Heart Failure (Cardiac Insufficiency): Drug Therapy

Therapeutic Targets

  • Improvement of symptomatology and “cardiac strength“.
  • Improvement of the quality of life

Therapy recommendations

Oxygen administration; Indications: Patients with hypoxia (SpO2 <90%), dyspnea, or acute heart failure.

Drug group Mechanism of action Acute HI Chronic HI
ACE inhibitors/alternatively, if intolerantAngiotensin II receptor subtype 1 antagonists (synonyms: AT1 antagonists, “sartans“). Lowering preload/afterload – +
Nitrates Lowering preload/afterload + (+)
Diuretics (here: MRA* * ) Excretion ↑ + +
Cardiac glycosides Contractility ↑ (+) for HRST* +
Catecholamines Contractility ↑ + –
Phosphodiesterase III inhibitors Contractility ↑ + –
Beta blocker Contractility ↓ + heart rate ↓ – +
Sinus node inhibitor Ivabradine – +

* chronic tachyarrhythmic atrial fibrillation* mineralocorticoid receptor antagonist.

Staged drug therapy according to NYHA classes in heart failure with reduced LVEF (left ventricular ejection fraction) [S3 guideline].

Prognosis Active ingredients NYHA I (asymp-tomatic LV dysfunction). NYHA II NYHA III NYHA IV (only in cooperation with cardiologists)
Prognosis-improving ACE inhibitors Indicated indexed indexed indexed
Angiotensin receptor blocker For ACE inhibitor intolerance in case of ACE inhibitor intolerance in case of ACE inhibitor intolerance in case of ACE inhibitor intolerance
Beta-receptor blockers After myocardial infarction or in hypertension indicated indexed indexed
Mineralocorticoid receptor antagonists Indicated indexed indexed
Ivabradine In beta-receptor blocker intolerance or additively in patients with heart rates ≥ 75 per minute In beta-receptor blocker intolerance or additive in patients with heart rate ≥ 75 per minute In beta-receptor blocker intolerance or additive in patients with heart rate ≥ 75 per minute
Sacubitril/valsartan As an ACE inhibitor/ARB replacement for persistent symptoms* . As an ACE inhibitor/ARB substitute in persistent symptomatology* . As an ACE inhibitor/ARB substitute in persistent symptomatology* .
Symptom-improving Diuretic For fluid retention Indicated indexed
Digitalis glycosides In sinus rhythm as a reserve agent (with low target serum level). With sinus rhythm as a reserve agent (with low target serum level).
For uncontrollable tachyarrhythmic atrial fibrillation.

* Despite guideline-compliant combination therapy with ACE inhibitor/ARB, beta receptor blocker, and mineralocorticoid receptor antagonist.

Note: Beta-blockers are the only medication that reduces mortality (death rate) in heart failure with preserved ejection fraction (HFpEF). Drug therapy for heart failure with preserved left ventricular ejection fraction (HFpEF) [S3 guideline]:

  • When comorbidities are present in patients with heart failure with preserved left ventricular ejection fraction, they should be treated according to the relevant guideline.
  • Patients with heart failure and preserved left ventricular ejection fraction and signs of fluid retention should be recommended symptom-targeted diuretics.

Pharmacotherapy of compensated chronic heart failure (according to the guidelines of the German Society of Cardiology).

NYHA I NYHA II NYHA III NYHA IV
ACE inhibitors/alternative if intolerantAngiotensin II receptor subtype 1 antagonists (synonyms: AT1 antagonists, “sartans“). + + + +
Thiazide diuretics (+) for RR↑ (+) for fluid retention + +
Loop diuretics – (+) for fluid retention + +
Aldosterone antagonists(mineral corticoid receptor antagonists (MRAs)) (+) after MI + + +
Cardiac glycosides [considered rerserve therapy]. Chronic tachyarrhythmic atrial fibrillation
Beta blocker (+) for MI, RR↑ + + +
Sinus node inhibitor – (+) (+) (+)

Legend

  • HRST (= cardiac arrhythmia).
  • MI (myocardial infarction/heart attack)
  • NYHA (New York Heart Association) – classification of heart failure.

Pharmacotherapy for acute and chronic heart failure (according to ESC guidelines).

According to the European Guidelines, when symptoms or signs of heart failure appear, diuretics should be used initially, followed by neuroendocrine blockade consisting of ACE (“angiotensin-converting enzyme”) inhibitors [alternatively AT1 (angiotensin II receptor subtype 1) antagonists if intolerant], beta-blockers, and mineralocorticoid receptor antagonists (MRA). Pharmacotherapy for systolic heart failure (Heart Failure with reduced Ejection Fraction or HFrEF) according to current European Society of Cardiology guideline recommendations:

Basic pillars of therapy (A + B). ACE inhibitors (in case of intolerance: AT1 receptor blockers) and beta blockers.
If symptoms persist (C). Mineral corticoid receptor antagonist (MRA) such as spironolactone or eplerenone (neurohumoral approach to action)
If symptoms persist even with this triple combination (A-C):patients with an ejection fraction <35% Replacement of an ACE inhibitor/AT1 blocker (A + B) with sacubitril/valsartan (angiotensin receptor neprilysin inhibitor (ARNI)) therapy.

Pharmacotherapy of decompensated chronic heart failure.

