DETERMINANTS OF VENTRICULAR FUNCTION CONTRACTILITY PRELOAD AFTERLOAD STROKE VOLUME Pathophysiology of Congestive Heart Failure. Determinants of ventricular function. Ventricular function, and cardiac function in general, depends upon the interaction of four factors that regulate the volume of blood expelled by the heart (the cardiac output): contractility, preload, afterload, and heart rate. The first three determine the volume of blood expelled with each beat (the stroke or ejection volume), while the heart rate affects the cardiac output by varying the number of contractions per unit time. These four factors, which are intrinsic regulators of heart function, are all influenced by the nervous system. In the failing heart, especially in ischemic heart disease, it is also important to consider some purely mechanical factors, such as the synergy of ventricular contraction, the integrity of the septum, and the competence of the atrioventricular valves. - Synergistic LV contraction - LV wall integrity - Valvular competence HEART RATE CARDIAC OUTPUT

SCOMPENSO CARDIACO CONGESTIZIO LAVORO SISTOLICO DETERMINATO DA: Lunghezza fibre Livello tono simpatico Frequenza Volume (precarico) Impedenza (postcarico)

PATHOPHYSIOLOGICAL MECHANISMS OF HEART FAILURE AND MAJOR SITES OF DRUG ACTION

ALTERAZIONI EMODINAMICHE Volume sistolico Frequenza Volume (e P) ventricolare telediastolico Volume (e P) ventricolare telesistolico Pressione arteriosa Resistenze vascolari sistemiche Pressione capillare polmonare Congestione venosa = SINTOMATOLOGIA Dispnea, ortopnea, tachipnea Edema polmonare Edemi periferici, epatomegalia

GLICOSIDI CARDIOATTIVI Anello lattonico e nucleo steroideo: necessari per l’attività Residui di zucchero: influenzano la farmacocinetica

GLICOSIDI CARDIOATTIVI Digitalis lanata Digitalis purpurea Strophantus gratus Strofantus kombé Scilla maritima Oleandro Digitossina Digossina K-strofantina G-strofantina

GLICOSIDI CARDIOATTIVI:MECCANISMO D’AZIONE

GLICOSIDI CARDIOATTIVI: MECCANISMO D’AZIONE

EFFETTI DELLA OUABAINA SU TESSUTO CARDIACO ISOLATO A concentrazione terapeutica: Durata potenziale d’azione Transiente di Ca2+ Tensione sviluppata A concentrazione tossica: Post-potenziali oscillatori Oscillazioni spontanee di Ca2+ Tensione sviluppata Post-contrazioni tardive

GLICOSIDI CARDIOATTIVI: EFFETTI DIRETTI AZIONE INOTROPA POSITIVA: Aumento forza sviluppata Aumento velocità di sviluppo della forza Effetto presente in tutti i punti delle curve di Starling aumento volume sistolico riduzione volume telesistolico

GLICOSIDI CARDIOATTIVI: EFFETTI DIRETTI EFFETTI SULL’ATTIVITA’ ELETTRICA Fibre del Purkinje: riduzione potenziale di riposo riduzione durata potenziale d’azione aumento automatismo (per aumento pendenza fase 4) Nodo SA e AV: depressione per effetto diretto a livelli tossici (e fibre specializzate atriali)

GLICOSIDI CARDIOATTIVI: EFFETTI INDIRETTI Marcato aumento tono vagale Riduzione tono simpatico Riduzione generazione impulsi nodo SA Aumento conduzione intra-atriale Rallentamento conduzione ed aumento ERP nodo AV Effetti sull’ECG Riduzione ampiezza onda T (ed inversione in alcune deviazioni) Accorciamento intervallo Q-T Talvolta allungamento P-R

GLICOSIDI CARDIOATTIVI: EFFETTI SU CUORE E CIRCOLAZIONE SOGGETTO NORMALE Aumento indici di contrattilità cardiaca Aumento volume sistolico Riduzione frequenza Aumento resistenze vascolari periferiche Lieve riduzione della gittata

