Biventricular Pacemaker. Health Technology Scientific Literature Review

Transcription

1 Biventricular Pacemaker Health Technology Scientific Literature Review Completed February 2003

2 Disclaimer This health technology scientific literature review was prepared by the Medical Advisory Secretariat, Ontario Ministry of Health and Long-Term Care arising from analysis, interpretation and comparison of scientific research and/or technology assessments conducted by other organizations. While every effort has been made to do so, this document may not fully reflect scientific research available. Additionally, other relevant scientific findings may have been reported since completion of the review. Please contact if you are aware of new research findings that should inform the report or would like further information. The Medical Advisory Secretariat Ministry of Health and Long-Term Care 56 Wellesley Street East, 8 th floor Toronto, ON CANADA M5S 2S3 MASinfo@moh.gov.on.ca ISBN

3 Table Of Contents Abbreviations/acronyms 4 Executive summary 5 Issue 6 Background 6 Clinical need 6 Current implantation technique for cardiac resynchronization 8 Mode of operation 8 Complications of pacemaker implantation 8 Biventricular pacemaker models and regulation 8 Alternative technology 10 Literature review 10 Objective 10 Methods 10 Results 11 Cardiac resynchronization meta-analysis (bradley et al., 2003) 24 Economic analysis 28 Literature review 28 Summary and conclusion 32 Summary and findings on effectiveness and cost-effectiveness 32 Conclusion 33 Existing guidelines regarding the utilization of the technology 33 References 35 Appendix 39 3

4 Abbreviations/Acronyms BiV CI CRT HF ICD IVCD LBBB LV LVEF MI NYHA OR RCT RV SR VT Biventricular Confidence interval Cardiac resynchronization therapy Heart failure Implantable cardioverter defibrillator Intraventricular conduction delay Left branch bundle block Left ventricle Left ventricular ejection fraction Myocardial infarction New York Heart Association Odds ratio Randomized controlled trial Right ventricle Sinus rhythm Ventricular tachycardia 4

5 EXECUTIVE SUMMARY Purpose and Method The Medical Advisory Secretariat (MAS) conducted a review of the effectiveness and cost-effectiveness of using biventricular (BiV) pacemakers for patients with chronic heart failure (HF). Results Randomized controlled trials (RCTs) [Level 1 evidence] reported improved cardiac function and quality of life up to 6 months of biventricular pacemaker (BiV) treatment, therefore there is Level 1 evidence that patients in ventricular dyssynchrony, and who are still symptomatic after medication could benefit from this technology. However, there is no evidence regarding the long term efficacy or safety of this device. Other studies have been prospective, yet, nonrandomized, not double-blind, uncontrolled and/or a limited/not calculated sample size. Short-term studies have focused on acute hemodynamic analyses. There is little information regarding the use of univentricular pacing compared to BiV pacing. One clinical trial indicated no significant difference in outcomes between left ventricular (LV) and BiV pacing, though this study had a number of methodological limitations. Currently, BiV pacing is the predominant mode of pacing being studied. The relative efficacy of BiV versus univentricular pacemakers in patients with HF who have a prolonged QRS interval has not been clearly established. Implantation and maintenance of a resynchronization device are associated with risks that are greater than those of a conventional right ventricular (RV) pacing device. In some patients, efforts to implant have been unsuccessful or were accompanied by dissection or perforation of the coronary sinus or cardiac vein. Serious complications included complete heart block, hemopericardium and cardiac arrest. LV lead dislodgment has also occurred in long term pacing which required lead repositioning or replacement. Much uncertainty still exists in biventricular pacing: It is still not known whether single LV pacing may provide equivalent or even better long term results compared to BiV pacing. Long-term benefits and effects on mortality are unknown. The baseline QRS interval that is necessary for improvement with BiV pacing needs to be determined. Lack of economic analyses. Implantation procedure is more complex than either the implantation of traditional pacemakers or ICDs alone. These devices would need to be implanted in select centres to maintain adequate patient volume as well as further refine the surgical technique as the technology evolves. To date, there is insufficient evidence to support the routine use of combined ICD/BiV devices in patients with chronic HF with prolonged QRS intervals. Several large randomized studies are being carried out or have recently stopped enrolling patients which should provide new evidence. The results of this assessment will need to be updated once results from these trials have been fully reported. 5

6 ISSUE The Medical Advisory Secretariat (MAS) conducted a review of the effectiveness and cost-effectiveness of using biventricular (BiV) pacemakers for patients with chronic heart failure (HF). BACKGROUND Clinical Need Chronic heart failure (HF) results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump It is estimated that 1-5 percent of the general population (all ages) in Europe have chronic heart failure (Cowie et al., 2002; Cleland et al., 2002). About half of the patients with heart failure are women and in affluent societies, approximately 40% of men and 60% of women with this condition will be > 75 years of age. The incidence of chronic heart failure is age dependent: 1-5 per 1,000 each year in the total population, to as high as per 1,000 population each year in people >75 years old. Hence, in an aging society, the prevalence of heart failure is increasing, despite a reduction in cardiovascular mortality. The Framingham heart study reported that in the 1980s, and annual age-adjusted incidence of HF among people >45 years was 7.2/1000 for men and 4.7/1000 for women, whereas age-adjusted prevalence of overt HF was 24/1000 in men and 25/1000 in women and the 5 year survival rate from the time of diagnosis was <40% (Ho et al., 1993). Levy et al. (2002) examined the long-term trends in the incidence of and survival with HF among subjects in the Framingham study. Compared to the rate in , there was no significant change in the age-adjusted incidence of HF among men in the 3 subsequent decades, however, among women the incidence of HF declined by 31 to 40 percent in the same period. Age adjusted survival rates after onset of HF improved over time. The overall trend across time periods was a decline in the risk of death of 12% per decade (p=0.01 for men and p=0.02 for women). A recent study revealed 28,702 patients were hospitalized for heart failure for the first time in Ontario between April 1994 to March 1997 (Jong et al., 2002). Fifty-one percent of the cohort were women. Eighty-five percent were 65 years of age or older, and 58% were 75 years or older. Patients with chronic heart failure have shortness of breath, limited capacity for exercise, high rates of hospitalization and rehospitalization and die prematurely (Hare, 2002). The New York Heart Association has provided a commonly used functional classification for the severity of heart failure (Braunwald, 2001): Class I Class II Class III Class IV No limitation of physical activity. No symptoms with ordinary exertion. Slight limitations of physical activity. Ordinary activity causes symptoms. Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest. Inability to carry out any physical activity without discomfort. Symptoms at rest. The National Heart, Lung and Blood Institute estimates that 35% of patients with heart failure are in functional NYHA class I, 35% in class II, 25% in class III and 5% in class IV (Farwell et al., 2000). Surveys suggest that between 5-15% of patients with HF have persisting severe symptoms and that the remainder is evenly divided between those with mild and moderately severe symptoms (Cleland et al., 2002). 6

7 Overall, patients with chronic, stable heart failure have an annual mortality of approximately 10% (Cleland et al., 2002). One-third of patients with new-onset heart failure will die within 6 months of diagnosis, and these patients do not survive to enter the pool of chronic heart failure. Approximately 60% of patients with incident heart failure will die within 3 years, with limited evidence that the overall prognosis has improved in the last 15 years. The diagnosis and management of chronic HF to date has concentrated on patients with the clinical syndrome of heart failure accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of heart failure and the results of large clinical trials. Treatment for chronic heart failure includes lifestyle management, drugs, cardiac surgery or implantable pacemakers and defibrillators. Despite pharmacologic advances, which includes diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone and digoxin, many patients remain symptomatic on maximal tolerated doses. Due to these limitations of pharmacologic therapy, cardiac transplantation and device therapies have been used in an attempt to further improve quality of life and survival of patients with chronic HF. Ventricular pacing is an emerging treatment option for patients with severe heart failure refractory to medical therapy. Traditionally, indications for pacing include bradyarrhythmia, sick sinus syndrome (SSS), atrioventricular (AV) block and other indications including combined SSS with AV block and neurocardiogenic syncope. More recently, it has also been advocated for conditions such as hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, long QT syndrome and after cardiac transplantation. Recently, biventricular (BiV) pacing as a new adjuvant therapy for patients with chronic HF and mechanical dyssynchrony has been investigated. Ventricular dysfunction is a sign of HF, and if associated with severe intraventricular conduction delay (IVCD), can cause dyssynchronous ventricular contractions resulting in decreased ventricular filling. The therapeutic intent is to activate both ventricles simultaneously, therefore improving the mechanical efficiency of the ventricles. Approximately 30% of patients with chronic heart failure have intraventricular conduction defects (Stevenson et al., 1995). These conduction abnormalities progress over time and lead to discoordinated contraction of an already hemodynamically compromised ventricle. Intraventricular conduction delay has been associated with clinical instability and an increased risk of death in patients with heart failure (Brophy et al., 1994). Hence, BiV pacing which involves pacing left and right ventricles simultaneously may provide a more coordinated pattern of ventricular contraction and potentially reduces both QRS duration and intraventricular and interventricular asynchrony. Individuals with advanced chronic HF, a wide QRS complex, low left ventricular ejection fraction (LVEF) and contraction dyssynchrony in viable myocardium and normal sinus rhythm represent the target patient group for BiV pacing. Half of all deaths in heart failure patients are sudden, and the mode of death is arrhythmic in most cases. Internal cardiac defibrillators (ICD) are therefore being increasingly considered for patients with heart failure at high risk of sudden death. Farwell et al. (2000) examined how many people might benefit from BiV resynchronization through a retrospective review of all patients admitted to a large UK hospital with a diagnosis of HF. All patients who were classified with a diagnosis of HF between October 1, 1997-September 30, 1998 were audited. Inclusion criteria used to assess benefit from BiV pacing consisted of: NYHA class III or IV; QRS >120 ms or bundle branch block pattern; and HF due to a dilated cardiomyopathy. Exclusion criteria were: second or third degree heart block; HF primarily due to valvular dysfunction; HF due to an acute myocarditis; poorly controlled arrhythmias; and pacemaker in situ. Out of 721 patients diagnosed with HF, 10% (n=72) fulfilled the authors criteria for BiV pacing. Since previous studies suggested that patients with a variety of QRS durations may benefit from BiV pacing, Farwell et al. (2000) did a subanalysis based on variations of the QRS interval. If a QRS duration 7

