Breathe Deeply: Safety Concerns Over Spiriva

Several months after concerns were raised about the safety of the blockbuster Spiriva inhaler that is used to treat chronic obstructive pulmonary disease, a previously unpublished epidemiological study has surfaced. And the data, which has been published in BMJ Open, indicates the medication is associated with an increased risk of angina, heart attacks and stroke compared with a long-acting beta agonist, although a lower risk of total mortality was found.

The data was actually contained in a 292-page briefing document that was submitted by Boehringer Ingelheim, which markets Spiriva, for a November 2009 FDA panel meeting (see page 158) and which we reported previously (read here). Until now, though, a full vetting of the study, which was known as THIN-II, had not been available for public consumption.

The publication is the latest development in a controversy over the medication and the difficulty in accessing data that might help physicians make appropriate treatment choices. Spiriva is a long-acting medication for chronic obstructive pulmonary disease and is sold as a mist that is delivered with the Respimat inhaler, and as a powder, which is delivered with a Handihaler device. The mist inhaler is available in 55 countries, but not yet approved in the US.

Last year, a meta-analysis published in the BMJ found that, when administered in the Respimat mist form, there was a 52 percent increase in mortality risk compared with a placebo (read here). Boehringer countered by citing published studies, including a pooled analysis, that indicated Spiriva – a $4.3 billion global seller – is safe and reduces the risk of cardiovascular events and deaths. COPD patients, by the way, are, generally, older and more likely to have compromised cardiovascular systems. BI added that safety and risks were reflected in product labeling.

Nonetheless, the safety assertions were called into question after a review of previously published studies, FDA briefing documents and company synopses of clinical data, which Boehringer Ingelheim has generally posted on its company web site, but can be difficult to find. Among these various strands was the THIN-II trial, which examined 4,767 Spiriva HandiHaler patients and another 6,073 people COPD patients who were prescribed a long-acting beta agonist, which was largely the Serevent med sold by GlaxoSmithKline.

The study compared usage over a six-month period for certain cardiovascular events, such as atrial fibrillation, cardiac arrest and heart failure, and Spiriva showed lower incidence and hazard ratios. But for angina, myocardial infarction, tachycardia and stroke, the inhaler displayed higher ratios - stroke was 1.49, 1.38 for angina and 1.26 for heart attacks (here is the abstract). The results were not statistically significant, but the authors note the findings were similar to results in another study called POET, which also compared Spiriva with Serevent and found an increased risk of serious cardiovascular adverse events, including angina, myocardial ischaemia and heart attacks.

That study was published last year in The New England Journal of Medicine, but as we noted previously, made little mention of cardiovascular events, except for a table showing a 1.12 rate ratio for patients using Spiriva HandiHaler compared with those using Serevent (here is the abstract). The supplemental appendix, however, shows a 1.5 rate ratio for myocardial infarction, and a 0.55 percent incidence rate for the HandiHaler compared with 0.37 percent for Serevent.

Several of the studies that Boehringer cited last year as evidence that Spiriva is safe were funded by the drugmaker and, in some cases, also by Pfizer, which co-markets Spiriva. And many of the authors were either Boehringer employees or have worked for the drugmaker as a consultant or advisory board member, or received research grants. The three authors of the newly published THIN-II study were also Boehringer employees, but now work elsewhere - Acorda Therapeutics and United Biosource. The drugmaker funded the study; work began when the authors were still employees.

So are they free now to speak their minds? A key message, they write, is that similarity in results between the THIN-II and POET studies "support the hypothesis that (Spiriva) HandiHaler can be associated with an increased risk of ischaemic cardiovascular events." They noted that, there is no statistical significance, and so the results should be "interpreted cautiously." Nonetheless, they argue that the findings "lend modest support to a considerable body of evidence of a serious cardiovascular safety risk with inhaled anticholinergic drugs."

We asked Boehringer for a response to the study findings and why the study was not published sooner, and will update you accordingly.

They also argue that the notion extends to another study cited by Boehringer as evidence Spiriva is safe. This was published three years ago in The New England Journal of Medicine and compared the HandiHaler with a placebo. Known as UPLIFT, the study concluded there was a reduction in cardiac adverse events associated with Spiriva HandiHaler, but a table showed relative risks were 1.44 for serious angina and 1.25 for cardiac failure (here is the abstract). And a more specific breakout appeared in the FDA briefing materials for the 2009 advisory panel that was held to review Spiriva Respimat – a table on page 115 shows that the incidence rate for atrial tachycardia was 0.08 compared with placebo and 0.08 again for tachyarrhythmia compared with 0.02 percent for placebo.

