COPD--safety of LABAs

The recent SUMMIT  study assessed the efficacy of combination steroid plus long acting b-agonist (LABA) therapy in patients with COPD, specifically looking at survival in those at high cardiovascular risk (see copd LABA steroid SUMMIT lancet2016 in dropbox, or Vestbo J. Lancet 2016; 387: 1817), finding no increased mortality. A drug company sponsored study. details:

--16,485 patients 40-80 yo from 1368 centers in 43 countries, with cardiovascular disease (CVD) or at high risk of CVD, and post-bronchodilator FEV₁ of 50-70% of predicted. Also at least 10 pack-years of smoking and modified MRC dyspnea scale of at least 2 (patient describing shortness of breath as: “I walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level”

--mean age 65, 25% women, 81% white/17% Asian, BMI 28, 47% current smokers, post-bronchodilator predicted FEV₁ 60% (with 8% reversibility by the bronchodilator), 16% on pre-study anticholinergic, 34% on LABA, and 33% on steroid inhaler, 60% without COPD exacerbation in prior year/25% with one episode, 51% with CAD, 20% PAD, 10% stroke, 17% prior MI, 9% diabetes, 90% hypertension, 66% hyperlipidemia, 56% on antithrombotic, 67% lipid lowering med, 70% RAAS antagonist, 34% b -blocker). So, overall, 71% had established cardiovascular disease or diabetes, and 28% were at high risk. All inhaled steroids or long-acting bronchodilators (which would include anticholinergics) were stopped prior to the study

--randomized to: placebo, fluticasone 100 mcg, the LABA vilanterol 25mcg, or the combo. All once a day. followed 1.8 yrs (max 4 yrs)

--results:

                --medication adherence was high: 97% were taking >80% of prescribed meds

                --primary outcome (all-cause mortality): 1037 deaths—not statistically different between groups, but varying from 6.7% on placebo to 6.0% on combo therapy. Mortality overall by diagnosis --cardiovasc: 3.0% (43% of the total); pulmonary: 0.9% (13% of total); 1.5% cancer (23% of total)

                --secondary outcome: composite of cardiovascular events (cardiovasc deaths, MI, stroke, unstable angina, TIA): no significant difference

                --secondary outcome: on-treatment decline in FEV₁: combo therapy reduced the decline (38 ml/year,  vs 46 ml/yr on placebo, similar results with fluticasone, but no diff between LABA and placebo         

     --very small numbers of COPD exacerbations, but significant differences in annual rates with each active med over placebo [but pretty small absolute differences]:

                --placebo: 0.35 for moderate and severe, and 0.07 for severe

                --either single agent LABA or fluticasone: 0.31 and 0.06

                --combo: 0.25 and 0.05

--adverse events. Not different between groups, including pneumonia

So, a few points:

--I think this is an important study for several reasons:

                --the literature up til now has been pretty mixed on the question of overall or cardiovascular mortality in those with COPD specifically related to LABAs, though no definitive trial had looked at this outcome. The best study so far did find reduced cardiovascular and pulmonary mortality on a secondary analysis: the TORCH study (Calverly PM. NEJM 2007; 356: 775) assessed fluticasone 500mcg plus salmeterol 50 mcg twice daily (an 8-fold  higher dose of steroid than in SUMMIT) and in patients with moderate to severe COPD but lower cardiovascular risk, finding an almost significant decrease in mortality (15.2% in placebo, 12.6% with combo therapy, an 18% decrease but p=0.052).

                --and, this CVD outcome is really important: not only do COPD and CVD have shared risk factors (eg, smoking, air pollution, systemic inflammation, endothelial dysfunction, sedentary lifestyle), but those with moderate symptomatic COPD are more likely to die from CVD than any other cause (and in the SUMMIT study, 43% of deaths were attributed to CVD)

--a few caveats:

                --most of these patients in SUMMIT were pretty stable (eg COPD GOLD B), with only 15% having had a history of 2 or more exacerbations in the prior year

                --the study unfortunately did not allow baseline use of anticholinergics (eg tiotropium), which is the first line drug in COPD I have been using, given the prior mixed reviews on cardiac mortality with LABAs. [though the 2013 GOLD recommendations do give equal weight to anticholinergic or LABA as first line (see copd gold guidelines 2013 in dropbox, or Vestbo J. Am J Respir Crit Care Med 2013; 347)]

                --though the combo steroid/LABA did increase statistically the FEV₁ (and was clearly better than placebo), the difference was not clinically significant (only 8 ml/yr). On reviewing the decline of FEV₁ over 3 years, the curves were really parallel (averaging a decline of about 40 ml) in all groups, suggesting that longer followup would be unlikely to further improve FEV₁ clinically. In fact, the only real difference in the curves was that at the 90-day mark, where they based the initial assessment of FEV₁ decline, there was an increase of around 40 ml in those with active treatment, so the measured decline was really based on an increase in the initial set-point, especially in the curves of patients on fluticasone.

                --it is difficult to compare the SUMMIT and TORCH trials, since in the latter, the patients had more severe COPD, were at lower CVD risk, but had much higher steroid dosing. the higher trend to increased survival in those in the TORCH study vs the SUMMIT study may well have been from the increased fluticasone dosing or other characteristics of the patient population. Perhaps the close-to-significant mortality benefit found in TORCH (which was equally spread through cardiovascular and pulmonary causes) would have been significant in a larger study such as SUMMIT, especially if the TORCH patients had higher CVD risk.  But there was the likely trade-off of increased pneumonia rate/year in TORCH (0.07 vs 0.039 in SUMMIT) likely related to the higher steroid dose.

--so, bottom line, SUMMIT was not a perfect study for COPD (since they did not use baseline tiotropium, and it was a very stable COPD  group with very few exacerbations). But it was very impressive that in this group with high cardiovascular risk, the combination of an inhaled steroid and LABA, or either individually, was not associated with increased mortality and specifically cardiovascular events (though, importantly, patients had moderately reasonable baseline CVD preventive meds). It was reassuring in this large study that there was no increase in pneumonia associated with the steroids, though they used a much lower dose than is often prescribed (100 mcg fluticasone). But the SUMMIT study does give more definitive and stronger support to using either LABA or anticholinergic as the first-line agent.