- Email: [email protected]
Multifactorial therapeutic approach to secondary prevention in coronary heart disease: Preliminary report after 3-year follow-up
CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 10, OCTOBER 1994
M U L T I F A C T O R I A L T H E R A P E U T I C A P P R O A C H TO S E C O N D A R Y PREVENTION IN CORONARY HEART DISEASE: PRELIMINARY R E P O R T A F T E R 3-YEAR F O L L O W - U P CESARE ALESSANDRI, 1 STEFANIA BASILI, 2 MASSIMO LEONARDO, 2 GIOVANNI PETTIROSSI, 2 MICHELE PARADISO, 2 LUIGI COPPOTELLI, 2 MARIO PERGOLINI, 2 AND CORRADO CORDOVA 2
llstituto di Terapia Medica Sistematica, and 2Istituto di Terapia Medica, Universitd "La Sapienza," Rome, Italy
ABSTRACT
Therapeutic guidelines for preventing long-term recurrent cardiovascular events in patients with coronary heart disease (CHD) are still debated. This problem is exacerbated by the lack of long-term clinical trials performed with a simultaneous treatment of all modifiable risk factors. Encouraging data from a 5-year follow-up study of patients with CHD in which this simultaneous strategy was carried out convinced us to report the preliminary results of the first 3 years. Seventyeight CHD patients, with or without previous myocardial infarction, were consecutively enrolled into the study, after a complete evaluation. Patients were instructed to adhere to a low-cholesterol diet, smokers were discouraged from cigarette smoking, and everyone received personalized pharmacologic treatment including lipid-lowering drugs, antiplatelet drugs (33 patients were given ticlopidine 500 mg/d and 39 were given acetylsalicylic acid 100 mg/d), hypoglycemic agents, calcium antagonists or beta-adrenoreceptor blockers, and nitrates. Follow-up end points were myocardial infarction, sudden cardiac death, newly developed angina, unstable angina, worsening New York Heart Association's (NYHA's) functional class, coronary artery bypass graft or coronary angioplasty, stroke, transient ischemic attack, severe arrhythmia, and other cardiovascular death. After the first 3 years of the follow-up we have observed only six minor cardiovascular events: a worsening in NYHA functional class in four patients, a transient ischemic attack in one patient, and arrhythmia episodes in another patient. These preliminary results, collected in a small number of patients, show that a complete therapeutic intervention aimed at secondary prevention could improve the natural history of CHD. INTRODUCTION T h e i m p o r t a n c e of the p r i m a r y p r e v e n t i o n for r e d u c i n g t h e m o r b i d i t y and m o r t a l i t y of atherosclerotic v a s c u l a r diseases b y m o d i f y i n g some cardio-
Address correspondence to: Prof. Corrado Cordova, Corse Trieste 38, 00198, Rome, Italy.
Received for publication on July 13, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1201
0011-393x/94/$3.50
SECONDARY PREVENTION IN CHD
vascular risk factors has been well documented and the management of at-risk patients has been established. 1-5 However, therapeutic guidelines for preventing long-term recurrent cardiovascular events in patients with coronary heart disease (CHD) are still uncertain and debated. Clinical and epidemiologic studies performed in patients with a previous myocardial infarction (MI) have generally suggested that: (1) some major risk factors (such as high serum levels of low-density lipoprotein cholesterol [LDL-C] or triglycerides; low serum concentrations of highdensity lipoprotein cholesterol [HDL-C]; hypertension; diabetes mellitus; smoking habit; and lifestyle) play an important role in atherosclerosis progression; (2) the risk progressively increases with the number of risk factors present in each patient; (3) the correction or at least the moderation of every risk factor significantly decreases the incidence of new cardiovascular events; and (4) long-term pharmacologic treatment with betaadrenoreceptor blockers, calcium channel blockers, or antiplatelet or anticoagulant drugs appears to be able to reduce the reinfarction frequency and the CHD mortality. 5-13 Nevertheless, the clinical efficacy of a simultaneous preventive approach, including the treatment of all modifiable risk factors and therapy for increasing coronary blood perfusion in CHD patients, is still unknown, since long-term clinical trials with all of these aims are not available. This incomplete therapeutic approach to secondary prevention in CHD patients could partly explain the high incidence of new vascular events, both in patients with pharmacologic therapy and in those with surgical correction of stenosis. Encouraging data from a 5-year follow-up study of CHD patients, in which this simultaneous preventive strategy was carried out, convinced us to report the preliminary results of the first 3 years (follow-up range, i to 60 months). P A T I E N T S AND M E T H O D S
Study Design Beginning in 1987, men and women younger than 75 years who were suffering from CHD, with or without previous MI, were consecutively enrolled into a 5-year follow-up study. To evaluate patients with a similar cardiac function and with a long-term life expectancy, only patients in New York Heart Association (NYHA) functional class I or II were included. Information on risk factors for cardiovascular disease and occurrence of disease end points was obtained by means of interviews, physical examination, and laboratory and instrumental tests in all patients. Patients with liver disease, insulin-dependent diabetes mellitus, secondary 1202
