Association of Major Modifiable Risk Factors Among Patients with Coronary Artery Disease - A Retrospective Analysis

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1 Original Article Association of Major Modifiable Risk Factors Among Patients with Coronary Artery Disease - A Retrospective Analysis V Achari, AK Thakur Abstract Background : The relative importance of various risk factors varies in different regions of India. This was a retrospective study of patients with recently diagnosed coronary artery disease to assess four major risk factors: dyslipidemia, hypertension, smoking and diabetes. Material and Methods : A total of 5748 patients (4952 males, 796 females) with recently diagnosed coronary artery disease were analysed from the records of Heart Hospital along with 8103 controls (6092 males and 2011 females). Absolute lipid levels as well as prevalence of dyslipidemia using the ATP III guidelines were assessed. They were classified into two major groups premature CAD (males < 45 years females < 55 years) and CAD at usual age (males 45 years, females 55 years). Results : The most common pattern of CAD was chronic stable angina (n=2773, 48.24%). Mean total cholesterol (TC), LDL cholesterol and TC/HDL ratio were significantly higher in subjects with CAD compared to subjects without CAD controls. The mean HDL cholesterol and triglyceride levels were similar in both groups. Elevated LDL cholesterol, decreased HDL cholesterol, elevated total cholesterol and abnormal TC/HDL ratios were more common in CAD patients as compared to controls (38.8% vs %, 29.3% vs 18.2%, 36.9% vs 32.5% and 59.05% vs 44.3% respectively). However lipid abnormalities were not significantly different in females 55 in CAD vs non-cad group. Smoking was significantly more common in subjects with CAD groups (30.97% vs %) as compared to subjects without CAD (P < ). It was most common in males with premature CAD (44.1% P < ). Hypertension was found in 1036 patients (18.02%) and diabetes in 763 (13.28%) as compared to 1126 (13.9%) hypertensives in non-cad group and 639 diabetics (7.89%) (P = 0.001), both were more common in males 45 and females 55 as compared to those with premature CAD (p < 0.01). Conclusion : Among the risk factors assessed, dyslipidemia (particularly abnormal TC/HDL ratio and elevated LDL cholesterol), smoking hypertension and diabetes were associated with coronary artery disease in decreasing order of prevalence. In premature CAD, dyslipidemia and (in males) smoking are of particular importance. INTRODUCTION With the explosive rise in the incidence of coronary artery disease (CAD), it is now estimated that this will be the leading cause of mortality and morbidity even in the developing world by the year Over 200 risk factors for CAD have been identified or postulated, of which dyslipidemia, hypertension and smoking appear to be the most important. 2 A major component of this epidemic is due to treatable factors, which if controlled will go a long way in Heart Hospital, Kankarbagh, Patna. Received : ; Accepted : stemming the epidemic. These risk factors have been classified ranging from class II (intervention likely to lower cardiovascular risk), class III (factors if modified might lower cardiovascular risk) and class IV (unmodifiable risk factors). 3 Dyslipidemia is classified partly as a class I risk factor (LDL cholesterol) and class II (triglycerides). Hypertension and smoking are regarded as class I risk factor while diabetes considered a class II risk factor. While there have been some studies on lipids and other factors in Delhi 4 and Vellore 5 and other cities there is a paucity of data on prevalence of such factors in many states including Bihar and this study is an effort to provide some information JAPI VOL. 52 FEBRUARY

