With expanding evidence for benefit with guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with improved ejection fraction (HFimpEF), clinicians commonly inquire on how to initiate, sequence, and uptitrate GDMT in patients with HF. In the following paragraphs, I will try to address these concepts in the context of evolving evidence.

Initiation of Quadruple Therapy is Recommended as the First Step for Patients with HFrEF

According to the 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America heart failure (HF) guidelines, initiation of quadruple therapy with renin-angiotensin-system inhibitors including angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blockers (ARBs)/angiotensin and neprilysin inhibitor (ARNI), beta-blocker, mineralocorticoid receptor antagonist (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are recommended as the first step of treatment in patients with HFrEF. United States guidelines indicate that these medications may be started simultaneously at initial low doses in certain patients. Obviously, initiation of all 4 drugs at the same time may not be feasible in all patients. Alternatively, these medications may be started sequentially, with sequence guided by clinical or other factors, without need to achieve target dosing before initiating next medication.

Which drug to initiate can be individualized, and sequence may not matter as long as the initiation of quadruple therapy is achieved quickly

Which agent or agents to initiate first may differ according to patient phenotype, hemodynamic characterization, specific etiology of HF, comorbidities, and affordability and availability of medications. Patients with tachycardia, active ischemia, recent myocardial infarction, or ventricular ectopy may be initiated on beta-blocker. Patients with significant congestion and volume overload may be initiated on SGLT2i or MRA after diuretics. Patients with New York Heart Association (NYHA) functional class IV symptoms can be initiated on ACEI, as current evidence supports use of ARNI only in patients with NYHA functional class II-III HF symptoms.  In the PARADIGM-HF trial (LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; NCT01035255), although there was a reduction in cardiovascular death or HF hospitalization rates with the use of sacubitril-valsartan compared with enalapril in patients with NYHA functional class I-II symptoms, there was no benefit in patients with NYHA functional class III-IV HF symptoms. Although fewer than 1% of the study population in the PARADIGM trial had NYHA functional class IV symptoms at baseline, the interaction between NYHA functional class and the primary endpoint was significant, suggesting heterogeneity and lack of benefit for these patients.  In the subsequent HFN-LIFE trial (Entresto [LCZ696] in Advanced Heart Failure; NCT02816736) in patients with advanced HFrEF and recent NYHA functional class IV symptoms, despite statistical insignificance, numerically higher HF event rates in the ARNI arm further raised the possibility of lack of efficacy with neprilysin inhibition in advanced HF patients. It is because of these results that the use of ARNI is recommended only in patients with NYHA functional class II-III HF in the HF guidelines. Regarding other specific phenotypes, SGLT2i and ARNI may be considered for earlier initiation before other agents in patients with HFrEF and chronic kidney disease but with a glomerular filtration rate (GFR) >20-25 mL/min/1.73 m2 (patients with estimated GFR <20 mL/min/1.73 m2 were usually excluded from HF clinical trials) because of their beneficial effects in slowing of a decline in GFR. These agents also have good safety profiles, including less risk of hyperkalemia or worsening renal function, and enable safe and successful initiation of other agents such as MRAs. In patients with diabetes, SGLT2i has a specific class I indication in patients with HF and diabetes regardless of left ventricular ejection fraction (LVEF).

Beyond the aforementioned specific phenotypes, there could be limitations to initiate certain drugs. For example, significant symptomatic bradycardia could be a contraindication for initiation of beta-blocker, symptomatic significant hypotension could be a challenge for initiation of ARNI, and preshock or shock could preclude initiation of quadruple therapy until hemodynamic stability is achieved. In the setting of hyperkalemia, SGLT2i or ARNI may be preferred to initiate first rather than MRA or ACEI.

It is important to recognize that regardless of order of initiation or sequence, timely initiation of all 4 classes of medications is important for clinical outcomes in patients with HFrEF. The order of sequence may not matter as long as all 4 drugs can be initiated in a timely manner.

Time is of the essence for early initiation of quadruple therapy

There is evidence of early benefit with GDMT in patients with HFrEF, as early as within the first 30 days of treatment with SGLT2i or ARNI, and within 2 weeks of initiation of SGLT2i in patients with HFmrEF or HFpEF. It is therefore important for quadruple therapy to be initiated within the first 4 to 6 weeks.

There is evidence that GDMT can be initiated safely in patients before discharge, and initiation of GDMT for patients hospitalized for HF after clinical stability is achieved is a class I recommendation in the guidelines.There are many different models of care through which GDMT can be initiated and optimized, including multidisciplinary care coordination, telehealth, and remote monitoring. Given the enabling role of newer HF therapies in initiation of other GDMT, their favorable effects on kidney function and potassium levels, and overall safety, laboratory monitoring may not be required as frequently as in the past, allowing virtual, remote, and or patient uptitration.