8 of 150 ms is considered appropriate for pacing, then 19 patients would be eligible. If 120 ms QRS duration is acceptable, 43 patients would be eligible. Stellbrink et al. (1999) retrospectively analyzed how many patients with an ICD indication may be candidates for left or BiV pacing as an adjunct therapy for chronic HF. Data were obtained from 384 patients with regard to NYHA HF class, mean QRS duration, mean PR interval, presence of a QRS > 120 ms and incidence of atrial fibrillation at the time of ICD implantation. A total of 28 patients (7.3%) fulfilled eligibility criteria for BiV pacing if NYHA III patients were considered candidates, and 48 (12.5%) if patients with NYHA II and ejection fraction <30% were included. Current Implantation Technique for Cardiac Resynchronization Conventional dual chamber pacemakers have only 2 leads-one placed in the right atrium and the other in the right ventricle. The technique used for BiV implantation also uses right atrial and ventricular pacing leads in addition to a left ventricle (LV) lead advanced through the coronary sinus into a vein that runs along the ventricular free wall (Figure 1). This allows early activation of the LV, which would otherwise be activated late during conduction, and permits simultaneous pacing of both ventricles to allow resynchronization of the LV septum and free wall. Some issues relating to cardiac resynchronization therapy by means of BiV stimulation still need to be clarified. For example, optimal pacing configuration has not been defined. Acute hemodynamic studies have indicated that LV pacing alone may be as effective or even more effective than BiV pacing (Blanc et al., 1997; Kass et al., 1999). It is not known if the right and left ventricle should be paced simultaneously or with an interventricular delay (Perego et al., 2001). Mode of Operation Permanent pacing systems consist of an implantable pulse generator that contains a battery and electronic circuitry, together with one (single chamber pacemaker) or two (dual chamber pacemaker) leads. Leads conduct intrinsic atrial or ventricular signals to the sensing circuitry and deliver the pulse generator charge to the myocardium. Complications of Pacemaker Implantation Complications are similar to standard pacemaker implantation, including: pneumothorax, perforation of the great vessels or the myocardium, air embolus, infection, bleeding and arrhythmias. Left ventricular pacing through the coronary sinus can be associated with rupture of the sinus as an additional complication. Biventricular Pacemaker Models and Regulation Medtronic The InSync System was approved by the FDA in 2001 and is licensed by Health Canada as a class 4 device (License # 10446). The InSync System includes the multisite, multichamber pulse generator (model 8040), the software (model 9980), and coronary sinus leads (model 2187 and 2188). The conditions of the FDA approval included a 12 month mortality assessment with an intention-to-treat analysis, and a 3 year evaluation of mortality on 1,000 patients (FDA, 2001). The FDA states the InSync System is indicated for reduction of the symptoms of moderate to severe heart failure (NYHA Class III/IV) in patients who remain symptomatic despite stable, optimal medical therapy and have a LVEF <35% and a QRS duration >130 ms. The InSync device has an atrial channel for atrial 8

9 pacing and sensing and 2 ventricular channels to provide simultaneous biventricular pacing and sensing from 2 ventricular leads. Three ports in the lead connector accommodate one atrial lead and 2 ventricular leads. InSync III (model 8042) and InSync Marquis ICD (model 7277) are licensed in Canada as class 4 devices (License # 29732, 60560). Health Canada states InSync III is indicated for implantable atrial synchronous BiV pacing for HF management and InSync System is indicated for correction to cardiac arrythmia. The Attain lead system (side wire and models 4193, 4189) is a Class 4 device (License # 12987, 26897, 20669) indicated for LV pacing of the heart via the cardiac vein. Guidant On May 2, 2002, the US Food and Drug Administration approved the Guidant CONTAK- CD/EASYTRAK (model 1823), a BiV pacing system that incorporates implantable cardioverterdefibrillators (ICDs) using the Easy Track lead system. This device is licensed in Canada as Class 4 (License # 17880) and indicated for HF pacing therapy with cardioverter defibrillator support. The EasyTrak lead system (models 4510, 4511, 4512, 4513) is also licensed as Class 4 (license # 19628), and is indicated for left side heart pacing with fixation and therapy delivery in the coronary veins on the LV. The CONTAK CD cardiac resynchronization therapy defibrillator system is indicated for use by the FDA for : 1) Patients at high risk of sudden cardiac death due to ventricular arrhythmias and who are NYHA Class III/IV including LV dysfunction (ejection fraction <35%) and QRS duration >120 ms and remain symptomatic despite stable optimal heart failure drug therapy. 2) Patients at high at risk of sudden cardiac death due to ventricular arrhythmias including but not limited to, those with: Survival of at least one cardiac arrest (manifested by the loss of consciousness) due to a ventricular tachyarrhythmia. Recurrent poorly tolerated sustained ventricular tachycardia. The clinical outcome of hemodynamically stable, sustained VT patients is not fully known. Safety and effectiveness studies have not been conducted. Prior myocardial infarction, LVEF <35%, and a documented episode of nonsustained VT with an inducible ventricular tachyarrhythmia. Patients suppressible with i.v. procainamide or an equivalent antiarrhythmic drug have not been studied. FDA approval was issued for CONTAK CD under the following conditions: 3 year evaluation of the long term safety and effectiveness of the system including mortality, lead performance and adverse events on 1,000 patients. Guidant will certify that physicians who implant the device complete a training program. In October 2002, the FDA approved the CONTAK CD 2 (a smaller, lighter system) for the treatment of heart failure. CONTAK CD2 is not currently licensed in Canada. CONTAK TR and Renewal are licensed in Canada as a Class 4 device (License # and respectively) and are indicated for simultaneous biventricular pacing for the treatment of HF. St. Jude Medical St. Jude Medical manufactures the Genesis System, a biventricular resynchronization system designed to treat heart failure and also suppress atrial fibrillation. Components of Genesis have received European regulatory approval. Frontier (BiV stimulator) and Alliance (catheter delivery system) are not currently licensed in Canada. Aescula (LV lead) is licensed by Health Canada as a Class 4 device (License # 61218). 9

10 ELA Medical ELA Medical produces a pacemaker based ventricular resynchronization system for the treatment of CHF. The system is composed of the Chorum MSP7336 or the Talent MSP313 cardiac stimulator; the Situs left ventricular lead; and Situs left ventricular access system. The Chorum MSP 7336 was commercially released in Europe and offers selection of right or biventricular pacing. Talent MSP 313 is ELA s new generation of biventricular multisite pacemakers. Chorum, Talent MSP 313, and Situs (ELA) are not currently licensed in Canada. Alternative Technology Initial studies of pacing therapy in chronic HF patients focused on the effects of shortening AV delay via physiologic (right atrium, right ventricle) pacing. Small, very short-term studies revealed hemodynamic benefits for patients with a long PR interval and presystolic mitral regurgitation (Brecker et al., 1992). However, this was not supported by larger, long-term prospective studies (Gold et al., 1995). Precise identification of any patients who may benefit is lacking. Acute hemodynamic studies in HF patients have suggested a benefit with both LV and BiV stimulation effects. Immediate hemodynamic effects of single site LV activation were often similar or even more prominent than those from BiV stimulation (Blanc et al., 1995; Auricchio et al., 1999; Kass et al., 1997). To date, BiV pacing remains the dominant method under investigation for HF pacing studies. A trial is currently underway in order to assess single site LV versus BiV pacing (BELIEVE) (Appendix Table 3). However, similar to BiV pacemaker insertion, the optimal univentricular (LV) pacing site remains to be confirmed (Pappone et al., 2000). Literature Review Objective Assess the effectiveness and cost-effectiveness of BiV resynchronization for severe chronic heart failure. Assess the effectiveness and cost-effectiveness of combined BiV resynchronization and defibrillation (ICD) for severe chronic heart failure. Methods Inclusion criteria: English language articles (January 1997-September 2002). Journal articles that report primary data on the effectiveness or cost effectiveness of BiV pacemakers. obtained in a clinical setting, or analysis of primary data maintained in registries or databases. Study design and methods must be clearly described. Systematic reviews, randomized controlled trials (RCTs), non-randomized controlled trials and/or cohort studies that have >20 patients, cost effectiveness studies. Exclusion criteria Studies that are duplicate publications (a study that is superceded by another publication by the same investigator group, with the same objective and data). Non-English articles. Non-systematic reviews, letters and editorials. 10

11 Animal and in-vitro studies. Case reports. Studies that do not examine the outcomes of interest. Studies which include patients receiving a BiV pacemaker for any conventional pacing indications. Patients Human subjects with severe chronic heart failure (NYHA class III/IV), IVCD (QRS >120 ms), LVEF <35%, and normal sinus rhythm. Patients who are refractive to exhaustive pharmacotherapy. Intervention BiV pacemaker implantation. Controls do not undergo BiV pacing, but receive optimal medical management. There are no established and medically accepted alternative technologies available to this particular patient subgroup with chronic HF. Outcome measures NYHA heart failure classification Quality of life Exercise capacity (6 minute walking test) Adverse effects QRS interval LVEF Mortality Economic analysis data Literature Search Cochrane database of systematic reviews ACP Journal Club DARE INAHTA Embase Medline References from extracted papers Results The Cochrane and INAHTA databases yielded no HTA on BiV pacemakers. The National Horizon Scanning Centre (2001) published a New and Emerging Technology Briefing regarding ventricular resynchronization for HF. A search of Medline and Embase was conducted using key words ventricular pacing, biventricular, and resynchronization. This search produced 153 studies of which 11 met the inclusion criteria. The quality of the included articles is presented below. 11

12 Quality of Evidence Study Design Level of Evidence Large randomized controlled trial, systematic reviews of RCTs 1 1 Large randomized controlled trial unpublished but reported to an 1(g) international scientific meeting Small randomized controlled trial 2 2 Small randomized controlled trial unpublished but reported to an 2(g) international scientific meeting Nonrandomized study with contemporaneous controls 3a 1 Nonrandomized study with historical controls 3b Nonrandomized study presented at international conference 3(g) Surveillance (database or register) 4a 2 Case series (multi-site) 4b 1 Case series (single site) 4c 3 Retrospective review, modeling 4d Case series presented at international conference 4(g) 1 g=grey literature Number of Eligible Studies 12

13 Biventricular Pacemakers The following largest randomized controlled studies have been selected for detailed analysis. MIRACLE Abraham et al. (2002) performed a large double-blind, multi-centre, randomized, level 1 evidence controlled trial (MIRACLE Study). Inclusion criteria were: moderate to severe heart failure (NYHA class III-IV) associated with an ejection fraction of <35% left ventricular end-diastolic dimension of >55 mm QRS interval of >130 ms, and a 6 minute walking distance of <450 m Patients received conventional treatments for heart failure including a diuretic, ACE inhibitor or angiotensin receptor blocker and usually digitalis and a β blocker. The doses of these background medications were stable for at least one month except for doses of the β blocker (which were stable for 3 months). Patients were excluded if they had: a pacemaker or ICD or an indication for or a contraindication to cardiac pacing a cardiac or cerebral ischemic event within the previous 3 months an atrial arrhythmia within the previous month a systolic blood pressure >170 or < 80 mm Hg a heart rate >140 bpm serum creatinine level >3.0 mg/dl Four hundred and fifty-three patients who were successfully implanted were randomly assigned to atrialsynchronized biventricular pacing (n=228) or to a control group (n=225) (no pacing) for 6 months, during which time medications for heart failure were kept constant. The primary endpoints of interest were the NYHA functional class, quality of life and distance walked in 6 minutes. Secondary endpoints included time on treadmill, peak O 2 consumption, LVEF, duration of QRS interval, and severity of mitral regurgitation. All endpoints were analyzed according to the intent-to-treat (ITT) principle. Sample size was estimated assuming the study would have 80% power to detect a difference in NYHA class of 0.75, quality of life (QOL) of 13 points or distance walked in 6 minutes of 50 metres. Five-hundred and seventy one patients agreed to participate in the study and of these, 47 patients were not enrolled. Failure to successfully implant the device was responsible in 43 of these patients. Seventy-one patients were randomized but agreed to enrollment in an initial 3 month pilot phase of the study only. The remaining 453 patients were enrolled in the 6 month study. Of the control group (n=225), 24 did not complete 6 months of follow-up due to the following reasons: 16 died 2 received heart transplant 1 had complications related to device 5 missed the 6 month visit Of the 228 BiV pacing patients, 13 did not complete follow-up: 12 died 1 had complications related to device All patients received the assigned treatment for the intended duration of the study, except for 10 patients in the control group who had to have their device reprogrammed to the cardiac resynchronization therapy (CRT) mode. The baseline QRS interval for the control group was (mean+sd) ms, and ms for the BiV pacing group. Over 90% of the patients in each of the control and treatment groups were 13