GLICOSIDI CARDIOATTIVI: EFFETTI SU CUORE E CIRCOLAZIONE SOGGETTO SCOMPENSATO Aumento indici di contrattilità cardiaca Aumento volume sistolico Riduzione frequenza Riduzione resistenze vascolari periferiche Riduzione volumi telediastolico e telesistolico Riduzione pressione venosa polmonare Aumento perfusione renale diuresi Aumento della gittata

DIGOXIN PHARMACOKINETIC PROPERTIES Oral absorption (%) Protein binding (%) Volume of distribution (l/Kg) Half life Elimination Onset (min) i.v. oral Maximal effect (h) Duration Therapeutic level (ng/ml) 60 - 75 25 6 24-36 h Renal 5 - 30 30 - 90 2 - 4 3 - 6 2 - 6 days 0.5 - 2

DIGOSSINA: FARMACOCINETICA Variazioni nella biodisponibilità (tra individui e tra preparazioni) L’instaurarsi dell’effetto terapeutico causa variazioni nella clearance La lentezza dell’insorgenza dell’effetto è legata alla lentezza del legame alla pompa Indice terapeutico: 2-3

DIGOSSINA: INTERAZIONI FARMACOLOGICHE INTERAZIONI FARMACOCINETICHE Variazioni nell’assorbimento: - colestiramina, neomicina, fibre alimentari +omeprazolo, tetraciclina, eritromicina Variazioni nella clearance: chinidina, verapamil, amiodarone, captopril, nifedipina, nitrendipina INTERAZIONI FARMACODINAMICHE Antiaritmici, inotropi negativi, diuretici (variazioni di K+)

DIGOSSINA: fattori che influenzano la sensibilità del paziente Alterazioni elettrolitiche: ipo- o iper-potassiemia ipomagnesemia ipercalcemia Squilibri dell’equilibrio acido-base Funzionalità renale Funzionalità epatica Tono simpatico Funzionalità tiroidea Terapie concomitanti

INTOSSICAZIONE DA DIGITALE Basso IT. Variazioni biodisponibilità. Spesso intossicazione per deplezione K+ da diuretici EFFETTI SUL CUORE Aritmie, disturbi di conduzione Bradicardia sinusale Tachicardia parossistica sopraventricolare Blocco A-V, ritmi giunzionali Depolarizzazioni ventricolari premature (bigemine, trigemine) EFFETTI GASTROINTESTINALI Anoressia Nausea, vomito Diarrea EFFETTI NEUROLOGICI Cefalea, torpore, affaticabilità Dolore neuralgico Confusione mentale Disturbi visivi (“visione bianca”, cromatopsia)

INTOSSICAZIONE DA DIGITALE: TRATTAMENTO Ospedalizzazione (ICU) Antiaritmici che non deprimono la conduzione A-V K+ Atropina Fabs antiglicoside

GLICOSIDI CARDIOATTIVI: USI TERAPEUTICI SCOMPENSO CARDIACO CONGESTIZIO Da soli o associati a: vasodilatatori, diuretici, ACE-inibitori FIBRILLAZIONE ATRIALE Per controllare la frequenza ventricolare FLUTTER ATRIALE Controllo frequenza ventricolare Inibizione improvvisi aumenti di frequenza Talvolta conversione a fibrillazione TACHICARDIA PAROSSISTICA

DIGOXIN EFFECT ON CHF PROGRESSION 30 Placebo n=93 DIGOXIN Withdrawal % WORSENING OF CHF 20 DIGOXIN: 0.125 - 0.5 mg /d (0.7 - 2.0 ng/ml) EF < 35% Also significantly decreased exercise time and LVEF. p = 0.001 10 Treatment of heart failure. Digoxin: Effect on morbidity The RADIANCE trial (multicenter, randomized, double-blind on the efficacy and safety of stopping digoxin in patients with heart failure who were receiving treatment with ACEI) analyzed clinical evolution in 178 patients with heart failure of functional classes II-III and LVEF < 35% treated with digoxin and diuretics and ACEI. Patients either maintained their dose of digoxin between 0.125-0.5 mg/d with serum levels of 0.7-2.0 ng/ml or were given placebo instead. After 100 days of treatment, digoxin withdrawal produced a significant worsening in heart failure which was greater than that observed in the group of patients in whom digoxin was maintained. Packer M et al (RADIANCE). N Engl J Med 1993;329:1 DIGOXIN n=85 RADIANCE N Engl J Med 1993;329:1 20 40 60 80 100 Days