2 on this subject. MATERIAL AND METHODS This was a retrospective study conducted between from the records of Heart Hospital, Kankarbagh, Patna. Patients were diagnosed as having CAD on the basis of at least one of the following criteria: 1. History of documented angina/infarction. 2. ECG findings namely Minnesota codes 1-1, 4-1, 5-1, 5-2 or 9-2 highly suggestive of silent MI A positive treadmill test or stress echocardiographyhighly suggestive of silent MI 4. History of angina/mi in past with ECG confirmation. 5. Angiographic evidence of CAD or history of PTCA/ CABG Five thousand seven hundred and forty-eight patients with complete data and newly diagnosed CAD were selected for study. The major risk factors that were assessed in the study included dyslipidemia, smoking, hypertension and diabetes mellitus. Criteria for dyslipidemia were those recommended by the National Cholesterol Education Programme (ATP III) guidelines. 7 All individual with a history of smoking (either present or within the past year) were classified as smokers. This included Bidi smokers and tobacco chewers. Hypertension was diagnosed and classified according to the JNC VI criteria. 8 A fasting plasma glucose 126 mg/dl or previous history of diabetes mellitus was required for the diagnosis of diabetes. 9 For lipid profile estimation blood samples were taken after on overnight fast. Patients with acute MI/acute coronary syndromes or cardiac surgery had lipid estimation two months after the event. Eight thousand one hundred and three individuals who attended the hospital for routine checkup or non-specific cardiovascular symptoms but in whom CAD was ruled out with appropriate investigations (ECG, echocardiography and treadmill testing) were taken as control. The lipid levels of the two groups as well as smoking habits were compared. Some of these individuals were the lipid profile (e.g. hypothyroidism, alcoholism, chronic liver disease, chronic renal failure, drug therapy) were excluded from the study. The number of patients with alcoholism/chronic liver disease (CAD) and on statin therapy (at the level of initial assessment) were 351 and 217 respectively among the subset with CAD; and 408 and 131 among subjects without CAD. These individuals were not included in the study. Statistical Analysis Numerical variables were reported as mean ± SD. The chi square test was used for categorical variables and t-test for continuous variables. A P value of < 0.01 was considered significant in view of the large sample size. The data were analysed using Minitab statistical software. RESULTS Five thousand seven hundred and forty-eight patients (4952 males, 796 females) were in the CAD group while among the 8103 subjects without CAD there were 6092 males and 2011 females) all the subjects with and without CAD were in the age group 30-80, the maximum number were in the age group (Table 1). The patients with CAD were classified as premature CAD (men < 45, women < 45) and CAD at usual age (mean 45, women 55). The prevalence of premature CAD was much higher in women as compared to men (82.2% as compared to 32.5% respectively) (p < 0.001). Among subjects < 45 almost equal number of males were studied in both the groups (with CAD, n = 1608; without CAD, n=1657). Table 1 : Age and sex distribution of subjects examined in CAD and non-cad group (n=5748) (n=8103) Males < * 1657 (Premature CAD) (27.97%) (20.44%) Males (58.17%) 4435 (54.73%) Females < * 1546 (Premature CAD) (11.38%) (19.08%) Females (2.47%) 465 (5.74%) *p<0.001 Subgroup analysis of the females subjects with and without CAD in three age groups - < 45, and 55 years indicated that there was a steep rise in the prevalence of CAD among females in the age group as compared to females < 45 years - (68.71% vs 13.44%, p = < 0.001) (Table 1a). Table 1a : Age distribution of females with and without CAD (n=796) (n=2011) Females 107 (13.44%)* 582 (28.91%)* < 45 years Females 547 (68.71%)* 964 (47.93%) < years Females 55 years 142 (17.85%) 465 (23.16%) *p = < Among the patterns of CAD found in the study population, the most common was chronic stable angina (2773 out of 5748, 48.24%). The next common group was those with positive treadmill test/stress echocardiography (30.4%) (17.9%) had documented