Heart failure is a clinical syndrome caused by the heart’s inability to provide adequate circulation to meet the body’s needs due to impaired pump function. It may result from various cardiac diseases and mechanisms.

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Typical symptoms include reduced exercise capacity and dyspnea. Typical signs include pulmonary congestion, elevated jugular venous pressure, and peripheral edema.

 

About 90% of heart failure cases are explained by coronary artery disease (chronic ischemia or post–myocardial infarction), hypertension, and left-sided valvular disease (aortic stenosis, mitral regurgitation).

 

Treatment depends on the underlying cause, left ventricular function, and symptom severity (NYHA class).

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Heart failure is divided by LV function into:

• Systolic HF: LVEF ≤ 40%

• Diastolic HF: LVEF > 40%

Heart failure with mid-range ejection fraction 41-49% (HFmrEF) is treated as diastolic heart failure

 

Cornerstones of Pharmacologic Therapy:

• Systolic HF (HFrEF):

  • ACE inhibitor/ARB

  • Beta-blocker

  • SGLT2 inhibitor

  • Spironolactone

  • (ARNI, if persistent symptoms)
     

• Diastolic HF (HFpEF):

  • ACE inhibitor/ARB

  • SGLT2 inhibitor

  • (Spironolactone, limited benefit)

  • ((Beta-blocker, mainly for hypertension or atrial fibrillation))

 

Clinical Stage Classification

Heart failure is categorized into four clinical stages:

• Stage A: At risk, no structural/functional heart disease, no symptoms.

• Stage B: Pre-HF. No symptoms, but structural (eg LVH) or functional abnormalities (reduced EF, abnormal diastolic function) or mildly elevated natriuretic peptides.

• Stage C: Symptomatic HF. Symptoms and signs due to impaired cardiac function. This is when pharmacological therapy begins. Symptoms may improve with treatment.

• Stage D: Advanced HF. Severe symptoms, recurrent hospitalizations, and end-organ dysfunction (kidneys, lungs, liver, peripheral circulation).
   

Goals of treatment:

• Stage A: treat risk factors.

• Stage B: manage structural heart disease to prevent HF.

• Stages C & D: relieve symptoms, reduce hospitalizations, and improve survival.

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Classification by Ejection Fraction

Classification is based on early drug trials demonstrating prognostic benefit when LVEF ≤ 40%.

• heart failure with reduced ejection, HFrEF: HF with reduced EF, LVEF ≤ 40%

• heart failure with mid-range (or mildly reduced) ejection fraction, HFmrEF (treated as diastolic heart failure): HF with mid-range EF, LVEF 41–49%

• heart failure with preserved ejection fraction, HFpEF: HF with preserved EF, LVEF ≥ 50%
   

In diastolic heart failure, LVEF is normal (LVEF ≥ 50%) or mildly reduced (LVEF 41–49%).

 

Prevalence and Epidemiology

Prevalence: 1–2%, probably underdiagnosed

Prevalence Increases sharply with age: ~1% <55 years; ~10% ≥70 years. Average patient age is ~75 years
Equally common in men and women
HFpEF is more frequent in the elderly (>75 years).

Among hospitalized patients: ~50% HFrEF, ~50% HFpEF. Among outpatients: ~60% HFrEF, ~40% HFpEF.

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Etiology

After diagnosing HF, determining the cause is crucial.

• 90%: coronary artery disease, hypertension, left-sided valvular disease (aortic stenosis, mitral regurgitation)

• 10%: very heterogeneous group: e.g. arrhythmias, cardiomyopathies. Patient history and echocardiographic findings may raise suspicion of a rare cause of heart failure, which can then guide further etiological investigations such as laboratory tests, advanced imaging studies, endomyocardial biopsy and genetic testing.
   

Valvular heart disease:

• Surgical or percutaneous correction is often required.

• valvular defect causes pressure (eg aortic stenosis) or volume (mitral regurgitation) overload

• Mitral/tricuspid regurgitation often secondary to HF. Secondary mitral and tricuspid regurgitation may regress with optimized therapy. Secondary MR often caused by annulus dilation.

• Regurgitation severity can fluctuate with ventricular remodeling and as heart failure improves or worsens. In a heart failure patient with valvular disease, worsening of symptoms often requires reassessment of the severity of the valvular defect.
   

Coronary disease:

• Post-MI scar → impaired contraction

• Chronic ischemia → fibrosis, impaired relaxation of LV→increased filling pressures, progressive LV dysfunction
   

Hypertension:

• Pressure overload → hypertrophy, fibrosis, diastolic dysfunction
   

Other causes:

• Toxins (alcohol, chemotherapy)

• Genetic predisposition

• Myocarditis, infiltrative or storage diseases

• Aging also increases myocardial fibrosis. The myocardium becomes stiffer, and diastolic function becomes impaired.
   

Pathophysiology:

Neurohormonal activation (RAAS, sympathetic system, endothelin, cytokines) → maladaptive remodeling → systolic and diastolic dysfunction. In systolic HF neurohormonal activation is central.

 

Diastolic HF: impaired LV relaxation/filling → elevated LV filling pressure → dyspnea, pulmonary congestion, pulmonary hypertension, right-sided HF. An increase in left atrial pressure, when prolonged and accompanied by neurohormonal responses, leads to elevated pulmonary artery pressure, elevated right ventricular filling pressure, and right atrial pressure.

