The anticholinergic product tiotropium (SPIRIVA) has been marketed as a powder for once-daily inhalation of 18 µg in chronic obstructive pulmonary disease (COPD) since 2002 (a-t 2002; 33: 74-5). The suspected increase in cardiovascular risk which emerged from meta-analyses of relatively small-scale studies of tiotropium bromide was not confirmed by the four-year-long UPLIFT* study, which involved 6,000 patients (a-t 2008; 39: 108 and 111) (1). Last year, an advisory committee of the U.S. Food and Drug Administration (FDA) voted by a large majority that the safety data from the UPLIFT study were persuasive and considered further studies unnecessary (2).

Since 2007, a second tiotropium preparation has been authorised in the EU: a solution inhaled with a new type of inhaler, RESPIMAT (SPIRIVA RESPIMAT). Because of improved delivery to the lungs, only 5 µg per dose should be needed. In two one-year placebo-controlled trials of SPIRIVA RESPIMAT involving a total of 1,990 COPD patients, numerically or significantly higher mortality was seen on the active substance with both 5 µg daily and the unauthorised double dose, respectively. The imbalance is partly due to the fact that the patients in the placebo group withdrew prematurely from the study more frequently and deaths among study drop-outs were not initially recorded because of the lack of follow-up. The results from post hoc follow-up of all of the patients who withdrew lessen the differences but do not eradicate them. A pooled analysis of all of the patients in both studies who were followed-up fully (98%)shows a relative risk (RR) of death of 1.6 for the 5 µg dose (95% confidence interval [CI] 0.7-3.6) and 1.9 for the 10 µg dose (95% CI 0.9-4.3). A similar imbalance was observed in early 2009 in another placebo-controlled one-year study, which involved 3,991 COPD patients and investigated only the authorised 5 µg dose. The mortality rate was monitored prospectively, including in the study dropouts, until the scheduled end of the study. The relative mortality risk in the active-substance group is 1.29 (95% CI 0.87-1.92) (3,4).

There is no adequate explanation for the findings. However, a post hoc sub-group analysis of the large one-year study suggests an increased mortality risk in patients with a history of heart disease, particularly cardiac arrhythmia (3) - an effect that would appear to be consistent with the anticholinergic mode of action. One explanation for a possible increase in risk with SPIRIVA RESPIMAT compared with conventional SPIRIVA could be that the systemic concentrations and peak levels are slightly higher on the new product (5). The Federal Institute for Drugs and Medical Devices (BfArM) sees "possible overdose tendencies with RESPIMAT" (6).

The SPIRIVA RESPIMAT Summary of Product Characteristics now includes a reference to the increase in mortality and a warning for patients with a history of arrhythmia (7). Since May 2010, the manufacturer, Boehringer Ingelheim, has been conducting a randomised, placebo-controlled comparison of the two tiotropium preparations in which 17,000 patients are to participate and which is expected to be completed at the end of 2013 (8).

–  Three one-year studies of the new tiotropium preparation SPIRIVA RESPIMAT indicate the risk of increased mortality.

–  Patients with arrhythmia or a history of cardiac damage may be particularly at risk.

–  According to present knowledge, the concerns do not apply to tiotropium powder for inhalation (SPIRIVA 18 micrograms), which the large UPLIFT study, conducted over several years, showed to be safe.

–  The differences between the tiotropium products may be due to greater systemic availability of tiotropium from SPIRIVA RESPIMAT.

–  Until the safety of SPIRIVA RESPIMAT has been proven, we advise against the use of this tiotropium preparation.

(R = randomised study)

R

1

TASHKIN, D.P. et al.: N. Engl. J. Med. 2008; 359: 1543-54

2

FDA: Summary Minutes of the Pulmonary-Allergy Drugs Advisory Committee, 19 Nov. 2009; http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ Pulmonary-AllergyDrugsAdvisoryCommittee/UCM196995.pdf

3

FDA: Briefing Document Pulmonary-Allergy Drugs Advisory Committee Meeting, 19 Nov. 2009; http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ Pulmonary-AllergyDrugsAdvisoryCommittee/UCM190463.pdf

4

FDA: Transcript Pulmonary-Allergy Drugs Advisory Committee, 19 Nov. 2009; http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ Pulmonary-AllergyDrugsAdvisoryCommittee/UCM198006.pdf

5

Boehringer Ingelheim: Briefing Document Pulmonary-Allergy Drugs Advisory Committee Meeting, 19 Nov. 2009; http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ Pulmonary-AllergyDrugsAdvisoryCommittee/UCM190466.pdf

6

BfArM: Letter, as at 13 Oct. 2010

7

Boehringer Ingelheim, Pfizer: Summary of Product Characteristics SPIRIVA RESPIMAT, as at Aug. 2010

8

Boehringer Ingelheim: Comparison of Tiotropium in the Handihaler versus the Respimat in Chronic Obstructive Pulmonary Disease, as at 18 Oct. 2010; http://www.clinicaltrials.gov/ct2/show/NCT01126437

*

UPLIFT = Understanding the Potential Long-Term Impacts on Function with Tiotropium