Dr. Imran Ahmed DM (Cardiology) Kolkata, India

Prevalence and Incidence rates are alarmingly high - Increasing HF hospitalizations - Increasing HF-attributable deaths - Spiraling cost of HF-care Worldwide 23 million people affected Prevalence increases with age (6-10% in > 65 yrs)

Heart Failure in the U.S - A Growing Public Health Problem. Approximately 5 million patients in this country have HF (1.5 2% of population) Over 550,000 patients are diagnosed with HF for the first time each year Primary reason for 12 to 15 million office visits and 6.5 million hospital days each year In 2001, nearly 53,000 patients died of HF as a primary cause

HF is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood [ACC focused update 2009]

Stages of Heart Failure At Risk for Heart Failure: STAGE A High risk for developing HF STAGE B Asymptomatic LV dysfunction Heart Failure: STAGE C Past or current symptoms of HF STAGE D Refractory / End-stage HF

Stages of Heart Failure Designed to emphasize preventability of HF Designed to recognize the progressive nature of LV dysfunction

Stages of Heart Failure COMPLEMENT, DO NOT REPLACE NYHA CLASSES NYHA Classes - shift back/forth in individual patient (in response to Rx and/or progression of disease) Stages - progress in one direction due to cardiac remodeling

Heart Failure as a Progressive Disorder Principal manifestation of progression change in the geometry and structure of the LV chamber dilation and/or hypertrophy becomes more spherical The collective process referred to as cardiac remodeling

Outcomes of Cardiac Remodeling Patients die before developing symptoms (in Stage A or B) Patients develop symptoms controlled by treatment Patients die of progressive/refractory HF *Sudden death can interrupt this course at any time

Refractory Heart Failure - Definition Persistence of symptoms that limit daily life (functional class III or IV of the New York Heart Association [NYHA]) despite optimal previous treatment with drugs of proven efficacy for the condition, i.e. ACE inhibitors, angiotensin II receptor antagonists (ARB), diuretics, digoxin, beta-blockers and nitrate-hydralazine (esp. in blacks) [Nohria A, JAMA 2002;287:628-40 and D. Feldman, Clin. Cardiol. 2008;31, 7, 297301]

Terminal Heart Failure Terminal HF is the last step in refractory HF, where there is a very poor response to all forms of treatment (by definition, heart transplantation is no longer indicated), with serious deterioration of quality of life - both physical and emotional, frequent hospitalization and life expectancy less than 6 months. [Rev Esp Cardiol 2004;57(9):869-83]

Refractory Heart Failure - Definition Corresponds to stage D heart failure - refers to patients with advanced structural heart disease and severe signs of HF at rest who are candidates in the absence of contraindications for other specialized interventions such as heart transplantation ventricular remodeling implantation of mechanical assistance devices intravenous inotropic drugs

Interventional Heart Failure Therapy Term coined by Daniel Burkhoff (2007) Vicious cycle of refractory HF - - progressive cardiovascular remodeling - deterioration of renal function - decreased exercise tolerance [Burkhoff D. SIS 2007 Yearbook;13:65-75]

Need for Interventional HF Therapy Even on max pharma therapy most patients exhibit - disease progression - repeated hospitalizations - ultimately succumb to their disease Evidence indicates that additional neurohormonal blockade may be detrimental The limit of neurohormonal and cytokine blockade in CHF may be reached Heart transplantation as a final treatment option also limited by the small number of donor hearts. [Mann DL. (RENEWAL). Circulation 2004;109:1594-1602]

Basis of Interventional HF Therapies Strengthening of cardiac contraction with cardiac contractility modulation Modification of ht rate with vagal nv stimulation Reduction of ventricular size with surgical ventricular restoration renal perfusion with targeted renal therapy fluid overload with ultrafiltration Improving cardiac output with continuous aortic flow augmentation (orqis) Reverse remodeling with ventricular assist devices [Burkhoff D. SIS 2007 Yearbook;13:65-75]

Use of electrical pulse generators to deliver an electric current to cardiac tissue ICDs & CRTs are the most important device-based treatment currently FDA approved for use in CHF ICDs shown to reduce mortality CRT shown to reduce symptoms and mortality Newer types under investigation - Cardiac Contractility Modulators (CCM) - Vagal Nerve Stimulation

Targets of Electrical HF Therapy Increased risk of ventricular arrhythmias Sudden death Intraventricular dyssynchrony Impaired cardiac contractility Unregulated sympathetic tone

