Intensive versus Moderate Lipid Lowering with Statins

after Acute Coronary Syndromes (PROVE-IT)

Cannon CP, Braunwald E, McCabe CH, et al. The New England

Journal of Medicine. 2004 Apr 8; 350 (15): 1495-504.

Name withheld
 Acute Coronary Syndrome (ACS)
Category of Coronary Heart Diseases (CHD)
– Unstable Angina
– Non-ST segment elevation MI (NSTEMI)
– ST segment elevation MI (STEMI)

Common feature: acute myocardial ischemia

due to mismatch between myocardial
oxygen demand & supply.
 Definitions
Unstable Angina (UA): chest pain, discomfort, or burning
sensation that is accelerating in frequency or severity without
myocardial damage.

STEMI: ACS with cardiac marker evidence of myocardial

necrosis (e.g., positive CK-MB) and new (or presumably new if
no prior ECG is available) ST-segment elevation on the
admission ECG.

NSTEMI: ACS in which there is cardiac marker evidence of

myocardial necrosis (e.g., positive CK-MB or troponin)
without new ST-segment elevation
 Precipitating Event

Thrombus
Clotting
cascade
Platelet
aggregation

Plaque
rupture
 Pathogenic Factors
• Lifelong atherosclerosis
• Systemic Inflammation
• Endothelial dysfunction
• Atherosclerotic plaque formation
 Epidemiology
• Higher incidence in males < 70 years
• Estrogen provides protective effect for women
• Prevalence (2009)  16, 800, 000 million
– Myocardial Infarction  7, 900,000 million
– Angina pectoris  9,800, 000 million
• Estimated direct & indirect costs: $165.4 billion

– Heart Disease & Stroke Statistics– 2009 Update

 Morbidity & Mortality
5.6 million annual ER visits due to chest pain

1.5 ACS events

220,000 deaths due to MI

Prognosis
• STEMI: greater for patients treated with
reperfusion therapy (fibrinolytics, PCI) than
those not receiving such therapy.

• Higher mortality: females and elderly

 Morbidity & Mortality
5.6 million annual ER visits due to chest pain

1.5 ACS events

220,000 deaths due to MI

Prognosis
• STEMI: greater for patients treated with
reperfusion therapy (fibrinolytics, PCI) than
those not receiving such therapy.

• Higher mortality: females and elderly

 Goals of Therapy
• Establish and maintain optimal myocardial
perfusion.
• Minimize or prevent symptoms of ischemia.
• Prevent secondary acute event
Pravastatin or Atorvastatin Evaluation and Infection
Therapy—Thrombolysis in Myocardial Infarction 22
(PROVE-IT TIMI 22)

Cannon CP, Braunwald E, McCabe CH, et al. The New England

Journal of Medicine. 2004 Apr 8; 350 (15): 1495-1504.
 Journal and Authors
• The New England Journal of Medicine
– Established 1812, peer-reviewed
• Christopher Cannon, MD (514)
– PLATO, REACH
• Eugene Braunwald, MD (220)
– IMPROVE-IT, TRITON-TIMI 38
• Carolyn McCabe, MD (75)
– TRITON-TIMI 38, MERLIN, CLARITY XX
 Purpose of Study & Objectives
• The role of statins in risk reduction of death &
cardiovascular events has been firmly established
along a spectrum cholesterol levels in patients with
& without a history of coronary artery disease.
• ATP III recommends LDL target of < 100 mg/dL
for established CHD or diabetes.
• Does intensified therapy reduce risk of cornary
events and improve survival?
• Does lower equate to better” or does intensive
statin therapy reach a point of diminishing
returns?
 Objectives, cont

Establishing sound, research-based answers

to this and other related questions is an
essential step in developing evidence-
based therapies in the clinical setting.