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Right-sided HF alone is rare, typically in pulmonary hypertension or arrhythmogenic RV dysplasia.

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Diagnosis

If a patient has symptoms and/or findings characteristic of heart failure, and reduced LVEF or echocardiographic findings consistent with diastolic dysfunction are present, the diagnostic criteria for heart failure are fulfilled.

 

Diastolic heart failure is a condition in which the patient has symptoms and findings consistent with heart failure, but the ejection fraction is not clearly reduced on imaging (e.g. echocardiography, cardiac MRI). LVEF is normal or only mildly reduced (41–49%), and the heart is not enlarged. However, diastolic left ventricular expansion and filling are impaired, either in terms of early diastolic active relaxation, late diastolic passive relaxation, or both.

Although LVEF appears normal on MRI or echocardiography, more sensitive methods have demonstrated that systolic function is also abnormal in diastolic heart failure (impaired contraction and response to increased load). Conversely, in systolic heart failure, diastolic function is often abnormal as well (diastolic dysfunction).

Because of left ventricular dysfunction, increases in systemic blood pressure and changes in peripheral vascular resistance have an unusually strong impact on the heart.

Impaired ventricular relaxation leads to increased ventricular filling pressure and pulmonary congestion, particularly during exertion. This causes dyspnea and reduced exercise tolerance and, if untreated over a longer period, results in elevated pulmonary artery pressure and signs of right-sided heart failure.

In diastolic heart failure, reduced cardiac output manifests especially during exercise or stress situations when the body requires higher cardiac output, such as during infection, fever, or surgery. Tachycardia shortens diastole—the filling phase—thereby reducing stroke volume, so cardiac output does not increase adequately, and may even decrease.

 

Symptoms

Most symptoms and clinical findings are nonspecific. Only about 30% of patients with typical symptoms and findings actually have heart failure.

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Diagnostic tools

ECG is rarely normal in patients with heart failure. If the ECG is completely normal, the probability of heart failure is only 2% in an acute presentation and 10–14% in a gradual presentation. On the other hand, the diagnostic accuracy of an abnormal ECG for heart failure is very limited (poor positive predictive value). ECG abnormalities in heart failure include Atrial fibrillation, PVCs, LVH, RVH, Q waves, LBBB, RBBB, LAFB

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Chest X-ray is a basic investigation when heart failure is suspected. Pulmonary venous congestion reflects left atrial pressure fairly well. Congestion on a chest X-ray strongly suggests heart failure.

The findings on a chest X-ray are less clear in chronic heart failure or in patients with chronic pulmonary disease.

A normal chest X-ray does not exclude heart failure.

 

BNP (B-type natriuretic peptide) is a hormone produced by the ventricles, with its synthesis and secretion activated within hours of the onset of increased cardiac load. It is possible to measure either BNP itself or the concentration of the N-terminal fragment (NT-proBNP) produced as a result of the metabolism of its precursor.

 

The upper limits for ruling out heart failure in the non-acute setting are 35 pg/mL for BNP, and 125 pg/mL for NT-proBNP.

Very high concentrations (e.g., NT-proBNP > 2,000 ng/L or BNP > 400 ng/L) indicate heart failure with high certainty.

 

The ESC Heart Failure Association recommends age-specific rule-in NT-proBNP thresholds for early diagnosis of HF (and guide to further evaluation and echo): ≥125pg/ml for patients aged under 50 years, ≥250pg/ml for patients aged 50-75 years, and ≥500pg/ml for patients over 75 years

 

following was found in the study which the recommendation is based upon:

NT-proBNP threshold ≥125pg/mL had sensitivity 94.6%, specificity 50.0%

Age-specific NT-proBNP thresholds performance:

Below 50 years (≥125pg/mL): Sensitivity 83.5 %, specificity 77.6% 

50 to 75 years ≥250pg/mL: Sensitivity 88.5%, specificity 67.8%

Above 75 years ≥500pg/mL: Sensitivity 84.4%, specificity 63.5%

 

Several factors influence natriuretic peptide concentrations. NT-proBNP levels increase with age, rising up to 6–7-fold. Concentrations are also higher in women than in men.

In renal impairment, NP levels are elevated:

• Mild impairment (GFR > 45 ml/min/1.73 m²) does not affect concentrations.

• Moderate impairment (GFR 31–45 ml/min/1.73 m²) doubles NT-proBNP concentrations.

• Severe impairment (GFR 15–30 ml/min/1.73 m²) increases NT-proBNP concentrations fourfold.
   

NP concentrations correlate with the severity of heart failure symptoms.

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With medical therapy (including diuretics administered for other reasons), symptoms may improve and NP concentrations may decrease.

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Ischemic heart disease is a common cause of heart failure. Coronary computed tomography angiography or invasive coronary angiography are usually used in diagnosis. Myocardial perfusion imaging/scintigraphy or stress echocardiography may also be utilized.

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Cardiac MRI is a key method in investigating the etiology of non-ischemic heart disease, and it can help guide further diagnostic studies (such as cardiac scintigraphy, PET, endomyocardial biopsy).

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Endomyocardial biopsy remains a useful diagnostic tool, particularly for accumulative diseases, cardiac sarcoidosis, and rapidly progressive myocarditis.

