Chronic Heart Failure : optimal medical therapy, guidelines and evidence

1. Chronic Heart Failure : optimal medical therapy, guidelines and evidence Carol Crosbie Heart failure specialist nurse Bridgewater Community Trust Trafford Division

2. Chronic heart failure • Evidence of left ventricular dysfunction with or without symptoms or clinical signs

4. Prevalence • It is estimated 900,000 patients have a diagnosis of heart failure in the UK (Petersen et al, 2002) • Chronic heart failure affects between 3-20 people per 1000 people of the population • Relative incidence doubles for each decade of life after the age of 45years (Gibbs et al, 2000)

5. Cost • Hospitalization risk for heart failure is approx 20% per annum • Readmission rates are as high as 50% over a 3 month period • This accounts for 1-2% of NHS expenditure – 70% of which is related to hospitalizations alone • Annual mortality ranges from 10 – 50%, depending on severity. (Nice, 2003)

7. Risk Factors for developing heart failure • Heart disease – responsible for up to 75% of all cases • Valvular disease • Alcohol excess • Viral (dilated cardiomyopathy) • Hypertension • Diabetes • Metabolic Disorders (Thyroid)

8. Signs & Symptoms • Breathlessness (variable degrees) • Oedema/ascites • Fatigue • Cough • Depression/anxiety • Orthopnoea • PND

9. New York Heart AssociationNYHA Class Class I – impaired LV but no symptoms Class II – breathless with moderate exertion e.g brisk walking, uphill walking Class III – Breathless with minimal exertion e.g walking around the house Class IV – breathless at rest e.g when talking or eating

10. NICE update: Diagnosis • Can be difficult • Refer to UK NICE Guideline (partial update 2010)

12. CHF updated NICE guidance 2010

13. Aims of management • Alleviate symptoms • Improve quality of life • Delay disease progression • Prolong patient survival • Reduce sudden cardiac death • Minimise hospital admissions/hospital care (costs)

14. Treatment options for patients with heart failure • Medical Rx • Device therapy: CRT/ICD • Ventricular assist device - short/long term • Cardiac transplantation • (Palliation)

17. CHF updated NICE guidance 2010

18. Pharmacological Management Important to bear in mind that patients may have side effects so it is better to apply a go slow approach to drug titration

20. Diuretic for heart failure Rapid relief of congestive symptoms and fluid retention, improving: • Breathlessness • Exercise performance • May be titrated according to need following initiation of subsequent therapies • No evidence for mortality benefit • No effect on disease progression

21. Loop Diuretics

22. Thiazides

23. ACE Inhibitors • Systematic overview of data from five long-term RCTs • Compared with placebo, ACE inhibitors reduce: • Mortality (P<0.0001) • Readmission (P<0.0001) • Reinfarction (P<0.0001) • Benefit begins early after the start of therapy and persists in the long-term ACE inhibitor ACE inhibitor Placebo Flather et al, Lancet; 2000

24. ACE Inhibitors • Angiotensin Converting Enzyme Inhibitor • Used mainly in the treatment of hypertension and heart failure • Also used in diabetes, kidney disease and post MI

25. Benefits of ACE in HF • Reduce the strain on the heart by decreasing the amount of fluid pumped around the body. • Also relaxes blood vessel thereby reducing the force needed by the heart to eject blood from the heart.

26. ACE- how do they work • Prevent the body from creating the hormone Angiotensin II – an active hormone which constricts blood vessels • This relaxes blood vessels helping to reduce the amount of water reabsorbed by the kidneys • Also improves blood pressure through vessel relaxation which in turn improves cardiac output - - essential for good blood pressure control

27. ACE INHIBITORS

28. Side Effects • Cough • Hypotension • High K • Renal Impairment

29. Angiotensin II receptor blockade for CHF:The CHARM Programme CHARMAlternative CHARM Added CHARMPreserved n=2028 LVEF 40%ACE inhibitor intolerant n=2548 LVEF 40%ACE inhibitor treated n=3025 LVEF >40%ACE inhibitor treated/not treated Primary outcome for each trial: CV death or CHF hospitalisation Pfeffer et al, Lancet 2003; Granger et al, Lancet, 2003; McMurray et al, Lancet, 2003; Yusuf et al, Lancet, 2003

30. Primary endpoint (death or CHF hospitalisation) from the CHARM programme p-value Placebo Candesartan 0.70 <0.0001 CHARM-Alternative 334/1013 406/1015 CHARM-Added CHARM - Preserved 483/1276 53/1272 0.85 0.010 0.86 0.051 Candesartan now licensed in UK for treatment of CHF and LVSD as add-on or alternative to ACE inhibitor 0.6 0.8 1.0 1.2 1.4 Candesartan better Adjusted hazard ratio Placebo better Pre-specified pooling of Alternative & Added trials Granger et al, Lancet 2003; McMurray et al, Lancet, 2003; Yusuf et al,Lancet, 2003; Young et al, Circulation, 2004

31. Angiotensin II Receptor blockers • Angiotensin II is a chemical in the body that causes the muscles around the blood vessels to contract – this narrows the blood vessel which in turn increases blood pressure – a contributing factor for developing heart failure and causing further deterioration of the ventricle