OVERALL MORTALITY % 50 40 30 20 10 Placebo n=3403 DIGOXIN n=3397 12 24 % Placebo n=3403 p = 0.8 Treatment of heart failure. Digoxin: Effect on survival The results obtained from 3 controlled studies which included patients at low risk (The German and Austrian Xamoterol Study Group, 1988; The Captopril-Digoxin Multicenter Research Group, 1988; DiBianco et al., 1989) indicate that the mortality was similar in the group of patients with placebo. The results of the Digitalis Investigator Group-DIG study, which included 7788 patients with heart failure in sinus rhythm, functional class II-III and LVEF < 45%. The patients were treated with digoxin or placebo, in addition to conventional therapy over a mean of 37 months (28 - 58 months). No differences in mortality were observed between the two treatment groups. Am Coll Cardiol 1996 DIGOXIN n=3397 12 24 36 48 N Engl J Med 1997;336:525 Months

INIBITORI DELLE FOSFODIESTERASI DI TIPO III BIPIRIDINE Inamrinone (t1/2: 2-3 h); milrinone (t1/2: 0.5-1 h) Trattamento a breve termine dello scompenso grave Effetto inotropo positivo Vasodilatazione vasi di resistenza e di capacitanza Trombocitopenia (inamrinone), movimento enzimi epatici Meno aritmogenici della digitale

DOPAMINA A dosi  5 g/ Kg/ min Stimolazione recettori D1 e D2 vasali Vasodilatazione splancnica, renale, coronarica Aumento della filtrazione glomerulare Scarsi effetti sulle resistenze periferiche totali Riduzione della secrezione di ormoni e citochine A dosi 5 - 10 g/ Kg/ min Prevalente effetto  agonista A dosi  10 g/ Kg/ min Prevalente effetto  agonista

DOPAMINA Effetti indesiderati Nausea, vomito Tachicardia Tachiaritmie Oliguria DOPEXAMINA Agonista D1, D2, 

DOBUTAMINA (miscela racemica) Stimolazione 1 e 2 Enantiomero (-): stimolazione 1 e 2 Enantiomero (+): bloccante  Non attivo sui recettori per la dopamina Effetto inotropo positivo Vasolilatazione: riduzione del post-carico Effetti sulla pressione e sulla frequenza cardiaca variabili Problemi: tolerance, difficile svezzamento

VASODILATOR DRUGS PRINCIPLES Normal Contractility Normal Contractility CO VV AV Diminished Contractility Diminished Contractility PRELOAD AFTERLOAD

VASODILATORS CLASSIFICATION Venous Vasodilatation VENOUS Nitrates MIXED Calcium antagonists a-adrenergic Blockers ACEI Angiotensin II inhibitors K+ channel activators Nitroprusside Arterial Vasodilatation ARTERIAL Minoxidil Hydralazine

NITRATES HEMODYNAMIC EFFECTS 1- VENOUS VASODILATATION Preload 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload 4- Others Pulmonary congestion Ventricular size Vent. Wall stress MVO2 Treatment of Heart Failure. Nitrates: Hemodynamic effects At therapeutic doses, nitrates produce venodilatation that reduces systemic and pulmonary venous resistances. As a consequence, right atrial pressure, pulmonary capillary pressure, and LVEDP decrease. The preload reduction improves the signs of pulmonary congestion and decreases myocardial wall tension and ventricular size, which in turn reduce oxygen consumption. With higher doses, nitrates produce arterial vasodilatation that decreases peripheral vascular resistance and mean arterial pressure, leading to a decrease in afterload, and thereby reduce oxygen consumption. This arterial vasodilatation increases cardiac output, counteracting the possible reduction caused by the reduction in preload caused by venodilatation. The overall effect on cardiac output depends on the LVEDP; when LVEDP is high, nitrates increase cardiac output, while when it is normal nitrates can decrease cardiac output. Nitrates can also produce coronary vasodilatation, as much through reducing preload as through a direct effect on the vascular endothelium. This vasodilatation can decrease the mechanical compression of subendocardial vessels and increases blood flow at this level. Additionally, nitrates reduce coronary vascular tone, overcoming vasospasm. • Cardiac output • Blood pressure

