{"id":129756,"date":"2023-02-20T14:22:39","date_gmt":"2023-02-20T14:22:39","guid":{"rendered":"https:\/\/ccs.ca\/?post_type=guideline&p=129756"},"modified":"2023-03-22T09:02:31","modified_gmt":"2023-03-22T09:02:31","slug":"chapter-2-standard-therapies","status":"publish","type":"guideline","link":"https:\/\/ccs.ca\/guideline\/2021-heart-failure-reduced-ef\/chapter-2-standard-therapies\/","title":{"rendered":"2. Standard Therapies"},"content":{"rendered":"\n
On the basis of new and emerging evidence for the pharmacologic treatment of HFrEF, updated treatment recommendations are provided herein. In the current era, patients with HFrEF should treated with 4 standard therapies, in the absence of contraindications, each representing a different class of medication with unique mechanism of action. Placing a high priority on reducing cardiovascular (CV) mortality and hospitalization for HF (HHF) in most patients, these medications include: (1) an ARNI, either as first-line therapy or switching from an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB); (2) a \u03b2-blocker; (3) a mineralocorticoid receptor antagonist (MRA); and (4) an SGLT2 inhibitor. Specific recommendations for each class of therapy, including the clinical settings in which these treatments may be prescribed, are outlined in detail in the sections that follow. Beyond these standard therapies, additional medications benefit important subgroups of patients with HFrEF, and should be initiated and titrated where indicated. In particular, the role and clinical settings for prescription of ivabradine (sinus node inhibitor), vericiguat (sGC stimulator), digoxin, and hydralazine\/nitrates are discussed under their respective headings. Table 1 highlights the quality of available evidence to support the use of each HFrEF therapy according to clinical setting.<\/p>\n\n\n\n
A simplified, HFrEF treatment algorithm is illustrated in Figure 1. Recognizing that any such algorithm cannot address all of the nuances and multiple considerations underpinning individualized HFrEF management in the current era, the approach presented places value on pragmatic considerations for most patients. Depending on the clinical practice environment, initiation and titration of standard therapies should be embraced by nonspecialists, whereas additional pharmacologic and interventional considerations might warrant input from specialists.<\/p>\n\n\n\n
It is worth noting that the \u201calgorithm\u201d in Figure 1 has been informed by best available evidence and the consensus of the Primary Panel, but to date, there is no proven superior approach to medication initiation and titration. For example, on the basis of clinical characteristics, it might be preferable to titrate doses of different classes of medications simultaneously (\u201cin-parallel\u201d approach), rather than fully titrate one medication class before initiating an additional agent (\u201cstrict sequential\u201d approach). Although newer medication classes such as ARNI and SGLT2 inhibitors were evaluated in patients with high background use of \u03b2-blockers, MRAs, and ACEIs or ARBs, there is currently no Primary Panel consensus endorsing a fixed sequence for medication prescription for patients with HFrEF. There is, however, consensus that all 4 classes of therapies should be used in patients with HFrEF and detailed evidence for each specific drug class is presented in the appropriate section.<\/p>\n\n\n
Recommendation<\/p>
1. We recommend that in the absence of contraindications, patients with HFrEF be treated with combination therapy including 1 evidence-based medication from each of the following categories: Values and Preferences<\/p> High value is placed on prescribing a combination of individual therapies that reduce CV mortality and HHF in well conducted randomized controlled trials. Medications such as ARNI and SGLT2 inhibitor have clinical benefits in patients treated with ACEIs or ARBs, \u03b2<\/span>-blockers, and MRAs as background therapy. The complementary mechanisms of action of these agents in patients with HFrEF provides further rationale for a multidrug approach.<\/p>\n Preference is given to the use of pharmacotherapy in patients with established HFrEF regardless of symptom severity.<\/p>\n The Committee acknowledges lack of evidence favouring one particular titration strategy for guideline directed medical therapy (GDMT) over another.<\/p>\n<\/div>\n\n\n Practical Tip<\/p> The approach to initiation and titration of standard therapies should be directed by clinical and other patient factors including hemodynamic status, renal function, access to medication, adherence, anticipated side effects and tolerability, and patient preference.