Coaated stents: a new era

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ACC 2005 Message from the trials

• Valentin Fuster MD
• Director, Cardiovascular Institute
• Mount Sinai Medical Center
• New York, NY
• Christopher Cannon MD
• Staff cardiologist
• Brigham and Women's Hospital
• Boston, MA
• James Ferguson MD
• Associate Director, Cardiology
• St Luke's Episcopal Hospital and Texas Heart
  Institute
• Houston, TX

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Topics

Women's Health StudyUse of aspirin for primary
prevention COMMIT and CLARITYUse of
clopidogrel in acute-MI patients TNTHigh-dose
atorvastatin in stable CHD patients
ASCOT-BPLA Calcium channel blocker plus ACE
inhibitor reduced all-cause mortality and other
cardiovascular end points
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Women's Health Study Use of aspirin for primary
prevention
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Women's Health Study Design

• Use of aspirin for primary prevention in women
• (N Engl J Med 2005 published March 7th)
• 39 876 initially healthy women 45 years of age or
  older
• Randomized to 100 mg of aspirin on alternate days
  or placebo
• Monitored for first major CV event (nonfatal MI,
  nonfatal stroke, or death from CV causes)
• 10-year follow-up

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WHS Cardiovascular end points
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WHS Stroke end points
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WHS Ambitious trial

• Glass half-full vs half-empty
• Reduces stroke in a primary- prevention
  population
• But does not reduce mortality, which may have
  been an ambitious end point, in retrospect

Ferguson
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WHS Surprising results
Benefit in stroke and myocardial infarction
reduction in women older than 65 years "You do
have to be at risk to get benefit from aspirin."
Cannon
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Gender differences

• Significant differences in stroke reduction in
  the Women's Health Study and the Physician's
  Health Study
• Does stroke occur earlier in women than it does
  in men?

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Gender differences

• Mean ages roughly the same, but different
  follow-up
• Physician's Health Study 5-year follow-up
• Women's Health Study 10-year follow-up
• "These are not apples and apples we're
  comparing."
• - Ferguson

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WHS Aspirin dose

• "We don't know what the right dose of aspirin is
  right now."
• - Ferguson
• Physician's Health Study used 325-mg dose
• Antithrombotic Trialist Collaboration suggests
  doses less than 75 mg/day not as effective

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WHS The guidelines

• Changing guidelines? No need . . .
• Aspirin used in primary prevention only when
  patient's risk-factor profile is intermediate
  based on Framingham risk score
• But may need to revisit the stroke reduction
  benefit

Fuster
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WHS Who gets aspirin?

• How low down the risk spectrum do we go?
• No benefit in younger patients
• Need to categorize women at high risk for stroke
  to direct aspirin therapy to them

Cannon
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WHS Not change practice

• "It's telling us what we sort of knew already.
  Not everybody needs to be taking aspirin."
• Benefits tied to the degree of risk
• Stroke-prevention data need to be teased out
  further

Ferguson
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COMMITClopidogrel and Metoprolol in Myocardial
Infarction Trial CLARITYClopidogrel as
Adjunctive Reperfusion Therapy - Thrombolysis in
Myocardial Infarction (TIMI) 28
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New data about clopidogrel

• CLARITY
• (N Engl J Med 2005 published March 9, 2005)
• 3500 patients
• Clopidogrel improved infarct-related artery
  patency in MI patients receiving thrombolysis
• -Reduced occluded arteries by 36
• -Reduced death, MI, or recurrent ischemia
  requiring revascularization at 30 days by 20

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New data about clopidogrel

• COMMIT
• 46 000 patients
• Addition of clopidogrel in patients with
  ST-segment-elevation MI with or without
  thrombolysis
• -Death/MI/stroke reduced by 9
• -Death reduced by 7

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CLARITY and COMMIT
This adds the final piece of the puzzle that
clopidogrel is beneficial in ST-segment-elevation
MI - Cannon
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CLARITY and COMMIT

• Substantial clinical benefit in keeping vessels
  open
• COMMIT counterintuitive most of the benefit in
  patients presenting within first 12 hours
• Trend toward benefit in patients also treated
  with fibrinolytics

Ferguson
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Mechanisms

• Same mechanism as aspirin?
• After 180 minutes, the arteries open more and
  stay open because of the combination
• Prevention of reocclusion is likely the operative
  mechanism
• "Two agents are better than one."

Cannon
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CLARITY and COMMIT

• If you have risk, more antiplatelet therapy
  provides incremental benefit
• Opportunity to significantly improve aspirin

Ferguson
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TNT Treating to New Targets High-dose
atorvastatin in stable CHD patients
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TNT Design

• Lowering LDL cholesterol levels in stable CHD
  patients substantially below current guidelines
• (N Engl J Med 2005 published March 8, 2005)
• Parallel-group study randomizing 10 001 patients
  to atorvastatin 10 mg or 80 mg
• Patients included were men and women aged 35
  years to 75 years with clinically evident CHD
• Primary end point was first major CV event (death
  from CHD, nonfatal MI, nonfatal and fatal stroke,
  or resuscitation after cardiac arrest)
• 5-year follow-up

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TNT LDL cholesterol levels
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TNT Primary efficacy outcomes
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TNT What does it add?
PROVE-IT showed that lower is better in ACS
patients, but did it apply to stable CHD
patients? Yes! Confirms and supports that lower
LDL cholesterol is better, but also expands the
principle to more than 30 million US patients
Cannon
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TNT What does it add?

