Management of Comorbidities in Heart Failure

Patients with heart failure (HF) often have multiple comorbid conditions that may interact with the syndrome of HF and/or the choice of therapies. Research into the common comorbid conditions has furthered the understanding of the pathophysiologic basis for symptoms or structural abnormalities of HF, aided in the refinement of the often-complicated management because of the competing therapies, and provided clarity regarding the diagnostic certainty (or uncertainty) as a result of competing causes for signs and symptoms of disease. In clinical practice, this is seen on a day-to-day basis, and thus understanding the management of HF requires consideration of all aspects of human health.

In most chronic HF registry, administrative, or trial data, the number of comorbid conditions exceeds five (including other related components of cardiovascular disease [e.g., atrial fibrillation]) for many patients. From the major registry data, the most common comorbid conditions and their approximate prevalence are depression (22%), chronic obstructive pulmonary disease (COPD) (20%–30%), diabetes (30%), and sleep-disordered breathing (40%). Other important cardiovascular conditions that interact with HF, such as atrial fibrillation ( see Chapter 38 ) or coronary artery disease ( see Chapter 19 ), are discussed elsewhere.

Importantly, although all of these comorbid conditions have a significant impact on prognosis, the specific treatment of the comorbid condition has generally not been shown to improve major clinical outcomes. For example, treating depression with sertraline did not lead to a reduction in cardiovascular events. This creates a unique situation for clinicians caring for patients with HF because they require expert management beyond the disease-disease and drug-drug interactions. Each disease (HF and a comorbid condition) can exacerbate or be a trigger for the other, or complicate the treatment course because therapies typically used for the comorbid condition of interest may indeed exacerbate HF (e.g., etanercept for rheumatoid arthritis). Likewise, some therapies can be used for both, allowing for rational selection of therapy (e.g., angiotensin-converting enzyme [ACE] inhibitors for HF and diabetes) or potentially synergistic effects (continuous positive airway pressure [CPAP] for sleep apnea may induce better control of atrial fibrillation and HF symptoms). Thus the interaction is often far more complex than first anticipated, and clinicians should be aware and ask five simple questions when faced with this situation ( Table 48.1 ). However, each situation will be unique, and where possible, an informed choice can be made by integrating information from the published literature, patient preferences, and in consultation with other health professionals.

TABLE 48.1

Five Questions to Ask When Reviewing the Comorbid Condition in a Patient With Heart Failure

	Question	Considerations	Example
1.	Does the comorbid condition affect the characteristics of a test used to diagnosis or manage HF?	Test sensitivity or specificity modified due to known or unknown confounders because of the comorbid condition.	BNP levels in patients who are obese are lower than nonobese patients.
2.	Does HF affect the characteristics of a test used to diagnosis or manage a comorbid condition?	HF may modify the underlying pathophysiology upon which the test is based.	Pulmonary function tests can be abnormal for patients with HF even in the absence of COPD.
3.	Did this comorbid condition or its related therapies “cause” or exacerbate HF in this patient?	Some disease-disease links are strong, whereas others are putative.	Diabetic cardiomyopathy; anthracyclines for cancer
4.	Does the comorbid condition modify the options for treatment of HF?	Some therapies used in HF need to be carefully selected so as not to worsen a comorbid condition.	The risk/benefit of ACE inhibitors in end-stage renal disease; volume management with diuretics in COPD; appropriateness of cardiac resynchronization therapy in advanced COPD
5.	Should we modify the management of the comorbid condition due to the presence of HF?	Known risks for some therapies may include exacerbating HF.	Etanercept for rheumatoid arthritis; Herceptin for breast cancer

ACE, Angiotensin-converting enzyme; BNP, B-type natriuretic peptide; COPD, chronic obstructive pulmonary disease; HF, heart failure.

Anemia and Iron Deficiency

Definitions, Prevalence, and Outcomes

Anemia is defined by the World Health Organization as a hemoglobin less than 13.0 g/dL in men and less than 12.0 g/dL in women. Additional other definitions are available, including those of the Centers for Disease Control and Prevention (<13.0 g/dL in men and <12.5 g/dL in women) and National Kidney Foundation (<13.5 g/dL in males and <12.0 g/dL in females) or by diagnosis (chart abstract coding) of anemia. Using these definitions, the prevalence of anemia in patients with chronic HF has been found to be vary substantially based on the location or context surveyed, severity of illness, age, gender, race, and whether or not they were patients with acute or chronic HF. Given the limitations listed previously, the prevalence is approximately 15% to 20% and approximately 30% to 50% in either acute HF populations or specialized clinics, summarized elsewhere.

