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Coronary Artery Disease in Patients with Heart Failure: Incidental, Coincidental, or a Target for Therapy?

Published:February 20, 2014DOI:https://doi.org/10.1016/j.amjmed.2014.01.041
      The prevalence of heart failure in the US and globally continues to increase
      • Heidenreich P.A.
      • Trogdon J.G.
      • Khavjou O.A.
      • et al.
      Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association.
      at a rate faster than the rate at which we expand our knowledge and understanding of this complex entity. Pharmacologic therapies targeting ventricular remodeling have contributed to incremental reductions in morbidity and mortality among ambulatory heart failure patients, primarily among those with reduced ejection fraction.
      • Owan T.E.
      • Hodge D.O.
      • Herges R.M.
      • Jacobsen S.J.
      • Roger V.L.
      • Redfield M.M.
      Trends in prevalence and outcome of heart failure with preserved ejection fraction.
      Unfortunately, the total number of US hospitalizations for heart failure has remained essentially unchanged over the last decade.
      • Chen J.
      • Normand S.L.
      • Wang Y.
      • Krumholz H.M.
      National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998-2008.
      The majority of patients with established heart failure have comorbid obstructive coronary artery disease or traditional coronary heart disease risk factors.
      • Fonarow G.C.
      • Stough W.G.
      • Abraham W.T.
      • et al.
      Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry.
      Great strides have been made in the treatment, overall care patterns, and outcomes of patients with coronary artery disease alone. Thus, translating these well-established aggressive therapies of ischemic heart disease to patients with heart failure holds significant promise. Patients with ischemic etiology for heart failure are at higher risk of adverse outcomes compared to their nonischemic counterparts in both inpatient
      • Mentz R.J.
      • Allen B.D.
      • Kwasny M.J.
      • et al.
      Influence of documented history of coronary artery disease on outcomes in patients admitted for worsening heart failure with reduced ejection fraction in the EVEREST trial.
      and outpatient
      • Bart B.A.
      • Shaw L.K.
      • McCants Jr., C.B.
      • et al.
      Clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy.
      settings. However, whether the additional risk related to coronary artery disease among heart failure patients can be lowered by noninvasive and invasive strategies is unclear and is debated.
      Until recently, the treatment of coronary artery disease and ischemia in heart failure patients has been largely empiric, with the expectation that the benefits demonstrated with therapies in patients with coronary artery disease without heart failure would apply to those with heart failure as well. The most recent iteration of the American College of Cardiology/American Heart Association (ACC/AHA) guidelines highlights this uncertainty but continues to advocate for the routine evaluation and management of coronary artery disease in select heart failure populations (Table).
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      National performance measures for comorbid coronary artery disease apply across cardiovascular populations, including those with heart failure. In the last decade, however, a number of landmark clinical trials have provided critical data mandating re-examination of coronary artery disease management in heart failure patients.
      • Gheorghiade M.
      • Sopko G.
      • De Luca L.
      • et al.
      Navigating the crossroads of coronary artery disease and heart failure.
      TableACC/AHA Guideline Recommendations Regarding CAD Management in Patients with Heart Failure
      Heart Failure PopulationRecommendationClassLevel of Evidence
      Initial evaluationInitial laboratory evaluation with serum lipid profileIC
      Coronary arteriography should be performed in patients presenting with HF who have angina or significant ischemia unless the patient is not eligible for revascularization of any kind.IC
      Coronary arteriography is reasonable for patients presenting with HF who have chest pain that may or may not be of cardiac origin who have not had evaluation of their coronary anatomy and who have no contraindications to coronary revascularization.IIAC
      Coronary arteriography is reasonable for patients presenting with HF who have known or suspected coronary artery disease but who do not have angina unless the patient is not eligible for revascularization of any kind.IIAC
      Noninvasive imaging to detect myocardial ischemia and viability is reasonable in patients presenting with HF who have known coronary artery disease and no angina unless the patient is not eligible for revascularization of any kind.IIAB
      Noninvasive imaging may be considered to define the likelihood of coronary artery disease in patients with HF and LV dysfunction.IIBC
      Stage A
      Patients at high risk for developing heart failure.
      In patients at high risk for developing HF, lipid disorders should be treated in accordance with contemporary guidelines.IA
      In patients at high risk for developing HF who have known atherosclerotic vascular disease, health care providers should follow current guidelines for secondary prevention.IC
      Stage B
      Patients with cardiac structural abnormalities or remodeling who have not developed heart failure symptoms.
      Coronary revascularization should be recommended in appropriate patients without symptoms of HF in accordance with contemporary guidelines.IA
      Stage C
      Patients with current or prior symptoms of HF.
      Coronary revascularization is reasonable in patients with HF and normal LVEF and coronary artery disease in whom symptomatic or demonstrable myocardial ischemia is judged to be having an adverse effect on cardiac function.IIAC
      Statins are not beneficial as adjunctive therapy when prescribed solely for the diagnosis of HF in the absence of other indications for their use.IIIA
      Physicians should recommend coronary revascularization according to recommended guidelines in patients who have both HF and anginaIA
      HF with concomitant disordersPhysicians should prescribe antiplatelet agents for prevention of MI and death in patients with HF who have underlying coronary artery disease.IB
      Patients with coronary artery disease and HF should be treated in accordance with recommended guidelines for chronic stable angina.IC
      ACC = American College of Cardiology; AHA = American Heart Association; CAD = coronary artery disease; HF = heart failure; LVEF = left ventricular ejection fraction; MI = myocardial infarction.
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      Patients at high risk for developing heart failure.
      Patients with cardiac structural abnormalities or remodeling who have not developed heart failure symptoms.
      Patients with current or prior symptoms of HF.