NITRATES CLINICAL USES Pulmonary congestion Orthopnea and paroxysmal nocturnal dyspnea CHF with myocardial ischemia In acute CHF and pulmonary edema: NTG s.l. or i.v. Treatment of Heart Failure. Nitrates: Use in Heart Failure Through venodilation, nitrates reduce LVEDP, PAD, and PCWP, thereby improving pulmonary congestion and exercise tolerance. The reduction in end-diastolic pressure and volume decrease wall tension and oxygen consumption. Cardiac output and arterial pressure are not significantly changed, although a decrease in the LVEDP of 12 mmHg can decrease cardiac output. Nitrates are particularly useful in patients with signs of pulmonary congestion (PCWP > 18 mm Hg) and normal cardiac outputs, or in patients with orthopnea and PND. Recommended doses are well tolerated and rarely cause reflex tachycardia or hypotension. In patients with acute heart failure accompanied by pulmonary edema nitroglycerine can be given sublingually or i.v. I.V. administration allows for immediate onset of action, and rapid disappearance of effect within 10-30 minutes of stopping the infusion. Patients receiving I.V. nitroglycerin should be monitored. In patients with low cardiac output, nitrates can be used in conjunction with arterial vasodilators, dopamine, or dobutamine. In the treatment of chronic heart failure preparations with long half-lives are used. Topical nitroglycerine and other nitrates administered qHS are effective in patients with orthopnea and PND.

DIURETICS Cortex Medulla Thiazides K-sparing Loop diuretics Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle Cortex K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule Treatment of heart failure. Diuretics: Classification and mechanisms of action Diuretics are drugs which eliminate Na and water by acting directly on the kidney. This category does not include other drugs with principle actions different from the diuretics, but which increase diuresis by improving heart failure or by mechanisms on the kidney which are incompletely understood. The diuretics are the primary line of therapy for the majority of patients with heart failure and pulmonary congestion. Diuretics (loop, thiazides and potassium-sparing) produce a net loss of Na and water acting directly on the kidney, decrease acute symptoms which result from fluid retention (dyspnea, edema). Diuretic drugs are classically divided into three groups: 1) thiazides, 2) loop diuretics and 3) potassium-sparing. Thiazide diuretics inhibit the active transport of Cl-Na in the cortical diluting segment of the ascending limb of the Loop of Henle. Loop diuretics inhibit the transport of Cl-Na-K in the thick portion of the ascending limb of the Loop of Henle. Potassium-sparing diuretics inhibit the reabsorption of Na in the distal convoluted and collecting tubules. Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Medulla Loop of Henle Collecting tubule

DIURETICI DELL’ANSA (furosemide, bumetanide, torsemide) Inibizione del simporto Na+-K+-Cl- nel tratto ascendente dell’ansa di Henle Inibizione del riassorbimento di Na+- K+- Cl- Inibizione della formazione di gradiente osmotico interstiziale Effetti: Incremento diuresi Perdita Na+ e K+ Inibizione capacità concentrazione e diluizione urine Aumento capacitanza venosa (effetto indipendente dall’azione diuretica)

DIURETICI TIAZIDICI Inibizione del cotrasporto Na+-K+ nel tubulo contorto distale Inibizione del riassorbimento di Na+-K+ Effetti: Incremento diuresi (minore che con diuretici dell’ansa) Perdita Na+ e K+ Inibizione capacità di diluizione (ma non di concentrazione) delle urine

