- Email: [email protected]
Short-term effect of atorvastatin (80 mg) on plasma lipids of patients with unstable angina pectoris or non–Q-wave acute myocardial infarction
betic as well in nondiabetic patients. One potential mechanism that explains the association of prodromal angina in the week before infarction with a favorable outcome is ischemic preconditioning.10 Therefore, a delayed adaptative mechanism may play a part in these favorable outcomes. The effects of delayed ischemic preconditioning have been identified in experimental models.11 Ischemic preconditioning occurs approximately 24 hours after the ischemic insult, and delayed ischemic preconditioning lasts much longer than the classic preconditioning effect reported by Murry and colleagues.10 However, the clinical significance of delayed preconditioning has not been established in patients with AMI. Only 1 study has analyzed the relation between preinfarction angina and prognosis in diabetics. Ishihara et al7 found that preinfarction angina had no protective effect in diabetics with regard to LVEF or in-hospital complications in contrast to the results of the present study. However, our study differs from that of Ishihara et al in 3 important aspects. First, we considered prodromal angina 1 week before myocardial infarction; under these circumstances, if ischemic preconditioning plays a role,10 the delayed mechanism (second window effect) would have had time to develop. Second, in the patients studied by Ishihara et al,7 reperfusion therapy was performed in 96% of patients compared with 60% in our series. Thrombolytic therapy may result in more rapid reperfusion in patients who had unstable angina during the week before infarction as was shown by Andreotti et al.12 Third, Ishihara et al studied only patients with anterior AMI.
In conclusion, angina pectoris within 1 week of a first AMI is associated with a lower incidence of in-hospital complications in diabetic patients, but it does not preserve LVEF. 1. Kannel W. Lipids, diabetes, and coronary heart disease: insights from the
Framingham study. Am Heart J 1985;110:1110 –1117. 2. Malmberg K, Ryden L. Myocardial infarction in patients with diabetes mel-
litus. Eur Heart J 1988;9:256 –264. 3. Stone PH, Muller JE, Hartwell T, York BJ, Rutheford JD, Parker CB, Turi ZG, Strauss W, Willerson JT, Robertson T, Braunwald E, Jaffe AS, and the MILIS Study Group. The effect of diabetes on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. J Am Coll Cardiol 1989;14:49 –57. 4. Zuanetti G, Latini R, Maggioni AP, Santoro L, Franzosi PG, for the GISSI-2 Investigators. Influence of diabetes on mortality in acute myocardial infarction: data from the GISSI-2 study. J Am Coll Cardiol 1993;22:1788 –1794. 5. Ottani F, Galvani M, Ferrini D, Sorbello F, Limonetti P, Pantoli D, Rusticali F. Prodromal angina limits infarct size: a role for ischemic preconditioning. Circulation 1995;91:291–297. 6. Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S, Gibson M, Poole K, Cannon C, McCabe C, Braunwald E, for the TIMI 4 Investigators. Previous angina alters in-hospital outcome in TIMI 4: a clinical correlate to preconditioning? Circulation 1995;91:37–45. 7. Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K, Kuono Y, Umemura T, Nakamura S, Sato H. Diabetes Mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infacrtion. J Am Coll Cardiol 2000;38:1007–1017. 8. Jime´ nez-Navarro M, Go´ mez-Doblas J, Alonso-Briales J, Herna´ ndez JM, Go´ mez G, Garcia A, Rodriguez-Bailo´ n I, Barrera A, Montiel A, Espinosa JS, De Teresa E. Does angina the week before protect against first myocardial infarction in elderly patients? Am J Cardiol 2001;87:11–15. 9. Zarich SW, Nesto RW. Diabetic cardiomyopathy. Am Heart J 1989;118:1000 – 1012. 10. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124 –1136. 11. Baxter GF, Ferdinand P. Delayed preconditioning of myocardium: current perspectives. Basic Res Cardiol 2001;6:329 –344. 12. Andreotti F, Pasceri V, Hackett DR, Davies GJ, Harder AW, Maseri A. Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infacrtion. N Engl J Med 1996;334:7–12.
