Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in Chronic Obstructive Pulmonary Disease. N Engl J Med 2008; 359: 1543–54. Published online October 5th 2008 DOI: 10.1056/NEJMoa0805800
This long-term randomised controlled trial of tiotropium versus placebo in patients with COPD did not show a benefit in its primary outcome of reducing FEV1 decline. There was a small reduction in exacerbations (about 12 fewer exacerbations for every 100 patients per year) but no reduction in exacerbations leading to hospitalisation, total number of exacerbations or number of days in hospital. A recent meta-analysis and observational study have signalled the possibility of an increased risk of cardiovascular (CV) events with inhaled anticholinergics in people with COPD. UPLIFT provides limited reassurance about these CV risk signals for tiotropium.
We expect that regulatory authorities will be reviewing this area, but for the present, patients and prescribers should continue to weigh this new data in discussions.
What is the background to this?
Earlier this year, the FDA announced a safety review of the anticholinergic bronchodilator tiotropium. This followed the announcement to the FDA by the manufacturers, that ongoing safety monitoring had identified a possible increased risk of stroke in patients taking it.
A recent MeReC Rapid Review blog discussed the possibility of an increased risk of cardiovascular events with inhaled anticholinergics in people with chronic obstructive pulmonary disease (COPD), although early release of safety data from the UPLIFT trial did not report an increased CV risk for tiotropium versus placebo. These data have now been published in full.
What does this study claim?
The UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) study was a 4-year prospective double blind RCT (n=5993) which compared tiotropium with placebo in patients with COPD. Approximately 45% of patients were using inhaled anticholinergics at baseline and patients randomised to placebo had this therapy discontinued. Patients were permitted to continue all other treatments (beta-agonists, corticosteroids, etc).
The co-primary endpoints were annual rate of decline in both pre- and post-bronchodilator mean FEV1.There were no statistically significant differences between the tiotropium and placebo groups.
In both groups, there was an initial improvement in quality of life, as measured by St George’s Respiratory Questionnaire (SGRQ). Significantly more patients in the tiotropium group had clinically significant improvements of 4 points or more in SGRQ score from baseline at all time points, but in both groups SGRQ declined over time and there was no statistically significant difference between the groups in the rate of decline.
Tiotropium was associated with a statistically significant reduction in the number of exacerbations*/patient/year: about 12 fewer exacerbations for every 100 patients per year, but not the number of exacerbations leading to hospitalisation /patient/year. There were also no statistically significant differences between the groups in the number of patients with exacerbations of any kind or the number with exacerbations leading to hospitalisation.
There were no statistically significant differences between groups in all cause mortality, risk of myocardial infarction or stroke although these outcomes were not pre-specified in the trial design.
* Exacerbations were defined as an increase in, or new onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnoea) lasting >3 days and requiring treatment with an antibiotic or oral steroid.
No statistically significant differences were seen in the co-primary endpoints in this study. There are therefore good statistical reasons for regarding the secondary outcome results (effects on exacerbation rates and quality of life) as hypothesis generating, not hypothesis testing.
An important improvement change in the management of COPD has been a shift in focus on the patient outcomes considered to be important. In the past, the effect of drug therapy on the rate of decline in FEV1 was used to assess its value as a treatment option, whereas reducing exacerbations and breathlessness, and improving quality of life and exercise performance are now considered more appropriate patient-oriented outcomes (POOs), i.e. does the patient live longer or have a better quality of life?
A major limitation of the study is the high drop out rate in both the tiotropium (36.2%) and placebo (44.6%) groups, mainly due to adverse events. Furthermore 44% of patients randomised to placebo were receiving inhaled anticholinergic drugs at study entry, which were therefore discontinued as part of the study procedure.
In contrast with a recent meta-analysis and observational study, UPLIFT did not show an increased risk of myocardial infarction or stroke with tiotropium. This provides some reassurance on the CV safety of tiotropium, but the trial was not designed to look at any CV endpoints, so there may have been differences in how these outcomes were reported. The confidence intervals for MI and stroke were wide, so there may have been too few events to show any differences between the two groups if they really existed. Data on whether patients were alive or dead were collected at a set point four years after initiation of study treatment, but other safety data were collected only while on treatment and for up to 30 days after drug discontinuation.
