The morbidity and mortality of heart failure (HF) patients represent a significant and growing burden for the health care system in Canada.1 The clinical syndrome of HF, whether with preserved ejection fraction or reduced ejection fraction (HFpEF and HFrEF, respectively), has reached epidemic proportions worldwide. At least 600 000 Canadians are living with HF and the clinical burden is increasing every year as the population ages; the epidemic has reached a level that requires system-wide

action and change. Improving uptake of guideline-directed therapy, promoting pragmatic assessment of HF patients, and supporting models of multidisciplinary care have become crucial.2–4 The resources needed to care for this population of patients also drive high healthcare costs; a recent Canadian report estimates that HF-related expenses approximate $3 billion per year.5 These costs are largely attributable to high 30-day readmission rates following HF-related hospitalizations.7,8 The

constantly evolving field of HF requires innovative approaches to delivering appropriate and optimal care within the Canadian healthcare context. In this article, we aim to provide guidance on patient risk stratification, application of guideline-directed medical therapy for HFpEF and HFrEF, and on the selection of appropriate candidates for HF-specific devices and advanced therapies.

reference to their specific population, endpoints, and variables. Risk scores can be helpful for clinicians and whenever possible, should be incorporated into practice, but clinical judgment and acumen remain essential and central to decision making. The Canadian Cardiovascular Society’s (CCS) Heart Failure Guidelines incorporate these prognostic scores into their latest recommendations.21

Heart Failure Prognosis

The general HF population suffers from persistently poor outcomes despite recent therapeutic advances.9 Reported mortality rates vary according to the population studied and are also influenced by adherence to guideline-directed medical therapy.10–13 For example, in Canada, patients hospitalized with HF have a risk of death >30% at 12 months, and the risk of re-hospitalization >20% at 30 days.14 While improved in-hospital mortality and length of stay have recently been reported,15 30-day readmission rates remain high.16 Large observational studies have also suggested that only a modest survival improvement after an initial diagnosis of HF.17,18 This highlights that substantial residual risk persists, despite recent advances in therapy for HF and is likely due to multiple factors, including inadequate medical management, inadequate adherence to guidelines, and suboptimal referral to HF specialists.

Risk Scores and Markers of Risk in Heart Failure Patients

Markers of Risk in Patients with HF

Prognosis is challenging and variable in the HF population. Various markers of risk have been established and a number of disease- specific risk scores are available to aid clinicians in determining prognosis. One meta-analysis involving nearly 40,000 patients with HF identified age, male sex, low EF, NYHA class, creatinine, diabetes mellitus, absence of β-blocker or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment, low systolic blood pressure, lower body mass, longer disease duration, smoking, and chronic obstructive pulmonary as the most significant predictors of mortality.19 Increased markers of cardiac injury and stretch such as hs-cTnT and natriuretic peptides, as well as markers of inflammation such as hsCRP are associated with increased mortality in patients admitted with decompensated HF.20 Natriuretic peptides have become widely accepted biomarkers in HF and have been extensively studied in the prevention, prognosis, diagnosis, and management of HF.21,22

Risk Scores for HF

As noted, several risk scores have been validated using different variables to assess long-term and short-term prognosis in the HF population.19,29–36 Figure 1 illustrates some of these scores with

Pharmacological Therapy for Heart Failure and Reduced Ejection Fraction

Standard newer pharmacologic therapies for HFrEF, developed over the past decade, are associated with improved survival and quality of life in this population. Novel agents, angiotensin receptor neprilysin inhibitors (ARNIs) and sinus node inhibitors (ivabradine) should now be considered in addition to the usual triad of HF medications consisting of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs). The most recent CCS guidelines recommend that most patients with HFrEF should be treated with ‘triple therapy’ at target doses or maximally tolerated evidenced-base doses.21 Diuretics or non-evidenced-based therapies affecting blood pressure and/or renal function should not be left in patients’ medical regimen at the expense of non-optimized guideline-directed medical therapies.