DIURETICI RISPARMIATORI DI K+ AMILORIDE, TRIAMTERENE Inibitori dei canali al Na+ nel tubulo contorto distale e dotto collettore inibizione riassorbimento di Na+ inibizione escrezione di K+ Modesto effetto diuretico ANTAGONISTI DELL’ALDOSTERONE (spironolattone, canrenone)

DIURETIC EFFECTS Volume and preload No direct effect on CO, but Improve symptoms of congestion No direct effect on CO, but excessive preload reduction may Improves arterial distensibility Neurohormonal activation Levels of NA, Ang II Exception: with spironolactone Treatment of heart failure. Diuretics: Mechanisms of action Diuretics decrease volume and preload, and as a result are very effective at improving the signs of pulmonary and systemic venous congestion. They do not change the cardiac output (CO), but CO may fall if an excessive decrease in preload occurs. They slightly improve arterial distensibility, but this effect is of no clinical relevance. The main drawback to diuretics use is their effect on the neurohormonal milieu, increasing the plasma levels of noradrenaline (NA), angiotensin II (Ang II) and aldosterone, and the plasma renin activity (PRA).

DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics Changes in electrolytes: Volume Na+, K+, Ca++, Mg++ metabolic alkalosis Metabolic changes: glycemia, uremia, gout LDL-C and TG Treatment of heart failure. Diuretics: Adverse effects of thiazide and loop diuretics Thiazide and loop diuretics create electrolyte imbalances: hypovolemia, hyponatremia, hypokalemia, hypomagnesemia, hypercalcemia and metabolic alkalosis. They also create metabolic changes (hyperglycemia, hyperuricemia, gout, increase in LDL-cholesterol and triglycerides), impotence and menstrual cramps. Hypokalemia can be treated with K+ supplements or with the simultaneous use of potassium-sparing diuretics. Cutaneous allergic reactions (rash, pruritis) are frequent. In addition, these are cross-reactions between the various thiazides (except chlorthalidone) and because of their chemical resemblance, with furosemide and bumetanide. Thiazides can aggravate myopia in pregnant women.

DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics Idiosyncratic effects: Blood dyscrasia, cholestatic jaundice and acute pancreatitis Gastrointestinal effects Genitourinary effects: Impotence and menstrual cramps Deafness, nephrotoxicity (Loop diuretics) Treatment of heart failure. Diuretics: Adverse effects of thiazide and loop diuretics Known adverse reactions include parenchymal (pancreatitis, cholestatic jaundice, hemolytic anemia, thrombocytopenia), gastrointestinal effects (ethacrynic acid), myalgias (bumetanide, piretanide) and muscle cramps related to electrolyte disorders. Loop diuretics are associated with ototoxicity with loss of hearing and balance and these are more frequent in patients with renal insufficiency or with concomitant use of aminoglycoside antibiotics. They may also cause interstitial nephritis.

DIURETICS ADVERSE REACTIONS K-SPARING DIURETICS Changes in electrolytes: Na+, K+, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions : Rash, pruritis Treatment of heart failure. Diuretics: Adverse reactions to potassium-sparing agents The main adverse reaction to these agents is hyperkalemia, which occurs mostly in patients with renal failure, particularly if they are also receiving ACE inhibitors. They may also create metabolic acidosis, muscle cramps and weakness, and cutaneous allergic reactions.

IL SISTEMA RENINA-ANGIOTENSINA

ACEI MECHANISM OF ACTION A.C.E. Kininase II VASOCONSTRICTION VASODILATION ALDOSTERONE PROSTAGLANDINS VASOPRESSIN Kininogen tPA SYMPATHETIC Kallikrein Angiotensinogen RENIN BRADYKININ Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors (ACEI) :Mechanisms of action ACE-inhibitors competitively block the converting enzyme that transforms angiotensin I into angiotensin II. The reduction in angiotensin II levels explains its arteriovenous vasodilatory actions, as angiotensin II is a potent vasoconstrictor that augments sympathetic tone in the arteriovenous system. Additionally, angiotensin causes vasopressin release and produces sodium and water retention, both through a direct renal effect and through the liberation of aldosterone. Since converting enzyme has a similar structure to kinase II that degrades bradykinin, ACE-inhibitors increase kinin levels that are potent vasodilators (E2 and F2) and increase release of fibrinolytic substances such as tPA. Angiotensin I A.C.E. Inhibitor Kininase II ANGIOTENSIN II Inactive Fragments

ACEI HEMODYNAMIC EFFECTS Arteriovenous Vasodilatation - PCWP and LVEDP - SVR and BP - CO and exercise tolerance No change in HR / contractility MVO2 Renal, coronary and cerebral flow Diuresis and natriuresis Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion. It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.