myocardial infarction with ECG changes (Minnesota codes). A much smaller number had angiographically proved CAD / history of PTCA / CABG or acute coronary syndromes. When the mean lipid levels were compared in the two groups it was observed that the mean total cholestrol, LDL cholesterol, TC:HDL-C ratio and mean LDL-C: HDL-C ratio were significantly higher in the subjects with CAD (p < 0.01 for all the lipid parameters). The difference in the mean VLDL, HDL cholesterol and triglycerides in both the groups was not significant (Table 2). It is apparent from a perusal of age and sex distribution of the lipid levels that the mean total cholesterol (TC), LDL JAPI VOL. 52 FEBRUARY 2004

3 choleserol (LDL-c) and total cholesterol/hdl (TC/HDL) were significantly higher in male subjects less than 45 years and more than 45 years. No significant difference was noted in the mean lipid parameters studied of the females > 55 years in the group with and without CAD. The most common type of dyslipidemia with was an elevated TC/HDL ratio > 4.5; it was found in 59.05% of patients and 44.3% of subjects without CAD (p < 0.01). The prevalence of elevated total cholesterol ( 200 mg/dl), low HDL cholesterol 40 mg/dl and LDL choleserol 130 mg/dl also markedly higher in patients as compared to non-cad group; these values were strongly significant (p=<0.01). On the contrary, hypertriglyceridemia did not seem to be an important association of CAD; nearly equal number of subjects in both groups had elevated triglycerides 150 gm/ dl (Table 4). The prevalence of smoking was 1780 (30.97%) in the patients group as compared to 1031 (12.72%) in non-cad group, this was strongly significant (p = < ). This was Table 2 : Patterns of CAD in the study population Symptoms and ECG findings No. of cases (% of cases) Chronic stable angina with ST-T changes in ECG 2773 (48.2%) Positive treadmill test/stress echocardiography 1745 (30.4%) Documented myocardial infarction with ECG 1027 (17.9%) changes (Minnesota codes) Angiographically proved CAD/history of PTCA/CABG 105 (1.8%) Acute coronary syndromes 98 (1.7%) Total 5748 (100%) Table 4 : Mean lipid levels (age and sex distribution) also true of tobacco chewers (p = < 0.001). Males had a higher prevalence of smoking in both age groups (CAD and non- CAD) (Table 5) as compared to females; this was particularly true of males with premature CAD (< 45). Seven hundred and fifty-two males below 45 with CAD (44.1%) had history of smoking or tobacco chewing as compared to 775 males 45 years (19.96%, p = < 0.001). Hypertension and diabetes were comparatively less common than lipid abnormalities and smoking respectively (Table 6). Both risk factors were uncommon in individuals <45 years but comparatively more common in middle-aged and elderly CAD. Hypertension was noted more often in subjects with CAD as compared to those without CAD (18.02% vs. 13.9%, p < 0.005) and similar data were true of Table 3 : Mean lipid levels in subjects with and without CAD Subjects with Subjects P CAD without CAD (n=5748) (n=8103) Mean total ± ± < 0.01 Mean LDL ± ± 37.9 < 0.01 Mean HDL ± ± NS Mean VLDL ± ± NS Mean TC/HDL ratio 4.62 ± ± 0.29 < 0.01 Mean LDL/HDL ratio 3.09 ± ± 0.29 < 0.01 TC/HDL - Total cholesterol / HDL cholesterol ratio; NS - not significant Males < 45 TC (mg/dl) * Males < 45 TC (mg/dl) * (n=1608) LDL-C ** (n=1657) LDL-C ** HDL-C HDL-C VLDL-C VLDL-C TG TG TC/HDL ratio ** TC/HDL radio ** Males 45 TC (mg/dl) Males 45 TC (mg/dl) * (n=3344) LDL-C ** (n=4435) ldl-c ** HDL-C HDL-C VLDL-C VLDL-C TG TG TC/HDL ratio ** TC/HDL ratio ** Females < 55 TC (mg/dl) * Females < 55 TC (mg/dl) (n=654) LDL-C ** (N=1546) LDL-C ** HDL-C HDL-C VLDL-C VLDL-C TG TG TC/HDL radio ** TC/HDL ratio Females 55 TC (mg/dl) Females 55 TC (mgdl) (n=142) LDL-C (n=465) LDL-C HDL-C HDL-C VLDL-C VLDL-C TG TG TC/HDL ratio TC/HDL ratio *p < 0.05 (cases vs controls); **p < (cases vs controls) JAPI VOL. 52 FEBRUARY

