We will now discuss the inhaled treatment detailed in the NICE guideline in more depth.

Tiotropium is currently the only long acting anti-muscarinic drug on the market. It has been shown in numerous studies to provide significant bronchodilation, which is long lasting. It improves patients symptoms and quality of life, and importantly reduces exacerbation rates. Tiotropium is available in the handihaler and the respimat device. The handihaler is a dry powder inhaler for once daily inhalation. A capsule is placed in the device and pierced by the mechanism. The device is prescribed once a year with monthly refills. For patients unable to use the handihaler then the respimat device is a superior alternative. Tiotropium provides consistent 24-hour bronchodilation (1) and has been shown to be equal to Seretide at reducing exacerbations. (2) 2 recent meta analysis have been performed by Singh both quoting an increase in cardiovascular death with anticholinergics (3) with worse outcomes with the Respimat device. (4) Meta analysis is notorious for the lack of statistical power and in these particular studies was associated with a low frequency of events and very wide confidence intervals. The UPLIFT study (a 4 year RCT) was reassuring in actually showing a reduction in cardiovascular events with Tiotropium. (5) We still currently recommend Tiotropium stays in its current position within NICE and wait for the outcome of a large RCT investigating mortality due to report in 2013.

LABA

The long acting beta agonists (Salmeterol and Formoterol) also known as LABAs have been use in the management of COPD for over a decade. They have recently been joined by a new generation of ultra long acting beta agonists, know as ULABAs. Indacaterol is currently the only ULABA on the market; these only need to be taken once daily. Indacaterol has excellent results from head to head studies against Tiotropium that until now was widely accepted as the best single bronchodilator in the management of COPD.

There is very good evidence that long acting beta agonists:

1. Improve exercise tolerance and quality of life
2. Reduce dyspnoea

There is less evidence that any of the LABAs reduce exacerbation rates. Formoterol and Salmeterol are now rarely used as monotherapy in the management of COPD and instead are prescribed in combination with an inhaled corticosteroid as Symbicort 400/12 one puff BD or Seretide 500 Accuhaler one puff BD as this combination almost doubles the bronchodilation achieved with the LABA alone and reduces exacerbation rates.

Indacaterol however is different. It is a once daily drug delivered in a dry powder inhaler similar to the tiotropium handihaler. It has very good head to head data vs. tiotropium but limited exacerbation data.

Indacaterol is marketed under the name Onbrez and licensed ultra-long for COPD patients with an FEV1<80%. It was launched in the UK in July 2010 as an alternative to Tiotropium. Although it has very good head to head data against tiotropium in terms of symptoms and FEV1 over a 12-month period, there is little exacerbation data. It is delivered in a dry powder inhaler very similar to the handihaler. There are 3 randomised control studies named INHANCE (vs. Tiotropium), INVOLVE (vs. formoterol) and INLIGHT (vs. salmeterol).

More details can be found here

This is a very exciting new drug development that will not only compete where currently tiotropium is prescribed but in combination with other bronchodilators. There are currently no studies published in combination with inhaled corticosteroids.

ICS/LABA Combinations are licensed for use in patients with COPD who have an FEV1<50% predicted and exacerbated 2 or more times per year. The products licensed are the Symbicort 400/12 Turbohaler and the Seretide 500 Accuhaler.
Both these inhaled treatments have been shown to reduce exacerbation rates, improve quality of life and improve FEV1 vs. placebo and their individual LABA and ICS components. The majority of the information regarding Seretide derives from the TORCH study; a randomised, double-blind trial comparing the Seretide 500 Accuhaler, with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. (6) Of the 6112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were found to be 12.6% in the combination therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. (P = 0.052) This study only just failed to reach significance.

Compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. Seretide, unlike Symbicort is licensed for use with an FEV1<60% in England and Wales based on this study. A similar symbicort study below lasted 12 months. Over 1000 COPD patients with mean prebronchodilator FEV1 36% predicted (so more severe than TORCH) were randomised to Symbicort 320/9 mg, budesonide 400 mg, formoterol 9 mg or placebo for 12 months. (7) Postmedication FEV1 improved by 0.21 L and SGRQ by 4.5 units after run-in.  Patients on Symbicort had fewer exacerbations (1.38 versus 1.80 exacerbations per patient per year), had higher prebronchodilator peak expiratory flow, and showed clinically relevant improvements in SGRQ versus placebo (-7.5 units).

(1) Casaburi R, Briggs DD, Donohue JF, Serby CW, Witek TJ. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD. Chest 2000;118:12941302

(2) Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177:1926

(3) Singh S, Loke YK and Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomized controlled trials. JAMA 2008;300:1439-50

(4) Singh S, Loke YK, Enright P and Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomized controlled trials. BMJ 2011;342:d3215

(5) Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, and Decramer M for the UPLIFT Study Investigators. A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease. N Engl J Med 2008; 359:1543-1554

(6) Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease. N Engl J Med. 2007 February 22, 2007;356(8):775-89.

(7) Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003 December 1, 2003;22(6):912-9.