. With 39% of patients persisting on treatment in the alendronate group at 6 months, this absolute difference represents an approximately 47% improvement in persistence for patients receiving once-monthly ibandronate plus patient support. Indeed, hazard ratio analyses revealed that, from day 30 until the end of the study at 6 months, patients in the ibandronate/PSP group were approximately half as likely to cease treatment compared with patients receiving alendronate. Results were consistent across all age strata.
The definition of persistence employed in the study was stringent but consistent with other similar studies and the DIN-LINK UK general practice database (12
). In PERSIST, patients failing to fill their monthly prescription within 14 days of the expected date were considered non-persistent. A patient who, for example, failed to persist at month 2 but subsequently collected medication as expected during months 3–6, would have been classified as a non-persisting patient from month 2 onwards. Secondary endpoints measuring patient adherence were also employed during this study. The proportion of patients remaining on treatment at the end of the study, estimated from the number of patients refilling a prescription at 6 months, was significantly higher in the ibandronate/PSP group compared with the alendronate group (75% vs. 68%). Similarly, the number of discontinuations (20% vs. 25%) and the number of patients refilling five of the six monthly prescriptions (80% vs. 73%), were also statistically different in favour of patients receiving ibandronate plus patient support.
Cross-study comparisons of persistence rates are invalid unless the definitions of persistence employed are similar. Boccuzzi et al.
) used a similar definition to that employed in the PERSIST study, and reported persistence rates over 12 months for daily and weekly alendronate of 19% and 22% respectively. Persistence rates at 12 months of 32% and 44% for daily and weekly alendronate were reported by Cramer et al.
) in another study that employed a similar definition of persistence. Higher rates of persistence at 12 months (67–84%) were reported in a UK study of daily raloxifene treatment; however, persistence was defined less stringently as ‘continuing to take tablets for more than seven of any 14 days immediately before the 1-year visit’ (18
Tolerability issues, in particularly gastrointestinal adverse events, are a significant cause of early discontinuation from bisphosphonate treatment (5
). Both ibandronate and alendronate were well tolerated during the PERSIST study. Unsurprisingly, given the patient population and study medication, gastrointestinal and musculoskeletal/connective tissue disorders were the most commonly reported adverse events.
One potential limitation of PERSIST was the 6-month duration of the study. However, data from a GP record database in the UK indicate that rates of persistence on weekly alendronate begin to stabilise approximately 3 months after the start of treatment (14
). Indeed, persistence rates in the PERSIST study declined at a slower rate after the third month of treatment. It is not unreasonable to suggest that most of the patients who were persistent with treatment at 6 months were likely to continue with treatment beyond this point.
The efficacy of bisphosphonate treatment was not measured during the PERSIST study. The safety and efficacy of the bisphosphonates are well established (6
), and the objective of PERSIST was to measure and compare persistence on treatment of patients receiving two commonly prescribed bisphosphonate preparations. Although persistence rates obtained from prescription data do not equate exactly to rates of patient adherence to medication, the measurement of prescription refills is a well-established method of indirectly monitoring adherence and persistence on treatment. There is no standard method of measuring adherence, and other methods such as the biochemical analysis of drug concentrations in the blood or urine are costly and inconvenient for patients (19
Compared with clinical practice, adherence to treatment in a clinical trial setting may be enhanced and result in falsely elevated persistence treatment rates. Trial selection criteria may be biased towards patients more likely to adhere to treatment and, once selected, trial patients may be afforded longer consultation times and provided with more information about their medication than patients in clinical practice. The PERSIST study was designed to reflect everyday clinical practice and to minimise the impact of trial participation on persistence rates. Patients requested and obtained each month's medication via a method very similar to that employed in most primary care centres in the UK. The futility analysis showed that, 4 months into the study, persistence in the alendronate group was not elevated compared with ‘real-life’ persistence data from a computerised GP record database.
In keeping with the naturalistic design of the study, patients randomised to receive ibandronate were also enrolled into a patient support programme. This programme is available to all patients in the UK who are prescribed once-monthly ibandronate. Patients enrolling in the programme are provided with monthly reminder telephone calls and are able to obtain advice on osteoporosis and their medication. Patient support programmes are increasingly used to improve adherence and persistence in chronic conditions such as obesity (20
), and are consistent with calls to involve patients in any initiative designed to improve treatment adherence (19
). In a recent UK study, patient support – in the form of treatment monitoring by nurses – improved adherence by 57% and increased the average length of time patients persisted with treatment by 25% (18
). In the same study, monitoring by nurses had a greater impact on adherence and persistence than the provision of bone marker results to patients. To date, there is no patient support programme in the UK for patients prescribed weekly alendronate. In the PERSIST study, enrolment of patients randomised to receive alendronate into a patient support programme would therefore not have reflected UK clinical practice.
Although calculating the effect of increased persistence on fracture risk and other measures of bisphosphonate efficacy was beyond the scope of this 6-month study, the available evidence suggests that adherence to treatment is associated with improved patient outcomes. Various studies have shown that increases in BMD are greater in patients who strictly adhere to oral bisphosphonate regimens (21
). In a UK-based randomised controlled study, Clowes et al.
) demonstrated an association between adherence to osteoporosis treatment and positive changes in hip BMD and bone-marker resorption (18
). Fracture rates are also lower in patients with osteoporosis who adhere to treatment. Studies in clinical practice showed that patients who adhered to various osteoporosis medications experienced a 16% lower fracture rate and a 24% reduction in fracture risk compared with non-adherent patients (24
). In another study, adherence to bisphosphonate treatment was associated with a 36% reduction in the relative risk of hip fracture over 2 years (26
). As well as improving patient outcomes, increased adherence and persistence is likely to significantly reduce healthcare costs associated with osteoporosis treatment.
In summary, the PERSIST study demonstrated that persistence on treatment was increased in patients receiving once-monthly ibandronate plus patient support compared with once-weekly alendronate. Increased persistence on bisphosphonate treatment in patients with postmenopausal osteoporosis is expected to improve patient outcomes and decrease the social and economic burden of this debilitating condition.