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“High”dralazine-Does Dosage Matter In Heart Failure? Manish Khullar, BSc Pharm Interior Health Pharmacy Resident Cardiology Rotation January 23, 2014 Learning Objectives • Describe the pathophysiology of heart failure (HF) • List the therapeutic alternatives for HF • To be able to explain the evidence of the different doses of hydralazine used in patients with HF Our Patient ID RS is a 71 year old male admitted on January 12th, 2014 CC/HPI Shortness of breath for 3 days that has been getting progressively worse Fatigue and weakness Non-productive cough Nausea, vomiting (stopped all medications 3 days prior to admission) Allergies NKAs Social History Lives in a house alone No alcohol Quit smoking 25 years ago Our Patient Past Medical History Medications Prior to Admission Congestive Heart Failure Carvedilol 12.5mg po BID Spironolactone 12.5mg po daily Hydralazine 50mg po TID Nitropatch 0.4mg/hr Furosemide 80mg po daily Coronary Artery Disease (MI in 2006) ASA 81mg po daily Carvedilol 12.5mg po BID Amlodipine 10mg po daily Hypertension Amlodipine 10mg po daily Carvedilol 12.5mg po BID Spironolactone 12.5mg po daily Hydralazine 50mg po TID Chronic Kidney Disease Ø Our Patient Past Medical History Medications Prior to Admission Type 1 Diabetes Insulin glargine 14U qam and 24U qpm Insulin aspart 2-5U with meals Polymyalgia Rheumatica Prednisone 10mg po daily Hypothyroidism Levothyroxine 137mcg po daily Gout Hydromorphone 2mg po q4-6h prn GERD Pantoprazole 40mg po BID Diabetic Neuropathy Gabapentin 300mg po BID Depression Escitalopram 20mg po daily Insomnia Mirtazapine 30mg qhs Review of Systems Vitals T: 37.1 BP: 181/67 HR: 70 RR: 26 SaO2: 79% RA CNS GCS x 15, A+O x 3, dizzy HEENT Normal RESP Shortness of breath Non-productive cough CVS JVP > 3cm ASA Pedal edema GI Abdominal distension GU SrCr: 197umol/L (baseline: 210umol/L) eGFR: 29mL/min MSK/DERM Ø ENDO Random glucose: 10mmol/L HEME WBC: 11.2 Neutrophils: 9.3 LYTES Na: 140 K: 3.3 Investigations • Diagnostics: – Chest x-ray (upon admission) • Enlarged heart • Bilateral pleural effusions • Pulmonary edema – ECHO (2012) • EF: 15-20% Current Problems and Medications HF Exacerbation Furosemide 40mg IV BID Carvedilol 12.5mg po BID Spironolactone 12.5mg po daily Hydralazine 50mg po QID Nitropatch 0.6mg/hr qam and remove qHS Hypertension Amlodipine 10mg po daily Hydralazine 50mg po QID Carvedilol 12.5mg po BID Spironolactone 12.5mg po daily Nitropatch 0.6mg/hr Hypokalemia Potassium chloride 300mg po BID CAD ASA 81mg po daily Carvedilol 12.5mg po BID Amlodipine 10mg po daily Type 1 Diabetes Insulin glargine 14U qam and 24U qpm Insulin aspart 2-5U with meals Current Problems and Medications CKD Ø GERD Pantoprazole 40mg po BID Diabetic Neuropathy Gabapentin 300mg po BID Gout Hydromorphone 2mg po q4-6h prn Polymyalgia Rheumatica Prednisone 10mg po daily Hypothyroidism Levothyroxine 137mcg daily Depression Escitalopram 20mg po daily Insomnia Mirtazapine 30mg po qhs VTE Prophylaxis Heparin 5000 SC q12h Course in Hospital • Furosemide poIV on admission • Hydralazine TID QID (200mg/day) • Nitroglycerin patch 0.4mg 0.6mg List of DTPs 1) RS is at risk of mortality, MI, stroke and further exacerbations of HF secondary to uncontrolled hypertension 2) RS is at risk of mortality, exacerbations of HF, hospitalizations, and worsening kidney function secondary to not being on an ACEI/ARB 3) RS is at risk of mortality, exacerbations, and hospitalizations secondary to not being on an optimal dose of carvedilol 4) RS is at risk of mortality, exacerbations, and hospitalizations secondary to not being on an optimal dose of spironolactone 5) RS is at risk of mortality, exacerbations, and