What drugs, dosages, patient population, and results were reported in the PROVE‑IT TIMI‑22 trial evaluating intensive low‑density lipoprotein cholesterol lowering in adults (average age mid‑60s) hospitalized for acute coronary syndrome (unstable angina, non‑ST‑elevation myocardial infarction, or ST‑elevation myocardial infarction) within 10 days?

PROVE IT-TIMI 22 Study: Key Details and Clinical Significance

The PROVE IT-TIMI 22 trial demonstrated that intensive LDL-cholesterol lowering with atorvastatin 80 mg daily is superior to standard therapy with pravastatin 40 mg daily in reducing cardiovascular events after acute coronary syndrome, achieving a 16% relative risk reduction in the composite primary endpoint over 2 years. 1

Study Design and Population

Patient Population:

• 4,162 men and women aged >18 years hospitalized for acute coronary syndrome (ACS) within the preceding 10 days 1, 2
• ACS included unstable angina, non-ST-elevation myocardial infarction, or ST-elevation myocardial infarction 1
• 2,986 patients were statin-naïve at enrollment 3
• 2,868 patients underwent percutaneous coronary intervention (PCI) for ACS just prior to enrollment 4

Study Duration:

• Mean follow-up time was 24 months (2 years) 1
• Benefit of intensive treatment was apparent as early as 30 days and remained consistent over time 2

Drug Regimens and Dosages

Intensive Therapy Arm:

• Atorvastatin 80 mg daily 1, 2
• Achieved median LDL-C of 62 mg/dL (1.6 mmol/L) during follow-up 2
• Produced 51% LDL-C reduction at 30 days 2

Standard Therapy Arm:

• Pravastatin 40 mg daily 1, 2
• Achieved median LDL-C of 95 mg/dL (2.5 mmol/L) during follow-up 2
• Produced 22% LDL-C reduction at 30 days 2

LDL-C Difference:

• The difference in achieved LDL-C between groups was 33 mg/dL (35%) 1

Primary Results and Outcomes

Primary Composite Endpoint (death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization performed ≥30 days after randomization, and stroke):

• 16% relative risk reduction with atorvastatin 80 mg versus pravastatin 40 mg (95% CI: 5%-26%; P=0.005) 1, 2
• Absolute event rates: 21.5% with atorvastatin versus 26.5% with pravastatin 4
• Hazard ratio: 0.78 (95% CI: 0.67-0.91, P=0.002) 4

Total Cardiovascular Events (including recurrent events):

• Atorvastatin 80 mg reduced both first events (464 vs. 537) and subsequent events (275 vs. 340) 5
• Overall, 138 fewer primary efficacy events occurred with atorvastatin (739 vs. 877 total events) 5
• Rate ratio: 0.85 (95% CI: 0.77-0.94, P=0.001) 5

Mortality Trends:

• Nonsignificant trend toward reduction in total mortality (P=0.07) 1
• Nonsignificant trend for death or myocardial infarction (P=0.06) 1

Revascularization Outcomes:

• Target vessel revascularization: 11.4% with atorvastatin versus 15.4% with pravastatin (P=0.001) 4
• Non-target vessel revascularization: 8.0% with atorvastatin versus 10.5% with pravastatin (P=0.017) 4

Safety Profile

Tolerability:

• High-dose atorvastatin 80 mg was well tolerated 1
• No cases of severe myopathy (rhabdomyolysis) observed in either treatment group 1

Liver Enzyme Elevations:

• Alanine aminotransferase elevations >3-fold upper limit of normal: 3.3% with atorvastatin versus 1.1% with pravastatin (P=0.003) 1

Discontinuation Rates:

• 30% of patients discontinued therapy over the course of follow-up 1

• Only 5.3% discontinued atorvastatin due to laboratory abnormalities or side effects; remainder stopped due to patient or physician preference 1

Very Low LDL-C Safety:

• Among patients achieving LDL-C <40 mg/dL (11% of atorvastatin-treated patients), there were no significant differences in safety parameters including muscle abnormalities, liver abnormalities, retinal abnormalities, intracranial hemorrhage, or death 6
• Patients with LDL-C <40 mg/dL and 40-60 mg/dL actually had fewer major cardiac events compared to those achieving 80-100 mg/dL 6

Baseline LDL-C and Treatment Benefit

Relationship Between Baseline LDL-C and Benefit:

• The benefit of intensive therapy was strongly dependent on baseline LDL-C levels 3
• Patients in the highest quartile (baseline LDL-C >132 mg/dL) experienced significant reductions in both primary (HR: 0.63, P=0.002) and secondary (HR: 0.57, P=0.001) endpoints 3
• The benefit progressively declined as baseline LDL-C decreased 3
• Patients in the lowest quartile (baseline LDL-C ≤92 mg/dL) experienced similar event rates with both treatments (primary endpoint HR: 0.93, P=0.63) 3
• Atorvastatin 80 mg was associated with improved outcomes only when baseline LDL-C was >66 mg/dL 3

Important Caveat:

• 72% of patients had baseline LDL-C levels <125 mg/dL, and in this large subgroup, the modest trend toward benefit of atorvastatin over pravastatin was not statistically significant 1

Clinical Implications and Guideline Impact

Guideline Recommendations Based on PROVE IT:

• Intensive therapy should be considered for all patients admitted to the hospital for acute coronary syndromes 1
• PROVE IT makes a strong case for achieving an optional LDL-C goal of <70 mg/dL in ACS patients 1
• Choice of drug and dosage should be guided by measurement of LDL-C within 24 hours of hospital admission 1

Treatment Algorithm for ACS Patients:

• If baseline in-hospital LDL-C is relatively low, an LDL-C <70 mg/dL may be achieved with standard-dose statin 1
• If baseline LDL-C is higher, high-dose statin or combination therapy (standard-dose statin plus ezetimibe, bile acid sequestrant, or nicotinic acid) may be required 1
• Consideration should be given to both safety and efficacy for the individual patient 1

Broader Context:

• PROVE IT greatly strengthened evidence for benefit of intensive LDL lowering in the first 2 years after acute coronary syndromes 1
• The results suggest that more intensive LDL-C-lowering therapy reduces major cardiovascular events in ACS patients compared with less intensive therapy 1
• The data indicate that patients recently hospitalized for ACS benefit from early and continued lowering of LDL cholesterol to levels substantially below previous guideline recommendations 2