<\/p>\n Every attempt should be made to titrate medications as soon as feasible after the diagnosis. It is reasonable to aim for titration of all standard therapies concurrently to target doses, or maximally tolerated doses, within 3-6 months from diagnosis.<\/p>\n Because of the superiority of ARNI over ACEIs or ARBs in the setting of HFrEF, prescribing ARNI as first-line therapy or before full titration of ACEIs\/ARBs might facilitate more rapid optimization of GDMT.<\/p>\n If a drug with proven mortality or morbidity benefits does not appear to be tolerated (eg, low blood pressure [BP], low heart rate, or renal dysfunction), concomitant drugs (eg, diuretics) with less proven benefit should be carefully reevaluated to determine whether their dose can be reduced or the drug discontinued.<\/p>\n GDMT for HFrEF should be continued at the usual dose during acute intercurrent illness unless they are not tolerated or could potentially worsen severity of illness. Whenever possible, GDMT withheld during a hospitalization should be restarted before discharge.<\/p>\n In the event of a life-threatening complication, GDMT maybe discontinued abruptly, but generally, if there is concern about their use, the dose should be decreased by one-half, and the patient should be reassessed. If the dose is reduced, the previous tolerated dose should be resumed as soon as safely possible.<\/p>\n If symptomatic hypotension persists with GDMT, consider separating the administration of the dose from RECOMMENDATION the timing of other medications that could also lower BP.<\/p>\n<\/div>\n\n\n Recommendation<\/p> 2. We recommend preferentially use of drugs at target doses that have been proven to be beneficial in clinical trials as optimal medical therapy. If these doses cannot be achieved, the maximally tolerated dose is acceptable (Table 2; Strong Recommendation; High Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n\n Registry data continue to identify suboptimal initiation and titration of goal-directed medical therapy in patients with ambulatory HF.[4]<\/a><\/sup> Thus, HHF represents an ideal time to recalibrate, and optimize the treatment plan by initiating GDMT. ARNI therapy is now a well established treatment recommendation in patients with chronic HFrEF who have been previously exposed to either ACEIs or ARBs. The multicentre, randomized, double-blind, parallel group, active controlled study to evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic HFrEF (Prospective Comparison of ARNi With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]) trial[5]<\/a><\/sup> showed superior efficacy of ARNI therapy over enalapril in chronic HF patients already receiving maximally tolerated dose of a renin-angiotensin system inhibitor (RASi). More recently, the safety and efficacy of this strategy has been explored in patients hospitalized with acute HF, including de novo HF, with or without previous exposure to RASi. The Comparison of Pre-discharge and Post-Discharge Treatment Initiation With LCZ696 in Heart Failure Patients With Reduced Ejection Fraction Hospitalized for an Acute Decompensation Event (TRANSITION) study[6]<\/a><\/sup> was an open-label multicentre randomized controlled trial of 1002 patients, which showed the safety of initiating ARNI in patients with left ventricular ejection fraction (LVEF) 40% admitted to hospital with decompensated HF (median 7 days from admission) compared with initiation of ARNI therapy after discharge (median 10 days from admission). There was no difference in the proportion of patients who achieved maximum dose of sacubitril-valsartan at 10 weeks of follow-up (45.4% vs 50.7%; relative risk [RR] 0.90 [95% CI 0.79-1.02] in the pre and post-discharge initiation groups, respectively). Similarly, there was no difference in the proportion of patients tolerating any dose of drug at 10 weeks with either strategy (86.0% vs 89.6%; RR, 0.96 [95% CI 0.92-1.01]). In a recent TRANSITION substudy 286 patients with de novo HF were compared with 705 patients with established HF and those with newly diagnosed HF were shown to be more likely to achieve target dose of sacubitril-valsartan at 10 weeks (56% vs 45%; RR, 1.30 [95% CI 1.12-1.52]; P < 0.001) with fewer serious adverse reactions.[7]<\/a><\/sup> Patients with de novo HFrEF who started ARNI therapy had a greater decrease in N-terminal pro hormone brain natriuretic peptide (NT-proBNP) and lower rates of rehospitalization without compromising up-titration of other guideline-directed HF therapies. Practical Tip<\/p> In patients suitable for switching to an ARNI, an ACEI can be discontinued at the time of hospital admission enabling ARNI prescription at 36 hours after admission. A 36 hour wash-out period is not necessary for those receiving ARB therapy at the time of hospitalization.<\/p>\n<\/div>\n\n\n Recommendation<\/p> 3. We recommend that an ARNI be used in place of an ACEI or ARB, in patients with HFrEF, who remain symptomatic despite treatment with appropriate doses of GDMT to decrease CV death, HF hospitalizations, and symptoms (Strong Recommendation; High-Quality Evidence).<\/p>\n 4. We recommend that patients admitted to hospital for acute decompensated HF with HFrEF should be switched to an ARNI, from an ACEI or ARB, when stabilized and before hospital discharge (Strong Recommendation; Moderate-Quality Evidence).<\/p>\n 5. We suggest that patients admitted to hospital with a new diagnosis of HFrEF should be treated with ARNI as first-line therapy, as an alternative to either an ACEI or ARB (Weak Recommendation; Moderate-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Values and Preferences<\/p> These recommendation place high value on evidence that supports the safety and efficacy of initiating ARNI therapy in hospitalized patients with or without previous RASi exposure.<\/p>\n<\/div>\n\n\n Practical Tip<\/p> In hospitalized and ambulatory patients with HF, without previous exposure to either an ACEI or ARB, an ARNI should be considered as first-line therapy when BP and renal function\/potassium levels permit. Because a washout period is needed with ACEIs, initial therapy with this class in a hospitalized patient with HFrEF will delay the initiation of ARNI treatment.<\/p>\n ARNI might reduce diuretic requirements and diuretic dosing should be carefully evaluated when starting ARNI therapy.<\/p>\n Drug tolerability, side effects, and laboratory monitoring of ARNIs is similar to that of ACEIs or ARBs.<\/p>\n Appropriate clinical and laboratory follow-up (renal function and electrolytes) is essential after discharge to monitor for adverse events.<\/p>\n Currently, sacubitril-valsartan is the only available ARNI in Canada. Initial dosing and titration schedule should be individualized (Table 2).<\/p>\n<\/div>\n\n\n\n The benefits of GDMT for patients with HFrEF, including ACEIs and ARBs, are drawn from large randomized controlled trials of ambulatory patients. Previous guideline recommendations for ACEI\/ARB therapy in patients with HFrEF reflect this evidence.[12]<\/a><\/sup> In contrast, recommendations regarding the role of RASi in the management of acute HF is largely consensus-based, with no good-quality evidence to support treatment recommendations in the hospitalized setting.[12]<\/a><\/sup> Practically, an HHF event represents an opportunity to optimize and\/or reevaluate therapy including switch from an ACEI\/ARB to an ARNI in eligible patients with HFrEF to improve postdischarge patient outcomes, as discussed in the previous section.<\/p>\n\n\n\n ACEI\/ARB initiation and continuation during HF hospitalization.<\/strong> ACEIs and ARBs do not have a clear role in the early management of acute or worsening HF, because there are no robust randomized controlled trial data regarding in hospital ACEI\/ARB initiation. Observational data from the Get With The Guidelines-HF Registry showed that among 16,052 patients, those who started ACEI\/ARB treatment before discharge had lower mortality and readmission rates up to 1 year.[13]<\/a><\/sup> Nevertheless, a significant number of patients hospitalized for HFrEF have worsening hemodynamics and\/or worsening renal function, which might lead to reluctance with initiating or continuing hemodynamically active therapies.[14]<\/a>–[16]<\/a><\/sup> One analysis showed that ACEI\/ARB medications were reduced or discontinued because of acute kidney injury (57%), hypotension (23%), and hyperkalemia (10%); serum creatinine and systolic at admission were significant independent predictors of in-hospital dose reduction or discontinuation.[17]<\/a><\/sup> Although renal dysfunction was noted as the most common cause for reduction of ACEI\/ARB therapy, 24% of patients had no significant in-hospital rise in creatinine level, and medication changes were made in anticipation of deteriorating renal function rather than documented change in renal function.[17]<\/a><\/sup><\/p>\n\n\n\n A matched-cohort analysis of Medicare beneficiaries hospitalized for HF between 1998 and 2001 showed that patients who initiated ACEI\/ARB treatment had lower 30-day readmission rates (18% vs 24%) and all-cause mortality (7% vs 14%) compared with those for whom ACEI\/ARB treatment was discontinued.[18]<\/a><\/sup><\/p>\n\n\n\n ACEIs\/ARBs after acute myocardial infarction.<\/strong> It is well established that ACEIs should be administered to patients with impaired LVEF (\u2264 40%) or those who have experienced HF in the early phase post myocardial infarction (MI).[19]<\/a>–[21]<\/a><\/sup> A systematic review[22]<\/a><\/sup> of 4 trials of early ACEI initiation (0-36 hours) post ST-elevation MI including more than 98,000 patients, showed a 7% relative reduction in 30-day mortality compared with placebo. Importantly, 40% of the survival benefit was seen after the first day of treatment, underscoring the value of initiating ACEI treatment early in hemodynamically stable patients.<\/p>\n\n\n\n ARBs as an alternative to ACEIs, in the context of ST-elevation MI, have been evaluated in 2 clinical trials. In the Op<\/strong>timal T<\/strong>rial i<\/strong>n M<\/strong>yocardial Infarction With the A<\/strong>ngiotensin II A<\/strong>ntagonist L<\/strong>osartan (OPTIMAAL)[23]<\/a><\/sup> trial, losartan failed to show either superiority or noninferiority compared with captopril for the primary end point at the 2.7-year follow-up (18% vs 16%). Conversely, in the Val<\/strong>sartan i<\/strong>n A<\/strong>cute Myocardial In<\/strong>farct<\/strong>ion (VALIANT) trial,[19]<\/a><\/sup> 14,703 patients with acute MI (0.5 and 10 days) and HF or evidence of left ventricular systolic dysfunction \u2264 40% were randomly assigned to valsartan alone, full-dose captopril, or both (80 mg twice daily and 50 mg 3 times daily). The primary end point of all-cause mortality was similar in the 3 groups (valsartan 19.9%, captopril 19.5%, both 19.3%), but discontinuations were more frequently seen in patients who received captopril. Therefore, valsartan, at the dosages used in the trial, represents an alternative to ACEIs.<\/p>\n\n\n Practical Tip<\/p> ACEI intolerance describes a patient who is unable to tolerate ACEI therapy secondary to a bothersome cough (approximately 10%) or those who experience angioedema (< 1%). ARB therapy is a reasonable alternative in both of these cases, however, caution should be used in patients who develop angioedema while receiving ACEI therapy because there have been case reports of patients who subsequently develop angioedema with ARB therapy. There is no significant difference in rates of hypotension, hyperkalemia, or renal dysfunction between ACEIs and ARBs to warrant substitution.<\/p>\n<\/div>\n\n\n Recommendation<\/p> 6. We recommend an ACEI or ARB in those with ACEI intolerance, in patients with acute MI with HF or an LVEF < 40% post-MI to be used as soon as safely possible post-MI (Strong Recommendation; High-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Practical Tip<\/p> An increase in serum creatinine or decrease in estimated glomerular filtration rate (eGFR) of up to 30% in the absence of oliguria is not unexpected when an ACEI or ARB is introduced; if the increase stabilizes at 30%, there is no immediate need to decrease the drug dose but closer long-term monitoring might be required.<\/p>\n BP might fall when an ACEI or ARB is introduced, especially if introduced at a high dose or in combination with diuretic therapy. Check BP with the patient supine and standing to detect whether hypotension is present, which might suggest that a slower up-titration is warranted.<\/p>\n Caution is warranted in patients with marginal BP; although low-dose captopril is sometimes used to initiate an ACEI in hemodynamically tenuous patients this approach has never been tested in randomized controlled trials.<\/p>\n Longer-acting ACEIs such as perindopril or ramipril might be associated with less hypotension in patients with chronic HF, particularly in older patients.<\/p>\n<\/div>\n\n\n\n Since the 2017 comprehensive update of the CCS guidelines for the management of HF, no large randomized clinical trials of \u03b2-blockers in patients with HFrEF have been published. Previous landmark trials of carvedilol,[24]<\/a>,[25]<\/a><\/sup> sustained release metoprolol succinate,[26]<\/a><\/sup> and bisoprolol[27]<\/a><\/sup> 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, \u03b2-blockers prevented 3.8 deaths and were associated with 4 fewer hospitalizations per 100 patients in the first year of treatment.[28]<\/a><\/sup><\/p>\n\n\n\n For patients admitted to hospital with worsening HF, \u03b2-blocker initiation, before discharge in stabilized patients, has been associated with improved short- and intermediate-term outcomes[29]<\/a>,[30]<\/a><\/sup> without intolerance or extended length of hospital stay. Available evidence also strongly suggests that patients with HFrEF receiving \u03b2-blockers at the time of admission for acute HF have higher rates of death and recurrent HHF when \u03b2-blockers are not resumed before discharge.[31]<\/a>–[34]<\/a><\/sup><\/p>\n\n\n\n A recent meta-analysis of 5 observational studies and 1 randomized trial confirmed this association; \u03b2-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]<\/a><\/sup> The totality of available evidence suggests that \u03b2-blockers should be continued or reinitiated before discharge in those with HFrEF who are hospitalized for worsening HF, whenever clinically feasible.<\/p>\n\n\n\n In addition to including \u03b2-blockers as part of standard medical HFrEF therapy, the following recommendations on \u03b2-blocker use in HFrEF have remained unchanged from the 2017 comprehensive update of the CCS guidelines for the management of HF.<\/p>\n\n\n Recommendation<\/p> 7. We recommend that \u03b2-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 \u03b2-blocker treatment in stabilized patients (Strong Recommendation; High-Quality Evidence).<\/p>\n 8. We recommend patients with NYHA class IV symptoms be stabilized before initiation of \u03b2-blocker treatment (Strong Recommendation; High-Quality Evidence).<\/p>\n 9. We recommend that \u03b2-blockers be initiated in all patients with an LVEF < 40% with previous MI (Strong Recommendation; Moderate-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Practical Tip<\/p> Objective improvement in cardiac function might not be apparent for 6-12 months after \u03b2-blocker initiation. The absence of LVEF recovery is not justification to stop treatment.<\/p>\n Treatment of patients with NYHA class I or II symptoms can be safely initiated and titrated with a \u03b2-blocker by nonspecialist physicians.<\/p>\n Patients with NYHA class III or IV symptoms should have \u03b2-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.<\/p>\n \u03b2-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 up-titration of \u03b2-blockers and might require assessment of diuretic dosage (eg, might consider deferring dosage reduction).<\/p>\n If concomitant reactive airways disease is present, consider using more selective \u03b2-1 blockade (eg, bisoprolol).<\/p>\n 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\u2019s history of arrhythmia will help guide the most appropriate treatment modifications.<\/p>\n<\/div>\n\n\n\n MRA use in patients with HFrEF.<\/strong> 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 \u03b2-blocker medications), there remains uncertainty or reluctance for widespread use. A report of the recent US CHAMP-HF registry[36]<\/a><\/sup> showed that MRA was used in only 33.4% of patients with HFrEF without documented contraindication. On the basis of data from the R<\/strong>andomized Al<\/strong>dactone E<\/strong>valuation S<\/strong>tudy (RALES),[37]<\/a><\/sup> the E<\/strong>plerenone P<\/strong>ost-Acute Myocardial Infarction H<\/strong>eart Failure E<\/strong>fficacy and Su<\/strong>rvival S<\/strong>tudy (EPHESUS),[38]<\/a><\/sup> and the E<\/strong>plerenone in M<\/strong>ild P<\/strong>atients H<\/strong>ospitalization a<\/strong>nd S<\/strong>urvi<\/strong>val S<\/strong>tudy in H<\/strong>eart F<\/strong>ailure (EMPHASIS-HF),[39]<\/a><\/sup> 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 \u2264 35% and NYHA class III-IV symptoms; (2) post MI with signs and symptoms of acute HF and LVEF \u2264 40%, or post MI with diabetes and LVEF \u2264 40% (regardless of HF symptoms); and (3) LVEF \u2264 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).<\/p>\n\n\n\n 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.[40]<\/a>,[41]<\/a><\/sup> Moreover, in the T<\/strong>reatment o<\/strong>f P<\/strong>reserved C<\/strong>ardiac Function Heart Failure With an A<\/strong>ldosterone Ant<\/strong>agonist (TOPCAT) trial HHF reduction was observed in patients with HF and LVEF \u2265 45% despite trial challenges in the population recruited,[42]<\/a>,[43]<\/a><\/sup> which might lessen the reluctance to treat HF patients on the basis of reduced ejection fraction alone.<\/p>\n\n\n\n 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.[8]<\/a><\/sup><\/p>\n\n\n\n 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.<\/p>\n\n\n\n In addition to including MRAs as part of standard medical HFrEF therapy, the following recommendation has been updated.