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Genetic Testing

Genetic testing is indicated only when there is a clinical suspicion of an inherited cardiomyopathy.

An inherited cardiomyopathy should be particularly suspected if:

• The patient is young (<50 years), or

• A first-degree relative has a confirmed cardiomyopathy (dilated, hypertrophic, arrhythmogenic right ventricular), or

• Two or more family members have atrial fibrillation before age 40, or had an arrhythmia requiring pacemaker implantation
   

In idiopathic dilated cardiomyopathy, where other etiologies have been excluded, approximately 30–50% of cases are due to inherited cardiac disease.

Establishing a molecular genetic diagnosis should be pursued, as these conditions may lead to severe heart disease and may ultimately require heart transplantation.

 

Pharmacological Treatment of Heart Failure

HF stage A (at risk) & B (structural cardiac abnormalities) : treat risk factors and underlying disease (eg HTN, CAD, valvular disease).

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Stage C & D (symptomatic HF): disease-modifying therapy.

 

Clinical heart failure is considered present only when it becomes symptomatic for the first time. The cornerstone medications for symptomatic heart failure include an ACE inhibitor (or an ARB), an SGLT2 inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist. The evidence for prognostic benefit is stronger the lower the ejection fraction is.

 

Cornerstones of pharmacological treatment in heart failure

Systolic heart failure (HFrEF):

• ACE inhibitor (ARB if ACEi intolerant)

• SGLT2 inhibitor

• Beta-blocker

• Mineralocorticoid receptor antagonist

  • Clear prognostic benefit in systolic heart failure

• Diuretic if fluid retention

  • Symptom relief only, no prognostic benefit

(ARNI (angiotensin receptor–neprilysin inhibitor))

The combination of an angiotensin receptor blocker and a neprilysin inhibitor can be used in systolic heart failure as a replacement for an ACE inhibitor or ARB in patients who continue to have limiting heart failure symptoms (NYHA II–IV) despite maximal conventional therapy.

 

Diastolic heart failure (HFpEF / HFmrEF):

• ACE inhibitor / ARB

• SGLT2 inhibitor

• (Mineralocorticoid receptor antagonist)

  • Limited evidence of prognostic benefit in diastolic heart failure; may be tried in symptomatic patients despite maximal therapy, or in those with hypertension

• ((Beta-blocker))

  • Often indicated for the treatment of atrial fibrillation; otherwise, in diastolic heart failure, mainly for blood pressure control

  • Based on randomized and observational studies beta-blockers offer no benefit and may even be harmful in diastolic heart failure if there is no other indication for their use

• Diuretic if fluid retention

  • Symptom relief only, no prognostic benefit

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General Principles of Pharmacological Treatment

Medication is titrated upward every 1–4 weeks. At the start of therapy and during dose increases, excessive blood pressure reduction is common. A temporary reduction in diuretic dose often helps patients tolerate therapy better, allowing gradual up-titration to the target dose.

Excessive blood pressure reduction can be defined as systolic blood pressure < 85–90 mmHg, mean arterial pressure < 65 mmHg, or symptomatic hypotension.

 

When adjusting the doses of ACE inhibitors, ARBs, diuretics, spironolactone, or ARNI, monitoring of sodium, potassium, and creatinine is recommended within 1–2 weeks.

 

Titration of heart failure medication to the highest tolerated doses is effective therapy. Rapid up-titration reduces clinical endpoints and is both effective and safe.

 

Heart failure medication is generally permanent. There are few studies on discontinuing therapy. Discontinuation of beta-blockers or drugs acting on the renin–angiotensin–aldosterone system in heart failure patients has led to worsening of symptoms, adverse structural remodeling of the heart, and poorer prognosis.
In certain transient or fully reversible causes of heart failure (e.g., peripartum cardiomyopathy, Takotsubo syndrome, severe myocarditis, corrected valvular disease), stopping therapy can be considered once the patient has recovered and left ventricular function has normalized. However, there is very little research the subject.

 

Treatment in elderly patients is based on meta-analyses or studies conducted in younger patients. Orthostatic hypotension is common in the elderly, and therefore the risk of falls should be minimized by avoiding excessively high doses of blood pressure–lowering medications.

 

ACE inhibitors

Reduce mortality and hospitalizations in patients with systolic heart failure.

ACE inhibitors and angiotensin receptor blockers may also reduce rehospitalizations in patients with diastolic heart failure. Most of the evidence suggests that these drugs relieve symptoms in these patients.

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An ACE inhibitor or an ARB is started at a low dose, which is increased every 1–2 weeks to the target dose or the maximum dose tolerated by the patient.

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Combined use of an ACE inhibitor and an angiotensin receptor blocker does not improve prognosis and increases adverse effects, and therefore is not recommended.

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The most common side effect of ACE inhibitors, dry cough, can appear even long after starting therapy. An ACE inhibitor can be replaced with an ARB if the patient develops an ACE inhibitor–related dry cough. If a patient is already taking an ARB at the time of HF diagnosis, there is no need to switch to an ACE inhibitor.

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If plasma potassium rises above 5.5 mmol/L, the dose should be reduced; if it rises above 6.0 mmol/L, the drug should be paused or discontinued.