      Select Targets

      Traditional metrics and risk factors used to guide the treatment of coronary artery disease may not be applied readily to patients with heart failure. Serum lipid levels are inversely associated with outcomes in hospitalized patients and outpatients with heart failure.
      • Greene S.J.
      • Vaduganathan M.
      • Lupi L.
      • et al.
      Prognostic significance of serum total cholesterol and triglyceride levels in patients hospitalized for heart failure with reduced ejection fraction (from the EVEREST Trial).
      Higher body mass index is associated with improved mortality and hospitalization risk, even in patients with relatively early-stage heart failure.
      • Ballo P.
      • Betti I.
      • Barchielli A.
      • et al.
      Body mass index, gender, and clinical outcome among hypertensive and diabetic patients with stage A/B heart failure.
      Similarly, systolic blood pressure represents a strong inverse predictor of postdischarge outcomes in patients hospitalized for heart failure at the time of admission
      • Gheorghiade M.
      • Abraham W.T.
      • Albert N.M.
      • et al.
      Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure.
      and after stabilization.
      • Ambrosy A.P.
      • Vaduganathan M.
      • Mentz R.J.
      • et al.
      Clinical profile and prognostic value of low systolic blood pressure in patients hospitalized for heart failure with reduced ejection fraction: insights from the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial.
      Prostaglandins and prostacyclins, potent vasodilatory hormones that are inhibited by aspirin, may counterbalance the negative effects of circulating neurohormones in patients with heart failure.
      • Schrier R.W.
      • Abraham W.T.
      Hormones and hemodynamics in heart failure.
      The presence of viable, but dysfunctional, myocardium has not been independently associated with outcomes in patients with heart failure and severely reduced ejection fraction, when adjusted for other comorbidities.
      • Bonow R.O.
      • Maurer G.
      • Lee K.L.
      • et al.
      Myocardial viability and survival in ischemic left ventricular dysfunction.
      Similarly, inducible myocardial ischemia as assessed by noninvasive stress testing and quantification of jeopardized myocardium has not been universally predictive of adverse clinical end points in this population.
      • Panza J.A.
      • Holly T.A.
      • Asch F.M.
      • et al.
      Inducible myocardial ischemia and outcomes in patients with coronary artery disease and left ventricular dysfunction.

      The Treatments

      A number of effective pharmacotherapies in the current chronic heart failure armamentarium target coronary artery disease. In fact, mainstays of chronic heart failure regimens, including angiotensin-converting enzyme (ACE) inhibitors and beta-blockers, have been shown to reduce rates of myocardial infarction and cardiovascular death in patients with chronic heart failure.
      • Al-Gobari M.
      • El Khatib C.
      • Pillon F.
      • Gueyffier F.
      Beta-blockers for the prevention of sudden cardiac death in heart failure patients: a meta-analysis of randomized controlled trials.
      • Flather M.D.
      • Yusuf S.
      • Kober L.
      • et al.
      Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group.
      Thus, a component of the observed benefit of these life-prolonging agents may be anti-ischemic, in addition to their more recognized role in myocardial remodeling. This commentary will focus on the debated role of 3 specific interventions targeting stable coronary artery disease in heart failure: lipid-lowering therapies, antiplatelet agents, and revascularization.

