It's Time to Move on from Counting Co-Morbidities to Curing Them: The Case of Chronic Heart Failure–Chronic Obstructive Pulmonary Disease Co-Morbidity

A few weeks ago an excellent review by Helgo Magnussen et al.,1 ‘What can we learn from pulmonary function testing in heart failure?’, was published in the Journal. In my view, it marks an important step forward to achieve a reasonable share of both cultural understanding and good clinical practice in the orphan domain of lung and cardiovascular co-morbidities, in particular the association of chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD), which among the frequent morbidities associated with CHF is nowadays one of the most prevalent. A few following comments may highlight the increasing importance of this clinical problem, the inadequacy of our current response, and a few ways through which we could improve our approach. Currently, the global mortality from cardiovascular disease and from respiratory disease accounts for about 45% and 6% of all-cause deaths, respectively.2, 3 The prevalence of COPD, derived from a meta-analysis of 123 population studies reporting spirometry-based diagnoses is 14% in men and 8% in women,3 much higher than the prevalence of CHF, which is estimated at around 2% of the adult population in developed countries, rising to >10% among people >70 years of age. The prevalence of both CHF and COPD is estimated to increase in the near future, though both age-standardized incidence and mortality rates of CHF are decreasing, at least in developed countries.4, 5 The prevalence of the CHF–COPD co-morbidity is reported as 10–20% in ambulatory heart failure (HF) studies vs. 20–30% or more in hospitalized HF studies.6 The finding of a higher prevalence of CHF–COPD in hospitalized patients than in the ambulatory population is recurrent in the literature. In the specific setting of the US Medicare hospital network, among nearly 100 000 unselected patients aged ≥65 years hospitalized for HF and included in the Get With the Guidelines HF registry, 35% of patients were diagnosed as CHF–COPD co-morbid (physician-reported COPD diagnosis), with the proportion increasing from 32% in the group with reduced left ventricular ejection fraction (HFrEF) to 40% in patients with preserved left ventricular ejection fraction (HFpEF) In 28% of patients, a respiratory process had been considered as the precipitant factor for HF hospitalization.7 A comparative overview of the mortality rate of the CHF–COPD association and the death rates of patients with isolated CHF or COPD estimated an increase in mortality from CHF–COPD co-morbidity of around 30–50%.8 In Europe, interesting features on the CHF–COPD relationship have been reported in a community study performed in a Swedish county population (313 977 individuals).9 Heart failure was diagnosed in 19% patients with COPD vs. 1.6% in non-COPD patients. The age-standardized prevalence was 10% and 1.5%, respectively. Standardized relative risk for the diagnosis of HF in patients with COPD with respect to non-COPD was 6.6. The levels of other co-morbidity were significantly higher (three- to six-fold) in patients with coexisting HF and COPD compared with patients with either HF or COPD alone. In a recent large European HF registry conducted by the European Society of Cardiology (ESC) across 21 countries, including more than 16 000 patients collected by national networks of cardiology centres, 1334/6920 (19.3%) hospitalized HF patients and 1322/9409 (14.1%) ambulatory CHF patients were diagnosed with COPD.6 The CHF–COPD co-morbidity seems, therefore, a significant public health issue in all settings explored. The current respiratory and cardiac guidelines are rather perfunctory in dealing with the question of CHF–COPD co-morbidity. The 2017 GOLD Report on COPD,10 after reporting few epidemiological data and sounding the vague but strong alarm that ‘the prevalence of systolic or diastolic HF in COPD patients ranges from 20% to 70%’, do not spend further words on comments or recommendations, apart from alerting that unrecognized HF may mimic or accompany acute exacerbations of COPD and underscoring the appropriateness of the use of selective beta-1 blockers in stable patients. In all, 63 words and four references. The 2017 GOLD pocket guide to COPD diagnosis, management, and prevention does not mention at all the CHF–COPD co-morbidity.10 In turn, in the 2016 ESC guidelines on HF,11 the CHF–lung disease co-morbidity (including COPD and asthma) comes in 13th place among the considered co-morbidities (after central nervous system diseases, erectile dysfunction, gout, and arthritis…), and it consists of 346 words, mostly addressing therapy, in particular beta-blockade, which substantially share the standard guidelines' positions of the GOLD Report. The thrift of current guidelines in managing concomitant CHF and COPD is, however, not surprising given that outcomes and therapy of the co-morbidity have not been addressed in any long-term prospective study. Management of these patients is based mainly on clinical expertise and observational data. The scientific contribution from the cardiology side is mostly based on retrospective analyses performed on databases of large randomized controlled trials that are focused on topics that have nothing to do with CHF–COPD co-morbidity. And hence with diagnoses of physician-reported COPD, usually confirmed by spirometry in only a minority of patients, which is a mandatory criterion for COPD diagnosis in international COPD guidelines. The situation is similar for large observational studies focused on HF. For instance, in the previously mentioned recent large European HF registry, the diagnosis of COPD reported by the treating physicians was based on spirometry in only 20% of patients hospitalized for HF and in 31% of ambulatory CHF patients.6 Such diffuse inconsistency in COPD diagnosis leads to a number of complications in the clinical interpretation and use of data collected in cardiology settings. This may cause interdisciplinary communication gaps, in turn generating a fragile environment for sharing clinical research and therapeutic strategies. This reason may be why the 2016 ESC guidelines on HF pragmatically read ‘Both correctly and incorrectly labelled COPD are associated with worse functional status and a worse prognosis in HFrEF’.11 Considering the high prevalence of CHF–COPD co-morbidity and the limitation of available specific treatments – most were investigated for approval 20–30 years ago when CHF–COPD co-morbid patients were generally excluded – CHF–COPD co-morbidity emerges as a macroscopic unmet clinical need, actually ‘an urgent need for integrated care’ as appropriately stated in a recent comprehensive and thoughtful review.12 How do physicians behave in such a complex context with no specific guidance? A survey performed a few years