More recently, there has been a better understanding that iron deficiency may be more important than the hemoglobin itself. Table 48.2 highlights the definitions for iron deficiency, with a recognition that the most common definition in clinical trials is a ferritin less than 100 ng/mL, or iron saturation less than 20% if the ferritin ranges from 100 to 300 ng/mL.

TABLE 48.2

Diagnostic Assays of Clinical Use for the Cause of Anemia

Category	Etiology	Test	Possible Results	Other Notes
General		Peripheral smear	Microcytic, normocytic, or macrocytic	Nondiagnostic but helpful for further testing
		Reticulocyte count/index	RI 1%–2% = normal; RI <2% with anemia = blood loss or inadequate bone marrow response; RI >3% bone marrow compensation	Helpful for determining bone marrow response to therapy
		Bone marrow biopsy	Variable	Invasive; often used for diagnosis in selected diseases
Blood loss	Gastrointestinal	Endoscopy	Ulcers, erosions, masses, polyps	Consider all antiplatelet, anticoagulant, and NSAID use
		Fecal occult blood	Positive compatible with IDA or blood loss	Consider further testing to identify source
Nutritional deficiency	Folate	Serum folate	<4 ng/mL	Can drop in acute illness
		RBC folate	Variable based on assay	Indicative of folate deficiency
		Serum B ₁₂	<200 pg/mL	May need additional testing for pernicious anemia
	Iron	Serum transferrin saturation	<20% compatible with IDA
		Ferritin	<50 ng/mL compatible with IDA	Can be elevated due to inflammation in HF
Sickle cell		Hemoglobin electrophoresis	HbSS, HbSC
Thalassemia		Hemoglobin electrophoresis	% αβδ Hb
Other		Ultrasound of kidneys, liver, spleen	Medicorenal disease; cirrhosis; splenomegaly

Hb, Hemoglobin; HF, heart failure; IDA, iron deficiency anemia; NSAID, nonsteroidal antiinflammatory drug; RBC, red blood cell; RI, reticulocyte index.

Anemia has been associated with poor clinical outcomes. The within-person changes to hemoglobin over time may have additional importance. In the Valsartan Heart Failure trial (Val-HEFT), 16.9% of patients developed new-onset anemia, and a decline in hemoglobin over 12 months was strongly related to subsequent clinical outcomes even after adjusting for prognostic markers such as B-type natriuretic peptide (BNP) and estimated glomerular filtration rate (eGFR). Most of the studies of patients with anemia and HF highlight a 1.5- to 2-fold increase in short- and long-term mortality even after adjustment for other clinical variables.

Diagnosis of Anemia

The diagnosis of anemia is a combination of symptoms, signs, and biomarkers related to the hematopoietic system. Given the substantial overlap of symptoms of HF and anemia (e.g., fatigue, shortness of breath), there are no specific symptoms that appear to aid diagnosis. Similarly, given the lack of specificity of physical signs of anemia, there are no additional signs to aid in the diagnosis of anemia in a patient with HF.

The biomarkers for diagnosing and exploring the cause or subtype of anemia are multiple and well developed (see Table 48.2 ). They are aimed at diagnosing the most common conditions (nutritional deficiency or blood loss), ruling out other related diseases (bone-related malignancy, thyroid disease, sickle cell anemia, thalassemia), or establishing a diagnosis of anemia of chronic disease related to HF. Most patients will require some combination of the testing and repeat testing if an intervention is done (e.g., iron therapy should be followed by a repeat hemoglobin, iron saturation, and ferritin).

Given the variety of causes for anemia, targeted diagnosis and therapy are important ( Fig. 48.1 ). However, many patients (up to 46%l in one series ) may have hemodilution as a cause of their anemia, so judicious measurement of hemoglobin after euvolemia is attained is essential when evaluating patients with anemia.

Fig. 48.1, Possible mechanisms involved in the genesis of anemia in heart failure.

Treatment

Once a clear or working diagnosis is obtained, therapy will be targeted to the potential cause. The general approach to the treatment of anemia is beyond the scope of this chapter; thus the remainder of this section will focus on the results of randomized controlled trials (RCTs) that specifically enrolled patients with HF.

