- Email: [email protected]
Effects of atorvastatin 80 mg daily early after onset of unstable angina pectoris or non–Q-wave myocardial infarction
Effects of Atorvastatin 80 mg Daily Early After Onset of Unstable Angina Pectoris or Non–Q-Wave Myocardial Infarction Furio Colivicchi, MD, Vincenzo Guido, MD, Marco Tubaro, MD, Fabrizio Ammirati, Nicola Montefoschi, MD, Antonio Varveri, MD, and Massimo Santini, MD his clinical investigation was designed and undertaken to test the hypothesis that the addition of T high-dose atorvastatin (80 mg/day) to conventional medical treatment early after either unstable angina pectoris (UAP) or non–Q-wave acute myocardial infarction (AMI) could reduce ischemic recurrences. •••
All patients consecutively admitted to our institution between January 1999 and July 2001 for UAP or non–Q-wave AMI were prospectively screened for inclusion in the study. In all cases the diagnosis of UAP or non–Q-wave AMI was made in accordance with previously reported criteria.1 To be enrolled in the trial, patients were required to meet the following criteria: (1) angiographic evidence of severe and diffuse coronary artery disease, that was not amenable to direct revascularization by coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, as determined by a cardiac surgeon and an interventional cardiologist during the index admission; (2) objective evidence of symptomatic reversible myocardial ischemia (ⱖ0.1 mV ST-segment depression on the electrocardiogram) at a low exercise workload (⬍4 METs) while receiving medical treatment (ⱖ2 antianginal medications at maximal tolerated doses), as assessed by treadmill ergometry (Bruce’s protocol) before discharge; and (3) left ventricular ejection fraction ⬎35%. Exclusion criteria were the presence of congestive heart failure, the need for continuous use of intravenous antianginal medications, and the presence of any major concurrent illness. The study was planned as an open-label, prospective, randomized, controlled trial with parallel groups. Before enrollment, all patients were receiving maximal conventional combination therapy (nitrates, calcium antagonists, and  blockers), including ⱖ2 medications at maximal tolerated doses in all cases. All patients provided informed consent to take part in the investigation. At discharge from the hospital, included patients were assigned to 1 of the 2 study arms according to a computer-generated randomization list: (1) Control group (conventional medical treatment)—all patients randomized to this arm were discharged on the maximal tolerated combination therapy, which was begun From the Division of Cardiology, S. Filippo Neri Hospital, Rome, Italy. Dr. Colivicchi’s address is: Dott. Furio Colivicchi, Dipartimento per le Malattie Cardiovascolari, Ospedale “S. Filippo Neri,” Viale Gorgia da Leontini 330, 00124 Rome, Italy. E-mail: [email protected]. Manuscript received March 29, 2002; revised manuscript received and accepted June 9, 2002.
