1	New Frontiers in the Treatment of African Americans with Heart Failure
2	Understanding Heart Failure in African Americans Malcolm P. Taylor, MD, FACC Clinical Assistant Professor of Medicine University of Mississippi Director, CHF Clinic Mississippi Heart Institute
3	Definition of Heart Failure Heart failure (HF) is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood¹ The cardinal manifestations of HF are dyspnea and fatigue, which may limit exercise tolerance, and fluid retention, which may lead to pulmonary congestion and peripheral edema¹
4	Heart Failure - An Increasing Public Health Burden Affects 5 million U.S. residents 2.3% of the population 550,000 new cases annually Lifetime risk 20% for men and women Causes or contributes to 300,000 deaths annually Annual impact on health care resources ~3 million office visits ~1 million hospital discharges Number 1 cause of hospitalizations in the elderly Direct and indirect costs: ~$28 billion
5	Consequences of Heart Failure
6	Progressive Mechanisms of Heart Failure
7	Heart Failure and African Americans
8	Manifestations of Heart Failure in Black Patients HF has a more aggressive natural history in black patients Occurs at an earlier age¹ Associated with more advanced LVD at diagnosis¹ Differing etiology Incidence of MI is consistently lower¹ More likely to be associated with a history of HTN¹ Worse prognosis Higher rate of hospitalization than in white patients² Higher mortality rate than in white patients; applies to both men and women²
9	African-American Patients Are an Understudied Population in Randomized Heart Failure Trials
10	Etiology of Heart Failure in Black Patients
11	Goals of Heart Failure Management Improve symptoms Decrease risk for hospitalization Improve overall survival
12	Primary Heart Failure Therapies: Prior to A-HeFT
13	Primary Heart Failure Therapies: Diuretics Loop diuretics (bumetanide, furosemide, and torsemide): Generally, preferred class because they retain efficacy unless renal function is severely impaired Thiazide diuretics: May be utilized in patients with mild fluid retention Morbidity and mortality: No long-term studies of effects on morbidity and mortality Necessary for fluid management in the majority of patients with HF
14	Primary Heart Failure Therapies: ACE-Is ACE-Is suppress production of angiotensin II and enhance the actions of kinins¹ In HF clinical trials, patients with impaired LVF receiving ACE-Is exhibited a reduced risk of mortality and reduced risk of hospitalization for HF¹ ACE-Is attenuate cardiac remodeling¹ African Americans have been generally under studied in major HF trials with ACE-Is^2-4
15	Primary Heart Failure Therapies: ARBs ARBs are used in patients with HF who are intolerant to ACE-Is¹ Use as an alternative to ACE-Is controversial Data on combining ARBs with ACE-Is are conflicting² African-American patients have been poorly represented in ARB trials, hence, difficulty in assessing true efficacy in this population²
16	Primary Heart Failure Therapies: bBlockers b-blockers attenuate the adverse effects of overactivation of the sympathetic nervous system In HF clinical trials, patients with impaired LVF receiving b-blockers exhibited a reduced risk of mortality and reduced risk of hospitalization for HF A consistent class effect has not been demonstrated In b-blocker clinical trials, a survival advantage has been observed in African-American patients, but confidence intervals are large because of the small numbers of African-American patients studied
