HPS - Statins in secondary prevention & patients with diabetes
Bottom-line: In patients with existing CVD or diabetes, statin therapy reduced the risk of death (NNT 56) & all major vascular events (NNT 19) over 5 years.
In this population that initially tolerated simvastatin during a 4-6 week run-in phase & was not taking other lipid-lowering therapy, moderate-dose simvastatin did not increase the risk of cancer, cognitive impairment, liver enzyme abnormalities, myalgias or myopathy.
Patients (n=20,536)
- Included
- Age 40-80 y
- Total cholesterol (non-fasting) 3.5+ mmol/L
- High risk for coronary death based on a past medical history of any of:
- CAD (past ACS, stable angina, CABG or PCI)
- Cerebrovascular disease (non-disabling non-hemorrhagic stroke, TIA, carotid endarterectomy)
- PAD (intermittent claudication)
- Other arterial surgery or angioplasty
- Diabetes (type 1 or 2)
- None of the above, but >65 y/o male with treated HTN
- Excluded
- Statin "clearly indicated"
- Severe HF
- Chronic liver disease (cirrhosis, hepatitis or ALT >1.5x ULN)
- Creatinine >200 umol/L
- Muscle disease (inflammatory muscle disease or CK >3x ULN)
- Concurrent treatment with cyclosporine, fibrates or high-dose niacin
- 63,603 screened -> 32,145 entered run-in -> 20,536 randomized -> 20,469 analyzed
- "Typical" study patient
- Age >64 y 46%
- Female 25%
- PMHx
- MI 41%
- Other CAD 24%
- No coronary hx 35%
- Cerebrovascular disease 9%
- PAD 13%
- Diabetes 19%
- HTN as only inclusion criterion 1%
- Lipids: Total cholesterol 5.9 mmol/L, LDL 3.4 mmol/L, apoB 1.14 g/L
- Meds (CAD subgroup)
- ASA 63% (77%)
- ACEI 20% (10%)
- Beta-blocker 26% (23%)
Interventions
- I: Simvastatin 40 mg PO once daily
- Adherence to >80% of doses: 89% @ 1 y, 82% @ 5 y
- C: Matching placebo
- Open-label statin use: 4% @ 1 y, 32% @ 5 y
Results @ mean 5 years
- LDL
- @ baseline: 3.4 mmol/L
- Difference: -1.3 mmol/L @ 1 y, -0.7 mmol/L @ 5 y
- Death: Simvastatin 12.9%, placebo 14.7% (hazard ratio 0.87, 0.81-0.94), NNT 56
- Major vascular event (components below): 19.8% vs 25.2% (HR 0.76, 0.72-0.81), NNT 19
- Non-fatal MI or coronary death: 8.7% vs 11.8%
- Stroke: 4.3% vs 5.7%
- Coronary revascularization: 5.0% vs 7.1%
- Non-coronary revascularization: 4.4% vs 5.2%
- Adverse effects
- Cancer: 7.9% vs 7.8%
- Cognitive impairment: 23.7% vs 24.2%
- ALT >4x ULN: 0.4% vs 0.3%
- Unexplained muscle pain/weakness reported at least once: 32.9% vs 33.2%
- CK
- 4-10x ULN: 0.2% vs 0.1%
- >10x ULN: 0.11% vs 0.06%
- Subgroup analyses demonstrated consistent relative risk reduction in major vascular event across different high-risk inclusion criteria, so absolute benefit dependent on baseline risk. 5-year risk in placebo group (NNT with statin) in relevant subgroups:
- CAD only: 22.5% (NNT 16)
- No CAD
- Cerebrovascular disease: 23.6% (NNT 18)
- PAD: 30.5% (NNT 14)
- Diabetes: 18.6 (NNT 23)
Generalizability
- Represents a wide spectrum of patients with existing vascular disease or diabetes with poor use of other secondary CV prevention interventions, particularly in the CAD subgroup
- Run-in phase: Placebo x4 weeks, then simvastatin 40 mg/d x4-6 weeks
- To ensure long-term adherence + "responsiveness" to LDL lowering
- 36% who entered run-in did not undergo randomization, mostly due to unwillingness or inability to adhere for a planned 5 years
- Therefore, represents a population that did not have intolerable adverse events after a month of statin therapy
Internal validity
Low risk of allocation, performance, detection & attrition bias
Central telephone randomization
Patients, clinicians, adjudicators unaware of treatment allocation
Loss-to-follow-up <0.5%
Intention-to-treat analysis
High risk of contamination bias
By year 5, 32% of patients in placebo group were receiving an open-label statin
This acts as a conservative bias, as it attenuates the apparent benefit of statin therapy