The FDA, in any event, later concluded that data from Uplift adequately addressed the potential safety signal of stroke and adverse cardiovascular outcomes. But THIN-II authors disagree. "A few points help explain these divergent conclusions," they write. "First, we consider the entire body of evidence pertaining to class effects, and we consider each study on its merits. In particular, studies should not be disregarded merely because they are not randomized or they include an another medication as a control group instead of a placebo group.

They continue by maintaining that they do not assume results that are not statistically significant provide evidence that an increased risk does not exist, even when considering small effects on rare adverse events. "This is especially important when increases in risk are small or studies were not large enough to detect such risks as statistically significant. It is important to consider the magnitude of effect estimates and the precision with which they are measured," they write.

They cite the UPLIFT study, which notes higher rates of serious angina and ischaemic stroke with Spiriva than a placebo and "so can hardly provide reassurance about the absence of such risks. In addition, results from composite end points do not necessarily apply to each of their components. Thus, decreased rates of total mortality and total stroke can mask increased rates of cardiovascular mortality or ischaemic stroke," they continue.

"Finally, adverse effects do not occur in every patient and may not be apparent in every population or every study. Heterogeneity of results is not evidence against a causal effect, but is an interesting finding that should be interpreted in consideration of the impact of both non-causal as well as causal explanations; the latter include differences in populations, durations of follow-up and doses. Thus, the absence of an increased risk of myocardial infarctions in the Uplift study does not negate increases in risk of MI" the Lung Health Study (an older study that analyzed Atrovent, a short-acting version of Spiriva), the POET Study or their THIN-II study, each of which indicated an increased risk of angina."

They conclude by writing that increased risks of tachyarrhythmias and angina have been reported in connection with inhaled anticholinergic drugs in both non-randomized and randomized studies, which examined various patient populations over various periods, and compared Spiriva and Atrovent with placebo and other medication. "Pharmacological and clinical evidence, therefore, supports these cardiovascular events as class effects of inhaled anticholinergic drugs," they write. "Small increased rates of stroke have been observed fairly consistently across studies, while MI and cardiovascular death, have been associated in different studies both positively and negatively with anticholinergic medication."

[UPDATE: On May 30, Boehringer Ingelheim finally responded with a statement: "Data from the Thin II study have been available publicly for some time and were specifically submitted to and discussed with the FDA and other global health authorities several years ago. We evaluated the THIN II study data with input from internal and external experts, and provided the final report to FDA and global regulatory authorities beginning in 2008. The THIN II data set was also formally reviewed within the context of the review of safety/efficacy information associated with the 2009 supplement to the NDA for Spiriva HandiHaler, which also included the UPLIFT study report.

"Our actions ensured both robust dialogue with experts and regulators and transparency, as these data were disclosed and discussed publicly for the 2009 Advisory Committee. FDA’s independent expert Advisory Committee and the FDA itself concluded - based on the totality of the evidence including findings from this epidemiological study - that the data do not support an association between Spiriva HandiHaler and stroke, heart attack, or death.

"As Jara et al state, the findings of this epidemiological study regarding stroke, angina, tachycardia and myocardial infarction, as summarized in their assessment of the THIN datasets are not statistically significant. We believe that it is important to note the statistically significant finding of the study: that Spiriva HandiHaler reduced total mortality. Any individual study, including the THIN dataset, is part of a much broader set of information, including prospective randomized clinical trials and retrospective analyses such as this, which we take into account as we continually assess the overall risk-benefit profile of this product. Boehringer Ingelheim continues to invest in research to understand the benefits and risks of tiotropium."]

EDITOR'S NOTE: It is worth noting that the THIN II study was available publicy, but only in the FDA briefing documents, which did not list the study in an index or contents, so one would not know that study data could be found unless one waded through the materials. The drugmaker did not respond to a question about why the study was not published earlier in a journal, given that the authors were BI employees at the time the study was undertaken.

Boehringer Ingelheim and Pfizer have demonstrated over the course of several years our commitment to responsibly investigating and resolving questions about the safety and efficacy of Spiriva Handihaler. We continue to believe firmly, based on the entire body of evidence, that Spiriva is an important option for patients with COPD. The efficacy and safety of Spiriva have been established by a robust clinical development program as well as post-marketing surveillance, and the product’s risk-benefit profile is appropriately described in the approved product labeling.