LA STIMOLAZIONE BIVENTRICOLARE Stato dell’arte e Update 2005 Dott. M. Viscusi A.O.R.N. San Sebastiano U.O.C. Elettrostimolazione ed Elettrofisiologia Dipartimento di Scienze Cardiologiche

Prevalenza dei ritardi di conduzione inter- o intraventricolari nei pts con scompenso Popolazione con scompenso in generale1,2 Popolazione con scompenso moderato o severo 3,4,5 IVCD 15% IVCD >30% Approximately 15% of all heart failure patients have an inter- or intraventricular conduction delay (QRS > 120 msec)1-2. Over 30% of moderate to severe heart failure patients have a prolonged QRS. The prevalence of conduction defects increases with severity of heart failure.3-5 Shenkman and colleagues found the factors associated with prolonged QRS included: Older age, Male gender, Caucasian race, Lower EF, Higher LVESD 1 Havranek EP, Masoudi FA, Westfall KA, Wolfe P, Ordin DL, Krumholz HM. Spectrum of heart failure in older patients: Results from the National Heart Failure Project. Am Heart J 2002;143:412-417 2 Shenkman HJ, McKinnon JE, Khandelwal AK, et al. Determinants of QRS Prolongation in a Generalized Heart Failure Population: Findings from the Conquest Study [Abstract 2993]. Circulation 2000;102(18 Suppl II) 3 Schoeller R, Andersen D, Buttner P, Oezcelik K, Vey G, Schroder R. First-or second-degree atrioventricular block as a risk factor in idiopathic dilated cardiomyopathy. Am J Cardiol 1993;71:720-726 4 Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development & prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997; 95: 2660-2667. 5 Farwell D, Patel NR, Hall A, Ralph S, Sulke AN. How many people with heart failure are appropriate for biventricular resynchronization? Eur Heart J 2000;21:1246-1250 1 Havranek E, Masoudi F, Westfall K, et al. Am Heart J 2002;143:412-417 2 Shenkman H, McKinnon J, Khandelwal A, et al. Circulation 2000;102(18 Suppl II): abstract 2293 3 Schoeller R, Andersen D, Buttner P, et al. Am J Cardiol. 1993;71:720-726 4 Aaronson K, Schwartz J, Chen T, et al. Circulation 1997;95:2660-2667 5 Farwell D, Patel N, Hall A, et al. Eur Heart J 2000;21:1246-1250 September 2001

QRS largo: aumento della mortalità QRS Duration (msec) <90 90-120 120-170 170-220 The VEST Study demonstrated QRS duration was found to be an independent predictor of mortality. Patients with wider QRS (> 200 ms) had five times greater mortality risk than those with the narrowest (< 90 ms). Resting ECG is a powerful yet accessible and inexpensive marker of prognosis in patients with DCM and CHF. - - - - ACC 1999; Abstract: 847-4 The Resting Electrocardiogram Provides a Sensitive and Inexpensive Marker of Prognosis in Patients with Chronic Congestive Heart Failure Venkateshwar K. Gottipaty, Steven P. Krelis, Fei Lu, Elizabeth P. Spencer, Vladimir Shusterman, Raul Weiss, Susan Brode, Amie White, Kelley P. Anderson, B.G. White, Arthur M. Feldman For the VEST investigators; University of Pittsburgh, Pittsburgh PA, USA Background: Patients with dilated cardiomyopathies (DCM) routinely undergo 12-lead electrocardiographic (ECG) evaluation. Although ECGs are inexpensive and readily available, their utility in the management of patients with DCM has not been defined. We hypothesized that QRS duration (QRSd), a measure of cardiac depolarization, might provide a marker of risk in patients with DCM and congestive heart failure (CHF). To test this hypothesis we evaluated the resting baseline ECG in patients enrolled in the VEST trial, which assessed the efficacy of vesnarinone in patients with Class II-IV CHF. Methods: 3654 ECGs were digitally scanned and QRSd in lead II was measured by blinded readers, using electronic calipers. Follow- up data were censured at 1 yr and analyzed using multivariate Cox proportional hazards regression, and Kaplan-Meier survival analysis. Results: The following clinical variables were found to be independent predictors of mortality in an analysis (p < 0.0001): age, creatinine, LVEF, heart rate, and QRSd. Cumulative survival from all-cause mortality decreased proportionally with QRSd. The relative risk of the widest QRSd group was 5 times greater than the narrowest. Conclusion: We conclude that the resting ECG is a powerful yet accessible and inexpensive marker of prognosis in patients with DCM and CHF. >220 1 Gottipaty V, Krelis S, et al. ACC 1999 [Abstr];847-4. Adapted from Gottipaty et al. September 2001