17	Which Therapy Should Be Next?
18	Poor Representation of African-American Patients in ARB Trials
19	Which Therapy Should Be Next?
20	Aldosterone Antagonists RALES Addition of spironolactone in patients with HF already taking diuretics (100%) and ACE-Is (~95%); only ~10% were taking β-blockers 1663 patients with NYHA class III-IV HF were randomized to receive 25 mg of spironolactone (n=822) or placebo (n=841) QD Race: ~87% white, exact percentage of black patients unknown Results: All-cause mortality reduced by 30% in the group taking spironolactone (P<.001)
21	Aldosterone Antagonists (cont’d) EPHESUS Addition of eplerenone to treatment in patients 3–14 days post-MI with LVEF ≤40% already taking diuretics (60%), ACE-Is/ARBs (86%), and βblockers (75%) 6632 patients with NYHA class III-IV HF were randomized to receive a target dose of 50 mg of eplerenone (n=3313) or placebo (n=3319) QD Race: 90% white, 9% other races, 1% black Results: All-cause mortality reduced by 15% in the group taking eplerenone (P=.008)
22	Which Therapy Should Be Next? ISDN/HYD is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status There is little experience in patients with NYHA class IV heart failure Most patients in the clinical trial supporting effectiveness (A-HeFT trial) received a loop diuretic, an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, and a beta-blocker, and many also received a cardiac glycoside or an aldosterone antagonist
23	A-HeFT: Study Design A-HeFT¹ Hypothesis: Fixed dose of ISDN/HYD will improve outcomes in black patients with moderate-to-severe symptomatic HF 169 sites² 1050 randomized self-identified black patients (60% male; BiDil [n=518], placebo [n=532])^1,2 >95% NYHA class III Maintained on stable background therapy Target dosage was 40 mg of ISDN/75 mg of HYD TID or to the maximum tolerated dose^1,2 ≤18 months of follow-up^1,2 No patient lost to follow-upfor vital status¹ Study initiated 5/29/01 and terminated early on 7/19/04 because of significant survival benefit in the BiDil group^1-3
24	A-HeFT: Significant Improvement in All Components of Composite Score With BiDil^®
25	A-HeFT: Additional 43% Reduction in Mortality Beyond Current Standard Therapies
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27	HF Management in African Americans: Different Than in Other Patients? HF management: similar for all populations AA with HF benefit from ISDN/HYD added to standard therapy 2005 ACC/AHA HF Guidelines: endorse addition of ISDN/HYD for AA patients with moderate to severe HF, already on ACEI/ARB and b-blocker (Class II, level of evidence A)
28	ACC/AHA Heart Failure Guidelines Acknowledge Treatment of Special Populations Recommendations for Treatment of Special Populations “Class IIa – The addition of isosorbide dinitrate and hydralazine to a standard medical regimen for HF, including ACE Inhibitors and beta-blockers, is reasonable and can be effective in blacks with NYHA class III or IV HF....” (Level of Evidence: A)^1,2
29	Primary Heart Failure Therapies for Black Patients
30	Conclusion Heart failure continues to increase in prevalence and mortality African Americans have higher rates of heart failure associated with higher mortality than others Risk factor modification is essential to prevent heart failure morbidity and mortality Newer approaches include the combination of isosorbide dinitrate/hydralazine and ARBs added to conventional therapy Cultural competence is key to delivering the best possible health care to the African American patient with heart failure
31	ABC Brochure
32	Summary HF disproportionately affects the African-American population HTN, as opposed to CAD, is the dominant cause of HF in this population African-American patients should be well represented in HF trials because race-specific differences influence clinical outcomes A-HeFT provides the richest source of data on HF in African-American patients Insights from this trial have improved our understanding of the management of HF in African-American patients
33	Case Studies
34	Case Study #1 African-American male, aged 38 years, presents with SOB on minimal exertion. Symptoms have worsened over the past week. His past history is notable for poorly controlled HTN BP 138/72 mmHg; HR 77 reg; RR 16; JVP distended to 5 cm upright Auscultation soft S3 gallop, regular rhythm, grade 2/6 pansystolic murmur Apex is displaced, +1 pedal edema, normal peripheral pulses CNS examination unremarkable Abdomen slightly protuberant, no organomegaly or tenderness
35	Case Study #1 (cont’d) EKG: sinus rhythm and nonspecific ST-segment changes Echo: mild LVH, EF 35%, moderate MR on Doppler Patient was titrated on captopril (50 mg TID) and carvedilol (up-titrated over 3 months from 3.125 mg BID to 25 mg BID) and commenced on furosemide 20 mg daily Discussion points Long-standing HTN is common in African-American patients Common in many patients in A-HeFT Although his BP is not markedly elevated, symptoms may be caused by significant LVD