After optimization and appropriate medication titration, persistently symptomatic patients (NYHA II-IV) should be considered for ARNI in place of background ACEi/ARB and for ivabradine when heart rate >70 beats/minute, based on the landmark studies “Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF)37 and the “Systolic Heart failure treatment with the If inhibitor Ivabradine Trial” (SHIFT), respectively.38 Apart from the persistence of symptoms, specific criteria for the replacement of ACEIs/ARBs for ARNIs include an EF ≤ 40% and a washout period of at least 36 hours after cessation of ACEIs to decrease the risk of angioedema.21 When BB therapy is at target dose or maximally-tolerated dose, Ivabradine should be considered in symptomatic (NYHA ≥II) HFrEF patients in sinus rhythm and a resting heart rate >70 beats/minute with an HF hospitalization in the last 12 months. Different heart rate cut-offs have been approved for ivabradine depending on the province in Canada.

Older trials looking at the use of hydralazine and isosorbide dinitrate in HF.39–41 are important components of therapy in the African-American population as an adjunct to standard guideline-directed medical therapy with HFrEF and persistent symptoms.21 In patients with renal failure and/or persistent hyperkalemia, this combination might be considered to replace

ACEIs, ARBs, or ARNIs. To further relieve moderate to severe symptoms and decrease the risk of HF hospitalization, digoxin may be considered for HFrEF patients in sinus rhythm who are persistently symptomatic.21 Digoxin confers no survival benefit and does not decrease other cardiovascular hospitalizations.42

A recent network meta-analysis showed that incremental use of combinations of disease-modifying therapies has

resulted in progressive improvement in all-cause mortality and hospitalization outcomes in HFrEF patients.43 It is important to emphasize that titration of optimal therapy should be completed in a timely fashion, with close monitoring of renal function and hyperkalemia for most HF medications. Efforts also should be made to follow guideline-directed medical therapy, preferably through the parallel support of an HF disease program, and to

involve patients as much as possible in their care to enhance medication adherence.

Pharmacological Therapy for Heart Failure and Preserved Ejection Fraction

In contrast to HFrEF, clinical trials of pharmacologic therapy for HFpEF have not shown significant mortality benefits and there are no current trials that clearly modify the natural history of this condition. Patient care is focused on treatment of comorbid conditions that might contribute to exacerbations, symptom control, and the thorough evaluation of potential etiological factors that may be implicated in the development of HF.21 While there are no drugs that reduce mortality in HFpEF, there is evidence that ARBs and MRAs reduce HF hospitalizations, as shown in the “Candesartan in HF Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved” trial44 and the TOPCAT trial (demonstrating a benefit of spironolactone in the subgroup of patients enrolled in the Americas.45 To date, there is no good quality evidence to support BB or nitrate use in HFpEF, and therefore they should not be used in this population solely based on clinical HF.21 Recently, the “Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF” (PARAGON-HF) trial failed to show a significant reduction in HF hospitalizations or cardiovascular death with sacubitril/valsartan, although several key supportive analyses and secondary endpoints suggest a modest benefit with respect to the quality of life and renal function.46 In subgroup analyses, women and patients in the lower end of the EF range included in the study (45 to 57%) seemed to benefit most from sacubitril/valsartan in terms of cumulative HF hospitalizations or cardiovascular death. Further analysis and understanding of the role of ARNIs in patient subgroups may define the potential role of this therapy for HFpEF.

Associated comorbidities such has hypertension and diabetes should be treated aggressively following the Canadian Hypertension Education Program hypertension guidelines as well as the Canadian Diabetes Association guidelines. The American College of Cardiology and American Heart Association guidelines for hypertension in HFpEF patients with persistent hypertension after the management of volume overload recommended a systolic blood pressure target <130 mmHg.26 Emerging diabetes therapy will be addressed in accompanying articles of this HF series. Diuresis with loop diuretics should be used in these patients to control symptoms of volume overload and pulmonary congestion.21

Indications for Device Therapy

To frame the discussion around device therapy for HF, consider a typical clinical scenario:

A 52-year-old man presents to your office for follow-up of ischemic cardiomyopathy; he suffered an anterior myocardial infarction after watching an intense Habs hockey game 5 months earlier. He underwent PCI of the left anterior descending artery successfully with 3 drug- eluting stents with good results. The proximal circumflex artery had a focal 30-40% stenosis. The right coronary artery was occluded, receiving collaterals from the left coronary circulation. Before discharge from the hospital, he underwent an echocardiogram which showed an EF of 28%. He has never had ventricular arrhythmias.

