Prognostic significance of cerebrovascular disease in 11,526 chronic coronary artery disease patients

Prognostic Significance of Cerebrovascular Disease in 11,526 Chronic Coronary Artery Disease Patients Henrietta Reicher-Reiss, MD, Michael Jonas, MD, David Tanne, MD, Lori Mandelzweig, MPH, Uri Goldbourt, PhD, Avraham Shotan, MD, Valentina Boyko, MSc, and Solomon Behar, MD, for the Bezafibrate Infarction Prevention (BIP) Study Group oronary artery disease (CAD) and cerebrovascular disease are among the leading causes of morbidity C and mortality. These diseases share common risk factors, and although ischemic heart disease remains a frequent cause of death in stroke patients,1 extracranial and intracranial arterial atherosclerosis is common in patients with CAD.2 A few studies have suggested that prior cerebrovascular event (CVE) may contribute to a poor prognosis after an initial acute myocardial infarction,3– 6 whereas others have not.7,8 Because information is scarce, we compared the fate of patients who had experienced stroke or transient ischemic attack to patients without similar comorbidity, thereby assessing the effects of a CVE history on total and cardiac mortality in a large population of chronic CAD patients, remote from an acute myocardial infarction. •••

A total of 15,502 patients, aged 45 to 74 years, with chronic CAD were screened between February 1990 and January 1993 for participation in the Bezafibrate Infarction Prevention (BIP) study—a secondary prevention trial recently completed in Israel. Diagnosis of clinically established CAD was based on a verified history of myocardial infarction between 6 months and 5 years before screening, and/or stable angina pectoris with symptoms present during the 2 years preceding examination, together with an objective documentation of the related CAD. The diagnosis of acute myocardial infarction was based on the presence of typical chest pain lasting $30 minutes, unequivocal new electrocardiographic changes (Q/QS and/or ST segment and T-wave changes) or an increase of $2 of the serum cardiac enzymes (creatine kinase-MB, glutamic oxaloacetic transaminase, and lactate dehydrogenase) to .1.5 times the upper limit of normal. Methods of data acquisition, criteria for screening and inclusion, and definition of variables have been previously reported.9 Demographic and clinical data were systematically collected for all 15,502 screened patients. Physical examination and laboratory blood profile were performed. Data on prior CVE were systematically collected by patient report or from medical records present at the screening visit. No attempt was From the Neufeld Cardiac Research Institute, Sheba Medical Center, Tel Hashomer, Israel. Dr. Reicher-Reiss’s address is: Neufeld Cardiac Research Institute, Sheba Medical Center, Tel Hashomer, 52621, Israel. Manuscript received April 15, 1998; revised manuscript received and accepted July 15, 1998.

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made to differentiate between ischemic versus hemorrhagic stroke during the screening evaluation. History of CVE was defined as any event of rapid development of focal loss of cerebral function with symptoms lasting more (stroke) or less (transient ischemic attack) than 24 hours, and without any apparent cause other than a vascular one. Three thousand one hundred twenty-two patients were included and followed in the BIP study in an attempt to assess the efficacy of long-term administration of bezafibrate on the reduction of fatal and nonfatal coronary events among patients with CAD who had normal or moderately elevated total cholesterol and low high-density lipoprotein cholesterol. These patients, included in the BIP study, were excluded from the present analysis. A further 854 patients were excluded due to incomplete data. The remaining 11,526 screened patients were the subject of this analysis. Mortality data through September 1996 were obtained for all patients from the death certificates and records of the National Population Registry, the cause of death being categorized according to the ICD-9 International Coding (cardiac mortality codes 410 to 429). The mean follow-up period was 5.1 years. SAS software (Cary, North Carolina) was used for statistical analysis. The chi-square test was used to compare proportions of discrete variables between groups. The Student’s t test was used to compare group means for continuous variables. Multivariate analysis of long-term mortality was performed using the Cox proportional-hazard model. Variables were examined in a stepwise manner, with p 5 0.15 for entry and p 5 0.1 for removal (procedure PHREG10). The validity of proportional hazards associated with prior CVE was examined by running a model including prior CVE and a time-dependent explanatory variable and testing the null hypothesis that the regression parameter for the time-dependent variable was equal to zero. The p value for the results obtained, assuming no increase or decrease in the relative hazard over time was 0.08. The Kaplan-Meier method and logrank test were used to calculate and compare survival curves.11 Among the 11,526 patients with chronic CAD, 306 patients had a history of preexisting cerebrovascular disease, representing 2.6% of the study population. The control group included the 11,220 remaining patients. Baseline characteristics of the study group according to CVE history are presented in Table I. DECEMBER 15, 1998