36	ACC/AHA Heart Failure Guidelines 2005 Recommendations for patients with reduced LVEF “Class I – Diuretics and salt restriction are indicated in patients with current or prior symptoms of HF and reduced LVEF who have evidence of fluid retention” (Level of Evidence: C) “Class I – ACE-Is are recommended for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated” (Level of Evidence: A) “Class I – Beta-blockers (using 1 of the 3 proven to reduce mortality, ie, bisoprolol, carvedilol, and sustained released metoprolol succinate) are recommended for all stable patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated” (Level of Evidence: A) “Class I – ARBs approved for the treatment of HF are recommended in patients with current or prior symptoms of HF and reduced LVEF who are ACE-I intolerant” (Level of Evidence: A)
37	Case Study #1 (cont’d) He could now benefit from the addition of BiDil Commence with one tablet of BiDil TID and up-titrate to two tablets TID. Reduce loop diuretic and back-titrate if hypotensive Use acetaminophen PRN for headaches Additionally, patient commenced on aspirin 81 mg daily
38	Case Study #1: Patient’s Symptoms Improved At 3 months, the patient reported: Increased exercise tolerance Decreased peripheral edema Decreased SOB Increased energy levels At 6 months: Improved EF on repeat echo
39	Case Study #2 African-American male, aged 57 years, with a 5-year history of CHF. Normal coronary arteries on catheterization 8 years previously Presents with SOB after walking short distances, and gross edema EKG: Normal sinus rhythm, nonspecific ST changes EF: 22% and LVIDD = 7.4 cm HR 68 regular; BP: 125/86 mmHg; weight 292 lbs; height 6’; BMI: 39.6 Taking carvedilol (12.5 mg BID), furosemide (40 mg BID), spironolactone (12.5 mg daily), amlodipine (10 mg daily), aspirin (81 mg daily), lisinopril (20 mg daily)
40	Case Study #2 (cont’d) What should be the next step? Should the dose of ACE-I be increased to 40 mg? Data from the ATLAS trial suggest no added mortality benefit from low-dose versus high-dose ACE-I therapy Should the dose of b-blocker be increased? YES Data suggest increased mortality benefit and improved EF (but patient numbers small) What should you do with amlodipine? Discontinue treatment Guidelines suggest avoiding calcium channel blockers in CHF. If ACE-I dose is increased, discontinuing amlodipine will help recover BP Could BiDil benefit this patient? YES
41	Case Study #2 (cont’d) Treatment with BiDil should be initiated at a dose of one BiDil tablet, 3 times a day.¹ The dosage may be decreased to as little as one-half BiDil tablet 3 times a day if intolerable side effects occur. Efforts should be made to titrate up as soon as side effects subside At 3 months: BP now 122/84 mmHg; initially 125/86 mmHg EF improved from 22% to 28%, LVH unchanged LVIDD decreased to 6.3 cm
42	Case Study #3 African-American female, aged 72 years, with long-standing HTN and LVD and a 3-year history of HF symptoms NYHA class III with dyspnea on exertion at one block, PND, and orthopnea Comorbidities include HTN and hyperlipidemia (no diabetes) Past history significant for CHD with a previous MI of the inferior wall in 2000 Underwent angioplasty and stenting of two vessels Height 5’ 5”; weight 208 lbs; BMI 34.6 Complains of fatigue and occasional ankle edema; denies chest pain BP 104/80 mmHg; HR 69 reg; JVP slightly elevated with positive HJ reflux. Echo EF 18% Creatinine 1.2 mg/dL, potassium 4.3 mmol/L, Hgb 11.4 g/dL; creatinine clearance 63 mL/min
43	Case Study #3 (cont’d) Patient currently taking carvedilol (25 mg BID), lisinopril (40 mg daily), furosemide (40 mg one or two daily), aspirin (81 mg daily), lanoxin (.125 mg daily), simvastatin (40 mg daily), spironolactone (12.5 mg daily), and has an ICD What could be the next step? Patient could benefit from the addition of BiDil Treatment with BiDil should be initiated at a dose of one BiDil tablet, 3 times a day¹ The dosage may be decreased to as little as one-half BiDil tablet 3 times a day if intolerable side effects occur. Efforts should be made to titrate up as soon as side effects subside Symptomatic hypotension may occur: Particularly with upright posture, even with small doses of BiDil. Therefore, BiDil should be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive Counsel patient on methods to slowly rise from supine or reclined positions in order to prevent episodes of symptomatic hypotension while up-titrating
44	Case Study #3 (cont’d) At 3 weeks patient reported: Improvement in exercise tolerance to three to four blocks at 3 weeks PND symptoms diminished At 6 months: Echo revealed poor but slightly improved LV function, EF ~22% BP increased to 110/82 mmHg
45	Back-up Slides: Supplemental Data
46	What Were the Trial Designs and Results of V-HeFT I and V-HeFT II?
47	V-HeFT I: Study Plan
48	V-HeFT I: Survival in All Patients
49	V-HeFT II: Study Plan
50	V-HeFT II: Survival in All Patients
51	Why Was A-HeFT Conducted in African-American Patients?
52	The Road to BiDil
53	V-HeFT I and II: Rationale for Retrospective Analysis Clinical response of black patients with HTN to such therapy as ACE-Is has differed from that of white patients HF in black patients is associated with poorer prognosis than in white patients Carson et al reanalyzed data from the V-HeFT trials in order to assess differences in racial response to specific therapies within these studies
54	V-HeFT II Retrospective Analysis: Baseline Variables
55	V-HeFT II Retrospective Analysis: Effect on All-cause Mortality in Black Patients
56	V-HeFT I Retrospective Analysis: Baseline Variables
57	V-HeFT I Retrospective Analysis: Favorable Survival Trend in Black Patients
58	Summary of V-HeFT I and II Retrospective Analysis Retrospective analysis of V-HeFT I and II suggested that ISDN/HYD may be beneficial in black patients with HF A prospective trial among black patients was needed to systematically study the hypothesis generated by the retrospective analysis
59	How Were the Components of the Primary Composite End Point Scored?
60	A-HeFT: Primary End-point Composite Score End-point Composite Score of Death, First Hospitalization, and Patient-reported Functional Status Death (at any time during the trial) = -3 Alive at end of trial = 0 Hospitalization for heart failure (adjudicated) = -1 No hospitalization = 0 Responses to the MLHF^® Questionnaire at 6 months (or last measurement, if earlier than 6 months) Improvement ³10 units = +2 Improvement ³5 and <10 units = +1 Change <5 units = 0 Worsening ³5 and <10 units = -1 Worsening ³10 units = -2 Possible Score: -6 to +2
61	What Questions Are Contained in the Minnesota Living With Heart Failure^® Questionnaire?
62	Minnesota Living With Heart Failure^® Questionnaire
63	Minnesota Living With Heart Failure^® Questionnaire (cont’d)
64	Minnesota Living With Heart Failure^® Questionnaire (cont’d)
65	Does NitroMed Have a Patient Assistance Program ?
66	What Is NitroMed Cares^™? NitroMed is committed to making sure that all patients who need BiDil get it. In order to achieve this goal, NitroMed has established the NitroMed Cares^™ Patient Support Program. This comprehensive program will ensure that even uninsured patients will have affordable access to BiDil or, in some cases, receive free access.
67	What Is NitroMed Cares^™? (cont’d)
68	The NitroMed Cares^™ Program Was Established to Ensure That Uninsured Patients Who Need BiDil Can Get It
69	Step 1: Patient Completes Application – 1 Form
70	Step 2: Physician Completes Application – 1 Form
71	NitroMed Cares^™
72	NitroMed Cares^™/Eligibility Criteria Eligibility: To be accepted into this Reduced Income Without Prescription Drug Insurance Program, a patient must meet the following criteria: Must be a US resident Must be under the care of a doctor/prescriber who has prescribed BiDil as medically appropriate for the patient Must be ineligible for any public prescription drug insurance including Medicare, Medicaid, and any other state or federal prescription drug program Must lack private prescription drug insurance Must earn less than three times the HHS Poverty Guideline ($30,000 per individual, $40,000 per couple)
73	NitroMed Cares^™: Reduced Income Without Prescription Drug Insurance Physician applies on behalf of his or her patient: Physician’s office should call the toll-free number between 9 AM and 7 PM EST or apply online at www.rxhope.com Required: Completed application form Supply: Up to a 90-day supply, renewable quarterly Ship to: Free product mailed to physician’s office Note: Every 3 months the physician must indicate via e-mail, telephone, or mail that the patient is continuing therapy. Physician must reapply for the patient annually
74	NitroMed Cares^™
75	NitroMed Cares^™: Uninsured Pharmacy Card ($25 BiDil) Eligibility: To be accepted into one of the NitroMed Patient Support Programs, a patient must meet the following criteria: Must be a US resident Must be under the care of a doctor/prescriber who has prescribed BiDil as medically appropriate for the patient Must be ineligible for any public prescription drug insurance including Medicare, Medicaid, and any other state or federal prescription drug program Must lack private prescription drug insurance
76	NitroMed Cares^™: Uninsured Pharmacy Card ($25 BiDil) (cont'd) Physician Applies on Behalf of His or Her Patient: Physician’s office should call the toll-free number between 9 AM and 7 PM EST or apply online at www.rxhope.com Required: Completed application form Supply: Up to a 30-day supply will be available for $25 when patient presents the BiDil pharmacy benefit card to a retail pharmacy with a valid prescription Mailed: Pharmacy card (redeemable for product with a $25 co-pay per up to 30-day prescription) is mailed to patient’s home Note: Every 3 months the physician must indicate via e-mail, telephone, or mail that the patient is continuing therapy. Physician must reapply for the patient annually
77	Online BiDil Processing
78	Online BiDil Processing (cont'd)
79	Online BiDil Processing (cont'd)
80	Online BiDil Processing (cont'd)
81	Mortality Risk Reduction From the Use of ACE-Is in Heart Failure
82	Effect of ACE-Is on Mortality Risk Reduction in Patients With Heart Failure
83	Mortality Risk Reduction From the Use of β-Blockers in Heart Failure
84	Effect of b-Blockade on Mortality Risk Reduction in Patients With Heart Failure
85	What Effect Did BiDil Have on Blood Pressure During A-HeFT?
86	BiDil: Effects on Blood Pressure Patients treated with BiDil in A-HeFT, had randomly measured blood pressures on average 3/3 mmHg lower than did patients on placebo The contribution of the difference in blood pressure to the overall outcome difference is unknown Whether both hydralazine and isosorbide dinitrate contribute to the overall outcome difference has not been studied in outcome trials
87	Back-up Slides: Additional Data to Answer Unsolicited Questions
88	BiDil Dosing Advice for Patients With Lower Blood Pressures
89	BiDil: Dosing Advice for Patients With Lower Blood Pressures BiDil should be used with caution in patients who are hypotensive.
90	What Happened to Patients With Lower Blood Pressure in A-HeFT?
91	BiDil: Effects on Patients With Lower Blood Pressure In A-HeFT, 25% of patients treated with BiDil had baseline SBP between 80 mmHg and 112 mmHg In this subgroup, SBP was shown to increase an average of 5 mmHg to 10 mmHg as measured at 3 month intervals up to 18 months
92	A-HeFT: Effect of BiDil on Left Ventricular Remodeling
93	A-HeFT: Treatment With BiDil Significantly Improves Ejection Fraction
94	A-HeFT: Treatment With BiDil Significantly Improves Ejection Fraction
95	A-HeFT: Significant Difference vs Placebo in LVIDD at 6 Months
96	A-HeFT: Significant Difference vs Placebo in LVIDD at 6 Months
97	A-HeFT: Effect on Plasma BNP
98	A-HeFT: Significant Difference vs Placebo in Plasma BNP at 6 Months
99	A-HeFT: Significant Difference vs Placebo in Plasma BNP at 6 Months
100	Endothelial Dysfunction and Nitric Oxide
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103	African-American Patients Are an Understudied Population in Randomized Heart Failure Trials