Conseguenze Cliniche della Dissincronia Ventricolare Movimento anormale della parete del setto interventricolare1 Ridotto dP/dt3 Tempo di riempimento diastolico ridotto1,2 Durata prolungata del rigurgito mitralico (MR)1,2 Key Messages: Ventricular dysynchrony has been associated with paradoxical septal wall motion, reduced LV pressure, prolonged mitral regurgitation duration, and reduced diastolic filling times in studies comparing patients with left bundle branch block with normals or with comparable patients without LBBB. Animation Filename: “4-chamber.avi”. The animation can be started by positioning the mouse-cursor over the image and clicking once. To stop or restart the animation video at anytime, click once on the image. Using simultaneous ECG, phonocardiogram, radionuclide ventriculograms, and 2D and M-mode echoes, Grines et al studied 18 patients with LBBB (and no other underlying cardiac disease) compared with 10 normals. In LBBB patients she found significant delays in LV systolic and diastolic events, reduced diastolic filling times, abnormal interventricular septal wall motion, and a loss of septal contribution to global ejection fraction. [Grines C, Bashore T, Boudoulas H, et al. Functional abnormalities in isolated left bundle branch block: the effect of interventricular asynchrony. Circulation 1989;79:845-853]. Xiao et al (1991) in a study of 52 pts with DCM, 12 of whom had LBBB, found that those with LBBB had prolonged MR and shortened LV filling time. [ Xiao Lee C, Gibson D. effect of left bundle branch block on diastolic function in dilated cardiomyopathy. Br Heart J 1991;66:443-447] Xiao et al (1992) studied 50 DCM patients with functional MR, finding a positive correlation between QRS duration and MR duration, and negative correlation between QRS duration and the peak rate of rise in LV pressure. [Xiao H, Brecker S, Gibson D. Effects of abnormal activation on the time course of left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J 1992;68:403-407]. Click to Start/Stop 1 Grines CL, Bashore TM, Boudoulas H, et al. Circulation 1989;79:845-853. 2 Xiao, HB, Lee CH, Gibson DG. Br Heart J 1991;66:443-447. 3 Xiao HB, Brecker SJD, Gibson DG. Br Heart J 1992;68:403-407. September 2001

Animazione – Dissincronia Ventricolare This animation shows the normal heart changing into a dilated, remodeled heart, followed by a depiction of a mechanical perspective of ventricular dysynchrony. An ECG showing intra- or interventricular conduction delays is displayed along the bottom. Animation Filename: “Clip1-Vdysynchrony.mpg.” The animation can be started by positioning the mouse-cursor over the image and clicking once. To stop or restart the animation video at anytime, click once on the image. September 2001

Cardiac Resynchronization Migliora il pattern di attivazione Ottimizza l’intervallo atrio-ventricolare The animation illustrates cardiac resynchronization with the Medtronic InSync® system. During resynchronization, notice the stabilization of the septal wall and the restoration of a more coordinated ventricular systolic contraction. A dilated heart with ventricular dysynchrony appears toward the end of the video to further highlight the paradoxical septal wall motion that occurs when CRT therapy is not applied. Animation Filename: “Clip3-CardiacResynch.mpg.” The animation can be started by positioning the mouse-cursor over the image and clicking once. To stop or restart the animation video at anytime, click once on the image. September 2001

