THE TROUBLED HEART
From the 2006 Primary Update: Improving Patient Care, sponsored by the Interstate Postgraduate Association of
North America
| HEART FAILURE —Jan N. Basile, MD, Professor of Medicine, Medical University of South Carolina, and Director of
Primary Care Service Line, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC
|
| Types of heart failure (HF): reduced ejection fraction (EF)—systolic dysfunction; normal (preserved) EF—
diastolic dysfunction; patients with hypertension and normal EF (70%-80%) may develop left ventricular hypertrophy
(LVH) and present with signs and symptoms similar to those of HF with reduced EF (50% die from progressive HF, 50%
from sudden death); difficult to differentiate types of HF unless EF used; large overlap between systolic HF (usually seen
with underlying atherosclerotic cardiovascular disease) and diastolic HF (more commonly seen with hypertension or diabetes);
patients with HF with reduced EF may have unrecognized abnormalities of diastolic function; determine EF to use
evidence-based strategy for improving outcome
|
| Presentations: HF with preserved EF—severe LVH; long-standing hypertension; fluid overload; lower extremity
edema; shortness of breath; orthopnea; paroxysmal nocturnal dyspnea (PND); EF 70%; volume-to-mass ratio, 0.3; HF
with reduced EF (dilated cardiomyopathy)—long-standing atherosclerotic disease; EF 20%; unrecognized myocardial
infarction (MI); same signs and symptoms as HF; volume-to-mass-ratio, 0.8; differences based on pathophysiology, anatomy,
and EF
|
| Staging: stage A—high risk for HF; no evidence of structural heart disease; no symptoms; trials show HF can be prevented
by lowering blood pressure (BP) with angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker
(ARB) (eg, losartan, irbesartan); stage B—patients usually post-MI; unrecognized MI (eg, from serial observations on
electrocardiography [ECG]); structural heart disease; no symptoms; trials show reduction in risk with ACE inhibitor, ARB,
and β-blocker; stages C and D—structural heart disease; symptoms; echocardiography or multiple-gated acquisition
(MUGA) scan needed to evaluate signs; stage D refractory HF
|
| HF with normal EF: patients present with signs and symptoms of HF; patients with clinical HF with preserved EF often
have S4 gallop and narrow cardiac silhouette (patients with reduced EF often have S3 gallop and dilated or enlarged heart on x-
ray); Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trial found forms of HF
could not be differentiated clinically; etiology may suggest HF with preserved EF, but echocardiography or MUGA scan provides
differentiation
|
| Hypertension: Framingham Heart Study—data show ≈60% of women with HF have greatest population attributable risk
for HF from hypertension, nearly 40% in men; although valvular heart disease and post-MI care more likely to cause HF on
individual basis, high prevalence of hypertension results in greatest impact on causing clinical HF; in Framingham Heart
Study, ≈91% of HF patients presented with previously unrecognized high BP or antecedent history of hypertension
|
| Frank-Starling curve: 1) due to salt intake and water reabsorption, increased volume and pressure develop in LV; patients
with normal Frank-Starling curve able to diurese pressure by urinating and do not have symptoms of clinical HF; 2)
in patient with long-standing poorly controlled hypertension, salt intake results in left shift in Frank-Starling curve and
development of inordinate pressure in LV; patient develops shortness of breath due to increased pressure, even though
volume same as in person with normal curve; patient presents to emergency department (ED) with florid HF and EF of
70%; heart pumps vigorously but relationship between volume and pressure (ie, compliance in LV) abnormal
|
| Diastolic HF: prevalent (30%-50% of cases of HF have normal systolic function); occurs mostly in elderly with underlying
hypertension, diabetes, LVH, and coronary heart disease (CHD); predilection for women; hypertensive hypertrophic
cardiomyopathy of elderly—older women who present to ED with EF ≥70% and clinical HF; accounts for ≈50% of all
hospitalizations for HF, mostly in elderly women; mortality rate 50% that of systolic HF, but 4 times that of persons without
HF
|
| Management of diastolic HF: little evidence for one strategy over another; improve symptoms and quality of life;
avoid or reduce hospitalizations; slow disease progression by treating underlying coronary disease and BP; reverse or
minimize LVH by reducing afterload, lowering BP, and blocking neurohormonal activation; prolong life; no evidence renin-angiotensin
system blockers prolong life; recent study suggests statin-based therapy may decrease first incidence of
HF and recurrent HF; CHARM trial—no evidence that candesartan (≤32 mg daily) significantly reduces cardiovascular
death or hospitalization for HF, despite reduction in systolic and diastolic BP; Food and Drug Administration (FDA) does