If renal function declines (serum creatinine rises by more than (30–)50% from baseline or exceeds 266 µmol/L, or eGFR falls below (25–)30 ml/min/1.73 m²), the dose should be reduced or the drug discontinued

A 10% to 20% increase in serum creatinine or <20% fall in GFR can be anticipated in patients as therapy with ACE inhibitors is initiated, especially in patients with chronic kidney disease. This is not in itself an indication to discontinue treatment. The serum creatinine should stabilize or decline in 4 to 8 weeks of therapy intiation. A continuous decline in GFR should prompt closer follow-up and reduction in ACEi dose particularly if the GFR progressively decreases after 4-8 weeks.

The GFR is especially dependent on Angiotensin II during dehydration, in patients with atherosclerotic disease in smaller preglomerular vessels, in patients with afferent arteriolar narrowing due to hypertension, high-grade bilateral renal artery stenosis, or stenosis of a dominant or single kidney, as in a renal transplant recipient.

The risk of ACE inhibitor–induced acute renal failure is also higher in patients with chronic renal insufficiency of any cause. Patients with few surviving nephrons have adaptive changes that maintain the GFR, including a hyperfiltration response. Reversal of this hyperfiltration by ACE inhibitors is believed to be one of the mechanisms of benefit in these patients even though it will inevitably lead to an initial fall in GFR and rises in blood urea nitrogen and serum creatinine.

Severe hyperkalemia with ACE inhibitors is uncommon. In the SOLVD trials, only 6.4% of the 1285 patients given enalapril developed serum potassium levels >5.5 mEq/L. The most relevant factor for predicting hyperkalemia is CKD and an elevated baseline serum creatinine >1.6 mg/dL (144 μmol).

 

Angiotensin receptor blockers

There are currently no compelling indications to routinely use ARBs as first-line treatment instead of ACE inhibitors in HF.

In a large meta-analysis, the effect of angiotensin receptor blockers (ARBs) in reducing mortality or morbidity in systolic heart failure was similar to that of ACE inhibitors.

ARBs were associated with significantly fewer adverse effects leading to treatment discontinuation compared to ACE inhibitors. They can therefore be used in the treatment of heart failure in patients who cannot tolerate ACE inhibitors due to side effects.

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The impact of ARBs on prognosis and symptoms in patients with diastolic heart failure has been considered modest. However, most patients with diastolic heart failure also have hypertension, and ARBs are effective medications for treating blood pressure.

 

SGLT2 Inhibitors

Empagliflozin and dapagliflozin have demonstrated prognostic benefit in both systolic and diastolic heart failure. They reduce mortality and hospitalizations.

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Always given at a standard dose (dapagliflozin 10 mg once daily, empagliflozin 10 mg once daily).

 

With long-term use, SGLT2 inhibitors have a protective effect on the kidneys. However, initiation of therapy is often associated with a mild increase in serum creatinine or a decrease in glomerular filtration rate (eGFR). Following continuous treatment of SGLT2i, there is a partial eGFR recovery and an improvement in the slope of the eGFR decrease in the long term.

Traditionally, RAAS inhibitors have been recommended to be adjusted or reevaluated in accordance with the current guideline or recommendation when an abrupt decline in eGFR of ≥30% occurs after starting RAS inhibitors, and the threshold in eGFR decline of 30% has been also applied into the case of SGLT2i treatment. This probably should not be the case.

Initiation of an SGLT2i in a population of patients with heart failure results in a “dip” in eGFR of >10% in fewer than half of the patients within the first month of therapy, with an average for the population a modest 3 to 6 mL/min/1.73 m2 reduction in eGFR. This “dip” is generally small and may actually be associated with long-term benefit.

Given that larger declines (>30% worsening in eGFR or >0.5 mg/dL increase in serum creatinine) are uncommon with SGLT2i initiation, a large creatinine increase should prompt evaluation for other factors contributing to the change in creatinine (eg dehydration or nephrotoxin exposure)

In a study published in AHA journals it was concluded that an abrupt initial decline of eGFR >30% following SGLT2i therapy initiation may be a sign of a higher risk for increased serum potassium variability, hyperkalemia, and hypokalemia, and patients should undergo further evaluation and treatment for the underlying risk factors if they experience this. In contrast, an initial eGFR decline of <30% should be tolerated following SGLT2i treatment as there is no such correlation in this group, and therapy should not be discontinued for an acute decline in kidney function within this range.

in the DELIVER heart failure trial, an initial dip over 10 % was not associated with adverse kidney outcomes in patients on dapagliflozin, supporting continuation rather than stopping.

In a study published in Circulation it was concluded that continuing SGLT2 inhibitors—even in those experiencing dips of ≤10 %, >10 %, or even >30 %—was associated with reduced risk of adverse cardiovascular and kidney outcomes, compared with stopping. Concerns about eGFR dipping should not preclude use, and occurrence of eGFR dip after SGLT2i initiation may not warrant discontinuation.

Physicians should be aware that the initial “dip” in eGFR dip occurs shortly and if eGFR drops >30% consequent electrolyte changes might follow and this should prompt more intensive follow-up.

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Beta-Blockers

Reduces mortality and hospitalizations in patients with systolic heart failure

The strongest evidence comes from studies with bisoprolol, carvedilol, and metoprolol.