The patient’s current medications include bisoprolol 7.5 mg daily, sacubitril/valsartan 24/26 mg BID, spironolactone

12.5mg daily, furosemide 20 mg BID, aspirin 81 mg daily, ticagrelor 90 mg BID and atorvastatin 80 mg QHS. There has been no change in the past 3 months. He is NYHA class II and well-compensated. Further titration of his current medical therapy is limited by low blood pressure.

On examination, heart rate is 62 beats per minute and blood pressure is 92/65 mmHg. He is euvolemic with no lower leg edema and clear lung fields.

An electrocardiogram reveals sinus rhythm with a left bundle branch block and a QRS of 139 milliseconds.

A repeat echocardiogram performed 2 days ago showed no improvement in heart function.

Are device therapies indicated in this patient?

Implantable Cardioverter Defibrillator (ICD)

Primary Prevention

Patients with NYHA class II-III with ischemic or non-ischemic HF with an EF <35% and patients with an EF <30% regardless of their NYHA class have improved survival with primary prevention ICD therapy.21 As per current evidence, there is no survival benefit for early ICD implantation (<40 days) after myocardial infarction.47–50 Despite some controversy around ICD use in non-ischemic cardiomyopathy (CMP), a meta-analysis of primary prevention ICDs (including the recent DANISH trial) favored ICD implantation for patients with non-ischemic CMP with a significant reduction of all-cause mortality.51,52 ICDs should not be implanted in NYHA class IV patients who are also not a candidate for advanced therapies such as mechanical circulatory support or heart transplantation.21 Irrespective of indication, decision-making around ICDs must be individualized, and the risks and benefits of this therapy must be carefully discussed with patients in collaboration with device specialists.21,53

Secondary Prevention

In patients with a history of cardiac arrest, sustained ventricular tachycardia, ventricular fibrillation, or unexplained syncope in the presence of an EF <35%, ICDs are indicated to prevent sudden cardiac death and reduce all-cause mortality.21

Cardiac Resynchronization Therapy (CRT)

As demonstrated in systematic reviews, CRT significantly reduces mortality and HF hospitalizations in appropriately selected HFrEF patients with mild to severe symptoms.54–59 CRT may improve left ventricular function in patients with significant electrical conduction delay, typically with left bundle branch block morphology, by resynchronizing the contraction of both ventricles. The benefits of CRT are greatest in those patients with a broader QRS complex, typically >150 milliseconds.60–64 In the latest CCS guidelines, CRT is recommended for patients in sinus rhythm with NYHA II-III or ambulatory IV despite optimal medical therapy, with a left ventricular EF ≤35% and QRS >135 milliseconds with left bundle branch clock morphology.21

persistent or progressing functional impairment and NYHA class III-IV symptoms.21 Adopted from the CCS Guidelines, characteristics that may accompany advanced disease and trigger referral to an HF specialist are shown in Figure 2.

The following “I NEED HELP” acronym taken from the American College of Cardiology expert consensus decision pathway for optimization of HF treatment may be used to guide referral to an HF disease program.65

I:Intravenous inotropes

N:New York Heart Association (NYHA) class III/IV or persistently elevated natriuretic peptides

E:End-organ dysfunction

E:EF ≤35%

D:Defibrillator shocks

H:Hospitalizations >1

E:Edema despite escalating diuretics

L:Low systolic BP ≤90, high heart rate

P:Prognostic medication; progressive intolerance or down-titration of guideline-directed medical therapy

When to Refer for Advanced Therapies and Interventions

Mechanical Circulatory Support (MCS) and Heart Transplantation (HTx)

Appropriate timing of referrals for evaluation of MCS and HTx candidacy is crucial and the key to optimizing the benefits from advanced HF therapies. Advanced therapies also include palliative care involvement and optimization of their quality of life when appropriate.

