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Drug therapy for heart failure
This document discusses drug therapy for heart failure. It begins by defining heart failure and describing the stages and phenotypes. The main causes of heart failure are then outlined, including ischemic heart disease, hypertension, cardiomyopathy, infections, toxins, and valvular disease. The document discusses the pathophysiology of heart failure in terms of ventricular dysfunction, compensatory mechanisms like the Frank-Starling mechanism and neurohormonal activation, and the determinants of ventricular function. General treatment measures and pharmacological management are described for different stages of heart failure.
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Drug therapy for heart failure
- 1. Drug Therapy ofHeart Failure Dr Ranjita Santra (Dhali) Assistant Professor Dept. of Clinical & Experimental Pharmacology School of Tropical Medicine Kolkata
- 2. Cardiac cycle Thecardiac events that occur from the beginning of one heart beat to the beginning of the next. Events : Electrical Mechanical Electrical and mechanical events occur in a co-ordinated manner to generate effective contractions • Duration – 0.8 seconds ( systole – 0.27 seconds, diastole – 0.53 seconds when the HR = 75/minute) William F. Ganong. The heart as a Pump. Review of Medical Physiology, Lange, 2010: 507-512
- 3.
- 4. Atrial systole • Priorto atrial systole, blood has been flowing passively from the atrium into the ventricle through the open AV valve. • During atrial systole the atrium contracts and tops off the volume in the ventricle with only a small amount of blood. Atrial contraction is complete before the ventricle begins to contract.
- 5. …….. Atrial systole JVP– ‘a’ wave ECG – P wave preceeds the atrial systole. PR segment – depolarization proceeds to the AVN. The brief pause allows complete ventricular filling Heart sounds - S 4 – pathological. Vibration of the ventricular wall during atrial contraction. Heard in ‘stiff’ ventricle like in hypertrophy and in elderly. Also heard in massive pulmonary embolism, cor pulmonale, TR
- 6. Isovolumetric contraction • Theatrioventricular (AV) valves close at the beginning of this phase. • Electrically, ventricular systole is defined as the interval between the QRS complex and the end of the T wave (the Q-T interval). • Mechanically, ventricular systole is defined as the interval between the closing of the AV valves and the opening of the semilunar valves (aortic and pulmonary valves).
- 7. ………… Isovolumetric contraction JVP – ‘c’ wave → due to the bulging of the Tricuspid valve into RA secondary to increased pressure in the ventricle. ‘x’ descent ECG – Interval between QRS complex and T wave (QT interval) Heart Sounds – S1 : closure of the AV valves. Normally split as mitral valve closure preceeds tricuspid valve closure.
- 8. Ejection • When LVpres > 80 mm Hg RV pres > 8 mm Hg, The aortic and pulmonary valves open. • Rapid Ejection – 70% emptying in first 1/3 • Slow Ejection – 30% in last 2/3 • The pressure in the ventricle keeps decreasing until it becomes lower than that of the great vessels
- 9. …………. ejection JVP– no waves ECG – T wave Heart sounds – none Aortic pressure - Rapid rise in the pressure = 120 mm Hg Even at the end of systole pressure in the aorta is maintained at 90 mm Hg because of the elastic recoil
- 10. Isovoulumetric relaxation • Whenventricle pressure < arterial pressure→ backflow of blood → forces semilunar valves to close. • For 0.03-0.06 s, ventricle relaxes despite no change in its volume • Meanwhile, atria fill up and atrial pressure gradually rises • Pressures in ventricle keep falling till it is < atrial pressure
- 11. …………… isovolumetric relaxation JVP – ‘v’ wave – due to venous return to the atria from SVC and IVC ECG- no deflections Heart sounds – S2 : closure of the semilunar valves. Normally split because aortic valve closes slightly earlier than the pulmonary valve Aortic pressure curve – INCISURA - when the aortic valve closes. Caused by a short period of backflow before the valve closes followed by sudden cessation of the backflow when the valve closes.
- 12. Ventricular filling • Beginswith the opening of AV valves • Rapid filling – first 1/3 of diastole • Reduced filling (Diastasis) – middle 1/3 of diastole • Atrial contraction – last 1/3 of diastole • As the atrial pressures fall, the AV valves close and left ventricular volume is now maximum → EDV (120 ml in LV)
- 13. …………… ventricular filling JVP – ‘y’ descent ECG – no deflections Heart sounds - S3 - Pathological in adults. Seen in dilated congestive heart failure, MI, MR, severe hypertension. Normal in children.
