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b-Blockers |
Since the 2017 comprehensive update of the CCS guidelines for the management of HF, no large randomized clinical trials of b-blockers in patients with HFrEF have been published. Previous landmark trials of carvedilol, sustained release metoprolol succinate, and bisoprolol27 have shown unequivocal reductions in mortality and hospitalization, and improvement in HF symptoms among patients with HFrEF and New York Heart Association (NYHA) functional class II-IV symptoms at baseline. In a meta-analysis of more than 10,000 patients, b-blockers prevented 3.8 deaths and were associated with 4 fewer hospitalizations per 100 patients in the first year of treatment. |
For patients admitted to hospital with worsening HF, b-blocker initiation, before discharge in stabilized patients, has been associated with improved short and intermediate-term outcomes without intolerance or extended length of hospital stay. Available evidence also strongly suggests that patients with HFrEF receiving b-blockers at the time of admission for acute HF have higher rates of death and recurrent HHF when b-blockers are not resumed before discharge. |
A recent meta-analysis of 5 observational studies and 1 randomized trial confirmed this association; b-blocker withdrawal in the setting of HHF increased the risk of in-hospital mortality (RR, 3.72 [95% CI 1.51-9.14]), mortality at 60-180 days (RR, 1.78; [95% CI 1.13-2.79]), and combined short term rehospitalization or mortality (RR, 1.84; [95% CI 1.08-3.1]).35 The totality of available evidence suggests that b-blockers should be continued or reinitiated before discharge in those with HFrEF who are hospitalized for worsening HF, whenever clinically feasible. |
In addition to including b-blockers as part of standard medical HFrEF therapy, the following recommendations on b-blocker use in HFrEF have remained unchanged from the 2017 comprehensive update of the CCS guidelines for the management of HF. |
Practical tip. Objective improvement in cardiac function might not be apparent for 6-12 months after b-blocker initiation. The absence of LVEF recovery is not justification to stop treatment. |
Practical tip. Treatment of patients with NYHA class I or II symptoms can be safely initiated and titrated with a b-blocker by nonspecialist physicians. |
Practical tip. Patients with NYHA class III or IV symptoms should have b-blocker therapy initiated by a specialist experienced in HF management and titrated in the setting of close follow-up, such as can be provided in a specialized clinic, if available. |
Practical tip. b-Blockers should be started at low doses and increased slowly (eg, double the dose every 2-4 weeks). Transient fluid retention might occur with initiation or uptitration of b-blockers and might require assessment of diuretic dosage (eg, might consider deferring dosage reduction). |
Practical tip. If concomitant reactive airways disease is present, consider using more selective b-1 blockade (eg, bisoprolol). |
Practical tip. If atrioventricular (AV) block is present, consider decreasing other AV node-blocking drugs, such as digoxin or amiodarone (when appropriate). The type and severity of AV block and the patient’s history of arrhythmia will help guide the most appropriate treatment modifications. |
RECOMMENDATION |
7. We recommend that b-blockers be initiated as soon as possible after the diagnosis of HF, including during the index hospitalization, provided that the patient is hemodynamically stable. Clinicians should not wait until hospital discharge to start b-blocker treatment in stabilized patients |
(Strong Recommendation; High-Quality Evidence). |
8. We recommend patients with NYHA class IV symptoms be stabilized before initiation of b-blocker treatment |
(Strong Recommendation; High-Quality Evidence). |
9. We recommend that b-blockers be initiated in all patients with an LVEF < 40% with previous MI |
(Strong Recommendation; Moderate-Quality Evidence). |
MRAs |
MRA use in patients with HFrEF. Despite access to MRA therapy for the treatment of HF, and despite established guideline recommendations to initiate MRAs as part of standard therapy (along with RASi and b-blocker medications), there remains uncertainty or reluctance for widespread use. A report of the recent US CHAMP-HF registry showed that MRA was used in only 33.4% of patients with HFrEF without documented contraindication. On the basis of data from the Randomized Aldactone Evaluation Study (RALES), the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), there are 3 clinical scenarios in which mineralocorticoid receptor antagonism in the absence of significant renal dysfunction or hyperkalemia are supported by randomized control trial evidence: (1) LVEF 35% and NYHA class III-IV symptoms; (2) post MI with signs and symptoms of acute HF and LVEF 40%, or post MI with diabetes and LVEF 40% (regardless of HF symptoms); and (3) LVEF 30% (or if LVEF 31%-35% with QRS > 130 ms), NYHA class II symptoms, and another high risk feature (eg, age > 55 years, HHF within the previous 6 months, or elevated natriuretic peptide levels). |
A more generalized role for MRAs in HF management is further supported by contemporary trials that have shown a consistent benefit of newer therapies for which background treatment with MRAs has been > 50% among patients enrolled. Moreover, in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial HHF reduction was observed in patients with HF and LVEF 45% despite trial challenges in the population recruited, which might lessen the reluctance to treat HF patients on the basis of reduced ejection fraction alone. |
