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Annals of Internal Medicine Article Outcome of Congestive Heart Failure in Elderly Persons: Influence of Left Ventricular Systolic Function The Cardiovascular Health Study John S. Gottdiener, MD; Robyn
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Annals of Internal Medicine Article Outcome of Congestive Heart Failure in Elderly Persons: Influence of Left Ventricular Systolic Function The Cardiovascular Health Study John S. Gottdiener, MD; Robyn L. McClelland, PhD; Robert Marshall, MD; Lynn Shemanski, PhD; Curt D. Furberg, MD; Dalane W. Kitzman, MD; Mary Cushman, MD; Joseph Polak, MD, MPH; Julius M. Gardin, MD; Bernard J. Gersh, MB, ChB, DPhil; Gerard P. Aurigemma, MD; and Teri A. Manolio, MD, MHS Background: Most persons with congestive heart failure are elderly, and many elderly persons with congestive heart failure have normal left ventricular systolic function. Objective: To evaluate the relationship between left ventricular systolic function and outcome of congestive heart failure in elderly persons. Design: Population-based longitudinal study of coronary heart disease and stroke. Setting: Four U.S. sites: Forsyth County, North Carolina; Sacramento County, California; Allegheny County, Pennsylvania; and Washington County, Maryland. : 5888 persons who were at least 65 years of age and were recruited from the community. Measurements: Total mortality and cardiovascular morbidity and mortality. Results: Of 5532 participants, 269 (4.9%) had congestive heart failure. Among these, left ventricular function was normal in 63%, borderline decreased in 15%, and overtly impaired in 22%. The mortality rate was 25 deaths per 1000 person-years in the reference group (no congestive heart failure and normal left ventricular function at baseline); 154 deaths per 1000 person-years in participants with congestive heart failure and impaired left ventricular systolic function; 87 and 115 deaths per 1000 person-years in participants with congestive heart failure and normal or borderline systolic function, respectively; and 89 deaths per 1000 personyears in persons with impaired left ventricular function but no congestive heart failure. Although the risk for death from congestive heart failure was lower in persons with normal systolic function than in those with impaired function, more deaths were associated with normal systolic function because more persons with heart failure fall into this category. Conclusions: Community-dwelling elderly persons, especially those with impaired left ventricular function, have a substantial risk for death from congestive heart failure. However, more deaths occur from heart failure in persons with normal systolic function because left ventricular function is more often normal than impaired in elderly persons with heart failure. Ann Intern Med. 2002;137: For author affiliations, see end of text. Congestive heart failure is the most frequent cause of hospitalization in persons 65 years of age or older, accounting for more than admissions each year in the United States (1). Moreover, aging of the population, increased susceptibility of elderly hypertensive persons to congestive heart failure (2), decreasing incidence of and death from stroke, and improved survival after acute myocardial infarction have increased the number of patients at risk for congestive heart failure (1, 3, 4). The clinical syndrome of congestive heart failure occurs over a broad range of underlying left ventricular systolic function (5 7). Compared with persons younger than 65 years of age, more elderly persons with congestive heart failure have normal systolic function (5, 8). Elevated pulmonary venous pressure, which accounts at least in part for the clinical manifestations of congestive heart failure, is likely to result from impaired diastolic ventricular filling (9). This impairment may be the consequence of diminished systolic function or of other causes (10 14) that may result in decreased myocardial compliance in the absence of systolic dysfunction. The probability of survival diminishes substantially after congestive heart failure is diagnosed (15, 16). However, studies have differed about the impact of left ventricular systolic function on survival (17 23). We tested the hypothesis that congestive heart failure confers increased morbidity and mortality in elderly persons even in the presence of normal or only mildly impaired left ventricular systolic function. We also hypothesized that impaired systolic function would be independently associated with greater risk than normal or borderline function. METHODS Study Sample The Cardiovascular Health Study, designed to assess cardiovascular disease, cardiovascular disease outcomes, and risk factors, identified adults from the Health Care Financing Administration Medicare enrollment lists in four widely separated U.S. communities, along with other household members who were older than 65 years of age at study enrollment. Recruitment centers were located in Washington County, Maryland; Forsyth