Heart Failure Treatment in African American Patients
Transcript of Heart Failure Treatment in African American Patients
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Heart Failure Treatment in African
American Patients
Theresa Kline, PharmD & Lauren Kemp, PharmD
University of North Carolina Medical Center
Residency Program Director: Ian B. Hollis, PharmD, BCPS-AQ Cardiology
December 5, 2019
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Disclosures
• We have no disclosures to report
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Objectives
• Understand how heart failure etiology and pathophysiology differ in African
American patients versus Caucasian patients
• Analyze the literature for heart failure with reduced ejection fraction (HFrEF)
guideline directed therapies with respect to African American (AA) representation
• Evaluate new literature regarding novel HFrEF therapies and how to apply these
in African American patients
• Design an individualized treatment plan for African American patients with HFrEF
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Patient Case: Scenario 1
• MS is a 57 year old African American female that presents with complaints of
worsening shortness of breath and fatigue for 2 weeks. Symptoms noticeably
worsened after enjoying Thanksgiving dinner with her family.
• PMH: HTN, T2DM, GERD
• Home medications: hydrochlorothiazide 25 mg daily, metformin 1000 mg BID,
atorvastatin 40 mg daily, famotidine 20 mg daily PRN
• Vitals: HR 98, BP 146/92, RR 22, oxygen saturation 94%
• Imaging: Echo 30-35%, Chest x-ray unremarkable, EKG normal sinus rhythm
• Labs: WBC 5.0, HgB 11.8, PLT 202, Na 136, K 4.3, Mg 1.9, Scr 1.1, BUN 22,
Troponin <0.034, Pro-BNP 2034 pg/mL, A1C 7.4%
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Patient Case: Scenario 1
• MS is diagnosed with HFrEF and treated with IV diuretics
• After 48 hours of IV diuresis, MS is ready to transition to oral diuretics and
begin medication optimization.
• 12/5/2019:
• Vitals: HR 96, BP 138/90, RR 16, oxygen saturation 96%
• Labs: WBC 5.0, HgB 11.7, PLT 197, Na 138, K 4.0, Mg 1.9, Scr 0.80, BUN 20
• In addition to stopping hydrochlorothiazide, what medication changes do you
want to make before discharge?• A: Start metoprolol tartrate and lisinopril
• B: Start metoprolol succinate and spironolactone
• C: Start carvedilol and lisinopril
• D: Start carvedilol and hydralazine/isosorbide dinitrate
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Objectives
• Understand how heart failure etiology and pathophysiology differ in African
American patients versus Caucasian patients
• Analyze the literature for heart failure with reduced ejection fraction (HFrEF)
guideline directed therapies with respect to African American (AA) representation
• Evaluate new literature regarding novel HFrEF therapies and how to apply these
in African American patients
• Design an individualized treatment plan for African American patients with HFrEF
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Epidemiology
• African Americans with HFrEF are considered a “high-risk” population
• Relative incidence 50% higher than the general population
• African American men: 1.8-fold increased mortality
• African American women: 2.4-fold increased mortality
Earlier ageNon-ischemic >
Ischemic
Increased
severity of LV
dysfunction
Faster
progression
Increased
hospitalizations
Increased
mortality
Franciosa JA. Congest Heart Fail. 2010;16(1):27-38
Yancy CW. J Natl Med Assoc. 2003;95(1):1-9
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Epidemiology
• Differences in outcomes are NOT solely due to socioeconomic factors • Multivariate analysis of SOLVD (Studies of Left Ventricular Dysfunction) prevention and treatment trials
after adjustment for education and financial distress:
Franciosa JA. Congest Heart Fail. 2010;16(1):27-38
Dries DL. N Engl J Med. 1999;340(8):609-16.