class II than those free of a past CVE. Lipid profiles were comparable in the 2 groups. Cerebovascular As seen in Table II, total mortalEvent Others ity was .2-fold in the group of pa(n 5 306) (n 5 11,220) p Value tients with a history of a CVE comAge (yrs) 62 6 6 60 6 7 ,0.001 pared with the control group (28.1% Men 242 (79%) 8,786 (78%) NS and 12.9%, respectively). This trend Diabetes mellitus 102 (33%) 2,379 (21%) ,0.001 was observed for both cardiac and Peripheral vascular disease 42 (14%) 438 (4%) ,0.001 Current smoking 39 (13%) 1,270 (11%) NS noncardiac mortality. Deaths due to Previous acute myocardial infarction 227 (75%) 7,926 (71%) NS CVE were more frequent in those NYHA 21 114 (37%) 3,121 (28%) ,0.001 patients who had a CVE history Hypertension 175 (57%) 3,687 (33%) ,0.001 (3.6% compared with 2.5% in those Total cholesterol (mg/dl) 225 6 43 226 6 43 NS who had not). The survival curve LDL cholesterol (mg/dl) 155 6 38 155 6 37 NS HDL cholesterol (mg/dl) 38 6 10 39 6 11 NS shown in Figure 1, comparing the Triglycerides (mg/dl) 162 6 87 165 6 102 NS 5-year survival in patients with and Fibrinogen (mg/dl)* 376 6 96 350 6 77 0.03 without a previous CVE, shows a *Examined in a subgroup of 3,600 patients. poorer survival for patients with a HDL 5 high-density lipoprotein; LDL 5 low-density lipoprotein; NYHA 5 New York Heart Association history of CVE. Similar survival functional class II or greater. curves for cardiac mortality are shown in Figure 2. Multivariate analysis adjusted for age, history of CVE, past myocardial infarction, peTABLE II Mortality According to History of Cerebrovascular ripheral vascular disease, chronic lung disease, funcEvent tional capacity class, diabetes mellitus, current smokCerebrovascular ing, angina, hypertension, and gender showed that a Event Others history of stroke and/or transient ischemic attack was (n 5 306) (n 5 11,220) p Value associated with an adjusted 86% elevation in total Total mortality 86 (28%) 1,449 (13%) ,0.001 mortality (relative risk 5 1.86; 95% confidence interCardiac mortality 52 (17%) 766 (7%) ,0.001 val 1.48 to 2.34), representing a predictor of mortality Noncardiac mortality 27 (9%) 463 (4%) ,0.001 as powerful as 10-year increments of age. Other inUnknown 7 (2%) 220 (2%) NS dependent predictors of mortality are shown in Table III. TABLE I Baseline Characteristics of Patients According to History of Cerebrovascular Event