C. ALESSANDRI ET AL.
hypercholesterolemia, body mass index >25 kg/m 2, unstable angina, or other conditions resulting in a probable life expectancy of less t h a n 2 years were not eligible for inclusion. Coronary angiography was also performed in some patients to evaluate whether coronary angioplasty or aortocoronary bypass implantation were indicated. All modifiable risk factors were corrected or at least moderated by advice on lifestyle, diet, and, when requested, by pharmacologic treatment. Patients were seen on a n outpatient basis every 6 months, at which time an interview, physical examination, blood analysis, electrocardiography, 24-hour Holter monitoring and, if necessary, echocardiography, electrocardiography stress test, and scintigraphy were performed. Every major and minor event occurring during the prior 6 months was recorded. Outcomes
During the follow-up period, the occurrence of cardiovascular complications was carefully analyzed. Nonfatal and fatal MI were considered as primary end points. Nonfatal MI was defined as rapid onset of typical symptoms consistent with acute MI plus either typical electrocardiographic changes (including new Q waves) or significant serum enzyme increase. Fatal MI had to be confirmed by autopsy diagnosis or death certificate diagnosis plus preterminal hospitalization, with a definite or suspected diagnosis of MI within 4 weeks of death. Definitions of individual secondary end points were: (1) sudden cardiac d e a t h - - d e a t h within 1 hour of the onset of severe cardiac symptoms, unrelated to other known causes; (2) newly developed angina; (3) unstable angina; (4) worsening NYHA's functional class; (5) coronary artery bypass graft or coronary angioplasty; (6) s t r o k e - - a rapid onset of a neurologic deficit persisting for at least 24 hours attributed to obstruction or rupture in the arterial brain system; (7) transient ischemic a t t a c k - - r a p i d onset of a focal neurologic deficit lasting more than 30 seconds and less t h a n 24 hours, presumed to be due to cerebral ischemia, with no evidence of an underlying nonvascular cause; (8) severe arrhythmia; and (9) other cardiovascular d e a t h - - p r e s u m e d MI that did not meet diagnostic criteria or other cardiovascular causes. Only the first event occurring during the follow-up period was considered for each patient. Information related to study end points was collected by clinical staff, including at least one cardiologist. Baseline Measurements
Lipid and lipoprotein levels were measured according to a standardized protocol: blood samples were drawn between 8 and 9 AM from consent1203
SECONDARY PREVENTION IN CHD
ing patients after they had fasted overnight. The samples were analyzed for the following serum variables: total cholesterol (ESTM reagent, Beckm a n Instruments, Inc., Fullerton, California) and triglycerides (INT reagent, Beckman Instruments). HDL-C was estimated using the Beckman reagents. LDL-C was calculated according to Friedewald's formula: [total cholesterol - HDL-cholesterol - (triglycerides/5)]. A standard oral glucose (75 g) tolerance test was performed in all patients. CHD was confirmed by the results of successive diagnostic procedures consisting of clinical history, cardiac enzyme blood levels (creatine kinase [CK], CK isoenzyme associated with the heart [MB], aspartate transaminase, and lactate dehydrogenase), electrocardiography at rest, echocardiography, Holter electrocardiography, electrocardiography during an exercise test, myocardial scintigraphic images, and coronary angiography. This last diagnostic procedure was only performed in patients who were selected for surgical therapy according to the results of noninvasive diagnostic procedures. MI was recognized by clinical history, results of testing for cardiac enzyme levels, electrocardiography, echocardiography, and scintigraphy. Stable angina pectoris was diagnosed using results of electrocardiography at rest and according to Holter procedure, or during an exercise test. Hypertension was defined as systolic blood pressure exceeding 140 m m Hg, and diastolic blood pressure more than 90 mm Hg. Carotid Doppler testing and Doppler study of the lower limbs were also performed. A completed questionnaire concerning history of familial cardiovascular disease, lifestyle, smoking habits, and professional occupation was also obtained. Treatment Plan Patients were instructed to adhere to a restricted diet containing less than 300 mg/d of cholesterol with 30% of the calorie intake as fat and a polyunsaturated:saturated fat ratio greater than 0.8. Carbohydrate intake was less than 180 g/d in patients with type II diabetes mellitus or hyperinsulinemia. Patients were discouraged from cigarette smoking. A staff psychologist assisted the patients in the safe resumption of activities. Each patient received an individualized prophylactic pharmacologic treatment that included lipid-lowering drugs (simvastatin 10 to 40 mg/d or gemfibrozil 1200 mg/d), antiplatelet drugs (acetylsalicylic acid 100 mg/d or ticlopidine 500 mg/d), hypoglycemic agents (sulphonylureas), calcium antagonists or beta-adrenoreceptor blockers, and nitrates. Statistical Analysis Statistical analysis was carried out by using one-way analysis of vari1204