Short-Term Effect of Atorvastatin (80 mg) on Plasma Lipids of Patients With Unstable Angina Pectoris or Non–Q-Wave Acute Myocardial Infarction Luis C.L. Correia, MD, Andrei C. Spo´ sito, MD, PhD, Luiz C.S. Passos, MD, PhD, Jose´ C. Lima, MD, Ju´ lio C. Braga, MD, Ma´ rio S. Rocha, MD, J. Pe´ ricles Esteves, MD, and Argemiro D’Oliveira, Jr., MD, PhD t is not known if statin therapy is able to modify the lipid profile positively during the acute phase of Iunstable angina pectoris or non–Q-wave myocardial infarction. Such is the purpose of this report. •••
Patients admitted in the coronary care unit of our hospital due to unstable angina pectoris or non–QFrom the PhD Program, School of Medicine, Federal University of Bahia, Salvador; Cardiology Division, Portuguese Hospital, Salvador; and Heart Institute (InCor), University of Sa˜ o Paulo Medicine School, Sa˜ o Paulo, Brazil. Dr. Correia’s address is: Rua do Taruma˜ 90/ 1002, Salvador-BA-Brasil 41.810-440. E-mail: lucorrei@bahianet. com.br. Manuscript received January 9, 2002; revised manuscript received and accepted March 25, 2002.
162
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 July 15, 2002
wave acute myocardial infarction from December 2000 to September 2001 were considered candidates for the study. Inclusion criteria were defined as onset of chest discomfort in the last 48 hours and 1 of the following objective criteria for evidence of unstable coronary disease: (1) transient ST-segment depression (ⱖ0.5 mm) or T-wave inversion (ⱖ1.0 mm); and (2) positive troponin I (⬎1.0 ng/dl) or troponin T (⬎0.1 ng/dl). Patients were excluded if they presented with left bundle branch block, any liver disease, or had a history of statin intolerance, pregnancy, or lactation. The study was approved by the local ethics committee and all participants provided written informed consent. An initial blood sample to measure plasma lipids was drawn before initiation of therapy. The 0002-9149/02/$–see front matter PII S0002-9149(02)02443-8
TABLE 1 Baseline Characteristics, Lipid Variables, and CReactive Protein Atorvastatin (n ⫽ 28)
Placebo (n ⫽ 28)
Age (yrs) 66 ⫾ 12 64 ⫾ 11 Men 13 (46%) 13 (46%) Diabetes mellitus 7 (25%) 9 (32.1%) Systemic hypertension 21 (75%) 19 (68%) Smokers 1 (4%) 4 (14%) Chronic use of aspirin 14 (50%) 10 (36%) Chronic use of statin 2 (7%) 5 (18%) Positive troponin 14 (50%) 9 (31%) ST-segment depression 10 (36%) 15 (54%) LV systolic dysfunction* 2 (8%) 1 (4%) 3-vessel disease (⬎70%) 4/18 (25%) 5/20 (22%) Total cholesterol (mg/dl) 198 ⫾ 39 205 ⫾ 48 HDL cholesterol (mg/dl) 43 ⫾ 15 40 ⫾ 9 LDL cholesterol (mg/dl) 127 ⫾ 38 132 ⫾ 39 Triglycerides (mg/dl) 151 ⫾ 93 156 ⫾ 60 LDL/HDL ratio 3.15 ⫾ 1.30 3.52 ⫾ 1.29 C-reactive protein (mg/dl) 0.81 ⫾ 0.93 0.77 ⫾ 1.17
p Value 0.62 1.0 0.55 0.55 0.16 0.28 0.23 0.15 0.18 0.68 0.47 0.55 0.30 0.66 0.60 0.31 0.92
*Ejection fraction ⬍55% on echocardiogram. LV ⫽ left ventricular.