- 14. Various pressure values CHAMBERSNORMAL RANGE (mm of Hg) Right Atrium 2 – 6 Right Ventricle ( systolic) (diastolic) 15 – 25 2 -8 Pulmonary Artery (systolic) (diastolic) 15 – 25 8 - 15 Left Atrium 6 - 12 Left Ventricle (systolic) (diastolic) 100 – 140 3 – 12
- 15. Heart Failure (HF):Definition • Heart Failure (HF) is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood • Unlike western countries where heart failure is predominantly a disease of the elderly, in India it affects younger age group • Echocardiography is the primary imaging modality of choice, through recently cardiac magnetic resonance imaging (MRI) has been found to play an increasing role • The life time risk of developing heart failure is estimated at about 20 per cent both in men and women. Source: Yancy et al. 2013 ACCF/AHA Heart Failure Guidelines.Circulation; 2013:e245 ACCF indicates American College of Cardiology Foundation; AHA, American Heart Association;
- 16. Definition of HeartFailure Classification Ejection Fraction Description I. Heart Failure with Reduced Ejection Fraction (HFrEF) ≤40% Also referred to as systolic HF. Randomized clinical trials have mainly enrolled patients with HFrEF and it is only in these patients that efficacious therapies have been demonstrated to date. II. Heart Failure with Preserved Ejection Fraction (HFpEF) ≥50% Also referred to as diastolic HF. Several different criteria have been used to further define HFpEF. The diagnosis of HFpEF is challenging because it is largely one of excluding other potential noncardiac causes of symptoms suggestive of HF. To date, efficacious therapies have not been identified. a. HFpEF, Borderline 41% to 49% These patients fall into a borderline or intermediate group. Their characteristics, treatment patterns, and outcomes appear similar to those of patient with HFpEF. b. HFpEF, Improved >40% It has been recognized that a subset of patients with HFpEF previously had HFrEF. These patients with improvement or recovery in EF may be clinically distinct from those with persistently preserved or reduced EF. Further research is needed to better characterize these patients.
- 17. New York HeartAssociation (NYHA) Functional Classification • Class I: No symptoms with ordinary activity • Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnoea, or angina • Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnoea, or anginal pain • Class IV: Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest
- 18. ACCF/AHA Stages ofHF • Stage A: At high risk for HF but without structural heart disease or symptoms of HF • Stage B: Structural heart disease but without signs or symptoms of HF • Stage C: Structural heart disease with prior or current symptoms of HF • Stage D: Refractory HF requiring specialized interventions
- 19. Causes of HF •Ischemic Heart Disease • Hypertension • Idiopathic Cardiomyopathy • Infections (e.g., viral myocarditis, Chagas disease) • Toxins (e.g., alcohol, cocaine, anabolic steroids, clozapine, anticancer agents – anthracyclines , trastuzumab, 5-FU, interferons) • Valvular Disease • Cardiac sarcoidosis, amyloidosis • Iron overload (primary haemochromatosis, beta- thalassemia major) • Prolonged Arrhythmias
- 20. Left Ventricular Dysfunction:Systolic and Diastolic Symptoms Dyspnea on Exertion Paroxysmal Nocturnal Dyspnea Tachycardia Cough Hemoptysis Physical Signs Basilar Rales Pulmonary Edema S3 Gallop Pleural Effusion Cheyne-Stokes Respiration
- 21. Compensatory Mechanisms • Frank-StarlingMechanism • Neurohormonal Activation • Ventricular Remodeling Phenomenon
- 22. • The Frank–Starlinglaw of the heart (also known as Starling's law or the Frank–Starling mechanism or Maestrini heart's law) states that the stroke volume of the heart increases in response to an increase in the volume of blood filling the heart (the end diastolic volume) when all other factors remain constant. Frank–Starling law
- 23. Ventricular dysfunction inheart failure Systolic: Impaired contractility/ejection Approximately two-thirds of heart failure patients have systolic dysfunction (70%) EF< 40% Diastolic: Impaired filling/relaxation (30%) EF> 40% Ejection fraction (Ef) is the fraction of the end-diastolic volume that is ejected with each beat; that is, it is stroke volume (SV) divided by end-diastolic volume (EDV):Ef (%) = SV/EDV ×100 Where the stroke volume is given by: SV = EDV-ESV Normal values: Ef (%) = 58% ( 55-70%) EDV = 120ml(65–240ml), SV = 70ml (55–100 ml)