HFrEF Etiology Pathophysiology
OutcomeRelative Risk in African Americans
(95% CI)P-value
Death from all cause 1.28 (1.08 – 1.51) P=0.004
Death from pump failure 1.38 (1.08 – 1.76) P=0.009
Death from any cause or
hospitalization for heart failure 1.37 (1.20 – 1.57) P<0.001
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Neurohormonal Pathways
Renin-Angiotensin-
Aldosterone
System (RAAS)
Sympathetic
Nervous System
(SNS)
Nitric Oxide (NO)
Pathway
Natriuretic
Peptides
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Pathophysiology: RAAS System
• RAAS: Renin – Angiotensin –
Aldosterone System • Vasoconstriction
• Sodium and water retention
• African Americans are less affected by
RAAS inhibition• Lower levels of plasma renin activity
• African Americans have higher levels of transforming growth factor-β1 (TGF-β1)
Yancy CW. J Natl Med Assoc. 2003;95(1):1-9
Image adapted from https://neoreviews.aappublications.org/content/16/10/e575
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Pathophysiology: SNS System
• Sympathetic Nervous System (SNS)• Increased heart rate and workload of heart leads to cardiac remodeling
• African Americans have decreased β-adrenergic receptor sensitivity and lower
norepinephrine levels • Genetic polymorphisms: glycine substituted for arginine at position 389
Yancy CW. J Natl Med Assoc. 2003;95(1):1-9
Image adapted from https://www.medscape.com/viewarticle/463477
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Pathophysiology: Nitric Oxide Pathway
• Nitric oxide (NO) leads to vasodilation
and inhibition of vascular smooth
muscle hypertrophy
• African Americans are less responsive
to nitric oxide• Decreased production of NO
• Decreased NO bioavailability
• Endothelial dysfunction and hypertrophy
Echols MR. Vasc Health Risk Manag. 2006;2(4):423-31.
Franciosa JA. Congest Heart Fail. 2010;16(1):27-38
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Objectives
• Understand how heart failure etiology and pathophysiology differ in African
American patients versus Caucasian patients
• Analyze the literature for heart failure with reduced ejection fraction (HFrEF)
guideline directed therapies with respect to African American (AA)
representation
• Evaluate new literature regarding novel HFrEF therapies and how to apply these
in African American patients
• Design an individualized treatment plan for African American patients with HFrEF
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Pharmacotherapy
Beta blockers
Angiotensin converting enzyme inhibitors/aldosterone receptor
blockers
Hydralazine/isosorbide dinitrate
Angiotensin receptor-neprilysin inhibitor
Aldosterone receptor antagonists
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Current Guidelines
Yancy CW. Circulation. 2017;136:e137–e161.
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Current Guidelines
Yancy CW. Circulation. 2017;136:e137–e161.
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Primary Literature Revisited
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African American Representation in Heart Failure Trials
1
2.5
3.6
5
5
5.1
7
7
20
27
28.5
100
0 10 20 30 40 50 60 70 80 90 100
EPHESUS
EMPHASIS-HF
CHARM
COPERNICUS
MERIT-HF
PARADIGM-HF
RALES
VAL-HeFT
US-Carvedilol
V-HeFT2
V-HeFT1
A-HeFT
Percent
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Guess that heart failure therapy
Shekelle PG. J Am Coll Cardiol. 2003;41(9):1529-38.
Relative Risk of All-Cause Mortality
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Guess that heart failure therapy
Relative Risk of All-Cause Mortality
in African Americans
Shekelle PG. J Am Coll Cardiol. 2003;41(9):1529-38.
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Beta Blockers
• Overall survival benefit demonstrated in HFrEF for all patients
• No significant difference in mortality detected in self-identified black patients
• Wide confidence intervals due to low enrollment
Shekelle PG. J Am Coll Cardiol. 2003;41(9):1529-38.
Packer M. Circulation. 2002;106(17):2194-9.
Merit-HF Study Group. Lancet. 1999;353(9169):2001-7.
Packer M. N Engl J Med. 1996;334(21):1349-55.