County, North Carolina; Sacramento County, California; and Allegheny County, Pennsylvania. Persons were excluded from the Cardiovascular Health Study if they were receiving active treatment for cancer, were wheelchair-bound or institutionalized, or were unable to participate in the examination. Prevalent coronary artery disease, stroke, and heart failure were not exclusion criteria. When we included both 2002 American College of Physicians American Society of Internal Medicine 631 Article Outcome of Congestive Heart Failure in Elderly Persons Context Most patients with congestive heart failure (CHF) are 65 years of age or older. Older patients more often have CHF with normal left ventricular systolic function than younger patients. How left ventricular systolic function affects prognosis of CHF in older patients is not clear. Contribution In this population-based study of 5532 older adults, 4.9% had CHF with normal (63%), borderline decreased (15%), or impaired (22%) left ventricular systolic function. Forty-five percent of those with CHF and 16% of those without CHF died within 6 to 7 years. Among those with CHF, death rates were higher with decreased versus normal left ventricular systolic function. The Editors the original cohort (recruited in 1989 to 1990) and those enrolled when the study was expanded to include more African-American persons (in 1992 to 1993), data were available from 5888 study participants. Details of the design, sampling, and recruitment of the Cardiovascular Health Study, as well as the interview and examination, have been published previously (24). Self-report of cardiovascular and pulmonary diseases was validated according to standardized criteria through assessment of medications, medical records, and relevant information obtained during the initial examination. Further evaluation involved fasting blood chemistry tests, measurement of blood pressure and heart rate, anthropometric measurements, electrocardiography, echocardiography, carotid ultrasonography, and other objective measurements. without an interpretable echocardiogram and those with significant aortic or mitral stenosis, greater than moderate mitral regurgitation, or at least moderately severe aortic regurgitation were excluded from our study. Adjudication of Congestive Heart Failure Details of the methods used to assess the prevalence of congestive heart failure among participants in the Cardiovascular Health Study have been reported previously (25, 26). An expert panel adjudicated the index event of congestive heart failure by reviewing all pertinent data on the hospitalization or outpatient visit, including history, physical examination, report of chest radiography, and medication usage. Self-report of a physician diagnosis of congestive heart failure was confirmed by documentation in the medical record of a constellation of symptoms (shortness of breath, fatigue, orthopnea, paroxysmal nocturnal dyspnea) and physical signs (edema, pulmonary rales, gallop rhythm, displaced left ventricular apical impulse) or by supporting clinical findings, such as those on chest radiography. Diagnosis of congestive heart failure was also confirmed if, in addition to having a previous physician diagnosis, the participant was receiving medical therapy for congestive heart failure (a current prescription of a diuretic and digitalis or a vasodilator [nitroglycerin, hydralazine, or angiotensinconverting enzyme inhibitor]). Adjudication of Outcome Events Throughout the follow-up period, participants were interviewed every 6 months and follow-up examinations Table 1. Baseline Characteristics of by Study Group* Characteristic No CHF, Normal LV Systolic Function (n 4864) No CHF, Borderline LV Systolic Function (n 263) No CHF, Impaired LV Systolic Function (n 136) Age, y Men, n (%) 1940 (39.9) 170 (64.6) 101 (74.3) African-American ethnicity, n (%) 613 (12.6) 30 (11.4) 15 (11.0) Weight, kg Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Hypertension, n (%) 2195 (45.1) 148 (56.3) 63 (46.3) Diabetes, n (%) 518 (10.7) 48 (18.3) 21 (15.4) Coronary heart disease, n (%) 725 (14.9) 92 (35.0) 79 (58.1) Serum creatinine concentration, mol/l (mg/dl) ( ) ( ) ( ) Serum cholesterol level, mmol/l (mg/dl) ( ) ( ) ( ) FEV 1, L/min Ankle arm index 0.9, n (%) 535 (11.0) 42 (16.0) 38 (27.9) Alcohol intake, drinks/wk Internal carotid intima media thickness, mm Common carotid intima media thickness, mm Atrial fibrillation on electrocardiography, n (%) 86 (1.8) 13 (4.9) 9 (6.6) Early mitral inflow velocity on Doppler ultrasonography, cm/s Late mitral inflow velocity on Doppler ultrasonography, cm/s Ratio of early to late mitral inflow velocity LV mass on electrocardiography, g Mitral regurgitation, n (%) 329 (6.8) 24 (9.1) 19 (14.0) * Values presented with plus/minus sign are the mean SD. Differences in all variables among the six groups (except late mitral inflow velocity) were statistically significant for unadjusted analyses and for analyses adjusted for age and sex (P 0.01). CHF congestive heart failure; LV left ventricular October 2002 Annals