ACEI FUNCTIONAL CAPACITY 100 No Additional Treatment Necessary (%) 95 Quinapril continued n=114 90 p<0.001 85 Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors: Effect on Mortality The effect of discontinuation of quinapril therapy on patients with class II-III heart failure in the Quinapril Heart Failure Trial is shown. At 20 weeks of treatment the group whose quinapril treatment was terminated had increased symptoms compared to the group who continued to receive quinapril therapy. The latter group maintained a stable functional status. This study, whose design was similar to PROVD and RADIANCE, again demonstrates the efficacy of ACE-inhibitors in the treatment of heart failure. Pflugfelder PW et al. J Am Coll Cardiol 1993;22:1557. Quinapril stopped Placebo n=110 80 Class II-III 75 12 6 2 10 4 8 18 20 14 16 Quinapril Heart Failure Trial JACC 1993;22:1557 Weeks

ACEI ADVANTAGES Inhibit LV remodeling post-MI Modify the progression of chronic CHF - Survival - Hospitalizations - Improve the quality of life In contrast to others vasodilators, do not produce neurohormonal activation or reflex tachycardia Tolerance to its effects does not develop Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI) : Advantages In class II-IV heart failure patients treated with diuretics and digitalis, ACE-inhibitors decrease symptoms, improve hemodynamics and functional class, and increase exercise tolerance. Additionally, they reduce left ventricular dimensions, improve the cardiothoracic index, improve renal function, and improve hyponatremia. More importantly, ACE-inhibitors are the best drugs to date for preventing expansion and dilatation of the left ventricle post infarction, thereby decreasing the number and duration of hospitalizations, and improving symptoms and survival. They also retard progression to heart failure in patients with asymptomatic ventricular dysfunction. ACE-inhibitors differ from other vasodilators in that they do not produce neurohormonal activation or reflex tachycardia, and tolerance to these agents does not seem to develop over time. ACE-inhibitors increase plasma renin, bradykinin, and angiotensin I activities, and reduce plasma and tissue levels of angiotensin II, and plasma levels of aldosterone and cortisol. ACE-inhibitors can also decrease plasma norepinephrine levels, especially after long-term therapy, which has been attributed to the suppression of the stimulating effect angiotensin II has on the synthesis and release of norepinephrine. ACE-inhibitors also reduce arginine-vasopressin levels.

Vent Dysfx / Clinical CHF ISIS-4 GISSI-3 SAVE SMILE AIRE ACEI Benefit Pt Selection Captopril Lisinopril Zofenopril Ramipril 0.5 / 5 wk 0.8 / 6 wk 4.2 / 3.5 yr 4.1 / 1 yr 6 / 1 yr All with AMI EF < 40 asymptomatic Ant. AMI, No TRL Clinical CHF TRACE Trandolapril 7.6 / 3 yr Vent Dysfx / Clinical CHF EF < 35 ACEI SURVIVAL POST MI Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI) : Survival Post-infarction studies. The results of the various studies that have compared ACE-inhibitors with placebo in the post-MI setting have differing results. Nonetheless, the benefit obtained in each study correlates with the degree of ventricular dysfunction of the selected patients. In this graph, the difference in mortality over time is seen in absolute terms (lives saved per 100 patients treated = % mortality in placebo group - % mortality in ACEI group/ follow-up time). Even though the studies demonstrated statistically significant differences between placebo and ACE-inhibitor therapy, the benefit of treatment is minimal in low-risk patients, probably not justifying its routine use in every post-MI patient (ISIS-4 and GISSI-3). Benefits are moderate in patients with higher risk (asymptomatic ventricular dysfunction) (SAVE and SMILE), and maximal in patients with sever ventricular dysfunction or clinical heart failure (TRACE and AIRE). ISIS-4: Lancet 1995; 345:669 GISSI-3: Lancet 1994;343:1115 SAVE: N Engl J Med 1992;327:669. SMILE: N Engl J Med 1992;332:80. TRACE: N Engl J Med. 1995; 333:1670. AIRE: Lancet 1993; 342: 821.