- 24. Left Ventricular Dysfunction Volume Overload Pressure Overload Lossof Myocardium Impaired Contractility LV Dysfunction EF < 40% Cardiac Output Hypoperfusion End Diastolic Volume Pulmonary Congestion End Systolic Volume
- 25. Neurohormonal Activation o Sympatheticnervous system (SNS) o Renin-angiotensin-aldosterone system (RAAS) o Vasopressin (a.k.a. antidiuretic hormone, ADH)
- 26. Compensatory Mechanisms: Renin-Angiotensin-Aldosterone (RAAS) Angiotensinogen AngiotensinI Angiotensin II Aldosterone Vasoconstriction Oxidative Stress Cell Growth Proteinuria LV remodeling Angiotensin Converting Enzyme Renin Vascular remodeling
- 27. CNS sympatheticoutflow Cardiac sympathetic activity Sympathetic activity to kidneys + peripheral vasculature 1 receptors 2 receptors 1 receptors 1 1 Activation of RAS Myocardial toxicity Increased arrhythmias Vasoconstriction Sodium retention Disease progression
- 28. Other Neurohormones &Endothelium-derived Vasoactive Substances • Natriuretic Peptides – Three known types: • Atrial Natriuretic Peptide (ANP) • Brain Natriuretic Peptide (hBNP) • C-type Natriuretic Peptide (CNP) • Endothelium-derived relaxing factors (EDRF) – Vasodilators: • Nitric Oxide (NO) • Bradykinin • Prostacyclin • Endothelium-derived constricting factors (EDCF) – Vasoconstrictors: • Endothelin I
- 29. General Measures Lifestyle Modifications: Weightreduction Discontinue smoking Avoid alcohol and other cardiotoxic substances Exercise Medical Considerations: Treat HTN, hyperlipidemia, diabetes, arrhythmias Coronary revascularization Anticoagulation Immunization Sodium restriction Daily weights Close outpatient monitoring
- 30. Right Ventricular Failure: Systolic and Diastolic Symptoms Abdominal Pain Anorexia Nausea Bloating Swelling Physical Signs Peripheral Edema Jugular Venous Distention Abdominal-Jugular Reflux Hepatomegaly
- 31. Determinants of VentricularFunction Contractility Stroke Volume Preload Afterload •Synergistic LV Contraction Heart rate •Wall Integrity •Valvular Competence Cardiac Output Cardiac Output (CO) = Heart Rate (HR) x Stroke Volume (SV)
- 32. Stages, Phenotypes andTreatment of HF STAGE A At high risk for HF but without structural heart disease or symptoms of HF STAGE B Structural heart disease but without signs or symptoms of HF THERAPY Goals · Control symptoms · Improve HRQOL · Prevent hospitalization · Prevent mortality Strategies · Identification of comorbidities Treatment · Diuresis to relieve symptoms of congestion · Follow guideline driven indications for comorbidities, e.g., HTN, AF, CAD, DM · Revascularization or valvular surgery as appropriate STAGE C Structural heart disease with prior or current symptoms of HF THERAPY Goals · Control symptoms · Patient education · Prevent hospitalization · Prevent mortality Drugs for routine use · Diuretics for fluid retention · ACEI or ARB · Beta blockers · Aldosterone antagonists Drugs for use in selected patients · Hydralazine/isosorbide dinitrate · ACEI and ARB · Digoxin In selected patients · CRT · ICD · Revascularization or valvular surgery as appropriate STAGE D Refractory HF THERAPY Goals · Prevent HF symptoms · Prevent further cardiac remodeling Drugs · ACEI or ARB as appropriate · Beta blockers as appropriate In selected patients · ICD · Revascularization or valvular surgery as appropriate e.g., Patients with: · Known structural heart disease and · HF signs and symptoms HFpEF HFrEF THERAPY Goals · Heart healthy lifestyle · Prevent vascular, coronary disease · Prevent LV structural abnormalities Drugs · ACEI or ARB in appropriate patients for vascular disease or DM · Statins as appropriate THERAPY Goals · Control symptoms · Improve HRQOL · Reduce hospital readmissions · Establish patient’s end- of-life goals Options · Advanced care measures · Heart transplant · Chronic inotropes · Temporary or permanent MCS · Experimental surgery or drugs · Palliative care and hospice · ICD deactivation Refractory symptoms of HF at rest, despite GDMT At Risk for Heart Failure Heart Failure e.g., Patients with: · Marked HF symptoms at rest · Recurrent hospitalizations despite GDMT e.g., Patients with: · Previous MI · LV remodeling including LVH and low EF · Asymptomatic valvular disease e.g., Patients with: · HTN · Atherosclerotic disease · DM · Obesity · Metabolic syndrome or Patients · Using cardiotoxins · With family history of cardiomyopathy Development of symptoms of HF Structural heart disease
- 36. Classification of Recommendationsand Levels of Evidence
