Adherence, persistence and cost–consequence comparison of bimatoprost topical ocular formulations

Keywords::

• Adherence
• Bimatoprost
• Glaucoma
• Intraocular pressure

The term ‘glaucoma’ encompasses a group of ocular disorders with diverse clinical manifestations; broadly portrayed by optic neuropathies that could lead to visual field loss and ultimately blindness if left untreated. High intraocular pressure (IOP) has been recognised as the principal risk factor. Nevertheless, glaucoma can occur in subjects experiencing what is perceived to be a normal IOP (10–21 mmHg). Glaucoma is the first leading cause of irreversible blindness and ranks only second –after cataracts– for reversible blindness worldwide. According to the World Health Organization (WHO), there are 12–13 million people blind from glaucoma with the number of those affected being estimated to be between 60 and 70 million globally. It is the leading cause of blindness amongst African Americans and is responsible for approximately 10–15% of UK blindness. Glaucoma affects 0.5–1% of those aged 50 or under and 10% of those over 80; early detection is crucial to slow down progression with the aid of pharmacotherapy and surgery.

Glaucoma can be broadly classified according to nature of impairment in aqueous humour dynamics (production, flow and drainage) into chronic open-angle glaucoma (COAG) (89.5%), primary angle-closure glaucoma (PACG) (9.5%) and secondary glaucoma (1%). COAG is a progressive chronic disease that can remain asymptomatic for years; the primary treatment objective of COAG is to reduce IOP in a patient specific manner to a target value that will diminish possible optic nerve damage and subsequent visual field deterioration. The vast majority of COAG patients initially receive topical IOP-lowering agents and may continue to do so for the rest of their lives.

Conventional IOP-lowering agents used for the management of COAG include topical miotics, topical adrenergic agonists, topical and oral carbonic anhydrase inhibitors and topical β-blocking agents. Topical ocular prostanoids (prostaglandin analogues and prostamides) are more contemporary modalities; they represent the first line – as are selected β-blocking agents – as they result in the most dramatic fall in IOP from baseline compared with other topical agents. Further, these newer agents offer superior efficacy and better patient acceptability compared with other ocular hypotensive agents.

Eye disorders are recognised to be amongst the top five conditions – along with sleep disorders and pulmonary diseases – where slow progression is primarily related to poor patient adherence (the extent to which patients follow the agreed treatment mode) and persistence (intended duration of treatment) to therapy. Compromised adherence and/or persistence with topical IOP-lowering agents are comparable to that with oral medications for hypercholesterolaemia, hypertension and other chronic asymptomatic conditions.

Lack of adherence to pharmacotherapy treatment can be manifested as: failure to use the medication, the use of sub-therapeutic dose or over-dose, failure to use the medication at the proper time of day, overuse of medication, and failure to persist with the treatment for the recommended length of time.

Recent reports reveal patients’ failure to collect repeats (refills) of their glaucoma prescriptions to be as high as 90% with less than 60% continuing to refill eye drop prescriptions at 1 year1,2,3,4. With COAG patients, the probability of remaining persistent with topical prostanoids over the first year of therapy is typically less than 60%; this is despite the encouraging overall patient persistence with topical prostanoids compared with all other classes of topical ocular hypotensives5–14. Interestingly, it has been reported that patient persistence with prostaglandin analogues is even inferior to that of other chronic therapies, including those for management of hyperlipidaemia (statins), osteoporosis (bisphosphonates), and type II diabetes (oral hypoglycaemic agents)15. Poor compliance with COAG treatment is augmented by the symptomless nature of the condition16.

Bimatoprost 0.01% (Lumigan 0.01%), a new ophthalmic formulation, is designed to offer the IOP-lowering efficacy of bimatoprost 0.03% (Lumigan* 0.03%) coupled with enhanced safety and tolerability. Two studies published in this issue of CMRO were undertaken to compare the adherence, persistence, clinical and cost–consequence relationship of patients using the two aforementioned bimatoprost formulations17,18.

