Appropriateness of Oral Drugs for Long-term Treatment of Lower Urinary Tract Symptoms in Older Persons

Results of a Systematic Literature Review and International Consensus Validation Process (LUTS-FORTA 2014)

Matthias Oelke; Klaus Becher; David Castro-Diaz; Emmanuel Chartier-Kastler; Mike Kirby; Adrianwagg; Martinwehling

Disclosures

Age Ageing. 2015;44(5):745-755. 

In This Article

Discussion

On the basis of our systematic literature search and analysis as well as subsequent rating process for frequently used drugs for the treatment of LUTS in older patients, only three were labelled FORTA B (beneficial), dutasteride, fesoterodine and finasteride. The majority of drugs should only be used with caution in older persons, for specific indications, and with safety monitoring (FORTA C), while alfuzosin, doxazosin, oxybutynin in standard dose/immediate release formulations, propiverine and terazosin should be avoided (FORTA D).

Key Findings on Urological Drug Appropriateness

The unique FORTA process makes clear that, within a given drug class, the appropriateness of individual drugs may substantially vary; such differences can be based on real differences in efficacy and safety (e.g. newer drugs may have optimised profiles), but also on the quality of the trial, and the specific patient population studied. Strict and citable evidence, as typically derived from RCTs, is an exception rather than the rule for the older population, although important if available. Likewise, data from studies in older people may reflect specific outcomes of interest, for example, cognition, rather than efficacy or tolerability and, therefore, may have not been given due emphasis. For example, those studies specifically examining the short-/medium-term cognitive safety of antimuscarinics in elderly people are rare.

Recognition of older patients as important recipients of pharmacological treatments for LUTS has increased over recent years, leading to a focus on the need for data specific to that population. Studies had previously only reported on older people taking part in registration trials of medications where those >65 years of age comprised approximately one-third of the total sample. Older people included in such trials were often unrepresentative of the general elderly, being healthier and with relatively fewer co-morbid conditions. Trials specifically in community-dwelling elderly [s29,[41]] and in the more medically complex elderly [s25] are relatively recent developments that should become a standard approach to testing of novel agents in therapeutic areas which predominantly affect older people. Likewise, older trials often fail to identify adverse events that may predominantly affect older people such as cognition.[42]

The antimuscarinic agent fesoterodine has been the subject of considerable testing in people aged ≥65 years, with purposive recruitment of patients aged ≥75 years [s25,s29,s30]. Fesoterodine has been found to be efficacious in the treatment of urinary urgency and urgency incontinence in older patients with beneficial outcomes in terms of health-related quality of life and in those with considerable co-morbidity and polypharmacy, with few adverse cognitive events over the period of the clinical trials. Darifenacin, in its single pre-planned study of efficacy in patients aged ≥65 years failed to reach statistical significance on its primary outcome but did note that the proportion of people who derived benefit from active treatment were greater than those who received placebo treatment.[43] The cognitive safety of darifenacin has also been extensively tested in a series of chronic dosing studies in cognitively intact older people.[44,45] Data on solifenacin, tolterodine and alternative preparations of oral oxybutynin are derived from post hoc pooled analyses of older people participating in registration trials [s34,s36] and as such, conclusions from such data are limited by their nature. Data on the efficacy of trospium, often touted as elder friendly due to its propensity not being able to cross the blood–brain barrier[46] and its lack of drug–drug interactions[47] are notably lacking; this may have hampered its FORTA rating. In the updated Beers list,[9] all antimuscarinics are classified as 'anticholinergics' to be avoided in people with constipation.

The FORTA classification presented here underlines clinically relevant differences between drugs in this class ranging from D to B ratings which are not adequately reflected in a pure negative list ('drugs to avoid') as opposed to the combined positive/negative approach of FORTA.

Mirabegron has only recently been introduced into clinical practice and data supporting its use in older patients [s38] naturally lag behind those drugs that have been on the market longer. Therefore, any update of this list in the future may result in different FORTA classifications.