Conseguenze emodinamiche della dissincronia ventricolare Normale Inizio del QRS mc ao ac mo BBS Ridotto tempo di riempimento diastolico time 1,2 Prolungato rigurgito mitralico 1,2 Ridotta funzione sistolica (dP/dt ridotto) 3,4 Movimento anomalo del setto 1 Dissincronia meccanica e temporale 4 mc = mitral valve closure; ao = aortic valve opening; ac = aortic valve closure; mo = mitral valve opening Key Messages: Ventricular dysynchrony has been associated with paradoxical septal wall motion, reduced LV pressure, prolonged mitral regurgitation duration, and reduced diastolic filling times in studies comparing patients with left bundle branch block with normals or with comparable patients but without LBBB. Using simultaneous ECG, phonocardiogram, radionuclide ventriculograms, and 2D and M-mode echoes, Grines et al studied 18 patients with LBBB (and no other underlying cardiac disease) compared with 10 normals. In LBBB patients she found significant delays in LV systolic and diastolic events , reduced diastolic filling times, abnormal interventricular septal wall motion, and a loss of septal contribution to global ejection fraction. [Grines C, Bashore T, Boudoulas H, et al. Functional abnormalities in isolated left bundle branch block: the effect of interventricular asynchrony. Circulation 1989;79:845-853]. Xiao et al (1992) studied 50 DCM patients with functional MR, finding a positive correlation between QRS duration and MR duration, and negative correlation between QRS duration and the peak rate of rise in LV pressure.[Xiao H, Brecker S, Gibson D. Effects of abnormal activation on the time course of left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J 1992;68:403-407]. Xiao et al (1991) in a study of 52 pts with DCM, 12 of whom had LBBB, found that those with LBBB had prolonged MR and shortened LV filling time. [ Xiao Lee C, Gibson D. effect of left bundle branch block on diastolic function in dilated cardiomyopathy. Br Heart J 1991;66:443-447] 1. Grines C, et al. Circulation 1989;79:845-853 2. Xiao, et al. Br Heart J 1991;66:443-447 3. Xiao et al. Br Heart J 1992;68:403-407 4. Curry C, et al. Circulation 2000;101:e2 September 2001

Effetto della CRT sul complesso QRS -------CRT OFF------- ---------CRT ON--------- v3 QRS=160 ms QRS=120 ms September 2001

Modificazione del complesso QRS con la stimolazione biventricolare Spontaneo CRT September 2001

Meccanismo d’azione Resincronizzazione Cardiaca Sincronia Intraventricolare Sincronia Atrioventricolare Sincronia Interventricolare  dP/dt,  EF,  CO ( Pulse Pressure) MR LA Pressure  LV Diastolic Filling  RV Stroke Volume This slide simply consolidates what we have already seen, and describes some interactions. This relies heavily on the aforementioned work of C-M Yu and colleagues. That study demonstrated evidence of reverse remodeling beyond the acute reductions in LVESV and LVESD, by turning CRT off after an extended period of therapy. Reverse remodeling is associated with reduced functional MR and improved intraventricular synchrony, creating a positive clinical outcomes loop. Likewise, the increase in LV diastolic filling will have a positive effect on stroke volume and therefore cardiac output.  LVESV  LVEDV RIMODELLAMENTO INVERSO Yu C-M, et al. Circulation 2002;105:438-445 September 2001