14 NYHA III at baseline. Pacemaker programming data (minimum ventricular pacing rate and whether the devices were all rate-responsive) were not reported. Compared to controls, patients assigned to BiV pacing had improvement in functional class (p<0.001), and quality of life (p=0.001), and distance walked in 6 minutes (p=0.005). The magnitude of these primary endpoints was not influenced by the use of β blockers, cause of heart failure (ischemic or nonischemic), or the configuration or baseline interval of the QRS complex. In addition, the left ventricular ejection fraction, left ventricular end diastolic dimension, and mitral regurgitant area all improved compared to controls (p<0.001). There was improvement in the 2 measures of maximal exercise performance: peak O 2 consumption (p=0.009), total exercise time (p=0.001); and QRS interval and area of mitral regurgitant jet decreased compared to controls (p<0.001). During the 6-month follow-up, there were 50 hospitalizations in 34 controls, totaling 363 hospital days for heart failure compared to 83 hospital days in 18 patients in the CRT group who required hospitalization. Fewer patients in the treated group required hospitalization (p=0.02) or i.v. medications for worsening heart failure (p=0.004). The implantation and maintenance of a BiV device was associated with a greater risk than a conventional pacing device. Adverse events occurred in 46 of the 571 participating patients. 2 - complete heart block requiring permanent cardiac pacing 2 - death (one hypotension and one cardiac arrest) 7 - infection requiring explantation 23 - coronary sinus dissection 12 - cardiac vein or coronary sinus perforation Of patients who underwent successful implantation, the median duration of the procedure was 2.7 hours ( hrs). After implantation, 20 patients required repositioning of the LV lead and 10 required replacement of the lead. Technical failure resulted in approximately 8% of the 571 participants being unable to receive and be maintained on CRT for the duration of treatment. This study was not designed to assess any possible effects on long term morbidity or mortality. This trial is the first and to-date the only double blind RCT to evaluate BiV pacing in HF patients. However, the full ability to double blind the study would be difficult to enforce, as viewing an ECG would unblind an investigator. The outcomes were reported for approximately 500 patients over a 6 month duration. It is possible that these outcomes may not reflect the effects that might be observed with longer follow-up. The FDA issued an approval for the Medtronic InSync BiV pacing system in 2001 with the following conditions (FDA, 2001): 12 month mortality assessment with an intention-to-treat analysis. 3 year evaluation of mortality, particularly sudden cardiac death, and chronic lead performance including electrical performance and adverse clinical events on 1,000 patients. The FDA expects that 1,500 patients will need to be enrolled in the 3 year study to allow for patient drop out and insure 1,000 patients are followed for the full 3 years. MUSTIC The MUSTIC-SR trial (Cazeau et al., 2001) was a small, multicentre, single blind, randomized controlled crossover study that examined the clinical efficacy and safety of biventricular pacing. Inclusion criteria were: NYHA class III (for at least one month while receiving the optimal treatment which included at least diuretics and ACE inhibitors at the maximal tolerated dose) Ejection fraction <35%, with normal sinus rhythm 14

15 End diastolic diameter of >60mm Sinus rhythm with a QRS interval duration of >150 Exclusion criteria consisted of: Hypertorphic or restrictive cardiomyopathy Suspected acute myocarditis Correctable valvulopathy Acute coronary syndrome lasting <3 months Recent coronary revascularization (during previous 3 months) or scheduled revascularization Treatment resistant hypertension Severe obstructive lung disease Inability to walk Reduced life expectancy not associated with cardiovascular disease (<1 year) Indication for ICD After implantation, the pacemaker was programmed to be inactive. The responses of the patients were compared during 2 periods: a 3 month period of inactive pacing (ventricular inhibited pacing at a basic rate of 40 bpm) and a 3 month period of active pacing (atriobiventricular). The basic pacing rate was set at 40 bpm and the upper rate limit at 85% of the maximal predicted heart rate according to the age and sex of the patient. No modification in medication other than adjustment of diuretic dose was permitted between enrollment and end of crossover. A sample size of 40 patients was calculated and analyses were based on intention-to-treat (ITT). The primary endpoint was the distance walked in 6 minutes. Secondary endpoints included quality of life, peak O 2 consumption, hospitalizations related to heart failure, the patients treatment preference (active vs. inactive pacing) and mortality. Sixty-seven patients with HF were included in the study. The baseline QRS interval was (mean+sd) ms. Forty-eight patients completed both phases of the study. Nineteen patients failed to complete the crossover study. 3 withdrew before implantation 2 - unstable heart failure (1 of whom died) 1 - preexisting indication for pacing 6 were removed before randomization 5 - failed implantation of LV lead 1 sudden death while device was inactive 5 did not complete the first crossover period 1 withdrew consent at time of randomization 2 uncorrectable loss of LV pacing efficacy 1 severe decompensation during inactive pacing leading to premature switch to active pacing 1 died suddenly after 26 days of active pacing 5 did not complete the second crossover period 1 decompensation with active pacing attributed to rapidly progressive aortic stenosis 1 died from acute MI few hours after a premature switch to active pacing due to severe decompensation 1 decompensation as persistent atrial fibrillation occurred during inactive pacing 1 died suddenly 2 hours after switching from inactive to active pacing 1 lung cancer The mean distance walked in 6 min was 23% greater with active pacing (mean + SD)( m vs m, p<0.001). Quality of life score improved by 32% (p<0.001), peak O 2 intake increased by 8% (p<0.03), hospitalizations decreased by two thirds (p<0.05), and active pacing was preferred by 85% of the patients (p<0.001). During active pacing, 3 hospitalizations for HF occurred versus 9 hospitalizations during inactive pacing, p<0.05. This was observed over a very short time interval (12 weeks). Optimal medical therapy involved 2 classes of drugs: ACE inhibitors and diruetics, prescribed at the maximal tolerated doses in 98% of 15

16 patients. β-blockers and spironolactone were prescribed to many fewer patients since these drugs were not recognized as effective treatments for severe HF at the time the protocol was approved. Since no changes in treatment were permitted between inclusion and end of the crossover phase, Cazeau et al. concluded that clinical changes were induced by pacing modes, natural history of HF or both. A weakness of the crossover design was that the treatments administered during the 1 st period may have had a carryover effect in the second period since there was no washout period between crossovers in their study design. However, the authors stated that there was no significant carryover effect for the main selected end points. This study also had a large number of patients who did not complete the study (19/67). Patients who were included in the study had to be NYHA III since patients had to be stable enough to withstand a 7.5 month study including a 6 month crossover phase (Cazeau et al., 2001). Cazeau et al. (2001) also state that earlier uncontrolled studies revealed that despite clinical improvement, mortality remained high in patients in NYHA IV whose condition was unstable as compared with the much lower mortality in patients who were in NYHA III at the time of implantation. In general, parallel trials with a larger study population are better suited to assessing treatments and evaluating long-term morbidity and mortality. The MUSTIC-SR trial was unable to demonstrate whether the CRT was safe or truly effective in reducing long term morbidity and mortality. A non-randomized, 6 month follow-up of the crossover phase of the MUSTIC trial (Linde et al., 2002) suggested that the benefits of BiV pacing observed during the crossover phase were sustained over 12 months. This follow-up study has several limitations. The calculation of the sample size was based on the previous randomized, crossover phase of the study. No consideration was given for sample size/power needed for a 12-month assessment. Furthermore, for the follow-up period, patients were paced according to their preferred type of pacing during the crossover phases. If no preference was expressed, the physician chose the type of pacing for that patient. PATH-CHF The PATH-CHF trial compared short and long term effects of atrial synchronous pre-excitation of univentricular and biventricular cardiac resynchronization. This small trial was a randomized, multicentre, patient-blinded, crossover study. The primary endpoints were O 2 uptake at peak exercise, O 2 uptake at anaerobic threshold and 6 min walking distance. Secondary endpoints included NYHA class and quality of life. Randomization was designed to achieve a 1:1 ratio for univentricular and BiV stimulation. Forty-one patients were randomized to 4 weeks of initial treatment with BiV or univentricular stimulation, followed by 4 weeks without treatment, and then four weeks of treatment with the alternate stimulation. Inclusion criteria were: NYHA class III or IV sinus rhythm > 55 bpm QRS duration >120 ms and a PR interval >150 ms. Exclusion criteria were: Primary operable valvular heart disease (other than mitral or tricuspid regurgitation) Indication for conventional pacemaker or ICD Noncardiac conditions that could limit exercise capacity and life expectancy Patients were implanted with 2 dual chamber pacemakers: one endocardially connected to the RA and RV at the apex, and the other independently and endocardially connected to the RA and epicardially to the LV via thoracotomy. At implantation, patients were instrumented for acute hemodynamic testing in order to select optimal univentricular stimulation and AV delay. Pacemakers were programmed according to results of hemodynamic testing. An atrial synchronous tracking mode without atrial pacing was programmed with a lower rate limit of 40 bpm. Crossover data was analyzed using the ITT principle. 16

17 Similar to Linde et al. (2002), at the end of the 2 nd treatment period, patients continued to receive CRT. The long-term therapy programming that provided the best therapeutic effect was based on the physician s judgment (nonrandomized). Patient s then returned for follow-up at 12 months. The initial sample size was calculated at 53 patients. Due to the availability of transvenous lead systems, the Data and Safety Monitoring Committee requested a reassessment of the sample size. A new sample size of 42 was chosen to limit the number of thoracotomies (Auricchio et al., 2002). In a separate report of the rationale, design and endpoints of the PATH-CHF trial, an interim analysis to assess the difference in benefit between pacing and no pacing was reported (Auricchio et al., 1999). The mid-study analysis revealed a trend toward improvement in all the primary and secondary endpoints during pacing. There was no trend toward a statistical difference between univentricular and BiV pacing. The interim analysis also demonstrated that a new minimum sample size of 35 patients including estimated dropouts were required to show a difference between pacing and no pacing. Thirty-six of the 42 (86%) HF patients were NYHA class III. Forty-one patients received implants. One patient was disqualified due to aortic stenosis. Thoracotomy was well tolerated. Twenty-four patients were initially randomized to BiV and 17 patients to univentricular stimulation. This imbalance was due to early study termination. The effect of the stimulation order during the randomized, crossover period was not significant for any clinical measure and there were no significant differences between the univentricular and biventricular stimulation effects on any endpoint. Seven patients did not complete the crossover study: 1 aortic stenosis unacceptable for implantation 2 died suddenly during first treatment period 1 ventricular arrhythmia during first treatment period 2 refused to have device switched off and voluntarily withdrew 1 elected for heart transplant 1 developed marked bradycardia requiring continuous atrial pacing at end of second treatment period One Year Follow-up The subsequent 9-month follow-up was not randomized. The physician chose not to reprogram the device in 29 patients. Two patients had the device reprogrammed from BiV to univentricular and 4 patients were reprogrammed from univentricular to BiV. After 12 months post implantation, 29 patients (12 BiV, 13 LV, 4 RV) returned for follow-up. The magnitude of improvement at 12 months was similar to that observed at 3 months post implantation, however the results were presented as a combination of BiV and univentricular device (general CRT), and therefore, no conclusion can be made between the two types of pacemakers. Of interest was the fact that the clinical differences between hemodynamically optimized biventricular and univentricular (mostly LV) resynchronization methods were not significant. However, there are several limitations to this study. Firstly, it is possible that differences between implantation methods may become significant after a longer follow-up. The 9-month follow-up following the initial randomized study was not randomized and treatment was left to the physician s discretion. The most contentious issue with the PATH-CHF study is the mid-study adjustment of sample size and objective which could contribute to publication bias. The final sample size was recalculated to detect an overall difference between pacing and no pacing. Interestingly, Auricchio et al. (1999) stated that the interim analysis revealed a difference in benefit with univentricular and BiV pacing that varied widely in many of the endpoints considered. No further detail or discussion was provided. However, this difference in benefit between pacing modes was not observed in Auricchio et al. (2002). Furthermore, Auricchio et al. (1999) clearly state that since the difference in benefit with univentricular and BiV pacing 17

