Pharmaceutical products often  debut to marketing fanfare and glowing reports of success in clinical trials. In clinical practice, however, physicians must often choose from among many therapies, selecting ones they judge most likely to benefit a particular patient. The choices are rarely clear-cut. In routine practice settings, patients are not preselected as they are in clinical trials, care is relatively unregimented, and patients frequently do not follow prescribed regimens.

This latter phenomenon, non-compliance, has long been studied in medicine, and further complicates the clinician's approach to therapy. If a prescribed therapy is not achieving the desired results, is the drug ineffective or is the patient not taking it as instructed? A newer area of research receiving increasing attention, called persistency, focuses one step upstream from compliance.

Persistency measures the time that a patient fills a prescription and stays on a prescribed therapy, which is a prerequisite to compliance. Persistency gains added importance for patients with chronic conditions such as hypertension or glaucoma. It is known that a substantial percentage of such patients discontinue therapy within the first six months and that the percentage discontinuing increases over time. Some of the reasons for variable persistency among alternative therapies relate to differences in the effectiveness and tolerability of medications, cost issues and understanding of the importance of taking medication.

This article reviews a recent study that assessed persistency with ocular hypertensive agents in a population-based cohort, as well as related studies.

The Study
This retrospective study evaluated a population of 28,741 ocular hypertensive or open-angle glaucoma patients who initiated intraocular pressure-lowering drug therapy between July 1996 and June 2002.1 These patients, identified from a large database of patients in commercial managed-care organizations, were all at least 20 years of age, new to ocular hypotensive therapy, using monotherapy, had not undergone glaucoma surgery within the previous 180 days, and were all continuously in an insurance plan with both medical and pharmaceutical coverage for 180 days. Patients were prescribed betaxolol, bimatoprost, brimonidine, dorzolamide, latanoprost, timolol, or travoprost.

The persistency analysis was based on prescription refill data at 90 days (if initially dispensed one bottle) and 180 days (if initially dispensed two bottles). Though earlier studies show that most patients receiving one bottle of an IOP-lowering drug refill their prescriptions within 40 to 75 days, some allowance was made for skipping doses or variation in dosing.

Table 1. Percentages of Patients Having Only  One Fill of Index Drug
n* Percent having only one fill
Latanoprost 6,086 34%
Timolol 11,110 48
Brimonidine 4,614 46
Betaxolol 2,261 52
Dorzolamide 1,249 48
Travoprost 294 50
Bimatoprost 312 54
* Includes patients continuously enrolled from index date through end of initial 90-day/180-day period.
The main outcome measures were either discontinuation of the initial (or index) drug, or discontinuation/change in the index drug. Discontinuation was defined as no further index drug refill after the last refill. The discontinuation date minus the initial prescription (or index) date was used to calculate the number of days on therapy before stopping. The discontinuation/change date minus the index date was used to calculate days on therapy before changing to another drug. The former reflects a patient-driven choice (not refilling the prescription), and the latter reflects a patient and physician-driven choice (changing to a different regimen).

The three most prescribed medications were timolol (prescribed to 43 percent of patients), latanoprost (33 percent), and brimonidine (18 percent). Newer prostaglandins, travoprost and bimatoprost, have since entered the market but, reflecting their then-recent commercial availability, only 1 percent of patients were prescribed to each. Nearly 60 percent of the subjects were women, and almost three-quarters were 65 years of age or older. About half of the patients for whom a diagnosis was recorded had primary open-angle glaucoma.

The percentages of patients who persisted with therapy were low across all of the agents. At 12 months, 33 percent of patients treated with latanoprost had not discontinued therapy, compared to 19 percent of those treated with each of the other therapies. The latter group was also less likely to fill a second prescription than were patients on latanoprost. The fact that persistency dropped off steeply during the first 12 months across all therapies parallels earlier findings in which 37 percent of newly diagnosed patients with asymptomatic elevation of IOP were lost to follow-up over a 12- to 20-month follow-up period, and most were lost within the first month.

Earlier studies using similar methodologies arrived at similar findings. Three retrospective cohort studies,2,3,4 each including more than 1,000 patients less than 65 years of age, compared medication persistency over 28 to 30 months in patients treated initially with beta-blockers, brimonidine, carbon anhydrase inhibitors or latanoprost. Patients treated initially with latanoprost monotherapy remained on therapy significantly longer than patients treated with other ocular hypotensive agents.

Another study of 2,850 patients age 20 or older followed for 21 months found that those receiving latanoprost were significantly less likely to discontinue or discontinue/ change their index therapy than those treated with betaxolol, brimonidine, dorzolamide or timolol.5

A study of 4,356 patients age 30 or older followed for 15 months compared persistency across three prostaglandin analogs. Patients treated with latanoprost were significantly more persistent than those receiving either bimatoprost or travoprost.6 Long-term persistency with all ocular hypotensive therapies in all of these studies was poor.

The percentage of patients who were continuously enrolled until the end of their prescription-refill period and failed to refill their index drug ranged from 34 percent for latanoprost to 54 percent for bimatoprost (See Table 1). Clinical studies have shown that latanoprost reduces intraocular pressure more effectively than brimonidine, dorzolamide or timolol, while its IOP-lowering is similar to that of bimatoprost and travoprost.7 In some studies, latanoprost has shown fewer systemic side effects than brimonidine or timolol, and produced less hyperemia than bimatoprost7,8,9 and travoprost.7,10,11 Hyperemia may lead to decreased ocular tolerability and may negatively affect persistency.

The methodology used in this study identifies a patient as not persistent based on a single discontinuation. Unpublished reports suggest, however, that some patients return to therapy after a large gap between refills. Therefore, restart rates will be important to future analyses.

This study benefits from several strengths. It included a large patient sample, and it was based on actual community practices in terms of refill rates. Also, it was able to assess the impact of differences in copayment levels in the various plans, and found no association between copayment levels and persistency.

The study was not, however, without flaws. Differences in the disease severity among patients taking different medications may have biased the results. Factors affecting compliance or persistency, including the cost of therapy, adverse effects, patient understanding of the seriousness of the disease, and the quality of the physician/ patient relationship, could not be evaluated.
Persistency is an important factor in the treatment of a chronic disease.

As physicians consider therapeutic options in cases of ocular hypertension and glaucoma, or reconsider such options when presented with a prescribed treatment regimen that appears not to achieve the desired outcomes, persistency will play a larger role in decision-making. 

Dr. Schwartz is in private practice and is a clinical assistant professor at the Wilmer Eye Institute, Johns Hopkins, and the University of Maryland.

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11. P.A. Netland PA, Landry T, Sullivan EK, et al., Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2001;132:472–484.