- 37. Recommendations for Treatmentof Stage B HF Recommendations COR LOE In patients with a history of MI and reduced EF, ACE inhibitors or ARBs should be used to prevent HF I A In patients with MI and reduced EF, evidence-based beta blockers should be used to prevent HF I B In patients with MI, statins should be used to prevent HF I A Blood pressure should be controlled to prevent symptomatic HF I A ACE inhibitors should be used in all patients with a reduced EF to prevent HF I A Beta blockers should be used in all patients with a reduced EF to prevent HF I C An ICD is reasonable in patients with asymptomatic ischemic cardiomyopathy who are at least 40 d post-MI, have an LVEF ≤30%, and on GDMT IIa B Nondihydropyridine calcium channel blockers may be harmful in patients with low LVEF III: Harm C
- 38. Pharmacological Therapy forManagement of Stage C HFrEF Recommendations COR LOE Diuretics Diuretics are recommended in patients with HFrEF with fluid retention I C ACE Inhibitors ACE inhibitors are recommended for all patients with HFrEF I A ARBs ARBs are recommended in patients with HFrEF who are ACE inhibitor intolerant I A ARBs are reasonable as alternatives to ACE inhibitor as first line therapy in HFrEF IIa A The addition of an ARB may be considered in persistently symptomatic patients with HFrEF on GDMT IIb A Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful III: Harm C
- 39. Pharmacological Therapy forManagement of Stage C HFrEF (cont.) Recommendations COR LOE Beta Blockers Use of 1 of the 3 beta blockers proven to reduce mortality is recommended for all stable patients I A Aldosterone Antagonists Aldosterone receptor antagonists are recommended in patients with NYHA class II-IV HF who have LVEF ≤35% I A Aldosterone receptor antagonists are recommended in patients following an acute MI who have LVEF ≤40% with symptoms of HF or DM I B Inappropriate use of aldosterone receptor antagonists may be harmful III: Harm B Hydralazine and Isosorbide Dinitrate The combination of hydralazine and isosorbide dinitrate is recommended for African-Americans, with NYHA class III– IV HFrEF on GDMT I A A combination of hydralazine and isosorbide dinitrate can be useful in patients with HFrEF who cannot be given ACE inhibitors or ARBs IIa B
- 40. Pharmacologic Therapy forManagement of Stage C HFrEF (cont.) Recommendations COR LOE Digoxin Digoxin can be beneficial in patients with HFrEF IIa B Anticoagulation Patients with chronic HF with permanent/persistent/paroxysmal AF and an additional risk factor for cardioembolic stroke should receive chronic anticoagulant therapy* I A The selection of an anticoagulant agent should be individualized I C Chronic anticoagulation is reasonable for patients with chronic HF who have permanent/persistent/paroxysmal AF but without an additional risk factor for cardioembolic stroke* IIa B Anticoagulation is not recommended in patients with chronic HFrEF without AF, prior thromboembolic event, or a cardioembolic source III: No Benefit B Statins Statins are not beneficial as adjunctive therapy when prescribed solely for HF III: No Benefit A Omega-3 Fatty Acids Omega-3 PUFA supplementation is reasonable to use as adjunctive therapy in HFrEF or HFpEF patients IIa B
- 41. Treatment of HFpEF RecommendationsCOR LOE Systolic and diastolic blood pressure should be controlled according to published clinical practice guidelines I B Diuretics should be used for relief of symptoms due to volume overload I C Coronary revascularization for patients with CAD in whom angina or demonstrable myocardial ischemia is present despite GDMT IIa C Management of AF according to published clinical practice guidelines for HFpEF to improve symptomatic HF IIa C Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension in HFpEF IIa C ARBs might be considered to decrease hospitalizations in HFpEF IIb B Nutritional supplementation is not recommended in HFpEF III: No Benefit C
- 42. Clinical Events andFindings Useful for Identifying Patients With Advanced HF Repeated (≥2) hospitalizations or ED visits for HF in the past year Progressive deterioration in renal function (e.g., rise in BUN and creatinine) Weight loss without other cause (e.g., cardiac cachexia) Intolerance to ACE inhibitors due to hypotension and/or worsening renal function Intolerance to beta blockers due to worsening HF or hypotension Frequent systolic blood pressure <90 mm Hg Persistent dyspnea with dressing or bathing requiring rest Inability to walk 1 block on the level ground due to dyspnea or fatigue Recent need to escalate diuretics to maintain volume status, often reaching daily furosemide equivalent dose >160 mg/d and/or use of supplemental metolazone therapy Progressive decline in serum sodium, usually to <133 mEq/L Frequent ICD shocks
