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Title: A proof of concept randomized control trial of atorvastatin as a stable therapy in bronchiectasis
Author: Mandal, Pallavi
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2014
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Background: Bronchiectasis is characterized by chronic cough, sputum production and recurrent chest infections. The pathogenesis is poorly understood but pulmonary pathology shows excess neutrophilic airways inflammation. Accumulating evidence suggests that statins have pleiotropic effects, including modulation of innate and adaptive immune system and anti-inflammatory effects and therefore is a potential novel anti inflammatory therapy for patients with bronchiectasis. Aim: The aim of this thesis was to (i) establish if atorvastatin could break the vicious circle of infection and inflammation in bronchiectasis and (ii) establish the anti inflammatory mechanisms of statins contributing to this. Methods: A RCT was conducted to test the hypothesis that aorvastatin could be a potential anti inflammatory therapy in bronchhiecatsis. In this RCT patients aged 18-79 years were recruited. Patients had clinically significant bronchiectasis, which is patients with cough and sputum production when clinically stable, with two or more chest infections in the preceding year and bronchiectasis confirmed on CT scan of the chest. We excluded: current smokers or ex-smokers of less than 1 year, those with a greater than fifteen pack year history or those with predominant emphysema on CT scan; cystic fibrosis; active allergic bronchopulmonary aspergillosis; active tuberculosis; poorly controlled asthma; pregnancy or breast feeding; known allergy to statins; currently on statins or statin use within 1 year; active malignancy; chronic liver disease; patients on long term oral macrolides; patients chronically colonized with Pseudomonas aeruginosa. Sequence generation was done by block randomization of four, by Tayside pharmaceuticals, NHS Tayside, for 30 patients to receive either atorvastatin 80mg or 30 to receive placebo orally, once daily for 6 months. The placebo (lactose) was not matched to the atorvastatin in appearance. Pharmacy directly dispensed study medications to the patients, hence allocation concealment was maintained at all times to the study investigators. The primary endpoint of this study was a reduction in cough at 6 months compared to baseline as measured by the Leicester Cough Questionnaire (LCQ) score. It is a 19 item self completed quality of life measure of chronic cough which ranges from 3-21, a lower score indicating a more severe cough. The minimum clinically important difference (MCID) is 1.3 Units. The LCQ score is repeatable over 6 months in stable disease. Analysis done was intention to treat. Secondary outcomes included: forced expired volume in one second, forced vital capacity; incremental shuttle walk test; qualitative and quantitative sputum bacteriology; exacerbation frequency; health related quality of life; sputum neutrophil numbers and apoptosis; sputum myeloperoxidase and free elastase activity; sputuminterleukin (IL)-8; systemic inflammation-white cell count, C-reactive protein (CRP) and erythrocyte sedimentation rate, additional systemic inflammatory markers (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and tumor necrosis factor-α) and safety of therapy. Findings: (i) RCT There was evidence of a difference in baseline to 6-month change in LCQ between the treatment groups, with a significant improvement in the statin treated group, with a mean difference 2.2, 95% CI for difference (0.5, 3.9) p=0.01. When analyzed as proportion of improvement in LCQ, in the statin treated group 40% patients had a 1.3 Units or more improvement in the LCQ compared with 17% in the placebo group; difference in proportion 23% (95% CI for difference 1%, 45%), p=0.04. There was significantly increased number of apoptotic airway neutrophils [mean difference of 8.9 (11.7); p=0.04] with a trend towards a decreased total number of neutrophils in the sputum; p=0.09; in statin treated group. Ten (33%) patients had an adverse event in the statin group compared to three (10%) in the placebo, difference in proportion 23% (95% CI for difference 3%, 43%), p=0.02. There were however no serious adverse events. (ii) In vitro studies Statins enhance apoptosis of neutrophils in vitro and this is consequent to reduction in stimuli induced increase in calcium flux. Interpretation (i) In this proof of concept study, six months of atorvastatin improved cough in bronchiectasis. Multi-centered studies are now needed to assess whether long-term statin therapy can reduce exacerbations. (ii) Further studies are needed to establish if statins regulate Ca2+ flux by altering the extracellular or intracellular pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available