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TREATMENT OF ADVANCED HEART FAILURE HEART DISEASE IN KENTUCKY Navin Rajagopalan, MD Assistant Professor of Medicine University of Kentucky Director, Congestive Heart Failure Medical Director of Cardiac Transplantation November 1, 2009 TOPICS FOR DISCUSSION ACE inhibitors & Beta-blockers Diuretics Cardiac resynchronization Cardiac transplantation ACE INHIBITORS Standard therapy for heart failure Best randomized trial data for captopril, lisinopril, and enalapril All are now generic and cheap! Start low dose and titrate upwards to goal Enalapril: 2.5 mg qd-bid to 10-20 mg bid Lisinopril: 2.5 mg qd to 20-40 mg qd ARB can be used if ACEi intolerant BETA BLOCKERS Standard therapy for heart failure Best randomized trial data for metoprolol succinate (Toprol XL) and carvedilol (Coreg) Both are now generic Start low dose and titrate upwards to goal Toprol XL: 25 mg qd to 200 mg qd carvedilol: 3.125 mg bid to 25 mg bid COMET trial suggested better outcomes with carvedilol than with metoprolol (although metoprolol tartrate was used) ACE inhibitors are commonly instituted first Beneficial effects of BB were found after use of ACE inhibitors was standard-care BB contraindicated if patients are significantly volume overloaded Is this titration scheme necessary? 1

Sliwa et al. (2004) evaluated initiation of therapy with carvedilol either before (n=38) or after (n=40) perindopril therapy in newly diagnosed NYHA II-III III HF patients Alternative agent was added at 6 months (target doses: carvedilol 25 mg bid, perindopril 8 mg qd) Endpoint: LVEF and functional class at 1 year Carvedilol first group @ 12 mo: Better improvement in NYHA class Better improvement in LVEF Lower dose of furosemide Higher dose of carvedilol (43 17 mg vs. 33 18 mg) Sliwa et al. JACC 2004;44:1825-30 CIBIS III study randomized 1010 patients with class II-III III systolic HF to monotherapy with bisoprolol (target dose 10 mg qd) or enalapril (target dose 10 mg bid) for 6 months, followed by their combination for 6-24 months Primary end-point: mortality or hospitalization Trend towards better survival in bisoprolol first group Trend towards more HF hospitalization in bisoprolol first group Safe and efficacious to initiate CHF treatment with beta- blockers Not necessary that ACE inhibitors be used before beta-blockers blockers Titration of both drugs can be accomplished at the same time Volume status needs to be managed before beta-blockers blockers are aggressively titrated ACE INHIBITORS ATLAS study randomized 3164 NYHA II- IV systolic HF patients to low dose lisinopril (2.5 to 5.0 mg qd) or high dose (32.5 to 35 mg qd) LVEF < 30% No BB use (trial published in 1999) 2

ACE INHIBITORS High-dose group had a nonsignificant 8% lower risk of death (p = 0.13) Significant 12% lower risk of death or hospitalization for any reason and 24% fewer hospitalizations for HF in high dose group ACE INHIBITORS Using dose that is similar to that used in clinical trials has meaningful benefit over low dose The differences between intermediate-dose dose and high-dose lisinopril is likely to be small, if present at all Is the same thing true of beta-blockers blockers in heart failure? Packer et al. Circ 1999;100:2312-2318 BETA-BLOCKERSBLOCKERS McAlister et al. (2009) performed a meta-analysis analysis on 23 BB trials in systolic HF to determine if the survival benefits were associated with BB dose or the magnitude of heart rate reduction Medications: metoprolol (5), carvedilol (9), bisoprolol (3), bucindolol (3), atenolol (1), and nebivolol (2) BETA-BLOCKERSBLOCKERS For every HR reduction of 5 beats/min, a significant 18% reduction in the risk of death occurred No significant relationship between all-cause mortality and BB dosing was observed McAlister et al. Ann Intern Med 2009;150:784-94. McAlister et al. Ann Intern Med 2009;150:784-94. BETA BLOCKERS Other investigators have observed that HF patients with higher baseline HR exhibit the greatest improvements in LVEF with BB therapy and that greater reductions in HR are associated with greater improvements in LVEF Optimal HR is unknown If substantial HR reduction is achieved with low-dose BB, should you keep titrating? Is there any benefit to using dosing higher than trial doses if HR reduction is suboptimal? MY OPINION If limited by BP, it is better to get a patient on small doses of both classes of medications, as opposed to a moderate dose of one Achieving i maximal dose of BB is likely l more important than achieving maximal dose of ACE inhibitor If tolerated, discharge patients with both medications, even if low dose 3