Clinical cardiac insufficiency ACEI INDICATIONS Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF < 35 % Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibits (ACEI) Indications. ACE-inhibitors probably constitute the cornerstone of drug therapy for heart failure, in that administration over time leads to amelioration of symptoms, beneficial hemodynamic changes, increased functional capacity, regression of structural changes, and, unequivocally, prolongation of survival. Thus, ACE-inhibitors are first-line therapy, not only in symptomatic heart failure patients, but also in patients with asymptomatic left ventricular dysfunction. The exact degree of ventricular dysfunction below which it is advisable to begin therapy with an ACE-inhibitor has not been defined; however, in general terms they can be helpful in patients with ejection fractions less than 35%.

ACEI UNDESIRABLE EFFECTS Inherent in their mechanism of action - Hypotension - Hyperkalemia - Angioneurotic edema Due to their chemical structure - Cutaneous eruptions - Neutropenia, thrombocytopenia - Digestive upset - Dry cough - Renal Insuff. Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI) : Undesirable Effects These can be classified into two groups. One group includes those effects that are inherent to its mechanism of action, and therefore are common to all ACE-inhibitors. The other includes those effects that are related to the specific chemical structure of the drug. In this case, substitution of one ACE-inhibitor for another could possibly reduce the intensity of the adverse reaction (e.g. choosing an ACE-inhibitor without a sulfhydryl moiety). - Dysgeusia - Proteinuria

ACEI CONTRAINDICATIONS Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects) Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors (ACEI) Contraindications. There are few absolute contraindications for the use of ACE-inhibitors. The most important one is the presence of renal artery stenosis. The most frequent contraindication is intolerance of the drug. Hypotension, the presence of renal insufficiency, or hyperkalemia limits their use, or the ability to administer adequate doses, in up to 20% of patients.

ANGIOTENSIN II INHIBITORS Angiotensin I ANGIOTENSIN II MECHANISM OF ACTION RENIN Angiotensinogen Angiotensin I ANGIOTENSIN II ACE Other paths AT1 RECEPTOR BLOCKERS Treatment of congestive heart failure. Angiotensin II inhibitors Angiotensin II has different effects mediated via specific receptors. There are two types of tissue receptors for angiotensin: AT1 and AT2. Stimulation of AT1 receptors has a proliferative and vasoconstrictor effect, while stimulation of AT2 receptors has the opposite effects, that is, vasodilatory and antiproliferative. In the treatment of heart failure, specific blockade of the AT1 receptors is desirable. Drugs which create a selective and competitive block of the AT1 receptors include:losartan, valsartan, irbersartan and candersartan. RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

Competitive and selective blocking of AT1 receptors AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candesartan Treatment of congestive heart failure. Angiotensin II inhibitors Drugs which create a selective and competitive block of the AT1 receptors include: losartan, valsartan, irbersartan and candersartan. Competitive and selective blocking of AT1 receptors

Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative Treatment of congestive heart failure. Possible benefits of beta adrenergic blockers The use of ß-blockers in patients with heart failure is controversial. Nevertheless, this slide lists some of the potentially beneficial effects of these drugs for patients in heart failure.

