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TREATMENT OF ADVANCED HEART FAILURE HEART DISEASE IN KENTUCKY Navin Rajagopalan, j g 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 & BetaBeta-blockers ACE INHIBITORS Diuretics Standard therapy for heart failure Best randomized trial data for captopril, lisinopril, and enalapril Cardiac resynchronization Start low dose and titrate upwards to goal – All are now generic i and d cheap! h ! Cardiac transplantation BETA BLOCKERS Standard therapy for heart failure Best randomized trial data for metoprolol succinate (Toprol XL) and carvedilol (Coreg) – – – – Both are now generic g 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) – Enalapril: 2.5 mg qd qd--bid to 10 10--20 mg bid – Lisinopril: 2.5 mg qd to 20 20--40 mg qd ARB can be used if ACEi intolerant ACE INHIBITORS AND BETABETA-BLOCKERS ACE inhibitors are commonly instituted first – Beneficial effects of BB were found after use of ACE inhibitors was standardstandard-care – BB contraindicated if patients are significantly volume overloaded Is this titration scheme necessary? 1 ACE INHIBITORS AND BETABETA-BLOCKERS Sliwa et al. (2004) evaluated initiation of therapy with carvedilol either before (n=38) or after (n=40) perindopril therapy in newly diagnosed NYHA IIII-III HF patients Alternative agent was added at 6 months (target doses: carvedilol 25 mg bid, perindopril 8 mg qd) ACE INHIBITORS AND BETABETA-BLOCKERS Carvedilol first group @ 12 mo: – Better improvement in NYHA class – Better B tt improvement i t in LVEF – Lower dose of furosemide – Higher dose of carvedilol (43 17 mg vs. 33 18 mg) Endpoint: LVEF and functional class at 1 year Sliwa et al. JACC 2004;44:1825-30 ACE INHIBITORS AND BETABETA-BLOCKERS CIBIS III study randomized 1010 patients with class II II--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 end--point: mortality or hospitalization ACE INHIBITORS AND BETABETA-BLOCKERS Not necessary that ACE inhibitors be used before betabeta-blockers Titration of both drugs can be accomplished at the same time Volume status needs to be managed before betabeta-blockers are aggressively titrated ACE INHIBITORS AND BETABETA-BLOCKERS 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 beta-blockers ACE INHIBITORS IS THE DOSE IMPORTANT? ATLAS study randomized 3164 NYHA II 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) (32.5 LVEF < 30% No BB use (trial published in 1999) 2 ACE INHIBITORS IS THE DOSE IMPORTANT? High-dose group Highhad 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 IS THE DOSE IMPORTANT? Using dose that is similar to that used in clinical trials has meaningful benefit over low dose The differences between intermediateintermediate-dose and high-dose lisinopril is likely to be small, if present highat all Is the same thing true of betabeta-blockers in heart failure? Packer et al. Circ 1999;100:2312-2318 BETA-BLOCKERS BETAIS THE DOSE IMPORTANT? McAlister et al. (2009) performed a metameta-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) McAlister et al. Ann Intern Med 2009;150:784-94. BETA BLOCKERS IS THE DOSE IMPORTANT? BETA-BLOCKERS BETAIS THE DOSE IMPORTANT? 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 all BB dosing was observed McAlister et al. Ann Intern Med 2009;150:784-94. MY OPINION 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 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 Optimal HR is unknown A hi i maximal Achieving i ld dose off BB iis lik likely l more important than achieving maximal dose of ACE inhibitor If substantial HR reduction is achieved with lowlow-dose BB, should you keep titrating? Is there any benefit to using dosing higher than trial doses if HR reduction is suboptimal? If tolerated, discharge patients with both medications, even if low dose 3 DIURETICS Aldosterone antagonist (spironolactone) Loop diuretics SPIRONOLACTONE IN THE “REAL WORLD” Retrospective studies have identified inappropriate use of spironolactone in patients with renal insufficiencyy as well as less than ideal follow--up follow Bozkurt et al. in a retrospective review of 104 pts reported 10% rate of serious hyperkalemia (K+ > 6) SPIRONOLACTONE RALES randomized 1663 systolic heart failure patients (LVEF < 35%; NYHA class III/IV) to spironolactone or placebo l b 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 LOOP DIURETICS Loop diuretics (IV) are a mainstay of therapy for AHFS – 75 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 CARDIO--RENAL SYNDROME CARDIO Adverse neurohormonal activation – Increased plasma renin, aldosterone, norepinephrine Low cardiac output is not necessary and many patients have preserved LVEF (diastolic HF) and/or elevated BP In SOLVD trial, use of longlong-term diuretics was associated with a 1 1.33 33 fold increase in risk of arrhythmic death after correcting for other mortality risk factors 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 Postdiuretic sodium rebound as a result of poor dietary compliance – Given short halfhalf-life of diuretics, there is a significant amount of time where the tubular concentration of the diuretic is subtherapeutic. Gheorghiade et al. JACC 2009; 53: 557-73. 