of Internal Medicine Volume 137 Number 8 Outcome of Congestive Heart Failure in Elderly Persons Article were conducted annually at each local center. Outcome events were tabulated on the basis of report of physiciandiagnosed myocardial infarction or stroke and were then confirmed as described earlier. Deaths were confirmed by review of medical records and death certificates, as well as review of data on hospitalizations from the Health Care Financing Administration Medicare database on health care utilization. Cardiovascular death was classified according to criteria published previously (27). Briefly, myocardial infarction, stroke, sudden cardiac death, aortic aneurysm, peripheral vascular disease, mesenteric events, and congestive heart failure were included as immediate causes of death. Through these methods, as well as through interviews of contacts and proxies for participants lost to followup, we accounted for vital status in 100% of our participants. Echocardiography and Left Ventricular Systolic Function The design for echocardiographic study of participants in the Cardiovascular Health Study has been published previously (28). Briefly, two-dimensional echocardiography was performed at the baseline visit for the original cohort and at 2 years after the baseline visit for the second cohort. All echocardiograms were interpreted at a centralized core echocardiography laboratory by persons blinded to participants clinical information. To avoid lost statistical power due to an inability to determine left ventricular mass on echocardiography in a substantial number of participants, left ventricular mass was estimated by electrocardiography using methods published elsewhere (29). Valvular regurgitation and stenosis were assessed as previously described (28). Global left ventricular systolic function was qualitatively assessed on two-dimensional echocardiography as normal, borderline, or impaired, corresponding to an ejection fraction of 0.55 or greater, 0.45 to 0.54, and less than 0.45, respectively. Qualitative systolic function was assessable in 5649 (96%) of the original and second Cardiovascular Heath Study cohorts. The interreader agreement was 95% ( 0.32) based on quality-control rereads of 370 study echocardiograms, and the intrareader agreement was 99% in 158 rereads ( 0.92) (30). Clinical Assessment and Measurements At study enrollment, clinically evident coronary artery disease was determined as described previously (24 26). Diabetes mellitus was defined according to history reported on the questionnaire and current use of insulin or oral hypoglycemic medication. The ankle arm index (the ratio of supine systolic blood pressure at the ankle to that at the brachial artery, a measure of lower-extremity arterial occlusive disease [31]) was measured at baseline in both the original and second cohort. Baseline analyses of fasting serum chemistry values and fasting lipid measurements were also performed for both cohorts. Measures of pulmonary function, performed at the baseline visit for the original cohort and at 1 year after the baseline visit for the second cohort, included FVC and FEV 1. At the baseline visit for both cohorts, common and internal intima media thickness of the carotid artery was measured. Digitally recorded twelve-lead electrocardiograms, obtained at the baseline examination for both cohorts, were analyzed as described elsewhere (25, 26). Study Groups To evaluate the relationship between left ventricular systolic function and outcome of congestive heart failure, Table 1 Continued CHF, Normal LV Systolic Function (n 170) CHF, Borderline LV Systolic Function (n 39) CHF, Impaired LV Systolic Function (n 60) (44.1) 19 (48.7) 38 (63.3) 32 (18.8) 10 (25.6) 14 (23.3) (59.4) 28 (71.8) 34 (56.7) 45 (26.5) 14 (35.9) 14 (23.3) 98 (57.6) 27 (69.2) 47 (78.3) ( ) ( ) ( ) ( ) ( ) ( ) (22.9) 10 (25.6) 18 (30.0) (14.7) 5 (12.8) 3 (5.0) (9.4) 9 (23.1) 15 (25.0) 15 October 2002 Annals of Internal Medicine Volume 137 Number 8 633 Article Outcome of Congestive Heart Failure in Elderly Persons Table 2. Medication Use by Study Group* Group () -Blockers ACE Inhibitors Lipid-Lowering Drugs Diuretics Calcium-Channel Blockers Frequent Aspirin Use Digitalis 4OOOOOOOOOOOOOOOOOOOOOOOOO n (%) OOOOOOOOOOOOOOOOOOOOOOOOO3 Study subgroups No CHF, normal LV systolic function (n 4862) 607 (12.5) 303 (6.2) 263 (5.4) 1282 (26.4) 574 (11.8) 1138 (23.4) 283 (5.8) No CHF, borderline LV systolic function (n 261) 46 (17.6) 27 (10.3) 14 (5.4) 79 (30.3) 50 (19.2) 71 (27.2) 26 (10.0) No CHF, impaired LV systolic function (n 136) 20 (14.7) 12 (8.8) 11 (8.1) 42 (30.9) 30 (22.1) 43 (31.6) 26 (19.1) CHF, normal LV systolic function (n 170) 29 (17.1) 42 (24.7) 8 (4.7) 100 (58.8) 52 (30.6) 63 (37.1) 70 (41.2) CHF, borderline LV systolic function (n 39) 3 (7.7) 11 (28.2) 1 (2.6) 29 (74.4) 18 (46.2) 18 (46.2) 18 (46.2) CHF, impaired LV systolic function (n 60) 4 (6.7) 25 (41.7) 1 (1.7) 47 (78.3) 18 (30.0) 25 (41.7) 31 (51.7) Alternate subgroups No CHF (n 5259) 673 (12.8) 342 (6.5) 288 (5.5) 1403 (26.7) 654 (12.4) 1252 (23.8) 