Implantable Cardioverter Defibrillator Secondary prevention survivors of VF - documented haemodynamically unstable VT and/or VT with syncope, a LVEF of 40%, on optimal medical therapy, and with an expectation of survival with good functional status for 1 yr [ESC 2008, Class of recommendation I, level of evidence A] [Meta-analysis of AVID, CASH and CIDS studies. Eur Heart J 2000;21:20712078]

Implantable Cardioverter Defibrillator Primary prevention is recommended to reduce mortality in patients with non-ischemic dilated cardiomyopathy or ischemic LV dysfunction due to prior MI who are at least 40 days post-MI, have an LVEF 35%, in NYHA functional class II or III, receiving optimal medical therapy, and who have a reasonable expectation of survival with good functional status for 1 year [ESC 2008, Class of recommendation I, ICMP - level of evidence A DCM - level of evidence B]

ICD The Gender Bias! ICD therapy for the primary prevention of sudden cardiac death may not provide a mortality benefit to women with heart failure A recent meta-analysis of 5 large, RCTs including 934 women with HF revealed that primary prophylaxis with ICDs did not significantly decrease all-cause mortality (HR, 1.01; 95% CI, 0.76-1.33) Future guideline recommendations for the use of ICDs in women is of ongoing interest [Ghanbari H, Arch Intern Med.2009;169(16):1500-1506]

Cardiac Resynchronization Therapy

CRT - Recommendations

CRT - Issues Impact on symptoms and exercise tolerance All RCTs have confirmed a significant alleviation of symptoms and increase in exercise capacity conferred by CRT. On average, NYHA function class decreased by 0.50.8 points The 6 min walk distance increased by 20% Peak oxygen consumption increased by 1015% The functional benefits and quality of life improvements were sustained 1. Cleland JG. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:15391549 2. Linde C, MUSTIC study. J Am Coll Cardiol 2002;40:111118. 3. Cleland JG, The CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase. Eur Heart J 2006;27:19281932.

CRT - Issues Impact of CRT on morbidity In the COMPANION trial, CRT with or without an ICD, lowered the combined endpoint of all-cause mortality and rehospitalization for HF by 3540%, mainly driven by the 76% lower rate of hospitalizations. In CARE-HF, CRT-P lowered the proportion of unplanned hospitalizations for worsening HF by 52%, and of unplanned hospitalizations for major cardiovascular events by 39%. 1. Bristow MR, Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:21402150. 2. Cleland JG, The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:15391549.

CRT - Issues Impact of CRT on mortality In COMPANION, CRT-D showed a significant decrease in all- cause mortality (RR reduction: 36%; P = 0.003), while the 24% RR reduction with CRT-P was nearly significant (P =0.059). In CARE-HF, (only CRT-P), a 36% RR reduction in the risk of death (P , 0.002) was observed after a mean follow-up time of 29 months. In the CARE-HF extension study, a RR reduction of 40% (P = 0.0001) was observed, mainly due to HF-related deaths 1. Bristow MR, Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:21402150. 2. Cleland JG, The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:15391549. 3. Cleland JG, The CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase. Eur Heart J 2006;27:19281932

CRT - Issues Impact of CRT on cardiac function & structure All RCTs have consistently shown up to 15% absolute reduction in LVEDD and up to 6% increase in LVEF following CRT The effect was significantly greater in patients with non- ischaemic than in those with ischaemic heart disease. These observations provide consistent evidence of a substantial, progressive, and sustained reverse remodelling effect conferred by CRT. 1. Gervais R. Surface electrocardiogram to predict outcome in candidates for cardiac resynchronization therapy: a subanalysis of the CARE-HF trial. Eur J Heart Fail 2009;11:699705

CRT - Issues Ambulatory patients in NYHA class IV COMPANION enrolled 217 NYHA class IV patients termed ambulatory patients Patients with no scheduled or unscheduled admissions for HF during the last month and with a life expectancy of 6 months. Time to all-cause mortality or first all-cause hospitalization was significantly improved by both CRT-P and CRT-D vs OMT No significant benefit was observed on all-cause mortality. Data support the use of CRT to improve morbidity (but not mortality) in ambulatory class IV patients. 1. Lindenfeld J. Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure. Circulation 2007;115:204212

CRT - Issues QRS morphology: LBBB vs RBBB Favourable outcome in CARE-HF was defined as freedom from death or major cardiovascular event Baseline typical LBBB pattern predicted a favourable outcome. By multivariable analysis, prolonged PR interval and right bundle branch block (RBBB) were the only predictors of non- favourable outcome. 1. Gervais R. Surface electrocardiogram to predict outcome in candidates for cardiac resynchronization therapy: a subanalysis of the CARE-HF trial. Eur J Heart Fail 2009;11:699705.