C. ALESSANDRIETAL.
ance and (for multiple comparison) by using Student-Newman-Keuls test. Data are presented as mean + standard deviation. A P value less than 0.05 was regarded as statistically significant. All calculations were made using the computer program Stat View II (Abacus Concepts, Berkeley, California). RESULTS
Seventy-eight patients were admitted to the study. Four (5%) patients dropped out, while two (3%) were withdrawn from the study because of concomitant diseases. The remaining 72 patients included 61 (85%) men and 11 (15%) women, aged from 33 to 70 years (mean, 56 - 10 years). As shown in Table I, 35 patients had an MI less than 3 years prior to the study (group A), 23 had stable angina pectoris (group B), and 14 had a previous MI (more than 3 years before) and stable angina pectoris (group C). Twenty patients were current smokers (more than 10 cigarettes/d), 27 were exsmokers. Serum levels of total cholesterol, triglycerides, LDL-C, and HDL-C are reported in Table I. Forty-one patients had hyperlipoproteinemia type IIa: 23 of them were
Table I. Baseline characteristics of patients with coronary heart disease who had a myocardial infarction (MI) within the prior 3 years (group A), stable angina pectoris (SAP) (group B), or MI plus SAP more than 3 years prior to inclusion in study (group C). Group Characteristic*
A (n = 35)
B (n = 23)
C (n = 14)
Males Age (y) Follow-up (mon) Smokers Ex-smokers Diabetes mellitus or hyperinsulinemia Hypertension Total cholesterol (mg/dL) Triglycerides. . /mg/dL) . High-density hpoprotein cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) Fibrinogen (mg/dL) Stenosis
33 (94) 53 +- 8 30 -+ 22 10 (29) 14 (40) 6 (17) 7 (20) 253 -+ 55 t49 -+ 71 42 +_ 12 179 -+ 55 302 +- 87
18 (78) 61 +- 6 20 -+ 19 7(30) 7 (30) 7(30) 7 (30) 236 -+ 51 155 +- 116 42 -+ 12 167 -+ 54 324 -- 88
12 (86) 54 +_ 10 22 _+ 16 3 (21) 10 (71) 4 (29) 3 (21) 255 _ 65 131 + 60 48 +- 13 181 -- 69 289 +- 51
11 (31) 9 (26)
2 (9) 3 (13)
11 (31) 3 (9)
5 }~2) 0 )
(>50%) 1 vessel (>50%) 2 vessels Coronary grafts Angioplasty
4 (29) 5(36) (14) 5 (36) 0 (0)
* Table values are numbers of patients with characteristic (%), or mean value --- standard deviation. 1205
SECONDARY PREVENTION IN CHD
in group A, 11 in group B, and 7 in group C. Ten patients were affected by hyperlipoproteinemia type IIb: 4 patients each were in groups A and B, and 2 patients were in group C. Diabetes mellitus or hyperinsulinemia was observed in 17 patients, and 17 patients had mild-to-moderate hypertension. Plasma fibrinogen concentrations were significantly higher in all patient groups compared with normal values (314 Jr 82 mg/dL vs 220 + 45 dL; P < 0.001). Coronary angiography was performed in 49 (68%) patients and showed no significant stenosis (<50%) 14 in 8 patients; however, 17 patients had a significant stenosis of 1 vessel; 17, of 2 vessels; and 7, of 3 vessels. Coronary artery bypass grafts were implanted in 21 patients (11 in group A, 5 each in groups B and C), while angioplasty was performed in 3 patients from group A. The antiplatelet treatment was continuously given in each patient: 33 (46%) patients received ticlopidine and 39 (54%) received acetylsalicylic acid. After 6 months of dietary treatment, 28 hyperlipoproteinemic patients showing serum levels of total cholesterol or triglycerides higher than 240 mg/dL and 190 mg/dL, respectively, were treated with simvastatin (25 patients) or gemfibrozil (3 patients). Lipid-lowering therapy reduced (-21%) total cholesterol and increased (+24%) HDL-C. In all patients with diabetes mellitus, the low carbohydrate intake and sulphonylureas therapy resulted in a satisfactory metabolic control of the disease. In patients with hypertension, therapy with calcium antagonists or betaadrenoreceptor blockers normalized arterial blood pressure (data not shown). During the follow-up period, none of the patients experienced fatal or nonfatal MI, the primary end points of the study. Nevertheless, in 3 patients in group A, 2 in group B, and 1 in group C, 1 to 12 months after recruitment, a secondary end point was observed (Table II). These six patients (age range, 51 to 65 years; 1 woman and 5 men) each had a coronary stenosis of more than 50% of one or more vessels, and 3 patients had a coronary artery bypass graft. Four patients were ex-smokers, 1 was a nonsmoker, and 1 was a current smoker (fewer than 10 cigarettes/d). Two patients affected by hypercholesterolemia type IIa were treated with simvastatin and showed total cholesterol serum values between 200 and 240 mg/dL; moreover, two of the normocholesterolemic patients had HDL-C serum levels lower than 20% of the total cholesterol concentration. Two patients with diabetes mellitus, who were treated with sulphonylureas, had a fasting glucose serum level <150 mg/dL; two patients with hypertension, who were treated with calcium antagonists, had blood pressure values lower than 160/90 mm Hg. Five of six patients took acetylsalicylic acid and 1 patient took ticlopidine.
1206
-...3
M F M M M M
1 2 3 4 5 6
63 51 62 65 54 58
Age (y)
MIt + SAP SAP MI:~ SAP MI:~ MI:~
CHD 3 2 2 0 2 1
No No Yes Yes Yes No
Coronary Artery Bypass Graft ES N ES CS ES ES
Smoking Habit Ila + NIDD Ila None H None NIDD + H
Other Risk Factors ASA ASA ASA ASA TK ASA
Antiplatelet Agents
12 9 12 12 1 12
Monthsof Follow-up
Worsening TIA Worsening Worsening Arrhythmia Worsening
NYHA
NYHA NYHA
NYHA
End Point
M = male; MI = myocardial infarction; SAP = stable angina pectoris; ES = ex-smoker; N = nonsmoker; Ila = hypercholesterolemia type Ila; NIDD = non-insulin dependent diabetes; ASA = acetylsalicylic acid; NYHA = New York Heart Association; F = female; TIA = transient ischemic attack; CS = current smoker; H = hypertension; TK = ticlopidine. * Dietary and lifestyle modification and personalized pharmacologic treatment. t Previous MI (more than 3 years prior). :~ Recent MI (within 3 years).
Sex
Patient No.
No. of Vessels with Stenosis >50%
Table II. Clinical, laboratory, and treatment characteristics of six patients with coronary heart disease (CHD) who reached cardiovascular end point events despite interventional therapy* designed to modify risk factors.