enrolled patients were submitted to a randomized, double-blind, placebo-controlled program with either 80 mg atorvastatin or placebo administered once a day. No other type of antilipidemic therapy was offered to the patients. After 5 days of therapy, another blood sample was drawn for comparative analysis. Patients were observed with regard to clinical symptoms suggestive of liver or muscular toxicity; alanine transaminase, gamma-glutamyl transferase, or creatine kinase were measured as clinically indicated. Commercial enzymatic methods were used for determining total cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides (Dimension Clinical Chemistry System, Dade-Behring, Newark, Delaware).1 HDL cholesterol was determined by the same method used for total cholesterol after precipitation of apolipoprotein Bcontaining lipoproteins with magnesium phosphotungstate. Low-density lipoprotein (LDL) cholesterol levels were calculated by Friedewald’s formula. Because of the non-normality of the lipid variable measurements, nonparametric tests were performed. The Wilcoxon rank-sum test was used to compare changes in each variable during the 5-day treatment (intergroup analysis) between the 2 groups. For the paired difference between the first and second measurements of each lipid variable, the Wilcoxon sign-rank test was used (intragroup analysis). Adjustment for confounding variables on drug effects was performed by 2-way analysis of variance. Baseline categorical variables were compared by chi-square or Fisher’s exact test, and baseline continuous variables by unpaired Student’s t test or Wilcoxon rank-sum test. Fifty-six patients (30 women [54%], 26 men [46%], mean age 65 ⫾ 12 years) were enrolled. Twenty-three patients had acute myocardial infarction and 33 had unstable angina pectoris. Half of them were randomized to therapy with atorvastatin and the other half to placebo. Baseline characteristics were not statistically different between the groups, although more
patients had infarction in the atorvastatin group (Table 1). There were no significant differences in medical treatment between groups: all patients took aspirin, 68% in the atorvastatin group took clopidogrel, 82% took low molecular weight heparin, 86% took nitrates, 86% took  blockers, 61% took angiotensin-converting enzyme inhibitors, and 18% took tirofiban. In the placebo group, 64% took clopidogrel (p ⫽ 0.78), 100% took low molecular weight heparin (p ⫽ 0.05), 89% took nitrates (p ⫽ 1.0), 89% took  blockers (p ⫽ 1.0), 46% angiotensin-converting enzyme inhibitors (p ⫽ 0.28), and 11% took tirofiban (p ⫽ 0.70). The time from the beginning of clinical symptoms and blood draw to measuring plasma lipids was 18 ⫾ 13 hours. Eight of the 56 patients (6 in the placebo arm and 2 in the treatment arm) were not in a fasting state at the time of the first determination of plasma lipids. The levels of total cholesterol before treatment, as well as the other lipid fractions, did not differ between the atorvastatin (198 ⫾ 39 mg/dl) and placebo (205 ⫾ 47 mg/dl, p ⫽ 0.55) groups (Table 1). All patients completed treatment and there were no clinical adverse events related to drug therapy. Between the first and second analysis of lipid profile, 4.9 ⫾ 0.6 days elapsed. Significant reductions in total cholesterol (⫺44 ⫾ 20 mg/dl, p ⬍0.001) and LDL cholesterol (⫺37 ⫾ 23 mg/dl, p ⬍0.001) were observed in the atorvastatin group, but not in the placebo group (⫺1.6 ⫾ 35 mg/dl, p ⫽ 0.82; ⫺5.3 ⫾ 34 mg/dl, p ⫽ 0.46, respectively). When these changes in total cholesterol and LDL cholesterol were compared between groups, a significant difference was found (p ⬍0.001 and p ⫽ 0.001, respectively). Because acute