1. 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

2. Topics Women's Health Study Use of aspirin for primary prevention
COMMIT and CLARITY Use of clopidogrel in acute-MI patients
TNT High-dose atorvastatin in stable CHD patients
ASCOT-BPLA
Calcium channel blocker plus ACE inhibitor reduced all-cause mortality and other cardiovascular end points

3. Use of aspirin for primary prevention
Women's Health Study
Use of aspirin for primary prevention

4. Women's Health Study: Design
Use of aspirin for primary prevention in women
(N Engl J Med 2005: published March 7th)
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

5. WHS: Cardiovascular end points
Events (n), aspirin
(n=19 934)
Events (n), placebo (n=19 942)
Relative risk p
Major CV event
477
522
0.91
0.13
Stroke MI
221
198
266
193
0.83
1.02
0.04
Death from CV causes
120
126
0.95
0.68

6. WHS: Stroke end points End point Events (n), aspirin (n=19 934)
Events (n), placebo
(n=19 942)
Relative risk p
Stroke
221
266
0.83
0.04
Ischemic
170
0.76
0.009
Hemorrhagic 51 41
1.24
0.31
Fatal 23 22
1.04
0.90
Nonfatal
198
244
0.81
0.02

7. 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

8. 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

9. 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?

10. 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

11. 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

12. 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

13. 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

14. 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

15. COMMIT Clopidogrel and Metoprolol in Myocardial Infarction Trial
CLARITY Clopidogrel as Adjunctive Reperfusion Therapy - Thrombolysis in Myocardial Infarction (TIMI) 28

16. 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%

17. New data about clopidogrel
COMMIT
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%

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

19. 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

20. 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

21. CLARITY and COMMIT
If you have risk, more antiplatelet therapy provides incremental benefit
Opportunity to significantly improve aspirin
Ferguson

22. Treating to New Targets High-dose atorvastatin in stable CHD patients
TNT
Treating to New Targets
High-dose atorvastatin in stable CHD patients

23. 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 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

24. TNT: LDL cholesterol levels
Atorvastatin 10 mg (n=5006)
Atorvastatin 80 mg (n=4995)
Mean baseline LDL cholesterol levels (mg/dL) 98 97
Final LDL cholesterol levels (mg/dL)
101 77

25. TNT: Primary efficacy outcomes
Atorvastatin 10 mg (n=5006)
Atorvastatin 80 mg (n=4995)
Hazard ratio
(95% CI) p
Total major cardiovascular events (%)
10.9
8.7
0.78
( )
<0.001
Death from coronary heart disease (%)
2.5
2.0
0.80
( )
0.09
Nonfatal MI (%)
6.2
4.9
( )
0.004
Resuscitation after cardiac arrest (%)
0.5
0.96
( )
0.89
Fatal or nonfatal stroke (%)
3.1
2.3
0.75
( )
0.02

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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 (p<0.001)

32. 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

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

34. 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

35. 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

36. Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm
ASCOT-BPLA
Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm

37. 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

38. ASCOT-BPLA: Design
hypertensive patients with at least 3 other cardiovascular risk factors
Patients had to have a baseline BP of
>160 mm Hg systolic or >100 mm Hg diastolic untreated or
>140 mm Hg systolic or >90 mm Hg diastolic despite being on treatment

39. 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 ( mg)
as well as further treatment as required to reach a target BP <140/90 mm Hg

40. Amlodipine/perindopril vs atenolol/bendroflumethiazide
End point
Hazard ratio
95% CI p
All-cause mortality
0.86
0.005
Primary end point: nonfatal MI and fatal CHD
0.90
0.12
Total coronary end point: primary end point + new- onset angina + fatal and nonfatal heart failure
0.0048
Fatal and nonfatal stroke
0.77
0.0007
All CV events and revascularization procedures
0.84
<0.0001
CV mortality
0.76
0.0017

41. 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

42. 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

43. 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 medicines—moves calcium-channel blockers up
Cannon

44. ASCOT: New onset diabetes with amlodipine/perindopril vs atenolol/ bendroflumethiazide
End point
Hazard ratio
95% CI p
New diabetes mellitus
0.68
<0.0001

45. 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

46. 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

47. 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

48. 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

49. Summary TNT Lower LDL cholesterol levels better in stable CHD patients
ASCOT-BPLA
Amlodipine/perindopril-based strategy significantly reduced all-cause mortality and other cardiovascular end points in hypertensive patients

50. 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

51. 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