~3
O9
>
p
SECONDARYPREVENTIONIN CHD
D I S C U S S I O N AND C O N C L U S I O N
The aim of a correct therapeutic approach to patients affected by CHD is to prolong survival by preventing further cardiovascular events or death. An appropriate evaluation of patient health and cardiac function by noninvasive testing and coronary angiography, when there is the possibility for a revascularization attempt, must be performed. This is the first aim in the management of cardiovascular atherosclerotic disease. That the identification and modification of atherosclerotic risk factors must be the second medical objective, resulting in secondary prevention, is underlined by results of clinical trials. A further step is to begin or revise a therapeutic treatment to improve coronary blood perfusion and to prevent thrombogenesis in coronary vessels. Several drugs (beta-adrenoreceptor blocking agents, calcium channel antagonists, nitrates, anticoagulants, and antiplatelet agents) are used in the prophylaxis of secondary events in patients affected by CHD, but a standardized protocol is not available. Clinical long-term trials, in fact, report contrasting or inconclusive results on the efficacy of oral nitrates or calcium channel antagonists in preventing subsequent MI episodes, s - n Beta-adrenoreceptor blockers have produced a significant reduction in sudden death and nonfatal reinfarction in trials conducted for periods greater than 2 to 3 years on patients with previous MI episode, s - n Nevertheless, clear data are not available on the efficacy of these drugs in preventing primary MI episodes in CHD patients. Longterm administration of antiplatelet agents after recovery from MI appears to be very effective in reducing mortality and cardiovascular morbidity in patients surviving MI. s'n Long-term anticoagulant therapy has shown beneficial effects, notwithstanding more frequent hemorrhagic events, s'n We carried out a preventive strategy on patients with CHD, with and without a previous MI episode. After the first 3 years of the follow-up period, we have observed six minor cardiovascular events (4, worsening in NYHA functional class; 1, transient ischemic attack; 1, arrhythmic episodes), with a percentage of survivors of 100%. Moss and Benhorin, 6 analyzing the results of some studies on the clinical course of patients surviving a first MI episode, reported that the overall annualized rates of cardiac mortality and nonfatal reinfarction were 6.2% and 4.5%, respectively. Our results, although collected by a pilot study of only 72 patients, show that a coherent diagnostic approach and a complete therapeutic intervention could reduce incidence of secondary cardiovascular events. We evaluated the cardiac function and the atherosclerotic risk factors of every patient; then a simultaneous dietary and lifestyle modification and pharmacologic approach was started. Although all patients were treated with antiplatelet drugs, six had minor cardiovascular events. Despite interventional therapy, four of these patients still showed an abnormal lipidemic pattern (high total cholesterol and/or low HDL-C), 1208
C. ALESSANDRIETAL.
and one was a current smoker. A more aggressive approach to risk factor modification may have been more effective in preventing secondary events; the benefit of such intervention on reduction of atherosclerotic risk factors might be verified on a larger patient sample. Although ourpreliminary data are encouraging, they must be verified by a multicenter study using a larger number of patients affected by CHD.
Acknowledgments This study was supported by the National Research Council (C.N.R.)Target Project "Prevention and Control Disease Factors" (F.A.T.M.A.)Subproject 8-Contract no. 91.00070.41. References: 1. Report of the National Cholesterol Education Program expert panel on detection, evaluation and treatment of high blood cholesterol in adults. Arch Intern Med. 1988;148:3669. 2. American Heart Association. Special report: The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol and coronary heart disease. Circulation. 1990;81:1721-1733. 3. Sytkowski PA, Kannel WB, D'Agostino RB. Changes in risk factors and the decline in mortality from cardiovascular disease. The Framingham Heart Study. NEJM. 1990;322: 1635-1641. 4. Peto R, Yusuf S, Collins R. Cholesterol-lowering trial results in their epidemiologic context. Circulation. 1985;72(Suppl III):45. 5. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. NEJM. 1990;322:1700-1707. 6. Moss AJ, Benhorin J. Prognosis and management after a first myocardial infarction. NEJM. 1990;322:743-753. 7. Miller M, Seidler A, Kwiterovich PO, Pearson TA. Long-term predictors of subsequent cardiovascular events with coronary artery disease and desirable levels of plasma total cholesterol. Circulation. 1992;86:1165-1170. 8. Hinstridge V, Speight TM. An overview of therapeutic interventions in myocardial infarction. Emphasis on secondary prevention. Drugs. 1991;42:8-20. 9. McGovern PG, Folsom AR, Sprafka M, et al. Trends in survival of hospitalized myocardial infarction patients between 1970 and 1985. The Minnesota Heart Survey. Circulation. 1992;85:172-179. 10. Rossouw JE, Lewis B, Rifkind BM. The value of lowering cholesterol after myocardial infarction. NEJM. 1990;323:1112-1119. 11. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease: Treatments following myocardial infarction. JAMA. 1988;260:2088-2093. 12. Alderman EL, Bourassa MG, Cohen LS, et al. Ten-year follow-up of survival and myo1209
S E C O N D A R Y PREVENTION IN C H D
cardial infarction in the randomized coronary artery surgery study. Circulation. 1990; 82:1629-1646. 13. Rogers WJ, Coggin J, Gersh BJ, et al. Ten year follow-up of quality of life in patients randomized to receive medical therapy or coronary artery bypass graft surgery. The coronary artery surgery study (CASS). Circulation. 1990;82:1647-1658. 14. Harris PJ, Behar VS, Conley MJ, et al. The prognostic significance of 50% coronary stenosis in medically treated patients with coronary artery disease. Circulation. 1980; 62:240-248.
