A tale of two trials: a comparison of the post-acute coronary syndrome lipid-lowering trials A to Z and PROVE IT-TIMI 22.
BACKGROUND
The Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trials compared intensive and moderate statin therapy after acute coronary syndromes, with seemingly disparate results. We analyzed the design, implementation, and results of the two trials in an attempt to clarify the effects of early intensive statin therapy.


RESULTS
Study design, end points, and definitions were compared. In each trial, comparisons were made between intensive and moderate arms for both trials' primary end points and death/myocardial infarction. Analyses were performed over various time points: at the end of the trials, < or =4 months, and >4 months. Subjects in A to Z had higher-risk demographics. More PROVE IT subjects were enrolled in the United States and underwent prerandomization revascularization. The low-density lipoprotein (LDL) difference was greater in A to Z than in PROVE IT early (< or =4 months) but less late. Significant C-reactive protein reduction was earlier in PROVE IT. With common end points, event rates were higher in A to Z, and early favorable separation of event curves was seen in PROVE IT but not in A to Z. Clinical end point rates and reductions were similar in both trials after 4 months.


CONCLUSIONS
An early benefit was seen in PROVE IT but not in A to Z. Late-phase results were similar. Factors that may explain this disparity include the intensity of therapy in the early phase, timing, and magnitude of LDL and C-reactive protein lowering, differences in early revascularization, and the play of chance. Taken together, the results of these trials support a strategy of early intensive statin therapy coupled with revascularization when appropriate in patients after acute coronary syndrome.
The TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. swiviott@partners.org
Stephen D
SD
Wiviott
James A
JA
de Lemos
Christopher P
CP
Cannon
Michael
M
Blazing
Sabina A
SA
Murphy
Carolyn H
CH
McCabe
Robert
R
Califf
Eugene
E
Braunwald
D000368:Aged; D000789:Angina, Unstable / Q000453:epidemiology; D000069059:Atorvastatin; D002097:C-Reactive Protein / Q000032:analysis; D002318:Cardiovascular Diseases / Q000401:mortality; D019090:Case Management; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D015897:Comorbidity; D015986:Confounding Factors, Epidemiologic; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015993:Life Tables; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009203:Myocardial Infarction / Q000453:epidemiology; D017202:Myocardial Ischemia / Q000097:blood / Q000188:drug therapy* / Q000628:therapy; D009204:Myocardial Revascularization / Q000706:statistics & numerical data; D017035:Pravastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012107:Research Design; D012306:Risk; D012307:Risk Factors; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020521:Stroke / Q000453:epidemiology; D000077466:Tirofiban; D016896:Treatment Outcome; D014443:Tyrosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011758:Pyrroles; D014443:Tyrosine; D002097:C-Reactive Protein; D000069059:Atorvastatin; D019821:Simvastatin; D000077466:Tirofiban; D017035:Pravastatin