      Lipid-lowering Therapy

      In national inpatient heart failure registries, rates of use of statins are approximately 40%, regardless of ejection fraction.
      • Fonarow G.C.
      • Stough W.G.
      • Abraham W.T.
      • et al.
      Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry.
      Lipid-lowering therapy does appear to be of value in preventing or prolonging onset of heart failure in high-risk patients.
      • Pedersen T.R.
      • Kjekshus J.
      • Berg K.
      • et al.
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). 1994.
      Consistently, statins appeared to be of benefit among heart failure patients in observational studies.
      • Krum H.
      • McMurray J.J.
      Statins and chronic heart failure: do we need a large-scale outcome trial?.
      On the other hand, in patients with chronic heart failure and reduced ejection fraction, 2 large clinical trials evaluating statin therapy failed to meet primary end points and did not appear to reduce all-cause mortality in patients with heart failure and coronary artery disease.
      • Kjekshus J.
      • Apetrei E.
      • Barrios V.
      • et al.
      Rosuvastatin in older patients with systolic heart failure.
      • Gissi H.F.I.
      • Tavazzi L.
      • Maggioni A.P.
      • et al.
      Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
      However, a recent meta-analysis of available data suggests that statins may reduce the burden of heart failure hospitalizations and contribute to relative improvement in ventricular function.
      • Lipinski M.J.
      • Cauthen C.A.
      • Biondi-Zoccai G.G.
      • et al.
      Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure.
      The Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA) trial further demonstrated a reduction in fatal or nonfatal myocardial infarctions/strokes in heart failure patients treated with rosuvastatin.
      • Kjekshus J.
      • Apetrei E.
      • Barrios V.
      • et al.
      Rosuvastatin in older patients with systolic heart failure.
      Post hoc analyses of these trials suggest that certain biomarkers reflecting underlying inflammatory or profibrotic state may predict favorable statin response, but these studies remain hypothesis generating.
      • McMurray J.J.
      • Kjekshus J.
      • Gullestad L.
      • et al.
      Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): a retrospective analysis.
      • Gullestad L.
      • Ueland T.
      • Kjekshus J.
      • et al.
      Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).

      Antiplatelet Agents

      Rates of utilization of aspirin at the time of admission for heart failure are roughly 40% in unselected heart failure populations.
      • Fonarow G.C.
      • Stough W.G.
      • Abraham W.T.
      • et al.
      Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry.
      Previous concerns about the concomitant use of aspirin with ACE inhibitors, due to a prostaglandin-mediated interaction,
      • Al-Khadra A.S.
      • Salem D.N.
      • Rand W.M.
      • Udelson J.E.
      • Smith J.J.
      • Konstam M.A.
      Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial.
      were mitigated in a subsequent meta-analysis of 4 clinical trials that confirmed mortality benefit of ACE inhibition, regardless of aspirin administration.
      • Teo K.K.
      • Yusuf S.
      • Pfeffer M.
      • et al.
      Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review.
      The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial detected no differences in outcomes among patients randomized to aspirin, clopidogrel, or warfarin.
      • Massie B.M.
      • Collins J.F.
      • Ammon S.E.
      • et al.
      Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.
      In fact, a slight increased heart failure hospitalization risk was observed in these trials in the aspirin arm.
      • Massie B.M.
      • Collins J.F.
      • Ammon S.E.
      • et al.
      Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.
      • Cleland J.G.
      • Findlay I.
      • Jafri S.
      • et al.
      The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure.
      It is, at present, unclear whether heart failure patients with comorbid coronary artery disease would benefit from antiplatelet therapies.
      • Gheorghiade M.
      • Vaduganathan M.
      • Fonarow G.C.
      • et al.
      Anticoagulation in heart failure: current status and future direction.