Iron therapy has remained the mainstay of therapy for iron deficiency anemia. Many guidelines recommend a trial of oral iron therapy, although this had not been subjected to rigorous study in patients with cardiovascular disease until the Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUT-HF) trial. In this trial, 225 patients with left ventricular ejection fraction (LVEF) less than 40% and iron deficiency were randomized to 150 mg of iron polysaccharide or placebo for 16 weeks. There was no difference between groups in 6-minute walk test, quality of life, N-terminal pro – B-type natriuretic peptide (NT-proBNP), or exercise capacity. Intravenous iron injections have recently been the subject of RCTs. The Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial assessed patients with New York Heart Association (NYHA) class II or III, LVEF of less than or equal to 45%, and a hemoglobin between 95 and 135 g/dL, with iron deficiency anemia (ferritin <100 μg/L or was between 100 and 299 μg/L and transferrin saturation <20%). For the primary end point at 24 weeks of Patient Global Assessment (PGA) and compared with a placebo, patients randomized to intravenous iron (and titrated to iron indices) had a twofold chance of improving (by PGA or one NYHA class). Similar positive outcomes were seen for the EQ-5D, KCCQ (Kansas City Cardiomyopathy Questionairre), and 6-minute walk test without any significant safety signal (or efficacy for clinical events) ( Fig. 48.2 ). Three other trials have had similar results, summarized elsewhere, and there are ongoing studies ( clinicaltrials.gov : NCT00384657 , NCT01453608 , NCT03037931 ). Adequately powered RCTs such HEART-FID are required to assess if important clinical outcomes are altered. In the interim, it appears that intravenous iron is a reasonable therapeutic choice for carefully selected patients with the goal of improving symptoms.

Fig. 48.2, Ferinject assessment in patients with iron deficiency and chronic heart failure trial results.

Erythropoiesis-stimulating agents (ESAs), including erythropoietin and darbepoetin, are used in patients with chronic kidney disease to increase the hemoglobin level. In the RED-HF trial, 2278 patients with a LVEF less than or equal to 40%, NYHA II-IV, and a hemoglobin between 9.0 and 12.0 g/dL were randomized to darbepoetin or a placebo and a target hemoglobin of 13.0 g/dL and followed for a median of 28 months. Overall, there was no meaningful difference between the groups for important clinical outcomes, including quality of life, symptoms, death, or rehospitalization; thus there was no additional benefit in a strategy of increasing hemoglobin via an ESA for clinical outcomes.

Summary/Conclusions

Ongoing trials of intravenous iron replacement for anemic patients or as an agent to improve clinical outcomes even in nonanemic patients are key steps in understanding if the correction of anemia can alter clinical outcomes. Key interactions between the bone marrow, the hematologic system, and the vasculature have both shed light on the mechanisms of anemia and helped in the understanding of other pathophysiologic roles of new molecules (e.g., hepcidin), “old” systems (e.g., renin-angiotensin-aldosterone), or new targets (iron receptors).

Chronic Obstructive Pulmonary Disease

Definitions, Prevalence, and Outcomes

The diagnosis of COPD is done by a combination of clinical history and physical examination findings and is confirmed by spirometry. The most commonly used criteria are the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria that define COPD as a postbronchodilator fixed ratio of FEV ₁ /FVC of 0.70 or less ( Table 48.3 ). Both obstructive and restrictive components of COPD are recognized as important and can coexist.

TABLE 48.3

Classification of Chronic Obstructive Lung Disease

Adapted from Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med . 2007;176(6):532–555.

Stage	FEV ₁ /FVC	Predicted FEV ₁
Stage I: mild	<0.70	>80%
Stage II: moderate	<0.70	50%–79%
Stage III: severe	<0.70	30%–49%
Stage IV: very severe	<0.70	<30% or <50% plus chronic respiratory failure ^a

FEV ₁ , Forced expiratory volume in 1 second; FVC, forced vital capacity.

a Respiratory failure: arterial partial pressure of oxygen (Pa o ₂ ), 8.0 kPa (60 mm Hg) with or without arterial partial pressure of CO ₂ (Pa co ₂ ). 6.7 kPa (50 mm Hg) while breathing air at sea level.

Given the significant overlap in symptoms, such as shortness of breath, fatigue, and other descriptors, studies have not shown that the two diseases can be distinguished based on symptoms. Studies using the Framingham or other diagnostic symptom-based criteria are less useful given this overlap and can provide erroneous estimates of incidence, prevalence, or outcome relationships. Similarly, the physical signs of HF may overlap, and specifically right ventricular failure signs may be evident in both diseases related to secondary pulmonary hypertension and direct myocardial effects. The overlap is summarized elsewhere.

