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

Evidence Synthesis

Literature Search

In total, 897 abstracts were potentially relevant based on the search in PubMed/Medline. As shown in Figure 1 (PRISMA flow chart, [s16]), 34 papers were identified from those abstracts that seemingly met the inclusion criteria and were further checked as full text; only 25 papers contained results on clinical trials on older patients or explicitly reported data from subgroups of older patients aged ≥65 years (which is the most commonly used, but unauthorised definition of 'elderly') for the 16 drugs of interest. Explicit results on clinical trials for older patients were reported for the 5α-reductase inhibitors dutasteride [s15, s17, s18] and finasteride [s15, s19], the α1-blockers alfuzosin [s20], doxazosin [21] and tamsulosin [s18, s22], the antimuscarinic drugs darifenacin [s23, s24], fesoterodine [s25-s30], oral oxybutynin [s31-s33], solifenacin [s33, s34], tolterodine [s26, s35, s36], and trospium [s37], the β3-agonist mirabegron [s38] and the PDE5 inhibitor tadalafil [s39, s40]. As seen in Table 2, the number of studies reporting data on older patients to support drug efficacy and safety was one for alfuzosin, doxazosin, trospium, and mirabegron, two for darifenacin, solifenacin, tadalafil and tamsulosin, three for oxybutynin (both formulations) and for tolterodine, and six for fesoterodine. Several studies were small (<100 patients) with the SOFIA trial, exposing 392 elderly patient to fesoterodine in the double-blind phase, being one of the largest RCTs dedicated to older patients [s30]. Only 18 of the 25 papers reported on randomised, controlled clinical trials (RCTs).

Figure 1.

Flow diagram for the systematic review according to the PRISMA statement [s16].

Safety data from these trials were heterogeneous, in several cases not detailed, and a clear and comparable overview was difficult to achieve. Therefore, the integral and consensual assessment of all data including those from the SmPCs is additionally given as summary in Table 2 (right column).

No specific reports in older patients were available for the α1-blockers silodosin, or terazosin, respectively, or the antimuscarinic drug propiverine.

Analysis of Summary of Product Characteristics

No package inserts, with the exception of that for oxybutynin, explicitly mentioned the elderly population. A summary of the published evidence is provided as Supplementary data, Appendix S1, available in Age and Ageing online http://ageing.oxfordjournals.org/content/44/5/745/suppl/DC1. The amount of information available on side effects and contraindications of particular interest in the elderly population was highly variable. For example, for many agents, study results are available on typical geriatric problems such as dementia (or cognition overall), falls, anticholinergic effects or constipation, while other side effects of specific relevance such as the serotonin syndrome were not mentioned in any of the reviewed SmPC.

Delphi Process Leading to the Final FORTA Classification

Final ratings after round 2 are shown in Table 1. Proposed ratings were confirmed in 94% of cases (deviation for 1/17 items). Only 3 of the 16 studied drugs were re-rated in the second survey (Table 1). Ratings changed for propiverine (C → D) and trospium (B → C). Table 2 summarises the rationales (key points) behind the categorisation of the individual drugs.

The ratings showed little variance with a corrected consensus coefficient of >0.8 in all but four cases which had to be re-rated in the second round. Trospium was finally assigned a C rating, but with only a one vote majority (2 B, 3 C).

Eventually, no drug was labelled with FORTA A. Out of the 17 items for 16 drugs, only 3 were assigned the FORTA B (beneficial) classification: dutasteride, fesoterodine and finasteride. The majority of agents were rated with FORTA C (careful) (in alphabetical order): darifenacin, mirabegron, oral oxybutynin (low dose/extended release), silodosin, solifenacin, tadalafil, tamsulosin, tolterodine and trospium, labelling them as potentially harmful if not properly monitored for effects and adverse events; this does not entirely preclude their use, as in Category D but mandates close clinical surveillance and individualisation of use. Furthermore, the following agents were assigned a FORTA D classification (avoid): alfuzosin, doxazosin, oral oxybutynin (immediate release), propiverine and terazosin.

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