• Baseline LDL cholesterol levels low in TNT
• No longer good enough to simply "put a statin in
  the drinking water"
• Level of LDL cholesterol matters need to get it
  down even further than we thought we did

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Is it all about the LDL?

• Looking down the road to tease out benefit
• What happens when patients are stratified by LDL
  cholesterol levels coming into the study?
• Is it all LDL? What happens above and beyond
  LDL lowering?

Ferguson
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Beyond the guidelines

• Patient with angina and prior MI
• Goal to bring LDL cholesterol level to 70 mg/dL
• Do I start treatment at the maximum 80-mg dose of
  atorvastatin?

Fuster
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ACS vs stable CHD

• In ACS patients, start with a high-dose statin,
  as PROVE-IT showed benefit emerged after 10 days
• In stable CHD patients, slower titration is an
  option, but getting control of LDL and CRP is
  key

Cannon
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TNT Safety issues
1.2 of patients treated with atorvastatin 80 mg
had a persistent elevation in alanine
aminotransferase, aspartate aminotransferase, or
both, compared with 0.2 of patients receiving
atorvastatin 10 mg (plt0.001)
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TNT Safety issues

• 99 of the patients didn't need any dose
  adjustment with atorvastatin 80 mg
• "It seems to me that in the future we will start
  looking at LDL cholesterol levels after the
  patient is treated, rather than before."
• - Fuster

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Evolution of therapy
Changing patient populations for aspirin,
clopidogrel, and statin therapy "If a drug
works, it works." - Cannon
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Evolution of therapy

• "The chronic treatment arena is a whole different
  scenario . . ."
• Side effects, drug interactions, tolerance, and
  compliance become issues
• "Time will tell as we begin to get experience."

Ferguson
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Challenges
Changing definitions of "chronic" therapy "The
question in the chronic phase is going to be
compliance and to be sure that side effects don't
come along."
Fuster
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ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes
Trial Blood Pressure Lowering Arm
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ASCOT-BPLA Stopped early

• Primary outcome measure for the BP-lowering trial
  was nonfatal MI and fatal CHD
• Stopped by the ASCOT steering committee in
  November 2004 on the recommendation of the
  trial's data and safety monitoring board

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ASCOT-BPLA Design

• 19 257 hypertensive patients with at least 3
  other cardiovascular risk factors
• Patients had to have a baseline BP of

• gt160 mm Hg systolic or gt100 mm Hg diastolic
  untreated or
• gt140 mm Hg systolic or gt90 mm Hg diastolic
  despite being on treatment

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ASCOT-BPLA Design

• Randomized to

• Amlodipine (5/10 mg) with or without perindopril
  (4/8 mg) or
• Atenolol (50/100 mg) with or without the
  bendroflumethiazide (1.25-2.5 mg)
• as well as further treatment as required to reach
  a target BP lt140/90 mm Hg

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Amlodipine/perindopril vs atenolol/bendroflumethia
zide
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ASCOT-BPLA Results
Amlodipine plus an ACE inhibitor vs atenolol
plus a diuretic achieved similar blood-pressure
control, and yet the results are quite different

Fuster
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ASCOT Targeted therapy

• "My initial gut reaction was that the results
  were a little bit of a surprise."
• The mechanistically targeted therapy more
  effective than older strategies
• More going on than a simple reduction in blood
  pressure, but not sure if ACE inhibitor is
  driving the results

Ferguson
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ASCOT Surprising results

• "My take-away is that calcium-channel blockers
  are back."
• Amlodipine plus an ACE inhibitor "looks terrific"
  in these patients
• Shifts the order we start choosing
  medicinesmoves calcium-channel blockers up

Cannon
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ASCOT New onset diabetes with amlodipine/perindop
ril vs atenolol/ bendroflumethiazide
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ASCOT Diabetes data

• Is the benefit providing a better milieu and a
  less likelihood for developing diabetes, or is
  the diabetes driving the negative results for
  atenolol?
• My guess is that the diabetes is not the driving
  force here
• - Ferguson

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ASCOT Diabetes data

• Time for diabetes to translate into excess MI or
  mortality is longer than the duration of the
  study
• But the risk of developing diabetes should be a
  factor in deciding which therapy to select
• - Cannon

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Other drug effects

• When you give a drug to move a parameter, such as
  blood pressure or LDL cholesterol, these drugs
  often have other effects
• Other biologic effects may have more of an impact
  on the overall end point

Fuster
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Summary
WHS Aspirin continues to be a good drug and is
effective in preventing stroke in women CLARITY
and COMMIT Clopidogrel now shown to be effective
in acute MI
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Summary
TNT Lower LDL cholesterol levels better in stable
CHD patients ASCOT-BPLA Amlodipine/perindopril-bas
ed strategy significantly reduced all-cause
mortality and other cardiovascular end points in
hypertensive patients

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ACC 2005 Advances

• "I was delighted to see an advance forward in
  ST-elevation MI."
• In the past, at least 12 other agents failed to
  improve STEMI outcomes

Cannon
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ACC 2005 Back to biology

• "We've come back to the biology, but the biology
  as it impacts clinical care."
• Trials are also getting more complicated, looking
  at multiple end points
• Newer generation of clinical trials incorporates
  a broader understanding of the biology

Ferguson