Trial Beta BlockerTotal
N% Black
RR White
(95% CI)
RR Black
(95% CI)
RR Overall
(95% CI)NNT
COPERNICUS Carvedilol 2,287 5.3% 0.66 (0.53-0.82) 0.62 (0.19-2.01) 0.65 (0.52-0.81) 15
US Carvedilol
HF TrialsCarvedilol 1,094 19.8% 0.38 (0.20-0.70) 0.53 (0.19-1.48) 0.35 (0.20-0.61) 22
MERIT-HFMetoprolol
succinate3,991 5.2% 0.67 (0.54-0.82) 0.79 (0.36-1.76) 0.66 (0.53-0.81) 27
CIBIS-II Bisoprolol 2647Not
reported-- -- 0.66 (0.54-0.81) 19
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Beta Blockers
• Overall benefit in targeting the SNS in African Americans• Carvedilol:
– Decreased combined endpoint of mortality plus all cause hospitalizations
– Cumulative rates of survival without hospitalization similar to non-black patients
Yancy CW. N Engl J Med 2001; 344:1358-1365
Yancy CW. J Natl Med Assoc. 2003;95(1):1-9
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Beta Blockers
• Overall benefit in targeting the SNS in African Americans• Carvedilol:
– Decreased combined endpoint of mortality plus all cause hospitalizations
– Cumulative rates of survival without hospitalization similar to non-black patients
Yancy CW. N Engl J Med 2001; 344:1358-1365
Yancy CW. J Natl Med Assoc. 2003;95(1):1-9
Beta blockers should be initiated
in all African Americans with
HFrEF unless contraindicated
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ACE Inhibitors and ARBs
• SOLVD Treatment: the only major
trial to report out subgroup data
in black patients
• Enalapril group:
• 7.9 more hospitalizations per
100-patient years (95% CI 5.3 –
10.6) in African American
patients vs white patients
Exner DV, et al. N Engl J Med. 2001;344(18):1351-7.
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Patient Case: Scenario 1
• MS is diagnosed with HFrEF and treated with IV diuretics
• After 48 hours of IV diuresis, MS is ready to transition to oral diuretics and
begin medication optimization.
• 12/5/2019
• Vitals: HR 96, BP 138/90, RR 16, oxygen saturation 96%
• Labs: WBC 5.0, HgB 11.7, PLT 197, Na 138, K 4.0, Mg 1.9, Scr 0.80, BUN 20
• In addition to stopping hydrochlorothiazide, what medication changes do you
want to make before discharge?• A: Start metoprolol tartrate and lisinopril
• B: Start metoprolol succinate and spironolactone
• C: Start carvedilol and lisinopril
• D: Start carvedilol and hydralazine/isosorbide dinitrate
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Patient Case: Scenario 2
• MS presents to clinic 3 months after discharge for routine follow-up. She reports
shortness of breath when walking up more than 1 flight of stairs. She reports no
symptoms consistent with volume overload and appears euvolemic on exam.
• Current medications: carvedilol 25 mg BID, lisinopril 10 mg daily, metformin 1000 mg BID,
atorvastatin 40 mg daily, torsemide 20 mg daily
• Vitals: HR 78, BP 118/88, RR 16
• Labs: WBC 5.0, HgB 11.7, PLT 197, Na 138, K 4.7, Mg 1.9, Scr 0.85, BUN 20
• What medication change(s) should you make in clinic today?• A: Increase lisinopril to 20 mg daily
• B: Add hydralazine 25 mg/isosorbide dinitrate 10 mg TID
• C: Add spironolactone 25 mg daily
• D: Stop lisinopril and start sacubitril/valsartan 24/26 mg BID after 36 hour washout
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Hydralazine/Isosorbide dinitrate (HI): VHeFT I
• Evaluate the addition of vasodilator therapy in 642 HFrEF patients• Intervention: Prazosin 20 mg/day (N=183) vs. HI 300/160 mg/day (N=186) vs. placebo (N=273)
Carson P. J Card Fail. 1999;5(3):178-87.
Cohn JN. NEJM. 1986. 314(24):1547-52.
