European Heart Journal (1992) 13 (Supplement B), 7-10
Long-term experience with lovastatin treatment in patients with coronary heart disease and hyperlipoproteinaemia type II I. ZHUKOVA, A. YURENEV, V. KUKHARCHUK, E. POMERANTSEV, V. TITOV, B. SHABALKIN* AND A. MARTINOV*
USSR Cardiology Research Center and USSR Surgery Research Center*, Moscow
Introduction
Correspondence: Irina M. Zhukova, MD, Institute of Clinical Cardiology, USSR Cardiology Research Center, 3rd Cherepkovskaya str. 15A, Moscow 121552, USSR.
0195-668X/92/0B0O07 + 04 $03.00/0
Patients and methods Six hundred and eleven patients suffering from CHD (including angina of effort) and atherosclerosis of the coronary arteries confirmed by coronary angiography were screened. This group comprised 604 males and seven females aged 32-65 years. All eligible screened patients with either triglyceride levels above 350 mg.dr 1 , blood glucose above 150 mg.dl"1, transaminase 20% above the normal levels, unstable angina, hypothyroidism, or who had undergone coronary bypass surgery less than 4 months earlier were not studied. Patients were seen on an outpatient basis at the Institute of Clinical Cardiology, USSR Cardiology Research Centre. During each control visit a clinical survey of the patients and an ECG were performed. Detailed eye examinations, which included a slit-lamp examination and Scheimpflug photography, were obtained prior to therapy with lovastatin; the examination was repeated at 6- to 12-month intervals. Blood samples for lipid and lipoprotein analysis were obtained after an overnight fast and put into tubes containing 1 mg.dl"1 EDTA as anticoagulant. Quantitative determination of the levels of total cholesterol (TC) and triglycerides was performed using the enzyme-calorimetric method and a set of reactives supplied by Hope (Finland). High density separation of cholesterol in lipoprotein fractions was carried out with the help of phosphorwolframic acid. The value of VLDL cholesterol was determined by calculating the level of triglycerides.5"1. LDL-ch was calculated using the Friedewald formula. After excluding those patients mentioned before, the remaining 280 patients with TC concentrations equal to or more than 250 mg.dr 1 were invited to the study and were prescribed a hypolipidaemic diet for 2 weeks. The influence of the hypolipidaemic effect of lovastatin on the frequency of angina and exercise capacity was assessed in a subgroup of 88 randomly selected patients. After the 2 weeks on hypolipidaemic diet the patients received placebo for 4 weeks, followed by lovastatin. The patients were blinded with regard to when they started with active treatment. All 280 patients were prescribed lovastatin therapy at a starting dose of 20-40 mg per day. © 1992 The European Society of Cardiology
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A growing body of information obtained in epidemiological studies strongly indicates that hypercholesterolaemia is a primary risk factor for coronary heart disease (CHD). Moreover, this conclusion has been supported by trials such as The Lipid Research Clinics Coronary Primary Prevention Trial!12). The results of this study provided a clear-cut conclusion that a decrease in low density lipoprotein (LDL) cholesterol through dietary modification combined with bile acid sequestrant cholestyramine treatment reduced the frequency of CHD mortality and morbidity in hypercholesterolaemic individuals. Over the past 30 years much effort has been directed into the search for agents potentially effective in the reduction of lipids known to increase the risk of atherosclerosis. This effort has resulted in the development of a new class of cholesterol-lowering drugs, HMG-CoA reductase inhibitors, which have been found effective both as monotherapy'3"6' and in combination with other cholesterol-lowering drugs'7"9'. The remarkable efficacy of lovastatin as a lipid-lowering drug was demonstrated initially in normocholesterolaemic volunteers'10' and subsequently in small studies in patients with heterozygous familial hypercholesterolaemiat10-15' and non-familial hypercholesterolaemia'11', and later in five multicentre controlled studies involving over 1000 patients. The efficacy and mechanism of action of lovastatin have been evaluated in detail in several recent reviews'16"18!. The hypolipidaemic effect of lovastatin is based on its ability to inhibit the liver enzyme, hydroxy-methyl-glutaryl-CoAreductase, and thus to decrease the formation of mevalonic acid, the result of which limits the speed of cholesterol biosynthesis'19'. Lovastatin decreases LDL cholesterol by two mechanisms: stimulation of the creation of LDL receptors I10-20!; decrease in the formation of LDL particles. In his review Grundy'16' concluded that lovastatin and other HMG-CoA reductase inhibitors are a promising new class of cholesterol-lowering drugs that should reduce the risk of coronary heart disease by 50% to 60%. They appear to be remarkably free of serious side effects, with the rare exception of rhabdomyolysis. The aim of this study was to assess the hypolipidaemic
effect of lovastatin on the frequency of angina and exercise capacity in patients with established CHD and hyperlipoproteinaemia type II.