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The main objective in dosing of a beta-blocker is heart rate reduction. In clinical trials, mortality reduction has been associated with the degree of heart rate lowering.

In stable patients with sinus rhythm, the appropriate resting heart rate is usually 60–70 bpm.

In patients with atrial fibrillation and heart failure, the target resting heart rate is about 70–90 bpm.

Treatment should begin with a low dose, with dose increments every 2–4 weeks until the target dose or the maximum tolerated dose is reached.

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In unstable severe systolic heart failure, dose escalation of a beta-blocker may be associated with hypotension or worsening heart failure symptoms due to negative inotropic effect.

 

Mineralocorticoid receptor antagonists

MRAs (spironolactone or eplerenone) are recommended in all patients with HFrEF to reduce mortality, the risk of HF hospitalization and to improve symptoms.

In systolic heart failure, they improve left ventricular ejection fraction, exercise capacity, and left ventricular remodeling.

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In diastolic heart failure, MRA can be introduced if the patient continues to have limiting symptoms of heart failure or elevated blood pressure despite maximal treatment with an ACE inhibitor and an SGLT2 inhibitor. Spironolactone may reduce mortality and rehospitalizations in patients with diastolic heart failure.

 

The starting dose of spironolactone is 12.5 mg/day. The dose can be increased to 25–50 mg/day after 4–8 weeks.

 

Check serum creatinine and electrolytes at 1 and 4 weeks after starting/increasing dose and at 8 and 12 weeks; 6, 9, and 12 months; 4-monthly thereafter.

 

Use of a mineralocorticoid receptor antagonist may be associated with an increase in serum potassium levels and a decline in renal function. Spironolactone is best avoided in patients with a GFR <30 mL/min.

A meta-analysis of the RALES, EMPHASIS-HF and TOPCAT Americas trials revealed that only 2.6% of the participants had an eGFR ≤30 ml/min/1.73 m2. Also steroidal MRAs had a neutral effect on composite CV outcomes in patients with an eGFR ≤30 ml/min/1.73 m2, differing significantly from other eGFR categories. Thus the use of steroidal MRAs in patients with an eGFR <30 ml/min/1.73 m2 lacks strong evidence.

If K rises above 5.5 mmol/L or creatinine rises to 221 lmol/L (2.5 mg/dL) or eGFR declines to <30 mL/min/1.73 m2, halve the dose and monitor blood chemistry closely.

If K rises to >6.0 mmol/L or creatinine to >310 lmol/L (3.5 mg/dL) or eGFR declines to <20 mL/min/1.73 m2, stop MRA, monitor blood chemistry closely and search for other causes of hyperkalemia (eg hypovolemia and AKI). If MRA is initiated again, monitor closely.

 

As with RAAS inhibitors, treatment dose usually reduced or treatment is stopped if eGFR declines >30% from baseline especially if it continues to decline after 4-8 weeks. In BARACK-D trial spironolactone was discontinued if a participant’s eGFR decreased 20% between visits or 25% from their baseline.

Age, higher level of NT-proBNP and lower eGFR are potential predictors of worsening of RF after initiation of MRA treatment. Caution should be advised when using spironolactone in patients with CKD and potassium of ≥5.0 mmol/L and eGFR ≤45 ml/min/1.73 m2 and NT-proBNP concentration >1550 ng/L for safety reasons.

The use of spironolactone in patients with chronic kidney disease (CKD) also has potential benefit but is complicated by risks of hyperkalemia and worsening kidney function. 

Increased serum creatinine levels after the initiation of MRAs are caused by renal haemodynamic effects. A US-based HF registry, encompassing 157 439 patients with HF and a left ventricular ejection fraction (LVEF) <40%, revealed that >60% of these patients also had CKD. There was an obvious decrease in prescription rates of MRAs with lower eGFR categories: 45%, 40%, 35%, 26%, 14% and 5% for eGFR ≥90, 60–89, 45–59, 30–44, <30 ml/min/1.73 m2 and dialysis, respectively.

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ARNI (sacubitril–valsartan)

Can be used in systolic heart failure (LVEF < 35%) as a replacement for an ACE inhibitor or an angiotensin receptor blocker in patients who continue to have heart failure symptoms (NYHA II-IV) despite optimized therapy.

 

therapy is started at a low initial dose, with gradual up-titration to the target dose

 

When switching from an ACE inhibitor to sacubitril–valsartan, the ACE inhibitor must be discontinued 36 hours before the first dose of sacubitril–valsartan to avoid angioedema. An angiotensin receptor blocker can be switched directly to sacubitril–valsartan without a washout period.

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Diuretics

Used for symptom relief and to reduce exacerbations in patients with fluid retention. There is no randomized trial evidence that diuretic therapy improves prognosis in patients on adequate heart failure medication.

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If a patient has fluid retention, diuretic therapy is initiated, e.g., with furosemide at a starting dose of 20–40 mg once or twice daily. The dose is increased or decreased according to clinical response.

Since diuretic therapy is not known to affect prognosis, it may be discontinued in asymptomatic patients without a tendency for fluid retention.

 

The most commonly used diuretic for heart failure in Europe is the loop diuretic furosemide.

 

Use the lowest effective dose (usually 20–160 mg/day divided into 1–2 doses). Renal impairment and chronic use of diuretics increase the required dose.

