“High”dralazine-Does Dosage Matter In Heart Failure?

Manish Khullar, BSc PharmInterior 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 PatientID 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 weaknessNon-productive coughNausea, vomiting (stopped all medications 3 days prior to admission)

Allergies NKAsSocial History Lives in a house alone

No alcoholQuit smoking 25 years ago

Our PatientPast Medical History Medications Prior to Admission

Congestive Heart Failure Carvedilol 12.5mg po BIDSpironolactone 12.5mg po daily Hydralazine 50mg po TIDNitropatch 0.4mg/hr Furosemide 80mg po daily

Coronary Artery Disease (MI in 2006) ASA 81mg po dailyCarvedilol 12.5mg po BIDAmlodipine 10mg po daily

Hypertension Amlodipine 10mg po daily Carvedilol 12.5mg po BIDSpironolactone 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 qpmInsulin 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 breathNon-productive cough

CVS JVP > 3cm ASAPedal 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 dailyHydralazine 50mg po QID Nitropatch 0.6mg/hr qam and remove qHS

Hypertension Amlodipine 10mg po dailyHydralazine 50mg po QIDCarvedilol 12.5mg po BID Spironolactone 12.5mg po dailyNitropatch 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 qpmInsulin 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 DTPs1) 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 HydralazineHeart failure

Limits a. Englishb. Humansc. 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 editorsGuidelines• ACC AHA 2013 guidelines• CCS 2006 guidelines

VHeFTDesign Randomized, double blind, placebo controlled trial

Patient Inclusion:18-75 years of ageMale onlyLVEF <45%Reduced exercise tolerance Exclusion:Exercise tolerance was limited due to chest painSignificant CAD or MI within prior 3 monthsValvular diseaseLong 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

Hydralazine 300mg + ISDN 120mg

Prazosin 20mg daily Placebo0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

38.7%

49%44%

% Mortality

N Engl J Med 1986; 314:1547-1552

N Engl J Med 1986; 314:1547-1552

VHeFT Results: SafetyPlacebo 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 ageSelf identified as African AmericanEvidence 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: EfficacyISDN +

hydralazine (N=518)

Placebo(N=532)

P-value NNT

Primary Composite score (death from any cause, 1st hospitalization for HF, change in QOL)

-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 -

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) Hydralazine 75mg po QID (300mg/day)2) Spironolactone 25mg po daily3) Nitropatch 0.8mg/hour4) Continue carvedilol 12.5mg po BID5) 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 PlanEfficacy Degree of Change When

S: Fatigue SOBOrthopnea

Absence AbsenceAbsence

Daily dailyOngoing

O: Vitals: BP, RR, HR, Sa02Daily weight Abdominal distensionPeripheral edema

Stable Return to baseline Return to baselineReturn to baseline

Daily DailyDaily Daily

Toxicity Degree of Change When

S: DizzinessHeadache GI upset

Presence Presence Presence

Daily DailyDaily

O: Vitals: BP, HRRashKSrCr

↓ BP, ↑ HRPresence↑↑

Daily DailyDailyDaily

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!!!!)