hospitalizations secondary to not being on an optimal dose of hydralazine List of DTPs 6) At risk of arrhythmias secondary to hypokalemia due to furosemide 7) RS is at risk of death and reinfarction secondary to not being on a statin for secondary prevention of MI 8) RS is at risk of recurrent gout attacks secondary to not being on prophylaxis therapy 9) RS is at risk of C. difficile infection, pneumonia and vitamin B12 deficiency secondary to being on twice daily PPI DTP Focus RS is at risk of mortality, HF exacerbations and hospitalizations secondary to not being on an optimal dose of hydralazine Goals of Therapy • Prolong survival • Reduce morbidity • Exacerbations • Hospitalizations • Minimize symptoms • Prevent adverse events • Improve QOL Background: Pathophysiology Treatment Approach in HF Can J Cardiol 2006; 22:23-45 Background: • Hydralazine: – Vasodilation of arterioles with little effect on veins ↓ systemic vascular resistance ↓ afterload • Nitroglycerin: – Relaxation of both arteries and veins ↓ preload and afterload ↓ myocardial oxygen demand Background: Classification of HF • New York Heart Association: • NYHA I: No symptoms with normal activites • NYHA II: Symptoms with ordinary activity (symptoms if walk more than 1 set of stairs or hurrying on the level) • NYHA III: Symptoms with less than ordinary activity (<100m or 1 flight of stairs) • NYHA IV: Symptoms at rest or minimal activity AHA Guidelines • “A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated…” • Recommended target dose: 300mg daily in divided doses AHA 2013 Canadian Guidelines • A combination of ISDN and hydralazine may be considered for heart failure patients unable to tolerate other recommended standard therapy • Recommended target dose: 225mg daily in divided doses Can J Cardiol 2006; 22:23-45 Clinical Question • In a patient with NYHA III heart failure, is a total daily dose of 225mg of hydralazine as compared to 300mg daily as effective at reducing mortality, number of exacerbations, hospitalizations and symptoms? Literature Search Databases Medline, embase, google scholar Search Terms Hydralazine Heart failure Limits a. English b. Humans c. Full text, RCT, MA, SRs Results 24 articles: • 0 articles for head-to-head comparison • 2 RCTs • Excluded: non-relevant articles -Cost effectiveness, exercise tolerance, letters to the editors Guidelines • ACC AHA 2013 guidelines • CCS 2006 guidelines VHeFT Design Randomized, double blind, placebo controlled trial Patient Inclusion: 18-75 years of age Male only LVEF <45% Reduced exercise tolerance Exclusion: Exercise tolerance was limited due to chest pain Significant CAD or MI within prior 3 months Valvular disease Long acting nitrates, CCBs, BBs, any other antihypertensive drugs other than diuretics Baseline: N=642, mean age 58.4 years, alcoholism ~40%, hypertension 41%, CAD 44%, BP 119/76, EF 30%, vasodilators 37.8%, antiarrhythmics 27% Intervention Prazosin 20mg daily vs hydralazine 300mg daily + ISDN 160mg daily vs placebo Outcomes Primary Outcome: mortality at 2 years N Engl J Med 1986; 314:1547-1552 VHeFT Results: Efficacy 60.0% 49% 50.0% 44% 40.0% % Mortality 38.7% 30.0% 20.0% 10.0% 0.0% Hydralazine 300mg + ISDN 120mg Prazosin 20mg daily Placebo N Engl J Med 1986; 314:1547-1552 N Engl J Med 1986; 314:1547-1552 VHeFT Results: Safety Placebo Prazosin Hydralazine + ISDN Discontinued Treatment 22% 27% 22% Cardiac events 4.8% 2.2% 2.2% Headache 1 8 23 Dizziness 5 13 12 GI effect 5 3 7 N Engl J Med 1986; 314:1547-1552 Limitations of VHeFT • Small sample size • Patients were not on modern background therapy • Only 55% reached target dose at 6 months • Younger patient population • Men only • Limited generalizability