4 CARDIO--RENAL SYNDROME CARDIO CARDIO--RENAL SYNDROME CARDIO Animal studies have demonstrated that temporary elevation of CVP can lead to worsened renal function via congestion of the renal veins Mullens et al. 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 di diuresis i and d naturesis t i than th 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? DIURETICS Use lowest dose possible to achieve effective diuresis Oral torsemide may be better and more reliably absorbed than either furosemide or bumetanide, with more consistent bioavailability Loop + thiazide combination and consideration of continuous infusion are options for those difficult to diurese Furosemide in particular has variable absorption Worsening renal function is a not a contraindication to diuretic therapy Response to intravenous doses likely to be similar 5 CARDIAC RESYNCHRONIZATION THERAPY (CRT) Biventricular pacemaker / ICD Left ventricular dyssynchrony prevalent in systolic HF Indicated in: Right Atrial Lead Left Ventricular Lead – Chronic systolic HF on optimal medical Rx – NYHA class III/IV – QRS duration > 120 seconds Right Ventricular Lead CARDIAC RESYNCHRONIZATION THERAPY (CRT) CRT alone (without ICD) improved survival in chronic class III/IV HF patients ti t with ith 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 endend-systolic volumes MADIT-CRT was designed to determine if CRT MADITcould improve outcomes in NYHA 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 CARDIAC TRANSPLANTATION Future guidelines may incorporate the latest data suggesting benefit of CRT in class I/II HF, particularly those with QRS duration > 150 msec Treatment option for systolic heart failure refractory to maximal medical therapy Li it d b Limited by supply l off d donor organs Procedure does have increased risk compared to ICD alone – 3000 3000--4000 heart transplants / year in US Extensive patient evaluation required Cost effectiveness? – Medical, psychosocial, insurance, etc. 6 TRANSPLANT EVALUATION WHEN TO REFER Symptoms limiting quality of life Recurrent heart failure admissions despite maximal therapy W Worsening i endend d-organ function f ti (renal, ( l h hepatic) ti ) – 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 RECIPIENTS ADULT HEART TRANSPLANTATION Functional Status of Surviving Recipients Kaplan--Meier Survival by Era (Transplants: 1/1982 – 6/2006) Kaplan 100 (Follow--ups: 1995 - June 2006) (Follow 100% Surv vival (%) All comparisons significant at p < 0.0001 80 80% 60 60% 1982-1991 (N=18 (N=18,854) 854) 40 1992-2001 (N=35,146) 40% 2002-6/2006 (N=12,369) 20 20% HALF-LIFE 1982-1991: 8.8 years; 1992-2001: 10.5 years; 2002-6/2006: NA No Activity Limitations 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years ISHLT 2008 J Heart Lung Transplant 2008;27: 937-983 14 15 Performs with Some Assistance Requires Total Assistance 0% 1 Year (N = 15,388) ISHLT 3 Years (N = 13,600) 5 Years (N = 11,698) 2008 J Heart Lung Transplant 2008;27: 937-983 CONTRAINDICATIONS 7 Years (N = 9,306) Last updated based on data as of December 2006 VAD Active substance abuse Lack of social support Severe peripheral vascular disease Severe lung disease Active viral hepatitis / HIV Recent malignancy Option for patients with end--stage HF and who are end 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 L--VAD Rose EA et al. NEJM 2001;345:1435-43 129 patients with endend-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 HEARTMATE II 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 Pagani FD et al. JACC 2009;54:312-21 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 Mean 11-year Medicare payments for inpatient care was $178714 in the primary device group and $111769 in the post post--cardiotomy group CONCLUSION QUESTIONS? – 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 post--cardiotomy group 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: [email protected] Phone: 800800-888888-5533 (UK MD) Cell: 859859-317317-0775 8 For each of the following medications used in chronic HF, specify if they improve mortality, worsen mortality, or are neutral A. B. C. D. E. Enalapril Digoxin Amlodipine Dobutamine Nesiritide IMPROVE NEUTRAL NEUTRAL WORSEN ???????? ACE INHIBITORS AND BETABETA-BLOCKERS Which of the following statements is true about management of chronic HF? A. B. C. D. E. DIURETICS IN HEART FAILURE 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 (p (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% 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 Patient is referred to Electrophysiology. What device is recommended by the current heart failure guidelines? A. No device ACE inhibitors should be started before beta blockers Carvedilol is the only FDA approved betabeta-blocker for heart failure ACE inhibitors are contraindicated in HF patients with serum creatinine > 2.0 Despite benefits seen with hydralazine / nitrates in African Americans, African Americans with HF should still be started on ACE inhibitors first 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 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 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 B. Dual chamber pacemaker C. Biventricular pacemaker / ICD (i.e CRT) D. Dual chamber ICD 9