Desired outcome= decreased events of

secondary infarction and death
 Background Literature
I. Scandinavian Simvastatin Survival Study (1994): Long-term
statin therapy is safe and improves survival.
II. CARE Trial (1996): demonstrated reduced risk of coronary events
in CHD patients with “average” TC < 240 mg/dL.
III. LIPID Study (1998): statin therapy mortality from CHD and overall
mortality were decreased; significant impact on use of statins in
CHD patients.
IV. MRC/BHF Heart Protection Study (2002); UK study; statin
therapy shown to reduce risk of primary & secondary event in
high-risk patients in context with other treatment modalities.
V. Air Force/Texas Coronary Atherosclerosis Prevention Study
(1998) reported beneficial effects of statin therapy on “healthy”
subjects average to TC & LDL and below average HDL. Called for
re-evaluation of pharmacologic guidelines
 Methods: Study Population
• Multi-center, 8 countries
– 4,126 patients enrolled, randomized
– 349 sites within 8 countries
– Approved by relevant institutional review boards
– Written, informed consent obtained from all
patients
• TIMI Study Group, Cardiovascular Division
– Brigham and Women’s Hospital; Boston, MA
 Methods: Inclusion Criteria
• Men or women, minimum of 18 years
• Hospitalization for acute coronary syndrome (ACS)
within past 10 days: STEMI, NSTEMI, UA
• Stable at enrollment--if percutaneous revasculature
procedure was planned, enrollment eligible only
afterwards.
• Total Cholesterol  240 mg/dL
– Measured at “local hospital” within first 24-hours
after onset of ACS
– Up to 6 months earlier if no sample within 24 hours
• Patients receiving “long-term” lipid therapy at the time
of event required total cholesterol of  200 mg/dL at the
time of “screening” at local hospital
 Methods: Exclusion Criteria
• Coexisting condition that shortened life expectancy to < 2 years.
• Any statin therapy at dose of 80 mg per day at time of index event
• Therapy with fibric acid derivatives or niacin that could not be discontinued
before randomization.
• Receipt of “strong” CYP 3A4 inhibitor within the month before
randomization or expected to require treatment during study period.
• Recipient of PIC within previous 6 months other than the ACS event that
qualified them for study .
• Recipient of CABG within previous 2 months or scheduled in response to
index event.
• Factors that prolong QT interval
• Obstructive hepatobiliary disease
• Unexpected increase in serum creatine kinase more than 3X UL
independent of MI
• Serum creatinine > 2.0 mg/dL
 Methods: Study Protocol

• Double-blind, double-dummy
• “Standard medical and interventional treatment”--
ASA 75 to 325 mg daily with or without clopidogrel or
warfarin.
• Patients not permitted to be treated with any other
lipid-modifying drug other than study drug.
• Blood samples obtained at randomization
 N = 4162

40 mg 1:1 ratio 80 mg
pravastatin atorvastatin
daily daily

Follow up: 18 to 24 months

 Protocol: Follow-up
• “Dietary counseling”: 30 days, 4 months, and every 4
months until final visit
• Lab samples: 30 days, 4, 8, 12, 16 months and final
visit
– Lipids
– Safety parameters
• Attrition accountability: patients discontinuing the
study drug were followed by telephone.
• Duration of follow-up: 18 to 36 months (avg. 24 mos.)
• Termination point: 925 reported events
 Protocol: Titration
• Pravastatin dose blindly increased to 80 mg if
LDL exceeded 125 mg/dL on two consecutive
visits.
• Pravastatin or atorvastatin dose could be
halved in the event of abnormal LFTs, elevated
CK, or reported myalgias
 Endpoints
Primary Endpoint (Composite) Secondary Endpoint
Time from randomization until • Risk of death from CHD
first occurrence of: • Risk of nonfatal myocardial
• Death from any cause; infarction
• Myocardial infarction; • Risk of revascularization
• Documented unstable angina within 30 days of
requiring hospitalization; randomization
• Revascularization (CABG or • Risk of individual
PIC) within 30 days of components of primary
randomization; endpoint
• Stroke
 Goal of Study
Establish the “noninferiority” of standard dosing
of pravastatin to intensive dosing of
atorvastatin in terms of time from
randomization to primary end-point event.
 H0 : μ C ≥ μ E H1: χC < χE

μC μE
Control: Experimental
Pravastatin Atorvastatin
40 mg daily 80 mg daily
 Statistical Analysis
• Efficacy Analysis: analysis of two-year event rate.
• Cox Proportional-Hazards Model: hazard ratio with
corresponding 95% CI
• Pre-specified boundary for non-inferiority:
– UL of the one-tailed 95% CI of relative risk = 1.17
– Hazard ratio throughout follow-up: 1.198
• Restricted randomization: Permuted-Block
– Guarantees balanced between groups throughout
duration of study
• Kaplan-Meier: tracking of occurrence of primary
endpoint
 Power (1-)
Assumptions:
• Two-year event of atorvastatin: 22%
• Equal efficacy of treatment between groups
Enrollment: 2000 subjects per group
Statistical power: 87%
Efficacy Analysis: Intention to Treat
• Kaplan-Meier Curve: estimate at 24 months
– Advantage: estimates survival rate over time, accounting
for drop-outs & differences in follow-up time among
patients
• Two-by-two factorial design
– Detect potential interactions between statin &
gatifloxacin treatment
• Assessment of superiority: two-tailed
confidence interval
 Execution of Study
• Study design: investigators will full access to
data
• Data coordination: Nottingham Clinical
Research Group
• Joint data Analysis:
– TIMI investigators
– Sponsor
– Nottingham Clinical Research Group
 Results
• Well balanced baseline parameters between
treatment groups.
– Exception: peripheral arterial disease (PAD) more common
in pravastatin treatment group (P= 0.03).
• Selected baseline values
– Age: 58 years
– Proportion women: 22%
– Prior MI: 18%
– Prior statin therapy: ~25%
– DM: ~17%
– Median LDL value: 106 mg/dL
 Concomitant Medication Administration
% Concomitant Use