A HeFT Design Randomized, double-blind, placebo-controlled trial x 18 months Population Inclusion: NYHA class III /IV HF for at least 3 months and dilated ventricles > 18 years of age Self identified as African American Evidence of LVEF <35% Receiving standard therapy (ACEIs/ARBs, BBs for 3 months prior to randomization, digoxin, spironolactone, and diuretics) Excluded: ACS or stroke in prior 3 months, cardiac surgery, or PCI within 3 months, valvular heart disease, uncontrolled hypertension Baseline: N=1050; mean age 57, NYHA III ~95%, BP ~126/76, LVEF ~24%, renal insufficiency 17%, diabetes 40% Diuretics 90%, ACEI 69%, ARB 17%, BB 74% (carvedilol 55%), digoxin 60%, spironolactone 38% $ Intervention Hydralazine 225mg total daily dose divided TID + ISDN 120mg vs placebo Outcomes Primary endpoint: Composite of death from any cause, a first hospitalization for HF, and change in quality of life Scoring System New Engl J Med 2004;351:2049-2057 Results: Efficacy ISDN + hydralazine (N=518) Placebo (N=532) P-value NNT -0.1 +/- 1. 9 -0.5 /- 2 0.01 - Death from any cause 6.2% 10.2% 0.02 25 First hospitalization 16.4% 24.4% 0.001 13 Change in QOL score -5.6 -2.7 0.02 - Primary Composite score (death from any cause, 1st hospitalization for HF, change in QOL) New Engl J Med 2004;351:2049-2057 Results: Safety ISDN + hydralazine (%) Placebo (%) P-value Exacerbations 8.7 12.8 0.04 Headache 47.5 19.2 <0.001 Dizziness 29.3 12.3 <0.001 New Engl J Med 2004;351:2049-2057 Limitations of AHeFT • No power calculation defined • Examined a population where efficacy is more likely to be established • Only 68% percent reached target dose • Younger population • Generalizability • African Americans, ACEIs/ARBs, digoxin, excluded uncontrolled hypertension Bottom Line of AHeFT • “The addition of a fixed dose ISDN + hydralazine to standard therapy for HF is efficacious and increases survival among black patients with advanced heart failure” Bottom Line of Hydralazine 225mg daily vs. 300mg daily… • No head-to-head comparison • Unknown which is more effective • Guideline recommendations are based on underpowered trials or trials with limited generalizability! Patient Specific Factors • Patient’s comorbidities • Tolerability • Cost Our Options • • • • • • Add ACEIs/ARB Increase beta blockers Hydralazine 225mg daily divided TID Hydralazine 300mg daily divided QID Increase nitropatch dose to 0.8mg/hr Increase spironolactone dose to 25mg daily Therapeutic Recommendation 1) 2) 3) 4) 5) Hydralazine 75mg po QID (300mg/day) Spironolactone 25mg po daily Nitropatch 0.8mg/hour Continue carvedilol 12.5mg po BID Continue furosemide 80mg po daily Other Recommendations 1) Initiated potassium chloride 40mEq po BID x 1 day 2) Initiated allopurinol 100mg po daily 3) Changed pantoprazole 40mg to once daily Monitoring Plan Efficacy Degree of Change When S: Fatigue SOB Orthopnea Absence Absence Absence Daily daily Ongoing O: Vitals: BP, RR, HR, Sa02 Daily weight Abdominal distension Peripheral edema Stable Return to baseline Return to baseline Return to baseline Daily Daily Daily Daily Toxicity Degree of Change When S: Dizziness Headache GI upset Presence Presence Presence Daily Daily Daily O: Vitals: BP, HR Rash K SrCr ↓ BP, ↑ HR Presence ↑ ↑ Daily Daily Daily Daily Follow-up • Janurary 14th: Repeat chest x-ray: • pulmonary edema and pleural effusions improved significantly • Cardiomegaly improved slightly but still persists • January 15th: Patient improved clinically and no longer symptomatic • Discharged on Jan 16th: Medications were reconciled Counselled the patient on adherence and medication changes Patient discharged Questions… ? (Logged a personal best of 21 DTPs for this patient!!!!)