Randomized controlled trial data regarding in-hospital initiation of MRA therapy among patients with HFrEF is limited to the EPHESUS trial. However, patients with worsening HF are often admitted to hospital, creating opportunity for improving HF therapies before discharge. In the PIONEER-HF study it was noted that in patients admitted with acute decompensated HF and reduced ejection fraction, 65% had a history of HF but only 10% were receiving an MRA at the time of admission. |
Patients with HF have multiple comorbidities adding complexity to their care. In-patient care for any one of these medical concerns is an opportunity to enhance HF therapy. In contrast, medications are often interrupted during acute medical illness and reintroduction at maximum tolerated doses before discharge is encouraged. In addition to including MRAs as part of standard medical HFrEF therapy, the following recommendation has been updated. |
Practical tip. MRAs recommended for patients with HFrEF include spironolactone and eplerenone. |
Practical tip. MRAs should generally be avoided when eGFR is < 30 mL/min/1.73 m2. |
Practical tip. MRAs can increase serum potassium, especially during an acute dehydrating illness in which renal dysfunction can worsen. Monitoring of serum creatinine and potassium should be repeated within 1 week of initiation or dose change. |
Practical tip. Temporary reduction or interruption of MRA therapy might be necessary when potassium levels are moderately (5.6-5.9 mmol/L) or severely (> 5.9 mmol/L) elevated, with a return to maximum tolerated dose when other modifiable factors are corrected and potassium levels are 5.0 mmol/L. |
Practical tip. MRAs, when used for HF, have very little effect on BP. |
RECOMMENDATION |
10. We recommend MRA treatment for patients with acute MI and LVEF 40%, and HF symptoms or diabetes, to reduce mortality, CV mortality, and hospitalization for CV events |
(Strong Recommendation; High-Quality Evidence). |
SGLT2 INHIBITORS |
When to start SGLT2 inhibitor treatment in patients with HFrEF. The benefits of SGLT2 inhibitors in patients with established HFrEF have been shown in 2 large clinical trials and 1 meta-analysis, with consistency of benefit regardless of diabetes status.40,41,44 These agents should be considered as standard or foundational therapy in patients with HFrEF (Fig. 1). |
The results of the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial were described in the previous CCS HF guideline update. Over a median 18-month follow-up of 4744 patients with HFrEF, treatment with dapagliflozin significantly reduced the composite primary end point of time to first worsening of HF or death from CV causes (hazard ratio [HR], 0.74 [95% CI 0.65-0.85]; P < 0.001), as well as HHF (HR, 0.70 [95% CI 0.59 - 0.83]) and CV death (HR, 0.82 [95% CI 0.69 - 0.98]). Importantly, 55% of patients in this trial did not have diabetes at baseline, and the effect of dapagliflozin was similar at any hemoglobin A1c level. Ancillary studies have shown that benefits accrued as early as 30 days after treatment initiation. Other notable substudy findings were that diuretic dose was not modified during the trial for most patients, quality of life was improved, and BP was reduced by an average of approximately 2 mm Hg. Importantly, baseline kidney function did not modify the effect of dapagliflozin on outcomes and treatment was associated with a slower eGFR decline compared with placebo in diabetic and nondiabetic cohorts. |
The results of the recently published EMPEROR-Reduced trial, in which empagliflozin 10 mg daily was compared with placebo in patients with symptomatic HFrEF, were concordant with those of DAPA-HF. Participants included those with an LVEF < 40% and elevated NT-proBNP levels that varied according to LVEF and atrial fibrillation status. Enrollment could occur with an eGFR as low as 20 mL/min/ 1.73 m 2. During a median follow-up of 16 months, the primary outcome of CV death or HHF occurred in 19.4% of participants in the empagliflozin group and in 24.7% of the placebo group (HR, 0.75 [95% CI 0.65-0.86]; P < 0.001); this benefit was comparable for patients with and without diabetes. The total number of HHF was lower in the empagliflozin group (HR, 0.70 [95% CI 0.58-0.85]; P < 0.001), as was the annual rate of decline in eGFR (0.55 vs 2.28 mL/min/1.73 m2 per year; P < 0.001). |
The use of background pharmacological therapy for HFrEF was excellent in both trials. Of particular note, sacubitrilvalsartan served as a RASi among approximately 11% of patients in DAPA-HF and in approximately 19% in EMPEROR-Reduced at enrollment. Cardiac resynchronization therapy (CRT) was used in 7.5% of participants in DAPA-HF and in 12% of those in EMPEROR-Reduced, whereas implantable cardioverter defibrillators (ICDs), with or without CRT, were used in 26% and 31%, respectively. There were no treatment interactions between SGLT2 inhibitor and the baseline therapies used. SGLT2 inhibitor treatment was safe with no excess in hypovolemia, hypoglycemia, or renal side effects compared with placebo. |