ARB

ACE

Beta-blocker

Plavix

Warfarin

ASA

0% 100%
Pravastatin 40 mg

106 to 95 mg/dL
Atorvastatin 80 mg

106 to 62%
 Results: Follow-up Data
Pravastatin Atorvastatin

Naïve statin use (30 d)* 22% decrease (mdn) 51% decrease

Previous statin use (30d)* unchanged 32%

HDL* 8.1% increase 6.5% increase

C-reactive protein (mg/L)* 12.3 to 2.1 mg/dL 12.3 to 1.3 mg/dL

* P < 0.001
Kaplan Meier Risk Assessment

2- yr
estimate

Pravastatin:
26.3%

Atorvastatin:
22.4%
 End-points: Advantage of Atorvastatin

Primary Endpoint Secondary Endpoint

2-year event rate: 22.4% 2-year event rate: 19.7 to
to 26.3% 22.3%
• 16% RRR. • 25% RRR

• P < 0.001
• P = 0.005

• 95% CI: 5-26%

 Significant Advantages of Atorvastatin Regarding End-
points
• 14% reduction in need for revascularization (P = 0.04)
• 29% reduction in risk in recurrent unstable angina (P =
0.02)
• Advantage of atorvastatin found among subgroups
– Men & women
– Unstable angina
– Past MI
– With & without DM
– Minimal baseline LDL cholesterol ≥ 125 mg/dL
Non-inferiority of pravastatin was not established
 Primary End-point: NNT

• 16% RR
• Absolute Risk Reduction (ARR): 3.9%
• NNT = 100/ARR
– 100/3.9 = 25.6
26 people needed to be treated with
intensive therapy atorvastatin to prevent
1 death
 Author’s Conclusion
While outcome favored an intensive statin regimen in
high risk patients, this does not discredit the efficacy
of standard dosing.

Other factors besides LDL cholesterol level that

contribute to reduced risk cannot be ruled cannot be
ruled out.

The effect of statins upon non-HDL cholesterol levels &

subsequent risk reduction warrants further study.
 Safety & Adverse Effects
Pravastatin D/C Atorvastatin D/C
• 1-yr: 21.4% (P=0.30) • 1-yr: 22.8% (P = 0.30)
• 2-yr: 33.0 % (P = .11) • 2-yr: 30.4% (P = 0.11)
D/C by investigator
ALT x3 > UL
• Pravastatin: 2.7%
• Pravastatin: 1.1%
Atorvastatin • Atorvastatin: Pravastatin
dose 3.3% dose
• Atorvastatin:
• (P = 0.23) 3.3%
adjustments adjustments
(P < 0.001)
•
• 1.9% (side effects & •
• Increase (80 mg): 8%
abn. LFTS) • Halved dose: 1.4%
(P = 0.20)
 Abstract Critique
• Succinct

• Neutral; no observed bias or inaccuracies

 Critique
Strengths Weaknesses
• Well balanced study groups • Many uncontrolled
variables.
• Good baseline study for • Details regarding follow-up
future control trials. period are vague.
• Study design by
• Little subject loss to follow- investigators with full access
up; 8 patients (0.2%) to data.
• Funded by Bristol-Myers
Squibb.
– Investigators affiliation with
Bristol-Myers Squibb &
Novartis.
 Presenter’s Conclusions
In spite of the uncontrolled variables in the PROVE-IT
study, I believe the right general outcome was
reached.

I do not believe that treatment guidelines should have

been changed on the merit of this study alone.

However, the PROVE-IT this study was not sufficiently

powered to detect smaller differences within study
groups.
 Random thoughts
• Addition of third study group receiving atorvastatin
at equipotent dose to pravastatin.

• Additional control for adjunctive medications.

• Pravastatin or Pravachol?

• Why were only concomittant CYP 450 3A4 inducers

excluded? What about 3A4 inhibitors?
 References
1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart Disease and Stroke
Statistics—2009 Update; A Report From the American Heart Association
Statistics Committee and Stroke Statistics Subcommittee.
Circulation 2009;119: e21-e181.
2. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus Moderate
Lipid Lowering with Statins after Acute Coronary Syndromes
(PROVE-IT) The New England Journal of Medicine. 2004 Apr 8; 350
(15): 1495-504.