After initiation of quadruple therapy, the second step is to optimize doses

In the U.S. HF guidelines, after initiation of quadruple therapy, medication doses are recommended to be increased to target doses as tolerated.  There is evidence for higher benefit from optimal dose of beta-blocker and ACEI  in patients with HF, and evolving evidence suggests benefit with even modest doses of ARNI and MRA. Importantly, there is evidence of reversal of remodeling in patients with HFrEF with newer agents such as ARNI and SGLT2i, as well as with older agents such as beta-blocker. In addition, there is evidence of reduction in sudden cardiac death with the newer agents. These underscore the importance of optimization of GDMT doses before consideration of device therapies such as implantable cardioverter-defibrillators in HF. In the guidelines, titration and optimization of guideline-directed medications are specified to be considered as frequently as every 1 to 2 weeks depending on the patient’s symptoms, vital signs, and laboratory findings.

Next steps after initiation and optimization of doses of quadruple therapy in patients with HFrEF

After initiation and optimization of doses of quadruple therapy, the following steps are important to consider in patients with HFrEF. Hydralazine and nitrates are indicated in African-American patients with NYHA functional class III-IV HFrEF. For patients with symptomatic stable chronic HFrEF in sinus rhythm with a heart rate of ≥70 beats/min despite beta-blocker, ivabradine can be beneficial. In patients with symptomatic HFrEF, digoxin might be considered to decrease hospitalizations for HF. In selected high-risk patients with HFrEF and recent worsening of HF, vericiguat may be considered to reduce HF hospitalization and cardiovascular death. In patients with LVEF <35% and NYHA functional class II-III symptoms on chronic GDMT, who have reasonable expectation of meaningful survival for >1 year, implantable cardioverter-defibrillator therapy is recommended. Patients with left bundle branch block and wide QRS interval also have indications for cardiac resynchronization therapy.  Important additional considerations include appropriate treatment strategies for comorbidities, such as iron deficiency, atrial fibrillation, ischemic heart disease, valvular heart disease, sleep apnea, and diabetes, and treatment of specific etiologies, such as cardiac amyloidosis or sarcoidosis.

Treatment of patients with HFmrEF, HFpEF, and HFimpEF

Recent evidence with 2 large scale randomized trials support treatment of patients with HFmrEF, HFpEF, and HFimpEF with SGLT2i. With evidence being limited to post hoc analyses and secondary endpoints of existing trials, class IIb indications are given to ARNI, ACEI, ARB, MRA, and beta-blocker for patients with HFmrEF1 and to ARNI, ARB, and MRA for patients with HFpEF. Owing to lack of evidence for benefit, beta-blocker is not recommended in patients with HFpEF. Regardless of LVEF, in patients with HF who have fluid retention, diuretic agents are recommended to relieve congestion in all HF patients. Similarly to patients with HFrEF, patients with HFmrEF and HFpEF can also benefit from appropriate treatment of comorbidities such as diabetes, hypertension, atrial fibrillation, and sleep apnea and life style modification.

Putting it all together: Induction, consolidation, and maintenance therapies in HF

In other disease states, such as cancer, the first standard treatment given for a disease is usually defined as induction therapy. Disease-modifying effects of quadruple therapy resulting in early and significant improvements in clinical outcomes, including cardiovascular death and HF hospitalizations, in HF fit the characteristics of a first-line standard therapy, similarly to induction therapy in other disease states (Figure 1).

Strategies for Initiation and Optimization of Guideline-Directed Medical Therapies in Heart Failure

Conceptualization of initiation of first-line quadruple guideline-directed medical therapy (GDMT) with renin-angiotensin-system inhibitors including angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker/angiotensin and neprilysin inhibitor (ARNI), beta-blocker (BB), mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter 2 inhibitor (SGLT2i), followed by additional therapies such as hydralazine nitrates in African-American patients, device therapies such as implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy with defibrillator (CRT-D) in certain patients, and appropriate treatment strategies for comorbidities such as iron deficiency, atrial fibrillation, ischemic heart disease, valvular heart disease, sleep apnea, diabetes; treatment of specific etiologies. ∗Class I indication in self-identified African-American patients. DM = diabetes mellitus; IV = intravenous.

Subsequent steps in HF management entail optimization of doses of first-line quadruple therapy, followed by addition of other therapies, such as hydralazine and nitrates in African-American patients; consideration of additional therapies, and treatment of comorbidities (Figure 1). These additional therapies are similar in concept to therapies categorized as consolidation therapy in other disease states, such as cancer, given after induction therapy to consolidate the gains obtained with an intent to further improve outcomes.

Finally, similarly to maintenance therapy recommended in other disease states, continuation of GDMT is recommended to prevent relapse of HF and left ventricular dysfunction in patients with HF, even in individuals who may have resolution of symptoms or signs and improvement in their LVEF after treatment. A significant proportion of patients may relapse with recurrence of symptoms, signs, and left ventricular dysfunction if GDMT is withdrawn.

Thus the overall therapies in HF are similar to other disease management strategies and entail first-line therapy similarly to induction therapy, optimization with additional therapies similarly to consolidation therapy, and continuation of GDMT similarly to maintenance therapy. With these strategies, we envision improved outcomes, preventing progression of HF, diagnosing and treating HF at earlier stages, and achieving full and early remission in patients with HF.

This article is reproduced from JACC journals.

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