1. “High”dralazine-Does Dosage Matter In Heart Failure? Manish Khullar, BSc Pharm Interior Health Pharmacy Resident Cardiology Rotation January 23, 2014

2. 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

3. Our Patient IDRS is a 71 year old male admitted on January 12 th, 2014 CC/HPIShortness 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) AllergiesNKAs Social HistoryLives in a house alone No alcohol Quit smoking 25 years ago

4. Our Patient Past Medical HistoryMedications Prior to Admission Congestive Heart FailureCarvedilol 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 HypertensionAmlodipine 10mg po daily Carvedilol 12.5mg po BID Spironolactone 12.5mg po daily Hydralazine 50mg po TID Chronic Kidney DiseaseØ

5. Our Patient Past Medical HistoryMedications Prior to Admission Type 1 DiabetesInsulin glargine 14U qam and 24U qpm Insulin aspart 2-5U with meals Polymyalgia RheumaticaPrednisone 10mg po daily HypothyroidismLevothyroxine 137mcg po daily GoutHydromorphone 2mg po q4-6h prn GERDPantoprazole 40mg po BID Diabetic NeuropathyGabapentin 300mg po BID DepressionEscitalopram 20mg po daily InsomniaMirtazapine 30mg qhs

6. Review of Systems VitalsT: 37.1 BP: 181/67 HR: 70 RR: 26 SaO2: 79% RA CNSGCS x 15, A+O x 3, dizzy HEENTNormal RESPShortness of breath Non-productive cough CVSJVP > 3cm ASA Pedal edema GIAbdominal distension GUSrCr: 197umol/L (baseline: 210umol/L) eGFR: 29mL/min MSK/DERMØ ENDORandom glucose: 10mmol/L HEMEWBC: 11.2 Neutrophils: 9.3 LYTESNa: 140 K: 3.3

7. Investigations Diagnostics: – Chest x-ray (upon admission) Enlarged heart Bilateral pleural effusions Pulmonary edema – ECHO (2012) EF: 15-20%

8. Current Problems and Medications HF ExacerbationFurosemide 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 HypertensionAmlodipine 10mg po daily Hydralazine 50mg po QID Carvedilol 12.5mg po BID Spironolactone 12.5mg po daily Nitropatch 0.6mg/hr HypokalemiaPotassium chloride 300mg po BID CADASA 81mg po daily Carvedilol 12.5mg po BID Amlodipine 10mg po daily Type 1 DiabetesInsulin glargine 14U qam and 24U qpm Insulin aspart 2-5U with meals

9. Current Problems and Medications CKDØ GERDPantoprazole 40mg po BID Diabetic NeuropathyGabapentin 300mg po BID GoutHydromorphone 2mg po q4-6h prn Polymyalgia RheumaticaPrednisone 10mg po daily HypothyroidismLevothyroxine 137mcg daily DepressionEscitalopram 20mg po daily InsomniaMirtazapine 30mg po qhs VTE ProphylaxisHeparin 5000 SC q12h

10. Course in Hospital Furosemide po  IV on admission Hydralazine TID  QID (200mg/day) Nitroglycerin patch 0.4mg  0.6mg

11. 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

12. 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

13. DTP Focus RS is at risk of mortality, HF exacerbations and hospitalizations secondary to not being on an optimal dose of hydralazine

14. Goals of Therapy Prolong survival Reduce morbidity Exacerbations Hospitalizations Minimize symptoms Prevent adverse events Improve QOL

15. Background: Pathophysiology

16. Treatment Approach in HF Can J Cardiol 2006; 22:23-45

17. 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

18. 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

19. 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

20. 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

21. 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?

22. Literature Search DatabasesMedline, embase, google scholar Search TermsHydralazine Heart failure Limitsa. English b. Humans c. Full text, RCT, MA, SRs Results24 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

23. VHeFT DesignRandomized, double blind, placebo controlled trial PatientInclusion: 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% InterventionPrazosin 20mg daily vs hydralazine 300mg daily + ISDN 160mg daily vs placebo OutcomesPrimary Outcome: mortality at 2 years N Engl J Med 1986; 314:1547-1552

24. VHeFT Results: Efficacy N Engl J Med 1986; 314:1547-1552

26. VHeFT Results: Safety PlaceboPrazosinHydralazine + ISDN Discontinued Treatment 22%27%22% Cardiac events4.8%2.2% Headache1823 Dizziness51312 GI effect537 N Engl J Med 1986; 314:1547-1552

27. 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

28. A HeFT $ DesignRandomized, double-blind, placebo-controlled trial x 18 months PopulationInclusion: 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% InterventionHydralazine 225mg total daily dose divided TID + ISDN 120mg vs placebo OutcomesPrimary endpoint: Composite of death from any cause, a first hospitalization for HF, and change in quality of life

29. Scoring System New Engl J Med 2004;351:2049-2057

30. Results: Efficacy ISDN + hydralazine (N=518) Placebo (N=532) P-valueNNT Primary Composite score (death from any cause, 1 st hospitalization for HF, change in QOL) -0.1 +/- 1. 9-0.5 /- 20.01- Death from any cause 6.2%10.2%0.0225 First hospitalization 16.4%24.4%0.00113 Change in QOL score -5.6-2.70.02- New Engl J Med 2004;351:2049-2057

31. Results: Safety ISDN + hydralazine (%) Placebo (%) P-value Exacerbations8.712.80.04 Headache47.519.2<0.001 Dizziness29.312.3<0.001 New Engl J Med 2004;351:2049-2057

32. 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

33. 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”

34. 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!

35. Patient Specific Factors Patient’s comorbidities Tolerability Cost

36. 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

37. Therapeutic Recommendation 1)Hydralazine 75mg po QID (300mg/day) 2)Spironolactone 25mg po daily 3)Nitropatch 0.8mg/hour 4)Continue carvedilol 12.5mg po BID 5)Continue furosemide 80mg po daily

38. 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

39. Monitoring Plan EfficacyDegree of ChangeWhen S:Fatigue SOB Orthopnea Absence Daily daily Ongoing O:Vitals: BP, RR, HR, Sa02 Daily weight Abdominal distension Peripheral edema Stable Return to baseline Daily ToxicityDegree of ChangeWhen S:Dizziness Headache GI upset Presence Daily O:Vitals: BP, HR Rash K SrCr ↓ BP, ↑ HR Presence ↑ Daily

40. Follow-up Janurary 14 th :  Repeat chest x-ray: pulmonary edema and pleural effusions improved significantly Cardiomegaly improved slightly but still persists January 15 th :  Patient improved clinically and no longer symptomatic Discharged on Jan 16 th :  Medications were reconciled  Counselled the patient on adherence and medication changes  Patient discharged

41. Questions… ? (Logged a personal best of 21 DTPs for this patient!!!!)