      Revascularization

      Although prompt revascularization after myocardial infarction reduces risk of incident heart failure,
      • Guerci A.D.
      • Gerstenblith G.
      • Brinker J.A.
      • et al.
      A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coronary angioplasty.
      coronary revascularization has not been shown to benefit heart failure patients definitively.
      • Bonow R.O.
      • Maurer G.
      • Lee K.L.
      • et al.
      Myocardial viability and survival in ischemic left ventricular dysfunction.
      • Velazquez E.J.
      • Lee K.L.
      • Deja M.A.
      • et al.
      Coronary-artery bypass surgery in patients with left ventricular dysfunction.
      While it failed to meet its primary end point of a reduction in all-cause death, closer examination of the Surgical Treatment for Ischemic Heart Failure (STICH) trial reveals a 5% absolute reduction in cardiovascular death and a 10% absolute reduction in composite all-cause mortality and hospitalization with bypass surgery over optimal medical therapy at 56-month median follow-up.
      • Velazquez E.J.
      • Lee K.L.
      • Deja M.A.
      • et al.
      Coronary-artery bypass surgery in patients with left ventricular dysfunction.
      In addition, roughly 13% of patients in STICH crossed over between treatment arms, and subsequent analyses of per-protocol and crossover STICH patient populations suggested a mortality benefit favoring coronary artery bypass grafting.
      • Doenst T.
      • Cleland J.G.
      • Rouleau J.L.
      • et al.
      Influence of crossover on mortality in a randomized study of revascularization in patients with systolic heart failure and coronary artery disease.
      A time-varying analysis highlighted late benefit of coronary revascularization, partially balanced by an early hazard of adverse events.
      • Velazquez E.J.
      • Lee K.L.
      • Deja M.A.
      • et al.
      Coronary-artery bypass surgery in patients with left ventricular dysfunction.
      Viability assessment
      • Bonow R.O.
      • Maurer G.
      • Lee K.L.
      • et al.
      Myocardial viability and survival in ischemic left ventricular dysfunction.
      and stress testing to uncover inducible ischemia,
      • Panza J.A.
      • Holly T.A.
      • Asch F.M.
      • et al.
      Inducible myocardial ischemia and outcomes in patients with coronary artery disease and left ventricular dysfunction.
      however, did not appear to identify individuals more likely to benefit from revascularization.

      Is Coronary Artery Disease a Target for Therapy in Heart Failure?

      Coronary artery disease in heart failure represents a challenging substrate for targeted interventions. Adverse remodeling and scar formation from long-term ischemic damage may not be amenable to traditional coronary artery disease management. Similar to other chronic conditions such as chronic kidney disease, there may be a disconnect between traditional markers and risk factors of cardiovascular disease and outcomes in heart failure. This lack of association may pose distinct challenges to drug development, optimal dose finding, and drug monitoring. Furthermore, markers useful in predicting incident heart failure may be distinct from those that inform clinical worsening in existing heart failure. Thus, the efficacy of these interventions may depend on timing of initiation and individual patient risk profiles. Additionally, heart failure patients may be subject to strong competing risks, including worsening heart failure and sudden cardiac death. Interventions focused on reducing burden of coronary artery disease may not show benefit within the limited lifespan of an elderly heart failure patient. In fact, rates of clinically apparent ischemic events in the postdischarge period in patients hospitalized for heart failure are remarkably low,
      • O'Connor C.M.
      • Miller A.B.
      • Blair J.E.
      • et al.
      Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program.
      despite nontrivial cardiac enzyme release in this population.
      • Kociol R.D.
      • Pang P.S.
      • Gheorghiade M.
      • Fonarow G.C.
      • O'Connor C.M.
      • Felker G.M.
      Troponin elevation in heart failure prevalence, mechanisms, and clinical implications.
      Despite neutral primary results from studies examining coronary artery disease interventions in heart failure, certain patient-centered outcomes such as hospitalizations are reduced by lipid-lowering therapy and revascularization. More nuanced approaches for patient selection that diverge from traditional coronary artery disease risk paradigms may be required, including use of biomarker profiles. Important considerations in the decision-making calculus to prescribe or to withhold therapies include time course of benefit, cost-effectiveness, and patient preference. For now, with clinical equipoise, it may be prudent for clinicians to follow general ACC/AHA coronary artery disease guidelines for the treatment of this high-risk heart failure population.
      • Fihn S.D.
      • Gardin J.M.
      • Abrams J.
      • et al.
      2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: Executive summary.
      Antiplatelet therapy and statins should remain a part of comprehensive heart failure management in many patients with heart failure and coronary artery disease, given that they are relatively inexpensive, well tolerated, and widely available. In the absence of definitive evidence, decisions about revascularization in heart failure should be individualized. Clinicians may consider omitting coronary artery disease interventions in select heart failure patients at high short-term risk of progressive heart failure by clinical estimates, those undergoing heart transplant/ventricular assist device placement evaluation, and patients pursuing palliative care options.
      Future clinical trials should evaluate these interventions in important heart failure and coronary artery disease subsets to better determine which patient populations derive the greatest benefit. Ischemic cardiomyopathy has been the focus of novel treatment strategies including stem cell-based therapies. Stem cells may be particularly beneficial in this cardiac substrate given their neovascular growth effects in addition to their regenerative capacity.
      • Jackson K.A.
      • Majka S.M.
      • Wang H.
      • et al.
      Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.
      We are currently awaiting more definitive clinical trial data evaluating stem cells in heart failure and coronary artery disease. Testing coronary artery disease therapies in earlier-stage heart failure populations with less myocardial scar may select patients more likely to benefit. Further data are required to determine whether aggressive coronary artery disease management in contemporary heart failure patients truly alters disease course and progression.

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