8
I. Zhukova et al.
Table 1 Some clinical characteristics of seven females and 273 males aged 32-65 years included in a 2-year treatment regimen with lovastatin Age
Duration of CHD Patients with past MI Patients after bypass operation
49+7 years 7 + 4 years 122 (44%) 78 (28%)
An analysis of the coronary angiography data shows the average number of coronary arteries with atherosclerotic lesions was 2-4 ± 1-6, with an ejection fraction of 60 + 4 %, and an end-diastolic pressure of 13-3 ± 0-4 mmHg. Analysis of lipid profile changes during the 2-year period revealed a statistically significant reduction in total plasma cholesterol levels, from 334-4 ± 14-33 to 220-84 ± 7-74 tng.dr 1 (36%) (P < 0001). LDL cholesterol decreased from 253-8 + 16-4 to 161-9 ± 10-4 mg.dr 1 (34%) (P < 0-001), triglycerides from 172-2 ± 12 to 1361 ± 9-5 mg.dr 1 (19%) (P < 0-01) and HDL cholesterol increased from 37-7 + 2-5 to 41-5 ± 3-4 mg.dr 1 (10%) (P < 005) (Fig. 1). Concentration of apo B decreased from 1711 ± 0-4 to 140-9 ± 0-9 mg.dr 1 (18%) (P < 005), while apo AI increased from 89-6 ± 4-1 to 98-7 ± 3-9 mg.dr 1 (10%) (P < 0-05). We examined the results of repeated bicycle exercise tests in 88 randomly selected patients. The mean age of this subgroup was 50 years and the mean duration of CHD 8 years. A history of previous myocardial infarction was present in 34 patients (39%). There were 21 patients in the study who had had a bypass operation, but there were no significant clinical differences between this subgroup and the group as whole. The repeated bicycle tests demonstrated a statistically significant increase in exercise capacity from 600 ± 35 to 651 ± 31 kg.min"1 (P < 005) and with the total load from 4329 + 409 to 5181 + 379 kg (P < 0-05). Exercise duration increased from 11-1 + 0-7 to 12-3 ± 2.1 min (P < 0-05). Systolic and diastolic blood pressure as well as rate-pressure product was unchanged (Table 2). The number of patients who stopped the test because of angina or fatigue decreased from 32 to 22 (NS). The frequency of angina attacks and use of nitroglycerin ~
400
Results We have analysed the clinical characteristics of 280 patients included in this trial. The average duration of known coronary heart disease was 7 ± 4 years. The mean age of the 280 patients was 4 9 + 7 years (273 males, 7 females). The patient population included 122 (44%) with past myocardial infarction and 78 (28%) with coronary bypass surgery in their history (Table 1). Mild arterial hypertension was observed in 92 patients (33%) and heart failure in 20 (7%). One hundred and thirty-two patients were in angina functional class I—II (47%) and 148 patients (53%) were in class III.