myocardial infarction may be a confounding factor because it promotes cholesterol reduction by itself, we tested the influence of the drug on lipid profile, controlling for infarction, which was more prevalent in the atorvastatin arm. After adjustment by analysis of variance, the level of significance of the difference between atorvastatin and placebo was maintained (p ⫽ 0.0004), with no significant interaction between the variables “atorvastatin” and “infarction” (p ⫽ 0.10). Furthermore, when we compared the variation of total cholesterol only in patients with unstable angina, we also found a significant difference between atorvastatin and placebo (⫺30 ⫾ 21 vs ⫺9 ⫾ 35 mg/dl, p ⫽ 0.001, respectively) (Figure 1). With regard to HDL cholesterol, the paired analysis showed a significant reduction in the atorvastatin group (⫺3.7 ⫾ 7.7 mg/dl, p ⫽ 0.012), which was not seen in the placebo group (⫺0.96 ⫾ 6.9 mg/dl, p ⫽ 0.45). When this variation was compared between the groups, the difference did not reach statistical significance (p ⫽ 0.12). Analysis of patients with unstable angina showed a trend toward a decrease in HDL cholesterol in the atorvastatin arm (⫺3.2 ⫾ 7.9 mg/dl, p ⫽ 0.06) as opposed to patients in the placebo arm (⫺0.6 ⫾ 6.7 mg/dl, p ⫽ 0.61), p ⫽ 0.30 for intergroup comparison. The LDL/HDL ratio slightly decreased in the atorvastatin arm (⫺0.3 ⫾ 1.3, p ⬍0.001), which was not observed in the placebo arm (⫹0.3 ⫾ 1.6, p ⫽ 0.90). There was a reduction in triglycerides in the atorvastatin arm (⫺19 ⫾ 70 mg/dl, p ⫽ 0.08), as well as an BRIEF REPORTS
163
FIGURE 1. Variation of lipid profile between the first and fifth day of therapy with atorvastatin or placebo.
elevation in the placebo arm (⫹16 ⫾ 54 mg/dl, p ⫽ 0.34), although these were not statistically significant. The comparison of this variation between the groups showed a trend toward statistical significance (p ⫽ 0.091). After excluding patients who were not fasting at study entry, the findings remained the same: in the atorvastatin arm significant reductions were seen in total cholesterol (⫺44 ⫾ 20 mg/dl, p ⬍0.001), LDL cholesterol (⫺36 ⫾ 23 mg/dl, p ⬍0.001), and HDL cholesterol (⫺4.6 ⫾ 7.2 mg/dl, p ⫽ 0.003), with a nonsignificant reduction in triglycerides (⫺17 ⫾ 72 mg/dl, p ⫽ 0.24). In the placebo arm, there were no significant changes in total cholesterol (⫺3.3 ⫾ 34 mg/dl, p ⬍0.66), LDL cholesterol (⫺11.0 ⫾ 30.8 mg/dl, p ⫽ 0.12), HDL cholesterol (⫺0.3 ⫾ 6.4 mg/dl, p ⫽ 0.95), and triglycerides (⫹21 ⫾ 57 mg/dl, p ⫽ 0.11).
HDL cholesterol measured in the sixth week of therapy was seen, followed by a significant increase in the 16th week.2 Similarly, in the Atorvastatin and Simvastatin on Atherosclerosis Progression (ASAP) trial, a 13% increase in HDL cholesterol levels was equally observed after a 2-year treatment period with either atorvastatin 80 mg/day or simvastatin 40 mg/day in patients with familial hypercholesterolemia.3 Therefore, this short-term effect to reduce HDL cholesterol probably reverts after a longer period of treatment. Regardless of this change in HDL cholesterol, the LDL/HDL ratio decreased in the atorvastatin group, and did not change in the placebo group, which suggests a favorable balance between atherogenic and antiatherogenic lipoproteins in the bloodstream. In future trials, the variation of plasma lipids in the weeks after the initial therapy should be addressed.
•••
In conclusion, in patients with acute coronary syndromes without ST-segment elevation, we demonstrated the effectiveness of high-dose atorvastatin to reduce LDL cholesterol in 5 days. In addition, the same therapy reduced HDL cholesterol; this last result is of uncertain clinical meaning.