The specific definition of advanced HF somewhat differs across international guidelines but generally considers patients on optimal medical therapy or maximally tolerated therapy with

The important take-home message when reviewing the above “high-risk features” is that the evaluation of patients should be personalized along with careful clinical judgement, and referral to HF teams should be initiated earlier in the disease course rather than too late.

Role of Disease Management Programs

Multiple trials and meta-analyses have addressed the importance of a “Heart Team” in the multidisciplinary management of HF patients.66–68 The CCS HF guidelines strongly recommend the involvement of interprofessional members (i.e., physician, nurse,

pharmacist) for all outpatient HF clinics and disease management programs, especially for patients with recurrent hospitalizations.21 The benefits of a multidisciplinary management approach include improved symptom control, decreased mortality, and less intensive care utilization.66,68 To transform care delivery, the mandate of a disease management program in HF should be to improve both morbidity and mortality as well as the quality of life in this complex population.69 It has been shown that a multidisciplinary team can safely facilitate transitions of care (in and outpatient services) and reduce the all-cause readmission rates of HF patients.70,71

Additional specific roles of a disease management program as outlined in the CCS Guidelines include assessment of multimorbidity, cognitive impairment, dementia, frailty, and depression; factors that may all impact therapeutic decisions, compliance, follow-up, and prognosis.21

Furthermore, with the evolution of novel device therapies, heart transplantation and mechanical circulatory support options, shared decision-making has become increasingly relevant and patients should become active members of their own personalized interprofessional treating team.70,72 That role extends to patients’ families who can participate in encouraging patient self-care and improving comprehension of the disease through family education.21 When advanced therapies cannot be offered, frequent readmissions to hospital are expected, and medical therapy may no longer be tolerated; the role of the disease management program also includes discussion around advanced directives with patients and their families. In these situations, referral to palliative care specialists should strongly be considered to improve quality of life as the primary focus of care.21

Remote Monitoring

Monitoring of patients’ clinical status at a distance can be performed through various methods and tools such as telephone support, standalone devices at home (e.g., blood pressure monitors), cardiac implantable electronic devices, and wearable technologies (e.g., smartwatches). A Cochrane review based primarily on small studies showed a 44% reduction of all-cause mortality and a 21% reduction in HF hospitalizations.73 However, the Tele-HF trial showed no difference for the primary outcome of death or HF hospitalization at 180 days between usual care and telephone- based monitoring for HF.74 Despite these conclusions, telephone support remains a central part of care in disease management programs, mainly performed by specialized HF nurses for patients who have recently been hospitalized or for those who require closer monitoring. Standalone devices are often used by patients and many studies and trials have looked at the potential beneficial use of this type of data acquisition and sharing it via telephone, internet or mobile communication.75 The results of these studies are controversial, and few of them demonstrated

decreased all-cause mortality or reduced days lost due to death or hospitalizations,76 whereas others failed to find any difference in outcomes.77–79 or had mixed results.80

Remote monitoring of patients with HF continues to generate interest as new strategies to improve the rapid detection of decompensation, rates of hospitalizations, as well as compliance and optimization of medical therapy have been developed.75 The Heart Failure Society of America published a white paper on remote patient monitoring in which the authors advised against the routine use of external monitoring devices, as there were no consistent benefits in large randomized trials.81 Implanted devices, including monitors of pulmonary artery pressure (CardioMems), have shown improved patient outcomes in a small number of studies and may be beneficial for carefully selected patients.82 Further studies are required to explore the role and potential benefits of novel remote monitoring technologies in practice, with particular attention to both clinical and cost-effectiveness.

Future Directions

The management of HF is constantly evolving as newer therapies arise. Knowledge translation in HF care, as well as a better understanding of patients’ perspective of their disease, are persistent gaps that require further attention. Multidisciplinary recognition and management of HF comorbidities is another important aspect of care requiring better integration into disease management programs. With the advent of so many novel therapeutic strategies improving patient survival and quality of life, this is indeed an exciting time for the care of HF patients.

Conflicts of Interest

Dr. Boulet: None.

Dr. Giannetti: Honoraria: AstraZeneca, BMS/Pfizer Alliance, Medtronic, Novartis, Pfizer, Servier, Abbott Clinical Trials: Novartis, Servier, Amgen, Boehringer Ingelheim.

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