Baseline
Figure 1 Changes in lipid plasma concentrations (±SEM) after lovastatin treatment (20-80mg.day"')• ***P
Long-term experience with lovastatin treatment in patients with coronary heart disease and hyperlipoproteinaemia type II I. ZHUKOVA, A. YURENEV, V. KUKHARCHUK, E. POMERANTSEV, V. TITOV, B. SHABALKIN* AND A. MARTINOV*
USSR Cardiology Research Center and USSR Surgery Research Center*, Moscow
Introduction
Correspondence: Irina M. Zhukova, MD, Institute of Clinical Cardiology, USSR Cardiology Research Center, 3rd Cherepkovskaya str. 15A, Moscow 121552, USSR.
0195-668X/92/0B0O07 + 04 $03.00/0
Patients and methods Six hundred and eleven patients suffering from CHD (including angina of effort) and atherosclerosis of the coronary arteries confirmed by coronary angiography were screened. This group comprised 604 males and seven females aged 32-65 years. All eligible screened patients with either triglyceride levels above 350 mg.dr 1 , blood glucose above 150 mg.dl"1, transaminase 20% above the normal levels, unstable angina, hypothyroidism, or who had undergone coronary bypass surgery less than 4 months earlier were not studied. Patients were seen on an outpatient basis at the Institute of Clinical Cardiology, USSR Cardiology Research Centre. During each control visit a clinical survey of the patients and an ECG were performed. Detailed eye examinations, which included a slit-lamp examination and Scheimpflug photography, were obtained prior to therapy with lovastatin; the examination was repeated at 6- to 12-month intervals. Blood samples for lipid and lipoprotein analysis were obtained after an overnight fast and put into tubes containing 1 mg.dl"1 EDTA as anticoagulant. Quantitative determination of the levels of total cholesterol (TC) and triglycerides was performed using the enzyme-calorimetric method and a set of reactives supplied by Hope (Finland). High density separation of cholesterol in lipoprotein fractions was carried out with the help of phosphorwolframic acid. The value of VLDL cholesterol was determined by calculating the level of triglycerides.5"1. LDL-ch was calculated using the Friedewald formula. After excluding those patients mentioned before, the remaining 280 patients with TC concentrations equal to or more than 250 mg.dr 1 were invited to the study and were prescribed a hypolipidaemic diet for 2 weeks. The influence of the hypolipidaemic effect of lovastatin on the frequency of angina and exercise capacity was assessed in a subgroup of 88 randomly selected patients. After the 2 weeks on hypolipidaemic diet the patients received placebo for 4 weeks, followed by lovastatin. The patients were blinded with regard to when they started with active treatment. All 280 patients were prescribed lovastatin therapy at a starting dose of 20-40 mg per day. © 1992 The European Society of Cardiology
Downloaded from by guest on August 19, 2015
A growing body of information obtained in epidemiological studies strongly indicates that hypercholesterolaemia is a primary risk factor for coronary heart disease (CHD). Moreover, this conclusion has been supported by trials such as The Lipid Research Clinics Coronary Primary Prevention Trial!12). The results of this study provided a clear-cut conclusion that a decrease in low density lipoprotein (LDL) cholesterol through dietary modification combined with bile acid sequestrant cholestyramine treatment reduced the frequency of CHD mortality and morbidity in hypercholesterolaemic individuals. Over the past 30 years much effort has been directed into the search for agents potentially effective in the reduction of lipids known to increase the risk of atherosclerosis. This effort has resulted in the development of a new class of cholesterol-lowering drugs, HMG-CoA reductase inhibitors, which have been found effective both as monotherapy'3"6' and in combination with other cholesterol-lowering drugs'7"9'. The remarkable efficacy of lovastatin as a lipid-lowering drug was demonstrated initially in normocholesterolaemic volunteers'10' and subsequently in small studies in patients with heterozygous familial hypercholesterolaemiat10-15' and non-familial hypercholesterolaemia'11', and later in five multicentre controlled studies involving over 1000 patients. The efficacy and mechanism of action of lovastatin have been evaluated in detail in several recent reviews'16"18!. The hypolipidaemic effect of lovastatin is based on its ability to inhibit the liver enzyme, hydroxy-methyl-glutaryl-CoAreductase, and thus to decrease the formation of mevalonic acid, the result of which limits the speed of cholesterol biosynthesis'19'. Lovastatin decreases LDL cholesterol by two mechanisms: stimulation of the creation of LDL receptors I10-20!; decrease in the formation of LDL particles. In his review Grundy'16' concluded that lovastatin and other HMG-CoA reductase inhibitors are a promising new class of cholesterol-lowering drugs that should reduce the risk of coronary heart disease by 50% to 60%. They appear to be remarkably free of serious side effects, with the rare exception of rhabdomyolysis. The aim of this study was to assess the hypolipidaemic
effect of lovastatin on the frequency of angina and exercise capacity in patients with established CHD and hyperlipoproteinaemia type II.