Endpoint Prazosin HI Placebo RR P-value NNT
Overall Mortality 49.7% 38.7% 44.0% NA 0.093 --
Mortality at 2 years -- 25.6% 34.3% 0.75 <0.028 12
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Hydralazine/Isosorbide dinitrate (HI): VHeFT I
• Evaluate the addition of vasodilator therapy in 642 HFrEF patients• Intervention: Prazosin 20 mg/day (N=183) vs. HI 300/160 mg/day (N=186) vs. placebo (N=273)
African American Subgroup White Subgroup
HI vs. PL P<0.041 HI vs. PL P<0.48
Carson P. J Card Fail. 1999;5(3):178-87.
Cohn JN. NEJM. 1986. 314(24):1547-52.
Endpoint Prazosin HI Placebo RR P-value NNT
Overall Mortality 49.7% 38.7% 44.0% NA 0.093 --
Mortality at 2 years -- 25.6% 34.3% 0.75 <0.028 12
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Hydralazine/Isosorbide dinitrate (HI): VHeFT II
• Enalapril 20 mg/day vs. HI 300/160 mg/day• Mortality at 2 years: Enalapril 18% vs. HI 25% (P=0.016, NNT 15)
Carson P. J Card Fail. 1999;5(3):178-87.
Cohn JN. NEJM. 1991. 325(5):303-310.
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Hydralazine/Isosorbide dinitrate (HI): VHeFT II
• Enalapril 20 mg/day vs. HI 300/160 mg/day• Mortality at 2 years: Enalapril 18% vs. HI 25% (P=0.016, NNT 15)
• White patients responded better to enalapril than HI
• African American patients responded to both therapies
African American Subgroup White Subgroup
E vs. HI P<0.95 E vs. HI P<0.02
Carson P. J Card Fail. 1999;5(3):178-87.
Cohn JN. NEJM. 1991. 325(5):303-310.
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Hydralazine/Isosorbide dinitrate (HI): AHeFT
• Evaluate the efficacy of HI in black patients with NYHA
class III or IV heart failureObjective
• Randomized, double-blind, placebo-controlled
• HI 225 mg/120 mg/day vs. placebo in addition to standard
HFrEF therapiesMethods
• Weighted composite score of death, 1st heart failure
hospitalization and change in quality of life (QoL)Primary Outcome
Taylor AL. NEJM. 2004. 351(20):2049-2057.
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AHeFT: Baseline Characteristics
CharacteristicHI
(N=518)
Placebo
(N=532)
Age (yr) 56.7 56.9
Male (%) 55.8 63.9
Heart Failure Etiology (%)
• Ischemic
• HTN
• Other
23.4
40.0
36.7
22.7
37.4
39.8
NYHA (%)
• I
• II
• III
• IV
0.0
0.2
96.7
3.1
0.0
0.0
94.7
5.3
Ejection Fraction (%) 23.9 24.2
Diabetes (%)* 44.8 37.0
Systolic Blood Pressure (mmHg) 127.2 125.3
Medications (%)
• Diuretic
• Ace Inhibitor/ARB
• Beta Blocker
• Digoxin
• Spironolactone
88.0
86.6
74.1
58.5
40.2
91.5
86.0
73.5
60.7
37.6
*P=0.01
Taylor AL. NEJM. 2004. 351(20):2049-2057.
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AHeFT: Outcomes
Outcome HI Placebo P-value NNT
Primary composite score -0.1±1.9 -0.5±2.0 0.01 NA
Death from any cause 6.2% 10.2% 0.02 25
1st hospitalization for heart failure 16.4% 24.4% 0.001 13
Change in quality of life score at 6 months -5.6±20.6 -2.7±21.2 0.02 NA
Scoring System for Composite Endpoint
Death -3
Survival to end of trial 0
1st hospitalization for heart failure -1
No hospitalization 0
Change in QoL
• Improvement by >10 units
• Improvement by 5-9 units
• Change by <5 units
• Worsening by 5-9 units
• Worsening by >10 units
+2
+1
0
-1
-2
Taylor AL. NEJM. 2004. 351(20):2049-2057.