4 Table 5 : Prevalence of dyslipidemia (ATP III criteria) and abnormal TC/HDL ratio (N=5748) (N=8103) Males Females Total Males Females Total (n=4952) (n=746) (n=6092) (n=2011) TC 200 md/dl ** (37.6%) (34.71%) (36.9%) (33.3%) (30.29%) (32.5%) LDL-C 130 mg/dl * (37.52%) (35.12%) (36.8%) (33.4%) (32.37%) (33.14%) HDL-C<40 mg/dl * (30.4%) (23.86%) (29.3%) (18.9%) (16.17%) (18.2%) Triglycerides 150 mg/dl (45.05%) (39.94%) (45.74%) (46.41%) (48.09%) (46.84%) TC/HDL ratio > * (60.3%) (54.7%) (59.05%) (47%) (36.46%) (44.3%) *p = < 0.001; **p = < 0.01 Table 6 : Prevalence of smoking and CAD (n = 5748) (n=8103) Smokers Tobacco Total Smokers Tobacco Total chewers chewers Males < 45 (premature CAD) * * (n=1608)+ (38.2%) (8.9%) (8.9%) (19.59%) (3.31%) (22.9%) Males 45 (n=3344) (16.02%) (3.94%) (19.96%) (10.05%) (2.1%) (12.15%) Females < 55 (premature ** ** CAD) (n=654) (14.3%) (2.14%) (15.44%) (4.27%) (1.1%) (5.37%) Females ** ** (12.68%) (4.22%) (16.9%) (5.14%) (0.86%) (6%) Total *p=<0.001 (male subjects with CAD vs males without CAD, male CAD < 45 vs CAD 45); **p=0.003 (females patient vs female control); +p=<0.001 (males vs females with CAD) Table 7 : Prevalence of hypertension and diabetes mellitus N Hypertension Type II diabetes N Hypertension Type II diabetes Mellitus Mellitus Males < 45 years (Premature * * 58 CAD) (11.2%) (5.5%) (4.65%) (3.5%) Males 45 years ** 549* * 409* (21.2%) (16.4%) (16.23%) (9.2%) Females < 55 years * (15.4%) (15.3%) (15.71%) (8%) Females 55 years * 27* (19%) * 48* (32.4%) (18.9%) (10.3%) Subject with CAD vs *p = < 0.01 subjects without CAD +p = < 0.01 (premature CAD vs CAD in middle age) diabetes (13.28% vs. 7.89%, p < 0.001). There was no significant sex difference in the prevalence of hypertension or diabetes in either patients or non-cad subjects. DISCUSSION A number of risk factors have been identified in CAD, 3 of the factors analysed in this study smoking and hypertension are class I risk factors. Elevated LDL cholesterol is also a class I risk factors. Hypertriglycerdemia and diabetes mellitus are known as class II risk factors. The most obvious findings was the very high prevalence of premature CAD in women (82.2% of all women with CAD) as compared to only 32.5% of men with premature CAD. This can be partly explained by early menopause in Indian women which to a great extent reduces the protective effect of estrogens. 3 Although, the age of menopause was not recorded in most of the data, the abrupt rise in the prevalence of CAD among women between years of age as compared to younger women indicates that this is likely. In this large retrospective study of subjects with and without CAD, dyslipidemia, as manifested by an abnormal TC/HDL ratio (present in 59.5% of CAD patients) was the JAPI VOL. 52 FEBRUARY 2004

5 most common form of lipid abnormality as well as the most common of the risk factors analysed. There was no significant difference in the prevalence of hypertriglyceridemia in CAD cases as compared to non-cad individuals. In terms of absolute mean values, only total cholesterol, LDL cholesterol, TC/HDL and LDL/HDL choleserol ratios were significantly higher in CAD group. On analyzing the four groups (males < 45 with CAD; males 45 with CAD; females < 55 with CAD; females 55 with CAD as compared to corresponding non- CAD individuals of these age groups), mean total cholesterol, LDL cholesterol, TC/HDL ratios were higher in both groups of males and also in females below 55; however females 55 with CAD did not show any significant difference in their mean lipid levels or TC/HDL ratio as compared to non-cad females. Most international studies e.g. the MRFIT Study Group; 10 Seven Countries Study 11 and Framingham Study 12,13 emphasized the importance of elevated LDL and TC in the development of CAD. They also considered these factors as more important than the other risk factors studied (hypertension, smoking and diabetes). Several studies have been performed in different regions of India and have revealed considerable varying results with respect to prevalence and type of dyslipidemia. Most studies have observed elevated total