CRT - Issues CRT-D in patients with an indication for an ICD MIRACLE ICD and a large meta-analysis support the choice of a CRT-D in patients in NYHA class III/IV, with LVEF of 35%, QRS of 120 ms with a conventional indication for an ICD 1. Abraham WT. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation 2004;110:28642868. 2. Lam SK, Owen A. Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network meta-analysis of randomised controlled trials. Br Med J 2007;335:925

CRT - Beyond Current Guidelines CRT in Patients With Narrow QRS Complex CONQUEST (Congestive Heart Failure and QRS Duration: Establishing Prognosis) study, with 3,000 HF patients, showed that 42% of the patients had a QRS duration < 120 ms Echo studies have shown that 40% - 50% of HF patients with a narrow QRS complex may also exhibit LV dyssynchrony Echo predictors of response to CRT (small studies) - septal to lateral or opposing segment delay of 65 ms - standard deviation of time to peak tissue velocity >32 ms 1. Abraham J. Is echocardiographic assessment of dyssynchrony useful to select candidates for cardiac resynchronization therapy? Circulation: Cardiovascular Imaging. 2008; 1: 79-85. 2. Bommel V. CRT Beyond Current Guidelines . JACC; 56:10, 2010 Aug 31,75462

CRT in Narrow QRS Complex CRT in Patients With Narrow QRS Complex CONQUEST (Congestive Heart Failure and QRS Duration: Establishing Prognosis) study, with 3,000 HF patients, showed that 42% of the patients had a QRS duration < 120 ms Echo studies have shown that 40% - 50% of HF patients with a narrow QRS complex may also exhibit LV dyssynchrony Echo predictors of response to CRT (small studies) - septal to lateral or opposing segment delay of 65 ms - standard deviation of time to peak tissue velocity >32 ms 1 VO2 2 NYHA

CRT in Patients With Narrow QRS Complex ESTEEM-CRT & RethinQ Trials - no improvement in primary endpoints peak Vo2 or LVEF - significant improvement in 2 endpoint of NYHA class Limitations of ESTEEM-CRT and RethinQ - included few patients with limited follow-up (up to 6 months) - did not focus on rehospitalization and long-term survival Results from ESTEEM-CRT & RethinQ make the expansion of CRT to HF pts with narrow QRS complex currently unlikely Ongoing Echo-CRT trial with speckle tracking will determine whether CRT is an effective Rx modality in this specific group 1. Leon AR. Evaluation of CRT in Narrow QRS Patients With Mechanical Dyssynchrony From a Multicenter Study (ESTEEM-CRT). Paper presented at Heart Rhythm Society Congress; May 15, 2008; SanFrancisco, CA 2. Beshai JF. RethinQ. N Engl J Med 2007;357:246171

CRT - Beyond Current Guidelines CRT in patients with mild heart failure MIRACLE ICD II trial - 186 patients in NYHA class II with LVEF 130 ms and a Class I indication for an ICD At 6 months of follow-up, patients in the CRT-ON group had a greater reduction in LV diastolic & systolic volumes (p< 0.05) and significant improvement in NYHA class (p=0.05) Similar results reported by the CONTAK-CD trial, with significant reductions in LV dimensions

CRT - Beyond Current Guidelines CRT in patients with mild heart failure Results of CONTAK-CD and MIRACLE ICD II showed that LV reverse remodeling was a better predictor of long-term survival than clinical improvement Effect - 2 large clinical trials were conducted to investigate whether CRT could prevent or attenuate disease progression and induce LV reverse remodeling in mild heart failure - The REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) [J Am Coll Cardiol 2009;54:18371846] - The MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) [Circulation 2010 10.1161/CIRCULATIONAHA.110.955039]

CRM6-4403-0810 2010 Boston Scientific. All rights reserved. 40 MADIT-CRT Main Inclusion Criteria Ischemic heart disease (NYHA Class I or II) or non- ischemic heart disease (NYHA Class II) for at least three months prior to entry Optimal pharmacologic therapy Beta blockers, ACE/ARB, and statins (ischemic patients) unless not tolerated or contraindicated Left ventricular ejection fraction 30% QRS duration 130 ms Sinus rhythm

