What were the drug, dosage, patient population, and main outcomes of the Heart Protection Study (HPS) regarding intermediate‑density lipoprotein (IDL) management?

Heart Protection Study (HPS): Drug, Dosage, Population, and Results

Study Design and Drug Regimen

The Heart Protection Study used simvastatin 40 mg daily versus placebo in a randomized, double-blind trial lasting a mean of 5 years. 1, 2, 3

• The study enrolled 20,536 adults aged 40-80 years in the United Kingdom 1, 2, 3
• Participants were randomized to receive either simvastatin 40 mg once daily or matching placebo 1, 2, 3
• Mean follow-up duration was 5 years (range 5-5.5 years) 1, 2, 3

Patient Population Characteristics

HPS specifically recruited high-risk patients who had been excluded from previous statin trials, including those with baseline cholesterol levels considered "normal" by prior standards. 1, 3

Inclusion Criteria:

• Adults aged 40-80 years with high cardiovascular risk 1, 2
• Coronary disease, other occlusive arterial disease, or diabetes mellitus 1, 2
• Peripheral arterial disease (6,748 participants) 2
• Minimum total cholesterol ≥3.5 mmol/L (135 mg/dL) at entry 3

Baseline Lipid Levels (measured on non-fasting samples):

• Average total cholesterol: 228 mg/dL 1
• Average triglycerides: 186 mg/dL (non-fasting) 1
• Average HDL cholesterol: 41 mg/dL 1
• Average direct LDL cholesterol: 131 mg/dL 1
• Calculated fasting LDL cholesterol: approximately 150-155 mg/dL 1

Critical Population Subgroups:

• 42% had baseline LDL ≤213 mg/dL (5.5 mmol/L) 1
• Approximately one-third had baseline LDL <116 mg/dL 1
• 5,963 participants had diabetes mellitus 1
• Women and elderly patients (>75 years) were specifically included 1, 3
• 2,912 diabetic patients without diagnosed coronary or other occlusive arterial disease at entry 1

Lipid-Lowering Effects

Simvastatin 40 mg daily achieved an average LDL cholesterol reduction of 1.0 mmol/L (39 mg/dL) compared to placebo. 2

• This represents approximately a 25-30% reduction in LDL cholesterol from baseline 1
• The lipid difference was maintained throughout the 5-year study period 2

Primary and Secondary Outcomes

All-Cause Mortality:

Simvastatin reduced all-cause mortality by 13% (P=0.0003), representing a 12% reduction in total mortality overall. 1, 3

Major Vascular Events:

The primary composite endpoint of major vascular events (myocardial infarction, coronary death, stroke, or revascularization) was reduced by 24%. 1, 3

• Coronary death rate reduced by 18% 1
• Vascular mortality reduced by 17% 3
• Nonfatal myocardial infarction plus coronary death reduced by 27% 1
• All strokes reduced by 27% 3
• Non-coronary revascularizations reduced by 16% 3

Peripheral Vascular Events:

Among all participants, simvastatin reduced first peripheral vascular event by 16% (5-25% relative reduction). 2

• Non-coronary revascularization procedures reduced by 20% (8-31% relative reduction) 2
• Among participants with peripheral arterial disease specifically, major vascular events reduced by 22% (15-29%) 2
• Absolute reduction: 63 per 1000 patients with PAD and 50 per 1000 without pre-existing PAD 2

Critical Subgroup Analyses

Low Baseline LDL Cholesterol:

Benefits were consistent regardless of baseline LDL cholesterol, including in patients with LDL <100 mg/dL at baseline. 1, 4

• Similar relative risk reductions observed in subgroups with initial LDL <135 mg/dL, <116 mg/dL, or <100 mg/dL 1
• Among 2,426 diabetic participants with baseline LDL <116 mg/dL, event rates were 27% lower on simvastatin 1
• This finding challenged the prevailing paradigm that only patients with elevated cholesterol benefit from statin therapy 4

Diabetes Mellitus Subgroup:

Among 5,963 individuals with diabetes, simvastatin reduced first-event rates by approximately 25% for major coronary events, strokes, and revascularizations. 1

• Event reductions were similar to those in non-diabetic patients 1
• In 2,912 diabetic patients without diagnosed vascular disease at entry, simvastatin reduced risk by approximately one-third 1
• In diabetic patients without vascular disease and LDL <116 mg/dL, a marginally significant 30% risk reduction was observed 1

Age and Gender:

Benefits were consistent in women, patients >75 years old, and all other prespecified subgroups. 1, 3

• The study provided definitive evidence for statin benefit in elderly patients and women, populations previously underrepresented in trials 3, 5

Safety Profile

No significant adverse effects of simvastatin therapy were reported over 5 years. 1

• No significant increase in myopathy 1
• No increase in cancer incidence 1
• No increase in hospitalization for any other non-vascular cause 1
• The study provided reassurance that aggressive statin therapy is safe 4

Study Compliance Considerations

Approximately two-thirds of participants complied with the original intention-to-treat design throughout the study. 3

• Patients and doctors were permitted to add non-study statins if desired during the 5.5-year period 3
• Despite this dilution of treatment effect, results remained highly significant 3

Implications for IDL Management

While HPS did not specifically measure intermediate-density lipoprotein (IDL), the study's methodology has important implications for understanding lipid particle measurement. 1

• Baseline LDL was measured by direct method (131 mg/dL average) 1
• If calculated by Friedewald equation (which includes IDL in the LDL fraction), baseline LDL would have been approximately 150-155 mg/dL 1
• This 15% difference between direct and calculated LDL reflects the inclusion of IDL cholesterol in the calculated LDL fraction 1
• The consistent benefit across all cholesterol levels suggests that lowering apoB-containing particles (including IDL) provides cardiovascular benefit regardless of baseline levels 1, 4

Paradigm Shift from HPS

HPS fundamentally changed lipid management by demonstrating that cardiovascular risk, not baseline cholesterol level, should determine treatment decisions. 4, 5

• The study showed no threshold cholesterol value below which statin therapy lacks benefit in high-risk patients 3, 4
• Benefits were observed even in patients with pre-treatment cholesterol below national recommended targets 3
• The emphasis shifted from treating cholesterol numbers to treating cardiovascular risk 5
• HPS findings suggest the optimal LDL cholesterol level is well below previously established target levels 4