Taken together, as shown in a meta-analysis by Zannad and colleagues, the results of these 2 landmark trials show that SGLT2 inhibitor reduces morbidity and mortality in patients with symptomatic HFrEF, whether type 2 diabetes is present or not. |
The recently published Dapagliflozin in Patients With Chronic Kidney Disease (DAPA-CKD) trial showed that dapagliflozin, when used in addition to standard therapy, also prevents renal and CV outcomes in patient with established chronic kidney disease. Among 4304 participants, with or without type 2 diabetes, with an eGFR between 25 and 75 mL/ min/1.73 m2 and proteinuria (a urinary albumin-to-creatinine ratio of 22.6-565.6 mg/mmol) who were randomly assigned to dapagliflozin 10 mg daily or placebo, the primary composite outcome of a sustained decline in eGFR of at least 50%, end-stage kidney disease, or death from renal or CV causes was reduced by 44% (HR, 0.56 [95% CI 0.45-0.68]; P < 0.001). The hazard ratio for the composite of death from CV causes or HHF was 0.71 ([95% CI 0.55-0.92]; P ¼ 0.009). All-cause mortality was also significantly reduced (HR, 0.69; [95% CI 0.53-0.88]; P ¼ 0.004) and the safety profile of dapagliflozin was confirmed in this group. |
Practical tip. In EMPEROR-Reduced and DAPA-HF, SGLT2 inhibitor treatment was initiated in addition to maximally tolerated GDMT. However, recognizing the significant residual risk of patients with HFrEF despite GDMT and the benefits associated with dapagliflozin and empagliflozin, it would be reasonable to start this class of therapy early in the disease course for eligible patients. |
Practical tip. EMPEROR-Reduced excluded patients with an eGFR < 20 mL/min/1.73 m2 and DAPA-HF excluded patients with an eGFR < 30 mL/min/1.73 m2. Data supporting the use of these agents in patients with HFrEF and eGFR < 30 mL/min/1.73 m2 are very limited. |
Practical tip. The Canadian Heart Failure Society (CHFS) has published “Practical Approach to SGLT2 Inhibitors for Treatment of Cardiovascular Disease,” which includes contraindications, cautions, drug initiation, special considerations, and sick day management tips. |
Additional Practical Tips related to SGLT2 inhibitor prescription from the previous 2020 HF guideline update2 remain relevant and are included as follows: |
Practical tip. SGLT2 inhibitors are currently contraindicated for patients with type 1 diabetes. |
Practical tip. The most common adverse effect of this class of medications are genital mycotic infections (GMIs). Women (10%-15% risk), those with previous GMIs, and uncircumcised men are at highest risk. Typically, GMIs can be managed with antifungal drugs and do not require discontinuation of therapy. |
Practical tip. SGLT2 inhibitor use might result in temporary reduction of eGFR up to 15%, which generally resolves within 1-3 months. SGLT2 inhibitors have also been associated with acute kidney injury and increased monitoring is warranted in those at risk. |
Practical tip. SGLT2 inhibitors rarely cause hypoglycemia in the absence of concomitant insulin and/or secretagogue therapy. Background therapies might need to be adjusted to prevent hypoglycemia. |
Practical tip. SGLT2 inhibitors should be held in the setting of concomitant dehydrating illness as part of “Sick Day” management. Patients should be educated on “Sick Day” management. |
Practical tip. These agents have been associated with diabetic ketoacidosis (incidence 0.1%). Patients might present with normal or only modestly elevated blood glucose level (< 14 mmol/L). On rare occasions, SGLT2 inhibitors might be associated with normal anion gap acidosis, which is best detected with measurement of serum ketones. Nonspecific symptoms associated with diabetic ketoacidosis include: shortness of breath, nausea, vomiting, abdominal pain, confusion, anorexia, excessive thirst, and lethargy. |
Practical tip. Careful attention to volume status is required when SGLT2 inhibitors, ARNIs, and loop diuretics are used in combination because of their concomitant effects to promote diuresis. |
RECOMMENDATION |
11. We recommend an SGLT2 inhibitor, such as dapagliflozin or empagliflozin, be used in patients with HFrEF, with or without concomitant type 2 diabetes, to improve symptoms and quality of life and to reduce the risk of HF hospitalization and/or CV mortality |
(Strong Recommendation; High-Quality Evidence). |
12. We recommend an SGLT2 inhibitor, such as empagliflozin, canagliflozin, or dapagliflozin be used for treatment of patients with type 2 diabetes and atherosclerotic CV disease to reduce the risk of HF hospitalization and death |
(Strong Recommendation; High-Quality Evidence). |
13. We recommend an SGLT2 inhibitor, such as dapagliflozin, be used in patients with type 2 diabetes who are older than 50 years with additional risk factors for atherosclerotic CV disease to reduce the risk of HF hospitalization |
(Strong Recommendation; High-Quality Evidence). |
14. We recommend SGLT2 inhibitors such as canagliflozin or dapagliflozin be used in patients with albuminuric renal disease, with or without type 2 diabetes, to reduce the risk of HF hospitalization and progression of renal disease |
(Strong Recommendation; High-Quality Evidence). |
Values and preferences. These recommendations place weight on the results from large randomized, placebo-controlled trials that consistently showed a benefitof SGLT2 inhibitor treatment on HF prevention and treatment among patients with and without type 2 diabetes. |
SINUS NODE INHIBITION |
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