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Title: Heart failure and chronic obstructive pulmonary disease : common partners, common problems
Author: Hawkins, Nathaniel Mark
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2010
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Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are common partners with common problems. Both are chronic systemic disorders incurring significant morbidity and mortality. Although around one third of patients with HF have concurrent COPD,1 remarkably few reports have addressed this often ignored combination. The systematic review presented within this thesis defines the diagnostic challenges, prevalence and prognostic implications of HF with coexistent COPD. I then critically appraise the twin controversies of β-blockade in COPD and β-agonists in HF. The two are inextricably linked, each therapy exerting the reverse pharmacologic activity of the other. The evidence for symptomatic or prognostic benefit from either therapy is limited, and in the case of β-agonists adverse consequences appear more likely. A Cochrane meta-analysis concluded that long term cardioselective β-blockade is safe and well tolerated in patients with moderate to severe or reversible COPD.2 Although often cited,3 these conclusions are simply not true. Of the 20 randomised controlled trials included in the meta-analysis, 11 involved single doses and only one lasted longer than a month. The 9 ‘long term’ studies (defined as more than a single treatment dose) involved 147 young, predominantly male patients with moderate airways obstruction (mean forced expiratory volume in 1 second (FEV1) 1.8 litres). The effect on health status has never been assessed in any cohort with COPD. The long term impact of β-blockade on pulmonary function, symptoms and quality of life is therefore largely unknown. Most importantly, no study has included patients with HF. I randomised 27 patients with HF and coexistent moderate or severe COPD to receive bisoprolol or placebo, titrated to maximum tolerated dose over 4 months. Patients were elderly and predominantly male. Cardiovascular comorbidity, smoking history and pulmonary function were similar in each group (mean FEV1 1.37L vs 1.26L). There were several key findings. A reduction in FEV1 occurred after 4 months following treatment with bisoprolol compared with placebo (–70 ml vs +120 ml, p=0.01). Reversibility following inhaled β2-agonist and static lung volumes were not impaired by bisoprolol. All measures of health status exhibited a consistent non-significant improvement, including the Short Form 36 physical and mental component scores, Minnesota Living with Heart Failure Questionnaire, and Chronic Respiratory Questionnaire. The mean number of COPD exacerbations was similar in the bisoprolol and placebo groups. Although recruitment was limited, the results pose crucial questions and provide direction for larger randomised controlled trials. I analysed cross-sectional data from 61 primary care practices (377,439 patients) participating in the Scottish Continuous Morbidity Recording scheme. The prevalence of COPD in patients with HF increased year on year from 19.8% in 1999 to 23.8% in 2004. These changes may previously have been attributed to an ageing population or increasing age of presentation. However, the trend remained significant after age standardisation. A clear socioeconomic gradient was observed, with prevalence greatest in the most deprived. Consultation rates for HF or COPD in those with both conditions were greater than disease specific contact rates in patients with either condition alone. Cardiovascular comorbidity was similar in HF patients with and without COPD, despite differences in smoking history (respectively 76% vs 47%, p<0.001). This is concerning and suggests that common cardiovascular conditions are being under diagnosed (and likely under treated) in patients with HF and COPD. Although overall β-blocker prescribing increased over time, the adjusted odds of β-blocker prescription in patients with COPD was low (odds ratio 0.30 [95% CI 0.28–0.32], p<0.001). Whether the gap between patients with and without COPD is improving was previously unknown. Despite the overall improvement in beta-blocker prescribing, the relative difference in prescribing between those with and without COPD remained unchanged. By 2004, only 18% of individuals with HF and COPD were prescribed β-blockers. COPD is consistently an independent predictor of death and HF hospitalisation in patients with HF. However, the causes of increased mortality were unclear. I examined the relationship between COPD and cardiovascular outcomes in patients with myocardial infarction (MI) complicated by heart failure, left ventricular systolic dysfunction (LVSD), or both enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) trial. COPD was an independent predictor of mortality, largely due to increased non-cardiovascular (HR 1.86 [1.43–2.42]) and sudden death (HR 1.26 [1.03–1.53]). However, after multivariate adjustment COPD was not an independent predictor of atherosclerotic events (MI or stroke: HR 0.98 [0.77–1.23]). This is an important finding, as atherosclerotic consequences of chronic systemic inflammation in COPD have been postulated. These appear of limited clinical significance, at least during intermediate follow-up. Part of the adverse risk associated with COPD may be attributable to bronchodilators. The prognosis of patients with HF prescribed bronchodilators is however ill defined. I examined the prognostic implications of bronchodilator use in patients with HF enrolled in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme. The diversity and magnitude of adverse outcomes associated with bronchodilator therapy was surprising. Bronchodilator use was associated with increased all cause mortality (HR 1.26 [1.09–1.45]), cardiovascular death (HR 1.21 [1.03-1.42]), death due to HF progression (HR 1.40 [1.07-1.82]) and HF hospitalisation (HR 1.49 [1.29-1.72]). Although association is not causation, it is possible that bronchodilators compound maladaptive remodeling and further depress myocardial function. Finally, β-blockers were independently associated with better survival in both VALIANT and CHARM. No significant interaction was observed between either COPD or bronchodilators and β-blockade with respect to mortality. Furthermore, β-blocker use was not associated adversely with any pre-specified outcome in patients with COPD or those prescribed bronchodilators, including non-cardiovascular mortality. Although recruitment bias and the absence of spirometry limit inference to patients with severe or reversible airflow obstruction, the results should encourage β-blockade in patients with COPD. In summary, the studies presented in this thesis extend our understanding of HF with concurrent COPD. Only large randomised controlled trials will solve the quandary of β-blockers and β-agonists. Justification for these trials evolves from observational data and smaller prospective studies such as my own. In the meantime, I hope the evidence presented will stimulate physicians to re-evaluate the management of patients with HF and COPD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General) ; RM Therapeutics. Pharmacology