The present study demonstrates for the first time the efficacy of high-dose atorvastatin (80 mg/day) in reducing total and LDL cholesterol during the first 5 days of unstable angina pectoris or non–Q-wave myocardial infarction. The plasma concentration of HDL cholesterol significantly decreased after 5 days of atorvastatin treatment, and this was not observed in the placebo group. The difference between the 2 groups did not reach statistical significance (p ⫽ 0.12), but the paired analysis was more sensitive than the intergroup analysis. It is possible that short-term treatment with atorvastatin promotes a significant reduction in HDL cholesterol. In the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering with atorvastatin study, a nonsignificant decrease in 164 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 90
1. Flegg H. An investigation of the determination of serum cholesterol by an enzymatic method. Ann Clin Biochem 1973:79 –84. 2. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711–1718. 3. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577–581.
JULY 15, 2002
In conclusion, angina pectoris within 1 week of a first AMI is associated with a lower incidence of in-hospital complications in diabetic patients, but it does not preserve LVEF. 1. Kannel W. Lipids, diabetes, and coronary heart disease: insights from the
Framingham study. Am Heart J 1985;110:1110 –1117. 2. Malmberg K, Ryden L. Myocardial infarction in patients with diabetes mel-
litus. Eur Heart J 1988;9:256 –264. 3. Stone PH, Muller JE, Hartwell T, York BJ, Rutheford JD, Parker CB, Turi ZG, Strauss W, Willerson JT, Robertson T, Braunwald E, Jaffe AS, and the MILIS Study Group. The effect of diabetes on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. J Am Coll Cardiol 1989;14:49 –57. 4. Zuanetti G, Latini R, Maggioni AP, Santoro L, Franzosi PG, for the GISSI-2 Investigators. Influence of diabetes on mortality in acute myocardial infarction: data from the GISSI-2 study. J Am Coll Cardiol 1993;22:1788 –1794. 5. Ottani F, Galvani M, Ferrini D, Sorbello F, Limonetti P, Pantoli D, Rusticali F. Prodromal angina limits infarct size: a role for ischemic preconditioning. Circulation 1995;91:291–297. 6. Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S, Gibson M, Poole K, Cannon C, McCabe C, Braunwald E, for the TIMI 4 Investigators. Previous angina alters in-hospital outcome in TIMI 4: a clinical correlate to preconditioning? Circulation 1995;91:37–45. 7. Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K, Kuono Y, Umemura T, Nakamura S, Sato H. Diabetes Mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infacrtion. J Am Coll Cardiol 2000;38:1007–1017. 8. Jime´ nez-Navarro M, Go´ mez-Doblas J, Alonso-Briales J, Herna´ ndez JM, Go´ mez G, Garcia A, Rodriguez-Bailo´ n I, Barrera A, Montiel A, Espinosa JS, De Teresa E. Does angina the week before protect against first myocardial infarction in elderly patients? Am J Cardiol 2001;87:11–15. 9. Zarich SW, Nesto RW. Diabetic cardiomyopathy. Am Heart J 1989;118:1000 – 1012. 10. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124 –1136. 11. Baxter GF, Ferdinand P. Delayed preconditioning of myocardium: current perspectives. Basic Res Cardiol 2001;6:329 –344. 12. Andreotti F, Pasceri V, Hackett DR, Davies GJ, Harder AW, Maseri A. Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infacrtion. N Engl J Med 1996;334:7–12.