CRM6-4403-0810 2010 Boston Scientific. All rights reserved. 41 MADIT-CRT Results The primary endpoint was a composite of death from any cause and non-fatal HF-related adverse events. Mean follow-up of 2.4 years Results showed that CRT-D was associated with a 34% reduction in the relative risk of the primary endpoint Benefit attributable primarily to a 41% decrease in HF-related adverse It was subsequently discovered and validated that in the LBBB subgroup, patients received substantial benefit from CRT-D. Non-LBBB patients did not show evidence of benefit. The LBBB sub-group made up approximately 70% of the total MADIT-CRT population. 3% mortality in both groups 34% 57%

CRM6-4403-0810 2010 Boston Scientific. All rights reserved. MADIT-CRT Results of Minor Endpoints 42

REVERSE Trial Inclusion criteria (N =610) - patients treated with an optimal medical regimen - NYHA function class I or II and NSR - LVEF 40%, QRS duration 120 ms, LVEDD55 mm - All patients had a history of HF symptoms Method - implantation of a CRT-D (85%) or CRT-P (15%) and compared between activated (CRT-ON) vs CRT-OFF Primary endpoint was the percentage of clinically worsened patients, ascertained by the use of a composite endpoint. Secondary endpoint was echocardiographic change in LV end-systolic volume index [Linde C. REVERSE trial. J Am Coll Cardiol 2008;52:18341843]

After 12 months, no significant difference observed in the primary endpoint However, a significant degree of reverse LV remodelling was observed among patients on CRT, manifested by decreases in the LVESVi (p < 0.0001) and LVEDV, and an increase in LVEF(p < 0.0001) Significant reverse remodelling linked to reduced HF morbidity indicates that CRT may potentially modify disease progression in mild HF patients.

Inferences from MADIT-CRT & REVERSE MADIT-CRT & REVERSE demonstrated reduced morbidity No significant improvement seen in NYHA I class pts at baseline (18% of pts in REVERSE & 15% pts in MADIT-CRT) Improvement primarily in pts with QRS 150 ms and/or typical LBBB. In MADIT-CRT, women with LBBB demonstrated a particularly favourable response. Survival advantage is not established. In MADIT-CRT the extent of reverse remodelling was concordant with & predictive of improved clinical outcomes [ESC guidelines . Focussed update. European Heart Journal (2010) 31, 267787]

Electrical Therapy for CHF Cardiac Contractility Modulation (CCM) Therapy Mech. - To enhance the strength of cardiac muscular contraction, non-excitatory electrical signals are delivered during the absolute refractory period of the cardiac cycle The CCM signals delivered by OPTIMIZERdevice is via 3 cardiac leads (1 right atrial and 2 right ventricular septal)

Cardiac Contractility Modulation Therapy The OPTIMIZER system was studied in the FIX-CHF-4 trial - enrolled 164 subjects; ineligible for CRT; EF 8weeks) home inotropic therapy as destination therapy in patients of advanced heart failure or as BTT. Int J Cardiol. 2005;99(1):47-50.

Continous Inotropic Support Continuous intravenous infusion of a positive inotropic agent may be considered for palliation of symptoms in patients with refractory end-stage HF (ACC Class IIb / Level of Evidence: C) The use of continuous IV support to allow hospital discharge should be distinguished from the intermittent administration of infusions of such agents to patients who have been successfully weaned from inotropic support Intermittent outpatient infusions of vasoactive drugs such as nesiritide or positive inotropic drugs have not shown to improve symptoms or survival in patients with advanced HF 1. Jessup M. 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: Developed in Collaboration With the International Society of Heart and Lung Transplantation. Circulation. 2009;119(14):1977-2016..

Interventional Fluid Removal Decompensated HF is comlicated by sodium and fluid retention Limitations of loop diuretics have led to the development of interventional approaches to fluid removal such as - Interventional vasodilatation - Ultrafiltration

Interventional Vasodilatation A novel technique that aims to target the kidneys directly, with drugs administered directly into the renal arteries One approach called Targeted Renal Therapy (TRT) can be achieved with the Benephit Renal Infusion System A bifurcated femoral catheter that can be advanced through the ascending aorta and into the renal arteries This catheter can then be used to deliver vasodilators directly into the renal arteries in attempts to improve renal perfusion & GFR thus limiting the systemic effects of the medication

Interventional Ultrafiltration Ultrafiltration is currently a class IIa recommendation by the ACC/AHA guidelines and is indicated for patients with refractory congestion not responding to medical therapy One type of ultrafiltration device, the Aquadex system consists of a peripheral venous access catheter, a disposable 0.12 m2 polysulphone filter circuit and a console unit