ago across 370 US hospitals collecting 164 494 adults admitted with, treated for, and discharged with a diagnosis of decompensated HF, showed that besides conventional therapy for acute HF 53% of patients received also acute respiratory therapies (short-acting inhaled bronchodilators, antibiotics, high-dose corticosteroids) during the first two hospital days and most of them also afterwards. As expected, respiratory treatment was more frequent among the 60 690 hospitalizations with chronic lung disease, in which treatment with acute respiratory therapy during the first two hospital days was associated with higher adjusted odds of adverse outcomes.13 Hence, in an internal medicine setting, the pragmatic diagnostic and therapeutic approach of the physicians was to try to cover both respiratory and cardiovascular systems possibly involved in the clinical worsening process. The principle of precision medicine is penetrating the complex pathophysiology of heterogeneous diseases such as CHF and COPD, strongly supported by genomics and deep basic pathophysiology investigations. Both clinical and basic researchers are increasingly interested in endotyping both CHF and COPD patients (at the moment not in a combined condition), which is identifying different patient groups with specific disease mechanisms who might respond differently to tailored treatments.14 It looks easy to foresee that this process will lead to a better understanding of the components of the presently nebulous mix of pathophysiological profiles unified under apparent uniform clinical patterns called COPD and CHF. However, it is also easy to foresee that the sets of multiple geno-phenotypes resulting from the disentanglement of such complex clinical entities will compose puzzles that are likely to be difficult to manage in multimorbid patients. Hence, the uncertainty that presently paves the clinicians' way in caring for multimorbid patients might persist longer than expected. Besides these presumably radical innovations expected in coming years, recent technical advances on the clinical front offer a number of potentially powerful opportunities to extend clinical research and clinical care, and increase both general knowledge and manufacturers' interest in the CHF–COPD condition. A technical innovation consists in high-performance mini-portable imaging devices usable by any trained person, including patients, that allow high quality recording of heart and lung (and of any other body area) images by sonographic technique (the minidigital stethoscope) that can be analysed in real time and/or sent remotely as part of a monitoring programme or epidemiological investigation.15 This service can be coupled with other now available portable devices that record spirometry variables and lung diffusion capacity for carbon monoxide outside hospital-based pulmonary lung function laboratories.1 Airflow obstruction and hyperinflation are the most important lung function abnormalities associated with COPD. Among the spirometry metrics, FEV1/FVC under the lower limit of normality and the ratio of FEV1 to slow vital capacity are generally used to indicate airway obstruction.1 DLCO is a measure of carbon dioxide gas diffusion from the alveolar space to the blood. These measurements are generally lacking in patients not diagnosed in a lung disease setting, but are a requisite for COPD diagnosis. The easier and repeatable collection of these findings could also favour the use of such techniques in the cardiology community, filling the present gap between lung and heart disease settings. Importantly, recent data show that in HF patients without evidence of concomitant pulmonary disease and in patients with HFpEF and overt pulmonary hypertension, impaired DLCO can independently predict prognosis.1, 16 Of course, the recording and interpretation of these data by a vast array of non-specialists may expose patients to high risk of misinterpretation of the recorded signals. Accordingly, a close cooperation among professionals with different expertise and experience will be vital for an appropriate implementation of such techniques in clinical practice. A remarkable insight into the management of CHF patients came from a recent study, the CHAMPION trial.17 This study was a prospective, multicentre, randomized, single-blinded clinical trial designed to evaluate the safety and efficacy of pulmonary artery pressure (PAP) monitoring-guided conventional therapy vs. usual care. The aim of the study was to evaluate the clinical efficacy of an invasively implanted PAP sensor (wireless implantable CardioMEMS system), monitored remotely, to guide the usual treatment in New York Heart Association (NYHA) class III CHF patients. Among the 550 patients enrolled, during a mean follow-up of 15 ± 7 months, a 37% reduction in HF hospitalization rates (P < 0.0001) and a 49% reduction in respiratory hospitalization rates (P = 0.0061) were observed.17 Among the patients enrolled, one-third (187 patients) met the criteria for inclusion in a CHF–COPD subgroup (although, once more, just a minority underwent spirometry examination). In this co-morbid subgroup, the treatment group had a 41% reduction in HF hospitalization rates (P = 0.0009) and a 62% reduction in respiratory hospitalization rates (P = 0.0023).18 The consecutive general use, following the device approval by the US Food and Drug Administration, were carefully monitored. The analysis of the first 2000 consecutive implanted patients found a population of users approximately a decade older compared with the pivotal CHAMPION clinical trial with higher baseline PAP and greater PAP reduction over time.19 Recently, the first 5500 MEMS patients implanted in the USA over the first 3 years of the device's general use were analysed from the safety perspective: 2.8% serious complications (pulmonary artery injury, haemoptysis and death) were recorded and demonstrated the comparable estimated overall adverse event rates with the CHAMPION trial (2.6% with 575 implant attempts).20 Similar to other interventional therapies, a learning curve for the most serious observed complications and technological refinement can be expected. In conclusion, while waiting for a better understanding of and new treatments for CHF–COPD co-morbidity, the findings summarized briefly here open up promising new pathways that will optimize current therapy for CHF–COPD co-morbid patients by remotely monitoring appropriate targets for individual patients.21 This will gain further insight into the pathophysiology of CHF–COPD co-morbidity by using the technology advances faster and more widely and, importantly, move on to a much closer cooperation among cardiologists and pneumonologists. This will be led hopefully by the relative Scientific Societies, as authoritative pneumonologists are strongly advising.12, 22 Conflict of interest: none declared.