8
I. Zhukova et al.
Table 1 Some clinical characteristics of seven females and 273 males aged 32-65 years included in a 2-year treatment regimen with lovastatin Age
Duration of CHD Patients with past MI Patients after bypass operation
49+7 years 7 + 4 years 122 (44%) 78 (28%)
An analysis of the coronary angiography data shows the average number of coronary arteries with atherosclerotic lesions was 2-4 ± 1-6, with an ejection fraction of 60 + 4 %, and an end-diastolic pressure of 13-3 ± 0-4 mmHg. Analysis of lipid profile changes during the 2-year period revealed a statistically significant reduction in total plasma cholesterol levels, from 334-4 ± 14-33 to 220-84 ± 7-74 tng.dr 1 (36%) (P < 0001). LDL cholesterol decreased from 253-8 + 16-4 to 161-9 ± 10-4 mg.dr 1 (34%) (P < 0-001), triglycerides from 172-2 ± 12 to 1361 ± 9-5 mg.dr 1 (19%) (P < 0-01) and HDL cholesterol increased from 37-7 + 2-5 to 41-5 ± 3-4 mg.dr 1 (10%) (P < 005) (Fig. 1). Concentration of apo B decreased from 1711 ± 0-4 to 140-9 ± 0-9 mg.dr 1 (18%) (P < 005), while apo AI increased from 89-6 ± 4-1 to 98-7 ± 3-9 mg.dr 1 (10%) (P < 0-05). We examined the results of repeated bicycle exercise tests in 88 randomly selected patients. The mean age of this subgroup was 50 years and the mean duration of CHD 8 years. A history of previous myocardial infarction was present in 34 patients (39%). There were 21 patients in the study who had had a bypass operation, but there were no significant clinical differences between this subgroup and the group as whole. The repeated bicycle tests demonstrated a statistically significant increase in exercise capacity from 600 ± 35 to 651 ± 31 kg.min"1 (P < 005) and with the total load from 4329 + 409 to 5181 + 379 kg (P < 0-05). Exercise duration increased from 11-1 + 0-7 to 12-3 ± 2.1 min (P < 0-05). Systolic and diastolic blood pressure as well as rate-pressure product was unchanged (Table 2). The number of patients who stopped the test because of angina or fatigue decreased from 32 to 22 (NS). The frequency of angina attacks and use of nitroglycerin ~
400
Results We have analysed the clinical characteristics of 280 patients included in this trial. The average duration of known coronary heart disease was 7 ± 4 years. The mean age of the 280 patients was 4 9 + 7 years (273 males, 7 females). The patient population included 122 (44%) with past myocardial infarction and 78 (28%) with coronary bypass surgery in their history (Table 1). Mild arterial hypertension was observed in 92 patients (33%) and heart failure in 20 (7%). One hundred and thirty-two patients were in angina functional class I—II (47%) and 148 patients (53%) were in class III.
Baseline
Figure 1 Changes in lipid plasma concentrations (±SEM) after lovastatin treatment (20-80mg.day"')• ***P