- 43. Pharmacologic Treatment forStage C HFrEF HFrEF Stage C NYHA Class I – IV Treatment: For NYHA class II-IV patients. Provided estimated creatinine >30 mL/min and K+ <5.0 mEq/dL For persistently symptomatic African Americans, NYHA class III-IV Class I, LOE A ACEI or ARB AND Beta Blocker Class I, LOE C Loop Diuretics Class I, LOE A Hydral-Nitrates Class I, LOE A Aldosterone Antagonist AddAdd Add For all volume overload, NYHA class II-IV patients
- 44. Drugs Commonly Usedfor HFrEF (Stage C HF) Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials ACE Inhibitors Captopril 6.25 mg 3 times 50 mg 3 times 122.7 mg/d (421) Enalapril 2.5 mg twice 10 to 20 mg twice 16.6 mg/d (412) Fosinopril 5 to 10 mg once 40 mg once --------- Lisinopril 2.5 to 5 mg once 20 to 40 mg once 32.5 to 35.0 mg/d (444) Perindopril 2 mg once 8 to 16 mg once --------- Quinapril 5 mg twice 20 mg twice --------- Ramipril 1.25 to 2.5 mg once 10 mg once --------- Trandolapril 1 mg once 4 mg once --------- ARBs Candesartan 4 to 8 mg once 32 mg once 24 mg/d (419) Losartan 25 to 50 mg once 50 to 150 mg once 129 mg/d (420) Valsartan 20 to 40 mg twice 160 mg twice 254 mg/d (109) Aldosterone Antagonists Spironolactone 12.5 to 25 mg once 25 mg once or twice 26 mg/d (424) Eplerenone 25 mg once 50 mg once 42.6 mg/d (445)
- 45. Drugs Commonly Usedfor HFrEF (Stage C HF) (cont.) Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials Beta Blockers Bisoprolol 1.25 mg once 10 mg once 8.6 mg/d (118) Carvedilol 3.125 mg twice 50 mg twice 37 mg/d (446) Carvedilol CR 10 mg once 80 mg once --------- Metoprolol succinate extended release (metoprolol CR/XL) 12.5 to 25 mg once 200 mg once 159 mg/d (447) Hydralazine & Isosorbide Dinitrate Fixed dose combination (423) 37.5 mg hydralazine/ 20 mg isosorbide dinitrate 3 times daily 75 mg hydralazine/ 40 mg isosorbide dinitrate 3 times daily ~175 mg hydralazine/90 mg isosorbide dinitrate daily Hydralazine and isosorbide dinitrate (448) Hydralazine: 25 to 50 mg, 3 or 4 times daily and isorsorbide dinitrate: 20 to 30 mg 3 or 4 times daily Hydralazine: 300 mg daily in divided doses and isosorbide dinitrate 120 mg daily in divided doses ---------
- 46. Therapies in theHospitalized HF Patient Recommendation COR LOE HF patients hospitalized with fluid overload should be treated with intravenous diuretics I B HF patients receiving loop diuretic therapy, should receive an initial parenteral dose greater than or equal to their chronic oral daily dose, then should be serially adjusted I B HFrEF patients requiring HF hospitalization on GDMT should continue GDMT unless hemodynamic instability or contraindications I B Initiation of beta-blocker therapy at a low dose is recommended after optimization of volume status and discontinuation of intravenous agents I B Thrombosis/thromboembolism prophylaxis is recommended for patients hospitalized with HF I B Serum electrolytes, urea nitrogen, and creatinine should be measured during the titration of HF medications, including diuretics I C
- 47. Therapies in theHospitalized HF Patient (cont.) Recommendation COR LOE When diuresis is inadequate, it is reasonable to a) Give higher doses of intravenous loop diuretics; or b) add a second diuretic (e.g., thiazide) IIa B B Low-dose dopamine infusion may be considered with loop diuretics to improve diuresis IIb B Ultrafiltration may be considered for patients with obvious volume overload IIb B Ultrafiltration may be considered for patients with refractory congestion IIb C Intravenous nitroglycerin, nitroprusside or nesiritide may be considered an adjuvant to diuretic therapy for stable patients with HF IIb B In patients hospitalized with volume overload and severe hyponatremia, vasopressin antagonists may be considered IIb B
