1 The Clinical Pharmacology of Heart Failure

2 Heart Failure Chronic heart failure is a syndrome characterised –by progressive cardiac dysfunction –breathlessness –tiredness –neurohormonal disturbances –sudden death

3 Chronic heart failure –affects 2-10% of the population –incidence rises with increasing age –commonly due to coronary artery disease –has a poor prognosis with a 5 year mortality of 50% rising to 80% in a year for some patients

4 A prevalent condition Prevalence of HF (per 1000 population) Age (years) All ages Men Women

5 A growing burden Vital Statistics of the United States, National Center for Health Statistics Deaths from HF (USA)

6 Physiology Normal circulation and circulatory volume are maintained by means of two opposing systems –Salt and water retaining and vasoconstrictor system –Salt and water excretion and vasodilatation

7 Salt and water retaining and vasoconstrictor system –The renin-angiotensin-aldosterone system –The sympathetic system –The endothelin system Salt and water excretion and vasodilatation –Natriuretic peptide system –EDRF

8 Heart failure usually occurs –following myocardial damage i.e. an MI Systolic Dysfunction –Following upon sustained hypertension Diastolic Dysfunction As a result cardiac output falls as does perfusion The body registers this as a loss in circulatory volume The salt and water retaining systems are activated (RAAS) The vasoconstrictor systems are activated (Sympathetic systems)

9 The RAAS causes the release of –angiotensin II a potent vasoconstrictor and hypertrophogenic and fibrogenic peptide –and aldosterone a potent antinatriuretic peptide The result is salt and water retention, vasoconstriction and hypertrophy and fibrosis of cardiac myocytes

10 Activation of the Sympathetic System causes the release of noradrenaline and adrenaline –both are potent vasoconstrictors –both stimulate renin release –both are also hypertrophogenic

11 Systolic Dysfunction According to the Frank-Starling Law if the muscle of a healthy heart is stretched it will contract with greater force and so pump out more blood. In the failing or damaged heart this relationship is lost As the circulatory volume increases the heart dilates, as the heart dilates the force of contraction weakens and the cardiac output drops further This fall in cardiac output then activates the RAAS further

12 The result is a vicious cycle in which the RAAS is activated, circulatory volume increases and cardiac performance deteriorates further As the heart starts to dilate the cardiac myocytes undergo hypertrophy and then fibrosis and thus the heart is further weakened

13 The Final Result A failing heart that can not pump out sufficient blood to supply the needs of the body Progressive retention of salt and water which results in oedema, pulmonary oedema Progressive myocyte death and fibrosis

14

15

16 Usual treatment today has two aims To improve symptoms Diuretics Digoxin ACE inhibitors To improve survival ACE inhibitors  Blockers Oral nitrates plus hydralazine Spironolactone Aims of heart failure management Davies et al. BMJ 2000;320:

17 Treatment Regimes Symptomatic treatment Inhibition of detrimental neurohormonal adaptations Enhancement of beneficial neurohormonal adaptations Enhancement of cardiac function

18 Symptomatic Treatment –Loop Diuretics –the mainstay of symptomatic treatment –FRUSEMIDE or BUMETANIDE Blocking detrimental hormonal changes Sympathetic activation –CARVEDILOL, BISOPROLOL and METOPROLOL are beta blockers which are of proven benefit in the treatment of CHF

19 RAAS Angiotensin II –Two groups of drugs available to block the effects of angiotensin II –ACE Inhibitors (ENALAPRIL, CAPTOPRIL) –Angiotensin antagonists (LOSARTAN) but these are not as effective (ELITE II) Aldosterone –Effects blocked by SPIRONOLACTONE –Produces a significant reduction in morbidity (RALES)

20 Enhancement of cardiac function Positive Inotropes –These drugs improve the ability of the heart to pump and so improve cardiac status –DIGOXIN is the only drug in common use Vasodilators –The nitrovasodilators by reducing preload and after load improve cardiac function (ISOSORBIDE MONO or DINITRATE –Hydralazine an arterial dilator has also been shown to improve cardiac function

21 Mortality remains high ACEi Risk reduction 35% (mortality and hospitalizations)  Blockers Risk reduction 38% (mortality and hospitalizations) Oral nitrates and hydralazine Benefit vs. placebo; inferior to enalapril (mortality) However: 4-year mortality remains ~ 40% Davies et al. BMJ 2000;320: Gibbs et al. BMJ 2000;320:

22 The Drugs Loop Diuretics (FRUSEMIDE) –The main stay of treatment –It is essential to remove excess salt and water before introducing other agents –The loop diuretics induce profound diuresis –Act by inhibiting the NA-K-Cl transporter in the Loop of Henle –Work at very low glomerular filtration rates –Prevent the reabsorption of 20% of filtered sodium and water

23

24 In the most severely affected patients or in resistant patients they can be used in combination with thiazide diuretics This combination is very powerful and may induce a diuresis of 5-10 litres a day Adverse Drug Reactions –Dehydration –Hypotension –Hypokalaemia, Hyponatraemia –Gout –Impaired glucose tolerance, diabetes

