Disclosures. Heart Failure Pearls for the Hospitalist. Outline. Patient 1

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1 I have nothing to disclose Disclosures Heart Failure Pearls for the Hospitalist Ronald Witteles, M.D. Stanford University School of Medicine October 21, Outline n Admission for Heart Failure Exacerbation? n Three different patient types, three different problems How can we provide the best possible care for each patient? n Final thoughts Patient 1 68 y.o. man with dilated nonischemic cardiomyopathy Baseline echo: Moderate LV dilatation, LVEF 25% Comes to ER for gradually worsening SOB/edema Baseline meds (stable over last 6 months): Carvedilol 25 mg bid Lisinopril 20 mg bid Furosemide 40 mg bid Spironolactone 25 mg qd Digoxin 0.25 mg qd 1

2 Exam & Labs Physical exam: Wt 90 kg (up from 85 kg one month ago) BP 115/65, HR 65, SaO2 94% RA Scant bibasilar crackles No significant murmurs/gallops 3+ LE edema Labs: Na 137, K 4.1, Cr 1.3 (baseline 1.4) NT-Pro BNP 6100, Troponin I <0.1 Digoxin level (random): 0.3 (subtherapeutic) CXR: Cardiomegaly, mild pulmonary edema ECG: Sinus rhythm at 65 bpm, old LBBB What Do You Do? The patient says he wants to stop any medications which aren t clearly helping him. What do you do with the digoxin? 1) Stop digoxin 2) Continue digoxin What Do You Do? The patient says he wants to stop any medications which aren t clearly helping him. What do you do with the digoxin? 1) Stop digoxin 2) Continue digoxin Digoxin DIG Trial (1997) 6800 patients with EF 45% Digoxin vs. placebo All patients in sinus rhythm Outcomes: Primary: All-cause mortality Secondary: CV death, worsened HF & hospitalizations 2

3 All-Cause Mortality Death or HF Hospitalization placebo digoxin Adapted from NEJM. 1997;336: Adapted from NEJM. 1997;336: Cochrane Review: Risk of Clinical Deterioration if Stop Dig A Recent Story Adapted from Hood et al. Cochrane Library. 2004, Issue 4. 3

4 A Recent Story I was nervously thinking about this talk I was nervously thinking about this talk Will they like it? A Recent Story A Recent Story I was nervously thinking about this talk Will they like it? Will my jokes fall flat? A Recent Story I was nervously thinking about this talk Will they like it? Will my jokes fall flat? I developed a tension headache. 4

5 A Recent Story I was nervously thinking about this talk Will they like it? Will my jokes fall flat? I developed a tension headache. I took 600 mg of ibuprofen. A Recent Story I was nervously thinking about this talk Will they like it? Will my jokes fall flat? I developed a tension headache. I took 600 mg of ibuprofen. My headache went away. I was happy. A Recent Story I was nervously thinking about this talk Will they like it? Will my jokes fall flat? I developed a tension headache. I took 600 mg of ibuprofen. My headache went away. I was happy. A Recent Story I was nervously thinking about this talk Will they like it? Will my jokes fall flat? I developed a tension headache. I took 600 mg of ibuprofen. My headache went away. I was happy. Note: I never thought I was going to live longer by taking the ibuprofen. 5

6 A Recent Story I was nervously thinking about this talk Will they like it? Will my jokes fall flat? I developed a tension headache. I took 600 mg of ibuprofen. My headache went away. I was happy. Note: I never thought I was going to live longer by taking the ibuprofen. A Recent Story I was nervously thinking about this talk Will they like it? Will my jokes fall flat? I developed a tension headache. I took 600 mg of ibuprofen. My headache went away. I was happy. Note: I never thought I was going to live longer by taking the ibuprofen. Should I have been denied the opportunity to take the ibuprofen??? Should I have been denied the opportunity to take the ibuprofen??? Why do we hold digoxin to such a higher standard? What Do You Do? What should you do with the digoxin dose? 1) Continue digoxin at 0.25 mg qd 2) Increase to 0.50 mg qd 3) Check a true digoxin trough level & increase dose to 0.50 mg qd if still subtherapeutic What Do You Do? What should you do with the digoxin dose? 1) Continue digoxin at 0.25 mg qd 2) Increase to 0.50 mg qd 3) Check a true digoxin trough level & increase dose to 0.50 mg qd if still subtherapeutic 6

