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Risks and benefits of tiotropium in the treatment of COPD

Peter Burrill
BPharm(Hons) MRPharmS DipPresSci FCPP FFPMM
Specialist Pharmaceutical Adviser for Public Health
Derbyshire County Primary Care Trust

It has been suggested that the use of inhaled anticholinergic drugs increases the risk of cardiovascular events in chronic obstructive pulmonary disease. Peter Burrill takes a look at the results of the UPLIFT trial, and the implications for treatment

Previous analyses have indicated that tiotropium should be considered as the firstline long acting bronchodilator in chronic obstructive pulmonary disease (COPD).1–3 However, a recently published meta-analysis in the Journal of the American Medical Association (JAMA), which was widely reported in the media, suggested that inhaled anticholinergic drugs increase the risk of cardiovascular events in people with COPD.4

The Newcastle Regional Drug and Therapeutics Centre appraisal report of this meta-analysis concludes: "The small increase in cardiovascular risk needs to be balanced against the potential benefits of inhaled anticholinergics. More prospective, robust studies are needed to establish whether inhaled anticholinergics are associated with an increase in cardiovascular risk in patients with COPD. Until such time, a change in prescribing practice is not recommended."4

The UPLIFT study has now been published and does not support an increase in cardiovascular risk with tiotropium.5 UPLIFT tested whether tiotropium would reduce the rate of decline in FEV1 and evaluated the long-term effects on health-related quality of life, exacerbations, related hospitalisations, and mortality.

Method
UPLIFT was a four-year, randomised, double-blind, placebo-controlled, parallel-group trial involving patients with moderate-to-very-severe COPD.

The two coprimary endpoints were the yearly rate of decline in the mean FEV1 before the use of the study drug and short acting bronchodilators in the morning (prebronchodilator) and after the use of study drug (postbronchodilator) from Day 30 (steady state) until completion of double-blind treatment.
Secondary outcome measures included the rate of decline in the mean forced vital capacity (FVC) and slow vital capacity (SVC); health-related quality of life as measured on the St George's Respiratory Questionnaire (SGRQ); exacerbations and related hospitalisations; and death from any cause and from lower respiratory conditions.

Criteria for participation included a diagnosis of COPD, an age of 40 years or more, a smoking history of at least 10 pack years, and a postbronchodilator FEV1 of 70% or less of the predicted value.

A power calculation was performed (90% at a significance level of 5%) and the sample size chosen to be sufficiently large to undertake subgroup analyses of the primary endpoint in smokers.

Participants received either 18 mg of tiotropium or a matching placebo once daily, delivered through the HandiHaler inhalation device. All respiratory medications, except other inhaled anticholinergics, were permitted during the trial.
All patients who underwent randomisation and received a study drug, and who had at least three postrandomisation data points (at least two for the SGRQ), were included in the analyses.

Results
Of the 8,020 patients who were recruited, 5,993 underwent randomisation. Of these patients, 4,383 (73%) completed two years, 3,891 (65%) completed three years, and 3,569 (60%) completed at least 45 months. The median duration of treatment was 1,436 days in the tiotropium group and 1,435 days in the placebo group. A higher proportion of patients did not complete at least 45 months of treatment in the placebo group (44.6%) than in the tiotropium group (36.2%,
P adverse events.

Baseline characteristics and concomitant use of respiratory medications were similar in the two study groups. The mean age was 65±8 years among the patients, of whom 75% were men and 30% were current smokers. The mean prebronchodilator FEV1 was 39% of the predicted value, and the mean postbronchodilator FEV1 was 48% of the predicted
value. More than 90% of patients were receiving respiratory medications at baseline (long-acting beta-agonist 60%; inhaled corticosteroid 62%; theophylline 28%).

There were no significant differences between study groups in the rate of decline in the mean values for FEV1 and FVC, either before or after bronchodilation from Day 30 to the end of study-drug treatment. In the tiotropium group, the mean values for FEV1 and FVC before and after bronchodilation showed significant improvements that were maintained at all time points after randomisation. Mean improvements in FEV1 in the tiotropium group, as compared with the placebo group, ranged from 87 ml to 103 ml before bronchodilation and from 47 ml to 65 ml after bronchodilation (P

Significant differences in favour of tiotropium were observed at all time points for the mean absolute change in the SGRQ total score (ranging from 2.3 to 3.3 units, P

Tiotropium was associated with a significant delay in the time to the first exacerbation, with a median of 16.7 months (95% CI, 14.9 to 17.9) in the tiotropium group and 12.5 months (95% CI, 11.5 to 13.8) in the placebo group. Tiotropium was also associated with a significant delay in the time to the first hospitalisation for an exacerbation. In the tiotropium group, the associated hazard ratios were 0.86 (95% CI, 0.81 to 0.91) and 0.86 (95% CI, 0.78 to 0.95), respectively. Tiotropium was also associated with a reduction in the mean number of exacerbations of 14% (P

During a period of four years plus 30 days (1,470 days) included in the intention-to-treat analysis, 941 patients died: 14.9% in the tiotropium group and 16.5% in the placebo group (hazard ratio, 0.89; 95% CI, 0.79 to 1.02). For the four-year, protocol-defined study period up to day 1,440, among patients for whom vital-status information was available, 921 patients died: 14.4% in the tiotropium group and 16.3% in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 0.99).