18 varied widely in many of the endpoints considered, the new sample size was not calculated to detect a difference between the two pacing modes, and the study focused on overall pacing versus no pacing. Due to mid-study sample size adjustment, mid-study change of objective, non standard implant technique, and lack of randomization/appropriate sample size between treatments of interest in the follow-up analysis, the rigour of this study is poor overall. While there were no differences in outcome during the first 3 months, no conclusions can be drawn from the long-term follow-up. Observational/Registry Studies Zardini et al. (2000) reported the clinical outcome of the first 190 patients enrolled in the InSync Italian Registry. No specific inclusion or exclusion criteria were established by the registry. The selection of patients was the responsibility of the implanting physician, as was the choice of the preoperative, short and long term clinical evaluation tests. The clinical data included in the registry assessed the nature of the underlying cardiac disease; sinus rhythm or atrial fibrillation; morphology; and width of the QRS complex, and presence of a previously implanted pacemaker, NYHA class, LVEF, QOL, and 6 min walk test. The patient population was divided into 2 groups: one group consisted of conventional indications for BiV pacing (NYHA III/IV, LVEF <35%, and QRS >120 ms), and the other group consisted of patients with NYHA class I/II, LVEF >35%, and QRS <120 ms. The results of the latter group were excluded from this assessment, due to the nonstandard criteria for BiV pacing. Mean (+SD) follow-up was 10+5 months (range 1-28 months). The QRS interval, NYHA class, QOL, and 6 minute walk test all significantly improved from baseline (p<0.0001). The patients were also divided into two groups depending on the pre-implant QRS interval: >150ms (125 patients); >120 ms and <150 ms (26 patients). For the QRS>150 ms group, the QRS interval, NYHA class, QOL and 6 minute walk test all significantly improved from baseline, p< For the QRS<150 ms group, the QRS interval and NYHA class significantly improved from baseline (p<0.0001), as did the QOL (p<0.02). Overall, this study provides poor quality and weak evidence as it was an uncontrolled, unblinded, registry study without a priori inclusion and exclusion criteria. Ongoing/Incomplete/Unpublished Trials VIGOR CHF The VIGOR CHF trial was a prospective randomized, crossover trial evaluating the use of biventricular pacing in patients with moderate to severe heart failure. Patients were to be implanted via a thoracotomy. However, the study was terminated in September 2000 after 53 device implants due to slow patient recruitment (Saxon et al., 2002). Factors that contributed to slow enrollment were the need for a minithoracotomy for placement of the epicardial LV lead, as well as competing trials that used a less invasive transvenous coronary sinus approach for inserting the LV lead (Saxon et al., 2002). RELEVENT The RELEVANT trial was planned as a pilot study that would blend into a mortality study comparing optimal medical therapy versus optimal medical therapy in addition to LV or BiV pacing. The study was terminated because the proposed study size would have to be much larger than initially predicted (Cleland et al., 2002). Patients were to be assessed at 1 and 6 months, and then at every 6 and 12 months for 2 years. Inclusion criteria consisted of NYHA III, QRS>140 ms and LVEF <35% and sinus rhythm. Endpoints were echocardiography, quality of life and safety/mortality. 18

19 CARE HF The CArdiac REsynchronization in Heart Failure study is designed to evaluate the long term effect of BiV resynchronization on the morbidity and mortality of patients with heart failure due to left ventricular systolic dysfunction (Cleland et al., 2001). The patients will already have been receiving diuretics and optimal medical therapy with ACE inhibitors and β blockers. If the intervention reduces morbidity and/or mortality, the cost-effectiveness of this intervention will be evaluated. Approximately 800 patients are expected to be enrolled in this open label study (400 control and 400 resynchronization). Inclusion criteria consists of a QRS interval >150 ms or >120 ms with core laboratory verified left ventricular dyssynchrony by echocardiography. The primary end-point is the composite of all cause mortality or unplanned cardiovascular hospitalization using a time to first event analysis. Secondary outcomes of interest include worsening heart failure, days alive and out of hospital and health economic analysis. A minimum follow-up of 18 months is scheduled. The study is expected to close in VECTOR The VECTOR 6 month, randomized crossover trial is evaluating BiV pacing versus no pacing. Inclusion criteria consists of NYHA II-IV, QRS >140 ms and LVEF<35%. Primary objectives are 6 min walk distance and quality of life. PATH-CHF 2 The Pacing Therapies for Congestive Heart Failure (part 2) randomized crossover trial is evaluating: 1) the acute benefit of LV pacing; 2) the chronic benefit of optimized univentricular pacing with or without ICD indications; and 3) acute and chronic effects of pacing in patients with a wide QRS interval (>150 ms) to those with a narrower QRS interval ( ms). Preliminary, incomplete data were presented at the North American Society of Pacing and Electrophysiology 23 Annual Scientific sessions (Auricchio, 2002). Inclusion criteria consisted of: NYHA II-IV HF VO 2 max < 18 ml/kg/min Ejection fraction <30% Dilated cardiomyopathy QRS >120 ms Age years Optimal drug therapy for HF Exclusion criteria were: Atrial fibrillation within past 6 months Acute HF or dependency on intravenous inotropes Aortic/mitral valve stenosis CABG or PTCA scheduled or completed within 3 months prior to study Unstable angina Recent acute MI The primary endpoints were peak VO 2 uptake, anaerobic threshold and 6 min walk distance. Secondary endpoints included quality of life and NYHA class. Patients received pacing therapy for 3 months and off therapy for 3 months. The study was designed to detect differences of 12.5% in the primary endpoints with 80% power, and an α of 0.05 between pacing and no pacing separately in the two QRS study groups (Stellbrink et al., 2000). The study enrolled 101 patients, 89 were randomized, and 71 patients completed crossover. Forty-six patients had a long QRS interval (>150 ms). All but 3 patients with right bundle branch block were implanted with a LV pacemaker. LV pacing had a significant effect on all endpoints for long QRS interval patients, however, the narrow QRS group did not reach significance in any of the endpoints. A 19

20 large number of patients dropped out of the crossover phase of the study. Full, peer-reviewed data from this study are not currently available. Summary Individuals with advanced heart failure (NYHA III/IV), a wide QRS complex (>120 ms), low LVEF (<35%), contraction dyssynchrony in viable myocardium, and regular normal sinus rhythm represent the target patient group for BiV pacing. The RCTs included in this review followed patients for only up to 6 months. Nevertheless, over these short periods, all studies demonstrated symptomatic improvement in chronic HF compared to no pacing. The majority of HF patients in the RCTs were NYHA III. Prospective observational nonrandomized studies, limited by inadequate attention to sample size and statistical power also reported short term acute hemodynamic benefits for BiV. There is some inter-trial variation in clinical characteristics among patient populations enrolled in these trials, though the majority of patients treated for chronic HF have been stable on medical therapy, NYHA class III/IV, QRS duration > ms, ejection fraction<30-35%, no bradycardia indications and no atrial fibrillation. Implantation and maintenance of a resynchronization device are associated with risks that are greater than those of a conventional pacing device, as it requires insertion of an additional pacing lead into the coronary sinus and advancement into a cardiac vein to pace the LV. In some patients, efforts to implant have been unsuccessful or were accompanied by dissection or perforation of the coronary sinus or cardiac vein. Complications include complete heart block, hemopericardium and cardiac arrest. LV lead dislodgment has occurred in long term pacing requiring lead repositioning or replacement. Uncertainty remains with BiV pacing: There are a small number of trials that have evaluated BiV pacing in chronic HF patients. It is not known if BiV pacing reduces symptoms or outcomes in patients 3-9 months after first diagnosis of HF. The length of follow-up has been of a short duration. Long-term benefits and effects on mortality are unknown. Identification of patients who do not improve clinically following BiV pacing. Difficulty in full ability to blind many of the trials (viewing an ECG could unblind an investigator). Patients in the RCTs had regular normal sinus rhythm, and patients with atrial fibrillation were generally excluded to allow for atrial synchronization. As HF worsens, the incidence of atrial fibrillation increases, and currently patients with atrial fibrillation would not be eligible for BiV pacing. The optimal site for the LV lead is yet to be determined. LV lead technology will need to be improved. The baseline QRS interval that is necessary for improvement with BiV pacing needs to be determined. Biventricular Pacemakers Combined With Implantable Cardioverter Defibrillator Devices (ICD) InSync 7272 ICD Kuhlkamp et al. (2002) reported initial experience with an ICD incorporating ventricular resynchronization therapy. The InSync 7272 ICD has a 5 port header for connection of 4 leads, which have 3 pacing electrodes and 2 defibrillation coils. Resynchronization and antitachycardia pacing (ATP) can be programmed to right, left or BiV stimulation. The inclusion criteria for this prospective, noncomparative, multicentre study were: Indication for ICD therapy due to symptomatic sustained ventricular tachycardia and/or survival of cardiac arrest Symptomatic heart failure despite appropriate HF therapy LVEF <35% QRS interval >130 ms. 20