Effetto della CRT sulla funzione cardiaca Movimento anormale della parete del setto interventricolare1 Ridotto dP/dt3 Tempo di riempimento diastolico ridotto1,2 Durata prolungata del rigurgito mitralico (MR)1,2 Key Messages: Ventricular dysynchrony has been associated with paradoxical septal wall motion, reduced LV pressure, prolonged mitral regurgitation duration, and reduced diastolic filling times in studies comparing patients with left bundle branch block with normals or with comparable patients without LBBB. Animation Filename: “4-chamber.avi”. The animation can be started by positioning the mouse-cursor over the image and clicking once. To stop or restart the animation video at anytime, click once on the image. Using simultaneous ECG, phonocardiogram, radionuclide ventriculograms, and 2D and M-mode echoes, Grines et al studied 18 patients with LBBB (and no other underlying cardiac disease) compared with 10 normals. In LBBB patients she found significant delays in LV systolic and diastolic events, reduced diastolic filling times, abnormal interventricular septal wall motion, and a loss of septal contribution to global ejection fraction. [Grines C, Bashore T, Boudoulas H, et al. Functional abnormalities in isolated left bundle branch block: the effect of interventricular asynchrony. Circulation 1989;79:845-853]. Xiao et al (1991) in a study of 52 pts with DCM, 12 of whom had LBBB, found that those with LBBB had prolonged MR and shortened LV filling time. [ Xiao Lee C, Gibson D. effect of left bundle branch block on diastolic function in dilated cardiomyopathy. Br Heart J 1991;66:443-447] Xiao et al (1992) studied 50 DCM patients with functional MR, finding a positive correlation between QRS duration and MR duration, and negative correlation between QRS duration and the peak rate of rise in LV pressure. [Xiao H, Brecker S, Gibson D. Effects of abnormal activation on the time course of left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J 1992;68:403-407]. Click to Start/Stop 1 Grines CL, Bashore TM, Boudoulas H, et al. Circulation 1989;79:845-853. 2 Xiao, HB, Lee CH, Gibson DG. Br Heart J 1991;66:443-447. 3 Xiao HB, Brecker SJD, Gibson DG. Br Heart J 1992;68:403-407. September 2001

Effetto della CRT sulla funzione cardiaca Ottimizzazione intervallo AV Riduce il rigurgito mitralico1,2,3 Aumenta il tempo di riempimento diastolico Migliora il dP/dt del ventricolo sinistro Diastolic mitral regurgitation occurs with wide QRS as a result of delayed left ventricular activation and late initiation of the left lateral papillary muscle. Pre-emptive activation of the lateral wall of the left ventricle may lead to early activation of the papillary muscles and decreased mitral regurgitation. Video Filename: “mitral-regurg.avi” The animation can be started by positioning the mouse-cursor over the image and clicking once. To stop or restart the animation video at anytime, click once on the image. Nishimura RA, et al. Mechanism of hemodynamic improvement by dual chamber pacing for severe left ventricular dysfunction: an acute doppler and catheterization hemodynamic study. J Am Coll Cardiol 1995;25: 281-288. 15 pts with left ventricular systolic dysfunction (mean EF 19%, 7 ischemic, 8 idiopathic) studied acutely during AV sequential pacing at various AV intervals (60, 100,120, 140, 180, 240 ms). 4 had LBBB, 1 had RBBB, 2 were paced. Measured SBP, LA pressure, Tau, CO (thermodilution), diastolic filling period, LVEDP. Identified 8 pts with PR intervals > 200 ms who had improvement with optimal AV delay vs. baseline in CO, LVEDP, diastolic filling duration, and abolished diastolic MR. In remaining 7 pts, with normal AV conduction at rest, CO decreased during pacing and diastolic filling period did not change. Walker S, et al. Left ventricular remodeling with chronic biventricular pacing. Europace 2000;I (supplement D): abstract 212/5 21 HF pts with mean QRS of 171 ms. Echo study at baseline, after 3 months of BiV pacing, and immediately no pacing. MR area (cm2) was significantly improved with CR versus baseline (5.9±5.5 vs. 7.1±5.4, p<0.05), but there was no difference after 3 months of no CR (7.6±6.5) versus baseline. Brecker SJD, et al. Effects of dual chamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet 1992;340:1308-1312. Acute study in 12 pts with DCM and LV or RV filling times < 200 ms due to MR or TR. 4 with permanent pacemaker. Of other 8 pts, 5 with PR interval > 200 ms, 5 with QRS > 120 ms, 4 with both. LV fill time = RR-MR duration. Measured HR, MR & TR durations, LV & RV filling times (= RR-MR or TR duration), and CO (by echo). Measurements at various AV intervals. Shortest AV delay was 6 ms in non pacemaker pts and 31 ms in PM pts. Best outcomes reported at shortest AV intervals. Increases in CO and exercise duration.   Click to Start/Stop 1 Nishimura et al. J Am Coll Cardiol. 1995; 25:281. 2 Walker et al. Europace 2000;I(suppl D): abstract 212/5. 3 Brecker et al. Lancet. 1992;340:1308. September 2001