Uncertainty still exists regarding the cardiovascular safety of inhaled anticholinergics in people with COPD. A long term RCT specifically designed to look at CV outcomes is necessary to confirm and quantify any possible increased CV risk.
The FDA has announced (7th October) that it expects to receive the complete report for UPLIFT in November 2008. Results from this trial will also help to address some issues raised about tiotropium in the two recent publications referred to above. Due to the amount of data collected in UPLIFT, a complete review of the results could take several months, at which time FDA will update this communication with the final results of the UPLIFT analysis, as well as all the available data regarding tiotropium and stroke risk.
Patients: 5992 patients >40 years (mean age 65+8 years) with COPD (post-bronchodilator FEV1 <70% predicted and FEV1:FVC ratio <70%). 30% of patients were current smokers at baseline and patients with a history of asthma were excluded.
Intervention and comparison: Patients were randomised to tiotropium 10 micrograms/day via HandiHaler (n=2986) or matching placebo (n=3006). All other COPD medications were permitted, except inhaled anticholinergic drugs. After randomisation, clinic visits occurred at 1 month and 3 months, and then every 3 months throughout the 4-year study period. Allocation appears to have been concealed, according to the additional data supplement.
Outcome and results: For the co-primary endpoints ― pre- and post-bronchodilator annual rate of decline in the mean FEV1 (forced expiratory volume in 1 second) beginning on day 30 – there were no statistically significant differences between the tiotropium and placebo groups respectively: mean decline ±standard error [SE] pre-bronchodilator 30+1ml/year vs. 30+1ml/year; post-bronchodilator 40+1ml/year vs. 42+1ml/year.
For secondary endpoints ― rate of decline in mean FVC (forced vital capacity) ― there was no significant difference between groups, either before or after bronchodilation: difference between tiotropium and placebo: mean (95%CI) difference pre-bronchodilator 4+4ml/year (-4 to 12), P=0.30; post-bronchodilator 1+4ml/year (-7 to 9), P=0.84.
Exacerbations ― tiotropium was associated with a statistically significant reduction in the time to first exacerbation (median of 16.7 months in the tiotropium group versus 12.5 months in the placebo group) and the number of exacerbations/patient/year: (mean±SE 0.73±0.02 exacerbations/pt/year with tiotropium versus 0.85±0.02 with placebo, relative risk [RR] 0.86, 95%CI 0.81 to 0.91, P<0.001). However, there was no difference in the number of exacerbations leading to hospitalisation /patient/year (mean±SE 0.15±0.01 vs 0.16±0.01, RR 0.94, 95%CI 0.82 to 1.07, P<0.34) There were also no statistically significant differences between the groups in the number of patients with any exacerbations, the number with exacerbations leading to hospitalisation, or the number of hospitalisation days per patient per year.
Health related quality of life – Mean SGRQ scores were statistically significantly better in the tiotropium group than in the placebo group at all time points, but these differences were less than the 4 point difference (on a 100 point scale) generally considered to be clinically significant. A higher proportion of patients in the tiotropium group than in the placebo group had an improvement of 4 points or more in the SGRQ total scores from baseline at 1 year (49% vs. 41%), 2 years (48% vs. 39%), 3 years (46% vs. 37%), and 4 years (45% vs. 36%) (P<0.001 for all comparisons) There was no statistically significant or clinically meaningful difference between groups in the rate of decline in SGRQ scores from 6 months to end of study: difference between tiotropium and placebo 0.04+0.13, 95%CI -0.2 to 0.3, P=0.78.
All cause mortality ― during a period of 4 years and 30 days, in the intention-to-treat analysis, 14.9% vs. 16.5% of patients had died in the tiotropium and placebo groups respectively (hazard ratio [HR] 0.89, 95%CI 0.79 to 1.02, P=0.09).
Other adverse events ― there were no statistically significant differences between groups in the risk of myocardial infarction (RR 0.73, 95%CI 0.53 to 1.00) or stroke (RR 0.95, 95%CI 0.70 to 1.29).
Sponsorship: Boehringer Ingelheim and Pfizer