21 Exclusion criteria were not reported. Patients were examined when discharged from hospital and on an outpatient basis at 1 and 3 months of follow-up. At follow-up visits the following were assessed: 6 min walk, quality of life, echocardiogram, and NYHA classification. Results A total of 84 patients were included in the study: 26 NYHA II (32%); 48 NYHA III (59%); and 7 NYHA IV (9%). A significant improvement in the 6 minute walk test was seen at both 1 and 3 month follow-up visits compared to baseline. NYHA class III/IV patients had a significant improvement in the walk test (p<0.001), whereas improvement in patients with NYHA class II did not reach statistical significance. A significant improvement (p<0.001) in quality of life was demonstrated for NYHA III/IV patients. NYHA II patients had an almost unchanged quality of life score. Sixty-seven percent of NYHA III/IV patients improved by at least one NYHA class versus 85% of NYHA II patients remained unchanged. Overall, there were significantly more successfully terminated episodes of fast ventricular tachycardia with BiV antitachycardia pacing (ATP) versus RV ATP, p< In 81/84 patients the LV lead was successfully implanted. Cardiac resynchronization therapy was not possible in 3 patients, and these 3 patients were not included by the authors in all data analysis except for the analysis of the ICD and/or lead associated complications. The 3 failures were due to inability to cannulate the coronary sinus in one patient, LV lead dislodgment while retracting the guiding catheter in one patient, and coronary sinus perforation in one patient. The following complications were reported in the 84 patients studied: Peri-implant complications n Cardiac perforation/coronary sinus dissection 4 Unable to position LV lead 3 Hematoma requiring drainage 3 Pneumothorax 2 Dislodgement of LV lead 1 Hematothorax 1 Pulmonary edema 1 Pneumonia 1 Total 16 Follow-up complications n LV lead dislodgement With loss of capture Without loss of capture 2 4 Infection of the ICD and/or lead 2 Stimulation of the diaphragm 1 Device migration 1 Right atrial lead dislodgement 1 Total 11 Total procedure time for implantation was min (range min). Mean time for the placement of the LV lead was min (range min). Of 84 patients, 77 were successfully implanted at first attempt and 4 patients were successfully implanted after a second attempt. Five non-device/implantation related deaths occurred during a mean follow-up of 178 days. The survival at 3 and 6 months was 96+2%. The major weakness of this study was the lack of a control group with comparable severity of heart failure receiving an ICD alone. This study does not address to what extent an ICD with BiV pacing may improve symptoms and/or prognosis of heart failure patients compared to a control group. 21

22 Ongoing/Incomplete/Unpublished Trials CONTAK-CD The CONTAK-CD 6-month trial evolved from the terminated VENTAK CHF study. The VENTAK CHF device was designed to provide an implantable defibrillator and cardiac resynchronization but required a thoracotomy, whereas the CONTAK-CD device is delivered transvenously. Higgins et al. (2000) reported preliminary data from the single blind, randomized, crossover VENTAK CHF study suggesting BiV pacing diminishes the need for ICD therapy in HF patients. However, these results have not been confirmed in any larger trials and any findings from Higgins et al. (2000) were preliminary data from a larger, incomplete, unpublished trial that was terminated and used an outdated implantation methodology. Thackray et al. (2001) summarized research developments regarding the CONTAK-CD study from presentations at a meeting of the European Society of Cardiology (Table 3). Inclusion criteria for the CONTAK-CD trial consisted of: NYHA II-IV on contemporary drug therapy Left ventricular ejection fraction <35% QRS > 120 ms Normal sinus mode function Indication for conventional ICD therapy (the indication for ICD included the criteria used in the MADIT trial) Exclusion criteria consisted of: Indication for RV pacing Chronic atrial arrhythmias Life expectancy <6 months. The primary endpoint was a composite of all-cause mortality, hospitalization for heart failure, or worsening heart failure requiring intervention or appropriate ICD discharge. Overall, 501 patients received the device, of whom 490 were randomized into the study. This is the largest trial to date. Two-hundred and fifteen patients received a system under the VENTAK CHF study (cross-over design with 3 month treatments periods), and 286 patients received a system under the CONTAK-CD study (parallel group design with 6 month treatment periods). NYHA class was 33% in II, 58% in III, and 9% in IV. Results reported included: a mortality rate of 5%; proportion of patients with worsening heart failure was 21%; appropriate ICD discharges occurred in 13%. Cardiac resynchronization improved NYHA class (33% of control group were class I/II versus 80% of patients on cardiac resynchronization by the end of the reported study). Trends for improved quality of life and corridor walk distance were reported to be not significant. Weaknesses of the CONTAK-CD trial is its short follow-up and the inclusion of many NYHA II patients, as well as patients who had a less marked QRS interval than some other studies. To date, it is not known whether implantation of a combined BiV and ICD device leads to greater prognostic benefit, without adverse effects, than implantation of a BiV device alone. FDA approval was issued for CONTAK CD under the following conditions: 3 year evaluation of the long term safety and effectiveness of the system including mortality, lead performance and adverse events on 1,000 patients. physicians who implant the device complete a training program. 22

23 COMPANION The Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure ( COMPANION ) trial is a randomized, open-label, 3 arm study of patients in NYHA class III or IV with an ejection fraction of <35% and a QRS interval of >120 ms (Bristow et al., 2000). The target recruitment is 2,200 patients. Patients are randomized to: 1. optimal pharmacological therapy alone (control arm, n=440), or 2. optimal pharmacological therapy plus ventricular resynchronization therapy (n=880), or 3. optimal pharmacological therapy plus ventricular resynchronization therapy combined with ICD capability (n=880). The primary endpoint of the COMPANION trial is the reduction of combined all cause mortality and hospitalization. Secondary endpoints include the reduction of cardiac morbidity, improvement of cardiac performance and quality of life, and increase in total survival. Follow-up is expected to last 2 years. Patients who have an existing indication for an ICD are excluded from COMPANION, therefore, it will be assessing the use of prophylactic ICD in patients not at risk of arrhythmias. In November 2002, the COMPANION trial was terminated early as recommended by the independent Data and Safety Monitoring Board due to achievement of the primary endpoint. Study findings are expected to be presented and published in early BELIEVE The Bi-versus Left Ventricular Pacing study is an Italian randomized pilot study of BiV versus LV pacing in patients indicated for an ICD. Inclusion criteria consists of NYHA II-IV, LVEF<35%, QRS>130 ms, and ICD indication. Endpoints are echocardiography and freedom from device complications. MIRACLE ICD The MIRACLE ICD trial was a double blind, parallel arm, randomized controlled trial that compared BiV pacing with an active ICD (InSync ICD) against no pacing with an active ICD in patients with NYHA II- IV HF and an ICD indication. Except for the ICD indication, the patient inclusion criteria and study design were similar to that previously reported in the MIRACLE trial. The indication for an ICD at study entry was an established indication as stated in the American College of Cardiology/American Heart Association guidelines for implantation of cardiac pacemakers and antiarrhythmia devices (Gregoratos et al., 1998). Specifically, cardiac arrest due to ventricular tachyarrhythmia or ventricular fibrillation without a transient reversible cause or spontaneously sustained ventricular tachyarrhythmia or inducible ventricular fibrillation or sustained ventricular tachyarrhythmia (Young et al., 2003). Preliminary data were available from 6 months of follow-up. Implants were attempted in 638 patients, 570 had successful implants, and 555 were randomized. Two hundred and eighty-three patients received inactive pacing (106 NYHA II, 177 NYHA III/IV) and 272 patients received active pacing (85 NYHA II, 187 NYHA III/IV). For purposes of FDA approval, only data from NYHA III/IV were available (FDA, 2002). Reasons for implants not attempted in NYHA III/IV patients included: 4 not satisfy inclusion criteria 2 unable to obtain venous access 2 deaths 1 indication for conventional pacing 1 cancer diagnosis Reasons for NYHA III/IV patients receiving implants, but not undergoing randomization included: 4 patients unstable/pacing required 3 LV lead dislodgment 1 respiratory arrest 1 heart transplant 1 death 23

24 Preliminary data revealed that patients who were implanted with the InSync ICD for 6 months had an improvement in QOL (p=0.02) and NYHA class (p=0.01), however, there was no significant difference in the 6 min walk test (p=0.43) compared to controls (FDA, 2002). Functional improvement compared to the control group was not as dramatic as in MIRACLE trial which raises the question whether the addition of an ICD negatively impacts BiV pacing. There were no statistically significant differences in mortality, number of hospitalizations, or incidence of malignant ventricular arrhythmias between control and treatment group. As of June 26, 2002 Medtronic received FDA conditional approval for InSync ICD. Conditions that were recommended to Medtronic by the FDA advisory panel included: A 3 year evaluation of mortality and chronic system performance, including adverse clinical events on 1000 patients to assess long-term safety. Physicians are required to undergo training by the sponsor prior to implanting the system. In May 2003, the MIRACLE ICD study was published (Young et al., 2003). Three hundred and sixtynine patients were randomized; 182 assigned to receive ICD plus optimal medical treatment and 187 assigned to receive ICD plus biventricular pacing plus optimal medical treatment (Young et al., 2003). Of patients who completed the 6 month followup,162 were from the treatment arm and 165 from the control arm. As in the MIRACLE study (Abraham et al., 2002), the 3 primary efficacy endpoints were NYHA functional class, quality of life score, and distance covered during the 6 minute walk test at 6 months. Similar to the preliminary data, patients who were implanted with the InSync ICD for 6 months had an improvement in QOL (p=0.02) and NYHA class (p=0.01), however, there was no significant difference in the 6 min walk test (p=0.36) compared to controls. Similar to the preliminary results, no significant differences were observed in secondary endpoints including LV size or function, overall HF status, survival, and rates of hospitalization. Similar to the MIRACLE study, the MIRACLE ICD trial was not designed or powered to detect a mortality or morbidity difference between control and treatment groups and the follow-up period was relatively short (6 months). Cardiac Resynchronization Meta-Analysis (Bradley et al., 2003) Immediately after completion of this report (January, 2003), a meta-analysis of cardiac resynchronization therapy was published (Bradley et al., 2003). A review of the meta-analysis was undertaken and added to the report. Bradley et al. (2003) conducted a meta-analysis of cardiac resynchronization and death from progressive heart failure. Inclusion criteria consisted of studies that reported death, hospitalization for heart failure, or ventricular arrhythmia as outcomes. To assess ventricular arrhythmia, data derived from trials using ICDs were used. No other inclusion criteria were reported. Studies were excluded if another report with more complete and/or updated data was available from the same trial or if a report concerned research design only with no available mortality, hospitalization, or ventricular arrhythmia outcomes. Bradley et al. (2003) stated they focussed their analysis on the chronic effects of cardiac resynchronization, therefore, the authors excluded trials in which follow-up during the randomized portion of the study was < 3 months. Of 6,883 potentially relevant reports initially identified, 11 reports of 4 randomized trials with 1,634 total patients were included in the meta-analysis. The RCTs that were included were two BiV pacemaker studies [MIRACLE trial (Abraham et al., 2002) and MUSTIC (Cazeau et al., 2001)]; and two unpublished 24