not allow any pharmaceutical company or drug class to claim evidence of benefit in patients with HF with preserved EF
|
| Management of HF with reduced EF: ACE inhibitors and evidence-based β-blockers shown to improve longevity
and reduce symptoms; if patient not taking, must document why; ACE inhibitors— shown to reduce mortality; use correct
dosage; no specific evidence one ACE inhibitor better than another; β-blockers—long-acting metoprolol succinate (Toprol
XL) or carvedilol (Coreg) approved by FDA; no evidence for atenolol; metoprolol tartrate shown inferior to carvedilol; start
with low doses and uptitrate no sooner than every 2 wk to highest dose tolerated; chronic obstructive pulmonary disease
(COPD) alone not contraindication (contraindication based on severity, forced expiratory volume in 1 sec [FEV1 ], and bronchospasm)
|
| African-American Heart Failure Trial (A-HeFT): study of combination of isosorbide and hydralazine (BiDil) in
black patients with mainly New York Heart Association class III or IV HF with reduced EF; 40 mg isosorbide and 75 mg hydralazine
tid resulted in reduction in mortality and first hospitalizations for HF, and significant improvement in quality of life;
most patients already on ACE inhibitor and β-blocker or ACE inhibitor, β-blocker, and ARB; isosorbide and hydralazine upregulate
nitric oxide production (known to be reduced in blacks); evidence not as good in other ethnicities
|
| Using ARB in patients intolerant of ACE inhibitors: valsartan (160 mg bid) improved outcome, compared to
placebo; candesartan (32 mg daily) reduced cardiovascular death and hospitalization; valsartan and candesartan can be
used in patients with ACE inhibitor intolerance and on evidence-based β-blocker; no evidence of dose or dosing frequency
with other ARBs
|
| Adding ARB to conventional HF therapy: Valsartan Heart Failure Trial (Val-HeFT)—adding valsartan as
third neurohormonal blocker caused worse outcome (cardiovascular death and hospitalization) than placebo plus ACE inhibitor
and β-blocker; CHARM-Added trial—candesartan added to ACE inhibitor and β-blocker; found reduction in
primary end point (cardiovascular death or hospitalization) with candesartan (titration up to 32 mg or highest dose patient
accepts; mean dose 24 mg); candesartan improved secondary end points (MI, stroke, revascularization); in subgroup
analysis, patients appear to do better on highest recommended dose of ACE inhibitor and β-blocker; summary—for patients
with HF with reduced EF who are taking ACE inhibitor and β-blocker, addition of candesartan appears beneficial;
valsartan and candesartan indicated in patients with HF who are intolerant of ACE inhibitor; candesartan indicated in patients
with HF not on ACE inhibitor
|
| Reducing mortality: all the following reduced 1-yr mortality 1) adding enalapril twice daily to digoxin and diuretic; 2)
adding Toprol XL to patients on diuretic, digoxin, and ACE inhibitor; 3) adding candesartan to standard of care (ACE inhibitor
and β-blocker; with digoxin and diuretic for symptomatic therapy)
|
| Management of classic signs and symptoms of HF: renin-angiotensin system inhibitor may be used but no good
evidence; loop diuretic for fluid retention; clinical HF—if patient has EF of 30% with recognized MI, slight inferior
wall motion abnormality, and would not benefit from bypass or stent, start with ACE inhibitor and add β-blocker; if patient
ACE-inhibitor intolerant, use ARB and β-blocker; if symptoms continue, consider adding evidence-based ARB (ie,
candesartan); consider BiDil in black patients; aldosterone blockade— spironolactone (Aldactone) used in class III and
IV HF to decrease mortality; eplerenone tested post-MI in patients with clinical HF or reduced EF
|
| Summary: stage A HF—risk factor reduction; patient involvement; family education; healthy lifestyle; control of other
disease states; ACE inhibitor or ARB; stage B HF—ACE inhibitor; if patient post-MI, use β-blocker; if patient ACE-inhibitor
intolerant, use ARB; symptomatic CHD—ACE inhibitor; β-blocker; ARB; stage D HF—inotropic therapy for
refractory patient in ED; ventricular-assist devices, especially for widened left bundle branch block with QRS >130 ms;
transplantation; aldosterone blockade
|
| CARDIAC DISEASE IN WOMEN —Nanette K. Wenger, MD, Professor of Cardiology, Emory University School of Medicine,
and Chief of Cardiology, Grady Memorial Hospital, Atlanta, GA
|
| Cardiovascular disease in women: leading cause of death in women; ≈250,000 deaths per year; every minute, 1
woman in United States dies from cardiovascular disease; more women than men die per year from cardiovascular disease;
1 in 8 to 9 women 45 to 64 yr of age have CHD; 1 in 3 women on Medicare have CHD; initial manifestations of
CHD occur ≈10 yr later in women; ≈20,000 women <65 yr of age per year die from MI (one third <55 yr of age); every
year, nearly 10,000 women <45 yr of age have MI
|
| Facts vs perceptions: 2005 American Heart Association (AHA) survey found awareness of cardiac disease has improved,