1210
M U L T I F A C T O R I A L T H E R A P E U T I C A P P R O A C H TO S E C O N D A R Y PREVENTION IN CORONARY HEART DISEASE: PRELIMINARY R E P O R T A F T E R 3-YEAR F O L L O W - U P CESARE ALESSANDRI, 1 STEFANIA BASILI, 2 MASSIMO LEONARDO, 2 GIOVANNI PETTIROSSI, 2 MICHELE PARADISO, 2 LUIGI COPPOTELLI, 2 MARIO PERGOLINI, 2 AND CORRADO CORDOVA 2
llstituto di Terapia Medica Sistematica, and 2Istituto di Terapia Medica, Universitd "La Sapienza," Rome, Italy
ABSTRACT
Therapeutic guidelines for preventing long-term recurrent cardiovascular events in patients with coronary heart disease (CHD) are still debated. This problem is exacerbated by the lack of long-term clinical trials performed with a simultaneous treatment of all modifiable risk factors. Encouraging data from a 5-year follow-up study of patients with CHD in which this simultaneous strategy was carried out convinced us to report the preliminary results of the first 3 years. Seventyeight CHD patients, with or without previous myocardial infarction, were consecutively enrolled into the study, after a complete evaluation. Patients were instructed to adhere to a low-cholesterol diet, smokers were discouraged from cigarette smoking, and everyone received personalized pharmacologic treatment including lipid-lowering drugs, antiplatelet drugs (33 patients were given ticlopidine 500 mg/d and 39 were given acetylsalicylic acid 100 mg/d), hypoglycemic agents, calcium antagonists or beta-adrenoreceptor blockers, and nitrates. Follow-up end points were myocardial infarction, sudden cardiac death, newly developed angina, unstable angina, worsening New York Heart Association's (NYHA's) functional class, coronary artery bypass graft or coronary angioplasty, stroke, transient ischemic attack, severe arrhythmia, and other cardiovascular death. After the first 3 years of the follow-up we have observed only six minor cardiovascular events: a worsening in NYHA functional class in four patients, a transient ischemic attack in one patient, and arrhythmia episodes in another patient. These preliminary results, collected in a small number of patients, show that a complete therapeutic intervention aimed at secondary prevention could improve the natural history of CHD. INTRODUCTION T h e i m p o r t a n c e of the p r i m a r y p r e v e n t i o n for r e d u c i n g t h e m o r b i d i t y and m o r t a l i t y of atherosclerotic v a s c u l a r diseases b y m o d i f y i n g some cardio-
Address correspondence to: Prof. Corrado Cordova, Corse Trieste 38, 00198, Rome, Italy.
Received for publication on July 13, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1201
0011-393x/94/$3.50
SECONDARY PREVENTION IN CHD
vascular risk factors has been well documented and the management of at-risk patients has been established. 1-5 However, therapeutic guidelines for preventing long-term recurrent cardiovascular events in patients with coronary heart disease (CHD) are still uncertain and debated. Clinical and epidemiologic studies performed in patients with a previous myocardial infarction (MI) have generally suggested that: (1) some major risk factors (such as high serum levels of low-density lipoprotein cholesterol [LDL-C] or triglycerides; low serum concentrations of highdensity lipoprotein cholesterol [HDL-C]; hypertension; diabetes mellitus; smoking habit; and lifestyle) play an important role in atherosclerosis progression; (2) the risk progressively increases with the number of risk factors present in each patient; (3) the correction or at least the moderation of every risk factor significantly decreases the incidence of new cardiovascular events; and (4) long-term pharmacologic treatment with betaadrenoreceptor blockers, calcium channel blockers, or antiplatelet or anticoagulant drugs appears to be able to reduce the reinfarction frequency and the CHD mortality. 5-13 Nevertheless, the clinical efficacy of a simultaneous preventive approach, including the treatment of all modifiable risk factors and therapy for increasing coronary blood perfusion in CHD patients, is still unknown, since long-term clinical trials with all of these aims are not available. This incomplete therapeutic approach to secondary prevention in CHD patients could partly explain the high incidence of new vascular events, both in patients with pharmacologic therapy and in those with surgical correction of stenosis. Encouraging data from a 5-year follow-up study of CHD patients, in which this simultaneous preventive strategy was carried out, convinced us to report the preliminary results of the first 3 years (follow-up range, i to 60 months). P A T I E N T S AND M E T H O D S
Study Design Beginning in 1987, men and women younger than 75 years who were suffering from CHD, with or without previous MI, were consecutively enrolled into a 5-year follow-up study. To evaluate patients with a similar cardiac function and with a long-term life expectancy, only patients in New York Heart Association (NYHA) functional class I or II were included. Information on risk factors for cardiovascular disease and occurrence of disease end points was obtained by means of interviews, physical examination, and laboratory and instrumental tests in all patients. Patients with liver disease, insulin-dependent diabetes mellitus, secondary 1202
