Call for worldwide withdrawal of tiotropium Respimat mist inhaler

BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e7390 (Published 09 November 2012) Cite this as: BMJ 2012;345:e7390

Re: Call for worldwide withdrawal of tiotropium Respimat mist inhaler

Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of morbidity and early mortality in the world. There is a paucity of effective treatment, with smoking cessation and long term oxygen therapy the only established disease modifying options available. Recently subgroup analysis of the UPLIFT study provide the first hints that sustained bronchodilating pharmacotherapy by the inhaled anticholinergic tiotropium bromide could reduce the inevitable characteristic decline in lung function in younger1 and less obstructed patients2.

On this optimistic background Richard Beasley and colleagues call for worldwide withdrawal of tiotropium in the Respimat device. This drastic measure is justified by the results of various analyses of mortality data derived from studies where this was not the primary endpoint. I suggest such number crunching techniques should be viewed as generating hypotheses rather than reliable conclusions. The best comparison of these sewing sows’ ears shows they predict the result of the subsequent RCT a little over half the time3.

The authors are nothing if not consistent. They have been claiming adverse outcomes for anticholinergic therapy for decades culminating in a deeply flawed (even by the low standards of meta analysis) study purporting to show an increase in cardiovascular mortality and morbidity in association with tiotropium and ipratropium therapy4. Fortunately the exact opposite was shown later in the year by the UPLIFT RCT where tiotropium appeared to protect against cardiac death. A simple possible explanation is that the left heart, being located in the thorax, has to work less hard against the lower pressure swings caused by bronchodilation.

It is entirely possible that a drug which at low dose has beneficial effects may become adverse at higher doses. The Respimat device does indeed deliver a higher systemic dose of tiotropium, but in my experience it is the only device from which some patients are able to derive benefit. An adverse mortality signal has been detected as a secondary endpoint in some recent studies. I suggest our response should be not to carry out further data dredging since no amount of statistical sleight of hand can “confirm” any potential risk. Rather a properly constructed randomised trial should be performed to test this hypothesis. The Tio SPIR study recruited its first patient in May 2010 and is anticipated to run for 3.5 years. The co primary endpoints are death and exacerbation rate. Until this study reports I will take the pragmatic approach of maximizing my prescribing of this valuable agent via the Handihaler and using the Respimat in those who need it. To advocate the immediate withdrawal of a delivery device for an agent of clear and proven benefit in a dreadful disease on the basis of a statistical methodology which the author themselves have demonstrated to produce unreliable conclusions seems folly of the highest order.

Reference List

(1) Morice AH, Celli B, Kesten S, Lystig T, Tashkin D, Decramer M. COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT). Respir Med 2010; 104(11):1659-1667.
(2) Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009; 374(9696):1171-1178.
(3) LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med 1997; 337(8):536-542.
(4) Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 2008; 300(12):1439-1450.

Competing interests: Research & Clinical Trials/Consultancy/Lectures/Advisory Boards Boehringer Ingelheim, AstraZeneca, Chiesi Pharma Ltd, GlaxoSmithKline, Novartis Pharmaceuticals UK Orion Pharma UK, Proctor & Gamble Health Sciences, Pfizer, Pharmaxis, Profile Pharma, MPEX, PPD, Almirall, Seekacure, Philips Home Healthcare Solutions

19 November 2012
Alyn H Morice
University of Hull
Castle Hill Hospital Cottingham HU16 5JQ