•••

This analysis of a large population of chronic CAD patients provides evidence of a markedly increased mortality in patients with a previous stroke or transient ischemic attack compared with patients free of a past CVE. The most common and most important vascular disease that affects both the brain and the heart is atherosclerosis.12 In addition, patients with impaired cardiac function from CAD may be prone to stroke due to cardioembolism or impaired flow. A number of earlier studies have examined the aggravating relation between a previous CVE and long-term prognosis after acute myocardial infarction.3,4,7 A recent analysis from the Framingham study examined the effect of preexisting cardiovascular FIGURE 1. Five-year total mortality in patients with and without a history of CVEs. conditions on long-term prognosis after an initial myocardial infarction in 828 patients.8 A history of a CVE Patients with a history of a CVE were older, had a was present in 52 patients (6.3%) and was associated higher incidence of diabetes, hypertension, and pe- with a marginally elevated risk of mortality in women, ripheral vascular disease, and included a greater pro- but not in men. After adjusting for the traditional risk portion of patients in New York Heart Association factors before myocardial infarction, this association BRIEF REPORTS

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incidence of stroke or transient ischemic attack in the screened population. Multivariate analysis showed a history of preexisting CVE to be a significant independent predictor of mortality. Comparing the relative risk conferred by a previous CVE to other known risk factors (Table III) established it to be as powerful a predictor as a 10-year incremental increase in age. Although multivariate analysis accounts for differences in baseline characteristics, there may be other confounding factors or differences in severity of disease that may account for the possibility that a previous CVE may be a marker of more severe atherosclerosis. This represents an inherent limitation of this retrospective analysis. In addition, the cause of death included in the FIGURE 2. Five-year cardiac mortality in patients with and without a history of CVEs. National Death Registry is on occasion not fully detailed. This is a universal limitation in using this information in large population studies. TABLE III Predictors of Total Mortality in 11,526 Patients With Coronary Artery Disease: Multivariate Analysis Due to the diffuse nature of atherosclerosis, a history of CVE may suggest that the chronic CAD occurs Relative against a background of more severe atherosclerosis Risk 95% CI or a higher risk of thromboembolism; hence, adverse Age* 1.90 1.75–2.07 prognosis is made.13–15 Some of the increased mortalCerebrovascular event 1.86 1.48–2.34 ity could be potentially explained by other variables Past myocardial infarction 1.60 1.40–1.82 Peripheral vascular disease 1.56 1.29–1.88 not accounted for in our multivariate analysis, which Chronic obstructive pulmonary disease 1.49 1.19–1.86 are associated with increased risk of stroke as well as New York Heart Association functional 1.32 1.18–1.48 that of mortality. The greater use of multiple medicaclass II1 tions among patients with preexisting cerebrovascular Diabetes mellitus 1.36 1.18–1.57 disease may indeed suggest comorbidities. Our data, Current smoking 1.34 1.15–1.56 Angina pectoris 1.13 1.01–1.28 however, clearly demonstrate that preexisting cerebroWomen 0.83 0.73–0.94 vascular disease is a powerful marker of increased risk Glucose (mg/dl, increment: 50) 1.18 1.12–1.24 among patients with CAD. Triglycerides (mg/dl, increment: 100) 1.05 1.00–1.10 Heart rate (beats/min, increment: 10)

1.26

1.21–1.33

*Relative risk associated with 10-year increments. CI 5 confidence intervals.

was not sustained and it was concluded that CVE does not affect the subsequent risk of death. Unlike the above-mentioned observational studies related to acute myocardial infarction, our study followed a patient population with chronic CAD, suffering from angina or a history of remote myocardial infarction. A previous CVE was relatively infrequent (2.6%) in this large group of coronary patients. CVE was an exclusion criterion for the BIP study itself and bedridden patients with a major incapacitating stroke were not screened for this study. Therefore, it is unlikely that their propensity to increased mortality contributed to our results. Furthermore, the present analysis does not account for the fatal strokes that occurred in the 6 months after acute myocardial infarction. These facts may explain the relatively low 1534 THE AMERICAN JOURNAL OF CARDIOLOGYT