Short-Term Effect of Atorvastatin (80 mg) on Plasma Lipids of Patients With Unstable Angina Pectoris or Non–Q-Wave Acute Myocardial Infarction Luis C.L. Correia, MD, Andrei C. Spo´ sito, MD, PhD, Luiz C.S. Passos, MD, PhD, Jose´ C. Lima, MD, Ju´ lio C. Braga, MD, Ma´ rio S. Rocha, MD, J. Pe´ ricles Esteves, MD, and Argemiro D’Oliveira, Jr., MD, PhD t is not known if statin therapy is able to modify the lipid profile positively during the acute phase of Iunstable angina pectoris or non–Q-wave myocardial infarction. Such is the purpose of this report. •••
Patients admitted in the coronary care unit of our hospital due to unstable angina pectoris or non–QFrom the PhD Program, School of Medicine, Federal University of Bahia, Salvador; Cardiology Division, Portuguese Hospital, Salvador; and Heart Institute (InCor), University of Sa˜ o Paulo Medicine School, Sa˜ o Paulo, Brazil. Dr. Correia’s address is: Rua do Taruma˜ 90/ 1002, Salvador-BA-Brasil 41.810-440. E-mail: lucorrei@bahianet. com.br. Manuscript received January 9, 2002; revised manuscript received and accepted March 25, 2002.
162
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 July 15, 2002
wave acute myocardial infarction from December 2000 to September 2001 were considered candidates for the study. Inclusion criteria were defined as onset of chest discomfort in the last 48 hours and 1 of the following objective criteria for evidence of unstable coronary disease: (1) transient ST-segment depression (ⱖ0.5 mm) or T-wave inversion (ⱖ1.0 mm); and (2) positive troponin I (⬎1.0 ng/dl) or troponin T (⬎0.1 ng/dl). Patients were excluded if they presented with left bundle branch block, any liver disease, or had a history of statin intolerance, pregnancy, or lactation. The study was approved by the local ethics committee and all participants provided written informed consent. An initial blood sample to measure plasma lipids was drawn before initiation of therapy. The 0002-9149/02/$–see front matter PII S0002-9149(02)02443-8
TABLE 1 Baseline Characteristics, Lipid Variables, and CReactive Protein Atorvastatin (n ⫽ 28)
Placebo (n ⫽ 28)
Age (yrs) 66 ⫾ 12 64 ⫾ 11 Men 13 (46%) 13 (46%) Diabetes mellitus 7 (25%) 9 (32.1%) Systemic hypertension 21 (75%) 19 (68%) Smokers 1 (4%) 4 (14%) Chronic use of aspirin 14 (50%) 10 (36%) Chronic use of statin 2 (7%) 5 (18%) Positive troponin 14 (50%) 9 (31%) ST-segment depression 10 (36%) 15 (54%) LV systolic dysfunction* 2 (8%) 1 (4%) 3-vessel disease (⬎70%) 4/18 (25%) 5/20 (22%) Total cholesterol (mg/dl) 198 ⫾ 39 205 ⫾ 48 HDL cholesterol (mg/dl) 43 ⫾ 15 40 ⫾ 9 LDL cholesterol (mg/dl) 127 ⫾ 38 132 ⫾ 39 Triglycerides (mg/dl) 151 ⫾ 93 156 ⫾ 60 LDL/HDL ratio 3.15 ⫾ 1.30 3.52 ⫾ 1.29 C-reactive protein (mg/dl) 0.81 ⫾ 0.93 0.77 ⫾ 1.17
p Value 0.62 1.0 0.55 0.55 0.16 0.28 0.23 0.15 0.18 0.68 0.47 0.55 0.30 0.66 0.60 0.31 0.92
*Ejection fraction ⬍55% on echocardiogram. LV ⫽ left ventricular.