25 studies that examined the combined BiV/ICD device [CONTAK CD and InSync ICD]. Unpublished documents were identified from the FDA website that catalogues device approvals. The patient characteristics were different among the 4 combined studies. Patients with conventional ICD indications (1998 ACC/AHA Guidelines) were included in the CONTAK CD and InSync ICD study, but were excluded from MIRACLE and MUSTIC trials. Baseline β blocker use was variable between the 4 trials and ranged from 28% in MUSTIC to 60% in InSync ICD. The NYHA functional class of the patients in each of the trials was III-IV for MIRACLE, III for MUSTIC, and II-IV for CONTAK CD and InSync ICD. In the CONTAK CD study, 54 of the 490 randomized patients underwent LV lead insertion via thoracotomy. The remaining patients in CONTAK CD, MIRACLE, and InSync ICD received transvenous LV leads. Single blinding was used in the MUSTIC trial, and double blinding was used in the remaining 3 studies. Total hospitalization was reported by 2 of the 4 trials for patients with planned 6 month follow-up (InSync ICD and MIRACLE). Follow-up in the included trials ranged from 3-6 months. Pooled data from the 4 selected studies (BiV and combined BiV/ICD) revealed that cardiac resynchronization was associated with a reduction in death from progressive heart failure relative to controls, odds ratio (OR) 0.49; (95% CI ). Based on data from 3 trials (InSync ICD trial excluded, reason not stated), the combined endpoint of death from progressive HF or cardiac transplantation yielded an OR of 0.41; 95% CI Cardiac resynchronization was not associated with a statistically significant effect on non-heart failure mortality (OR 1.15; 95% CI ) or all cause mortality (OR 0.77; 95% CI ). Based on 3 studies (InSync ICD, CONTAK CD, and MIRACLE), cardiac resynchronization was associated with reduced hospitalization for HF (OR 0.71; 95% CI ). MUSTIC was excluded because data were reported as numbers of hospitalizations, not numbers of different patients hospitalized. Among patients with ICDs (CONTAK CD and InSync ICD), cardiac resynchronization was not associated with a statistically significant reduction in patients experiencing VT or VF (OR 0.92; 95% CI ). Sensitivity analyses revealed the effect of changing various assumptions on the association between BiV or BiV/ICD pacing and reduced mortality from HF: NYHA baseline class II-IV III-IV BiV vs. Combined BiV/ICD BiV Combined BiV/ICD Analysis with all studies except: CONTAK CD InSync ICD MIRACLE MUSTIC *Not statistically significant. No. of Trials No. of Patients Death from Progressive Heart Failure OR (95% CI) 0.49 ( ) 0.51 ( )* 0.40 ( )* 0.53 ( )* 0.51 ( )* 0.42 ( ) 0.53 ( )* 0.49 ( ) When NYHA class II patients were excluded from the analysis, combined BiV and BiV/ICD pacing was not associated with a statistically significant reduction in death from progressive HF. This is important since the target group for BiV and/or combined BiV/ICD pacing is patients with NYHA class III-IV. 25

26 Bradley et al. (2003) discussed how the unpublished reports that were included in the analysis had previously undergone scrutiny by the FDA. Conditions of FDA approval for the Medtronic InSync BiV pacing system referenced by Bradley et al. (2003) also included 12 month mortality data and a 3-year evaluation of mortality, particularly sudden cardiac death and chronic lead performance including electrical performance and adverse clinical events on 1,000 patients (FDA, 2001). The FDA expects that 1,500 patients will need to be enrolled in the 3 year study to allow for patient drop out and insure 1,000 patients are followed for the full 3 years. The CONTAK CD and InSync ICD also have similar conditions of approval (FDA, 2002). When outcomes were stratified for patients receiving BiV and the combined BiV/ICD separately, there was no statistically significant reduction in death from progressive HF for either device. Of note, one group of patients had indications for a BiV/ICD and the other group did not (BiV alone). It is arguable whether these two patient groups receiving different devices (for different indications) can be combined to determine a risk estimate. Bradley et al. (2003) state the point estimate of the OR of death from progressive heart failure for ICD patients was similar to the OR for pacemaker patients. There is no discussion about statistical significance. Bradley et al. (2003) state that upon excluding individual trials, the point estimates for the OR changed very little and ranged from 0.42 to Therefore no single study had a major impact on the point estimate of the pooled OR. There is no mention of the change in statistical significance. Analysis of all studies except the CONTAK CD trial produced an OR that was not statistically significant [OR 0.51 ( )], and upon excluding the MIRACLE trial the summary statistic was not significant 0.53 ( ). When the InSync ICD trial was excluded from analysis, the summary statistic was statistically significant [OR 0.42 ( )]. Bradley et al. (2003) analyzed the effects of reclassifying 8 deaths originally classified as cause unknown or pending by the trial events committee (the unpublished CONTAK CD and InSync ICD trials). Four deaths were among patients randomized to cardiac resynchronization on and four deaths were among patients randomized to cardiac resynchronization off. The authors subsequently calculated what the summary statistic would be if: all 8 deaths were due to progressive HF [0.55 ( )]; only the 4 deaths in the on group were due to progressive HF [0.63 ( )]; and if only the 4 deaths in the off group were due to progressive HF [0.43 ( )]. A sensitivity analysis was also performed for all-cause mortality and results were as follows: NYHA baseline class II-IV III-IV BiV vs. Combined BiV/ICD BiV Combined BiV/ICD Analysis with all studies except: CONTAK CD InSync ICD MIRACLE MUSTIC *Not statistically significant. No. of Trials No. of Patients Death from All Causes OR (95% CI) 0.77 ( )* 0.81 ( )* 0.76 ( )* 0.79 ( )* 0.82 ( )* 0.74 ( )* 0.79 ( )* 0.75 ( )* Bradley et al. (2003) state that, as with death from progressive heart failure the point estimates for the OR of death from all causes were stable under a range of assumptions and in all cases favoured cardiac resynchronization. The lack of statistical significance for all the point estimates for death from all causes was not discussed by the authors. 26

27 Limitations to this meta-analysis include: The calculation of chronic mortality risk estimates using data from a 3-6 month follow-up. Lack of general discussion of the statistical significance or insignificance of various risk estimates. Uncertainty as to why a reduced death from progressive HF did not translate into a statistically significant improvement in death from all causes. Initial inclusion of patients with NYHA class II HF. When patients with NYHA class III and IV (severe HF) only were included, the risk estimate for death from progressive heart failure and death from all causes was not statistically significant. It is unknown if there are any treatment interactions between cardiac resynchronization devices and ICDs or β blockers. Lack of discussion of the conditions of the device approval by the FDA. Studies within the meta-analysis required a different baseline QRS interval for inclusion in the trial (CONTAK CD, >120 ms; InSync ICD, >130 ms; MIRACLE, >130 ms; MUSTIC, >150 ms). A definitive, consistently applied baseline QRS interval needs to be established. 27

28 Economic Analysis Literature Review This review was unable to identify any studies that formally assessed the cost-effectiveness of BiV (or combined BiV/ICD) pacemakers compared to an alternate therapy. However, one of the outcomes of the ongoing CARE HF trial is a health economics analysis. The lack of a long-term follow-up makes conclusive evaluation of cost-effectiveness difficult. Procedures performed secondary to pacemaker lead or generator complications increase the cost of treatment. Patients who receive the device would still continue on pharmacotherapy after implantation. The cost of a pacemaker system increases with its degree of complexity and sophistication. The cost of a dual-chamber pacemaker system exceeds that of a single chamber system due to the cost of the generator (additional $1000 US), the second lead (approximately $900 US), additional implantation time and supplies as well as additional follow-up (Gregoratos et al., 2002). The implant costs and complication rate of dual chamber pacemakers also exceed those of single chamber pacemakers. Some pacemaker models offer more extensive diagnostics than others, at a cost premium. Approximately 16% of pacemaker implantations are for replacement of generators (Gregoratos et al., 2002). Of those, 76% are replaced because the batteries have reached end of service. Expert programming of pacemaker generators can have a major impact on longevity, prolonging the device by an average of 4.2 years (Crossley et al., 1996). However, there are constraints on the useful life of a pacemaker generator. For example, battery drain not directly related to pulse generation and the limited life expectancy of many pacemaker recipients (Gillis et al., 1996). The reuse of explanted pacemakers may contribute to the cost-effectiveness of cardiac pacing. A Canadian review (MacGregor, 1992) and a retrospective case-control study from Sweden (Linde et al., 1998) reported safety and cost savings of selective pacemaker resuse. In a small (n=16), uncontrolled Swedish study, Braunschweig et al. (2000) assessed whether BiV pacing affected both the total and heart failure related hospital days in severe heart failure patients who were eligible for BiV. In Sweden, health care expenditures for heart failure account for nearly 2% of the health care budget out of which 65-75% are related to hospital care. Inclusion criteria consisted of patients recruited from a HF clinic: NYHA class III-IV despite optimal drug treatment Clinically stable at implantation and no change of drug treatment allowed for at least 1 month prior to operation Left ventricular ejection fraction <40% QRS interval >150 ms; for patients who had been previously paced the QRS interval had to be >200 ms No further description was provided regarding previously paced patients (e.g., type of pacemaker, indication for pacing). Exclusion criteria consisted of: Unstable angina Need for revascularization CABG or PTCA performed within the last 6 months MI within last 3 months Traditional indication for a pacemaker or ICD Medication for heart failure was maintained unchanged over the study period except for diuretics which were adjusted as clinically needed. Patients were followed up at the outpatient clinic after 1, 6, and 12 months. 28

29 The need for hospitalizations, all cause and heart failure related hospital days were monitored and comparisons were based on the same follow-up period after as before the pacemaker implantation in each individual patient for a maximum of 1 year. The hospital records were reviewed to determine the exact cause and duration of the hospital stays. Pacemaker related hospitalizations and hospital days following the primary implantation of the BiV pacemaker were monitored separately. When a patient was hospitalized due to HF as the primary diagnosis, with a concomitant pacemaker related problem, an estimate was made that of the duration of hospitalization that related to each of these two reasons. The estimation of all costs were made in collaboration with the hospital administration. Sixteen patients were enrolled and successfully implanted and the mean follow-up time was (mean+sd) days. No patient was lost to follow-up. Two patients died at 120 and 224 days after implantation due to pneumonia following a hip fracture and progression of HF. The mean duration of HF prior to inclusion in the study was years. Patients were hospitalized days for implantation. There were 40 and 9 hospital days related to pacemaker implantation and pacemaker related complications respectively. Complications occurred in 3 patients and included LV lead dislodgement in 2 cases, and hematoma in the pacemaker pocket in 1 subject. The following were the reported total and HF related hospital days and hospitalizations (combined for all patients): Type of Hospital Care Hospital days before BiV Hospital days after BiV Hospitalizations before BiV Hospitalizations after BiV Total 253 (median 10) 45 (median 0) 42 (median 1.5) 8 (median 0) HF related 183 (median 9.5) 39 (median 0) 31 (median 1.5) 7 (median 0) The estimated costs for hospital care, pacemaker implantation, and follow-up and complications were as follows: Costs in Euro Costs/patient Hospital days (total number) Before BiV (253) 148,823 9,301 After BiV (45) 26,471 1,654 Difference 122,353 7,647 Pacemaker related costs Implantation procedure 7, Pacemakers 62,447 3,903 Standard leads 9, Coronary sinus leads 14, Hospital days for implantation (n=40) 20,004 1,250 Pacemaker follow-up (n=16) 7, Pacemaker related complications Reoperation (n=4) 2,000 NA Hospital days (n=9) 4,501 NA Coronary sinus lead (n=1) 882 NA Total Costs for Pacing 128,295 8,019 NA: not applicable Braunschweig et al. (2000) state the calculation was based on a daily cost estimation of 588 Euro per hospital day for heart failure. The authors did not provide an explanation as to why information regarding costs/patient for pacemaker related complications was not applicable. Any interpretation of this study is severely limited due to lack of a control group with a small, uncalculated sample size, a very wide QRS interval, and an extremely limited discussion of any economic analysis. 29