- 48. Hospital Discharge Recommendation orIndication COR LOE Performance improvement systems in the hospital and early postdischarge outpatient setting to identify HF for GDMT I B Before hospital discharge, at the first postdischarge visit, and in subsequent follow-up visits, the following should be addressed: a) initiation of GDMT if not done or contraindicated; b) causes of HF, barriers to care, and limitations in support; c) assessment of volume status and blood pressure with adjustment of HF therapy; d) optimization of chronic oral HF therapy; e) renal function and electrolytes; f) management of comorbid conditions; g) HF education, self-care, emergency plans, and adherence; and h) palliative or hospice care. I B Multidisciplinary HF disease-management programs for patients at high risk for hospital readmission are recommended I B A follow-up visit within 7 to 14 days and/or a telephone follow-up within 3 days of hospital discharge is reasonable IIa B Use of clinical risk-prediction tools and/or biomarkers to identify higher-risk patients is reasonable IIa B
- 49. Drug therapy Digoxin • Enhancesinotropy of cardiac muscle • Reduces activation of SNS and RAAS • Recommended in symptomatic LV dysfunction with AF and in symptomatic HF pts with standard therapy • Controlled trials have shown long-term digoxin therapy: Reduces symptoms, increases exercise tolerance Improves hemodynamics, decreases risk of HF progression Reduces hospitalization rates for decompensated HF (DIG trial) Does not improve survival, Mortality directly related to serum digoxin level and more in women Increased Hospitalisation due to worsening heart failure on withdrawal (RADIANCE,PROVED Study)
- 50. Diuretics Used to relievefluid retention Improve exercise tolerance Facilitate the use of other drugs (neurohormonal antagonists) indicated for heart failure Patients can be taught to adjust their diuretic dose based on changes in body weight Electrolyte depletion a frequent complication Should never be used alone to treat heart failure Diuretic resistance
- 51. ACE Inhibitors • Blocksthe conversion of angiotensin I to angiotensin II; prevents functional deterioration • Recommended for all heart failure patients • Relieves symptoms and improves functional status in HF patients ,only produce small benefits in exercise capacity • Reduces risk of death and decreases disease progression, stabilize LV remodeling • Benefits may not be apparent for 1-2 months after initiation, dose titration upto highest recommended range afforded maximun protection (GISSI-3,SOLVD trial) • Abrupt withdrawal of ACEI should be avoided • BP, renal function, potassium level should be evaluated within1-2wks of starting therapy and regularly thereafter • Efficacy in lowBP (<90mmHg),high creatinine(>2.5mg/ml)is not well established
- 52. Beta-Blockers • Cardioprotective effectsdue to blockade of excessive SNS stimulation • In the short-term, beta blocker decreases myocardial contractility; increase in EF after 1-3 months of use • Long-term, placebo-controlled trials have shown symptomatic improvement in patients treated with certain beta-blockers–bisoprolol (CIBISI,II,III), sustained release metoprolol (MERIT-HF) and carvedilol (COMET) • When combined with conventional HF therapy, beta-blockers reduce the combined risk of morbidity and mortality, or disease progression • Current guidelines recommend starting with an ACE inhibitor followed by the subsequent addition of a beta blocker • Not a class effect , genetic polymorphism in Beta1 adrenergic receptor may influence( Bucindolol significantly more effective in white>black-BEST trial). • Can safely be started in hospitalised pts before discharge provided they are stable and not in IV HF therapy. • Should be started with low dose and uptitrated no sooner than 2 wks . • Optimisation of diuretic dose is required
- 53. Aldosterone Antagonists (Spironolactone,Eplerenone) • Generallywell-tolerated • Shown to reduce heart failure-related morbidity and mortality (RALES,EPHESUS trials) • Generally reserved for patients with NYHA Class III-IV HF (EF<35%) who are on standard therapy (diuretics, betablockers, ACEI) • Side effects include hyperkalemia and gynecomastia. Potassium and creatinine levels should be closely monitored (within 3 days and again at 1 wk)
- 54. Angiotensin Receptor Blockers(ARBs) Block AT1 receptors, which bind circulating angiotensin II Examples: valsartan, candesartan, losartan Should not be considered equivalent or superior to ACE inhibitors .Opinion varies in different trials (ELITE-II vs VALIANT) but added benefit in combination with ACEI(CHARM –Added trial) In clinical practice, ARBs should be used to treat patients who are ACE intolerant due to intractable cough or who develop angioedema but not due to hyperkalemia or renal insufficiency Triple combination of ARB, ACEI and Aldosterone antagonist is not recommended because of hyperkalemia