C. ALESSANDRI ET AL.
hypercholesterolemia, body mass index >25 kg/m 2, unstable angina, or other conditions resulting in a probable life expectancy of less t h a n 2 years were not eligible for inclusion. Coronary angiography was also performed in some patients to evaluate whether coronary angioplasty or aortocoronary bypass implantation were indicated. All modifiable risk factors were corrected or at least moderated by advice on lifestyle, diet, and, when requested, by pharmacologic treatment. Patients were seen on a n outpatient basis every 6 months, at which time an interview, physical examination, blood analysis, electrocardiography, 24-hour Holter monitoring and, if necessary, echocardiography, electrocardiography stress test, and scintigraphy were performed. Every major and minor event occurring during the prior 6 months was recorded. Outcomes
During the follow-up period, the occurrence of cardiovascular complications was carefully analyzed. Nonfatal and fatal MI were considered as primary end points. Nonfatal MI was defined as rapid onset of typical symptoms consistent with acute MI plus either typical electrocardiographic changes (including new Q waves) or significant serum enzyme increase. Fatal MI had to be confirmed by autopsy diagnosis or death certificate diagnosis plus preterminal hospitalization, with a definite or suspected diagnosis of MI within 4 weeks of death. Definitions of individual secondary end points were: (1) sudden cardiac d e a t h - - d e a t h within 1 hour of the onset of severe cardiac symptoms, unrelated to other known causes; (2) newly developed angina; (3) unstable angina; (4) worsening NYHA's functional class; (5) coronary artery bypass graft or coronary angioplasty; (6) s t r o k e - - a rapid onset of a neurologic deficit persisting for at least 24 hours attributed to obstruction or rupture in the arterial brain system; (7) transient ischemic a t t a c k - - r a p i d onset of a focal neurologic deficit lasting more than 30 seconds and less t h a n 24 hours, presumed to be due to cerebral ischemia, with no evidence of an underlying nonvascular cause; (8) severe arrhythmia; and (9) other cardiovascular d e a t h - - p r e s u m e d MI that did not meet diagnostic criteria or other cardiovascular causes. Only the first event occurring during the follow-up period was considered for each patient. Information related to study end points was collected by clinical staff, including at least one cardiologist. Baseline Measurements
Lipid and lipoprotein levels were measured according to a standardized protocol: blood samples were drawn between 8 and 9 AM from consent1203
SECONDARY PREVENTION IN CHD
ing patients after they had fasted overnight. The samples were analyzed for the following serum variables: total cholesterol (ESTM reagent, Beckm a n Instruments, Inc., Fullerton, California) and triglycerides (INT reagent, Beckman Instruments). HDL-C was estimated using the Beckman reagents. LDL-C was calculated according to Friedewald's formula: [total cholesterol - HDL-cholesterol - (triglycerides/5)]. A standard oral glucose (75 g) tolerance test was performed in all patients. CHD was confirmed by the results of successive diagnostic procedures consisting of clinical history, cardiac enzyme blood levels (creatine kinase [CK], CK isoenzyme associated with the heart [MB], aspartate transaminase, and lactate dehydrogenase), electrocardiography at rest, echocardiography, Holter electrocardiography, electrocardiography during an exercise test, myocardial scintigraphic images, and coronary angiography. This last diagnostic procedure was only performed in patients who were selected for surgical therapy according to the results of noninvasive diagnostic procedures. MI was recognized by clinical history, results of testing for cardiac enzyme levels, electrocardiography, echocardiography, and scintigraphy. Stable angina pectoris was diagnosed using results of electrocardiography at rest and according to Holter procedure, or during an exercise test. Hypertension was defined as systolic blood pressure exceeding 140 m m Hg, and diastolic blood pressure more than 90 mm Hg. Carotid Doppler testing and Doppler study of the lower limbs were also performed. A completed questionnaire concerning history of familial cardiovascular disease, lifestyle, smoking habits, and professional occupation was also obtained. Treatment Plan Patients were instructed to adhere to a restricted diet containing less than 300 mg/d of cholesterol with 30% of the calorie intake as fat and a polyunsaturated:saturated fat ratio greater than 0.8. Carbohydrate intake was less than 180 g/d in patients with type II diabetes mellitus or hyperinsulinemia. Patients were discouraged from cigarette smoking. A staff psychologist assisted the patients in the safe resumption of activities. Each patient received an individualized prophylactic pharmacologic treatment that included lipid-lowering drugs (simvastatin 10 to 40 mg/d or gemfibrozil 1200 mg/d), antiplatelet drugs (acetylsalicylic acid 100 mg/d or ticlopidine 500 mg/d), hypoglycemic agents (sulphonylureas), calcium antagonists or beta-adrenoreceptor blockers, and nitrates. Statistical Analysis Statistical analysis was carried out by using one-way analysis of vari1204