and LDL cholesterol levels as well as triglycerides A recent study of Gupta et al1 4 indicated that elevated TC and LDL cholesterol, low HDL cholesterol and trglycerides was associated with CAD. On the contrary, a study by Pais et al 17 in survivors of acute myocardial infarction (AMI) showed no association of lipid abnormalities with CAD. In this study smoking showed the strongest association with CAD. Gopinath et al 18 who studied lipid profiles of subjects with and without CAD found that three major fractions of lipid profiles (TC, triglycerides and LDL cholesterol) were higher in both rural and urban population with CAD as compared to control while HDL cholesterol was lower. A recent population based study by Mohan et al in Chennai 19 showed that after multivariate analysis, only elevated LDL choleserol was associated with the presence of CAD. A recent study by Anand et al 20 (in Canada) among three ethnic groups showed that South Asians had the highest prevalence of CAD. Mean TC, LDL-C and triglycerides were significantly higher in South Asians while LDL-C was lower. Smoking was less common in this ethnic group while diabetes was significantly more common and compared to Europeans or Chinese. Our study indicates the major abnormalities in mean lipid levels as well as prevalence of dyslipidemia was (in order of prevalence) elevated TC/HDL ratio, elevated TC and LDL-C levels and low HDL-C, the last abnormality was more common in CAD group but mean HDL levels were not significantly different. Triglycerides did not seem to be significant either in absolute mean levels or relative prevalence of hypertriglyceridemia. The present study is in agreement with other studies on dyslipidemias with one significant difference in that triglycerides (either in terms of absolute level or in the prevalence of hypertriglyceridemia) did not seem to be an important risk factor. Smoking was the second most important factor and was significantly more common in males than females. Only 12.72% of the control population smoked as compared to nearly 31% in the CAD group. Smoking as well as tobacco chewing were significantly more common in all groups of CAD as compared to subjects without CAD, but it is most common in males with premature CAD (< 45). This is in agreement with the study of Pais 17 while Gupta et al 14 found a low prevalence of smoking in both cases and controls. Hypertension and diabetes were more closely associated than in the general population this is in keeping with the metabolic syndrome which is often seen in type 2 diabetics. Both these risk factors were markedly more common in CAD. However they had a much lower prevalence than lipid abnormalities or smoking. With the exception of premature CAD in females (< 55), hypertension and smoking were more common in subjects with CAD as compared to subjects without CAD. Premature CAD individuals had a comparatively lower prevalence of hypertension and diabetes mellitus. These results therefore indicate that dyslipidemia (abnormal TC/HDL ratios, elevated LDL cholesterol and total cholesterol), smoking, hypertension and diabetes mellitus, in that order of prevalence were the major risk factors or associations of CAD. Of theses dyslipidemia, hypertension and smoking are definitely treatable while diabetes mellitus is possibly treatable. This is in agreement with many other international studies e.g. MRFIT which have identified elevated cholesterol levels as the most important risk factor for CAD. Our study has the following limitations 1. Being a retrospective analysis it merely identified associations of coronary artery disease rather than risk factors in the real sense-the latter would require a long term follow-up of a population cohort. 2. As the data were collected over a relatively long period of time, it was not possible to analyse the change in relative importance of risk factors with changing population habits and lifestyles. It may therefore be concluded that a comprehensive multicentric Indian study of all regions of the country is required to provide a better picture of the risk factor profile for CAD in Indian subjects. In the mean time, emphasis should be on diagnosis and control of dyslipidemia, type 2 diabetes, hypertension and cessation of smoking which have been identified in this large study as major risk factors for coronary artery disease. REFERENCES 1. Reddy KS. Cardiovascular disease in India. Would Health Stat Q 1993;46: Castelli WP. Lipids risk factors and ischemic heart disease. JAPI VOL. 52 FEBRUARY