- 55. IVABRADINE(Procoralan) – Previously usedas an antianginal drug – It slows diastolic depolarisation in SA node (by reducing the ‘steepness’ of the If current slope) – It is recommended for slowing heart rate in moderate heart failure – Evidence proved in SHIFT study (Systolic Heart failure treatment with If inhibitor ivabradine Trial) (2006 -2010) – Study population- stable symptomatic chronic heart failure (NYHA class II, III, or IV in stable condition for > 4 weeks) with LVEF<35%, randomized to either ivabradine or placebo treatment on the top of optimised cardiovascular therapy in accordance with current guidelines. – The primary endpoint was the composite of cardiovascular death or hospital admission for worsening CHF. – The starting dose of ivabradine was 5 mg (or matching placebo) twice daily in all patients and dose adjusted on next visits according to resting heart rate, >60 bpm - 7.5 mg BD, <50 bpm or if patient is experiencing signs or symptoms of bradycardia - 2.5 mg BD, between 50 and 60 bpm -at 5 mg BD or matching placebo.
- 56. IVABRADINE-SHIFT study (contd.) • Ivabradinesignificantly reduced the risk of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death by 18% (P<0.0001) compared with placebo . These benefits were observed after 3 months of treatment. • It also significantly reduced the risk of death from heart failure by 26% (P=0.014) and hospitalization for heart failure by 26% (P<0.0001). • The improvements were observed throughout all prespecified subgroups: female and male, with or without beta- blockers at randomization, patients below and over 65 years of age, with heart failure of ischemic or non-ischemic etiology, NYHA class II class III or IV, with or without diabetes, and with or without hypertension • Elevated resting heart rate (HR) is a significant marker for mortality and morbidity in many cardiovascular diseases including heart failure (HF). Moreover, despite background treatment with β-blockers more than half of patients with heart failure and low ejection fraction have an elevated heart rate (≥70 bpm). • Based on these findings the European Medicine Agency, granted a new indication for ivabradine in heart failure patients in sinus rhythm with heart rate ≥75bpm in February 2012. • In May 2012 the new ESC guidelines for the diagnosis and management of heart failure included ivabradine by name in the main algorithm for the treatment of patients with chronic symptomatic systolic heart failure (NYHA functional class II–IV) and a heart rate ≥70 bpm.
- 57. CXL-1427 is anovel, improved second-generation prodrug that breaks down chemically to produce nitroxyl (HNO) and an inactive byproduct following intravenous administration. In extensive pre- clinical testing and in a Phase IIa human proof of concept study with Cardioxyl’s first-generation prodrug, HNO was shown to produce a unique and very attractive hemodynamic profile. The novel combination of effects produced by Cardioxyl’s HNO prodrugs distinguishes them from other therapies used in the treatment of congestive heart failure and provides a strong rationale for continuing the development of this important new class of drugs. Next-generation HNO prodrug targeting severe heart failure was well tolerated and showed hemodynamic activity in a Phase I clinical trial
- 58. About LCZ696 inheart failure LCZ696, a twice a day medicine being investigated for heart failure, has a unique mode of action which is thought to reduce the strain on the failing heart1. It acts to enhance the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful system (the RAAS). Currently available medicines for HFrEF primarily block the harmful effects and mortality remains very high with up to 50% of patients dying within 5 years of a diagnosis of heart failure The double-blind study is the largest ever of a heart failure treatment, and involved 8,842 patients in 47 countries who were followed for 27 months. The study targeted heart patients who had reduced ejection fraction, in which the heart muscle does not contract effectively. Results from the clinical trial showed the drug: reduced the risk of death from cardiovascular causes by 20 percent reduced heart failure hospitalizations by 21 percent reduced the risk of all-cause mortality by 16 percent Overall, the researchers also reported a 20 percent reduction in risk on the primary endpoint, a composite measure of cardiovascular death or heart failure hospitalization.