25

26 Drug Drug Interactions Frusemide and –aminoglycosidesaural and renal toxicity –lithiumrenal toxicity –NSAIDsrenal toxicity –antihypertensivesprofound hypotension –vancomycinrenal toxicity

27 Reducing Mortality Angiotensin Blockade Beta receptor blockade Aldosterone blockade

28 Angiotensin I Angiotensinogen (Liver) AT 1 AT 2 Angiotensin II ACE inhibitor Valsartan AT 1 receptor blocker Renin inhibitor Bradykinin Peptides Chymase Local Ang II synthesis is independent of ACE Several pathways of Ang II generation de Gasparo et al. Pharmacol Rev 2000; 52:415

29 GFR Proteinuria Aldosterone release Glomerular sclerosis Angiotensin-II plays a central role in organ damage A-II AT 1 receptor Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction LV hypertrophy Fibrosis Remodelling Apoptosis Stroke DEATH *Preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate Hypertension Heart failure MI Renal failure

30 Angiotensin Converting Enzyme Inhibitors ENALAPRIL, LISINOPRIL, CAPTOPRIL –A major breakthrough in the treatment of CHF –Improve symptoms, reduce mortality, slow down progressive deterioration in cardiac function –Competitively block angiotensin converting enzyme –Prevent the conversion of angiotensin I to angiotensin II –Reduce preload and after load on the heart

31 ACE Inhibitors Conclusively demonstrated in CHF patients to reduce –morbidity –mortality Post MI patients to reduce –morbidity –mortality –onset of heart failure Main studies CONCENSUS, SOLVD, SAVE, AIRE, ISSIS-4

32 Adverse Drug Reactions –First dose hypotension –Cough –Angioedema –Renal impairment –Renal failure –Hyperkalaemia Drug-Drug Interactions –NSAIDs acute renal failure –Potassium supplements hyperkalaemia –Potassium sparing diuretics hyperkalaemia

33 Angiotensin Receptor Blockers ARBs selectively block the angiotensin II, AT1 receptor. They are effective in the treatment of heart failure. –NOT AS EFFECTIVE AS ACEIs At present recommended for use in ACEI intolerant patients. Some suggestion that they may have benefit when added to ACEIs. Major outcome studies Elite II, Charm, ValHeft Valiant

Vasoconstriction Vascular proliferation Aldosterone secretion Cardiac myocyte proliferation Increased sympathetic tone Vasodilation Antiproliferation Apoptosis AT 1 AT 2 Angiotensin II Different roles of AT 1 and AT 2 receptors de Gasparo et al. Pharmacol Rev 2000; 52:415

35

Kaplan-Meier analysis of probability of survival Time since randomization (months) p = 0.80 Survival probability (%) Valsartan Placebo Cohn et al. NEJM 2001;345:1667

% risk reduction p= Significant benefits on combined mortality / morbidity endpoint 0 Event-free probability Placebo Valsartan Time since randomization (months) 0.7 Cohn et al. NEJM :1667

% risk reduction p = Event-free probability Time since randomization (months) Valsartan (n = 185) Placebo (n = 181) Cohn et al. AHA Scientific Sessions 2000 Primary endpoint: greatest benefits in patients not on ACE inhibitor therapy Combined all-cause mortality / morbidity

39 Aldosterone Antagonists Spironolactone (RALES Study) –Potassium sparing diuretic –Inhibits the actions of aldosterone –Acts in the distal tubule –Used in combination with loop diuretics –Particularly useful in resistant oedema Proven to reduce mortality when used in combination with ACEIs

40

41 Beta Blockers CARVEDILOL, BISOPROLOL, METOPROLOL –The use of beta blockers in the treatment of CHF is potentially hazardous and patients must be selected carefully –Block the actions of the sympathetic system –May precipitate severe deterioration in CHF –Have been demonstrated to reduce morbidity and mortality in mild/moderate and severe heart failure by 30% –Should be used only when a patient has been stabilized and not during an acute presentation –Specialist use only

42

43 Positive Inotropes DIGOXIN (The DIG Study) –Increases availability of calcium in the myocyte –Shown to reduce number of hospitalisations –No effect on mortality –Narrow therapeutic index –Arrhythmias –Nausea –Confusion

44 Anticoagulants WARFARIN –Dilated ventricle gives rise to thrombus formation and thrombo-embolic events –Warfarin has proven value in preventing these events

45 Therapeutic Regime Frusemide ± thiazideAppropriate dose Frusemide + pulsed metolazone ACE InhibitorAppropriate dose –Angiotensin receptor blocker Carvedilol, Bisoprolol, Metoprolol DigoxinTDM WarfarinTDM

46 Monitoring Benefit Symptomatic relief –SOB, tiredness, lethargy Clinical relief –Peripheral oedema, ascites, weight Monitor weight regularly –Patient performs daily weight assessment –Increase medication according to symptoms or weight Patient education