4 studies in U.S.; 1 in Australia/New Zealand ß BLOCKERS CARVEDILOL 4 studies in U.S.; 1 in Australia/New Zealand U.S. studies with control group Mortality with Placebo 8.2% Mortality with Carvedilol 2.9% Initial low doses, progressive Treatment of Heart Failure. Possible Benefits of Beta-Blockers. Carvedilol has been tested in various studies of patients with mild to moderate heart failure, none of which were designed to evaluate its effect on mortality. In the Carvedilol Program in Heart Failure in the U.S., 1094 patients with heart failure were included. The patients received carvedilol in doses ranging from 3 to 50 mg/day. The program, which included 4 studies of clinical efficacy for FDA approval, was suspended before reaching its predetermined objectives, after a significant decrease in mortality in the carvedilol group was seen. In the Australian-New Zealand study 415 patients with mild heart failure were randomized to receive carvedilol or placebo. Carvedilol therapy was associated with a decrease in the combination of death or hospitalization of cardiac etiology. Packer M, et al. N Engl J Med 1996;334:1349 Sackner J, et al. Circulation 1995;92:I:395 p < 0.0001

Not clearly established Begin with very low doses ß-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATION Not clearly established Begin with very low doses Slow augmentation of dose Slow withdrawal ? Treatment of Heart Failure. Indications for Beta-Blocker Therapy In spite of more than 20 years of clinical investigation, the indication for beta-blockers in patients with heart failure has not yet been precisely established. Nonetheless, it is suggested that treatment be started with doses much lower than those used for the treatment of angina, and the dose should be increased slowly.

ß-ADRENERGIC BLOCKERS IDEAL CANDIDATE? Suspected adrenergic activation Arrhythmias Hypertension Angina Treatment of Heart Failure. Possible Benefits of Beta-Blockers The ideal candidate for beta-blocker therapy has not yet been established. Nonetheless, having other indications for beta-blocker therapy could be an initial criterion for selection. Examples of these indications include sinus tachycardia, ventricular arrhythmia, hypertension, or angina in a heart failure patient.

ß-ADRENERGIC BLOCKERS CONTRAINDICATIONS Hypotension: BP < 100 mmHg Bradycardia: HR < 50 bpm Clinical instability Chronic bronchitis, ASTHMA Severe chronic renal insufficiency Treatment of Heart Failure. Beta-Blockers: Contraindications Contraindications to beta-blocker therapy in heart failure patients are the same as those for the general population.

CALCIUM ANTAGONISTS POTENTIAL EFFECTS Antiischemic Peripheral Vasodilatation Inotropy Treatment of Heart Failure. Possible Benefits of Calcium-channel Blockers Calcium-channel blockers are theoretically useful in heart failure for a number of reasons, including their vasodilatory action and their anti-ischemic effect, but some have a negative inotropic effect that could be detrimental, and preclude their use.

Ventricular Filling Pressure DRUGS HEMODYNAMIC EFFECTS Normal A I Stroke Volume A + V V Treatment of Heart Failure. Theoretical hemodynamic effects of different drugs for heart failure Effects of different treatments on the relationship between ventricular filling pressure (LVEDP) and stroke volume. Diuretics (D) and venous vasodilators (V) decrease the ventricular filling pressure in patients with heart failure and normal or elevated LVEDP, but except in patients with marked elevation of LVEDP, the stroke volume does not change. The pure arterial vasodilators (A) produce an increase in the stroke volume in patients with failure and an elevated LVEDP. Inotropic drugs (I) increase the stroke volume with a lesser effect of the ventricular filling pressure. CHF D Ventricular Filling Pressure

Mortality YES No Yes 13.3% 24.3% No 19.5% 27.7% ß BLOCKER n=2231 YES No Yes 13.3% 24.3% Treatment of Heart Failure. Possible Benefits of Beta-Blockers Other indirect data that suggest a beneficial effect of beta-blocker use in heart failure or LV dysfunction can be found in the SAVE trial. In this study, 2231 patients with EF < 40% post-AMI were included. A retrospective analysis of overall mortality (at median 42 months of follow-up) showed the results that are on this slide. Mortality was lower in patients who received beta-blockers, regardless of randomization to placebo or ACE-inhibitor therapy. Mortality was lowest when beta-blocker therapy was combined with ACE-inhibitors, and maximal when neither drug was used. SAVE. Circulation 1995;92:3132 ACEI No 19.5% 27.7% SAVE Circulation 1995;92:3132

Linee guida per il trattamento ambulatoriale dei pazienti con scompenso cardiaco