30 Eligible Population The prevalence of HF is 1%. This increases to 10% in people over 80 years of age (Farwell et al., 2000). Farwell et al. (2000) reports the incidence is 5 cases per thousand per annum. Recently, Cowie et al. (2001) reported the incidence of CHF to be 0.02 cases per 1000 population per year for those aged years, rising to 11.6 in those aged >85 years. In the US, approximately 5 million people have HF, and between 400,000 and 700,000 new cases are diagnosed annually (Abraham et al., 2000). Moller et al. in a conference abstract (2001) evaluated how many patients with severe heart failure (NYHA III/IV) were eligible for BiV pacing. Based on the size of the referral population, and the assumption that the findings were representative for all 2,531 patients with an ejection fraction <35%, it was calculated that a maximum of 145 patients per million inhabitants per year fulfilled the criterion of NYHA III/IV, ejection fraction <35%, and QRS >120 ms. This number was reduced to 51 patients if the QRS interval was set to >150 ms. The National Horizon Scanning Centre (2001) reported the device with the associated leads and delivery systems costs between 3,000-6,000. Follow-up of these patients was stated as being not much more time consuming than conventional pacing devices. Currently, it is not known how long the BiV pulse generator and leads will last. Some estimates are approximately 5-6 years, however, this needs to be considered with the remaining life expectancy of this particular patient group (NHS, 2001). Even though there are several trials with mortality as the primary endpoint, severe HF causes major health care costs and reduced quality of life, therefore, benefit may be sufficient without demonstrable effects on mortality (NHS, 2001). However, this would depend on accurate and restrictive selection of patients. NHS (2001) has estimated that implantation and follow-up costs for 20 patients are approximately 100, ,000, and costs for each 1,000 patients are approximately 5M- 7.5M. Using prevalence figures for UK people >65 years of age (men 40/1000; women 30/1000), and assuming 30% are currently in NYHA III/IV, NHS estimated that people in the UK could be eligible for BiV pacing. Prospective data in large patient cohorts with sufficient follow-up duration are need to determine the true number of patients that may benefit from the combined BiV/ICD device. Most studies of HF have described the major cause of sudden death as arrhythmic (Uretsky and Sheahan, 1997). This has led to interest in the potential effect of ICDs in the primary prevention of sudden cardiac death in HF (Uretsky and Sheahan, 1997). Stellbrink et al. (1999) speculated that a combined BiV/ICD device may lead to a reduction in sudden death (ventricular tachyarrhythmia) in HF patients. The retrospective analysis by Stellbrink et al. (1999) indicated that 28/384 (7.3%) patients who were implanted with an ICD fulfilled eligibility criteria for BiV pacing if NYHA class III patients with QRS >120 ms were considered candidates. NYHA IV patients were not considered in the analysis. Several studies are underway that are evaluating the efficacy of BiV/ICD in chronic HF and whether this therapy improves mortality. Cleland et al. (2002) estimate: Approximately 1% of population will have heart failure (10,000/million) Assume 20% with HF would remain moderately/severely symptomatic 20% have QRS>120 ms and 10% have QRS>150 ms Therefore, according to Cleland et al., per million may be candidates for intervention. Farwell (2000) estimated 3-10% of patients ( patients per million population per year) hospitalized for HF would be candidates. Approximately 13,000 patients/year hospitalized in Ontario with HF (Tu and Zhang, 1999). Using the estimation of Cleland et al. (2002): 30

31 20% of HF patients would still be moderately/severely symptomatic, n=2600 [20% of moderate/severe HF patients will have QRS>120 ms, n=520 10% of moderate/severe HF patients will have QRS>150 ms, n=260] Therefore, patients/year may be candidates for BiV in Ontario. Tu et al. (1999) provided numbers of patients aged 20 years and over hospitalized for congestive heart failure in Ontario. Data for LVEF in these patients was not reported. For the fiscal year, the total number of men and women >20 years old hospitalized for CHF was 12,938 and mortality rate was 32.0/100 CHF patients. The mean Ontario 30-day mortality rate for CHF patients >20years old, 1994/ /97 was 11.6%; the mean Ontario one year mortality rate was 33.0%. For men and women combined >20 years of age, between 1996/97, there were 277 hospitalizations for CHF/100,000 population. The actual length of stay for CHF cases in Ontario for was 7.33 days (number of eligible cases was 20,449). The adjusted length of stay (hospitalization not including days coded as alternate level of care or days above 97.5 percentile) was 7.29 days. Furosemide was used alone in about 25% of CHF patients in Ontario. >80% of CHF patients are discharged home with ACE inhibitors, however, at other centres <50% of all patients receive ACE inhibitors. This raises the question whether appropriate medical control is optimized in all patients with CHF in Ontario, especially since ACE inhibitors are currently recommended as first line therapy for the treatment of HF in Canada by the 1994 Congestive Heart Failure Consensus guidelines of the Canadian Cardiovascular Society. Jong et al. (2002) recently reported that the benefits of enalapril administration observed during active treatment of patients with LV dysfunction were sustained or amplified after termination of the study for a further decade. The full survival benefit of enalapril emerged only after several years of follow-up. Tu et al. (1999) acknowledged that β-blockers, and angiotensin II antagoinst drug (e.g., losartan) use in HF patients were not analyzed because major studies supporting their use were published after the time frame of their analysis. The β blocker carvedilol was shown to improve survival and decrease the need for hospitalization in HF patients (Packer et al., 1996). The Evaluation of Losartan in the Elderly (ELITE) study suggests losartan may be superior to captopril (an ACE inhibitor) in HF treatment (Pitt et al., 1997). The Digitalis Investigation Group (1997) revealed that treatment of HF patients with digoxin, a traditional HF drug, decreased hospitalizations for patients with chronic HF, however digoxin treatment had no effect on survival. Pharmacotherapy should be explored and optimized in all drugs used to treat chronic HF, as higher usage rates will likely decrease the need for hospitalization and improve long term survival. 31

32 Summary and Conclusion Summary and findings on effectiveness and cost-effectiveness Randomized controlled trials [Level 1 evidence] reported improved cardiac function and quality of life up to 6 months of BiV treatment, therefore there is some evidence that patients in ventricular dyssynchrony, and who are still symptomatic after medication may benefit from this technology. There is no evidence regarding the long term effectiveness of this device. Other studies have been prospective, yet, nonrandomized, not double-blind, uncontrolled and/or a limited/not calculated sample size. Short-term studies have focussed on acute hemodynamic analyses. There is some variation in clinical characteristics among patient populations enrolled in these trials. The majority of patients treated have been stable on medical therapy, NYHA class III and IV, QRS duration > ms, ejection fraction<30-35%, no bradycardia indications and no atrial fibrillation. The majority of HF patients in the trials were NYHA III. Implantation and maintenance of a resynchronization device are associated with risks that are greater than those of a conventional RV pacing device. In some patients, efforts to implant have been unsuccessful or were accompanied by dissection or perforation of the coronary sinus or cardiac vein. Serious complications included complete heart block, hemopericardium and cardiac arrest. LV lead dislodgment can occur which requires lead repositioning or replacement. Much uncertainty still exists in biventricular pacing for HF: There are a small number of completed trials evaluating BiV pacing in chronic HF patients. It is not known if BiV pacing reduces symptoms or outcomes in patients 3-9 months after first diagnosis of HF. The length of follow-up has been of a short duration. Long-term benefits and effects on mortality are unknown. Identification of patients who will not improve clinically following resynchronization therapy. Soft subjective nature of many of the endpoints (symptoms, exercise capacity, quality of life); paucity of harder endpoints (LVEF, QRS, mortality, implant success, LV lead complication rates). Difficulty in full ability to blind many of the trials (ECG can unblind an investigator). Lack of economic analyses. Patients in the trials had regular normal sinus rhythm, and patients with atrial fibrillation were generally excluded to allow for atrial synchronization. As HF worsens, the incidence of atrial fibrillation increases, and currently patients with atrial fibrillation would not be eligible for BiV pacing. The role of combination ICD/BiV devices in HF patients. The optimal site for the LV lead is yet to be determined. LV lead technology will need to be improved. The baseline QRS interval that is necessary for improvement with BiV pacing needs to be determined. Should physicians currently able to implant defibrillators be approved to begin implanting BiV pacemakers, and what training should they receive? It is not known if the combined use of a BiV/ICD is associated with reduction in mortality. There are no published large RCTs available evaluating the use of the combined BiV pacemaker/icd device in patients. However, there are ongoing or recently completed trials in progress, for both BiV pacemakers and combined biventricular pacemaker/icd devices. For both of these devices, implantation procedures are more complex than either the implantation of traditional pacemakers or ICDs alone. These devices would need to be implanted in select centres to maintain adequate patient volume as well as further refine the surgical technique as the technology evolves. 32

33 Pharmacotherapy (ACE inhibitors, β blockers, digoxin, spironolactone, diruetics) must be exhaustively explored and optimized in this patient group. Additional treatment strategies for HF include patient compliance programs, postdischarge follow-up, and specialized HF clinics. This review was unable to identify any studies that formally assessed the cost-effectiveness of BiV (or combined BiV/ICD) pacemakers compared to an alternate therapy. However, one of the outcomes of the ongoing CARE HF trial is a health economics analysis. The lack of a long-term follow-up makes conclusive evaluation of cost-effectiveness difficult. Conclusion There is sufficient Level 1 evidence of effectiveness for BiV in patients with chronic severe NYHA III/IV HF, LVEF<35%, QRS interval >120ms, normal sinus rhythm, and refractory to exhaustive drug therapy. Currently, due to limited follow-up in studies evaluating biventricular pacemakers (<6 months), there is insufficient evidence of long-term effectiveness and cost-effectiveness of this device in the treatment of patients with chronic NYHA III/IV HF, a wide QRS complex (>120 ms), low LVEF (<35%), contraction dyssynchrony in viable myocardium, and normal sinus rhythm. To date, there is insufficient evidence to support the routine use of combined ICD/BiV devices in patients with chronic NYHA III/IV HF, QRS >120 ms, LVEF <35%, contraction dyssynchrony in viable myocardium and normal sinus rhythm. Several large randomized studies are being carried out or have recently been completed which should provide new evidence. The results of this assessment will need to be updated once results from these trials have been fully reported. Existing guidelines regarding the utilization of the technology The American College of Cardiology/American Heart Association (ACC/AHA) Taskforce on Practice Guidelines for the evaluation and management of chronic heart failure in the adult does not recommend BiV pacing for heart failure patients (Hunt et al., 2001). Biventricular pacing is considered to be under active investigation and until the results of definitive trials are available, this intervention cannot be recommended for use in patients with heart failure. Hunt et al. (2001) also noted that the long term effects of cardiac resynchronization are unknown but are being evaluated in several studies. The American College of Cardiology/American Heart Association (ACC/AHA) Taskforce on Practice Guidelines has provided updated guidelines for implantation of pacemakers and antiarrhythmia devices expressed as follow (Gregoratos et al., 2002): Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial. Class II: Conditions for which there is conflicting evidence and /or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa: Weight of evidence/opinion is in favour of usefulness/efficacy. Class IIb: Usefulness/efficacy is less well established by evidence/opinion. Class III: Conditions for which there is evidence and/or general agreement that a procedure/treatment is not useful/effective and in some cases may be harmful. The committee also ranked evidence supporting current recommendations with the weight of evidence ranked as: Level A data derived from multiple RCTs involving a large number of patients. Level B data derived from a limited number of trials involving a comparatively small number of patients or from welldesigned data analyses of nonrandomized studies or observational data registries. Level C data derived from a consensus of experts. 33