872
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 October 15, 2002
MD,
during index admission. Whenever necessary during the study, the dosage of each medication could be modified to match clinical needs. Furthermore, to implement optimal care, adherence to the National Cholesterol Education Program guidelines was followed.2 In particular, all of these patients had to be treated to attain low-density lipoprotein (LDL) cholesterol levels ⬍100 mg/dl. For patients requiring statin treatment to reach the LDL cholesterol goal during the study, atorvastatin was started at the initial dosage of 20 mg/day. All patients already receiving other statins or any other lipid-lowering drug before inclusion were allowed to continue their treatment after randomization, but the dosage was titrated to reach LDL cholesterol levels ⬍100 mg/dl. (2) Conventional medical treatment plus atorvastatin 80 mg/day—maximal combination therapy was continued in all control subjects. Atorvastatin in the fixed dose of 80 mg/day was added to medical treatment at discharge and no other lipid-lowering treatment was allowed. Compliance with atorvastatin therapy was assessed by pill counting. Patients who withdrew because of intolerable side effects, adverse reactions, lack of adequate response to treatment, or any other reason were taken as complete cases for the intention-to-treat analysis. Clinical monitoring for ischemic events for 12 months after randomization was planned. A clinical follow-up visit, including physical examination and a 12-lead electrocardiogram, was programmed on a 2-month basis. Blood chemistry for serum lipid levels was performed 2, 6, and 12 months from randomization. The primary combined end point of the study was cardiac death, nonfatal AMI, or recurrent symptomatic myocardial ischemia with objective evidence (electrocardiographic, echocardiographic, or scintigraphic) requiring emergency hospitalization during the follow-up period. Secondary end points were the occurrence of any of the primary end point components. All end points were independently adjudicated by 2 cardiologists blinded to treatment assignment. For all included patients, formal study participation ended if any primary end point component occurred. The primary analysis of all outcomes was by intention-to-treat analysis. Moreover, an on-treatment analysis of the primary end point was also performed. Recurrence of ischemic events in the 2 treatment groups was tested using the odds ratio of the 2-binomial proportion analysis. The cumulative risk of recurrence of ischemic events within each group was estimated by means of the Kaplan-Meier method. Sur0002-9149/02/$–see front matter PII S0002-9149(02)02711-X
vival curves of the 2 different treatment groups were then formally compared using the log-rank test. Mean ⫾ SD was calculated for continuous variables, and frequencies were measured for categorical variables. Differences between groups were analyzed by unpaired Student’s t test for continuous variables and the chi-square test for categorical variables; a p value ⬍0.05 was considered significant. Sample size calculation was based on an expected 70%/year recurrence rate of ischemic events in the conventional medical treatment arm, and on an expected 50%/year recurrence rate in the atorvastatin arm. Consequently, with an ␣ level of 0.05 and a test power of 0.80, the resulting sample size was 46 patients for each treatment group. According to the study protocol, an interim analysis of safety and efficacy was planned every 6 months during the study. Enrollment was begun in January 1999, and the fifth formal interim analysis was performed on August 31, 2001. By that time, 81 patients had been enrolled and follow-up data were available in all cases. The interim analysis showed a significant effect in favor of atorvastatin compared with conventional medical treatment (p ⫽ 0.025). Consequently, a decision was made to terminate enrollment and follow-up. The study results were then reported as of September 10, 2001. During the recruitment period, 4,186 potentially eligible patients were initially screened. Among these patients, 81 (2%; 34 women and 47 men, mean age 69 ⫾ 12 years) met all inclusion and exclusion criteria, provided informed consent, and were randomized to 1 of 2 treatment groups. Forty-one patients were assigned to conventional medical treatment, whereas 40 patients were assigned to receive atorvastatin in addition to their pharmacologic therapy. The mean time from hospital admission to discharge and randomization was 12 ⫾ 4 days. All patients were followed up for ⱖ60 days after randomization. No patient was lost during the follow-up period. During follow-up, 1 patient in the atorvastatin arm was not assessable by on-treatment analysis because he discontinued atorvastatin treatment owing to intolerable side effects. Thus, the on-treatment analysis was performed in a total of 80 patients. The baseline characteristics of the 2 groups were similar and are listed in Table 1. In the intention-to-treat analysis, a primary end point event occurred in 19 of 41 patients (46%; 4 deaths, 7 nonfatal AMI, and 8 emergency admissions for symptomatic myocardial ischemia) in the conventional treatment arm, and in 9 of 40 patients (22%; 3 deaths, 4 nonfatal AMI, and 2 emergency admissions for symptomatic myocardial ischemia) in the atorvastatin arm. The difference was found to be significant (odds ratio 0.33, 95% confidence interval 0.12 to 0.88, p ⫽ 0.025), and similar results were found in the on-treatment analysis (odds ratio 0.29, 95% confidence interval 0.13 to 0.80, p ⫽ 0.015). The KaplanMeier actuarial estimates of a first recurrence of ischemic events after randomization in the intention-totreat analysis are shown in Figure 1. There were no significant differences in the occurrence of each primary end point component between the 2 study arms.
