LIPID

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LIPID study group writers. "Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group". The New England Journal of Medicine. 1998. 339(19):1349-1357.
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Clinical Question

In patients with hypercholestrolemia and previous MI or unstable angina, does pravastatin reduce mortality from CAD, as compared to placebo?

Bottom Line

In patients with hypercholestrolemia and previous MI or unstable angina, pravastatin significantly reduced mortality from CAD, as compared to placebo. Pravastatin

Major Points

Hypercholestrolemia is a known risk factor for CAD.[1][2] The Scandinavian Simvastatin Survival Study (4S) reported that a 3.3% absolute risk reduction in all-cause mortality with simvastatin as compared to placebo (11.5% vs. 8.2%; P=0.0003; NNT 30).[3] The WOSCOPS trial reported that pravastatin significantly prevented CV events (RR 0.69; 95% CI 0.57-0.83; P<0.001) in men with hyperlipidemia and no prior MI.[4]

The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial investigated the effects of pravastatin on the primary outcome- mortality from coronary artery disease (CAD) as compared to placebo. The trial randomized 9,014 patients to pravastatin or placebo. Pravastatin treatment significantly reduced the risk of mortality from CAD (relative risk reduction 24%, 95%CI 12-35%; P< 0.001) and all-cause mortality (relative risk reduction 22%, 95%CI 13-31%; P< 0.001). Pravastatin is safe, and did not increase the risk of ALT elevation or myopathy significantly.

The 4S, WOSCOPS, HPS and TNT trials on lipid-lowering with statin were included in a meta-analysis which concluded that intensive LDL-C lowering with statins is safe[3][4][5][6] . Reduction of LDL-C by 1·0 mmol/L is associated with a reduction of major vascular events risk by 20% approximately without any evidence of a threshold level.[7]

Guidelines

ACC/AHA Cholesterol Guidelines (2013, adapted)[8]

  • Secondary prevention with high-intensity statin therapy for patients ≤75 years in age with clinical ASCVD (i.e. stable CAD) unless contraindicated (grade A, class I, level A)
  • Moderate-intensity therapy for above group if contraindication to high-intensity statin therapy or risk for statin-associated adverse events (grade A, class I, level A)
  • For patients ≥75 years with clinical ASCVD, evaluate risks and benefits when initiating high- or moderate-intensity statin therapy (grade E, class IIa, level B)
  • Definition of intensity of statin therapy as:
    • High-intensity (LDL reduction ≥50%): Atorvastatin 40-80 mg, rosuvastatin 20-40 mg
    • Moderate-intensity (LDL reduction 30 to less than 50%): Atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg, lovastatin 40 mg, fluvastatin XL 80 mg, fluvastatin 40 mg BID, pitavastatin 2-4 mg
    • Lower-intensity (LDL reduction <30%): Simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg, fluvastatin 20-40 mg, pitavastatin 1 mg

Design

  • Multicenter, randomized, double-blind, placebo-controlled trial
  • N=9,014
    • Placebo (n=4,502)
    • Pravastatin (n=4,512)
  • Setting: 87 centers in Australia and New Zealand
  • Enrollment: 1990-1992
  • Median follow-up: 6.1 years
  • Analysis: intention-to-treat
  • Primary outcome: All-cause mortality

Population

Inclusion Criteria

Described elsewhere[9]

  • age 35-70 years
  • total cholesterol 155-271 mg/dl (4.0-7.0 mmol/L)
  • fasting triglyceride<445 mg/dl (5.0 mmol/L)
  • MI or unstable angina between 3-36 months prior to study

Exclusion Criteria

  • congestive heart failure, renal or hepatic disease
  • current use of any cholesterol-lowering agent
  • clinically significant medical or surgical event within 3 months prior to study entry

Baseline Characteristics

From the pravastatin group.

  • Demographics: Male 83%, median age 62 (55-67) years
  • Lipid levels: LDL-C 150 (130-170) mg/dl, HDL 36 (31-41)mg/dl, triglyceride 142 (104-196) mg/dl, total cholesterol 218 (196-241) mg/dl
  • Qualifying event: MI 64%; unstable angina 36%
  • Eligibility diagnosis: Angina 21%, infarction 63%, both 16%
  • Time since qualifying event to randomization: 1.1 (0.6-2.1) years
  • Other PMH: HTN 41%, claudication 10%, DM 9%, current smoker 9% (former 65%); obesity (BMI>30) 18%, stroke 4%, TIA 3%
  • PSH: CABG 27%, PTCA 11%, CABG and PTCA 3%
  • Medications: aspirin 83%, beta blocker 46%, calcium-channel blocker 35%, ACE-i 16%; insulin 1%, oral antihyperglycemic agents 5%