34 The ACC/AHA pacing recommendations for dilated cardiomyopathy and BiV pacing were Class IIa: Biventricular pacing in medically refractory, symptomatic NYHA class III or IV patients with idiopathic dilated or ischemic cardiomyopathy, prolonged QRS interval (> 130 ms), LV end-diastolic diameter >55 mm, and end ejection fraction <35%. (Level of Evidence: A) In summary, the ACC/AHA considers that the weight of evidence/opinion for BiV pacing is in favour of usefulness/efficacy, and this is supported by data from multiple RCTs involving a large number of patients. 34

35 References Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: the multicenter InSync randomized clinical evaluation (MIRACLE). Journal of Cardiac Failure. 2000;6: Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL et al. Cardiac resynchronization in chronic heart failure (MIRACLE). New England Journal of Medicine. 2002; 346: Auricchio A. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The pacing therapies for congestive heart failure study group. The Guidant congestive heart failure research group. Circulation. 1999;99: Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Mortensen P, Klein H for the PATH-CHF Study Group. The pacing therapies for congestive heart failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. American Journal of Cardiology. 1999;83:130D-135D. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Huth C, Schondube F, Wolfhard U, Bocker D, Krahnefeld, Kirkels H, Pacing Therapies in Congestive Heart Failure (PATH-CHF) Study Group. Long term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. Journal of the American College of Cardiology. 2002;39(12): Auricchio A. Pacing therapy for congestive heart failure (PATH-CHF)II. Presented at the North American Society of Pacing and Electrophysiology (NAPSE) 23 rd Annual Scientific Sessions. May, Blanc JJ, Etienne Y, Gilard M, Mansourati J, Munier S, Boschat J, Benditt DG, Lurie KG. Evaluation of different ventricular pacing sites in patients with severe heart failure: results of an acute hemodynamic study. Circulation. 1997;96: Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, Kass DA, Powe NR. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. Journal of the American Medical Association. 2003;289: Braunschweig F, Linde C, Gadler F, Ryden L. Reduction of hospital days by biventricular pacing. European Journal of Heart Failure. 2000;2: Brecker SJD, Xiao HB, Sparrow J, Gibson DG. Effects of dual chamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet. 1992;340: Bristow MR, Feldman AM, Saxon LA, COMPANION Steering Committee and COMPANION Clinical Investigators. Heart failure management using implantable devices for ventricular resynchronization: comparison of medical therapy, pacing and defibrillation in chronic heart failure (COMPANION) Trial. Journal of Cardiac Failure. 2000;6(3): Cardiac Care Network of Ontario (CCN). Consensus Panel on Arrhythmia Management Procedures in Ontario. Final Report and Recommendations. October, Cazeau S, Leclercq C, Lavergne T, Walker, Varma C, Linde C, Garrigue,S, Kappenberger L, Haywood GA et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay (MUSTIC). New England Journal of Medicine. 2001;34: Cleland JGF, Daubert JC, Erdmann E, Freemantle N, Gras D, Kapennaberger FL, Klein W, Tavazzi L et al. The CARE-HF study (Cardiac Resynchronization in Heart Failure study): rationale, design and end-points. European Journal of Heart Failure. 2001:3:

36 Cleland JGF, Thackray S, Goodge L, Kaye G, Cooklin M. Outcome studies with device therapy in patients with heart failure. Journal of Cardiovascular Electrophysiology. 2002;13(Suppl 1):S Cowie MR, Wood DA, Coats AJS, Thompson SG, Poole-Wilson PA, Suresh V, Sutton GC. Incidence and aetiology of heart failure: a population based study. European Journal of Heart Failure. 1999;20: Crossley GH, Gayle DD, Simmons TW, Haisty WK, Bailey JR, Davis-O Brien K, Hammon JW, Fitzgerald DM. Reprogramming pacemakers enhances longevity and is cost effective. Circulation. 1996;94:II245-II247. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. New England Journal of Medicine. 1997;336: Farwell D, Patel NR, Hall A, Ralph S, Sulke AN. How many people with heart failure are appropriate for biventricular resynchronization? European Journal of Heart Failure. 2000;21: Food and Drug Administration (FDA). Medtronic InSync Biventricular Pacing System. PMA P Summary of Safety and Effectiveness Food and Drug Administration (FDA). Guidant CONTAK CD CRT-D System. PMA P Summary of Safety and Effectiveness Food and Drug Administration (FDA). Medtronic InSync ICD Dual Chamber Implantable Cardioverter Defibrillator with Cardiac Resynchronization Therapy. PMA P Summary of Safety and Effectiveness Gillis A, MacQuarrie DS, Wilson SL. The impact of pulse generator longevity on the long term costs of cardiac pacing. PACE. 1996;19: Gold MR, Zenaida F, Gottlieb SS, Fisher ML. Dual chamber pacing with a short atrioventricular delay in congestive heart failure: a randomized study. Journal of the American College of Cardiology. 1995; Gregoratos G, Cheitlin MD, Conhill A et al. ACC/AHA guidelines for implantation of cardiac pacemakers and antiarrhythmia devices: executive summary. Circulation. 1998;97: Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, Kerber RE, Naccarelli GV, Schoenfeld MH, Silka MJ, Winters SL. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee on Pacemaker Implantation) Available at Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: a reort of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure) American College of Cardiology Web site. Available at Jong P, Vowinckel E, Liu P, Gong Y, Tu JV. Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population based study. Archives of Internal Medicine. 2002;162: Jong P, Yusuf S, Rousseau MF, Ahn SA, Bangdiwala SI. Enalapril improves survival and life expectancy in patients with reduced left ventricular ejection fractions the extended studies of left ventricular dysfunction. European Society of Cardiology (ESC) Congress August 31-September 4, Berlin Germany. 36

37 Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation. 1999;99: Kerwin WF, Botvinick EH, O Connell JW, Merrick SH, DeMarco T, Chatterjee K et al. Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony. Jounral of the American College of Cardiology. 2000; 35: Kuhlkamp V, InSync 7272 ICD World Wide Investigators. Initial experience with an implantable cardioverterdefibrillator incorporating cardiac resynchronization therapy. Journal of the American College of Cardiology. 2002;39(5): Leclercq C, Kass DA. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. Journal of the American College of Cardiology. 2002;39: Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KKL, Murabito JM, Vasan RS. Long term trends in the incidence of and survival with heart failure. New England Journal of Medicine. 2002;347: Linde C, Gadler F, Edner M, Nordlander R, Rosenqvist M, Ryden L. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. American Journal of Cardiology. 1995;75: Linde CL, Bocray A, Jonsson H, Rosenqvist M, Radegran K, Ryden L. Reused pacemakers as safe as new? A retrospective case-control study. European Heart Journal. 1998;19: Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, McKenna W, Fitzgerald M, Deharo JC, Alonso C, Walker S, Braunschweig F, Bailleul C, Daubert, Multisite Stimulation In Cardiomyopathies (MUSTIC) Study Group. Long term benefits of biventricular pacing in congestive heart failure: results from the multisite stimulation in cardiomyopathy (MUSTIC) study. Journal of the American College of Cardiology. 2002;40(1): Lozano I, Bocchiardo M, Achtelik M, Gaita F, Trape HJ, Daoud E, Hummel J, Duby C, Yong P et al. Impact of biventricular pacing on mortality in a randomized crossover study of patients with heart failure and ventricular arrhythmias. Pacing and Clinical Electrophysiology. 2000;23: McGregor M. The reuse of cardiac pacemakers. Canadian Journal of Cardiology. 1992;8: Moller M for the Diamond Study Group. How many patients with severe congestive heart failure are eligible for biventricular pacing? (Abstr). Abstract ID North American Society of Pacing & Electrophysiology (NASPE), Boston, MA National Horizon Scanning Centre. Ventricular pacing and resynchronization for heart failure. New and Emerging Technology Briefing. University of Birmingham. January Naylor CD, Slaughter PM (eds). Cardiovascular Health and Services in Ontario: An ICES Atlas. Toronto: Institute for Clinical Evaluative Sciences Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. New England Journal of Medicine. 1996;334: Pappone C, Rosanio S, Oreto G, Tocchi M, Gulletta S, Salvati A, et al. Cardiac pacing in heart failure patients with left bundle branch block: impact of pacing site for optimizing left ventricular resynchronization. Italian Heart Journal. 2000;1: Perego GB, Chianca R, Facchini M, Balla E, Negretto M, Vicini I, et al. Nonsynchronous versus synchronous biventricular stimulation may induce further increase in ventricular systolic performance (Abstr). PACE. 2001;24:

38 Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I et al. Randomized trial of losartan versus captopril n patients over 65 with heart failure (Evaluation of Losartan in the Elderly ). Lancet. 1997;349: Sack S, Franz R, Dagres N, Oldenburg O, Herrmann J, Golles A, Erbel R. Can right sided atrioventricular sequential pacing provide benefit for selected patients with severe congestive heart failure? American Journal of Cardiology. 1999;83:124D-129D. Saxon LA, Boehmer JP, Hummel J, Kacet S, De Marco T, Naccarelli G et al. Biventricular pacing in patients with congestive heart failure: two prospective randomized trials. American Journal of Cardiology. 1999;83:120D-123D. Stellbrink C, Auricchio A, Diem B et al. Potential benefit of biventricular pacing in patients with congestive heart failure and ventricular tachyarrhythmia. American Journal of Cardiology. 1999;83: Stellbrink C, Auricchio A, Butter C, Sack S, Vogt J, Bocker D, Block M, Kirkels H, Ramdat-Misier A, for the PATH-CHF II Study Group. Pacing therapies in congestive heart failure II study. American Journal of Cardiology. 2000;86(suppl):138k-143k. Thackray S, Coletta A, Jones P, Dunn A, Clark AL, Cleland JGF. Clinical trials update: highlights of the scientific sessions of heart failure A meeting of the working group on heart failure of the European Society of Cardiology. CONTAK-CD, CHRISTMAS, OPTIME-CHF. European Journal of Heart Failure. 2001;3: Tu JV, Austin P, Rochon P, Zhang H. Secondary prevention after acute myocardial infarction, congestive heart failure and coronary artery bypass graft surgery in Ontario. In Naylor CD, Slaughter PM (eds). Cardiovascular Health and Services in Ontario: An ICES Atlas Toronto: Institute for Clinical Evaluative Sciences. 1999: Tu JV and Zhang H. Congestive heart failure outcomes in Ontario. In Naylor CD, Slaughter PM (eds). Cardiovascular Health and Services in Ontario: An ICES Atlas Toronto: Institute for Clinical Evaluative Sciences. 1999: Uretsky BF, Sheahan RG. Primary prevention of sudden cardiac death in heart failure: will the solution be shocking? Journal of the American Journal of Cardiology. 1997;30: Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD trial. Journal of the American Medical Association. 2003;289: Zardini M, Tritto M, Bargiggia G, Forzani T Santini M, Perego GB, Bocchiardo M, Raviele A, Salerno-Uriarte JA on behalf of the InSync Italian Registry Investigators. European Heart Journal Supplements. 2000;2(Suppl J):J6- J22. 38

39 APPENDIX Figure 1. Transvenous approach to cardiac resynchronization. From: Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: the multicenter InSync randomized clinical evaluation (MIRACLE). Journal of Cardiac Failure. 2000;6: