Congestive Heart Failure Latest Guidelines and Recent Advances in Drug treatment of CHF

CHF latest guidelines. Recent advances in drug treatment of CHF included. Recent FDA approved drugs for treatment of CHF also included.

1. Recent guidelines for the treatment of CHF By-Dr. Rahul Kumar Bhati PG Pharmacology

2. Contents Introduction Definition Epidemiology Signs and symptoms Pathophysiology Pharmacotherapy Classification of HF Treatment Guidelines for HF Recent advances Newer drug targets Conclusion

3. Introduction Considerable advances have been made in management of heart failure over the past few decades. In outpatient-based clinical trials, mortality has more than halved in people with established systolic chronic heart failure; moreover, admissions have fallen and patients' quality of life has risen. Nevertheless, heart failure remains a major public-health issue, with high prevalence and poor outcomes. Management of this condition includes appropriate non- pharmacological strategies, use of drugs (particularly those that inhibit key activated neurohormonal systems), and implantation of devices in appropriate patients. Surgery and transplantation are also options for selected individuals with highly advanced disease.

4. Heart Failure The inability of the heart to pump sufficient blood to meet the needs of the tissues for oxygen and nutrients.

5. Definition HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood.

6. Definition contd... 1. Heart failure with reduced ejection fraction ( HFrEF ) — EF (%)<or=40 — Also referred to as systolic HF — coronary artery disease (CAD) with antecedent myocardial infarction (MI) is a major cause of HFrEF

7. Definition contd... 2. Heart failure with preserved ejection fraction ( HFpEF ) — EF(%) >or=50 — Also referred to as diastolic HF — Hypertension, obesity, CAD, diabetes mellitus, and hyperlipidemia are important cause of HFpEF

8. Epidemiology The lifetime risk of developing HF is 20% for Americans >or=40 years of age. HF incidence: >650 000 new HF cases diagnosed annually HF incidence increases with age, rising from approximately 20 per 1000 individuals 65 to 69 years of age to >80 per 1000 individuals among those >or=85 years of age. Mortality rates for HF remain approximately 50% within 5 years of diagnosis The total cost of HF care in the United States exceeds $30 billion annually, with over half of these costs spent on hospitalizations.

9. Signs and symptoms Left-Sided Heart Failure: — Results from LV dysfunction — Blood backs up into Left atrium — Pulmonary congestion and edema

10. Signs and symptoms Right-Sided Heart Failure: — Results from diseased right ventricle — Blood backs up into right atrium and venous circulation

11. Biomarkers in HF Natriuretic Peptides: — BNP (B-type natriuretic peptide) or NT- proBNP (N-terminal pro-B-type natriuretic peptide) — generated by cardiomyocytes in response to myocardial stretch — useful to support clinical decision making regarding the diagnosis of HF, especially in the setting of clinical uncertainty — useful for establishing prognosis or disease severity in chronic HF

12. Pathophysiology of HF In order to maintain normal cardiac output, several compensatory mechanisms play a role: — Compensatory enlargement in the form of cardiac hypertrophy, cardiac dilatation, or both. — Tachycardia (i.e. increased heart rate) due to activation of neurohumoral system e.g. • release of norepinephrine and atrial natriuretic peptide, • activation of renin-angiotensin aldosterone mechanism.

13. Pharmacotherapy of HF

14. Goals of Pharmacotherapy Relief of congestion/low cardiac output symptoms & restoration of cardiac performance: Inotropic drugs: digoxin , dobutamine , amrinone / milrinone . Diuretics: furosemide , thiazides . Vasodilators: ACE inhibitors/AT1 antagonist, hydralazine , nitrate. Beta blockers: metoprolol , bisprolol , carvedilol Arrest/ reversal of disease progression & prolongation of survival: ACE inhibitors/AT1 antagonist (ARBs). Beta-blockers Aldosterone antagonist: spironolactone

15. HF: Classification ACCF/AHA (American College of Cardiology Foundation/ American Heart Association) stages of HF NYHA (New York Heart Association) functional classification of HF ACCF/AHA stages of HF emphasize the development and progression of disease whereas NYHA classes focus on exercise capacity and symptomatic status of the disease

16. 2013 ACCF/AHA Guideline for the Management of Heart Failure A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines Goals of HF management: — Stage A: modifying risk factors — Stage B: treating structural heart disease — Stage C & D: reducing morbidity and mortality

17. Stage A: Recommendations Hypertension and lipid disorders should be controlled to lower the risk of HF. Other conditions that may lead to or contribute to HF, such as obesity, diabetes mellitus, tobacco use, and known cardiotoxic agents, should be controlled or avoided.

18. Diuretic-based antihypertensive therapy has repeatedly been shown to prevent HF in a wide range of patients; ACE inhibitors, ARBs, are also effective. Data are less clear for calcium antagonists and alpha blockers in reducing the risk for incident HF. Treatment of hyperlipidemia with statins reduces the likelihood of HF in at-risk patients

19. Stage B: Recommendations ACE inhibitors and Beta blockers should be used in all patients with a reduced EF to prevent HF In patients with MI or history of MI and reduced EF, ACE inhibitors or ARBs(in patients intolerant to ACEI) and beta blockers should be used to prevent HF In patients with MI, statins should be used to prevent HF Blood pressure should be controlled to prevent symptomatic HF Nondihydropyridine calcium channel blockers may be harmful in patients with low LVEF

20. Stage C HFrEF recomendations NYHA Class 1: ACEI or ARB and Beta Blocker NYHA Class 2,3,4 — for volume overload: add Loop diuretics — for persistently symptomatic: add vasodilators ( hydralazine and isosorbide dinitrate ) — LVEF <or=35%, estimated creatinine >30 mL /min and K+ <5.0 mEq / dL : add Aldosterone Antagonist Calcium channel blockers are not recommended as routine treatment in HFrEF

21. Diuretics: recommendations Diuretics should be prescribed to all patients who have evidence of or prior history of fluid retention. Diuretics should generally be combined with an ACE inhibitor, beta blocker, and aldosterone antagonist. Loop diuretics have emerged as the preferred diuretic agents for use in most patients with HF. Thiazide diuretics may be considered in hypertensive patients with HF and mild fluid retention because they confer more persistent antihypertensive effects.

22. Diuretics: recommendations contd... Diuretics increase urinary sodium excretion and decrease physical signs of fluid retention in patients with HF Diuretics are the only drugs used for the treatment of HF that can adequately control the fluid retention of HF. The most commonly used loop diuretic for the treatment of HF is furosemide , but some patients respond more favorably to other agents in this category (e.g., bumetanide , torsemide ) because of their increased oral bioavailability

23. Diuretics: recommendations contd... Patients may become unresponsive to high doses of diuretic drugs if they consume large amounts of dietary sodium or are taking agents that can block the effects of diuretics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], or have a significant impairment of renal function or perfusion Diuretic resistance can generally be overcome by the intravenous administration of diuretics or combination of different diuretic classes (e.g., metolazone with a loop diuretic)

24. ACE Inhibitors: recommendations ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, to reduce morbidity and mortality The benefits of ACE inhibition were seen in patients with mild, moderate, or severe symptoms of HF and in patients with or without CAD.

25. ARB: recommendations ARBs are recommended in patients with HFrEF with current or prior symptoms who are ACE inhibitor intolerant (cough, angioedema ), to reduce morbidity and mortality. ARBs are reasonable to reduce morbidity and mortality as alternatives to ACE inhibitors as first line therapy for patients with HFrEF , especially for patients already taking ARBs for other indications.

26. ARB: recommendations contd... Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are already being treated with an ACE inhibitor and a beta blocker in whom an aldosterone antagonist is not indicated or tolerated. Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful for patients with HFrEF .

