Effective Step-by-Step Strategy to optimise guideline-directed medical therapy in Heart Failure

Clinicians often ask how to start, sequence, and uptitrate GDMT in patients with HF because to growing evidence that it is beneficial for patients with heart failure with decreased ejection fraction (HFrEF), heart failure with slightly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with improved ejection fraction (HFimpEF).

For patients with HFrEF, starting quadruple therapy is advised as the first step.

The 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America heart failure (HF) guidelines recommend starting quadruple therapy, which includes beta-blockers, mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARBs), angiotensin and neprilysin According to US recommendations, these drugs may be begun concurrently in certain individuals at modest dosages. It goes without saying that not all people may be able to start taking all 4 medications simultaneously. Instead of needing to reach the target dose before starting the next medicine, these medications may be begun sequentially, with order being directed by clinical or other variables.

As long as the start of triple treatment occurs as soon as possible, the choice of medicine to begin may be tailored.

Depending on the patient's phenotype, hemodynamic profile, particular HF etiology, comorbidities, cost, and accessibility of drugs, the initial agent or agents to administer may vary. Beta-blockers may be started in patients who have tachycardia, active ischemia, a recent myocardial infarction, or ventricular ectopy. After using diuretics, patients with severe congestion and volume overload may begin taking SGLT2i or MRA. Given that ARNI should only be used in patients with NYHA functional class II–III HF symptoms, individuals with New York Heart Association (NYHA) functional class IV symptoms may start taking ACEI. In the PARADIGM-HF trial (LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; NCT01035255), patients with NYHA functional class I–II symptoms saw a decrease in cardiovascular death or hospitalization rates with sacubitril-valsartan use compared to enalapril, but patients with NYHA functional class III–IV HF symptoms saw no benefit.

The interaction between NYHA functional class and the main endpoint in the PARADIGM trial was significant, despite the fact that less than 1% of the study group reported symptoms that were NYHA functional class IV at baseline, indicating heterogeneity and lack of benefit for these individuals. Despite statistical insignificance, numerically higher HF event rates in the ARNI arm 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 further raised the possibility of a lack of efficacy with neprilysin inhibition in advanced HF patients despite statistical insignificance.

These findings led to the recommendation in the HF recommendations that ARNI only be used in patients with NYHA functional class II–III HF. 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 typically excluded from HF clinical trials), SGLT2i and ARNI may be considered for earlier initiation before other agents due to their beneficial effects in slowing a decline in GFR. These medications also allow for the safe and effective start of additional medications like MRAs because of their favorable safety profiles, which include reduced risk of hyperkalemia and deteriorating renal function. Regardless of left ventricular ejection fraction, SGLT2i has a particular class I indication in patients with diabetes and HF1.

Beyond the aforementioned particular characteristics, there can be restrictions on how certain medications can be started. For instance, considerable symptomatic bradycardia may make starting a beta-blocker dangerous, significant symptomatic hypotension might make starting an ARNI difficult, and preshock or shock might make starting quadruple treatment impossible until hemodynamic stability is attained. It may be preferable to start with SGLT2i or ARNI rather than MRA or ACEI in the presence of hyperkalemia.

It is crucial to understand that prompt commencement of all 4 classes of drugs is crucial for clinical outcomes in patients with HFrEF, regardless of the order or timing of initiation. As long as all 4 medications can be started promptly, the order of administration may not matter.

For early quadruple treatment beginning, time is of the importance.

Within the first 30 days of therapy with SGLT2i11 or ARNI, as well as within two weeks after the start of SGLT2i in patients with HFmrEF or HFpEF, there is evidence of an early benefit with GDMT in patients with HFrEF. Therefore, it's crucial to start triple treatment during the first 4 to 6 weeks.

There is evidence that GDMT can be started safely in patients before discharge, and the recommendations provide a class I recommendation for starting GDMT in HF patients who are hospitalized after achieving clinical stability. GDMT may be started and optimized using a variety of care models, such as multidisciplinary care coordination, telemedicine, and remote monitoring. Laboratory monitoring may not be necessary as often as in the past, allowing for virtual, remote, and/or patient uptitration due to the facilitating role of newer HF medications in the commencement of additional GDMT, their beneficial impact on kidney function and potassium levels, and their general safety.

The second stage after starting triple treatment is to optimize dosages.