- 59. Other DRUGS • Nitroglycerine-reliefby reducing the preload. • Morphine (2-5 mg IV) can be repeated every 10-25 minutes until an effect is seen >> decreases anxiety and increases venous capacitance >> lower of left atrial pressure (i.e. decreasing pre-load) >> improve the breathlessness. • Dopamine, dobutamine, noradrenaline-improves cardiac contraction in severe heart failure. • Calcium Channel Blockers-Amlodipine-vasodilator • Sodium nitroprusside- direct NO donor, rapid action • Hydralazine-isosorbide-dinitrate-V-HeFT I trial)- mortality in systolic dysfunction • PDE III inhibitors- Milrinone, IV in acute decompensation
- 60. PHARMACOGENETICS Tremendous heterogeneity indrug action among HF patients suggest underlying gene polymorphism All guidelines recommend titration of drug dosage, shown to be beneficial in RCT BUT- It does not allow dose optimization in pts metabolise/distribute drugs differently Clinical trials generally yeild binary results- beneficial/not beneficial Careful analysis of gene polymorphisms may help clinicians to develop personalised therapeutic regimens in HF pts Important gene polymorphisms- Pathway/Gene Polymorphism Functional Impact Impact on pharmacotherapy RAS ACE 287bp insertion(I) DD- ACE activity β blockers & ACEI - response DD or Deletion(D) worse clinical no effect- II/ID in intron 16 outcome Β1-AR Arginin,Glycine switch Adenyl Cyclase activity ARG389- LVEF with β at aa389 in response to agonist blocker & mortality in ARG389 3× > Gly389 with bucindolol Polygenic phenotype / SNP – Role of Human Genome Poject/HapMap
- 61. Metabolic MODULATION FFA isthe preferred fuel in normal heart but requires more oxygen than glycolysis to generate ATP, in failing heart later is more efficient Shifting energy utilisation from FFA to Glucose reverse abnormalities in cell & EF Partial inhibitors of Fatty acid oxidation (pFox): Carnitine palmitoyl transferaseI (CPT I) inhibitors- Etomoxir- Not much effective Oxfenicine- Toxicity ( hepatic, renal & cardiac mass) Perhexiline- used as antianginal drug, peak oxygen uptake, LVEF & QOL,?hepatotoxicity Adjunctive therapy in HF( Optimistic view) 3 keto acyl co-A thiolase inhibitor( 3 KAT inhibitor) Trimetazidine- LVEF, LVESV, Remodeling, QOL, EC in both ischemic & nonischemic HF Ranolazine-FDA approved for angina, No clinical studies in HF, Animal study- LVEF, SV, Other approaches - glucose substrate or pyruvate oxidation Till date insufficient studies, long duration well designed studies are required.
- 62. IMMUNOTHERAPY Inflammation plays arole in the pathogenesis of HF Methods- • Transcription of inflammatory gene ( by intracellular cAMP)- vesnarinone, pentoxifylline, milrinone, thalidomide and analogs. • Translation of inflammatory mediators- Dexamethasone,Prednisone.p38 inhibitors • TNF antagonists or anti TNF antidodies- Etanercept, Infliximab • Broad-based immunomodulation- IVIG, Statins, Irradiated(oxydized) blood(Celacade therapy) Clinical Trial Report- No favorable impact on mortality and morbidity in the following trials- RENEWAL(Randomizes Etanercept Worldwide Evaluation) –Anti cytokine approach ACCLAIM(Adavanced Chronic Heart Failure Clinical Assessment of Immuno Modulation Therapy) with IM inj of autologus blood subjected to stress ex vivo using a proprietory device(Celacade) Statins- Pleotropic effect –MOST PROMISING RESULT • Retrospective analysis of RCT- incidence of HF, mortality in HF with CAD • Also beneficial in dilated cardiomyopathy • Conflicting result- UNIVERSE trial-Rosuvastatin - LDL, no effect in LV Dimension , LVEF
- 63. Conclusion • HF isa syndrome with a high prevalence of comorbidities and multiple chronic conditions • Coexistence of additional diseases such as arthritis, renal insufficiency, diabetes mellitus, or chronic lung disease with the HF syndrome should logically require a modification of treatment, outcome assessment, or follow-up care • Finally, preventing the burden of this disease through more successful risk modification, sophisticated screening, perhaps using specific omics technologies (ie, systems biology) or effective treatment interventions that reduce the progression from stage A to stage B is an urgent need