7 High Digoxin Doses: Beware Eggerthella Lenta Purpose in life: To break down digoxin! 1970s: 10% of individuals found to excrete inactive dihydrodigoxin when given digoxin. 1983: Manuscript in Science identifies Eubacterium lentum as the culprit Fresh stool samples from two human volunteers who were known to be heavy digoxin reduction product excretors were cultured anaerobically in chopped meat glucose broth containing digoxin High Digoxin Doses: Beware Eggerthella Lenta Purpose in life: To break down digoxin! 1970s: 10% of individuals found to excrete inactive dihydrodigoxin when given digoxin. 1983: Manuscript in Science identifies Eubacterium lentum as the culprit Fresh stool samples from two human volunteers who were known to be heavy digoxin reduction product excretors were cultured anaerobically in chopped meat glucose broth containing digoxin God bless the basic scientists!!! Adapted from Saha et al. Science. 1983;220: Adapted from Saha et al. Science. 1983;220: An Inevitable Sequence of Events... Well-meaning physician targets digoxin levels for treatment of HF or atrial fibrillation A patient with eggerthella lenta ends up on an extremely high dose of digoxin Patient receives antibiotics (Z-pack, etc.) Patient gets dig-toxic An Inevitable Sequence of Events... Well-meaning physician targets digoxin levels for treatment of HF or atrial fibrillation A patient with eggerthella lenta ends up on an extremely high dose of digoxin Patient receives antibiotics (Z-pack, etc.) Patient gets dig-toxic 7

8 An Inevitable Sequence of Events... Well-meaning physician targets digoxin levels for treatment of HF or atrial fibrillation A patient with eggerthella lenta ends up on an extremely high dose of digoxin Patient receives antibiotics (Z-pack, etc.) Patient gets dig-toxic An Inevitable Sequence of Events... Well-meaning physician targets digoxin levels for treatment of HF or atrial fibrillation A patient with eggerthella lenta ends up on an extremely high dose of digoxin Patient receives antibiotics (Z-pack, etc.) Patient gets dig-toxic An Inevitable Sequence of Events... Well-meaning physician targets digoxin levels for treatment of HF or atrial fibrillation A patient with eggerthella lenta ends up on an extremely high dose of digoxin Patient receives antibiotics (Z-pack, etc.) Patient gets dig-toxic An Inevitable Sequence of Events... Well-meaning physician targets digoxin levels for treatment of HF or atrial fibrillation A patient with eggerthella lenta ends up on an extremely high dose of digoxin Patient receives antibiotics (Z-pack, etc.) Patient gets dig-toxic NOTE: This is the reason for antibiotic-digoxin medication interactions! 8

9 How to Avoid This? Step 1: Recognize we live in a world of antibiotics. It is not realistic to think your patient will not ultimately get an antibiotic prescription. Step 2: Don t target digoxin levels! You can estimate daily dose by 2 main things: GFR Amiodarone use Nobody should require a maintenance dose > 0.25 mg Remember: For the most part, low levels are okay! Particularly true if using for heart failure indication rather than rate control Reasons for checking digoxin levels: You suspect toxicity To check medication adherence DIG Trial: Post-hoc Analysis of Mortality vs. 1-month Digoxin Levels Adapted from Adams et al. J Am Coll Cardiol. 2005;46: What Do You Do? What about the lisinopril? 1) Continue lisinopril unchanged 2) Decrease lisinopril dose to 10 mg bid 3) Change lisinopril to ARB 4) Stop lisinopril & start sacubitril/valsartan next day 5) Change lisinopril to ARB x 36 hours, then change to sacubitril/valsartan What Do You Do? What about the lisinopril? 1) Continue lisinopril unchanged 2) Decrease lisinopril dose to 10 mg bid 3) Change lisinopril to ARB 4) Stop lisinopril & start sacubitril/valsartan next day 5) Change lisinopril to ARB x 36 hours, then change to sacubitril/valsartan 9