  • Oxygen administration or noninvasive/invasive ventilation.
  • Administration of diuretics (“dehydrating agents”) and opiates, and in the case of
    • RRsyst > 90 mmHg (without symptomatic hypotension/low blood pressure): vasodilators (vasodilating agents; for example, infusion of nitrates) (IIa/B).
    • RRsyst < 90 mmHg and/or evidence of hypoperfusion: inotropics (short-term) (IIb/C).

Pharmacotherapy of decompensated chronic heart failure.

  • Oxygen administration respectively non-invasive/invasive ventilation.
  • Administration of diuretics and opiates as well as in the case of
    • RRsyst > 90 mmHg (without symptomatic hypotension): vasodilators (for example, infusion of nitrates) (IIa/B).
    • RRsyst < 90 mmHg and/or evidence of hypoperfusion: inotropics (short-term) (IIb/C).

Other indications

  • Only patients with impaired left ventricular ejection fraction and regular sinus rhythm have a reduced risk of mortality by taking a beta-blocker
  • If symptoms persist during therapy with ACE inhibitors or angiotension II receptor antagonists (angiotensin receptor blockers, ARBs) plus a beta-blocker, not only infarct patients with a left ventricular ejection fraction (LVEF) ≤ 40% benefit from the administration of a mineralocorticoid receptor (MR) antagonist.
  • A sinus node inhibitor is indicated for persistent chronic systolic heart failure NYHA II-IV after therapy with ACE inhibitor, diuretic, beta-blocker + aldosterone antagonist and sinus rhythm > 70/min.
  • Aldosterone anatagonists (mineral corticoid receptor antagonists, MARs) in patients with persistent symptoms (NYHA class II-IV) and an ejection fraction <35%, despite treatment with an ACE inhibitor (alternatively angiotensin receptor blocker if intolerant) and beta-blockers)Mineralocorticoid receptor antagonists (MARs) reduce mortality in patients with severe heart failure by 30% (RALES study).
  • A network meta-analysis looking for the best medication in heart failure found the combination of an ARNI (sacubitril/valsartan (angiotensin receptor neprilysin inhibitor), beta-blocker, and MRA (mineralocorticoid receptor antagonist). This reduced mortality by 63% compared with placebo.
  • In patients with symptomatic mild heart failure (NYHA stage II) and wide QRS complex (ventricular complex; wide QRS complex ≥ 120 ms), cardiac resynchronization therapy (CRT) provided a significant long-term survival benefit.
    • Note: Even functional iron deficiency without anemia (ferritin 100-300 ng/ml and transferrin saturation < 20% ) worsens symptoms in heart failure patients and thus their prognosis.
    • Two groups should be distinguished in patients with iron deficiency:

      in a prospective observational study, only barely filled iron stores were associated with increased mortality and more frequent hospitalization for heart failure.

  • See below:
    • Recommendations for drugs that should not be used in heart failure!
    • Heart failure and diseases / disorders
  • Wg. therapy for diastolic heart failure (HFpEF): the European guideline statement on this is “No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFpEF or HFmrEF
  • See also under “Further therapy.”

Note: In acute decompensation of heart failure, early infusion treatment with a potent vasodilator (ularitide) sometimes accelerated patient recovery, but the therapy had no favorable effect on prognosis.

Agents (main indication) for lowering preload and afterload

ACE inhibitors

Active ingredients Duration of action Special features
Lisinopril 24 h Dose adjustment in renal insufficiencyKI in severe renal insufficiency.
Perindopril 24 h Dose adjustment for renal insufficiencyKI for hepatic insufficiency/severe renal insufficiency.
Quinapril 24 h Dose adjustment for renal insufficiency
Benazepril 24 h Dose adjustment for renal insufficiencyKI for hepatic insufficiency/severe renal insufficiency.
Fosinopril 24 h No dose adjustment necessary
Trandolapril 24 h Dose adjustment in renal/hepatic insufficiencyKI in severe renal/hepatic insufficiency.
Captopril 8-12 h Dose adjustment in renal/hepatic insufficiency.
Enalapril 18 h Dose adjustment in renal insufficiencyKI in hepatic insufficiencyTherapy side effects of enalapril occur more frequently with increasing patient age
Ramipril 48 h Dose adjustment for renal insufficiencyKI for hepatic insufficiency.
  • Mode of action: Angiotension-converting enzyme inhibition.
  • Gold standard in heart failure therapy → life extension.
  • Indications: Patients with asymptomatic or symptomatic left heart failure.
  • Dosing Instructions:
    • ACE inhibitors should be consistently increased at biweekly intervals to the highest target dose determined in studies or, if this cannot be achieved, to the maximum tolerated dose [S3 guideline].
    • Combination with beta-blockers in heart failure patients with reduced LVEF (left ventricular ejection fraction).
  • Contraindications: In the second and/or third trimester of pregnancy severe to life-threatening and even fatal fetopathy (oligohydramnios, fetal renal dysfunction up to anuria, joint contractures, pulmonary and cranial hypoplasia and vena cava thrombosis) + others see below special features.
  • Side effects: Hypotension, hyperkalemia, renal insufficiency (due to decrease in blood flow. Patients at risk: Renal artery stenosis, severe atherosclerosis in severely impaired renal function), dry cough, angioneurotic edema, allergic reactions; proteinuria, bone marrow depression rare.
  • Regular monitoring of renal parameters, electrolytes and blood pressure.
  • Increase in creatinine up to 15% in the first few weeks, then remains constant.
  • Note: Angiotensin receptor blockers should be recommended to patients with symptomatic heart failure (NYHA II-IV) who cannot tolerate ACE inhibitors [S3 guideline].

Other indications for ACE inhibitors

  • Essential hypertension
  • Diabetic nephropathy
  • Reinfarction prophylaxis

Angiotension II receptor antagonists (ARBs)*

Active ingredients Special features
Losartan Dose adjustment for hepatic insufficiency, if necessary.
Valsartan Dose adjustment in hepatic insufficiencyKI in severe renal/hepatic insufficiency.
Candesartan Dose adjustment in renal/hepatic insufficiencyKI in severe renal/hepatic insufficiency.

* AT-II-RB; ARB; angiotensin II receptor subtype 1 antagonists; angiotensin receptor blockers; AT1 receptor antagonists, AT1 receptor blockers, AT1 antagonists, AT1 blockers; angiotensin receptor blockers, sartans.

  • Mode of action: Inhibition of the effects of angiotensin-II at the AT1 receptor.
  • Indications: Especially in cases of intolerance or contraindications to ACE inhibitors.
  • Dosage information: Increase dose slowly
  • Contraindications: In the second and/or third trimester of pregnancy severe to life-threatening and also fatal fetopathy (oligohydramnios, fetal renal dysfunction up to anuria, joint contractures, pulmonary and cranial hypoplasia and vena cava thrombosis) + others see special features below.
  • Caution. ACE inhibitors and angiotensin II receptor antagonists should not be combined, as increased renal dysfunction occurred here.
  • Side effects: Hypotension, hyperkalemia, vertigo (dizziness), retention parameters ↑; rarely cough, angioneurotic edema.
  • Regular monitoring of renal parameters, electrolytes and blood pressure.

Other indications for angiotensin II receptor antagonists.

  • Essential hypertension

Agents (main indication) for increasing contractilityBetablockers

Active ingredients Selectivity Duration of action Special features
Metoprolol ß1 8-15 h Dose adjustment in severe hepatic insufficiency.
Bisoprolol ß1 15-24 h Dose adjustment in severe renal/cardiac failure.
Carvedilol – 15-24 h Dose adjustment for renal insufficiency
Nebivolol ß1 20-40 h Initial dose adjustment for renal insufficiency.
  • Mode of action Beta-blockers: competitive inhibition of adrenergic substances at ß-receptorsMode of action Carvedilol: α-blockade: vasodilation (decrease in peripheral vascular resistance) + β-blockade: decrease in plasma renin activity.
  • Improvement in mortality and morbidity in heart failure with impaired pump function (class IA indication).
  • Combination with ACE inhibitors!
  • Indications: both for heart failure patients with reduced ejection fraction and for patients with preserved ejection fraction.
  • All clinically stable, symptomatic patients (NYHA II-IV) with established heart failure and absence of contraindications should be recommended beta-receptor blockers (bisoprolol, carvedilol, or metoprolol succinate); patients over 70 years of age should alternatively be recommended nebivolol.
  • Beta-blocker therapy reduced the risk of mortality in HFmrEF patients by a relative 41% in 1.3 years, and cardiovascular mortality decreased by 52%, corresponding to an absolute risk reduction of 4.7% [S3 guideline].
  • Dosing Instructions: Beta-receptor blockers should be consistently titrated up to the target or maximum tolerated dose as follows:
    • Beginning with a low starting dose
    • At minimum bi-weekly intervals
    • Frequency-adapted (target heart rate 55-60/min)
    • Symptom-oriented (goal: maximum symptom control).
  • Only patients with impaired left ventricular ejection fraction and regular sinus rhythm have reduced mortality risk by taking a beta-blocker
  • Contraindications: decompensated heart failure; symptomatic hypotension, severe reactive airway disease (asthma, active bronchospasm), symptomatic bradycardia, or AV block without permanent pacemaker therapy
  • Side effects: Bradycardia, hypotension, bronchoconstriction, hypoglycemia (in diabetes mellitus), gastrointestinal, headache, dizziness.
  • Note: If a heart rate greater than 70 beats per minute is present on maximal baseline beta-blocker therapy or the beta-blocker is not tolerated or is contraindicated, then additive rate reduction with ivabradine is recommended in patients with sinus rhythm.

Aldosterone antagonists/mineralocorticoid receptor antagonists-in chronic heart failure (NYHA II-IV).

Agents Special features
Epleronon KI in severe renal/severe hepatic insufficiency.
Spironolactone KI in severe renal insufficiency, ANVUnfavorable benefit-risk ratio for elderly patients.
  • Mode of action of aldosterone antagonists: inhibit sodium reabsorption and potassium secretion in the distal tubule/collecting tube by binding to aldosterone receptors → max 3% diuresis.
  • Indications: Patients with persistent symptoms (NYHA class II-IV) and an ejection fraction <35% (a result of the Emphasis HF study), despite treatment with an ACE inhibitor (alternatively angiotensin receptor blocker if intolerant) and beta-blocker.
  • Combination with ACE inhibitor
  • Patients with diabetes, impaired renal function, or borderline hyperkalemia should also receive mineralocorticoid receptor antagonists when benefits and harms are critically weighed [S3 guideline].
  • Side effects: Hyperkalemia, gastrointestinal (nausea, diarrhea, ulcers).
  • Regular laboratory checks to determine electrolytes (see NW) and renal function.
  • Potassium substitution is not required without persistent hypokalemia (< 4 mmol/l).

Other indications

Sinus node inhibitor

Active ingredients Special features
Ivabradine Second-line treatmentDose adjustment in severe renal insufficiencyKI in severe hepatic insufficiencyUnfavorable benefit-risk ratio for elderly patients.
  • Mode of action: antianginal by lowering heart rate.
  • Indications [S3 guideline]:
    • LVEF ≤ 35%
    • Stable sinus rhythm
    • Therapy with ACE inhibitors (or angiotensin receptor blockers) and mineralocorticoid receptor antagonists.
    • Resting heart rate ≥ 75/min despite target dose or maximum tolerated beta-receptor blocker dose.
  • Persistent chronic systolic heart failure NYHA II-IV after therapy with ACE inhibitor, diuretic, beta-blocker + aldosterone antagonist and sinus rhythm > 70/min; should additional administration of the pacemaker channel blocker ivabradine be considered (IIa/B)
  • Side effects: severe bradycardia, visual disturbances, headache, dizziness.
  • Red Hand Letter (ÄkdÄ Drug Safety Mail, 36-2014):
    • Symptomatic treatment of patients with chronic stable angina only if the patient’s resting heart rate is greater than or equal to 70 beats per minute
    • Discontinue if angina symptoms do not improve within three months.
    • Concurrent use of ivabradine with verapamil or diltiazem is contraindicated.
    • Before initiation of treatment or when dose titration is being considered, heart rate should be monitored more frequently by repeated measurements, ECG, or 24-hour ambulatory monitoring.
    • Risk of developing atrial fibrillation is increased in patients treated with ivabradine.

Angiotensin receptor neprilysin antagonists (ARNI) / dual drug combination.

Active ingredients Special features
Sacubitril / valsartan A.I. ; see below.

Therapy side effects Sacubitril–valsartan occur more frequently with increasing patient age.

  • Mode of action: Inhibition of angiotensin and neprilysin actionNeprilysin is an enzyme (an endopeptidase; distributed mainly in the lungs and kidneys) that, among other things, degrades endogenous vasoactive substances such as bradykinin, which have dilating and thus antihypertensive effects. Neprilysin inhibitors thereby increase the effectiveness of bradykinin by inhibiting its degradation and thus strengthen its antihypertensive effect.
  • Film-coated tablet: 50 mg: sacubitril (24.3 mg), valsartan (25.7 mg).
  • Indications: symptomatic chronic heart failure (NYHA stages II-IV, predominantly stage II) and left ventricular dysfunction (ejection fraction < 35%) and elevated BNP levels (plasma BNP ≥ 150 pg/mL or a plasma NTproBNP ≥ 600 pg/mL)In the case of hospitalization for due toHI within the last 12 months: plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL + patients should tolerate an enalapril dose of 2 x 10 mg/die
  • Dosing Instructions: Independent of meals
  • Contraindications:
    • Concomitant use of an ACE inhibitor; intake must be administered no earlier than 36 hours after discontinuation of ACE inhibitor therapy. Known history of angioedema associated with prior treatment with an ACE inhibitor or ARB.
    • Concurrent use of the dual agent combination with aliskiren-containing drugs in patients with diabetes mellitus or patients with impaired renal function (GFR 2).
    • Severe renal impairment with eGFR 2 due to lack of data.
    • Pregnancy
  • Side effects: Hyperkalemia, hypokalemia, dizziness, headache, vertigo, hypotension, syncope, cough, diarrhea, nausea, angioedema. impaired renal function, renal failure (renal failure, acute renal failure), fatigue, asthenia.
  • PARADIGM-HF study of 8442 HFrEF patients: Risk of cardiovascular death reduced by 20% (p < 0.00004), risk of heart failure-related hospitalizations reduced by 21% (p < 0.00004), and all-cause mortality risk reduced by 16% (p < 0.0005) compared with enalapril (ACE inhibitor)
  • Acute exacerbation of heart failure (patients with left ventricular ejection fraction < 40%; NT-proBNP > 1,600 pg/ml) also experienced more rapid hemodynamic stabilization with sacubitril/valsartan therapy compared with enalapril. Troponin levels, indicating myocardial damage, also declined more rapidly with sacubitril/valsartan treatment.
  • Calculations by the authors, of the pivotal trial, calculated a life extension of 1 – 2 years for the neprilysin inhibitor sacubitril.
  • The European Society of Cardiology has included the neprilysin inhibitor sacubitril (in fixed combination with valsartan) in its updated guideline.
  • IQWiG: There is less benefit for patients with diabetes (dossier review, 2016): a post-hoc analysis showed that sacubitril/valsartan reduced HbA1c by 0.26% during the first year (enalapril 0.16%).

Phosphodiesterase III inhibitors

Active ingredients Special features
Milrinon Dose adjustment in renal insufficiency.
Enoximone Dose adjustment in renal/hepatic insufficiency.
  • Mode of action: Inotropy and vasodilation by inhibition of the enzyme phosphodiesterase III.
  • Indications: Indicated only for short-term therapy (maximum 2 days) of severe heart failure when other drugs are no longer sufficient.
  • Combination with catecholamines useful
  • Side effects: Cardiac arrhythmias, hypotension, gastrointestinal (nausea, diarrhea), thrombocytopenia, transaminases ↑

Gliflozines (SGLT-2 inhibitors; SGLT-2 blockers).

Active ingredient Special features
Dapagliflozin Patients with chronic renal insufficiency benefit significantly. In severe hepatic impairment, therapy should be started at 5 mg/d and then possibly increased to 10 mg.In chronic heart failure, hospital admissions for worsening heart failure and cardiovascular mortality were significantly reduced according to the DAPA-HF study; the same was true for patients without diabetes mellitus.
  • Mode of action: Selective inhibition of sodium–glucose cotransporter 2 (SGLT-2) by about 40-50% → inhibition of renal glucose absorption (glucosuria in healthy subjects: 60-70 g/d; in diabetics 80-120 g/d) → blood glucose lowering, weight loss, blood pressure reduction.
  • Indication: symptomatic heart failure with reduced ejection fraction (HFrEF) in adults with and without type 2 diabetes.
  • The lower the renal function, the lower the effect of SGLT-2 inhibitors: Not indicated in renal function impairment; with a GFR of 30-60 ml/min, only a 0.4% reduction in HbA1c can be expected
  • Contraindications: Hypersensitivity to the active substance; gravidity (due totoxicity in animal studies)Not recommended are SGLT-2 inhibitors in volume deficiency or diuretic therapy.Side effects: gastrointestinal (nausea), urinary tract infections, genital infections (vulvitis and vulvovaginitis in women and balanitis in men), back pain, dysuria, polyuria, dyslipidemia.

Active substances (main indication) to increase excretion

Diuretics

Drug group Active ingredients Special features
Loop diuretics Piretanide AI for anuria
Torasemide HWZ 6 hKI in anuria.
Furosemide HWL 2-2.5 hKI in anuria/severe hepatic failure.
Thiazide diuretics Hydrochlorothiazide (HCT) For treatment failure of loop diureticsDose adjustment for renal/hepatic insufficiencyKI for severe renal insufficiency.
Aldosterone antagonistsMineralocorticoid receptor antagonists (MRAs). Eplenerone KI in severe renal/severe hepatic insufficiency.
Spironolactone For treatment failure of loop diureticsKI for severe renal insufficiency, ANV.
  • Mode of action Loop diuretics: inhibit the sodium–chloride–potassium carrier in the loop of Henle; concomitant venous vasodilation→ max 40% diuresis.
  • Indications: Suitable for acute therapy! Furthermore, in heart failure patients with reduced ejection fraction and signs of fluid retention (eg, pulmonary congestion) for symptom relief.
  • Combination with ACE inhibitor
  • Side effects: Hypokalemia, hypocalcemia, hypomagnesemia; hyperuricemia, hypertriglyceridemia, gastrointestinal (nausea, diarrhea), hearing impairment.
  • Regular laboratory checks to determine electrolytes (see NW).
  • Patients receiving loop diuretics for the treatment of heart failure (specifically HFrEF, Heart Failure with reduced Ejection Fraction) had a significantly low risk of readmission for heart failure symptoms after discharge; likewise, the 30-day mortality risk was 27% lower during this time. However, no significance could be detected after 60 days.
  • Mode of action Thiazide diuretics: inhibit the sodium-chloride carrier in the distal tubule→ max 15% diuresis.
  • Indications: Use primarily in isolated systolic hypertension and in patients of color. Furthermore, in heart failure patients with reduced ejection fraction and signs of fluid retention (eg, pulmonary congestion) for symptom relief.
  • Side effects: Hypokalemia, hypomagnesemia, calcium retention, hyperuricemia, hypertriglyceridemia.
  • Regular laboratory checks to determine electrolytes (see NW).
  • Mode of action of aldosterone antagonists: inhibit sodium reabsorption and potassium secretion in the distal tubule/collector tube by binding to aldosterone receptors → max 3% diuresis.
  • Improvement in mortality and morbidity in heart failure with impaired pump function (class IA indication).
  • Indications: Patients with persistent symptoms (NYHA class II-IV) and an ejection fraction <35% (a result of the Emphasis HF trial), despite treatment with an ACE inhibitor (alternatively angiotensin receptor blocker if intolerant) and beta-blocker.
  • Combination with ACE inhibitor
  • Side effects: Hyperkalemia, gastrointestinal (nausea, diarrhea, ulcers).
  • Regular laboratory checks to determine electrolytes (see NW) and renal function (renal retention parameters).
  • Potassium substitution is not required without persistent hypokalemia (< 4 mmol/l).
  • Mineralocorticoid receptor antagonists (MARs) reduce mortality by 30% in patients with severe heart failure (RALES trial).

Potassium-sparing diuretics – in chronic heart failure.

Agents Special features
Amiloride(combination with HCT) Dose adjustment in renal insufficiencyKI in severe renal insufficiency.
Triampterene(combination with HCT) Dose adjustment in renal insufficiencyKI in severe renal insufficiency.
  • Mode of action: inhibit sodium channel in distal tubule/collecting tubes→ max 4% diuresis.
  • Combination with ACE inhibitors
  • Side effects: Hyperkalemia, gastrointestinal (nausea, diarrhea).
  • Regular laboratory checks to determine electrolytes (see NW).

Other indications

  • Edema of any genesis

Cardiac glycosides

Active ingredients Special features HWZ
Digoxin Renal eliminationDose adjustment in renal insufficiency. 1-2 d
ß-acetyldigoxin Renal eliminationDose adjustment in renal insufficiency. 1-2 d
ß-methyldigoxin Renal eliminationDose adjustment in renal insufficiency. ≈ 2 d
Digitoxin Hepatic elimination!Dose adjustment in severerenal AND hepatic insufficiency. 7-9 d
  • Mode of action: Inhibition of Na-K-ATPase leads to positive inotropy; simultaneously negative chronotropic and dromotropic (speed of electrical excitation conduction, especially in the AV node) and positive bathmotropic (sensitivity of cardiomyocytes to electrical excitation).
  • Indications:
    • Chronic tachyarrhythmic atrial fibrillation.
    • If necessary, sinus rhythm in NYHA II-IV under therapy with ACE inhibitor, diuretic, beta blocker, aldosterone antagonist (reserve).
  • Prognosis-improving with drug levels between 0.5-0.8 ng/ml→ regular level checks (in the morning before taking the drug).
  • Combination with beta-blocker useful
  • Side effects: Cardiac arrhythmias, often ventricular; gastrointestinal (nausea, abdominal pain, diarrhea), headache, fatigue, yellow-green vision, hallucinations, impaired consciousness, delirium.

Other indications for cardiac glycosides.

  • Tachyarrhythmia absoluta (TAA)
  • Paroxysmal supraventricular tachycardia

Acute heart failure

Nitrates

Active ingredients Special features
Glycerol trinitrate Dose adjustment in severe renal/hepatic insufficiency.
Isosorbide dinitrate (ISDN) No dose adjustment neededIndication if RR > 90 mmHg.
Nitroprusside sodium No dose adjustment neededKI: hypertensive crisis, cardiogenic shock.
  • Mode of action: Smooth muscle relaxation by nitrates (vasodilation)→ preload is decreased→ venous pooling.
  • Indications:
    • Use in chronic heart failure only in CHD.
    • In African American heart failure patients (NYHA III-IV) with isosorbide dinitrate and hydralazine in addition to therapy with ACE inhibitors and beta blockers.
  • Side effects: Headache, hypotension, reflex tachycardia, gastrointestinal (nausea, vomiting), flushing.
  • Nitroprusside sodium: afterload lowering.

Catecholamines

Active substances Special features
Dobutamine Agent of choice for acute systolic heart failureTolerance development.
Dopamine Unselective

Routine use of low-dose dopamine may no longer be warranted in nonhypotensive patients with heart failure

Norepinephrine In refractory shock during therapy with dobutamine
  • Mode of action: ß1-stimulation → positive inotropic and chronotropic, while maintaining stable oxygen consumption (at low doses).
  • Indications: Use only in acute heart failure when other measures are not effective.
  • For dopamine at doses >8 μg/kg bw/min α- and ß-stimulation.
  • Side effects: Angina pectoris, tachycardia, cardiac arrhythmias, gastrointestinal (nausea, vomiting).

Drugs that may adversely affect the clinical condition of patients with heart failure:

* Alpha blockers: in one study, alpha blockers were judged to be not only safe but also potentially beneficial in patients with heart failure: they were associated after 2 years of follow-up not with a higher but with a significantly lower rate of rehospitalization due to heart failure (39.8% vs. 41.7% ; hazard ratio: 0.95; 95% confidence interval [CI] 0.92-0.97; p < 0.0001) and also significantly lower mortality (42.8% vs. 46.5%; HR 0.93; 95% CI: 0.91-0.94; p < 0.0001).

Special features of heart failure therapy

  • After diagnosis of mental impairment from the disease, do not administer tricyclic antidepressants (negative inotropic, proarrhythmic).
  • Metformin and glitazones are contraindicated in coexisting diabetes mellitus and heart failure NYHA III-IV.
  • In renal failure, relax fluid restriction if necessary, check indication of prescribed drugs.

Notes on diastolic heart failure (HFpEF)

  • To date, all drug attempts to improve the prognosis of diastolic heart failure (heart failure with preserved ejection fraction/ejection fraction, HFpEF) in the long term have failed. See the European guideline statement, “No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFpEF or HFmrEF.
  • If there is evidence of volume overload, symptoms should be relieved with diuretics.
  • Beta-blockers: a single-center study showed beneficial effects with a beta-blocker on diastolic function in HFpEF (Bergström A et al. Eur J Heart Fail 6:453-461).
  • In an Aldo-DHF study with one year of observation, spironolactone showed an improvement in diastolic myocardial function, a decrease in hypertrophy (= reverse remodeling) and laboratory markers of heart failure (NTproBNP). However, this was not accompanied by improvement in symptoms or exercise capacity. The phase III TOPCAT study showed that in the short term, especially patients with diastolic heart failure in an advanced stage could benefit from treatment also in terms of hospitalization and prognosis.
  • Aldosterone antagonists improve mortality and morbidity in heart failure with impaired pump function (class IA indication).
  • Mineral corticoid receptor antagonists (MARs) reduce mortality by 30% in patients with severe heart failure (RALES trial).
  • PARAGON-HF trial (double-blind study involving 4,822 patients with symptomatic HFpEF (left ventricular ejection fraction ≥ 45%, NYHA class II-IV): ARNI therapy with sacubitril/valsartan “just missed” significance for the primary study endpoint.
  • Negative Studies
    • Long-term nitrates (isosorbide mononitrate) in one study caused patients, instead of exercising more, to actually reduce their activity while on nitrate therapy.

Further notes

Patients with heart failure with preserved left ventricular ejection fraction (= preserved systolic function of the left ventricle) often have the following typical comorbidities:

Drugs that may adversely affect the clinical condition of heart failure patients with preserved ejection fraction (HFpEF):

  • Analgesics (pain medications):
    • Nonsteroidal anti-inflammatory drugs (NSAID): salt and water retention by inhibiting prostaglandin production, increasing systemic vascular resistance, and decreasing diuretic action (effect of drainage).
    • Nonselective NSAIDs such as ibuprofen or diclofenac as well as the selective COX-2 inhibitors may contribute to worsening heart failure (AHA evidence level B)
  • Antidepressants (citalopram or escitalopram): risk of QT prolongation and thus also for torsade de pointes tachycardia (AHA evidence level A).
  • Calcium channel blockers (eg, diltiazem or verapamil).
  • Hydroxychloroquine due toproarrythmogenic potency.
  • Metformin (evidence level C): applies only in decompensated heart failure and severely impaired renal function.
  • Sulfonylureas: contradictory data situation.

Heart failure and depression

Heart failure and diabetes therapy

  • Appropriate, or recommended:
    • Metformin is contraindicated/not allowed in patients with advanced heart failure (heart failure; stage 3 to 4)! In stage 1 to 2, however, highly recommended due tolong-term survival benefit.
    • In therapy with sulfonylureas, glinides as well as insulin there are no restrictions.
    • It is possible that empagliflozin (gliflozines (SGLT-2 inhibitors; SGLT-2 blockers)) may directly positively affect the myocardium and improve cardiac function. In in vitro experiments, therapy with empagliflozin showed an improvement in the relaxation capacity of the myocardium, while the ability to contract remained unchanged. Empaglifozine has been studied in diabetic patients who also had cardiovascular disease: in one study, empagliflozin reduced cardiovascular mortality in high-risk patients with type 2 diabetes: cardiovascular-related death, myocardial infarction, and apoplexy (primary combined endpoint) were significantly reduced by additive treatment with empagliflozin, i.e., by 14% compared with placebo (10.5 versus 12.1%)
    • Empagliflozin (gliflozine (SGLT-2 inhibitors; SGLT-2 blockers)) significantly reduced cardiovascular mortality in high-risk patients with type 2 diabetes in one study: cardiovascular-related death, myocardial infarction, and apoplexy (primary composite end point) were significantly reduced by additive treatment with empagliflozin, ie. ie, by 14% compared with placebo (10.5 versus 12.1%)Furthermore, empagliflozin also reduced the risk of heart failure in diabetic patients with cardiovascular disease, and this was independent of whether heart failure was already present.SGLT-2 inhibitors also have nephroprotective effects.
    • DPP-4 inhibitors and GLP1 analogs appear to have beneficial effects on myocardial (heart muscle) function.Note: According to a meta-analysis, DPP-4 inhibitors do not appear to increase short-term heart failure risk. However, the rate of hospitalization is slightly increased with DPP-4 inhibitors.
    • The incretin mimetics (GLP-1 receptor agonists) liraglutide and semaglutide reduce cardiovascular events in high-risk patients with diabetes mellitus.
    • In cardiac decompensation, insulin therapy is the most reasonable option.
  • Not suitable, ie, should not be used:
    • Pioglitazone resulted in an increased incidence (frequency of new cases) of cardiac (heart-related) decompensations in numerous studies and is contraindicated in patients with heart failure (NYHA I-IV).
    • Thiazolidinediones (TZD), this are insulin sensitizers, led to worsening of heart failure, which is particularly evident from an accumulation of hospital admissions due to heart failure.

Heart failure and hypertension

  • Heart failure patients with hypertension (high blood pressure) and preserved left ventricular ejection fraction should be treated for normalization of blood pressure and reduction of morbidity according to current guidelines for the treatment of hypertension.
  • Several guidelines for initial blood pressure management of patients with heart failure recommend such drugs that have a synergistic effect on heart failure, ie, beta-blockers, ACE inhibitors (alternatively, AT-1 receptor antagonists), and aldosterone antagonists.

Heart failure and coronary artery disease (CAD)

  • Patients with structural myocardial changes but without heart failure symptoms or with stable CHD and heart failure should be treated according to current CHD guidelines.
  • CHD patients with heart failure should receive platelet aggregation inhibitors for myocardial infarction prophylaxis.
  • Patients with reduced ejection fraction after an acute coronary event for prophylaxis of heart failure symptoms and reduction of mortality should be treated with ACE inhibitors (in case of intolerance: AT1 receptor antagonists), beta blockers, and for prophylaxis of further coronary events with statins.
  • For the treatment of pectanginal symptoms in CHD patients with heart failure, several guidelines recommend beta-blockers because of their synergistic effects on heart failure.
  • For patients with coronary (coronary vessel-related) 2- or 3-vessel disease, LVEF ≤ 35%, and a mean age of 60 years, bypass surgery compared with drug-only therapy showed risk reduction (STICH study.CONCLUSION: In selected patients in this high-risk group, bypass surgery is a real alternative.

Heart failure and renal insufficiency

  • For patients with heart failure with sinus rhythm and reduced on ejection fraction (HFrEF) who also have limited renal failure, beta-blocker therapy is safe and mortality (death rate) is reduced by 23-29%:
    • EGFR (estimated GFR, the estimated glomerular filtration rate, a measure of renal function) 45-59 ml/min/1.73m2: relative risk reduction 23%; absolute risk reduction 4%.
    • EGFR 30-44 ml/min/1.73m2: relative risk reduction 29%; absolute risk reduction 4.7%.

    Patients with heart failure and atrial fibrillation did not benefit from mortality reduction with beta-blockers.

Heart failure and pain management

  • NSAIDs (nonsteroidal anti-inflammatory drugs) significantly increase the risk of mortality (death) and rehospitalization for myocardial infarction (heart attack) and heart failure in heart failure patients.
  • No use of nonsteroidal anti-inflammatory drugs (NSAID) because they cause sodium retention (sodium retention in the body) and vasoconstriction (blood vessel constriction). This leads to attenuation of the effect of ACE inhibitors and diuretics.

Heart failure and statin therapy

  • Statins (cholesterol synthesis enzyme inhibitors) cause a 25-50% decrease in plasma coenzyme Q10 levels. When coenzyme Q10 is deficient, energy provision for the heart muscle is massively impaired despite optimal substrate levels.
  • Patients with heart failure NYHA II-IV should not be treated with statins.
  • Clinical studies have repeatedly shown a clear association between decreased coenzyme Q10 levels and heart failure!(see below “Heart failure/Therapy with micronutrients” in relation to coenzyme Q10 substitution and heart failure).

Heart failure and thromboprophylaxis

  • Routine thromboprophylaxis is not recommended in heart failure. Of course, if heart failure is associated with atrial fibrillation (AF), oral anticoagulation (OAC; inhibition of blood clotting) is indicated.
  • Heart failure patients at high risk for venous thromboembolism could potentially benefit from thromboprophylaxis.

Heart failure and atrial fibrillation (VHF)

  • Approximately 14-50% of patients with HI also have VHF.
  • Atrial fibrillation is a trigger for progression of heart failure in patients with heart failure. This results in an approximately 4.5-fold increase in mortality (morbidity). In patients with heart failure with preserved pump function (heart failure with preserved ejection fraction, HF-PEF), it has been shown that atrial fibrillation significantly leads to a decrease in maximal oxygen uptake during exercise.
  • When ventricular arrhythmias occur, the precipitating causes, such as electrolyte disturbances, drug interactions, or ischemia, must be sought.
  • For drug frequency control in heart failure patients with persistent AF, several guidelines recommend beta-blockers as the first-line drug and digoxin if these are intolerant.Beta-blockers do not reduce mortality and hospitalization in patients with heart failure and VHF, or do so only to a much weaker extent than in patients with sinus rhythm.
  • Note: Administration of If-channel inhibitors such as ivabradine is not pathophysiologically useful in VHF.
  • For drug rhythm control, several guidelines recommend amiodarone.
  • Ranolazine causes greater VHF suppression in heart failure patients than in patients without heart failure and ventricular arrhythmias.Ranolazine may be a potential alternative to amiodarone and dofetilide in VHF patients with heart failure. Further studies are awaited.One antiischemic mechanism of action of ranolazine appears to be improvement of coronary flow reserve (CFR).
  • Catheter ablation for atrial fibrillation and heart failure.In a study of 203 patients with systolic heart failure and persistent atrial fibrillation, at a follow-up of 26 months on average, 70% of all patients were spared recurrent atrial fibrillation in the ablation group, whereas in the amiodarone group the proportion of recurrence-free patients was only 34%.
  • RACE 3 Trial: In patients who were new to persistent AF as well as heart failure, early aggressive treatment (statins, mineral corticoid receptor antagonists (MRA), ACE inhibitors and/or angiotensin receptor blockers, and a cardiac rehabilitation program) of risk factors in addition to rhythm control was more effective in halting disease progression than standard usual therapy. One year after electrical cardioversion, 75% of patients in the intervention group (versus 63% in the standard group) were in sinus rhythm most of the time.and NT-proBNP levels decreased significantly.
  • CASTLE-AF (catheter ablation for VHF in patients with heart failure; observation period: 3 years):
    • Decrease in number of patients who died or required hospitalization for heart failure within slightly more than 3 years: medical therapy (44.5%); ablation therapy (28.5%)-relative risk reduction 38%.
    • All-cause mortality (all-cause mortality rate): decrease from 25% to 13, 4% – relative risk reduction 48%.
  • Based on a meta-analysis using data from 11 randomized trials, the authors conclude that a strategy of rhythm control by catheter ablation is significantly more beneficial than a drug treatment strategy.

Phytotherapeutics

  • Hawthorn preparations (Crataegus Extract WS 1442; e.g., Crataegutt novo 450 mg); indication: for declining cardiac output.According to one study, the compound has positive inotropic (“affecting the contractile force of the heart”) and antiarrhythmic properties and can protect the myocardium (heart muscle) from ischemic damage, reperfusion damage (disease process, caused by restored blood flow after more or less prolonged reduced blood flow (ischemia) to an organ) and hypertensive hypertrophy (“enlargement caused by high blood pressure), improve endothelial functions such as NO synthesis, and delay endothelial senescence (“age-related change in the endothelium/cells of the innermost wall layer facing the vessel lumen). Side effects: none; even at the highest dosage (1.8 grams), no adverse side effects were detected in studiesInteractions: none.

Supplements (dietary supplements; vital substances)

Suitable dietary supplements should contain the following vital substances:

Note: The listed vital substances are not a substitute for drug therapy. Food supplements are intended to supplement the general diet in the particular life situation.