Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project.
BACKGROUND
Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety data.


RESULTS
The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively accumulated >112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin (40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With >243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline sampling was similar (>3x the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%] patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo.


CONCLUSIONS
This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated, with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic decisions regarding this pharmacological agent.
Pfeffer
Marc A
MA
Brigham and Women's Hospital, Boston, MA 02115, USA. mpfeffer@rics.bwh.harvard.edu
Keech
Anthony
A
Sacks
Frank M
FM
Cobbe
Stuart M
SM
Tonkin
Andrew
A
Byington
Robert P
RP
Davis
Barry R
BR
Friedman
Carola P
CP
Braunwald
Eugene
E
D000368:Aged; D000924:Anticholesteremic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000453:epidemiology; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000453:epidemiology / Q000517:prevention & control; D056486:Chemical and Drug Induced Liver Injury; D015331:Cohort Studies; D015897:Comorbidity; D003710:Demography; D004311:Double-Blind Method; D005260:Female; D005767:Gastrointestinal Diseases / Q000453:epidemiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy; D015994:Incidence; D008107:Liver Diseases / Q000201:enzymology / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009135:Muscular Diseases / Q000453:epidemiology; D017035:Pravastatin / Q000009:adverse effects* / Q000627:therapeutic use; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D051437:Renal Insufficiency / Q000453:epidemiology; D012306:Risk; D018570:Risk Assessment; D013995:Time
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin