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Here are the following information you must remember while generating the response.
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2) Seek context from the previous question.
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3) Do not give racist, sexist comments. Avoid such questions.
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4) If any question is out of context, tell, you only answer and comment on the context related to heart failure.
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5) HF is abbreviation of Heart Failure.
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6) You are a virtual assistant for HEART FAILURE management.
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CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction
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ABSTRACT
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In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a b-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.
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The Canadian Cardiovascular Society (CCS) Heart Failure Guidelines Program provides guidance to clinicians, policymakers, and health systems as to the evidence supporting existing and emerging management of patients with heart failure (HF). Since the 2017 comprehensive update of the CCS guidelines for the management of HF,1 substantial new evidence has emerged, particularly relevant to the management of patients with HF with reduced ejection fraction (HFrEF). The present CCS HF guideline update defines a contemporary standard of care for the HFrEF patient population on the basis of the totality of available evidence. This update focuses on the role of newer pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitor (ARNI), sinus node inhibitor, sodium glucose transport 2 (SGLT2) inhibitor, and soluble guanylate cyclase (sGC) stimulator, in conjunction with well established and conventional HFrEF therapies. Where evidence exists, updated recommendations are provided with respect to the clinical setting in which each of these agents may be prescribed; the potential value of each therapy is reviewed, where relevant, in the setting of chronic HF, new onset HF, and for HF hospitalization. A consensus approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.
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The scope of this guideline update is limited to key pharmacologic therapies for patients with HFrEF. A detailed description of nonpharmacologic management, including advance care planning, multidisciplinary care, remote monitoring, and diet and exercise prescription are not addressed. Management of important comorbidities including coronary disease, atrial fibrillation, functional mitral regurgitation, chronic kidney disease, diabetes, and iron deficiency have also been addressed in previous guideline updates,1,2 although the Panel acknowledges that evidence is quickly evolving in many of these areas.
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The composition and roles of the primary and secondary panels, systematic review strategy, and methods for formulating the recommendations are described at www.ccs.ca. The recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) standards. Primary panelists were responsible for writing and reviewing the document, and the secondary panelists provided critical input from provider and patient perspectives.
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STANDARD THERAPIES
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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 b-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. 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. It is worth noting that the “algorithm” 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 (“in-parallel” approach), rather than fully titrate one medication class before initiating an additional agent (“strict sequential” approach). Although newer medication classes such as ARNI and SGLT2 inhibitors were evaluated in patients with high background use of b-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.
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RECOMMENDATION
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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:
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a. ARNI (or ACEI/ARB);
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b. b-blocker;
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c. MRA; and
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d. SGLT2 inhibitor.
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(Strong Recommendation; Moderate-Quality Evidence).
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Values and preferences. 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, b-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. Preference is given to the use of pharmacotherapy in patients with established HFrEF regardless of symptom severity. The Committee acknowledges lack of evidence favouring one particular titration strategy for guideline-directed medical therapy (GDMT) over another.
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Practical tip. 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.
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Practical tip. 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.
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Practical tip. 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.
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Practical tip. 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.
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Practical tip. 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.
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Practical tip. In the event of a life-threatening complication, GDMT may be 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.
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Practical tip. If symptomatic hypotension persists with GDMT, consider separating the administration of the dose from the timing of other medications that could also lower BP.
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RECOMMENDATION
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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
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(Table 2; Strong Recommendation; High-Quality Evidence).
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ARNI
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Registry data continue to identify suboptimal initiation and titration of goal-directed medical therapy in patients with ambulatory HF. 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]) trial5 showed superior efficacy of ARNI therapy over enalapril in chronic HF patients already receiving maximally tolerated dose of a reninangiotensin 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 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. 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.
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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, and its open-label extension study. 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 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 ¼ 0.03). A recent additional analysis has shown that the efficacy and safety of sacubitril-valsartan is generally similar across various dose levels, 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.
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Practical tip. 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.
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Practical tip. 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.
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Practical tip. ARNI might reduce diuretic requirements and diuretic dosing should be carefully evaluated when starting ARNI therapy.
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Practical tip. Drug tolerability, side effects, and laboratory monitoring of ARNIs is similar to that of ACEIs or ARBs. Practical tip. Appropriate clinical and laboratory follow-up (renal function and electrolytes) is essential after discharge to monitor for adverse events.
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Practical tip. Currently, sacubitril-valsartan is the only available ARNI in Canada. Initial dosing and titration schedule should be individualized.
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RECOMMENDATION
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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
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(Strong Recommendation; High-Quality Evidence).
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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
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(Strong Recommendation; Moderate-Quality Evidence).
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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
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(Weak Recommendation; Moderate-Quality Evidence).
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Values and preferences. 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.
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ACEIs AND ARBs
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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. 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. 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.
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ACEI/ARB initiation and continuation during HF hospitalization. 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. 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. 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. 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.
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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.
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ACEIs/ARBs after acute myocardial infarction. It is well established that ACEIs should be administered to patients with impaired LVEF ( 40%) or those who have experienced HF in the early phase post myocardial infarction (MI). A systematic review 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.
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ARBs as an alternative to ACEIs, in the context of ST-elevation MI, have been evaluated in 2 clinical trials. In the Optimal Trial in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL) 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 Valsartan in Acute Myocardial Infarction (VALIANT) trial, 14,703 patients with acute MI (0.5 and 10 days) and HF or evidence of left ventricular systolic dysfunction 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.
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Practical tip. 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.
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Practical tip. 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.
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Practical tip. 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.
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Practical tip. 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.
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Practical tip. Longer-acting ACEIs such as perindopril or ramipril might be associated with less hypotension in patients with chronic HF, particularly in older patients.
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RECOMMENDATION
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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
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(Strong Recommendation; High-Quality Evidence).
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