10 PARADIGM-HF Neprilysin: Breaks down natriuretic peptides & angiotensin II Trial: Sacubitril-valsartan vs. Enalapril Double-blind, randomized trial of 8442 patients LVEF 40% NYHA II-IV Primary end-point: Time to CV death or HF hospitalization Stopped early after median follow-up of 27 months ACC/AHA/HFSA Guidelines: SWITCH NYHA Class 2-3 HFrEF patients from ACEi or ARB to sacubitril-valsartan (Class 1 recommendation!) Adapted from McMurray et al. New Engl J Med. 2014;371: Breakdown of Outcomes Adapted from McMurray et al. New Engl J Med. 2014;371: Breakdown of Outcomes Adapted from McMurray et al. New Engl J Med. 2014;371: Breakdown of Outcomes Adapted from McMurray et al. New Engl J Med. 2014;371:

11 What You Should Be Asking Yourself Which systolic HF patients should I not be putting on sacubitril/valsartan? Practicalities of Use Greater BP drop than with ACEi or ARB alone Must be off of ACEi for at least 36 hours (angioedema risk) All the more reason to get away from ACEi for new heart failure patients Make sure insurance approval in place! Adapted from McMurray et al. New Engl J Med. 2014;371: Dietary Restrictions What diet should you recommend? 1) Eat however you want! 2) Fluid restricted 3) Sodium restricted 4) Sodium & fluid restricted 5) Sodium & fluid & saturated fat restricted 6) Sodium & fluid & sugar & saturated fat restricted Dietary Restrictions What diet should you recommend? 1) Eat however you want! 2) Fluid restricted 3) Sodium restricted 4) Sodium & fluid restricted 5) Sodium & fluid & saturated fat restricted 6) Sodium & fluid & sugar & saturated fat restricted 11

12 American Dietetic Association: HF Diet Guidelines n Fluid intake should be between 1.4 and 1.9 L per day. n Fluid restriction will improve clinical symptoms and quality of life. Adapted from Other Dietary Advice n Brigham & Women s Hospital: Limit fluid to 2 quarts Your fluid restriction may at times leave you with thirst and a dry mouth. Here are a few suggestions to try: Eat fresh juicy fruits such as watermelon, grapes, oranges, peaches, etc. However, if you consume more than 3 servings/day of these juicy fruits, count each additional serving as fluid. (1 cup fruit = ½ cup fluid) Freeze or partially freeze pieces of fruit, like lemon wedges dipped in sugar, for a refreshing treat. Chill mouthwash and gargle for a fresh feeling. Google Search: Heart Failure Diet Recommendations n Cleveland Clinic: Limit of 2 liters per day, Even if you feel thirsty. n UCSF: If you drink too much fluid, your body s water content may increase and make your heart work harder. n Emory: You may be restricted to no more than 2 quarts of fluid per day. Fluid restrictions apply to beverages, high-moisture fruits, yogurt, pudding, ice cream, ice cubes, and any food that melts into a liquid Even if you are thirsty, do not drink more than the recommended allowance. Instead, you should suck on frozen lemon wedges to quench your thirst. Trial of Free-Fluid (FF) vs. Fluid-Restriction (FR) in Treatment of Patients Admitted with ADHF * Time to clinical stability = symptomatic improvement with no evidence of fluid overload, stable weight x 48h, off IV therapies x 48h, no change in cardiac medications for 48h. Adapted from Travers et al. J Card Fail. 2007;13:

13 Outpatients & Fluid Restriction n Randomized, cross-over study n Patients (n=65): CHF with LVEF <45% Stable outpatients without clinical signs of significant volume overload n Intervention (cross-over at mid-study): Restricted fluid group: Maximum intake of 1.5 L/day x 16 weeks Liberalized fluid group: Advised to limit intake to weight-based intake (averaged L/day) x 16 weeks Results n Diuretic changes: Restricted fluid group: 13 increases, 9 decreases Liberalized fluid group: 9 increases, 9 decreases n Hospitalizations: 5 (restricted) vs. 5 (liberalized) n No change in Na, Cr, weight, 6-minute walk Adapted from Holst et al. Scandinavian Cardiovascular Journal. 2008;42: Adapted from Holst et al. Scandinavian Cardiovascular Journal. 2008;42: Sense of Thirst Reported Difficulty to Adhere to Restriction 60 P< P<0.001 % of Patients % of Patients Restricted fluid Liberalized fluid 0 Restricted fluid Liberalized fluid Adapted from Holst et al. Scandinavian Cardiovascular Journal. 2008;42: Adapted from Holst et al. Scandinavian Cardiovascular Journal. 2008;42:

14 Conclusion re: Sodium/Fluid Intake When there is a problem, it is too much sodium, not too much water! Do not waste time/energy on fluid restricting unless patient is hyponatremic Patient s non-restricted water intake is based on maintaining sodium concentration if he/she takes in less salt, he/she will take in less water. Best advice (in normonatremic patient): Drink to quench thirst not more, not less. How to Institute Low Na Diet Most patients think low fat/sugar diet is most important for them. Multiple techniques to do low sodium diet. My advice: Stop the milligram counting! Best diet fresh meat/fruits/vegetables Nothing prepackaged/nothing that anyone has had the opportunity to add salt to. Is Any Device Therapy Indicated? 1) Consult for implantable loop monitor placement 2) Consult for ICD placement 3) Consult for biventricular pacemaker/icd placement 4) No device therapy is indicated Is Any Device Therapy Indicated? 1) Consult for implantable loop monitor placement 2) Consult for ICD placement 3) Consult for biventricular pacemaker/icd placement 4) No device therapy is indicated 14

15 COMPANION Trial (2004) 1520 patients NYHA Class III-IV LVEF 35% QRS 120 ms, PR > 150 ms Median QRS duration 160 ms Randomized to medical therapy vs. biventricular pacemaker vs. biventricular pacemaker/icd Median f/u: 29.4 months Primary endpoint: Death or hospitalization COMPANION Trial: Survival Without Hospitalization P<0.001 Adapted from Bristow et al. NEJM. 2004;350: COMPANION Trial: Survival P<0.001 CARE-HF Trial 813 patients NYHA Class III-IV LVEF 35% QRS 150 ms or ms with additional echo criteria Most patients = LBBB, Median QRS = 160 ms Randomized to resynchronization vs. no resynchronization No ICD therapy Median f/u: 29.4 months Primary endpoint: All-cause mortality or CV hospitalization Adapted from Bristow et al. NEJM. 2004;350:

16 CARE-HF Trial: Survival Without CV Hospitalization CARE-HF Trial: Overall Survival P<0.001 P<0.002 Adapted from Cleland et al. NEJM. 2005;352: Adapted from Cleland et al. NEJM. 2005;352: A Concerning Lab... You have diuresed the patient to apparent euvolemia. Repeat NT-proBNP = What should you do based on this result? 1) Discharge the patient as planned 2) Push forward with further diuresis 3) Further uptitrate neurohormonal antagonists A Concerning Lab... You have diuresed the patient to apparent euvolemia. Repeat NT-proBNP = What should you do based on this result? 1) Discharge the patient as planned 2) Push forward with further diuresis 3) Further uptitrate neurohormonal antagonists 16

17 TIME-CHF Trial 499 patients age >60 with NYHA II-IV HF All with HF hospitalizations within past year Intervention: Symptom-guided management or NT-proBNP-guided therapy Primary endpoints: 18 month survival free of hospitalization Quality of life at 18 months No Difference in Hospital-Free Surivival Adapted from Pfisterer et al. JAMA 2009;301: Adapted from Pfisterer et al. JAMA 2009;301: No Difference in QOL (If Anything Better Without NT-BNP!) Minnesota Living with Heart Failure Score BOT-AcuteHF Trial 271 patients hospitalized for ADHF, randomized Patients first treated with usual care until clinical stability, then randomized to: Conventional treatment (blinded to NT-proBP measurement), or NT-proBNP-guided treatment If NT-proBNP 3000 ng/l à treatment intensified (more neurohormonal blockade, inotrope treatment, and/or more loop diuretics) Primary endpoint: CV Death or CV rehospitalization at day 182 Mean furosemide discharge dose (P=0.077): Control: 164 mg NT-proBNP-guided: 198 mg Adapted from Pfisterer et al. JAMA 2009;301: Adapted from Castrini et al. J Cardiovasc Med. 2016;