C. ALESSANDRIETAL.
ance and (for multiple comparison) by using Student-Newman-Keuls test. Data are presented as mean + standard deviation. A P value less than 0.05 was regarded as statistically significant. All calculations were made using the computer program Stat View II (Abacus Concepts, Berkeley, California). RESULTS
Seventy-eight patients were admitted to the study. Four (5%) patients dropped out, while two (3%) were withdrawn from the study because of concomitant diseases. The remaining 72 patients included 61 (85%) men and 11 (15%) women, aged from 33 to 70 years (mean, 56 - 10 years). As shown in Table I, 35 patients had an MI less than 3 years prior to the study (group A), 23 had stable angina pectoris (group B), and 14 had a previous MI (more than 3 years before) and stable angina pectoris (group C). Twenty patients were current smokers (more than 10 cigarettes/d), 27 were exsmokers. Serum levels of total cholesterol, triglycerides, LDL-C, and HDL-C are reported in Table I. Forty-one patients had hyperlipoproteinemia type IIa: 23 of them were
Table I. Baseline characteristics of patients with coronary heart disease who had a myocardial infarction (MI) within the prior 3 years (group A), stable angina pectoris (SAP) (group B), or MI plus SAP more than 3 years prior to inclusion in study (group C). Group Characteristic*
A (n = 35)
B (n = 23)
C (n = 14)
Males Age (y) Follow-up (mon) Smokers Ex-smokers Diabetes mellitus or hyperinsulinemia Hypertension Total cholesterol (mg/dL) Triglycerides. . /mg/dL) . High-density hpoprotein cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) Fibrinogen (mg/dL) Stenosis
33 (94) 53 +- 8 30 -+ 22 10 (29) 14 (40) 6 (17) 7 (20) 253 -+ 55 t49 -+ 71 42 +_ 12 179 -+ 55 302 +- 87
18 (78) 61 +- 6 20 -+ 19 7(30) 7 (30) 7(30) 7 (30) 236 -+ 51 155 +- 116 42 -+ 12 167 -+ 54 324 -- 88
12 (86) 54 +_ 10 22 _+ 16 3 (21) 10 (71) 4 (29) 3 (21) 255 _ 65 131 + 60 48 +- 13 181 -- 69 289 +- 51
11 (31) 9 (26)
2 (9) 3 (13)
11 (31) 3 (9)
5 }~2) 0 )
(>50%) 1 vessel (>50%) 2 vessels Coronary grafts Angioplasty
4 (29) 5(36) (14) 5 (36) 0 (0)
* Table values are numbers of patients with characteristic (%), or mean value --- standard deviation. 1205
SECONDARY PREVENTION IN CHD
in group A, 11 in group B, and 7 in group C. Ten patients were affected by hyperlipoproteinemia type IIb: 4 patients each were in groups A and B, and 2 patients were in group C. Diabetes mellitus or hyperinsulinemia was observed in 17 patients, and 17 patients had mild-to-moderate hypertension. Plasma fibrinogen concentrations were significantly higher in all patient groups compared with normal values (314 Jr 82 mg/dL vs 220 + 45 dL; P < 0.001). Coronary angiography was performed in 49 (68%) patients and showed no significant stenosis (<50%) 14 in 8 patients; however, 17 patients had a significant stenosis of 1 vessel; 17, of 2 vessels; and 7, of 3 vessels. Coronary artery bypass grafts were implanted in 21 patients (11 in group A, 5 each in groups B and C), while angioplasty was performed in 3 patients from group A. The antiplatelet treatment was continuously given in each patient: 33 (46%) patients received ticlopidine and 39 (54%) received acetylsalicylic acid. After 6 months of dietary treatment, 28 hyperlipoproteinemic patients showing serum levels of total cholesterol or triglycerides higher than 240 mg/dL and 190 mg/dL, respectively, were treated with simvastatin (25 patients) or gemfibrozil (3 patients). Lipid-lowering therapy reduced (-21%) total cholesterol and increased (+24%) HDL-C. In all patients with diabetes mellitus, the low carbohydrate intake and sulphonylureas therapy resulted in a satisfactory metabolic control of the disease. In patients with hypertension, therapy with calcium antagonists or betaadrenoreceptor blockers normalized arterial blood pressure (data not shown). During the follow-up period, none of the patients experienced fatal or nonfatal MI, the primary end points of the study. Nevertheless, in 3 patients in group A, 2 in group B, and 1 in group C, 1 to 12 months after recruitment, a secondary end point was observed (Table II). These six patients (age range, 51 to 65 years; 1 woman and 5 men) each had a coronary stenosis of more than 50% of one or more vessels, and 3 patients had a coronary artery bypass graft. Four patients were ex-smokers, 1 was a nonsmoker, and 1 was a current smoker (fewer than 10 cigarettes/d). Two patients affected by hypercholesterolemia type IIa were treated with simvastatin and showed total cholesterol serum values between 200 and 240 mg/dL; moreover, two of the normocholesterolemic patients had HDL-C serum levels lower than 20% of the total cholesterol concentration. Two patients with diabetes mellitus, who were treated with sulphonylureas, had a fasting glucose serum level <150 mg/dL; two patients with hypertension, who were treated with calcium antagonists, had blood pressure values lower than 160/90 mm Hg. Five of six patients took acetylsalicylic acid and 1 patient took ticlopidine.
1206
-...3
M F M M M M
1 2 3 4 5 6
63 51 62 65 54 58
Age (y)
MIt + SAP SAP MI:~ SAP MI:~ MI:~
CHD 3 2 2 0 2 1
No No Yes Yes Yes No
Coronary Artery Bypass Graft ES N ES CS ES ES
Smoking Habit Ila + NIDD Ila None H None NIDD + H
Other Risk Factors ASA ASA ASA ASA TK ASA
Antiplatelet Agents
12 9 12 12 1 12
Monthsof Follow-up
Worsening TIA Worsening Worsening Arrhythmia Worsening
NYHA
NYHA NYHA
NYHA
End Point
M = male; MI = myocardial infarction; SAP = stable angina pectoris; ES = ex-smoker; N = nonsmoker; Ila = hypercholesterolemia type Ila; NIDD = non-insulin dependent diabetes; ASA = acetylsalicylic acid; NYHA = New York Heart Association; F = female; TIA = transient ischemic attack; CS = current smoker; H = hypertension; TK = ticlopidine. * Dietary and lifestyle modification and personalized pharmacologic treatment. t Previous MI (more than 3 years prior). :~ Recent MI (within 3 years).
Sex
Patient No.
No. of Vessels with Stenosis >50%
Table II. Clinical, laboratory, and treatment characteristics of six patients with coronary heart disease (CHD) who reached cardiovascular end point events despite interventional therapy* designed to modify risk factors.