If the required dose increases or hypokalemia develops, addition of a mineralocorticoid receptor antagonist (e.g., spironolactone 12.5–25 mg/day) may be considered.

 

For mild fluid retention, a thiazide diuretic (e.g., hydrochlorothiazide 12.5–25 mg/day) may also be used.

 

In selected cases (resistant fluid retention requiring large furosemide doses), hydrochlorothiazide (12.5–50 mg/day) or low-dose metolazone (2.5–5 mg once or twice weekly) can be used alongside furosemide. Combination therapy requires closer monitoring of serum sodium, potassium, and creatinine.

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Digoxin

Can be used for heart rate control in heart failure patients with atrial fibrillation when adequate rate reduction cannot be achieved even with maximal beta-blocker therapy.

 

Does not reduce mortality in patients with systolic heart failure.

May reduce symptoms and the need for rehospitalization in heart failure patients in sinus rhythm who remain symptomatic despite maximal therapy. However, the evidence is uncertain, as most studies on digoxin were conducted before the widespread use of modern heart failure medications.

 

Digoxin has a narrow therapeutic range; therefore, serum digoxin levels must be monitored to ensure safety.

Monitoring is necessary when the dose is adjusted, renal function declines, or drug interactions are suspected. In elderly patients, special caution is required, as aging is often associated with reduced renal function and decreased volume of distribution, both of which increase the risk of overdosing.

 

The goal should always be to use the lowest effective dose to control atrial fibrillation.

 

Therapeutic levels:

When used to prevent exacerbations of heart failure, older studies suggest that digoxin at low serum concentrations (0.5–0.9 ng/ml = 0.64–1.15 nmol/L) is as effective as at higher levels.

The general recommended target serum concentration is < 1.2 nmol/L, regardless of whether the patient has heart failure or atrial fibrillation. Serum concentrations above 1.5 nmol/L have been associated with an increased risk of mortality.

Toxic effects of digoxin become more common when trough concentrations exceed 2.5 nmol/L.

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Other Medications

Vericiguat improves endothelial function via nitric oxide–mediated pathways. When added to standard therapy, vericiguat reduces the number of hospitalizations in patients with systolic heart failure.

 

Ivabradine is a selective sinus node If-channel inhibitor that lowers heart rate in patients in sinus rhythm. In the SHIFT trial, ivabradine significantly reduced rehospitalizations but had no effect on mortality in patients with systolic heart failure who were in sinus rhythm with a resting heart rate above 70 bpm despite standard heart failure therapy.

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Anticoagulation and Antithrombotic Therapy in Patients with Sinus Rhythm

Heart failure patients in sinus rhythm do not benefit from routine anticoagulation therapy.

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Anticoagulation may be considered in a patient with systolic heart failure in sinus rhythm if there is a history of ischemic stroke, TIA, other arterial embolism, or venous thrombosis.

 

Up to 50% of newly diagnosed heart failure patients have atrial fibrillation, and conversely, about one-third of patients with newly diagnosed atrial fibrillation also present with heart failure.

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Prognosis

If left untreated, heart failure progresses, symptoms worsen, and functional capacity declines. Untreated heart failure is also associated with high mortality.

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Assessing prognosis in heart failure patients is challenging. The natural course includes exacerbations, and it may be difficult to distinguish between end-stage heart failure and an acute episode that is followed by recovery. Heart failure is a heterogeneous syndrome, and prognosis varies considerably depending on its clinical presentation.

 

Determinants of prognosis include:

• Etiology of heart failure

• Extent of myocardial injury at diagnosis

• Severity of cardiac dysfunction
   

Early initiation of effective pharmacological therapy and treatment of the underlying cause improve prognosis.

Although prognosis has improved with advances in therapy, it remains poor, particularly in elderly patients. Because heart failure develops as an end stage manifestation of cardiac disease, overall mortality remains high.

• Annual mortality in chronic HF: ~7–10%

• Five-year mortality: ~40–50%

Prognosis varies widely depending on severity and risk factors. Diastolic HF generally has a somewhat better prognosis than systolic HF.

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Causes of death:

• In systolic HF: sudden cardiac death and cardiovascular causes account for up to 80%

• In diastolic HF: about 50% of deaths are non-cardiovascular
   

Prognosis in Acute heart failure:

20–30% die within 1 year after hospitalization

5-year mortality ~70% after hospitalization. Average life expectancy after hospitalization is just ~2.4 years

If the precipitating cause of acute HF (e.g., valvular disease, severe hypertension, ischemia) is treatable without permanent structural or functional impairment, prognosis is significantly better.

 

End-stage HF

In end-stage HF, hospitalizations increase markedly. During the last 6 months of life, patients typically spend ~25% of the time in hospital.

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Ventricular Arrhythmias

Ventricular Tachycardia (VT)

• Patients with systolic heart failure have an increased risk of ventricular tachycardia, and implantable cardioverter-defibrillator (ICD) therapy is indicated for some patients.

• The most important treatment to prevent VT is optimal pharmacologic management of heart failure and the underlying cardiac disease.

• VTs are often monomorphic and result from scar tissue due to a prior infarction (electrical re-entry circuits around the scar).

• In inflammatory cardiomyopathies and acute ischemia VTs may be polymorphic.

• Management includes ICD implantation for secondary prevention of sudden cardiac death, antiarrhythmic drug therapy, and in some cases catheter ablation.
   

Management:

• The most common antiarrhythmic drugs in heart failure are beta-blockers.

• Sotalol or amiodarone may also be used.

  • Sotalol carries a risk of proarrhythmia due to QT prolongation (torsades de pointes) and is more often used in patients who already have an ICD for secondary prevention.

• If drug therapy fails to achieve sufficient effect, catheter ablation can be considered. In some cases—particularly in ischemic heart failure with scar-related tachycardia—ablation may even be suitable as a first-line therapy.

• Patients with recurrent VT should be considered for ablation.

• Monitoring of electrolytes, especially hypo- and hyperkalemia, is essential in arrhythmia prevention and management in heart failure.
   

Premature Ventricular Contractions (PVCs)

• PVCs are very common in heart failure patients and are often related to underlying cardiac disease.

• More than 10,000 PVCs/day (especially >20,000/day) may lead to impaired systolic function.

• A high burden of PVCs or short nonsustained VT episodes (NSVT) is associated with increased risk of mortality.
   

Management:

• Typically treated with beta-blockers (and potassium supplementation if indicated) alongside treatment of the underlying heart disease.

• In cases of very frequent PVCs, amiodarone or catheter ablation may be considered.

• In patients with cardiac resynchronization therapy devices (CRT), frequent PVCs may reduce the percentage of effective biventricular pacing. In these cases, ablation or amiodarone may be considered if beta-blockers are insufficient.

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Pacemaker Therapy in Heart Failure

Pacemaker therapy in heart failure patients may be indicated for:

• Treatment of bradycardia or correction of atrioventricular (AV) conduction disturbances

• Correction of wide QRS complexes due to left bundle branch block (LBBB) in systolic heart failure (cardiac resynchronization therapy = CRT)

• Management of severe arrhythmias and prevention of sudden cardiac death with an implantable cardioverter-defibrillator (ICD) or a combined resynchronization-defibrillator device (CRT-D, where D = defibrillator)

 

Pacemakers in AV Conduction Disorders

Pacemaker implantation is recommended for patients with heart failure, both in sinus rhythm and atrial fibrillation, regardless of NYHA class or QRS duration, if there is AV conduction disturbance requiring ventricular pacing.

Right ventricular pacing of more than 20% in bradycardia therapy may cause clinically significant LV dyssynchrony and impaired LV function in up to 20% of patients over couple of years. If symptomatic systolic heart failure develops (EF ≤ 35%) despite optimal medical therapy due to chronic ventricular pacing, upgrading to CRT should be considered.

 

Left Bundle Branch Block (LBBB) and CRT

LBBB is observed in 15–27% of heart failure patients. It causes dyssynchronous contraction of the LV walls, reducing pumping efficiency. QRS widening predicts increased mortality risk.

CRT improves LV contraction by restoring synchrony through pacing from both the right ventricle and the LV lateral wall.

Successful CRT improves contractility, reduces LV dilatation, and can relieve mitral regurgitation in some patients.

 

CRT improves prognosis and reduces hospitalizations in patients with poor LV systolic function (LVEF < 35%) and QRS duration > 140 ms despite optimal medical therapy.

For CRT to be effective, continuous biventricular pacing is required. If pacing percentage is < 90–95%, AV nodal–blocking therapy may be added, and AV node ablation considered if necessary, rendering the patient pacemaker-dependent.

The duration of the paced QRS complex is the best predictor of a favorable CRT response.

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In ischemic heart failure, CRT benefit may be reduced due to scar tissue.

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Patient Selection for CRT

CRT is not beneficial in patients with narrow QRS (≤ 130 ms), unless ventricular pacing is indicated for AV block.

CRT has no proven benefit in right bundle branch block (RBBB).

Prognostic impact of CRT has only been shown in patients in sinus rhythm. In persistent atrial fibrillation, CRT is considered only for severely symptomatic patients (NYHA III–IV) with EF ≤ 35% and QRS prolongation (≥ 130 ms, preferably ≥ 150 ms) and LBBB. Competing intrinsic conduction in AF reduces CRT effectiveness.

 

ICDs: Prevention of Sudden Cardiac Death

Severe systolic heart failure increases the risk of life-threatening ventricular arrhythmias.

Secondary prevention: ICD implantation is indicated after life-threatening ventricular arrhythmia (e.g., cardiac arrest, ventricular fibrillation, or sustained VT without a reversible cause). Cardiac arrest within 48h of acute MI is not an indication.

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Primary prevention: Prophylactic ICDs are intended to prevent sudden death in high-risk patients.

• Recommended in symptomatic ischemic cardiomyopathy with EF ≤ 35% despite ≥3 months of optimal therapy.

• May be considered in symptomatic dilated (non-ischemic) cardiomyopathy with EF ≤ 35% despite ≥3 months of therapy.

• Other cardiomyopathies (hypertrophic, arrhythmogenic, genetic forms, sarcoidosis) have specific ICD indications.

• If QRS > 130 ms, a CRT-D system should be considered.

 

Hypertension

Hypertension, along with coronary artery disease, is the most important underlying cause of heart failure.

Hypertension is present in 50–60% of patients with systolic heart failure, and the prevalence is even higher in those with diastolic heart failure.

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Impact of blood pressure reduction:

Lowering blood pressure by 10/5 mmHg reduces the risk of developing heart failure by approximately 40%. Greater reductions lower the risk even further.

In a randomized trial, a stricter blood pressure target (systolic BP < 120 mmHg) reduced the incidence of heart failure by nearly 40% compared with target of systolic BP < 140 mmHg. Achieving the stricter target required an average of 2.8 medications.

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Treatment targets:

The usual blood pressure goal for heart failure patients is < 130/80 mmHg. No strict lower limit is defined; instead, the aim is to use maximally tolerated doses of heart failure medications.

Cardioactive calcium channel blockers (diltiazem or verapamil) and nifedipine are contraindicated in systolic heart failure. Other dihydropyridine calcium channel blockers may be used in heart failure patients.

 

Coronary Artery Disease

Coronary artery disease, and particularly prior myocardial infarction, is the most important cause of heart failure. Its prevalence among heart failure patients is approximately 40–50%.

Ischemic etiology is more common in systolic heart failure (59%) compared with diastolic heart failure (43%).

At the time of diagnosing heart failure, it is important to evaluate the role of coronary artery disease in the development of the condition.

Myocardial ischemia may also cause episodes of worsening heart failure without typical angina pectoris symptoms.

Invasive treatment of heart failure patients can improve symptoms but has little effect on prognosis. The evidence for the effect of revascularization on prognosis and hospitalization rates due to heart failure is limited.

 

Electrolyte Disturbances

Hypokalemia and hyponatremia are common in heart failure patients.

Hyponatremia is the most frequent electrolyte abnormality (seen in up to 30% of patients) and is related both to neurohormonal activation (reduced water excretion) and to the use of diuretics.

Both hypokalemia and hyperkalemia increase the risk of arrhythmias.

 

Hyperkalemia management:

• Mild hyperkalemia (serum K 5.0–5.4 mmol/L): does not require discontinuation of heart failure medications, but any potassium supplements should be stopped.

• Moderate hyperkalemia (serum K 5.5–6.0 mmol/L): reduce the doses of potassium-raising medications (MRA, ACE inhibitors, ARBs).

• Severe hyperkalemia (serum K > 6.0 mmol/L): discontinue potassium-raising drugs. If symptoms or ECG changes are present, hospitalization is generally required.
   

Reintroduction of therapy:

• Heart failure medications should be restarted once potassium has decreased to < 5.0 mmol/L.

• Dose adjustments may be necessary to avoid recurrence of hyperkalemia.
   

Chronic hyperkalemia:

• Potassium-lowering therapy can be considered (sodium polystyrene sulfonate, sodium zirconium cyclosilicate, or patiromer).

• Long-term use of sodium polystyrene sulfonate is not recommended in heart failure patients.

• Patiromer contains less sodium compared to sodium zirconium cyclosilicate.

 

Iron Deficiency and Anemia

Iron deficiency and anemia are common findings in heart failure patients.

Iron deficiency is present in 30–40% of patients with systolic heart failure, although only some of them also have anemia.

 

Regular monitoring of hemoglobin (every 3–6 months) is necessary in heart failure patients.

 

Assessment of iron status:

Measurement of ferritin, transferrin saturation (TSAT), and soluble transferrin receptor (sTfR) is indicated in all anemic patients and in symptomatic patients (NYHA II–IV) even without anemia.

In practice, ferritin and TSAT are used to assess the need for iron therapy; threshold values for sTfR have not yet been defined.

Iron status should be reassessed annually

 

Intravenous Iron therapy:

IV iron therapy should be considered in patients with systolic heart failure who remain symptomatic despite optimal medical therapy and who meet the criteria for iron deficiency.

Criteria for Iron deficiency (S-ferritin < 100 µg/L or ferritin 100–300 µg/L with TSAT < 20%)

Treatment appears to improve subjective wellbeing and slightly improves objective exercise capacity in patients with chronic systolic heart failure (LVEF < 45%). There is no evidence for reduced mortality.

 

Atrial Fibrillation

Heart failure predisposes to atrial fibrillation. AF is the most common arrhythmia in both systolic and diastolic heart failure, with a prevalence of about 25–40%.

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When planning a treatment strategy (rate control vs rhythm control), special attention should be paid to the patient’s symptoms during AF.

In AF, cardiac output may decrease due to the lack of effective atrial contraction. A rapid ventricular rate shortens diastole, which often worsens heart failure symptoms, especially in diastolic heart failure.

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Rate control in persistent or permanent AF:

Controlling a rapid ventricular response is a key part of managing heart failure patients with AF.

In stable patients, the target resting heart rate is approximately 70–90 bpm.

Rate control is usually achieved with a beta-blocker, and digoxin may be added if needed. Amiodarone is very rarely used solely for rate control.

If drug therapy fails to achieve adequate rate control, atrioventricular node ablation with pacemaker implantation should be considered.

 

Lung disease

In heart failure, chronic obstructive pulmonary disease (COPD) or asthma may be overdiagnosed.

 

Pulmonary function tests are recommended only during a stable phase of heart failure, when the patient is free of significant fluid overload.

 

Heart failure causes reductions in lung volumes and forced expiratory capacity, which may be partly reversible.​​