Whereas much of the available data consider the use of these drugs in the community-dwelling, largely robust elderly, there has been scant attention paid to the needs of the frail elderly, a point clearly made in the 5th International Consultation on Incontinence guidelines for the frail elderly.[48]

Other drug delivery systems, such as transdermal or transvaginal formulations of oxybutynin or local injections of onabotulinum toxin[49] for the treatment of urgency or urgency incontinence, may be alternatives for orally administered drugs in older people. However, we have limited our literature search and analyses to oral medications as they represent the majority of prescriptions.[1] Additionally, transdermal, transvaginal or local application of drugs has not been subject of thorough investigations in older people, and therefore, scientific data for the age groups of interest are lacking. These facts were discussed by the rater group who explicitly recommended refraining from categorising these preparations to limit heterogeneity and maintain feasibility of the process. Nevertheless, these treatment options could be of interest in the future to avoid first pass effects, improve tolerability and lower/avoid adverse events particularly in the group of elderly or frail older patients. Transdermal oxybutynin could be seen, for example, as a reasonable, but understudied and not widely utilised alternative.

Methodological Considerations on Literature Analysis

To obtain a robust basis for the rating, the rater group applied a standard literature search that focused on the older population (age ≥65 years). Despite the fact that urological drugs are mainly used in this population, including the very old and frail elderly patient, there was a lack of published data for this population. In a recent hearing of the FDA as part of the Safety and Innovation Act of 2012, it was noted that the geriatric population is clearly under-represented in cardiovascular trials (only 9% of all patients included). We demonstrated in our literature search and analyses that the situation is not substantially different for drugs used to treat LUTS.[50]

To detect and include available information on studies in older people that may not have been published in PubMed/Medline or the Cochrane library, we also reviewed current summaries of product characteristics. Information about the safety of drugs has to be gathered by the respective drug manufacturers and—usually every 6 months—submitted to regulatory authorities (periodic safety update reports, PSUR).[51] Based on the European Union legislation 2309/93, articles 21 and 22, and the EU directive 75/319/EEC, articles 29c and 29d, and the ICH Guideline CPMP/ICH/377/95,[52] such information consists of spontaneous reports about adverse drug events, results of clinical studies and systematic literature searches on case reports and other sources. Given this background and in view of the paucity of published studies of relevance for our review, we also used this document as source for our assessment.

While, in principle, all manufacturers of a generic drug have to submit PSUR to the regulatory authorities, the prescribing information for the same drug marketed under different brands may differ due to varying update intervals but also due to differences in drugs with respect to auxiliary ingredients such as salts. Thus, if a drug was marketed under several brands, we chose the most frequently prescribed one as listed in the drug-prescribing report;[1] it is based on all prescriptions paid by the statutory health insurance in Germany and updated on an annual basis.

The rating process followed the Delphi procedure.[53] The consensus process was driven by an evidence-based approach, i.e. experts made their decision based on the results of the literature search, while their personal experience was secondary.

Limitations of the Study

It is possible that some inconsistencies were related to the multidisciplinary nature of this Delphi exercise. For instance, not all of the respondents had equal practical experience with the various drugs (e.g. mirabegron was launched in June 2014 in Germany and Spain but is still not available in France). Furthermore, the group was small and a larger set of experts (also from additional countries) might come to slightly different conclusions. However, the degree of consensus was notable given the fact that experts with different specialisations voted without knowing their colleagues' opinions. This is in line with the degree of rating consensus for the first round of the Delphi process for the published FORTA list[12] which was almost the same (92%) for a much larger group of raters (20 from different countries).

As the raters were collectively instructed about FORTA at the inaugural meeting, anonymity could not be warranted; however, communication of any voting opinion was suppressed at this meeting, and independence was ensured by formal agreement on not communicating the individual votes during the Delphi rounds.

Consensus aspects cannot be excluded from drug assessments in older people as limited evidence is the rule rather than the exception, and integration of all data including SmPC undoubtedly relies on personal assessment. This is underlined by the fact that even in the fesoterodine studies of older patients, those with significant cognitive impairment at baseline were excluded from participation, illustrating a typical gap of clinical evidence.

In some larger studies, which included patients with a mean age of 60–65 years with a typical age distribution, a substantial proportion of elderly/geriatric patients will be present but not reported separately. If the subgroups were not explicitly reported, these data remained unnoticed in our systematic review. For urological drugs, a limited amount of scientific evidence is currently available for the evaluation of active substances, potential therapeutic alternatives and indicated monitoring procedures.[11]

Although SmPC were thought to yield unpublished information, some valuable information from trials may not be detected by the screening procedure. The experiences from uncontrolled trials or even case reports are lost in such an approach, but they may add relevant information. The gold standard would have been a qualified meta-analysis which, however, would have failed in most instances or not added information as in most instances only singular or heterogeneous studies could have been included.

FORTA does not specifically address drug–drug interactions or contraindications that still need to be checked individually. Thus, (in)appropriateness in general terms does not necessarily imply the same in individual patients.

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