~3
O9
>
p
SECONDARYPREVENTIONIN CHD
D I S C U S S I O N AND C O N C L U S I O N
The aim of a correct therapeutic approach to patients affected by CHD is to prolong survival by preventing further cardiovascular events or death. An appropriate evaluation of patient health and cardiac function by noninvasive testing and coronary angiography, when there is the possibility for a revascularization attempt, must be performed. This is the first aim in the management of cardiovascular atherosclerotic disease. That the identification and modification of atherosclerotic risk factors must be the second medical objective, resulting in secondary prevention, is underlined by results of clinical trials. A further step is to begin or revise a therapeutic treatment to improve coronary blood perfusion and to prevent thrombogenesis in coronary vessels. Several drugs (beta-adrenoreceptor blocking agents, calcium channel antagonists, nitrates, anticoagulants, and antiplatelet agents) are used in the prophylaxis of secondary events in patients affected by CHD, but a standardized protocol is not available. Clinical long-term trials, in fact, report contrasting or inconclusive results on the efficacy of oral nitrates or calcium channel antagonists in preventing subsequent MI episodes, s - n Beta-adrenoreceptor blockers have produced a significant reduction in sudden death and nonfatal reinfarction in trials conducted for periods greater than 2 to 3 years on patients with previous MI episode, s - n Nevertheless, clear data are not available on the efficacy of these drugs in preventing primary MI episodes in CHD patients. Longterm administration of antiplatelet agents after recovery from MI appears to be very effective in reducing mortality and cardiovascular morbidity in patients surviving MI. s'n Long-term anticoagulant therapy has shown beneficial effects, notwithstanding more frequent hemorrhagic events, s'n We carried out a preventive strategy on patients with CHD, with and without a previous MI episode. After the first 3 years of the follow-up period, we have observed six minor cardiovascular events (4, worsening in NYHA functional class; 1, transient ischemic attack; 1, arrhythmic episodes), with a percentage of survivors of 100%. Moss and Benhorin, 6 analyzing the results of some studies on the clinical course of patients surviving a first MI episode, reported that the overall annualized rates of cardiac mortality and nonfatal reinfarction were 6.2% and 4.5%, respectively. Our results, although collected by a pilot study of only 72 patients, show that a coherent diagnostic approach and a complete therapeutic intervention could reduce incidence of secondary cardiovascular events. We evaluated the cardiac function and the atherosclerotic risk factors of every patient; then a simultaneous dietary and lifestyle modification and pharmacologic approach was started. Although all patients were treated with antiplatelet drugs, six had minor cardiovascular events. Despite interventional therapy, four of these patients still showed an abnormal lipidemic pattern (high total cholesterol and/or low HDL-C), 1208
C. ALESSANDRIETAL.
and one was a current smoker. A more aggressive approach to risk factor modification may have been more effective in preventing secondary events; the benefit of such intervention on reduction of atherosclerotic risk factors might be verified on a larger patient sample. Although ourpreliminary data are encouraging, they must be verified by a multicenter study using a larger number of patients affected by CHD.
Acknowledgments This study was supported by the National Research Council (C.N.R.)Target Project "Prevention and Control Disease Factors" (F.A.T.M.A.)Subproject 8-Contract no. 91.00070.41. References: 1. Report of the National Cholesterol Education Program expert panel on detection, evaluation and treatment of high blood cholesterol in adults. Arch Intern Med. 1988;148:3669. 2. American Heart Association. Special report: The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol and coronary heart disease. Circulation. 1990;81:1721-1733. 3. Sytkowski PA, Kannel WB, D'Agostino RB. Changes in risk factors and the decline in mortality from cardiovascular disease. The Framingham Heart Study. NEJM. 1990;322: 1635-1641. 4. Peto R, Yusuf S, Collins R. Cholesterol-lowering trial results in their epidemiologic context. Circulation. 1985;72(Suppl III):45. 5. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. NEJM. 1990;322:1700-1707. 6. Moss AJ, Benhorin J. Prognosis and management after a first myocardial infarction. NEJM. 1990;322:743-753. 7. Miller M, Seidler A, Kwiterovich PO, Pearson TA. Long-term predictors of subsequent cardiovascular events with coronary artery disease and desirable levels of plasma total cholesterol. Circulation. 1992;86:1165-1170. 8. Hinstridge V, Speight TM. An overview of therapeutic interventions in myocardial infarction. Emphasis on secondary prevention. Drugs. 1991;42:8-20. 9. McGovern PG, Folsom AR, Sprafka M, et al. Trends in survival of hospitalized myocardial infarction patients between 1970 and 1985. The Minnesota Heart Survey. Circulation. 1992;85:172-179. 10. Rossouw JE, Lewis B, Rifkind BM. The value of lowering cholesterol after myocardial infarction. NEJM. 1990;323:1112-1119. 11. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease: Treatments following myocardial infarction. JAMA. 1988;260:2088-2093. 12. Alderman EL, Bourassa MG, Cohen LS, et al. Ten-year follow-up of survival and myo1209
S E C O N D A R Y PREVENTION IN C H D
cardial infarction in the randomized coronary artery surgery study. Circulation. 1990; 82:1629-1646. 13. Rogers WJ, Coggin J, Gersh BJ, et al. Ten year follow-up of quality of life in patients randomized to receive medical therapy or coronary artery bypass graft surgery. The coronary artery surgery study (CASS). Circulation. 1990;82:1647-1658. 14. Harris PJ, Behar VS, Conley MJ, et al. The prognostic significance of 50% coronary stenosis in medically treated patients with coronary artery disease. Circulation. 1980; 62:240-248.
1210