Interventions

  • Potentially were given dietary advice aimed at reducing fat intake to <30% of total intake during an 8-week long single-blind placebo run-in phase
  • Plasma total cholesterol level was measured 4 weeks before randomization to determine eligibility, the inclusion criteria was:
    • total cholesterol 155-271 mg/dl (4.0-7.0 mmol/L)
    • fasting triglyceride<445 mg/dl (5.0 mmol/L)
  • Patients were randomized to pravastatin 40 mg once daily or placebo
  • Follow-up laboratory monitoring with centrally-controlled dose adjustments to 40 mg or 10 mg when lipids went out of range

Outcomes

Comparisons as placebo vs. pravastatin

Primary Outcome

Mortality from CAD
6.4% vs. 8.3% (relative risk reduction [RRR] 24%; 95% CI 12-35%; P<0.001)

Secondary Outcome

All-cause mortailty
11% vs. 14.1% (RRR 22%; 95% CI 13-31%; P<0.001)
Mortality from cardiovascular disease (CVD)
7.3% vs. 9.6% (RRR 25%; 95% CI 13-35%; P<0.001)
Mortality from CAD or non-fatal MI
12.3% vs. 15.9% (RRR 24%; 95% CI 15-32%; P<0.001)
MI
7.4% vs. 10.3% (RRR 29%; 95% CI 18-38%; P<0.001)
CABG
9.2% vs. 11.6% (RRR 22%; 95% CI 11-31%; P<0.001)
PTCA
4.7% vs. 5.6% (RRR 19%; 95% CI 3-33%; P=0.024)
CABG or PTCA
13% vs. 15.7% (RRR 20%; 95% CI 10-28%; P<0.001)
Any stroke
3.7% vs. 4.5% (RRR 19%; 95% CI 0-34%; P=0.048)
Change in lipid levels
Total cholesterol: reduction of 39 mg/dl (1 mmol/l) from 218 mg/dl (5.6 mmol/l), 18% greater reduction than placebo (P<0.001)
LDL-C: 25% greater reduction from baseline than placebo (P<0.001)
HDL-C: 5% greater increase from baseline than placebo (P<0.001)
Triglyceride: 11% greater reduction from baseline than placebo (P<0.001)
Hospitalization for unstable angina
22.3% vs. 24.6% (RRR 12%; 95% CI 4-19%; P=0.005)
Time in hospital
2.9 days less/patient as compared to placebo (P<0.001)
10% less time/admission (P=0.002)

Additional Analyses

Cessation of study medication or placebo
19% of patients discontinued pravastatin by end of study
24% in placebo group started cholesterol-lowering drug by end of study

Subgroup Analysis

No heterogeneity of treatment effect of pravastatin for the pre-specified subgroups

Adverse Events

Attributed to study medication
3.2% vs. 2.7% (P=0.16)

ALT elevation to >3x ULN

2 .1% vs. 1.9% (P=0.41)

Myopathy

8 vs. 10 cases (P=NS)

Malignancy

403 vs. 417 cases (P=0.43)
Breast: 10 vs. 10 cases (P=NS)

Criticisms

  • Study patients may have a lower CV risk than the patients with MI or unstable angina in general.
  • By the end of study, 19% in the pravastatin group discontinued the medication whereas 24% in placebo group started cholesterol-lowering drug.
  • Patients were recruited at least 3 months after the qualifying event, therefore it is not possible to determine the effects of pravastatin early after an ACS.

Funding

  • Bristol-Myers Squibb Pharmaceutical Research Institute
  • The National Heart Foundation of Australia

Further Reading

  1. Kannel WB et al. "Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study." Annals of Internal Medicine. 1961;55(1):33-50.
  2. Yusuf. S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364(9438):937-52
  3. 3.0 3.1 Pedersen TR, et al. "Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)". The Lancet. 1994. 344(8934):1383-1389.
  4. 4.0 4.1 Shepherd J, et al. "Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia". The New England Journal of Medicine. 1995. 333(20):1301-1308.
  5. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22.
  6. LaRosa JC, et al. "Intensive lipid lowering with atorvastatin in patients with stable coronary disease". The New England Journal of Medicine. 2005. 352(14):1425-1435
  7. Baigent C et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010. 376:1670-81.
  8. Stone NJ et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2014. 63:2889-934.
  9. Design features and baseline characteristics of the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) Study: a randomized trial in patients with previous acute myocardial infarction and/or unstable angina pectoris. Am J Cardiol. 1995;76(7):474-9.