As a comorbidity in community-based surveys, COPD is present in up to one-third of outpatients, distributed relatively between those with a reduced or preserved ejection fraction. Importantly, many RCTs of current evidence-based therapy excluded COPD or other respiratory disorders, so estimates of prevalence from RCTs should be evaluated cautiously. Hence, establishing the diagnosis of COPD in a patient with HF, or HF in a patient with COPD, requires clinical vigilance, understanding the overlapping risk factors (e.g., smoking), and testing for both diseases.

Pulmonary Function Tests and Heart Failure

Pulmonary function tests (PFTs) and spirometry involve establishing the key parameters of FEV ₁ , FVC, lung diffusion of carbon monoxide (DLCO), and peak expiratory flow rate. As discussed previously, the diagnosis of COPD may be evident as per the GOLD criteria, but there are limitations to consider. For example, interstitial edema may cause partial obstruction and increased bronchial sensitivity leading to an obstructive pattern on PFTs. This may partially or fully resolve after a patient diuresis if they were acutely ill. Interestingly, peak expiratory flow has recently been assessed for its use as a clinical end point for RCTs of acute HF therapy given the relatively dynamic change seen over the first 24 hours of therapy. Restrictive defects are also commonly evident and may be caused by underlying lung disease, respiratory muscle weakness, secondary drug effects (e.g., amiodarone), or concomitant diseases (e.g., sarcoidosis).

The diffusion capacity is measured by the DLCO and reflects both the ability of gases to go across the membrane and the volume of blood in the capillary bed. It can change acutely and is linked to abnormal lung mechanics and severity of HF and should be interpreted with caution. Nevertheless, PFTs should be done once the patient is clinically stable and preferably once adequately diuresed if the comorbid condition of COPD is being considered.

Treatment

Heart Failure–Related Treatment in Patients With COPD

The mainstay of therapy, including renin-angiotensin-aldosterone axis agents (e.g., ACE inhibitors, angiotensin receptor blockers [ARBs], mineralocorticoid receptor antagonists [MRAs]), have all been shown to be effective in patients with lung disease in the large RCTs and should be initiated and titrated accordingly. Other therapies, including defibrillators, cardiac resynchronization therapy, digoxin, nitrates, and diuretics, have limited data because of the limited enrollment in trials, and thus the results of RCTs should be applied with that caveat.

Beta-blockers and COPD have been controversial in terms of their use, effect on respiratory function, and clinical outcomes. Most of the earlier beta-blocker RCTs excluded patients with known COPD, given the concern of beta-receptor stimulation versus blockade in patients with reactive airways disease. As such, the RCT experience is limited, but no overt “risk” has been seen, and the small subgroups have shown a preserved (although underpowered) treatment effect in the larger RCTs. Large population-based analyses have shown that, after propensity matching, beta-blockers were associated with a reduced risk of mortality when used in patients with COPD and concomitant HF.

A small mechanistic trial of patients with severe COPD (baseline FEV ₁ = 1.3 L) tested the beta ₁ -selective beta-blocker bisoprolol versus a placebo on the FEV ₁ and noted a significant, small reduction in FEV ₁ but no alteration of the reversibility following beta-agonists and overall lung volumes and no negative symptoms, impairment of quality of life, or clinical events. One conclusion, given the limited sample size and large treatment effect in other populations, is that this reduction in FEV ₁ is of minimal clinical importance and overweighed by the potential reduction in clinical events related to HF. Thus selection of a beta ₁ -selective beta-blocker with clinical trial evidence is limited to that of bisoprolol and metoprolol succinate, and could be considered in preference to carvedilol in this select population.

New agents such as ivabradine may be an option for patients with concomitant COPD who are unable to tolerate a beta-blocker. In the SHIFT trial, 10% of patients with a clear indication for a beta-blocker were not on any beta-blocker, and of these, one-third identified COPD as the principal reason. In addition, in multivariable analysis, COPD was associated with being on a beta-blocker at less than 50% of target dose (odds ratio 0.67; 95% confidence interval [CI] 0.55–0.80), and the effects of ivabradine versus placebo were still preserved. This indicates that for many patients with concomitant COPD and HF, ivabradine may be an option for reducing morbidity or mortality.

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