Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z trial

James A de Lemos, Michael A. Blazing, Stephen D. Wiviott, Eldrin F. Lewis, Keith A A Fox, Harvey D. White, Jean Lucien Rouleau, Terje R. Pedersen, Laura H. Gardner, Robin Mukherjee, Karen E. Ramsey, Joanne Palmisano, David W. Bilheimer, Marc A. Pfeffer, Robert M. Califf, Eugene Braunwald

Research output: Contribution to journalArticle

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Abstract

Context: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. Objective: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. Design, Setting, and Participants: International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n=2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n=2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. Main Outcome Measure: The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke. Follow-up was for at least 6 months and up to 24 months. Results Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95% confidence interval [Cl] 0.76-1.04; P=.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1 %) patients in the 2 groups (HR, 0.75; 95% Cl, 0.57-1.00; P = .05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95% Cl, 0.83-1.25; P=.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR, 0.75; 95% Cl, 0.60-0.95; P=.02). Myopathy (creatine kinase > 10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P=.02). Conclusions: The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.

Original languageEnglish (US)
Pages (from-to)1307-1316
Number of pages10
JournalJournal of the American Medical Association
Volume292
Issue number11
DOIs
StatePublished - Sep 15 2004

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Simvastatin
Acute Coronary Syndrome
Placebos
Hydroxymethylglutaryl-CoA Reductase Inhibitors
LDL Cholesterol
Muscular Diseases
Creatine Kinase

ASJC Scopus subject areas

  • Medicine(all)

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Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes : Phase Z of the A to Z trial. / de Lemos, James A; Blazing, Michael A.; Wiviott, Stephen D.; Lewis, Eldrin F.; Fox, Keith A A; White, Harvey D.; Rouleau, Jean Lucien; Pedersen, Terje R.; Gardner, Laura H.; Mukherjee, Robin; Ramsey, Karen E.; Palmisano, Joanne; Bilheimer, David W.; Pfeffer, Marc A.; Califf, Robert M.; Braunwald, Eugene.

In: Journal of the American Medical Association, Vol. 292, No. 11, 15.09.2004, p. 1307-1316.

Research output: Contribution to journalArticle

de Lemos, JA, Blazing, MA, Wiviott, SD, Lewis, EF, Fox, KAA, White, HD, Rouleau, JL, Pedersen, TR, Gardner, LH, Mukherjee, R, Ramsey, KE, Palmisano, J, Bilheimer, DW, Pfeffer, MA, Califf, RM & Braunwald, E 2004, 'Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z trial', Journal of the American Medical Association, vol. 292, no. 11, pp. 1307-1316. https://doi.org/10.1001/jama.292.11.1307
de Lemos, James A ; Blazing, Michael A. ; Wiviott, Stephen D. ; Lewis, Eldrin F. ; Fox, Keith A A ; White, Harvey D. ; Rouleau, Jean Lucien ; Pedersen, Terje R. ; Gardner, Laura H. ; Mukherjee, Robin ; Ramsey, Karen E. ; Palmisano, Joanne ; Bilheimer, David W. ; Pfeffer, Marc A. ; Califf, Robert M. ; Braunwald, Eugene. / Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes : Phase Z of the A to Z trial. In: Journal of the American Medical Association. 2004 ; Vol. 292, No. 11. pp. 1307-1316.
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abstract = "Context: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. Objective: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. Design, Setting, and Participants: International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n=2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n=2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. Main Outcome Measure: The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke. Follow-up was for at least 6 months and up to 24 months. Results Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7{\%}) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4{\%}) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95{\%} confidence interval [Cl] 0.76-1.04; P=.14). Cardiovascular death occurred in 109 (5.4{\%}) and 83 (4.1 {\%}) patients in the 2 groups (HR, 0.75; 95{\%} Cl, 0.57-1.00; P = .05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95{\%} Cl, 0.83-1.25; P=.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR, 0.75; 95{\%} Cl, 0.60-0.95; P=.02). Myopathy (creatine kinase > 10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4{\%}) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P=.02). Conclusions: The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.",
author = "{de Lemos}, {James A} and Blazing, {Michael A.} and Wiviott, {Stephen D.} and Lewis, {Eldrin F.} and Fox, {Keith A A} and White, {Harvey D.} and Rouleau, {Jean Lucien} and Pedersen, {Terje R.} and Gardner, {Laura H.} and Robin Mukherjee and Ramsey, {Karen E.} and Joanne Palmisano and Bilheimer, {David W.} and Pfeffer, {Marc A.} and Califf, {Robert M.} and Eugene Braunwald",
year = "2004",
month = "9",
day = "15",
doi = "10.1001/jama.292.11.1307",
language = "English (US)",
volume = "292",
pages = "1307--1316",
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TY - JOUR

T1 - Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes

T2 - Phase Z of the A to Z trial

AU - de Lemos, James A

AU - Blazing, Michael A.

AU - Wiviott, Stephen D.

AU - Lewis, Eldrin F.

AU - Fox, Keith A A

AU - White, Harvey D.

AU - Rouleau, Jean Lucien

AU - Pedersen, Terje R.

AU - Gardner, Laura H.

AU - Mukherjee, Robin

AU - Ramsey, Karen E.

AU - Palmisano, Joanne

AU - Bilheimer, David W.

AU - Pfeffer, Marc A.

AU - Califf, Robert M.

AU - Braunwald, Eugene

PY - 2004/9/15

Y1 - 2004/9/15

N2 - Context: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. Objective: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. Design, Setting, and Participants: International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n=2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n=2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. Main Outcome Measure: The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke. Follow-up was for at least 6 months and up to 24 months. Results Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95% confidence interval [Cl] 0.76-1.04; P=.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1 %) patients in the 2 groups (HR, 0.75; 95% Cl, 0.57-1.00; P = .05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95% Cl, 0.83-1.25; P=.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR, 0.75; 95% Cl, 0.60-0.95; P=.02). Myopathy (creatine kinase > 10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P=.02). Conclusions: The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.

AB - Context: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. Objective: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. Design, Setting, and Participants: International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n=2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n=2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. Main Outcome Measure: The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke. Follow-up was for at least 6 months and up to 24 months. Results Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95% confidence interval [Cl] 0.76-1.04; P=.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1 %) patients in the 2 groups (HR, 0.75; 95% Cl, 0.57-1.00; P = .05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95% Cl, 0.83-1.25; P=.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR, 0.75; 95% Cl, 0.60-0.95; P=.02). Myopathy (creatine kinase > 10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P=.02). Conclusions: The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.

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