Terapia di Resincronizzazione Cardiaca L’intento terapeutico della stimolazione biventricolare è il ripristino della sincronia ventricolare Complementa la terapia farmacologica The InSync® Model 8040 cardiac resynchronization device is indicated for the reduction of symptoms of moderate to severe heart failure (NYHA Function Class III or IV) in those patients who remain symptomatic despite stable, optimal medical therapy, and have a left ventricular ejection fraction  35% and a QRS duration 130 ms. Using atrial-synchronized biventricular pacing in combination with optimal drug therapy has been shown to significantly improve a patient’s symptoms. September 2001

Indicazioni attuali all’ impianto di Pacemaker Biventricolare Scompenso cardiaco sintomatico (classe NYHA III-IV) nonostante terapia farmacologica ottimizzata Frazione di eiezione < 35% Diametro telediastolico del Vsx  55 mm QRS > 130 msec

Come ottenere la resincronizzazione cardiaca Approccio transvenoso per il posizionamento del catetere ventricolare sinistro in una branca del sistema venoso coronarico Cardiac Resynchronization is achieved through atrial based, biventricular pacing. Standard pacing leads are placed in the right atrium and right ventricle. Initially, left ventricular pacing was achieved with an epicardial approach requiring an open chest procedure. Complications from pneumonia, pleural effusion, and arrhythmias have been reported. Prof. Daubert and his group in Rennes, France together with the Val d’Or center outside Paris pioneered a transvenous approach to the left ventricle via the coronary sinus. Initially using standard, modified right ventricular leads or coronary sinus leads, a lead specifically for LV placement—the Attain LV-- was designed and manufactured by Medtronic based on this group’s requirements. The successful deployment of this lead to physician-guided development of left-heart delivery systems, and new LV leads to meet varying patient anatomies and physician preferences. The LV lead is placed via the coronary sinus in a cardiac vein, preferably a lateral or postero-lateral vein in the mid part of the LV. Please note that the heart illustration is protected by US copyright law. The permission from the Massachusetts Medical Society to use this illustration is restricted for use in an educational slide set used by Medtronic trainers and other personnel to present and answer questions about resynchronization therapy, in both printed and electronic (PowerPoint) formats. In other words it cannot be used in promotional materials or provided to customers or others for use in slide sets, etc. Figure 1. Placement of the Three Pacing Leads for Resynchronization Therapy. Two leads allow pacing of the right atrium and right ventricle. The third lead, which is advanced through the coronary sinus into a venous branch that runs along the free wall of the left ventricle, allows early activation of the left ventricle,which would otherwise be activated late during conduction. N Engl J Med 2002;346:1902-1905 Copyright 2002 Massachusetts Medical Society. All rights reserved. September 2001

Anatomia delle vene cardiache This animation is intended to illustrate the relative anatomical position of the cardiac venous anatomy. However, it is important to note that the location, size, and course of major cardiac or coronary veins vary considerably among patients. The Great Cardiac vein which leads to the anterior vein (also referred to as the anterior interventricular vein) and the Middle Cardiac vein are detectable via coronary venography in virtually all patients. Furthermore, at least one major vein is visible between the Posterior and Middle cardiac veins, but the existence of two or more veins is less common. (Source: Meisel E, et al. Circulation 2001;104:442-447). September 2001

