Cardiovascular Disease in COPD: Time to Quash the Silent Killer
Charlotte E Bolton1, Jennifer K Quint2, Mark T Dransfield3
- Nottingham Respiratory Research Unit, School of Medicine, University of Nottingham, Nottingham, UK
- Department of Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, UK
- Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham and Birmingham VA Medical Center, Alabama, USA
Correspondence:
Dr Mark Dransfield
Division of Pulmonary, Allergy & Critical Care Medicine
University of Alabama at Birmingham and Birmingham VA Medical Center
Alabama
USA
Email:
Word count: 854
Author contribution: CEB, JKQ and MTD contributed equally to this
Funding: N/A
Earlier this year, the SUMMIT study: a double-blind, randomized, placebo-controlled trial of fluticasone furoate and vilanterol in patients with chronic obstructive pulmonary disease (COPD) with heightened cardiovascular risk reported no effect on overall mortality or cardiovascular outcomes.1 It would be easy to sideline this to the history books as another failed mega-trial testing inhaled treatments to reduce COPD mortality but it brought back that nagging concern – what are we doing to address cardiovascular disease in this population? More than a quarter of all patients with COPD die of cardiovascular disease overall(over 40% in those with a cardiovascular history),1,2 and concomitant cardiovascular disease of some form is exceptionally common in people with COPD, the problem is we don’t routinely and systematically look for it. This is clearly a priority clinical issue. Whilst the combinationof inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) may not be the solution, are we utilizing the tools we do have sufficiently?
Roll back ten years to the publication of the TORCH (Towards a Revolution in COPD Health) study,the first prospective, randomized COPD clinical trial adequately powered to examine survival.3 Whilst no statistical significance was reached for overall mortality, apost-hoc analysis suggested thatcompared with placebo, the combination of fluticasone propionate and salmeterolreduced the probability of anadverse cardiac event over 3 years, including among those with a prior myocardial infarction, a finding that paved the way for SUMMIT.4The cardiovascular mortality in the placebo arms of the two studies appear broadly similar (roughly 1.55%/year in TORCH and 1.65%/year in SUMMIT) despite the patients in the SUMMIT study being theoreticallyat far greater cardiovascular risk. How could this be? Perhaps it is explained by the near universal prescription of cardioprotective medications in SUMMIT (97% of patients were on at least one versus only 39% in TORCH). Could the failure of ICS/LABA to reduce cardiovascular events in one study, and the suggestion that the combination was effective in the other, be simply the result of this marked discrepancy with little room to move the needle in SUMMIT and a clear opportunity for impact in TORCH?
Though not answerable, the logical follow up question is,couldimplementation of traditional cardiovascular therapies where indicated confer a survival benefit in patients with COPD? Crucial to this approach would be the systematic detection and assessment of cardiovascular riskand disease and not just a reliance on a patient-reported historywhich may miss these silent killers. Clinical trials, such as SUMMIT provide a platform to robustlyconsider and assessrisk through their inclusion criteria. But the lack of steer in current clinical COPD guidelines regarding the cardiovascular assessment at diagnosis of COPD,at subsequent clinic visits, and perhaps most critically during hospitalization where up to 60% of patients will have echocardiographic abnormalities and 75% an elevated cardiac troponin,presents a hurdle in this pathway.5-7Commendable to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) Strategy is a chapter dedicated to co-morbidities, reiterating that these may be under-recognized and that treatment for any co-morbidityshould follow that disease-specific guideline.8 Yet, none of the COPD guidelines currently recommenda core cardiovascular evaluation for patients with COPD. In fairness, such a recommendation may be partly precluded by the absence of robust evidence to suggest the approach improves outcomes or reduces cost in COPD. Others may debate whether standard cardiovascular risk scores need adaptation to accommodate the apparent increased risk from COPD or whether a blanket approach to primary prevention for all with COPD is required.9 But in the meantime, is failure to integrate assessment and management of traditional risk factors, other than smoking, into the COPD evaluation threatening lives?