The first study looks at patient adherence and persistence with two bimatoprost eye formulations, namely the new topical/ocular formulation bimatoprost (0.01%) and the original topical/ocular bimatoprost (0.03%) formulation. Both formulations are classified as simple aqueous solutions; the new formulation offers a comparable intraocular pressure-lowering efficacy yet displays improved ocular tolerability – lower tendency to produce conjunctival hyperaemia and ocular pruritis – hence patient acceptance is superior to that of the original bimatoprost (0.03%) formulation. The study targeted pharmacy claims from a vertical (longitudinal) database of prescription and medical claims for over 115 million patients throughout the USA. Patients who were prescribed and collected their first (index) bimatoprost 0.01% or 0.03% prescription between April and June 2011, and had records indicting no further claim for an ophthalmic prostaglandin or prostamide analogue (PGA) during the following 18 months, were identified and included in the study. Treatment adherence was reported as the proportion of days covered (PDC) with bimatoprost (either 0.01% or 0.03%) over the first 365 days after the index prescription was first dispensed. Kaplan–Meier survival analysis (with 30 day grace period allowed for prescription repeat/refill) was adopted to determine treatment persistence over the 12 month period following the first dispensing of the index prescription. Treatment status (on or off study medication) was determined at monthly intervals for 12 months post index prescription. This population study identified and analysed data for a total of 13,810 patients (7660 assessed for treatment persistence and 6150 for treatment adherence).

Results revealed that treatment adherence and persistence was significantly better with bimatoprost 0.01% than with bimatoprost 0.03%. Further, more of those on the 0.01% bimatoprost were found to be continuing or restarting treatment (‘on treatment’) than ones on the 0.03% bimatoprost. These findings were extrapolated to cohorts of ocular hypotensive, treatment-naïve patients and elderly patients (≥65 years). The authors concluded that “new topical bimatoprost 0.01% formulation offers adherence and persistency advantages over bimatoprost 0.03% in patients requiring ocular hypotensive therapy”.

The second study predicts the long-term direct medical costs and clinical consequences of improved adherence (comparing bimatoprost 0.01% compared with bimatoprost 0.03%) in the treatment of glaucoma. The research team designed and assembled a cost–consequence model with three adherence levels (high, moderate and low); for each adherence level four mean deviation (MD) defined health states (mild, moderate, and severe glaucoma; and blindness) were identified. Clinical efficacy was solely based on the IOP data obtained from previous randomized controlled clinical trials comparing the two bimatoprost strengths (0.01% versus 0.03%).

Medication adherence was based on analysis of a nationally representative pharmacy claims database, where patients with high, moderate and low adherence were assumed to receive 100%, 50% and 0% of the IOP reduction observed in the clinical trial, respectively. Each 1 mmHg reduction in IOP was assumed to result in a 10% reduction in the risk of glaucoma progression. Outcome measures were total costs, proportion of patients who progress and who become blind, and years of blindness. Deterministic sensitivity analyses were performed on uncertain model parameters.

Results revealed that improved adherence with bimatoprost 0.01% led to higher costs in the first 2 years; however, starting in year 3, bimatoprost 0.01% became more cost effective compared to bimatoprost 0.03% (total costs reduction reaching US$3433 over patient lifetime time). The percentage of patients progressing, becoming blind, and the time spent blind slightly favoured bimatoprost 0.01%. Deterministic sensitivity analyses demonstrated that results were robust, with the majority of analyses favouring bimatoprost 0.01%. The team concluded that “modelling the effect of greater medication adherence with bimatoprost 0.01% compared with bimatoprost 0.03% suggests that differences may result in improved economic and patient outcomes”; they identified short-term adherence data as a study limitation.

It should be emphasised that neither of the two studies accounted for any adherence, persistence or cost profiles beyond the first 12 months. No attempts have been made to differentiate between those patients that have been initiated on the therapy for the first time and those that have received the same form of the therapy albeit of different strength. Furthermore, both studies did not consider whether patients were actually residents of nursing homes, had health carers looking after them, had financial issues, all of which are likely to impact adherence and persistence. Direct comparison of the ocular tolerability profile of the 0.01% and the 0.03% formulations would have been another interesting dimension to help overcome some of the speculative aspects of the two studies, especially when adverse event costs were excluded from the model used in the first study.

Regardless, evidence drawn from both studies suggests that improved adherence and persistence leads to improved clinical outcomes that could best be achieved by using the 0.01% strength of bimatoprost. This is likely to offer benefits in the quest for vision preservation of COAG patients, which ultimately are more cost effective.

Transparency

Declaration of financial/other relationships

RGA has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.

Notes

*Lumigan is a registered trade name of Allergan Inc., Irvine, CA, USA