Disease Background

Heart failure is a condition that results from the inability of the heart to meet the body’s metabolic demands for oxygen because of structural or functional impairment of ventricular filling or ejection of blood.¹ The underlying etiologies include disorders of the pericardium, myocardium, endocardium, heart valves, or great vessels or certain metabolic abnormalities.¹ The primary symptoms of HF are dyspnea and fatigue and may also include fluid retention. Patients report that HF can have a profound impact on their physical, social, and emotional well-being, which dramatically affects their lives and the lives of their family caregivers. Their condition requires daily monitoring, adherence, and vigilance by patients to control the delicate balance of symptoms.

There are an estimated 669,000 Canadians older than 40 years with HF, with an age-standardized prevalence of 3.5%.² Between 2001 and 2013, the HF incidence rate in Canada has declined, as has the age-standardized all-cause mortality rate among people living with HF.² However, Canadians 40 years or older with HF are 6 times more likely to die than those without an HF diagnosis.² The economic burden due to HF is substantial, with costs associated with health care services, medications, and lost productivity. Hospitalizations due to HF are frequent, with 83% of patients hospitalized at least once, and 43% hospitalized 4 or more times after HF diagnosis.¹ Approximately half of those with HF have a reduced LVEF (≤ 40%); it is in this population that the evidence base regarding treatment is better established.¹

Standards of Therapy

The following text was based on input from clinicians consulted by CADTH for the purpose of this review.

The current paradigm of treating individuals with HFrEF is to focus on lifestyle modifications, drug therapy, and device implantation to reduce the burden of morbidity and mortality. Additionally, management of underlying comorbidities (e.g., diabetes, thyroid disease, anemia) should continue as per guidelines.

The lifestyle modification primarily focuses on adherence to salt and water restriction and exercise rehabilitation. The medication treatments include the use of beta-blockers, ACEIs, or ARBs, plus a mineralocorticoid receptor antagonist as the foundational therapy. If individuals are still symptomatic, then sacubitril-valsartan can replace ACEIs or ARBs, or ivabradine can be considered (if the heart rate is greater than 77 beats per minute and patients are not in permanent atrial fibrillation). Additional pharmacotherapies include hydralazine, nitrates, or digoxin. Diuretics are frequently prescribed to manage fluid status. Cardiac resynchronization device implantation may be indicated for individuals with left bundle branch block, and if patients have persistently reduced LVEF, an implantable cardioverter-defibrillator can be considered. Currently, SGLT2 inhibitors are recommended by Canadian guidelines, despite being off label in patients with HFrEF without type 2 diabetes.⁹

The main goals of treatment are to prolong life, improve quality of life, help patients maintain independence, avoid hospitalizations, and reduce caregiver burden, while minimizing the risk of adverse effects from treatment.

Drug

Dapagliflozin belongs to the SGLT2 inhibitor class of drugs, although its mechanism of action in HF is not known. Dapagliflozin is approved by Health Canada for use in adults, as an adjunct to standard of care therapy, for the treatment of HFrEF to reduce the risk of CV death, hospitalization for HF, and urgent HF visit.³ The sponsor requested reimbursement as per the indication.¹⁰

Dapagliflozin was previously approved in Canada as an adjunct to diet and exercise (as monotherapy or combination therapy) to improve glycemic control in adult patients with type 2 diabetes mellitus.³ It is also approved as an adjunct to diet, exercise, and standard of care therapy to reduce the risk of hospitalization for HF in adults with type 2 diabetes mellitus and CV risk factors or established CV disease. Dapagliflozin and dapagliflozin-metformin fixed-dose combination tablets were reviewed by CADTH in 2015 and 2016 for reimbursement in patients with type 2 diabetes to improve glycemic control.^4–6

Dapagliflozin is available as a 5 mg or 10 mg oral tablet. The recommended dosage for patients with HFrEF is 10 mg once daily, in conjunction with other HF therapies.³

Table 4

Key Characteristics of Dapagliflozin.