Safety was monitored through the collection of reports of adverse events, serious adverse events and fatal events while patients were receiving a study drug (including the last day of a study drug plus 30 days). Adverse events were reported by 92.6% of the tiotropium group and 92.3% of the placebo group. The proportions of serious adverse events were 51.6% in the tiotropium group and 50.2% in the placebo group. Fatal events occurred in 381 patients (12.8%) in the tiotropium group and 411 (13.7%) in the placebo group (hazard ratio, 0.84; 95% CI, 0.73 to 0.97).

In the tiotropium group, as compared with the placebo group, the most common adverse events were due to lower respiratory causes, including COPD exacerbations (64.8% and 66.1%, respectively; relative risk, 0.84; 95% CI, 0.79 to 0.89), pneumonia (14.5% and 13.9%; relative risk, 0.96; 95% CI, 0.84 to 1.10), and dyspnea (12.2% and 14.7%; relative risk, 0.75; 95% CI, 0.65 to 0.86). Respiratory failure developed in 88 patients in the tiotropium group and in 120 in the placebo group (relative risk, 0.67; 95% CI, 0.51 to 0.89).
Myocardial infarction developed in 67 patients in the tiotropium group and 85 in the placebo group (relative risk, 0.73; 95% CI, 0.53 to 1.00), and stroke developed in 82 in the tiotropium group and 80 in the placebo group (relative risk, 0.95; 95% CI, 0.70 to 1.29). Adverse events consistent with the known safety profile of tiotropium, such as dry mouth and constipation, were observed.

Serious adverse events reported by more than 1% of patients in either study group were cardiac or respiratory in nature. The incidence of such serious adverse events was lower in the tiotropium group than in the placebo group, including a reduced risk of congestive heart failure, COPD exacerbation, dyspnea, or respiratory failure.

Discussion/implications
The addition of tiotropium to other classes of respiratory medications for up to four years did not result in changes in the rate of decline in lung function. However, lung function was significantly better than in the placebo group throughout the trial. Slowing the rate of decline in FEV1 in COPD patients is difficult to achieve and no drug class has been shown to
do this. The only intervention that has met this criterion of disease-modifying therapy is smoking cessation.

In an analysis of those not receiving inhaled corticosteroids or LABAs at baseline, the difference in the rate of decline in postbronchodilator FEV1 were just statistically significant (P=0.046). However, this is a post hoc analysis and should be viewed as hypothesis generating.

There were improvements in health-related quality of life and rate of exacerbations. The authors highlight "there were important lung-function benefits associated with tiotropium that were maintained during the four years, as well as positive effects on health-related quality of life and a reduced risk of exacerbations and exacerbation-related hospitalisations consistent with a relevant effect on the clinical course of COPD. Finally, tiotropium reduced respiratory morbidity (including a decreased risk of respiratory failure) and reduced cardiac morbidity."

Significantly, more patients in the tiotropium group had clinically significant improvements of four points or more in SGRQ score from baseline at all time points (NNT of 11 at 4 years).

UPLIFT did not show an increased risk of MI or stroke with tiotropium. This provides some reassurance on the CV safety of tiotropium. There was no increase in mortality and there may even have been a decrease, with fatal adverse events occurring less often in the tiotropium group (NNT=111).
The results from UPLIFT, taken together with the other evidence for tiotropium, strongly suggest that tiotropium should be the firstline long-acting bronchodilator in COPD patients.

References
1. Salpeter SR, Buckley NS, Salpeter EE. Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD. J Gen Intern Med 2006;21:1011–19.
2. Barr RG, Bourbeau J, Camargo CA. Tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No: CD002876.
3. Rodrigo GJ, Nannini LJ, Rodríguez-Roisin R. Safety of long-acting beta-agonists in stable COPD:
a systematic review. Chest 2008;133:1079–87.
4. Regional Drug and Therapeutics Centre. Rapid appraisal. Available from: http://www.nyrdtc.nhs.uk/docs/rda/FinalRDTC.pdf
5. 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.om: http://www.nyrdtc.nhs.uk/docs/rda/FinalRDTC.pdf
5. 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.