18 Outcomes (at 182 Days) PRIMA II Trial 400 patients, randomized in 8 European centers Inclusion criteria: ADHF admission NT-proBNP 1700 ng/l Patients first treated with usual care until clinical stability, then randomized to: Conventional treatment (blinded to NT-proBP measurement), or NT-proBNP-guided treatment (targeting >30% NTproBNP reduction from admission to discharge) Followed treatment algorithm if NT-proBNP value <30% reduction at randomization Primary endpoint: All-cause mortality and HF readmissions in 180 days after randomization Adapted from Castrini et al. J Cardiovasc Med. 2016; Adapted from Steinen et al. J Card Fail. 2016;22: Results: Still, Not Published, but... Results: Still, Not Published, but... Adapted from accessed September 23, 2017 Adapted from accessed September 23,

19 Outcomes (at 180 Days) How Should You Diurese Him? 1) IV loop diuretics in bid bolus doses 2) IV loop diuretics with continuous drip 3) Take your pick it doesn t matter. Adapted from accessed September 23, 2017 How Should You Diurese Him? 1) IV loop diuretics in bid bolus doses 2) IV loop diuretics with continuous drip 3) Take your pick it doesn t matter. Should We Give Bolus or Infusional IV Diuretics? Multicenter, double-blind trial published in NEJM ADHF patients, comparing: Bolus dose every 12 hours vs. infusional Low-dose vs. high-dose (no significant differences) Primary endpoints: Patients global assessment of symptoms Change in serum Cr from baseline to 72 hours 19

20 Global Assessment of Symptoms Change in Creatinine Adapted from Felker et al. New Engl J Med. 2011;364: Adapted from Felker et al. New Engl J Med. 2011;364: Death, Rehospitalization, or ED Visit Patient #2 76 y.o. woman with HTN is taken to the ER from her 4 th of July BBQ because of sudden SOB PE: Wt 75 kg (baseline 74 kg) BP 185/110, HR 115, SaO2 85% RA, diffuse bibasilar rales. Baseline meds: ASA 325 mg qd, HCTZ 25 mg qd, amlodipine 10 mg qd, lisinopril 20 mg qd CXR: Normal cardiac silhouette, diffuse pulmonary edema ECG: Sinus tachycardia at 115 bpm, LVH criteria with repolarization abnormality Adapted from Felker et al. New Engl J Med. 2011;364:

21 Labs & Echo Labs: Na 137, K 4.1, Cr 1.6 (baseline 1.6) NT-pro BNP 450, troponin I <0.1 ABG: 7.49/28/54 on RA Baseline echo: Normal LV size/function Moderate LVH 2+ MR What Do You Do? What should you do immediately? 1) Intubation, furosemide 2) BIPAP, sublingual nitroglycerin, furosemide 3) BIPAP, nitroglycerin drip, furosemide 4) BIPAP, dobutamine, furosemide What Do You Do? What should you do immediately? 1) Intubation, furosemide 2) BIPAP, sublingual nitroglycerin, furosemide 3) BIPAP, nitroglycerin drip, furosemide 4) BIPAP, dobutamine, furosemide What is the Problem? Characteristic findings in a patient who develops flash pulmonary edema: Poorly compliant ventricle (often with LVH) Can be worsened by ischemia Small weight gain, relatively unimpressive BNP Often have significant mitral regurgitation Almost always hypertensive at presentation 21