but lowest in women at highest risk (ie, black and Hispanic women); physicians tend to perceive women as lower
risk, so less likely to prescribe preventive interventions
|
| Angina: predominant initial and subsequent presentation of CHD in women (in contrast to MI and sudden death in men);
women with chest pain should be carefully evaluated and risk stratified; women who present with initial MI more likely than
men to have antecedent stable angina; should be doing more during stable phase; women with angina likely to be older,
more hypertensive, and to have HF with intact systolic function; women less likely to have had previous MI or revascularization
procedure; prevalence of stable angina in women and men comparable; Finnish study—data show annual incidence
of angina same for women and men; “nitrate angina” (based on nitrate prescription) associated with increased
mortality in men and women; “test-positive angina” (based on exercise stress testing with or without imaging) associated
with greater mortality than nitrate angina; diabetes and test-positive angina contribute to mortality, more so in women than
men; European Heart Survey of Stable Angina—diagnosed by cardiologist; compared to men, women underwent less
exercise testing and less coronary arteriography (31% vs 49%), despite having higher severity of angina; women were prescribed
fewer statins and antiplatelet therapy, and underwent fewer coronary revascularization procedures; death from nonfatal
MI twice as high in women
|
| Women’s Ischemia Syndrome Evaluation (WISE) study: women with chest pain and ischemia on noninvasive
testing; ≈50% did not have flow-limiting obstructive disease on arteriography, but had persistent symptoms and significant
occurrence of objective coronary events; death or MI 13.6% in women with significant obstructive disease, 6.9% in
women with minimal obstruction, and 2.5% in women with “absolutely pristine” coronary arteries; women with no or minimal
obstructive disease had nearly 10% occurrence of death or MI over 1600 days; women may have different vasculopathy
that results in myocardial ischemia; intravascular ultrasonography (IVUS) showed sizable atherosclerotic burden
within arterial wall, even with no obstruction into lumen of coronary artery; small vessel disease and decreased coronary
flow reserve (directly correlates with major coronary events) also seen; consider role of inflammatory markers and oxidative
stress, risk factors (eg, metabolic syndrome), and other reasons for microvascular dysfunction; carefully address all
coronary risk factors in women with abnormal noninvasive test results (even if no significant obstructive disease present)
|
| Acute coronary syndromes (ACS): Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes
(GUSTO IIb) study—saw differences in clinical profiles, presentations, and outcomes between men and
women; women more likely to have unstable angina than ECG- or biomarker-documented MI; fewer women have ST-elevation
MI than men; women with unstable angina appear to do better than men; women were older with more diabetes,
hypertension, HF (intact systolic function), and complications (eg, bleeding); women had greater delay in seeking care
and fewer angiography procedures; women more likely to have “clinically insignificant” disease (ie, not amenable to angioplasty),
but had greater overall mortality; outcomes similar to those of men when adjusted for age and baseline characteristics;
European survey of ACS—>85% of 10,000-patient cohort had typical chest pain, but women had twice as
great severity in Killip class and more HF with intact systolic function (diastolic dysfunction HF hallmark of older
woman); Clopidgrel in Unstable angina to prevent Recurrent Events (CURE) trial—women had fewer invasive diagnostic
and revascularization procedures, more refractory ischemia, and more rehospitalizations; invasive testing done
only on rehospitalization
|
| Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early
implementation of the ACC/AHA guidelines (CRUSADE) registry for non-ST segment elevation
MI: quality improvement initiative; data on ≈35,000 patients (41% women) submitted by hospitals; women had greater
risk for in-hospital death, MI, HF, stroke, and transfusion; women less likely to receive heparin, ACE inhibitor, and glycoprotein
IIb/IIIa inhibitor; at discharge, women less likely to receive aspirin, ACE inhibitor, and statin; women had less
favorable outcomes
|
| Early invasive strategy for acute ACS: clinical trials conflicting; European studies saw benefits only in men and
suggested harm in women; US studies saw benefits in men and women; differences in risk status—angioplasty associated
with greater risk in women; high-risk women with ACS do better with interventions, despite associated risk; high-risk
women include women with pain and objective evidence of ECG and biomarker abnormalities; unknown why women at