Data from patients admitted withan acute cardiac syndrome (ACS) suggest that either under-recognition or under-treatment of cardiac risk in patients with COPD may indeed be contributing to deaths. Rothnie and colleaguesexamined UK data from MINAP (Myocardial Ischaemia National Audit Project)10and found that delay in diagnosis, a delay in an interventional approach, or not having an intervention at all,accounted for some of the increased in-hospital and 180-day mortality in the patients who had COPD. MINAPalso reports secondary preventionis less likely to be prescribed in patients with COPD and ACS. This was particularly evident for beta blockers (with an odds ratio 0.25-26 for non- ST elevation MI (STEMI) and STEMI),again likelyto account for a proportion of the 180-day mortality gap.
Whilst ACS may present as a COPD exacerbation, so too, exacerbations of COPD are particularly susceptible periods for ACS.11,12Irrespective of the likely reasons for this (heightened systemic inflammation, sympathetic drive, consequences of acute treatment), a tangible opportunity certainly exists to assess standard CV risk in these patients and optimize therapy. Should inpatient care include a cardiovascular cocktail of therapy prior to comprehensive cardiovascular risk stratification including cardiac stress testing?
Identifying clinically overt and hidden disease where there is a real potential to impact morbidity and survival of our patients with COPD is imperative. A systematic approach to identifying, assessing and managing cardiovascular disease needs to be incorporated into clinical COPD guidelines and be amajor focus for the COPD clinician.
References
1.Vestbo J, Anderson JA, Brook RD, et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet 2016; 387(10030): 1817-26.
2.McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007; 62(5): 411-5.
3.Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. The New England journal of medicine 2007; 356(8): 775-89.
4.Calverley PM, Anderson JA, Celli B, et al. Cardiovascular events in patients with COPD: TORCH study results. Thorax 2010; 65(8): 719-25.
5.Freixa X, Portillo K, Pare C, et al. Echocardiographic abnormalities in patients with COPD at their first hospital admission. Eur Respir J 2013; 41(4): 784-91.
6.Bhatt SP, Wells JM, Dransfield MT. Cardiovascular disease in COPD: a call for action. Lancet Respir Med 2014; 2(10): 783-5.
7.Hoiseth AD, Neukamm A, Karlsson BD, Omland T, Brekke PH, Soyseth V. Elevated high-sensitivity cardiac troponin T is associated with increased mortality after acute exacerbation of chronic obstructive pulmonary disease. Thorax 2011; 66(9): 775-81.
8.Global Initiative for Chronic Obstructive Lung Disease (Updated 2016). 2016
9.John M, McKeever TM, Al Haddad M, et al. Traditional and emerging indicators of cardiovascular risk in chronic obstructive pulmonary disease. Chron Respir Dis 2016.
10.Rothnie KJ, Smeeth L, Herrett E, et al. Closing the mortality gap after a myocardial infarction in people with and without chronic obstructive pulmonary disease. Heart 2015; 101(14): 1103-10.
11.McAllister DA, Maclay JD, Mills NL, et al. Diagnosis of myocardial infarction following hospitalisation for exacerbation of COPD. Eur Respir J 2012; 39(5): 1097-103.
12.Donaldson GC, Hurst JR, Smith CJ, Hubbard RB, Wedzicha JA. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010; 137(5): 1091-7.
Conflict of Interest: CEB has grants awarded by MRC/ABPI and GSK. She has honorarium received from Chiesi directly and to department from GSK.JKQ reports grants from MRC, Wellcome Trust, British Lung Foundation, personal fees from Boehringer Ingelheim, grants and other from GSK, personal fees from Astra Zeneca outside the submitted work. MTD has grants from the NIH and US Department of Defense, contracted clinical trials from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, PneumRx, Pulmonx, Yungjin, and consulting fees from AstraZeneca, Boehringer Ingelheim, Genentechand GlaxoSmithKline.