TABLE 1 Baseline Characteristics of Study Groups Variable Age (yrs) Women Diabetes mellitus Systemic hypertension Previous myocardial infarction Left ventricular ejection fraction Three-vessel CAD Previous coronary bypass Previous coronary angioplasty Previous bypass or angioplasty Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl)
Control Group Atorvastatin Group (n ⫽ 41) (n ⫽ 40) 68 ⫾ 14 17 (41%) 24 (58%) 37 (90%) 35 (85%) 48 (11) 40 (97%) 26 (63.4%) 16 (39%) 36 (88%) 219 ⫾ 39 129 ⫾ 28 39 ⫾ 10 165 ⫾ 39
69 ⫾ 14 17 (42%) 22 (55%) 35 (87%) 34 (85%) 49 (12) 40 (100%) 24 (60.0%) 17 (42%) 33 (82%) 221 ⫾ 41 131 ⫾ 27 40 ⫾ 12 169 ⫾ 42
Values are expressed as mean ⫾ SD or number (%). CAD ⫽ coronary artery disease; HDL ⫽ high-density lipoprotein.
FIGURE 1. Kaplan-Meier estimates of probability of remaining free of ischemic recurrences in 41 patients in the conventional treatment arm and in 40 patients in the atorvastatin arm in the intention-to-treat analysis.
Serum lipid levels at randomization were similar in the 2 groups (Table 1). During follow-up, LDL cholesterol levels decreased in both groups, but were constantly lower in the atorvastatin arm (Figure 2). In the control group, 34 of 41 patients (83%) received various statins, whereas 4 of 41 patients (10%) were treated with fibrates. In particular, 12 of 41 patients (29%) received atorvastatin (mean dosage 18 ⫾ 4 mg/day), 14 of 41 patients (34%) received simvastatin (mean dosage 19 ⫾ 2 mg/day), and 8 of 41 patients (19%) received pravastatin (mean dosage 37 ⫾ 7 mg/day). However, despite treatment with lipid-lowering drugs, in 6 of 41 patients included in the conventional treatment arm (15%; 2 taking atorvastatin, 2 taking simvastatin, 1 taking pravastatin, and 1 taking fibrates), LDL cholesterol levels exceeded 100 mg/dl in ⱖ1 of the controls during the study. Similar antianginal and antiplatelet pharmacologic treatment was administrated to patients included in the 2 study arms during both the index admission and the follow-up period (Table 2). In 1 patient, atorvastatin was withdrawn after 2 months of treatment, following the appearance of persistent muscle pain associated with a significant inBRIEF REPORTS
873
FIGURE 2. Low-density lipoprotein cholesterol (LDL-C) levels during the study in the conventional treatment arm and in the atorvastatin arm. *p <0.0001.
TABLE 2 Medications in Study Groups Variable
Control Group Atorvastatin Group (n ⫽ 41) (n ⫽ 40)
During index admission Aspirin Ticlopidine Heparin Glycoprotein IIb/IIIa inhibitors Nitrates  blockers Calcium antagonists ACE inhibitors Statins Fibrates
39 (95%) 4 (10%) 40 (97%) 17 (41%) 41 (100%) 36 (88%) 23 (56%) 33 (80%) 23 (56%) 2 (5%)
38 (95%) 5 (12%) 40 (100%) 14 (35%) 40 (100%) 35 (87%) 24 (60%) 31 (77%) 21 (52%) 3 (7%)
At follow-up Aspirin Ticlopidine Nitrates  blockers Calcium antagonists ACE inhibitors Trimedazidine
38 (93%) 3 (7%) 41 (100%) 37 (90%) 29 (71%) 34 (83%) 14 (34%)
38 (95%) 2 (5%) 40 (100%) 36 (90%) 28 (70%) 33 (82%) 13 (32%)
ACE ⫽ angiotensin-converting enzyme.