DIURETICS Aldosterone antagonist (spironolactone) Loop diuretics SPIRONOLACTONE RALES randomized 1663 systolic heart failure patients (LVEF < 35%; NYHA class III/IV) to spironolactone or placebo Serum Cr < 2.5, K < 5.0 Initial dose 25 mg qd, increased to 50 mg qd if no benefit, no side effects 94 % on ACEi; 10% on BB SPIRONOLACTONE IN THE REAL WORLD Retrospective studies have identified inappropriate use of spironolactone in patients with renal insufficiency as well as less than ideal follow-up Bozkurt et al. in a retrospective review of 104 pts reported 10% rate of serious hyperkalemia (K+ > 6) LOOP DIURETICS Loop diuretics (IV) are a mainstay of therapy for AHFS 75-80% in ADHERE received IV diuretics Reduce left ventricular filling pressures Reduce central venous pressure 40 mg furosemide = 20 mg torsemide = 1 mg bumetanide Bozkurt et al. JACC 2003; 41: 211-4. PROBLEMS WITH DIURETICS Adverse neurohormonal activation Increased plasma renin, aldosterone, norepinephrine In SOLVD trial, use of long-term diuretics was associated with a 1.33 fold increase in risk of arrhythmic death after correcting for other mortality risk factors Postdiuretic sodium rebound as a result of poor dietary compliance Given short half-life life of diuretics, there is a significant amount of time where the tubular concentration of the diuretic is subtherapeutic. CARDIO-RENAL RENAL SYNDROME Low cardiac output is not necessary and many patients have preserved LVEF (diastolic HF) and/or elevated BP Registry of 1004 patients admitted with CHF found worsening renal function during hospitalization (Cr rise > 0.3 mg/dl) in 27% which was statistically associated with hospital deaths and LOS > 10 days Gheorghiade et al. JACC 2009; 53: 557-73. 4

CARDIO-RENAL RENAL SYNDROME CARDIO-RENAL RENAL SYNDROME Animal studies have demonstrated that temporary elevation of CVP can lead to worsened renal function via congestion of the renal veins Mullens et al. (JACC 2009) recently showed in 145 patients with AHFS that patients who developed worsening renal function had greater CVP upon admission as well as greater CVP following medical therapy Renal function did not correlate with other hemodynamic variables Mullens et al. JACC 2009;53:589-96. COMBATING DIURETIC RESISTANCE Addition of thiazide diuretic to a loop diuretic results in greater diuresis i and naturesis than increasing dose of loop diuretic alone COMBATING DIURETIC RESISTANCE Dormans et al. (JACC 1996) randomized 20 CHF patient on high doses of oral lasix (> 250 mg/day) to intravenous bolus therapy versus the same dose given as a continuous infusion for 1 day Urinary volume and urinary excretion of sodium were both significantly greater at 8 hours and 24 hours in the continuous infusion group (mean daily dose of 690 mg) Less peak concentration with continuous infusion may lessen risk of ototoxicity Stewart JH et al. BMJ 1965; 5473: 1277-81 DOES THE CHOICE OF DIURETIC MATTER? Oral torsemide may be better and more reliably absorbed than either furosemide or bumetanide, with more consistent bioavailability Furosemide in particular has variable absorption Response to intravenous doses likely to be similar DIURETICS Use lowest dose possible to achieve effective diuresis Loop + thiazide combination and consideration of continuous infusion are options for those difficult to diurese Worsening renal function is a not a contraindication to diuretic therapy 5

CARDIAC RESYNCHRONIZATION THERAPY (CRT) CARDIAC RESYNCHRONIZATION THERAPY (CRT) Biventricular pacemaker / ICD Left ventricular dyssynchrony prevalent in systolic HF Indicated in: Chronic systolic HF on optimal medical Rx NYHA class III/IV QRS duration > 120 seconds Right Atrial Lead Left Ventricular Lead Right Ventricular Lead CRT alone (without ICD) improved survival in chronic class III/IV HF patients t with QRS > 120 ms over OMT Benefit greater in pts with QRS duration > 160 msec Cleland J et al. NEJM 2005; 352:1539-49 CRT CRT IN NYHA I/II HEART FAILURE Can CRT be utilized in patients with less severe heart failure? Previous studies have suggested that CRT can lead to positive remodeling including improvement in left ventricular end-systolic volumes MADIT-CRT was designed to determine if CRT could improve outcomes in NYHA I-II II HF patients with QRS duration > 130 ms Benefit of CRT driven by significant 41% reduction in HF events over 2.4 years (no difference in mortality) Benefit confined to those with QRS duration > 150 msec Moss AJ et al. NEJM 2009; 361 CRT Future guidelines may incorporate the latest data suggesting benefit of CRT in class I/II HF, particularly those with QRS duration > 150 msec Procedure does have increased risk compared to ICD alone Cost effectiveness? CARDIAC TRANSPLANTATION Treatment option for systolic heart failure refractory to maximal medical therapy Limited it by supply of donor organs 3000-4000 heart transplants / year in US Extensive patient evaluation required Medical, psychosocial, insurance, etc. 6