Anatomia delle vene cardiache CS Os Middle Posterior Postero-lateral Great Lateral Antero- lateral Anterior This animation is intended to illustrate the relative anatomical position of the cardiac venous anatomy. However, it is important to note that the location, size, and course of major cardiac or coronary veins vary considerably among patients. The Great Cardiac vein which leads to the anterior vein (also referred to as the anterior interventricular vein) and the Middle Cardiac vein are detectable via coronary venography in virtually all patients. Furthermore, at least one major vein is visible between the Posterior and Middle cardiac veins, but the existence of two or more veins is less common. (Source: Meisel E, et al. Circulation 2001;104:442-447). September 2001

Criteri di inclusione e stato degli studi controllati randomizzati NYHA QRS Sinus ICD indication? Status MIRACLE III, IV 130 Normal No Published MUSTIC SR III 150 MUSTIC AF 200* AF PATH CHF 120 CONTAK CD II-IV Yes Reported MIRACLE ICD Presented PATH CHF II CARE HF 120† COMPANION LVEF  35% for all trials * RV paced QRS † Echo-based criteria for QRS < 150 msec

La CRT migliora la qualità di vita e la classe funzionale NYHA QoL NYHA PATH-CHF1 (n=41) + + InSync (Europe)2 (n=103) + + InSync ICD (Europe)3 (n=84) + + MUSTIC4 (n=67) + MIRACLE5 (n=453) + + MIRACLE ICD6 (n=364) + + Follow-up data from both controlled and uncontrolled studies document symptomatic improvement in patients treated with cardiac resynchronization therapy. Most notably, MUSTIC, MIRACLE and MIRACLE ICD trials document that cardiac resynchronization is safe, well tolerated by patients, and clinically beneficial. These studies reported improvements in patient Quality of Life, exercise capacity, and NYHA functional class for patients receiving cardiac resynchronization therapy as well as improvement in many echocardiagraphic parameters. + Statistically significant improvement with CRT (p  0.05)  Not statistically significant or No statistical analysis performed on data Blank Indicates test neither performed nor reported 1 Auricchio A. Stellbrink C, Sack S., et al. J Am Coll Cardiol 2002;39:2026- 2033 2 Gras D, Leclercq C, Tang A, et al. Eur J Heart Failure 2002;4:311-320 3 Kuhlkamp V. JACC 2002;39:790-797 4 Linde C, Leclercq C, Rex S, et al. J Am Coll Cardiol 2002;40:111-118 5 Abraham W, Fisher W, Smith A, et al. N Engl J Med. 2002;346:1845-1853 6 Leon A. NASPE Scientific Sessions – Late Breaking Clinical Trials. May 2002; Medtronic Inc. data on file September 2001

La CRT migliora la capacità di esercizio 6 Min Walk Peak VO2 Exercise Time PATH-CHF1 (n=41) + + InSync (Europe)2 (n=103) + InSync ICD (Europe)3 (n=84) + MUSTIC4 (n=67) +  MIRACLE5 (n=453) + + + MIRACLE ICD6 (n=364)  + + Key Message: Results from studies, both observational and randomized, controlled are concordant in their finding that CRT improves exercise capacity measured parameters. Note: A subset of the MIRACLE and MIRACLE ICD patients provided paired data for these parameters. + Statistically significant improvement with CRT (p  0.05)  Not statistically significant or No statistical analysis performed on data Blank Indicates test neither performed nor reported 1 Auricchio A. Stellbrink C, Sack S., et al. J Am Coll Cardiol 2002;39:2026- 2033 2 Gras D, Leclercq C, Tang A, et al. Eur J Heart Failure 2002;4:311-320 3 Kuhlkamp V. JACC 2002;39:790-797 4 Linde C, Leclercq C, Rex S, et al. J Am Coll Cardiol 2002;40:111-118 5 Abraham W, Fisher W, Smith A, et al. N Engl J Med. 2002;346:1845-1853 6 Leon A. NASPE Scientific Sessions – Late Breaking Clinical Trials. May 2002; Medtronic Inc., data on file September 2001