enrolled patients were submitted to a randomized, double-blind, placebo-controlled program with either 80 mg atorvastatin or placebo administered once a day. No other type of antilipidemic therapy was offered to the patients. After 5 days of therapy, another blood sample was drawn for comparative analysis. Patients were observed with regard to clinical symptoms suggestive of liver or muscular toxicity; alanine transaminase, gamma-glutamyl transferase, or creatine kinase were measured as clinically indicated. Commercial enzymatic methods were used for determining total cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides (Dimension Clinical Chemistry System, Dade-Behring, Newark, Delaware).1 HDL cholesterol was determined by the same method used for total cholesterol after precipitation of apolipoprotein Bcontaining lipoproteins with magnesium phosphotungstate. Low-density lipoprotein (LDL) cholesterol levels were calculated by Friedewald’s formula. Because of the non-normality of the lipid variable measurements, nonparametric tests were performed. The Wilcoxon rank-sum test was used to compare changes in each variable during the 5-day treatment (intergroup analysis) between the 2 groups. For the paired difference between the first and second measurements of each lipid variable, the Wilcoxon sign-rank test was used (intragroup analysis). Adjustment for confounding variables on drug effects was performed by 2-way analysis of variance. Baseline categorical variables were compared by chi-square or Fisher’s exact test, and baseline continuous variables by unpaired Student’s t test or Wilcoxon rank-sum test. Fifty-six patients (30 women [54%], 26 men [46%], mean age 65 ⫾ 12 years) were enrolled. Twenty-three patients had acute myocardial infarction and 33 had unstable angina pectoris. Half of them were randomized to therapy with atorvastatin and the other half to placebo. Baseline characteristics were not statistically different between the groups, although more
patients had infarction in the atorvastatin group (Table 1). There were no significant differences in medical treatment between groups: all patients took aspirin, 68% in the atorvastatin group took clopidogrel, 82% took low molecular weight heparin, 86% took nitrates, 86% took  blockers, 61% took angiotensin-converting enzyme inhibitors, and 18% took tirofiban. In the placebo group, 64% took clopidogrel (p ⫽ 0.78), 100% took low molecular weight heparin (p ⫽ 0.05), 89% took nitrates (p ⫽ 1.0), 89% took  blockers (p ⫽ 1.0), 46% angiotensin-converting enzyme inhibitors (p ⫽ 0.28), and 11% took tirofiban (p ⫽ 0.70). The time from the beginning of clinical symptoms and blood draw to measuring plasma lipids was 18 ⫾ 13 hours. Eight of the 56 patients (6 in the placebo arm and 2 in the treatment arm) were not in a fasting state at the time of the first determination of plasma lipids. The levels of total cholesterol before treatment, as well as the other lipid fractions, did not differ between the atorvastatin (198 ⫾ 39 mg/dl) and placebo (205 ⫾ 47 mg/dl, p ⫽ 0.55) groups (Table 1). All patients completed treatment and there were no clinical adverse events related to drug therapy. Between the first and second analysis of lipid profile, 4.9 ⫾ 0.6 days elapsed. Significant reductions in total cholesterol (⫺44 ⫾ 20 mg/dl, p ⬍0.001) and LDL cholesterol (⫺37 ⫾ 23 mg/dl, p ⬍0.001) were observed in the atorvastatin group, but not in the placebo group (⫺1.6 ⫾ 35 mg/dl, p ⫽ 0.82; ⫺5.3 ⫾ 34 mg/dl, p ⫽ 0.46, respectively). When these changes in total cholesterol and LDL cholesterol were compared between groups, a significant difference was found (p ⬍0.001 and p ⫽ 0.001, respectively). Because acute myocardial infarction may be a confounding factor because it promotes cholesterol reduction by itself, we tested the influence of the drug on lipid profile, controlling for infarction, which was more prevalent in the atorvastatin arm. After adjustment by analysis of variance, the level of significance of the difference between atorvastatin and placebo was maintained (p ⫽ 0.0004), with no significant interaction between the variables “atorvastatin” and “infarction” (p ⫽ 0.10). Furthermore, when we compared the variation of total cholesterol only in patients with unstable angina, we also found a significant difference between atorvastatin and placebo (⫺30 ⫾ 21 vs ⫺9 ⫾ 35 mg/dl, p ⫽ 0.001, respectively) (Figure 1). With regard to HDL cholesterol, the paired analysis showed a significant reduction in the atorvastatin group (⫺3.7 ⫾ 7.7 mg/dl, p ⫽ 0.012), which was not seen in the placebo group (⫺0.96 ⫾ 6.9 mg/dl, p ⫽ 0.45). When this variation was compared between the groups, the difference did not reach statistical significance (p ⫽ 0.12). Analysis of patients with unstable angina showed a trend toward a decrease in HDL cholesterol in the atorvastatin arm (⫺3.2 ⫾ 7.9 mg/dl, p ⫽ 0.06) as opposed to patients in the placebo arm (⫺0.6 ⫾ 6.7 mg/dl, p ⫽ 0.61), p ⫽ 0.30 for intergroup comparison. The LDL/HDL ratio slightly decreased in the atorvastatin arm (⫺0.3 ⫾ 1.3, p ⬍0.001), which was not observed in the placebo arm (⫹0.3 ⫾ 1.6, p ⫽ 0.90). There was a reduction in triglycerides in the atorvastatin arm (⫺19 ⫾ 70 mg/dl, p ⫽ 0.08), as well as an BRIEF REPORTS
163
FIGURE 1. Variation of lipid profile between the first and fifth day of therapy with atorvastatin or placebo.