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AHeFT: Outcomes
Outcome HI Placebo P-value NNT
Primary composite score -0.1±1.9 -0.5±2.0 0.01 NA
Death from any cause 6.2% 10.2% 0.02 25
1st hospitalization for heart failure 16.4% 24.4% 0.001 13
Change in quality of life score at 6 months -5.6±20.6 -2.7±21.2 0.02 NA
Scoring System for Composite Endpoint
Death -3
Survival to end of trial 0
1st hospitalization for heart failure -1
No hospitalization 0
Change in QoL
• Improvement by >10 units
• Improvement by 5-9 units
• Change by <5 units
• Worsening by 5-9 units
• Worsening by >10 units
+2
+1
0
-1
-2
Taylor AL. NEJM. 2004. 351(20):2049-2057.
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Sacubitril/Valsartan
• PARADIGM-HF
• Primary endpoint: CV mortality and first HF hospitalization
• Low enrollment of black patients resulting in wide confidence interval
• Higher rates of angioedema (1.79% vs 0.44%)
• PIONEER
• Primary endpoint: time-averaged reduction in NT-proBNP
• Proportion of black patients more similar to population seen in clinical practice
Trial Subjects Total N % BlackWhite
(95% CI)
Black
(95% CI)
Overall
(95% CI)NNT
PARADIGM-
HF
Stable
HFrEF8399 5.1%
HR
0.81 (0.73-0.90)
HR
0.81 (0.57-1.15)
HR
0.80 (0.73-0.87)22
PIONEER ADHF 881 35.9%Ratio of change
0.68 (0.58-0.80)
Ratio of change
0.72 (0.57-0.89)
Ratio of change
0.71 (0.63-0.81)N/A
Mcmurray JJ, et al. N Engl J Med. 2014;371(11):993-1004.
Velazquez EJ et al. N Engl J Med. 2019;380(6):539-548.
POSTER PRESENTATION
Shi V, et al. Int J Cardiol. 2018;264:118-123.
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Aldosterone Receptor Antagonists
Trial ARATotal
N
%
Black
White
HR (95% CI)
Black
HR (95% CI)
Overall
HR (95% CI)NNT
RALES Spironolactone 1,663 7 0.70 (0.59-0.82) 0.87 (0.47-1.59) HR 0.70 (0.60-0.82) 10
Vardeny O, et al. Circ Heart Fail. 2013;6(5):970-6.
Pitt B, et al. N Engl J Med. 1999;341(10):709-17.
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Patient Case: Scenario 2
• MS presents to clinic 3 months after discharge for routine follow-up. She reports
shortness of breath when walking up more than 1 flight of stairs. She reports no
symptoms consistent with volume overload and appears euvolemic on exam.
• Current medications: carvedilol 25 mg BID, lisinopril 10 mg daily, metformin 1000 mg BID,
atorvastatin 40 mg daily, torsemide 20 mg daily
• Vitals: HR 78, BP 118/88, RR 16
• Labs: WBC 5.0, HgB 11.7, PLT 197, Na 138, K 4.7, Mg 1.9, Scr 0.85, BUN 20
• What medication change(s) should you make in clinic today?• A: Increase lisinopril to 20 mg daily
• B: Add hydralazine 25 mg/isosorbide dinitrate 10 mg TID
• C: Add spironolactone 25 mg daily
• D: Stop lisinopril and start sacubitril/valsartan 24/26 mg BID after 36 hour washout
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Patient-Specific Decision Making Tools
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Side-by-Side Comparison
NNT over 10 months (African Americans only)
• All-cause mortality: 25
• First hospitalization for HF: 13
NNT over 27 months (overall population)
• All-cause mortality: 36
• First hospitalization for HF: 36
Hydralazine/Isosorbide Dinitrate Sacubitril/Valsartan
Pro
• Minimal blood pressure reduction
• No direct effects on renal function or electrolytes
• Anti-anginal in patients with stable angina
Con
• Minimal blood pressure reduction
• Adherence to three times daily dosing
• High incidence of headaches
• Two copayments
Pro
• Large blood pressure reduction
• Twice daily dosing
Con
• Large blood pressure reduction
• Cost
• Hyperkalemia
• Hypotension
• No data for use in hemodialysis
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Patient Case: Scenario 3
• MS presents to clinic for routine follow-up and is doing well. She complains of
moderate headaches that are not resolved with acetaminophen approximately
3-4 times per week. During the interview, she mentions frequently missing her
midday dose of hydralazine/isosorbide dinitrate (HI).
• Current medications: carvedilol 25 mg BID, lisinopril 20 mg daily, hydralazine 75
mg/isosorbide dinitrate 40 mg TID, metformin 1000 mg BID, atorvastatin 40 mg daily,
torsemide 40 mg daily
• Vitals: HR 78, BP 128/89, RR 16
• Labs: WBC 5.0, HgB 11.7, PLT 197, Na 138, K 4.2, Mg 1.9, Scr 0.84, BUN 21
• What change(s) do you want to make to her medication regimen?• A: Stop HI and start sacubitril/valsartan 49/51 mg twice daily after 36 hour washout of lisinopril
• B: Decrease HI to 25 mg/10 mg TID
• C: Stop HI and start spironolactone 25 mg daily
• D: Stop HI and increase lisinopril to 40 mg daily
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Hydralazine/Isosorbide Dinitrate: Adverse Events
• AHeFT• HI discontinued because of headache: 7%
• Systolic blood pressure change: HI -1.9 mmHg vs. Placebo +0.8 mmHg
• AHeFT Extension • Adverse Events: headache: 34%, dizziness 16%, hypotension 6%
• Discontinuation due to adverse events: 6%
AHeFT Adverse Events HI Placebo P-value
Heart failure exacerbation 8.7% 12.8% 0.04
Severe heart failure exacerbation 3.1% 7.0% 0.005
Headache 47.5% 19.2% <0.001
Dizziness 29.3% 12.3% <0.001
Taylor AL. NEJM. 2004. 351(20):2049-2057.
Yancy CW. Am J Cardiol. 2007;100(4):684-9.
BiDil (isosorbide dinitrate and hydralazine hydrochloride) [prescribing information]. Atlanta, GA: Arbor Pharmaceuticals; March 2019.
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Hydralazine/Isosorbide Dinitrate: Adverse Events
• AHeFT• HI discontinued because of headache: 7%
• Systolic blood pressure change: HI -1.9 mmHg vs. Placebo +0.8 mmHg
• AHeFT Extension • Adverse Events: headache: 34%, dizziness 16%, hypotension 6%
• Discontinuation due to adverse events: 6%
AHeFT Adverse Events HI Placebo P-value
Heart failure exacerbations 8.7% 12.8% 0.04
Severe heart failure exacerbation 3.1% 7.0% 0.005
Headache 47.5% 19.2% <0.001
Dizziness 29.3% 12.3% <0.001
Taylor AL. NEJM. 2004. 351(20):2049-2057.
Yancy CW. Am J Cardiol. 2007 Aug 15;100(4):684-9.
BiDil (isosorbide dinitrate and hydralazine hydrochloride) [prescribing information]. Atlanta, GA: Arbor Pharmaceuticals; March 2019.
Acetaminophen can be used to treat headaches caused by HI
Headaches tend to improve with consistent dosing
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Hydralazine/Isosorbide Dinitrate: Compliance
• AHeFT• Mean number of tablets: HI 3.8±2.5 vs. placebo 4.7±2.2 (P<0.001)
• Target dose achieved in 68% of patients
• AHeFT Extension• Mean number of tablets: 3.7±1.8
• Mean dose: hydralazine 138 mg/day, isosorbide dinitrate 74 mg/day
• Compliance: 87%
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Hydralazine/Isosorbide Dinitrate: Compliance
• AHeFT• Mean number of tablets: HI 3.8±2.5 vs. placebo 4.7±2.2 (P<0.001)
• Target dose achieved in 68% of patients
• AHeFT Extension• Mean number of tablets: 3.7±1.8
• Mean dose: hydralazine 138 mg/day, isosorbide dinitrate 74 mg/day
• Compliance: 87%
• Get with the Guidelines-Heart Failure Registry• Prescribing rates at discharge
– African Americans: 22.7%
– ACE Inhibitor/ARB intolerance: 18.2%
• Prescription fill rate at 90 days
– African Americans: 46%
– ACE Inhibitor/ARB intolerance: 48%
Outcome at 3 years
(African American)
HI at
Discharge
(N=316)
No HI at
discharge
(N=1076)
P-value
All-cause mortality 53.9% 51.9% 0.39
All-cause readmission 85.7% 83.9% 0.53
Cardiovascular Readmission 68.9% 65.2% 0.33
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Patient Case: Scenario 3
• MS presents to clinic for routine follow-up and is doing well. She complains of
moderate headaches that are not resolved with acetaminophen approximately
3-4 times per week. During the interview, she mentions frequently missing her
midday dose of hydralazine/isosorbide dinitrate (HI).
• Current medications: carvedilol 25 mg BID, lisinopril 20 mg daily, hydralazine 75
mg/isosorbide dinitrate 40 mg TID, metformin 1000 mg BID, atorvastatin 40 mg daily,
torsemide 40 mg daily
• Vitals: HR 78, BP 128/89, RR 16
• Labs: WBC 5.0, HgB 11.7, PLT 197, Na 138, K 4.2, Mg 1.9, Scr 0.84, BUN 21
• What change(s) do you want to make to her medication regimen?• A: Stop HI and start sacubitril/valsartan 49/51 mg twice daily after 36 hour washout of lisinopril
• B: Decrease HI to 25 mg/10 mg TID
• C: Stop HI and start spironolactone 25 mg daily
• D: Stop HI and increase lisinopril to 40 mg daily
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Objectives
• Understand how heart failure etiology and pathophysiology differ in African
American patients versus Caucasian patients
• Analyze the literature for heart failure with reduced ejection fraction (HFrEF)
guideline directed therapies with respect to African American (AA) representation
• Evaluate new literature regarding novel HFrEF therapies and how to apply
these in African American patients
• Design an individualized treatment plan for African American patients with HFrEF
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Patient Case: Scenario 4
• MS presented in acute decompensated heart failure four days ago and was
initiated on dobutamine 5 mcg/kg/min with IV diuresis. Her home HF
medications were all held upon admission.
• Current Medications: furosemide 80 mg IV BID, atorvastatin 40 mg daily, enoxaparin 40 mg SC
daily, sliding scale insulin ACHS
• Labs: WBC 6.3, HgB 9.8, PLT 230, Na 135, K 3.8, Mg 1.8, Scr 1.2, BUN 23
• Vitals: BP 112/76, HR 96, RR 14, oxygen saturation 98%
Pulmonary artery pressure 43/30 mm Hg
Mean pulmonary artery pressure 34 mm Hg
Central venous pressure 15 mm Hg
Cardiac index 1.8 L/min/m2
Systemic vascular resistance 2294 dynes/cm5
Mixed venous oxygen saturation 47%
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Patient Case: Scenario 4
• The team plans to wean off inotropes and transition her to oral therapy over
the coming days.
• What afterload reducing agent would you use to support her dobutamine
wean?• A: Captopril
• B: Valsartan
• C: Sacubitril/valsartan
• D: Hydralazine/isosorbide dinitrate
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Afterload Reduction in ADHF
𝐶𝑎𝑟𝑑𝑖𝑎𝑐 𝑂𝑢𝑡𝑝𝑢𝑡 =𝐵𝑙𝑜𝑜𝑑 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒
𝑆𝑦𝑠𝑡𝑒𝑚𝑖𝑐 𝑉𝑎𝑠𝑐𝑢𝑙𝑎𝑟 𝑅𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒
Medication % African
American
Cardiac Index
(L/min/m2)
Systemic Vascular Resistance
(dynes/cm5)
Hydralazine/isosorbide dinitrate
and ACE inhibitor/ARB1
20% + 1.7 - 630
ACE inhibitor/ARB alone1 21% + 0.5 NS
Sacubitril/valsartan2 Not available + 0.76 - 738
1 Compared from hospital admission to follow-up2 Compared from pre and post initiation
Addition of hydralazine/isosorbide dinitrate to ACE inhibitor/ARB after ADHF event requiring invasive
hemodynamic monitoring:
• Reduction in all-cause mortality (34% vs 41%, p=0.04)
• Reduction in all-cause mortality and HF hospitalization (70% vs 85%, p=0.03)
Mullens W, et al. Am J Cardiol. 2009;103(8):1113-9.
Martyn T, et al. Poster presented at: HFSA Scientific Meeting 2019.
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Emerging Therapies in African Americans
Study Medication % African
American
Event Rate p-value for
interactionTreatment
n (%)
Control
n (%)
EMPA-REG
OUTCOME
Empagliflozin5.1 39 (16.4%) 14 (11.7%) 0.09
CANVAS Canagliflozin 3.3 18.6%a 37.0%a 0.40
DECLARE-TIMI 58 Dapagliflozin 3.5b 68 (3.9%) 70 (4.0%) 0.23
DAPA-HF Dapagliflozin 4.8 26 (21.3%) 32 (30.8%) >0.05
FAIR-HF Ferric
carboxymaltose0.002c Not available, only 1 non-white subject
enrolled
CONFIRM-HF Ferric
carboxymaltose1c Not available, only 2 non-white subjects
enrolled
IRONOUT-HF Iron
polysaccharide25 Data not presented
a Per 1000 patient years; b Non-Caucasian; c Non-white
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Objectives
• Understand how heart failure etiology and pathophysiology differ in African
American patients versus Caucasian patients
• Analyze the literature for heart failure with reduced ejection fraction (HFrEF)
guideline directed therapies with respect to African American (AA) representation
• Evaluate new literature regarding novel HFrEF therapies and how to apply these
in African American patients
• Design an individualized treatment plan for African American patients with
HFrEF
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All-Cause Mortality and Treatment Effect
Trial Medication% African
American
Follow-up Period
(months)
Overall Population
NNT
RALES Spironolactone 7 24 11
COPERNICUS Carvedilol 5 10.4 15
CIBIS-II Bisoprolol NA 16 19
US Carvedilol HF
TrialsCarvedilol 20 15.1 22
SOLVD Treatment Enalapril 9.5 41.4 23
A-HeFTHydralazine/
isosorbide dinitrate100 10 25
MERIT-HF Metoprolol succinate 5 12 27
PARADIGM-HF Sacubitril/valsartan 5.1 27 36
DAPA-HF Dapagliflozin 4.7 18.2 44
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HFrEF Treatment Plan in African Americans
Treatment of Stage C/D HFrEF
in African Americans
Beta blockers +
ACE inhibitors/ARBs
Add hydralazine/
isosorbide dinitrate
Change ACE inhibitor/ARB
to sacubitril-valsartanAdd spironolactoneAdd SGLT2 inhibitor
Type 2 Diabetes
SBP > 100 mm Hg
eGFR > 30 mL/min/1.73 m2
K < 5.2 mEq/L
CrCl > 30 mL/min
K < 5 mEq/L
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Summary
• African Americans with HFrEF are considered a “high-risk” population with a
larger burden of disease and more severe disease than the general population
• African American patients are severely underrepresented in clinical trials, making
application of guideline-directed therapies difficult
• Hydralazine/isosorbide dinitrate has the most robust evidence for benefit in the
African American population
• Use is limited by high incidence of headaches and adherence to three times daily dosing
• Use of emerging HFrEF therapies in African Americans is reasonable, but
continues to be limited by low enrollment
• Future research should focus on including a larger representation of African
Americans in landmark trials
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Heart Failure Treatment in African
American Patients
Theresa Kline, PharmD & Lauren Kemp, PharmD
University of North Carolina Medical Center
Residency Program Director: Ian B. Hollis, PharmD, BCPS-AQ Cardiology
December 5, 2019