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To improve this ominous outcome, we believe that a more aggressive approach in the treatment of these patients is needed: thorough implementation of control of existing risk factors16,17 together with a more active therapeutic approach in the acute phase of the disease. Although there has been much reservation about the use of thrombolysis in patients with prior CVE, due to fear of intracranial hemorrhage,18 some recent data have suggested that patients with a nonrecent prior ischemic stroke should not be automatically excluded from thrombolysis. In Israeli national surveys of 2,012 patients with acute myocardial infarction conducted in 1992 and 1994, none of the 29 patients with a prior CVE treated with thrombolysis experienced an intracranial hemorrhage.19 The 1-year mortality rate was almost half among thrombolyzed versus nonthrombolyzed patients. Therefore, revascularization by thrombolysis should be individually considered in the acute phase of CAD in patients with a past CVE. Alternative reperfusion DECEMBER 15, 1998

therapy, such as primary angioplasty or coronary artery bypass grafting, should also be more actively considered in these patients. 1. Adams H, Kassell N, Mazuz H. The patient with transient ischemic attacks. Is

this the time for a new therapeutic approach? Stroke 1984 ;15:371–375. 2. Hennerici M, Aulich A, Sandman W, Freud HJ. Incidence of asymptomatic

extracranial arterial disease. Stroke 1981;12:750 –758. 3. Rappaport E, Remedios P. The high risk patient after recovery from myocardial infarction: recognition and management. J Am Coll Cardiol 1983;1:391– 400. 4. Pradaens J, Lesaffre E, Willems JL, De Geest H. Multivariate survival analysis for the assessment of prognostic factors and risk categories after recovery from acute myocardial infarction: the Belgian situation. Am J Epidemiol 1985;122: 805– 820. 5. Tanne D, Goldbourt U, Zion M, Reicher-Reiss H, Kaplinsky E, Behar S, and the SPRINT Study Group. Frequency and prognosis of stroke/transient ischemic attack among 4808 survivors of acute myocardial infarction. Stroke 1993;24: 1490 –1495. 6. Tanne D, Reicher-Reiss H, Boyko V, Behar S, for the SPRINT Study Group. Stroke risk after anterior wall acute myocardial infarction. Am J Cardiol 1995; 76:825– 826. 7. Schlant RC, Forman S, Stamler J, Canner PL. The natural history of coronary heart disease: Prognostic factors after recovery from myocardial infarction in 2789 men. The 5-year findings of the Coronary Drug Project. Circulation 1982; 66:401– 414. 8. Cupples LA, Ganon DR, Wong ND, Ostfeld AM, Kannel WB. Preexisting cardiovascular conditions and long-term prognosis after initial myocardial infarction: The Framingham study. Am Heart J 1993;125;863– 872. 9. Goldbourt U, Behar S, Reicher-Reiss H, Agmon J, Kaplinsky E, Graff E, Kishon Y, Caspi A, Weisbort J, Mandelzweig L, et al, for the Bezafibrate Infarction Prevention Study Group. Rationale and design of a secondary preven-

tion trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (The Bezafibrate Infarction Prevention Trial). Am J Cardiol 1993;71:909 –915. 10. SAS Institute Inc. SAS Technical report P229. SAS/STAT software: changes and enhancements, release 6.07. Cary, NC:SAS Institute Inc., 1992;433– 480. 11. SAS Institute Inc. SAS/STAT User’s Guide. Version 6, Fourth edition, Volume 2. Cary, NC:SAS Institute Inc. 1989;1027–1070. 12. Caplan RL. Cerebrovascular disease and neurologic manifestations of heart disease. In: Hurst JW, Schlant RC, Rackley CE, Sonnenblick EH, Wenger NK, eds. Hurst’s The Heart. 8th ed. New York: McGraw-Hill, Inc. 1994;2148 –2153. 13. Loh E, Sutton MSJ, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, Lamas GA, Moye LA, Goldhaber SZ, Pfeffer MA. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997;336:251–257. 14. Reed DM. The paradox of high risk of stroke in populations with low risk of coronary heart disease. Am J Epidemiol 1990;131:579 –588. 15. Neaton JD, Wentworth DN, Cutler J, Stamler J, Kuller L, for the Multiple Risk Factor Intervention Trial Research Group. Risk factors for death from different types of stroke. Ann Epidemiol 1993;3:493– 499. 16. Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: The Copenhagen City Heart Study. BMJ 1994;309;11–15. 17. Pullicino PM, Xuereb M, Aquilina J, Piedmonte MR. Stroke following acute myocardial infarction in diabetics. J Intern Med 1992;231:287–293. 18. Tanne D, Gottlieb S, Hod H. Reicher-Reiss H, Boyko V, Behar S, for the Secondary Prevention Israeli Nifedipine Trial (SPRINT) and Israeli Thrombolytic Survey Groups. Incidence and mortality from early stroke associated with acute myocardial infarction in the prethrombolytic and thrombolytic eras. J Am Coll Cardiol 1997;30:1484 –1494. 19. Tanne D, Gottlieb S, Caspi A, Hod H, Palant A, Reisin L, Rosenfeld T, Peled B, Marmor A, Balkin J, Boyko V, Behar S, for the Israeli Thrombolytic National Survey Group. Treatment and outcome of patients with acute myocardial infarction and prior cerebrovascular events in the thrombolytic era. Arch Int Med 1998;158:601– 606.