crease in total serum creatine kinase (2 times the upper limit of normal). Both muscle pain and biochemical abnormalities resolved after discontinuation of the drug. No other major adverse effects were noted during the trial. •••
To the best of our knowledge, this is the first clinical trial aimed at assessing the effects of aggressive lipid-lowering treatment in a specific subset of patients with end-stage coronary artery disease. In this
874 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 90
high-risk population, the addition of atorvastatin 80 mg/day to conventional medical therapy significantly reduced the incidence of ischemic events over a 12month period after an acute coronary syndrome. In particular, a 24% absolute reduction in the primary combined end point (cardiac death, nonfatal AMI, or recurrent myocardial ischemia requiring emergency hospitalization) was noted. Treatment of approximately 4 patients was required to prevent 1 cardiac ischemic recurrence. Notably, aggressive lipid-lowering therapy was already associated with a lower incidence of the primary combined end point within 4 weeks of treatment. Statistical significance was reached after 6 weeks of therapy, while the actuarial curves describing event-free survival continued to diverge up to the eighth month of the study. Thus, as in a previous report,3 but different from secondary prevention trials,4,5 reduction in cardiovascular events could be documented in a relatively short time from the index admission for an acute coronary syndrome. This result seems noteworthy given the high shortterm cardiac morbidity after an acute ischemic event in patients with end-stage coronary artery disease.6 In conclusion, this trial provides evidence that adding early, aggressive, lipid-lowering treatment in addition to optimal combination therapy significantly reduces cardiac ischemic recurrences after an acute coronary syndrome in patients with endstage coronary artery disease. In our opinion, this result is clinically relevant, because the number of such high-risk patients is expected to further increase in the near future. 1. Maynard SJ, Scott GO, Riddell JW, Adgey AAJ. Management of acute coronary syndromes. Br Med J 2000;321:220 –223. 2. National Cholesterol Education Program. Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). Circulation 1994;890:1329 –1346. 3. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study: a randomized controlled trial. JAMA 2001;285:1711–1718. 4. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 5. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 6. Schoebel FC, Jax TW, Heintzen MP, Strauer BE, Leschke M, Frazier OH, Kadipasaoglu KA, Cooley DA, Jessurun GAJ, De Jongste MJL. Refractory angina pectoris in end-stage coronary artery disease: evolving therapeutic concepts. Am Heart J 1997;134:587–602.
OCTOBER 15, 2002
All patients consecutively admitted to our institution between January 1999 and July 2001 for UAP or non–Q-wave AMI were prospectively screened for inclusion in the study. In all cases the diagnosis of UAP or non–Q-wave AMI was made in accordance with previously reported criteria.1 To be enrolled in the trial, patients were required to meet the following criteria: (1) angiographic evidence of severe and diffuse coronary artery disease, that was not amenable to direct revascularization by coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, as determined by a cardiac surgeon and an interventional cardiologist during the index admission; (2) objective evidence of symptomatic reversible myocardial ischemia (ⱖ0.1 mV ST-segment depression on the electrocardiogram) at a low exercise workload (⬍4 METs) while receiving medical treatment (ⱖ2 antianginal medications at maximal tolerated doses), as assessed by treadmill ergometry (Bruce’s protocol) before discharge; and (3) left ventricular ejection fraction ⬎35%. Exclusion criteria were the presence of congestive heart failure, the need for continuous use of intravenous antianginal medications, and the presence of any major concurrent illness. The study was planned as an open-label, prospective, randomized, controlled trial with parallel groups. Before enrollment, all patients were receiving maximal conventional combination therapy (nitrates, calcium antagonists, and  blockers), including ⱖ2 medications at maximal tolerated doses in all cases. All patients provided informed consent to take part in the investigation. At discharge from the hospital, included patients were assigned to 1 of the 2 study arms according to a computer-generated randomization list: (1) Control group (conventional medical treatment)—all patients randomized to this arm were discharged on the maximal tolerated combination therapy, which was begun From the Division of Cardiology, S. Filippo Neri Hospital, Rome, Italy. Dr. Colivicchi’s address is: Dott. Furio Colivicchi, Dipartimento per le Malattie Cardiovascolari, Ospedale “S. Filippo Neri,” Viale Gorgia da Leontini 330, 00124 Rome, Italy. E-mail: [email protected]. Manuscript received March 29, 2002; revised manuscript received and accepted June 9, 2002.