La CRT migliora la funzione e la struttura cardiaca LVEF MR Other PATH-CHF1 (n=41) + LVEDP + LV dP/dtmax InSync (Europe)2 (n=103) + + Filling Time InSync ICD (Europe)3 (n=84) MUSTIC4 (n=67)   LVEDD,LVESD  Filling Time MIRACLE5 (n=453) + LVEDD, + LVEDV, LVESV MIRACLE ICD6 (n=362) + LVESV, + LVEDV Key Message: Results from studies, both observational and randomized, controlled are concordant in their finding that CRT improves many secondary efficacy endpoints measured by echocardiographic parameters. The MIRACLE ICD data reported here was presented at the 2002 ACC Scientific Sessions (n=362 here, rather than n=364 reported by Dr. Leon at the 2002 NASPE scientific session.) Note: A subset of the MIRACLE and MIRACLE ICD patients provided paired data for the echo parameters. + Statistically significant improvement with CRT (p  0.05)  Not statistically significant or No statistical analysis performed on data Blank Indicates test neither performed nor reported 1 Auricchio A. Stellbrink C, Sack S., et al. J Am Coll Cardiol 2002;39:2026- 2033 2 Gras D, Leclercq C, Tang A, et al. Eur J Heart Failure 2002;4:311-320 3 Kuhlkamp V. JACC 2002;39:790-797 4 Linde C, Leclercq C, Rex S, et al. J Am Coll Cardiol 2002;40:111-118 5 Abraham W, Fisher W, Smith A, et al. N Engl J Med. 2002;346:1845-1853 6 Young J. ACC Scientific Sessions – Late Breaking Clinical Trials III. March 2002; Medtronic Inc., data on file September 2001

La CRT riduce le ospedalizzazioni Admis Stay Days for HF Karolinska Sweden1 (n=16)  -79% Belfast Ireland2 (n=22) -96% Brescia Italy3 (n=30) -93% (total) MIRACLE4 (n=453) -77% MUSTIC5 (n=67) -86% PATH-CHF6 (n=41) -76% Results from studies, both observational and randomized, controlled are concordant in their finding that CRT reduces hospitalization A blank means the data were not collected or not reported. 1. Braunschweig F, et al. Eur J of HF 2(2000) 399-406 2. Dixon LJ, et al. ESC2002 Abstract 79 3. Curnis A, et al. Pharmacoeconomics in Press 4. Abraham WT, et al. NEJM 2002;346:1845-1853 5. Cazeau S. NEJM 2001;344:873-80 6. Auricchio A, JACC 2002; 39:1895-1898 September 2001

COMPANION: Mortalità per qualunque causa

Endpoint Primario (Mortalità per qualunque causa o ospedalizzazioni non previste e dovute a cause cardiovascolari) 500 1000 1500 0.00 0.25 0.50 0.75 1.00 HR 0.63 (95% CI 0.51 to 0.77) Event-free Survival Days P < .0001 CRT Medical Therapy The primary composite end-point (death or an unplanned admission to hospital for a major cardiovascular event) was reduced substantially by CRT. There was no early hazard from device implantation as had been planned for. The curves began to separate within the first 90 days and showed progress separation thereafter. The absolute difference in the number of patients reaching this endpoint over the 29.5 months of study was 16%. 12 patients in the CRT group and 10 in the control group had an unplanned admission for a major cardiovascular event in the 10 day period after randomisation that were not included in the primary endpoint. Including these events would not have an important effect on the results. Number at risk CRT 409 323 273 166 68 7 Medical Therapy 404 292 232 118 48 3 September 2001

Indicazioni alla CRT secondo le linee guida ACC/AHA

Indicazioni attuali all’ impianto di ICD Biventricolare Indicazioni al pacing biventricolare Indicazioni all’impianto di ICD Classe NYHA III - IV Refrattarietà alla terapia farmacologica EF < 35% DTD Vsx  55 mm QRS > 130 ms Episodio di arresto cardiaco TV spontanee sostenute Sincope + TV inducibili Pazienti MADIT Pazienti MADIT II