335 (6.4) CHF (n 269) 36 (13.4) 78 (29.0) 10 (3.7) 176 (65.4) 88 (32.7) 106 (39.4) 119 (44.2) Normal LV systolic function (n 5032) 636 (12.6) 345 (6.9) 271 (5.4) 1382 (27.5) 626 (12.4) 1201 (23.9) 353 (7.0) Borderline LV systolic function (n 300) 49 (16.3) 38 (12.7) 15 (5.0) 108 (36.0) 68 (22.7) 89 (29.7) 44 (14.7) Abnormal LV systolic function (n 196) 24 (12.2) 37 (18.9) 12 (6.1) 89 (45.4) 48 (24.5) 68 (34.7) 57 (29.1) * ACE angiotensin-converting enzyme; CHF congestive heart failure; LV left ventricular. For 115 participants, values for medications were missing. with significant valvular heart disease and missing or invalid results on echocardiography were excluded. P for comparisons among study subgroups. P for comparisons among study subgroups. P 0.2 for comparisons among study subgroups. Frequent aspirin use was defined as a prescription for aspirin or 7 days of use in the previous 2 weeks. six groups were identified by congestive heart failure status and left ventricular systolic function at baseline: 1) no congestive heart failure and normal left ventricular systolic function, 2) no congestive heart failure and borderline systolic function, 3) no congestive heart failure and impaired systolic function, 4) congestive heart failure and normal systolic function, 5) congestive heart failure and borderline systolic function, and 6) congestive heart failure and impaired systolic function. Statistical Analysis Chi-square tests or analysis of variance was used for unadjusted analyses of the associations among groups and baseline variables. Age- and sex-adjusted associations were investigated by using logistic regression models or analysis of covariance, using the six subgroups as predictors (32). Event rates per 1000 person-years at risk are presented for each type of incident event. Cox proportional hazard regression techniques were used to examine the association of the six subgroups with time to incident events after adjustment for covariates (33). Covariates included factors previously associated with poor outcome in other population-based investigations of survival, as well as baseline variables significantly associated with incident events in our study. These included age, sex, black ethnicity, weight, systolic blood pressure, diastolic blood pressure, diabetes, history of coronary heart disease, FEV 1, ankle arm index dichotomized at 0.9, atrial fibrillation on electrocardiography, intima media thickness for common and internal carotids, creatinine concentration, cholesterol level, alcoholic drinks per week, left ventricular mass, early and late mitral inflow velocity on Doppler ultrasonography, left atrial dimension, mitral regurgitation, medications ( -blockers, angiotensin-converting enzyme inhibitors, lipid-lowering drugs, diuretics, calcium-channel blockers, aspirin, digitalis), and clinic. In addition, we included a term to adjust for clustering within clinic, using the cluster(clinic) option of the coxph function in S-Plus 2000 (Insightful Corp., Seattle, Washington). The variables for mitral regurgitation, cholesterol level, and lipid-lowering medications were highly nonsignificant and did not behave as confounders for group in any of the models. That is, once these variables were removed from the model, estimates of hazard ratios for levels of the group variable changed at most in the second decimal place. In addition, removal of these variables improved the results of the overall tests of the proportional hazards assumption so that all models satisfied a P value greater than or equal to For these reasons, mitral regurgitation, cholesterol level, and lipid-lowering medications were omitted from all adjusted models. A statistic (mortality impact, also known as population attributable risk) was calculated to express the impact of the clinical condition (congestive heart failure with normal, borderline, or impaired systolic function) on the expected population mortality rate, based on the mortality risk and the prevalence of the condition in our population-based October 2002 Annals of Internal Medicine Volume 137 Number 8 Outcome of Congestive Heart Failure in Elderly Persons Article cohort (32). All statistical analyses were conducted by using S-Plus 2000, release 3. Role of the Funding Source This study was funded through contracts with the National Heart, Lung, and Blood Institute (NHLBI) and included substantial NHLBI involvement in data collection, analysis, and interpretation and manuscript preparation. Figure. Unadjusted Kaplan Meier survival curves for participants with no congestive heart failure (CHF) (top) and for those with CHF (bottom) based on left ventricular function (LVF). RESULTS Prevalence of Congestive Heart Failure and Left Ventricular Function Congestive heart failure was identified in 300 of 5888 participants (5.1%), and left ventricular systolic function was assessable in 5649 participants (96%). Of the 5532 participants remaining after those with significant valvular heart disease were excluded, 269 (
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