872
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 October 15, 2002
MD,
during index admission. Whenever necessary during the study, the dosage of each medication could be modified to match clinical needs. Furthermore, to implement optimal care, adherence to the National Cholesterol Education Program guidelines was followed.2 In particular, all of these patients had to be treated to attain low-density lipoprotein (LDL) cholesterol levels ⬍100 mg/dl. For patients requiring statin treatment to reach the LDL cholesterol goal during the study, atorvastatin was started at the initial dosage of 20 mg/day. All patients already receiving other statins or any other lipid-lowering drug before inclusion were allowed to continue their treatment after randomization, but the dosage was titrated to reach LDL cholesterol levels ⬍100 mg/dl. (2) Conventional medical treatment plus atorvastatin 80 mg/day—maximal combination therapy was continued in all control subjects. Atorvastatin in the fixed dose of 80 mg/day was added to medical treatment at discharge and no other lipid-lowering treatment was allowed. Compliance with atorvastatin therapy was assessed by pill counting. Patients who withdrew because of intolerable side effects, adverse reactions, lack of adequate response to treatment, or any other reason were taken as complete cases for the intention-to-treat analysis. Clinical monitoring for ischemic events for 12 months after randomization was planned. A clinical follow-up visit, including physical examination and a 12-lead electrocardiogram, was programmed on a 2-month basis. Blood chemistry for serum lipid levels was performed 2, 6, and 12 months from randomization. The primary combined end point of the study was cardiac death, nonfatal AMI, or recurrent symptomatic myocardial ischemia with objective evidence (electrocardiographic, echocardiographic, or scintigraphic) requiring emergency hospitalization during the follow-up period. Secondary end points were the occurrence of any of the primary end point components. All end points were independently adjudicated by 2 cardiologists blinded to treatment assignment. For all included patients, formal study participation ended if any primary end point component occurred. The primary analysis of all outcomes was by intention-to-treat analysis. Moreover, an on-treatment analysis of the primary end point was also performed. Recurrence of ischemic events in the 2 treatment groups was tested using the odds ratio of the 2-binomial proportion analysis. The cumulative risk of recurrence of ischemic events within each group was estimated by means of the Kaplan-Meier method. Sur0002-9149/02/$–see front matter PII S0002-9149(02)02711-X
vival curves of the 2 different treatment groups were then formally compared using the log-rank test. Mean ⫾ SD was calculated for continuous variables, and frequencies were measured for categorical variables. Differences between groups were analyzed by unpaired Student’s t test for continuous variables and the chi-square test for categorical variables; a p value ⬍0.05 was considered significant. Sample size calculation was based on an expected 70%/year recurrence rate of ischemic events in the conventional medical treatment arm, and on an expected 50%/year recurrence rate in the atorvastatin arm. Consequently, with an ␣ level of 0.05 and a test power of 0.80, the resulting sample size was 46 patients for each treatment group. According to the study protocol, an interim analysis of safety and efficacy was planned every 6 months during the study. Enrollment was begun in January 1999, and the fifth formal interim analysis was performed on August 31, 2001. By that time, 81 patients had been enrolled and follow-up data were available in all cases. The interim analysis showed a significant effect in favor of atorvastatin compared with conventional medical treatment (p ⫽ 0.025). Consequently, a decision was made to terminate enrollment and follow-up. The study results were then reported as of September 10, 2001. During the recruitment period, 4,186 potentially eligible patients were initially screened. Among