Following the commencement of triple treatment, drug dosages should be adjusted to target levels as tolerated, according to US HF guidelines. In patients with HF, there is evidence to support a larger benefit from the ideal combination of beta-blockers and ACEI, and emerging data point to benefits from even low doses of ARNI and MRA. Importantly, there is evidence that individuals with HFrEF may reverse remodeling with both newer drugs like ARNI and SGLT2i and older drugs like beta-blockers. Additionally, there is evidence that the newer medicines reduce the rate of sudden cardiac death.

These emphasize the need of GDMT dosage adjustment before considering device therapy such implanted cardioverter-defibrillators in heart failure (HF). The recommendations state that based on the patient's symptoms, vital signs, and laboratory results, titration and optimization of medicine prescribed in accordance with the guidelines should be taken into account as often as every one to two weeks.

Steps to take after starting and perfecting quadruple treatment in HFrEF patients

Following the start of triple treatment and dosage optimization, it's crucial to take the following actions with patients who have HFrEF. Patients who are African-American who have HFrEF with NYHA functional classes III–IV should take hydralazine and nitrates. Ivabradine may be helpful for individuals with symptomatic stable chronic HFrEF in sinus rhythm with a heart rate of less than 70 beats per minute despite using a beta-blocker. Digoxin may be recommended in individuals with symptomatic HFrEF to reduce HF hospitalizations. Vericiguat may be taken into consideration in some high-risk individuals with HFrEF and recent worsening of HF to lower HF hospitalization and cardiovascular mortality.

Implantable cardioverter-defibrillator treatment is advised for patients with LVEF 35% and NYHA functional class II–III symptoms on chronic GDMT who have a realistic expectation of meaningful life for more than a year. Patients who have broad QRS intervals and a left bundle branch block are candidates for cardiac resynchronization treatment. Treatment of specific etiologies, such as cardiac amyloidosis or sarcoidosis, as well as appropriate treatment strategies for comorbidities, such as iron deficiency, atrial fibrillation, ischemic heart disease, valvular heart disease, sleep apnea, and diabetes, are significant additional considerations.

Treatment of HFmrEF, HFpEF, and HFimpEF patients

Patients with HFmrEF, HFpEF, and HFimpEF may benefit from therapy with SGLT2i, according to recent findings from two large randomized studies. Class IIb indications are provided to ARNI, ACEI, ARB, MRA, and beta-blocker for patients with HFmrEF1 and to ARNI, ARB, and MRA for patients with HFpEF based on post hoc analysis and secondary endpoints of current studies. In patients with HFpEF, beta-blockers are not advised due to a lack of benefit-related data. Diuretic medications are advised for all HF patients to reduce congestion, regardless of LVEF, in those with fluid retention. Similar to patients with HFrEF, those with HFmrEF and HFpEF may gain advantages from life style changes and effective treatment of comorbidities such diabetes, hypertension, atrial fibrillation, and sleep apnea.

Compiling everything: The Three Phases of Heart Failure Treatment - Induction, consolidation, and maintenance therapies

Induction therapy is often used to describe the first conventional treatment for an illness in various disease states, such as cancer. Similar to induction treatment in other disease states, the disease-modifying effects of quadruple therapy in HF meet the features of a first-line standard medication, leading in early and substantial improvements in clinical outcomes, including cardiovascular mortality and HF hospitalizations.

Optimization of first-line quadruple therapy dosages is the initial step in HF care, which is then followed by the inclusion of other medications, such as hydralazine and nitrates in patients who are African-American; evaluation of further medicines; and management of comorbidities. These further treatments are conceptually related to treatments referred to as consolidation therapy in other disease states, such cancer, which are administered after induction therapy to consolidate the results attained with the aim of further improving outcomes.

Last but not least, continuation of GDMT is advised 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. This recommendation is similar to maintenance therapy advised in other disease states. If GDMT is stopped, a sizable number of patients may have a relapse with a return of symptoms, signs, and left ventricular failure.

Since first-line treatment is comparable to induction therapy, optimization with additional therapies is similar to consolidation therapy, and continued GDMT is similar to maintenance therapy, the total therapies for HF are therefore similar to other disease management regimens. With the use of these methods, we want to achieve better results, stop the course of HF, detect and treat it sooner, and put HF patients into complete and early remission.

Reference-

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