22 What is the Solution? Patient is in a vicious cycle Pulmonary edema/hypoxia à distress/raised BP à worsened pulmonary edema/hypoxia Pulmonary edema/hypoxia à ischemia à worsened pulmonary edema/hypoxia Time is of the essence you are at a crossroads Quick, decisive action à rapid improvement Delayed (or unaggressive) action à worsening of vicious cycle How to Treat this Patient Vasodilator at reasonable doses Nitroglycerin (sublingual!) Clevidipine/Nicardipine/Nitroprussid e/nesiritide Diuresis Important, but not as important Respiratory support Oxygen BIPAP (also helps lower preload) Intubation beware sudden hypotension! What to Tell this Patient Long Term This is the patient most sensitive to sodium intake Literally one indiscretion à flash pulmonary edema Focus on BP control Role of conventional heart failure medications not clear No indication for device therapy (e.g. ICD, resynchronization) Give this patient SL nitroglycerin tabs at discharge!!! Patient #3 45 y.o. man with idiopathic dilated cardiomyopathy à ER for nausea/vomiting, abdominal pain Exam: Vitals: AF BP 80/40 HR 120 RR 22 SaO2 95% RA + scleral icterus/mild jaundice JVP elevated to 20 cm H 2 O Loud S3 gallop Abd: Distended, diffusely tender but worst over RUQ, equivocal Murphy s sign Ext: Clammy extremities, 2+ bilateral LE edema 22

23 Meds/Labs Outpatient meds: Carvedilol mg bid Lisinopril 2.5 mg bid Furosemide 80 mg bid Digoxin mg qd Spironolactone 25 mg qd Labs: Na 128, K 5.6, Cr 2.0 (baseline 1.4) Bilirubin 5.4 (baseline 1.0), Alk phos 180, INR 1.5, AST 900, ALT 750 WBC 10k, NT-proBNP 3500, Lipase 60 Other Findings CXR: Cardiomegaly, mild interstitial thickening, no obvious pulmonary edema Baseline echo: Severe LV dilatation, LVEF 20%, 3+ MR, 2-3+ TR, RVSP = 55 mmhg ECG: Sinus tach at 120, nonspecific ST-T changes (unchanged from baseline except HR) ECG & Ultrasound STAT RUQ U/S: + gallbladder wall thickening possibly c/w cholecystitis, + ascites, normal CBD What Do You Do? 1) Consult surgery for cholecystectomy 2) Start on Abx/fluids for cholecystitis 3) Diurese 4) Diurese/afterload reduce 5) Diurese/pressors 6) Diurese/inotropes 23

24 What Do You Do? 1) Consult surgery for cholecystectomy 2) Start on Abx/fluids for cholecystitis 3) Diurese 4) Diurese/afterload reduce 5) Diurese/pressors 6) Diurese/inotropes What is the Diagnosis? Low output heart failure (e.g. cardiogenic shock) Keys to the diagnosis: Low BP, elevated JVP, S3 Frequently present differently than you might think GI complaints Elevated LFTs (can be bili or transaminase pattern) Worsened renal function Much less common: Pulmonary edema/hypoxia How to Functionally Manage This Patient Augment forward flow Afterload reduce if possible (cannot now due to hypotension) Inotrope (different from pressor!) Diurese Remember to look for an inciting cause! Big-picture considerations LVAD? Transplant? Hospice? Inotropes vs. Pressors These agents do three basic things: Vasodilate Vasoconstrict ( pressor ) Inotropy What agent to choose = what are you trying to achieve? Septic patient: Problem is inappropriate vasodilatation à use vasoconstrictor Hypertensive pulmonary edema (last patient): Problem is inappropriate vasoconstriction à use vasodilator Cardiogenic shock patient: Problem is weak muscle/low cardiac output à use inotropic agent + vasodilator (as tolerated) 24

25 IV Drips From Vasodilators to Pressors NTG/Nitroprusside/Nesiritide/ Nicardipine/Clevidipine Dobutamine/Milrinone Dopamine Epinephrine Norepinephrine Phenylephrine/Vasopressin Vasodilatation Inotropy Vasoconstriction Summary Avoid term heart failure exacerbation Multiple patients, multiple problems... multiple treatments! Standard HF admission: Remember: Digoxin, sacubitril-valsartan, salt restriction, cardiac resynchronization Generally avoid: Water restriction, loop diuretic drips, targeting digoxin level Pressure overload admission: Vasodilate! Sublingual NTG = most rapid/effective Low output admission: Inotropic/mechanical support Avoid pressors Remember: Abdominal sx, tricky presentations Final Thought: Question Dogma! Education consists mainly of what we have unlearned. Thank you! -Mark 25