these patients, 81 (2%; 34 women and 47 men, mean age 69 ⫾ 12 years) met all inclusion and exclusion criteria, provided informed consent, and were randomized to 1 of 2 treatment groups. Forty-one patients were assigned to conventional medical treatment, whereas 40 patients were assigned to receive atorvastatin in addition to their pharmacologic therapy. The mean time from hospital admission to discharge and randomization was 12 ⫾ 4 days. All patients were followed up for ⱖ60 days after randomization. No patient was lost during the follow-up period. During follow-up, 1 patient in the atorvastatin arm was not assessable by on-treatment analysis because he discontinued atorvastatin treatment owing to intolerable side effects. Thus, the on-treatment analysis was performed in a total of 80 patients. The baseline characteristics of the 2 groups were similar and are listed in Table 1. In the intention-to-treat analysis, a primary end point event occurred in 19 of 41 patients (46%; 4 deaths, 7 nonfatal AMI, and 8 emergency admissions for symptomatic myocardial ischemia) in the conventional treatment arm, and in 9 of 40 patients (22%; 3 deaths, 4 nonfatal AMI, and 2 emergency admissions for symptomatic myocardial ischemia) in the atorvastatin arm. The difference was found to be significant (odds ratio 0.33, 95% confidence interval 0.12 to 0.88, p ⫽ 0.025), and similar results were found in the on-treatment analysis (odds ratio 0.29, 95% confidence interval 0.13 to 0.80, p ⫽ 0.015). The KaplanMeier actuarial estimates of a first recurrence of ischemic events after randomization in the intention-totreat analysis are shown in Figure 1. There were no significant differences in the occurrence of each primary end point component between the 2 study arms.
TABLE 1 Baseline Characteristics of Study Groups Variable Age (yrs) Women Diabetes mellitus Systemic hypertension Previous myocardial infarction Left ventricular ejection fraction Three-vessel CAD Previous coronary bypass Previous coronary angioplasty Previous bypass or angioplasty Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl)
Control Group Atorvastatin Group (n ⫽ 41) (n ⫽ 40) 68 ⫾ 14 17 (41%) 24 (58%) 37 (90%) 35 (85%) 48 (11) 40 (97%) 26 (63.4%) 16 (39%) 36 (88%) 219 ⫾ 39 129 ⫾ 28 39 ⫾ 10 165 ⫾ 39
69 ⫾ 14 17 (42%) 22 (55%) 35 (87%) 34 (85%) 49 (12) 40 (100%) 24 (60.0%) 17 (42%) 33 (82%) 221 ⫾ 41 131 ⫾ 27 40 ⫾ 12 169 ⫾ 42
Values are expressed as mean ⫾ SD or number (%). CAD ⫽ coronary artery disease; HDL ⫽ high-density lipoprotein.
FIGURE 1. Kaplan-Meier estimates of probability of remaining free of ischemic recurrences in 41 patients in the conventional treatment arm and in 40 patients in the atorvastatin arm in the intention-to-treat analysis.
Serum lipid levels at randomization were similar in the 2 groups (Table 1). During follow-up, LDL cholesterol levels decreased in both groups, but were constantly lower in the atorvastatin arm (Figure 2). In the control group, 34 of 41 patients (83%) received various statins, whereas 4 of 41 patients (10%) were treated with fibrates. In particular, 12 of 41 patients (29%) received atorvastatin (mean dosage 18 ⫾ 4 mg/day), 14 of 41 patients (34%) received simvastatin (mean dosage 19 ⫾ 2 mg/day), and 8 of 41 patients (19%) received pravastatin (mean dosage 37 ⫾ 7 mg/day). However, despite treatment with lipid-lowering drugs, in 6 of 41 patients included in the conventional treatment arm (15%; 2 taking atorvastatin, 2 taking simvastatin, 1 taking pravastatin, and 1 taking fibrates), LDL cholesterol levels exceeded 100 mg/dl in ⱖ1 of the controls during the study. Similar antianginal and antiplatelet pharmacologic treatment was administrated to patients included in the 2 study arms during both the index admission and the follow-up period (Table 2). In 1 patient, atorvastatin was withdrawn after 2 months of treatment, following the appearance of persistent muscle pain associated with a significant inBRIEF REPORTS
873
FIGURE 2. Low-density lipoprotein cholesterol (LDL-C) levels during the study in the conventional treatment arm and in the atorvastatin arm. *p <0.0001.