32. How Do ARBs Work • Block the action of Angiotensin II which dilates the blood vessels and reduces blood pressure making it easier for the heart to pump

33. Angiotensin II receptor blockersARBs

34. Side Effects • Renal Impairment • High K • Hypotension • Dizziness

35. Beta - blocker therapy • Pooled data from 25 RCTs (6511 patients and 810 deaths) • Compared with placebo, beta-blockers reduced odds of death by 36% • (95% CI 25% to 45%) • Benefit is additional to that of ACE inhibitors Cleland et al, BMJ, 1999

36. Beta Blockers • Cardio selective Beta-blockers used for the treatment of LVSD • Also used for other cardiac problems: angina MI hypertension arrhythmia

37. How they work • Decreases contractility (negative inotrope) • Decreases relaxation rate • Decreases heart rate • Decreases conduction velocity • Smooth muscle contraction (mild vasoconstriction)

38. Beta Blockers

39. Side Effects • Bradycardia • Hypotension • AV Block

40. Spironolactone therapy • The Randomised Aldactone Evaluation Study (RALES) • 1663 patients with NYHA III or IV heart failure and ejection fraction ≤35% who were already treated with ACE inhibitor, diuretic ± digoxin • It compared spironolactone 25mg od vs placebo, and followed patients for an average of 2 years • The result was a 30% reduction in the risk of death (P<0.001) and a 35% reduction in risk of hospitalisation (P<0.001) among the patients randomised to spironolactone. RRR=0.30 (0.18-0.40) P < 0.001 Pitt et al, NEJM, 1999

41. Aldersterone antagonist therapy for post MI heart failure:EPHESUS AMI, LVEF  40%, Clinical HF, Standard Therapy Eplerenone 25–50 (42.6) mg od (n=3319) Placebon = 3313 Randomise 3–14 Days Post–AMI 1012 Deaths Primary End Points:• All-cause mortality • CV mortality/CV hospitalisation* Secondary End Points: • CV mortality • All-cause mortality/all-cause hospitalisations • CV hospitalisations *CV hospitalisation = hospitalisation for heart failure, MI, stroke, or ventricular arrhythmia Pitt B et al. Cardiovasc Drugs and Therapy 2001; 15: 79-87

42. EPHESUS results • During a mean follow-up of 16 months among those taking eplerenone there was a: • 15% relative reduction in the risk of death (all cause) (RR 0.85 [ 0.75 to 0.96]; P=0.008) • 13% relative reduction in the rate of cardiovascular death or hospitalization (RR 0.87 [ 0.79 to 0.95]; P=0.002) • 21% relative reduction in the rate of sudden cardiac death (RR 0.79 [0.64 to 0.97]; P=0.03) • Eplerenone lacks an effect on oestrogen/progestogen receptors (no gynaecomastia or breast tenderness), but K+ monitoring is still essential (as with spironolactone) Pitt et al, NEJM, 2003

43. Eplerenone in NYHA class II heart failure:EMPHASIS • 2737 patients with NYHA II, LVEF < 35%, mean age 68 years randomised to Eplerenone (mean dose 39 mg) or placebo in addition to standard Rx • Trial stopped prematurely at (median of 21 months) • 37% RRR in primary endpoint of CV death & HF hospitalisation (HR: 0.63 [0.54-0.74], P<0.001) • 26% RRR in all cause mortality (HR: 0.74 [0.62-0.93], P=0.008 & 42% RRR in HF hospitalisation • Significant increase in serum K in Eplerenone group Zannad et al, NEJM, 2010

44. Aldosterone Antagonists • Is a hormone that is present in the body • Produced in excessive amounts in severe heart failure • This increases salt and fluid retention • Which causes worsening symptoms • And further deterioration of cardiac function

45. How do Aldosterone Antagonist Work? • Blocks the effects of aldosterone by binding to receptors in the heart and on blood vessels • This reduces the harmful effects of aldosterone thereby improving symptoms • Improves survival • Reduces Hospitalisation

46. Aldosterone Antagonists

47. Aldosterone Side Effects • Gynaecomastia (in Spironolactone) • Renal Impairment • High K • Low Na • Hypotension

48. Digitalis therapy • 6,800 patients with CHF LVEF < 45% already on diuretic + ACE inhibitor • Randomised to Digoxin or placebo, 250mcg od (mean dose) and followed for average of 37 months • Deaths • 34.8% digoxin vs 35.1% placebo (RR = 0.99 [0.91-1.07] p=0.80) • Death or hospitalisation due to worsening heart failure 1041 patients on digoxin vs 1291 patients on placebo (RR = 0.72 [0.69-0.82] P < 0.001) already on diuretic + ACE inhibitor Placebo P<0.001 Dogoxin DIG, NEJM, 1997

49. Digoxin

50. Ivabradine in CHF: SHIFT • 6558 stable CHF patients with LVEF<35% randomised to ivabradine or placebo • Previous hospitalisation within 1 year, HR >70 bpm (SR) • Mean follow up 23 months, 89% on beta-blockers • 18% reduction in primary endpoint of CV death or HF hospitalisation (95% CI: 0.75-0.90) • 26% reduction HF hospitalisation (95% CI: 0.66-.083) • 26 % reduction in progressive HF death (95% CI: 0.58-0.94) Swedberg et al Lancet 2010