27. Beta Blockers: Recommendations Use of 1 of the 3 beta blockers proven to reduce mortality (e.g., bisoprolol , carvedilol , and sustained-release metoprolol succinate ) is recommended for all patients with current or prior symptoms of HFrEF , to reduce morbidity and mortality Like ACE inhibitors, beta blockers can reduce the risk of death and the combined risk of death or hospitalization

28. Aldosterone receptor antagonists: Recommendations Aldosterone receptor antagonists ( Spironolactone , Eplerenone ) are recommended in patients with NYHA class 2—4 HF and who have LVEF of 35% or less, to reduce morbidity and mortality. Aldosterone receptor antagonists are recommended to reduce morbidity and mortality following an acute MI in patients who have LVEF of 40% or less who develop symptoms of HF or who have a history of diabetes mellitus

29. Aldosterone receptor antagonists: Recommendations contd... To minimize the risk of life-threatening hyperkalemia , patients should have initial serum creatinine <2.5 mg/ dL (<2.0 mg/ dL for women) and serum potassium <5.0 mEq /L without a history of severe hyperkalemia .

30. Hydralazine & Isosorbide dinitrate : recommendations The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for patients with NYHA class Ill— IV HFrEF who remain symptomatic despite concomitant use of ACE inhibitors, beta blockers, and aldosterone antagonists. A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency.

31. Digoxin : recommendation Digoxin can be beneficial in patients with HFrEF , to decrease hospitalizations for HF treatment with digoxin for 1 to 3 months can improve symptoms, HRQOL (Health Related Quality of Life), and exercise tolerance in patients with mild to moderate HF treatment with digoxin for 2 to 5 years had no effect on mortality but modestly reduced the combined risk of death and hospitalization Digoxin can be used only in patients who remain symptomatic despite therapy with the neurohormonal antagonists or in patients with AF

32. Anticoagulation: Recommendations Patients with chronic HF with permanent/persistent/ paroxysmal AF and an additional risk factor for cardioembolic stroke (history of hypertension, diabetes mellitus, previous stroke or transient ischemic attack, or >or= 75 years of age) should receive chronic anticoagulant therapy. The selection of anticoagulant agent ( warfarin , dabigatran , apixaban , or rivaroxaban ) should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics. Chronic anticoagulation is reasonable for patients with chronic HF who have permanent/persistent/paroxysmal AF but are without an additional risk factor for cardioembolic stroke. Anticoagulation is not recommended in patients with chronic HFrEF without AF, a prior thromboembolic event, or a cardioembolic source.

33. Statins : recommendation Statins are not beneficial as adjunctive therapy when prescribed solely for the diagnosis of HF in the absence of other indications for their use Originally designed to lower cholesterol in patients with cardiovascular disease, statins are increasingly recognized for their favorable effects on inflammation, oxidative stress, and vascular performance. However, 2 large RCTs have demonstrated that rosuvastatin has neutral effects on long-term outcomes in patients with chronic HFrEF At present, statin therapy should not be prescribed primarily for the treatment of HF to improve clinical outcomes.

34. Omega-3 Fatty Acids: Recommendation Omega-3 polyunsaturated fatty acid (PUFA) supplementation is reasonable to use as adjunctive therapy in patients with NYHA class 2—4 symptoms and HFrEF or HFpEF , to reduce mortality and cardiovascular hospitalizations Trials in primary and secondary prevention of coronary heart disease showed that omega-3 PUFA supplementation results in a 10% to 20% risk reduction in fatal and nonfatal cardiovascular events.