TABLE 2 Medications in Study Groups Variable
Control Group Atorvastatin Group (n ⫽ 41) (n ⫽ 40)
During index admission Aspirin Ticlopidine Heparin Glycoprotein IIb/IIIa inhibitors Nitrates  blockers Calcium antagonists ACE inhibitors Statins Fibrates
39 (95%) 4 (10%) 40 (97%) 17 (41%) 41 (100%) 36 (88%) 23 (56%) 33 (80%) 23 (56%) 2 (5%)
38 (95%) 5 (12%) 40 (100%) 14 (35%) 40 (100%) 35 (87%) 24 (60%) 31 (77%) 21 (52%) 3 (7%)
At follow-up Aspirin Ticlopidine Nitrates  blockers Calcium antagonists ACE inhibitors Trimedazidine
38 (93%) 3 (7%) 41 (100%) 37 (90%) 29 (71%) 34 (83%) 14 (34%)
38 (95%) 2 (5%) 40 (100%) 36 (90%) 28 (70%) 33 (82%) 13 (32%)
ACE ⫽ angiotensin-converting enzyme.
crease in total serum creatine kinase (2 times the upper limit of normal). Both muscle pain and biochemical abnormalities resolved after discontinuation of the drug. No other major adverse effects were noted during the trial. •••
To the best of our knowledge, this is the first clinical trial aimed at assessing the effects of aggressive lipid-lowering treatment in a specific subset of patients with end-stage coronary artery disease. In this
874 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 90
high-risk population, the addition of atorvastatin 80 mg/day to conventional medical therapy significantly reduced the incidence of ischemic events over a 12month period after an acute coronary syndrome. In particular, a 24% absolute reduction in the primary combined end point (cardiac death, nonfatal AMI, or recurrent myocardial ischemia requiring emergency hospitalization) was noted. Treatment of approximately 4 patients was required to prevent 1 cardiac ischemic recurrence. Notably, aggressive lipid-lowering therapy was already associated with a lower incidence of the primary combined end point within 4 weeks of treatment. Statistical significance was reached after 6 weeks of therapy, while the actuarial curves describing event-free survival continued to diverge up to the eighth month of the study. Thus, as in a previous report,3 but different from secondary prevention trials,4,5 reduction in cardiovascular events could be documented in a relatively short time from the index admission for an acute coronary syndrome. This result seems noteworthy given the high shortterm cardiac morbidity after an acute ischemic event in patients with end-stage coronary artery disease.6 In conclusion, this trial provides evidence that adding early, aggressive, lipid-lowering treatment in addition to optimal combination therapy significantly reduces cardiac ischemic recurrences after an acute coronary syndrome in patients with endstage coronary artery disease. In our opinion, this result is clinically relevant, because the number of such high-risk patients is expected to further increase in the near future. 1. Maynard SJ, Scott GO, Riddell JW, Adgey AAJ. Management of acute coronary syndromes. Br Med J 2000;321:220 –223. 2. National Cholesterol Education Program. Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). Circulation 1994;890:1329 –1346. 3. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study: a randomized controlled trial. JAMA 2001;285:1711–1718. 4. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 5. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 6. Schoebel FC, Jax TW, Heintzen MP, Strauer BE, Leschke M, Frazier OH, Kadipasaoglu KA, Cooley DA, Jessurun GAJ, De Jongste MJL. Refractory angina pectoris in end-stage coronary artery disease: evolving therapeutic concepts. Am Heart J 1997;134:587–602.
OCTOBER 15, 2002