6 Atherosclerosis 1996;124:S1-S9. 3. Fuster V, Pearson TA. 27th Betheseda Conference. Matching the intensity of risk factor management with the hazard of coronary heart disease events. J Am Coll Cardiol 1996;27: Vashisht S, Narula J, Awtade A, Tandon R, Srivastava IM. Lipid and lipoproteins in normal controls and clinically documented coronary heart disease patients. Ann Nat Acad Med Sc 1990;26: Krishnaswamy S. Conventional risk factors for coronary heart disease in Indian patients: In Sethi KK (ed) Coronary Artery Disease in Indians: A global perspective New Delhi Cardiological Society of India 1998: Blackburn H, Prineaqs RJ, Crow PS. The Minnesota Code: Electrocardiographic Findings - Standards and Procedures for Measurement and Classifications: Littleton Mass Wright. 7. Executive Summary of the Third Report of the National Cholesterol Educatin Programme (NCEP) Expert Paneal on Detection. Elevation and treatment of high bliood cholesterol in adults (Adults treatment panel III). JAMA 2001;285: The sixth report of the national committee on prevention, detection, evaluation and treatment of high blood pressure (JNC VI). Arch Internal Med 1997;157: Report of The Expert Committee n the Diagnosis and Classification of Diabetes Mellitus. The Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes care 2001;24:S1-S Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking and death from coronary heart disease : Overall findings and differences by age for 316, 099 white men. Multiple risk factor intervention trial Research Group. Arch Int Med 1992: Keys A, Menotti A, Karvonen MJT AL. The Diet and 15 year death rate in the seven countries study. Am J Epidemiology 1986;124: Levy D, Kannel WB. Cardiovascular risks. New insights from framingham. Am Heart J 1988;116: Castelli WP. Epidemiology of caronary heart disease. The Framingham Study. Am J Med 1984;76(Supll.2A): Gupta R, Vashisht S, Bahl VK, Wasir HS, Correlation of lipoprotein (A) to angiograpically defined coronary artery disease in Indians. Int J Cardiol 1996;57: Sahi N, Pahlajani DB, Sainani GS. Apolipoprotein A1 and B as predictors of angiographically associated coronary artery disease. J Assoc Phy India 1993;41: Gupta R, Kaul V, Prakash H, Sarna M. Singhal Shalini, Gupta VP. Lipid abnormalities in coronary heart disease. A population based case control study. Indian Heart J 2001;53: Pais P, Pogue S, Gerstein H, Zachariah E, Savitha D, Jayprakash S, et al. Risk factors for acute myocardial infarction: A case control study. Lancet 1996;348: Gopinath N, Chadha SL, Sehghal A, Shekhawat S, Tandon R. What is a Desirable lipid profile. Ind Heart J 1994;46: Mohan V, Deepa R, Rani SS, Premalatha G. Prevalence of coronary artery disease and its relationship with lipids in a selected population in South India : The Chennai urban population study (CUPS No.5). J Am Coll Cardiol 2001;38: Anand Sonia S, Ysusf Salim Vuksan Vladimir, Devanesan Sudarshan, Teo Koon K, Montague Partricia A, et al. Differences in risk factors, atherosclerosis and cardiovascular disease between ethnic groups in Canada: The study of health assessment and risk in ethnic groups (SHARE). Lancet 2000;356: Announcement XXII Conference of Association of Physicians of India. Karnataka Chapter - KAPICON th, 15th and 16th May, 2004, Kuvempu Ranga Mandir, Shimoga, Karnataka For further details, please contact : Dr. PK Pai / Dr. KR Ravish, Organizing Secretaries, Conference Secretariat Sahyadri Hospital, OT Road, Shimoga Tel: , ; Fax: JAPI VOL. 52 FEBRUARY 2004