elevation in the placebo arm (⫹16 ⫾ 54 mg/dl, p ⫽ 0.34), although these were not statistically significant. The comparison of this variation between the groups showed a trend toward statistical significance (p ⫽ 0.091). After excluding patients who were not fasting at study entry, the findings remained the same: in the atorvastatin arm significant reductions were seen in total cholesterol (⫺44 ⫾ 20 mg/dl, p ⬍0.001), LDL cholesterol (⫺36 ⫾ 23 mg/dl, p ⬍0.001), and HDL cholesterol (⫺4.6 ⫾ 7.2 mg/dl, p ⫽ 0.003), with a nonsignificant reduction in triglycerides (⫺17 ⫾ 72 mg/dl, p ⫽ 0.24). In the placebo arm, there were no significant changes in total cholesterol (⫺3.3 ⫾ 34 mg/dl, p ⬍0.66), LDL cholesterol (⫺11.0 ⫾ 30.8 mg/dl, p ⫽ 0.12), HDL cholesterol (⫺0.3 ⫾ 6.4 mg/dl, p ⫽ 0.95), and triglycerides (⫹21 ⫾ 57 mg/dl, p ⫽ 0.11).
HDL cholesterol measured in the sixth week of therapy was seen, followed by a significant increase in the 16th week.2 Similarly, in the Atorvastatin and Simvastatin on Atherosclerosis Progression (ASAP) trial, a 13% increase in HDL cholesterol levels was equally observed after a 2-year treatment period with either atorvastatin 80 mg/day or simvastatin 40 mg/day in patients with familial hypercholesterolemia.3 Therefore, this short-term effect to reduce HDL cholesterol probably reverts after a longer period of treatment. Regardless of this change in HDL cholesterol, the LDL/HDL ratio decreased in the atorvastatin group, and did not change in the placebo group, which suggests a favorable balance between atherogenic and antiatherogenic lipoproteins in the bloodstream. In future trials, the variation of plasma lipids in the weeks after the initial therapy should be addressed.
•••
In conclusion, in patients with acute coronary syndromes without ST-segment elevation, we demonstrated the effectiveness of high-dose atorvastatin to reduce LDL cholesterol in 5 days. In addition, the same therapy reduced HDL cholesterol; this last result is of uncertain clinical meaning.
The present study demonstrates for the first time the efficacy of high-dose atorvastatin (80 mg/day) in reducing total and LDL cholesterol during the first 5 days of unstable angina pectoris or non–Q-wave myocardial infarction. The plasma concentration of HDL cholesterol significantly decreased after 5 days of atorvastatin treatment, and this was not observed in the placebo group. The difference between the 2 groups did not reach statistical significance (p ⫽ 0.12), but the paired analysis was more sensitive than the intergroup analysis. It is possible that short-term treatment with atorvastatin promotes a significant reduction in HDL cholesterol. In the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering with atorvastatin study, a nonsignificant decrease in 164 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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