The Aquadex Ultrafiltration System Can be used by a trained cardiologist, does not require a nephrologist or use of a dialysis unit Can remove fluid at a max rate of 500 mL/h for up to 8 hours Compared to intravenous diuretic therapy, the Aquadex system resulted in greater weight loss, net fluid loss, decreased frequency of hypokalemia at 48 hours, and with reduced heart failure rehospitalizations at 90 days 1. Wertman B. Ultrafiltration for the management of acute decompensated heart failure. J Cardiac Fail. 2008;14(9):754-759

Treatment of Valvular Disease HF leads to enlargement of the mitral annulus, displacement of the papillary muscles, and tethering of the mitral valve Benefit of treating functional MR in HF is not well established - class IIb recommendation according to the ACC/AHA guideline Despite lack of evidence surgical correction of functional MR is sometimes performed in patients with end-stage HF Minimally invasive tech for the treatment of MR have also been developed (Mitra clip) & may provide additional treatment options

Tissue Transplantation Tissue transplantation uses living cells or tissue to restore cardiac pump function It includes - cellular therapy - stem cell therapy - heart transplant

Cellular Cardiomyoplasty Cellular therapy or cellular cardiomyoplasty is an investigational approach to the treatment of ischemic cardiomyopathy Transplanted cell include - fetal and neonatal cardiomyocytes; - skeletal myoblasts - vascular endothelial cells; - bone marrow-derived stem cells - cardiac-derived stem cells; - embryonic stem cells Methods of delivering stem include - injection during an invasive procedure (CABG / VAD) - injection directly into the coronary arteries, - injection directly into the myocardium with the use of transcutaneous endoventricular catheters such as MyoCath

Cellular Cardiomyoplasty & Stem Cells Cellular cardiomyoplasty remains a promising interventional approach for the treatment of ischemic cardiomyopathy and has been associated with modest improvements in LV function in several human studies Future research is necessary to optimize selection of cell source, cell culture technique, method of cell delivery, and also to determine the long-term clinical benefit of therapy Stem cell therapy is also promising; however, their use is currently limited by scientific (increased arrhythmia) and ethical concerns (MAGIC trial, 2009)

Human Heart Transplant (HHT) Allogeneic HHT is a therapeutic option for patients with refractory end-stage HF, who have failed other options According to the 2009 update on heart disease and stroke from the AHA and Stroke Statistics Subcommittee, the 5-year survival after HHT is 72.3% for males and 67.4% for females Despite success, heart transplant is limited by the number of hearts available for transplant each year This limitation in resources reinforces the need for the development of other interventional therapies for the treatment of end-stage heart failure.

Palliative Care Palliative care describes a multidisciplinary approach to patient care that targets both the symptomatic and psychosocial issues associated with a disease Being recognized as an essential aspect of HF therapy because of the extreme physical and emotional symptoms that patients with HF experience Although the ultimate goal of interventional heart failure therapy is to prolong life and reduce symptoms, many of these therapies are associated with unique emotional complications that should be addressed with the principals of palliative care described by Goodlin in his state-of-the-art review article 1. Goodlin SJ. Palliative care in congestive heart failure. J Am Coll Cardiol. 2009;54(5):386-396

Self Care Self-care is defined as a naturalistic decision-making process involving the choice of behaviors that maintain - physiologic stability (self-care maintenance) - response to symptoms when it occurs (self-care management) Self-care maintenance includes adhering to LSMs such as taking prescribed medications, eating a low-sodium diet, restricting fluid intake, exercising and by recognizing signs of worsening HF Self-care management includes - reducing sodium or fluid intake, taking an extra dose of diuretic, or seeking medical help Chronicle (Medtronic), an implantable continuous hemodynamic monitor (ICHM) measures & stores information for outpatient monitoring 1. Bourge RC. Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: the COMPASS- HF study. J Am Coll Cardiol. 2008;51(11):1073-1079

Conclusions and Future The treatment options for patients with refractory end-stage heart failure are currently limited At this advanced stage, the goals of treatment frequently change from prolonging life to hospice / end-of-life care The role of interventional therapy promises additional treatment options to these patients Currently available interventional options include heart transplant, interventional medical therapy, VADs, TAHs. Future treatment options include the interventional treatment of mitral valve disease, cellular and stem cell therapy, and use of next generation VADs or TAHs & ambulatory monitoring devices