increased risk for bleeding in all studies; conclusions—invasive strategy effective for women, but because of higher
bleeding complications, should be targeted to higher-risk women who have ACS and ECG and biomarker abnormalities;
studies done with balloon angioplasty or bare metal stents, must be repeated with drug-eluting stents and newer adjunctive
therapies
|
| Acute MI: age-based mortality—study found women ≤70 yr of age had higher mortality than age-matched men; women
<40 yr of age had nearly same mortality as men 60 to 70 yr of age; tobacco smoking may be contributing factor; sex and
ethnicity—study looked at reperfusion with thrombolytic drugs or mechanical reperfusion and coronary angiography related
to hospital mortality; white women and black men ranked close to white men (standard); in black women, rate of reperfusion
10% less, angiography 24% less, and mortality 11% more; no change in trend from 1994 to 2002; black women at
highest risk for mortality, possibly related to fewer interventions
|
Suggested Reading
Alexander KP et al: Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: results from the CRUSADE
(Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/
AHA guidelines) initiative. Circulation 114:1380, 2006; Carmody MS et al: BiDil (isosorbide dinitrate and hydralazine):
a new fixed-dose combination of two older medications for the treatment of heart failure in black patients. Cardiol Rev
15:46, 2007; Demers C et al: ACE inhibitors in heart failure: what more do we need to know? Am J Cardiovasc Drugs
5:351, 2005; Hemingway H et al: Incidence and prognostic implications of stable angina pectoris among women and
men. JAMA 295:1404, 2006; Hermann F et al: Clinical trials report. CHARM-Added Trial. Curr Hypertens Rep 6:47,
2004; Krum H et al: Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results
from Val-HeFT. Eur J Heart Fail 6:937, 2004; McMurray JJ et al: Relationship of dose of background angiotensin-
converting enzyme inhibitor to the benefits of candesartan in the Candesartan in Heart failure: Assessment of Reduction in
Mortality and morbidity (CHARM)-Added trial. Am Heart J 151:985, 2006; McMurray JJ: Val-HeFT: do angiotensin-
receptor blockers benefit heart failure patients already receiving ACE inhibitor therapy? Nat Clin Pract Cardiovasc Med
2:128, 2005; Mistry NB et al: The angiotensin receptor antagonist valsartan: a review of the literature with a focus on clinical
trials. Expert Opin Pharmacother 7:575, 2006; Quyyumi AA: Women and ischemic heart disease: pathophysiologic
implications from the Women's Ischemia Syndrome Evaluation (WISE) Study and future research steps. J Am Coll Cardiol
47:S66, 2006; Shaw LJ et al: Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE)
Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic
strategies. J Am Coll Cardiol 47:S4, 2006; Solomon SD et al: Influence of ejection fraction on cardiovascular outcomes
in a broad spectrum of heart failure patients. Circulation 112:3738, 2005; Wong M et al: Signs and symptoms in chronic
heart failure: relevance of clinical trial results to point of care-data from Val-HeFT. Eur J Heart Fail 8:502, 2006.
Educational Objectives
| The goal of this program is to improve the management of heart failure (HF) and to increase awareness of the frequency and
severity of cardiac disease in women. After hearing and assimilating this program, the clinician will be better able to:
|
 | 1. Describe similarities between the presentations of HF with normal and reduced ejection fraction.
|
| 2. Choose evidence-based angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and β-blockers for
treatment of HF.
|
| 3. List differences between men and women in presentation of coronary heart disease (CHD).
|
| 4. Discuss trends in quality of care and outcomes of women with CHD.
|
| 5. Evaluate use of invasive strategies in high-risk women with acute coronary syndromes.
|
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts
were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial
interest. For this program, the following has been disclosed: Dr. Basile has received financial or research support, is a
consultant, and/or is on the Speakers’ Bureau for Abbott Laboratories, AstraZeneca LP, Boehringer Ingelheim Pharmaceuticals,
Inc., Daiichi Sankyo, Forest, GlaxoSmithKline, Merck & Co., Novartis, and Pfizer US Pharmaceutical Group. Dr.
Wenger has received financial or research support, is a consultant, and/or is on the Speakers’ Bureau for Abbott Laboratories,
AstraZeneca LP, Bristol-Myers Squibb Company, CV Therapeutics, Eli Lilly and Co., GlaxoSmithKline, NitroMed, Inc.,
Novartis, Pfizer US Pharmaceutical Group, Sanofi-aventis, and Schering-Plough Corp.
Acknowledgements
Drs. Basile and Wenger spoke in Newport Beach, CA, at 2006 Primary Update: Improving Patient Care, presented November
5-8, 2006, by the Interstate Postgraduate Medical Association of North America (IPMA). The Audio-Digest Foundation
thanks the speakers and the IPMA for their cooperation in the production of this program.
|