35. Device Therapy for HF Implantable cardioverter -defibrillator Cardiac resynchronization therapy Mechanical Circulatory Support Cardiac Transplantation

36. Stage C HFpEF recommendations Systolic and diastolic blood pressure should be controlled according to published clinical practice guidelines Diuretics should be used for relief of symptoms due to volume overload Management of AF according to published clinical practice guidelines for HFpEF to improve symptomatic HF Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension in HFpEF ARBs might be considered to decrease hospitalizations in HFpEF Nutritional supplementation is not recommended in HFpEF

37. Stage D recommendations Water Restriction: Fluid restriction (1.5 to 2 L/d) is reasonable in stage D, especially in patients with hyponatremia , to reduce congestive symptoms. Inotropic Support: Until definitive therapy (e.g., coronary revascularization, MCS, heart transplantation) or resolution of the acute precipitating problem, patients with cardiogenic shock should receive temporary intravenous inotropic support to maintain systemic perfusion and preserve end-organ performance. Continuous intravenous inotropic support is reasonable as "bridge therapy" in patients with stage D HF refractory to GDMT and device therapy who are eligible for and awaiting MCS or cardiac transplantation.

38. Short-term, continuous intravenous inotropic support may be reasonable in those hospitalized patients presenting with documented severe systolic dysfunction who present with low blood pressure and significantly depressed cardiac output to maintain systemic perfusion and preserve end-organ performance. Long-term, continuous intravenous inotropic support may be considered as palliative therapy for symptom control in select patients with stage D HF despite optimal GDMT and device therapy who are not eligible for either MCS or cardiac transplantation. Long-term use of either continuous or intermittent, intravenous parenteral positive inotropic agents, in the absence of specific indication or for reasons other than palliative care, is potentially harmful in the patient with HF. Use of parenteral inotropic agents in hospitalized patients without documented severe systolic dysfunction, low blood pressure, or impaired perfusion and evidence of significantly depressed cardiac output, with or without congestion, is potentially harmful.

39. Mechanical Circulatory Support: MCS is beneficial in carefully selected patients with stage D HFrEF in whom definitive management (e.g., cardiac transplantation) or cardiac recovery is anticipated or planned. Nondurable MCS, including the use of percutaneous and extracorporeal ventricular assist devices, is reasonable as a "bridge to recovery" or a "bridge to decision" for carefully selected patients with HFrEF with acute, profound hemodynamic compromise. Durable MCS is reasonable to prolong survival for carefully selected patients with stage D HFrEF . Cardiac Transplantation: Evaluation for cardiac transplantation is indicated for carefully selected patients with stage D HF despite GDMT , device, and surgical managernent .

40. Recommendations for Therapies in the Hospitalized HF Patient

41. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure The ACC, the AHA, and the Heart Failure Society of America (HFSA) recognize that the introduction of effective new therapies that potentially affect a large number of patients presents both opportunities and challenges. The introduction of an angiotensin receptor– neprilysin inhibitor (ARNI) ( valsartan / sacubitril ) and a sinoatrial node modulator ( ivabradine ), when applied judiciously, complements established pharmacological and device-based therapies and represents a milestone in the evolution of care for patients with heart failure (HF). Accordingly, the writing committees of the “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure” developed recommendations for the incorporation of these therapies into clinical practice.

42. Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations Renin-Angiotensin System Inhibition With Angiotensin -Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors, OR ARBs, OR ARNI in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic HFrEF to reduce morbidity and mortality. The use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality

43. The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACE inhibitors because of cough or angioedema . In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor. ARNI should not be administered to patients with a history of angioedema .

44. Ivabradine : Recommendation Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest.

45. Recent Advances in the management of HF

46. ARNI( valsartan / sacubitril )

47. Ivabradine

48. Activation of SERCA2a In patients with heart failure, there is decreased calcium content in the sarcoplasmic reticulum, which is partly due to the diminished sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a (SERCA2a) pump activity. Istaroxime is a molecule that has the unprecedented ability to increase the SERCA2a pump activity and cause myocardial relaxation. It also causes inhibition of Na+/K+- ATPase

49. Cardiac myosin ATPase activation During myocardial contraction, the myosin head works as an independent force generator if it is bound tightly to actin . However, the majority of myosin heads are not tightly bound to actin in the physiological state. This can be changed by omecamtiv mecarbil , which increases the number of myosin heads that are in force-generating configuration to get tightly bound to actin that leads to enhanced cardiac contraction.