Endothelium-Dependent Flow-Mediated Vasodilation in Coronary and Brachial Arteries in Suspected Coronary Artery Disease Bonpei Takase, MD, Akimi Uehata, MD, Takashi Akima, MD, Tomoo Nagai, Toshihiko Nishioka, MD, Akira Hamabe, MD, Kimio Satomura, MD, Fumitaka Ohsuzu, MD, and Akira Kurita, MD ndothelial dysfunction plays an important role in the pathogenesis of coronary artery disease and E is considered an early manifestation of atherosclero1– 4

sis,5,6 which is sometimes generalized and systemic.7,8 In the conduit arteries, a vasodilator response to an increment of blood flow is reportedly endothelium dependent.9,10 Such flow-mediated vasodilations have been investigated in both coronary and brachial arteries. In the latter, vasodilation can be performed noninvasively.11–16 It would be helpful to know how closely endothelial function in brachial arteries reflects endothelial function in coronary arteries. Although an earlier study, as assessed by acetylcholine, showed their significant correlation, it was weak.8 One reason for the poor correlation might have been a stimulus difference in the coronary and brachial arteries.17 Further, the existence of a progressive and hierFrom the Self Defense Force Central Hospital, Internal Medicine, Tokyo; and Internal Medicine-1 and Department of Medical Engineering, National Defense Medical College, Saitama, Japan. Dr. Takase’s address is: Self Defense Force Central Hospital, Internal Medicine, 1-2-24 Ikejiri, Setagaya-ku, Tokyo, Japan 154. Manuscript received March 6, 1998; revised manuscript received and accepted July 15, 1998. ©1998 by Excerpta Medica, Inc. All rights reserved.

MD,

archical impairment of endothelial function has been reported.3,17 The purpose of the present study was to test the hypothesis that a closer relation between endothelial functions of coronary and brachial arteries would be obtained if the same stimulus was used in the evaluation, and to determine whether flow-mediated vasodilation in a brachial artery can be used as a reliable index of that in a coronary artery. The stimulus used in the present study to evaluate endothelial functions of both arteries is an increase in flow, i.e., shear stress to the endothelium. •••

The study group consisted of 15 consecutive patients (10 men and 5 women; age range 38 to 77 years, average 57 6 8) with suspected coronary artery disease who were referred to the Division of Cardiology of the Self Defense Force Central Hospital and who also agreed to both coronary endothelial function and brachial ultrasound studies. Cardiac risk factors and selected clinical characteristics of the 15 patients are listed in Table I. Ten patients smoked cigarettes, 6 had hypertension, 9 had hyperlipidemia (hypercholesterolemia), 2 had diabetes mellitus, and 4 had a family history of premature atherosclerosis. Coronary artery 0002-9149/98/$19.00 PII S0002-9149(98)00702-4

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