<\/p>\n\n\n Recommendation<\/p> 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).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Practical Tip<\/p> MRAs recommended for patients with HFrEF include spironolactone and eplerenone.<\/p>\n MRAs should generally be avoided when eGFR is < 30 mL\/min\/1.73 m2.<\/p>\n 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.<\/p>\n 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 \u2264 <\/span>5.0 mmol\/L.<\/p>\n MRAs, when used for HF, have very little effect on BP.<\/p>\n<\/div>\n\n\n\n When to start SGLT2 inhibitor treatment in patients with HFrEF.<\/strong> 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]<\/a>,[41]<\/a>,[44]<\/a><\/sup> These agents should be considered as standard or foundational therapy in patients with HFrEF (Fig. 1).<\/p>\n\n\n\n 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.[2]<\/a><\/sup> 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.[40]<\/a><\/sup> Ancillary studies have shown that benefits accrued as early as 30 days after treatment initiation.[45]<\/a><\/sup> Other notable substudy findings were that diuretic dose was not modified during the trial for most patients,[46]<\/a><\/sup> quality of life was improved,[47]<\/a><\/sup> and BP was reduced by an average of approximately 2 mm Hg.[48]<\/a><\/sup> 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.[49]<\/a><\/sup><\/p>\n\n\n\n The results of the recently published EMPEROR-Reduced trial,[41]<\/a><\/sup> 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 m2. 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).<\/p>\n\n\n\n The use of background pharmacological therapy for HFrEF was excellent in both trials. Of particular note, sacubitril-valsartan 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.<\/p>\n\n\n\n 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.[44]<\/a><\/sup><\/p>\n\n\n\n
\na. ARNI (or ACEI\/ARB);
\nb. \u03b2<\/span>-blocker;
\nc. MRA; and
\nd. SGLT2 inhibitor.
\n(Strong Recommendation; Moderate-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n<\/figure>\n\n\n\n
ARNI<\/h3>\n\n\n\n
Further support for initiating ARNI as first-line HFrEF therapy in de novo or RASi-naive patients comes from the Comparison of Sacubitril\/Valsartan Versus Enalapril on Effect on Nt-Pro-Bnp in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF) trial,[8]<\/a><\/sup> and its open-label extension study.[9]<\/a><\/sup> In this double-blind randomized controlled trial, in-hospital initiation of sacubitril-valsartan was compared with enalapril in 881 HFrEF patients hospitalized with HF. Notably, one-third of patients enrolled did not have a history of HF and just more than half had no previous ACEI or ARB use. In-hospital initiation of sacubitril-valsartan resulted in a significantly greater proportional reduction in NT-proBNP compared with enalapril at weeks 4 and from baseline (mean time-averaged change in NT-proBNP, 46.7% vs 25.3%). This change was consistent across all subgroups, including those without previous HF and those who were RASi-naive. In the open-label extension, the clinical course of patients in the PIONEER-HF trial was evaluated for those who initiated sacubitril-valsartan treatment in-hospital as well as for those who switched from enalapril to sacubitril-valsartan treatment at week 8 of the trial protocol and were followed-up for an additional 4 weeks.[9]<\/a><\/sup> Among patients who continued sacubitril-valsartan for an additional 4 weeks, a further 17.2% reduction in NT-proBNP was observed; for patients who switched from enalapril to sacubitril-valsartan at week 8, a more significant 37.4% decline in NT-proBNP was seen over the following 4 weeks. Patients who started ARNI therapy in-hospital had a lower incidence of subsequent HHF or CV mortality through the entire 12-week trial period compared with patients who converted to ARNI after the first 8 weeks (13.0% vs 18.1%; P 1\u20444 0.03). A recent additional analysis has shown that the efficacy and safety of sacubitril-valsartan is generally similar across various dose levels,[10]<\/a><\/sup> supporting the rationale for in hospital initiation and continued post hospitalization use of sacubitril-valsartan broadly, including patients who might not tolerate early up-titration to target dose. Another recent analysis has shown the cost-effectiveness of this approach.[11]<\/a><\/sup><\/p>\n\n\nACEIs and ARBs<\/h3>\n\n\n\n
\u03b2-Blockers<\/h3>\n\n\n\n
<\/figure>\n\n\n\n
MRAs<\/h3>\n\n\n\n
SGLT2 inhibitors<\/h3>\n\n\n\n