TRANSPLANT EVALUATION WHEN TO REFER Symptoms limiting quality of life Recurrent heart failure admissions despite maximal therapy Worsening end-organ function (renal, hepatic) Before they become irreversible Refractory ventricular arrhythmias For younger patients, may be useful to be plugged into the system Mehra MR et al. Listing Criteria for Heart Transplantation. J Heart Lung Transplant 2006;25:1024-42. ADULT HEART TRANSPLANTATION Kaplan-Meier Survival by Era (Transplants: 1/1982 (Transplants: 1/1982 6/2006) ADULT HEART RECIPIENTS Functional Status of Surviving Recipients (Follow-ups: 1995 - June 2006) 100 All comparisons significant at p < 0.0001 100% Surv vival (%) 80 60 1982-1991 (N=18,854) 854) 40 1992-2001 (N=35,146) 2002-6/2006 (N=12,369) 20 HALF-LIFE 1982-1991: 8.8 years; 1992-2001: 10.5 years; 2002-6/2006: NA 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years 80% 60% 40% 20% 0% No Activity Limitations Performs with Some Assistance Requires Total Assistance 1 Year (N = 15,388) 3 Years (N = 13,600) 5 Years (N = 11,698) 7 Years (N = 9,306) ISHLT 2008 J Heart Lung Transplant 2008;27: 937-983 ISHLT 2008 J Heart Lung Transplant 2008;27: 937-983 Last updated based on data as of December 2006 CONTRAINDICATIONS Active substance abuse Lack of social support Severe peripheral vascular disease Severe lung disease Active viral hepatitis / HIV Recent malignancy VAD Option for patients with end-stage HF and who are not candidates for transplantation, or who cannot wait for transplant Requires major cardiothoracic surgery with similar contraindications as transplant Devices are getting smaller and safer Rose EA et al. NEJM 2001;345:1435-43 7

REMATCH (2001) DESTINATION L-VAD HEARTMATE II Rose EA et al. NEJM 2001;345:1435-43 129 patients with end-stage CHF, 80% requiring IV inotropic therapy, randomized to medical therapy versus HeartMate I LVAD (pulsatile device) Patients were not transplant candidates Cause of death in LVAD group was predominantly sepsis, LVAD failure, and CVA Pagani FD et al. JACC 2009;54:312-21 Continuous flow rotary pump External drive line still needed Smaller size allows for use in smaller patients, females Recent studies have shown lower adverse events (stroke, bleeding, infection) compared to older, larger devices HEARTMATE II WHAT ABOUT THE COST? HM II device appears to be safe for bridge to transplant and an improvement over older pulsatile devices No randomized study versus transplant Learning curve is present Outcomes not assessed after transplant does VAD prior to transplant constitute a risk factor for poor outcome? Hernandez et al. (JAMA, 2008) examined Medicare data for patients who underwent VAD implant between 2/2000 and 6/2006 Primary device group (n = 1476) Post cardiotomy (n =1467) 1 year survival was 51.6% in the primary device group and 30.8% in post-cardiotomy group Mean 1-year Medicare payments for inpatient care was $178714 in the primary device group and $111769 in the post-cardiotomy group CONCLUSION QUESTIONS? Advanced heart failure is a severe, debilitating illness that requires a multidisciplinary approach Evidence based therapy is still underutilized Referral for transplantation should be considered in acceptable candidates Navin Rajagopalan Email: n.rajagopalan@uky.edu Phone: 800-888-5533 (UK MD) Cell: 859-317 317-0775 8

For each of the following medications used in chronic HF, specify if they improve mortality, worsen mortality, or are neutral A. Enalapril IMPROVE B. Digoxin NEUTRAL C. Amlodipine NEUTRAL D. Dobutamine WORSEN E. Nesiritide???????? Which of the following statements is true about management of chronic HF? A. ACE inhibitors should be started before beta blockers B. Carvedilol is the only FDA approved beta-blocker blocker for heart failure C. ACE inhibitors are contraindicated in HF patients with serum creatinine > 2.0 D. Despite benefits seen with hydralazine / nitrates in African Americans, African Americans with HF should still be started on ACE inhibitors first E. If a HF patient develops cough from ACE inhibitor, it is advisable not to switch to an angiotensin receptor blocker (ARB) given the lack of data using ARBs in heart failure DIURETICS IN HEART FAILURE Which of the following has proven mortality benefit in patients with systolic heart failure? A. Furosemide B. Spironolactone C. Torsemide D. Chlortalidone E. None of the above DEVICE THERAPY 48 year old female presents with progressive SOB following mild viral illness Subsequent echo shows dilated LV (LVEDD 6.8 cm) and EF 20% ECG shows LBBB which is old (patient has known of LBBB since age 25). QRS duration 150 msec LHC showed no CAD Started on carvedilol and lisinopril and medications are titrated upwards Symptoms improve and patient is back to baseline, exercising, in NYHA class I Repeat echo in 3 months shows LVEF 25% DEVICE THERAPY Patient is referred to Electrophysiology. What device is recommended by the current heart failure guidelines? A. No device B. Dual chamber pacemaker C. Biventricular pacemaker / ICD (i.e CRT) D. Dual chamber ICD CARDIAC TRANSPLANTATION All of the following statements are true, except: A. Following cardiac transplantation, 5 year survival is 75% and 10 year survival is 50% B. History of drug abuse including smoking is a contraindication for cardiac transplantation C. For patients who unable to receive a heart transplant in time, left ventricular assist devices (VAD) can be utilized as a bridge to transplantation D. Referral for heart transplantation should be considered if a patient remains significantly limited despite optimal medical therapy 9