Boehringer Ingelheim and Pfizer have rejected claims from a meta-analysis published in the Journal of the American Medical Association which argues that the inhaled anticholinergics Spiriva and Atrovent are associated with significantly increased risk of cardiovascular death, myocardial infarction or stroke.
The study published in JAMA says that patients with chronic obstructive pulmonary disease who took Spiriva (tiotropium), or Boehringer’s older treatment Atrovent (ipratropium) for at least a month had a 58% higher risk of cardiac death, heart attacks or strokes than those on placebo or other treatments. The findings were based on an analysis of 17 controlled trials involving 14,783 patients carried out by a team of researchers led by Sonal Singh of the Wake Forest University School of Medicine in Winston-Salem.
The meta-analysis follows a Veterans Affairs study published in the Annals of Internal Medicine found that patients with COPD who used ipratropium were 34% more likely to die of a heart attack or arrhythmia than those using only a similar product called albuterol, or those who did not take any drugs. Furthermore in March, US regulators said they were reviewing the risk of stroke from an analysis by Boehringer of safety data from 29 studies testing either the Spiriva HandiHaler or the European-Union approved version, Spiriva Respimat, in around 13,500 patients with COPD.
However Boehringer and Pfizer have responded quickly to take the JAMA meta-analysis to task. Specifically, they have released a new analysis of 30 “rigorously-controlled” clinical trials confirming the long-term safety profile of Spiriva. That data, which is taken from 19,545 COPD patients, demonstrated that there is no increased risk of death or death due to cardiovascular events in patients treated with the drug.
The new and expanded safety data, which includes findings from the four-year UPLIFT study, “contradicts the conclusions about tiotropium in an article by Singh et al”, said Boehringer. Head of the firm’s R&D operations and chief executive-designate, Andreas Barner, confirmed that “we strongly disagree with the conclusion reached by Singh et al” and “patients and physicians can be confident that Spiriva is a safe and effective medication”.
Boehringer said that peer-reviewed meta-analyses “have their appropriate place in scientific research” but they have “well-recognised limitations, such as combining study summaries rather than analysing individual patient data, or not correcting for patients who dropped out of trials early”. The company added that the analysis by Dr Singh and colleagues is contributed by a single study, the Lung Health Study, involving ipratropium, in which most of the cardiovascular deaths occurred among patients who were not using their medication.
Other limitations include “the inability to adjust for treatment duration and accounting for patients who discontinue the trial early, apparent double-counting of trials and combining placebo and active comparator drugs in the control group”. Dr Barner added that in clinical trials and since the introduction of Spiriva, “we have collected extensive safety data adding up to an exposure of more than 10 million patient years.”
The complete findings from the UPLIFT study will be presented on October 5 during the European Respiratory Society 2008 Annual Congress in Berlin.