50. Relaxin Relaxin hormone, besides being produced by the corpus luteum and placenta, is also produced by the failing myocardium. It acts on a G-protein coupled receptor named RXFPI that is produced in the vasculature, heart and the kidneys. As a result, cAMP & nitric oxide production is increased Serelaxin (human recombinant relaxin ) causes greater vasodilation and improved vessel compliance In the end the trial(RELAX-AHF-2) was not strong enough to gain approval for serelaxin from the FDA or in Europe.

51. Natriuretic peptides ANP is mainly produced in atrial myocytes . The main stimulant for ANP release is atrial wall stretch resulting from increased intravascular volume ANP has vasodilatory , natriuretic , diuretic, and kaliuretic properties. Carperitide is a recombinant ANP that is currently approved in JAPAN for the treatment of acute heart failure syndrome. Urodilatin is a modified form of pro-ANP that is synthesized and secreted from the distal convoluted tubules in the kidney and regulates renal sodium reabsorption and water homeostasis Ularitide is a synthetically derived form of urodilatin

52. Ryanodine receptor stabilizers The ryanodine receptors that are present in the sarcoplasmic reticulum of the heart cause release of calcium on activation. Under resting conditions, the ryanodine receptor channel is maintained in a closed state by a protein calstabin-2. In HF the ryanodine receptor channel tends to remain inappropriately in the open state during diastole, resulting in calcium leakage from the sarcoplasmic reticulum. The depletion of calcium from the SR leads to weak muscle contractions in heart failure. This phenomenon is termed as diastolic sarcoplasmic reticulum calcium leak. JTV519 is a drug that can potentiate the binding of calstabin to ryanodine , and thus help it to retain its closed state S44121 is a ryanodine receptor stabilizer, studied in patients with heart failure who are at increased risk for ventricular arrhythmia.

53. Neuregulins The neuregulins are proteins that belong to the epidermal growth factor family of ligands that bring about their effects through ErbB tyrosine kinase receptors. reduced ErbB signaling in the failing myocardium increases its chance of cell death and rapid worsening of heart failure Recombinant NRG-1 β has been evaluated in several animal models of cardiac failure and found to improve the structural and functional indices for ventricular remodeling recombinant neuregulin -l improved the LVEF and reduced the LV remodeling by decreasing EDV and ESV

54. Sarcoplasmic reticulum calcium ATPase 2A gene therapy The enzyme SERCA2a catalyzes the adenosine triphosphate - dependent movement of calcium ions into the sarcoplasmic reticulum from the cytosol Increase of calcium levels by augmenting SERCA2a activity will improve cardiac function. This has led to the concept of overexpression of SERCA2a in the cardiomyocytes of the failing heart in order to improve the contraction velocity. Gene transfer using adenovirus as a vector for delivery of SERCA2a complementary DNA is being studied. But the HF Gene-Therapy Trial CUPID-2 failed to meet the primary end point, a composite of of HF hospitalization or ambulatory treatment for worsening heart failure at 12 months.

55. NEED FOR NEWER THERAPIES Available drugs treat only symptomatically Even the available drugs do not control symptoms effectively Associated side effects are more Needed life long treatment HF is associated with high morbidity and mortality

56. Conclusion Despite advances in management of heart failure, the condition remains a major public-health issue with high prevalence, poor clinical outcomes, and large health-care costs. Risk factors are well known and, thus, preventive strategies should have a positive effect on disease burden. Emerging strategies for heart failure management include individualisation of treatment, novel approaches to diagnosis and tracking of therapeutic response, pharmacological agents aimed at new targets, and cell-based and gene-based methods for cardiac regeneration.

57. Conclusion Agents directly acting on remodeling process may even reverse current pathological condition of heart failure. The newer therapeutics may be potential candidates in future for heart as there is increase in understanding of pathophysiology of heart failure.