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ACC 2003: SPORTIF III and ASCOT. Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, MA James Ferguson MD Associate Director, Cardiology - PowerPoint PPT Presentation
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Heartbeat – Apr 2003
ACC 2003
ACC 2003: SPORTIF III and ASCOT
Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, NY
Christopher Cannon MDCardiologistBrigham and Women's HospitalBoston, MA
James Ferguson MDAssociate Director, CardiologySt Luke's Episcopal Hospital and Texas Heart InstituteHouston, TX
Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, NY
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Trial design
Oral thrombin inhibitor in atrial fibrillation
• 3407 AF patients with at least 1 additional risk factor for stroke
• Noninferiority, randomized open-label trial of a fixed dose of ximelagatran (36 mg bid) vs adjusted-dose warfarin with a target INR of 2-3
• End points: combined rates of all strokes, both ischemic and hemorrhagic, and of systemic embolic events between treatments
• Primary analysis: intention to treat Secondary analysis: actual treatment received
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Primary events
0.0
0.5
1.0
1.5
2.0
2.5
Even
ts (
%)
Intention-to-treat On-treatment
Ximelagatran Warfarin
ACC 2003
p=0.018p=NS
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Bleeding events
ACC 2003
End point Ximelagatran (%)
Warfarin (%)
p
Intracerebral hemorrhage
0.2 0.5 NS
Major bleeding 1.3 1.8 NS
Major/minor bleeding
25.5 29.5 0.007
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Net clinical benefit
ACC 2003
Combined end point
Ximelagatran (%)
Warfarin (%)
RRR(%)
p
Death, major bleeding, primary events
4.6/year 6.1/year 25 0.022
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Shockwaves
"[SPORTIF III] probably will send shock waves through the oral antithrombotic world"
Gives us something at least as good as warfarin therapy, without all the downside
More studies in different conditions will follow
Ferguson
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Changing the landscape
"This is really going to change the landscape on how we are going to be dealing with atrial fibrillation"
Many physicians are not adept at providing warfarin for AF patients
A treatment that is:
easier to administerneeds less monitoringseemingly has better results
Weber
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Active treatment
Cannon
"The excitement is that this is an active antithrombotic agent, that it inhibits thrombin directly as opposed to warfarin, which basically depletes the body of clotting factors."
Ximelagatran can be initiated early, and the lack of need for INR monitoring eliminates need for very careful follow-up necessary for proper use
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Adverse effect
ACC 2003
Transanimase liver enzyme
Ximelagatran (%)
Warfarin (%)
p
ALT 3x upper limit of normal
6.5 0.7 0.001
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Drug-drug interactions
We need to learn if there will be interactions with other commonly used drugs
"…it's really only when you get up to a 5- or 7-fold increase in liver enzymes that you really have to start worrying about any sort of meaningful damage to liver cells. Three-fold doesn't seem to phase anybody."
Weber
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Liver function enzyme
Ferguson
The liver function enzyme rise occurred early, mostly in the first 3 months
It may be not require continued monitoring out for an extended period of time
You should be aware of it and watch out for it in patients in whom you initiate therapy
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Analogy with statins
Some cases of liver-enzyme rise were out to 18 months
"To do LFT monitoring is a pretty routine thing that we're used to with statins so I don't think that will limit [ximelagatran use]."
Constant effective anticoagulationis less risky for thrombotic events
Cannon
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Coronary artery disease
In long-term follow-up of patients with CAD we see evidence for chronic treatment with clopidogrel and aspirin
•CREDO•CURE
It seems oral anticoagulants and aspirin are doing as well as clopidogrel and aspirin if you can control the INR
Fuster
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Long-term CAD treatment
Recurrent MI in SPORTIF III trended higher (p=0.07)•Ximelagatran 1.0%•Warfarin .05%
Ximelagatran + aspirin may be able to compete with clopidogrel + aspirin due to ease of use
High-risk patients may get all 3
Cannon
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Effects of the drug
Antithrombins affect the clotting system, but the thrombin pathway is also a key pathway of platelet activation
"It seems to me the drug in itself, even on a theoretical basis, appears to be quite an interesting drug. . . . It seems to me that the potential is incredible for the future."
Fuster
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: The next study
Ferguson
Data from long-term use of warfarin suggests benefit from prolonged intense antithrombin therapy
"My hope would be that we would have the opportunity in the future to do the study that will determine who needs antithrombitic, who needs antiplatelet, and who needs combination therapy."
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Bleeding events
As we go from double therapy to triple therapy, we must be careful of bleeding events
"The potential for long-term secondary prevention is enormous, but we are going to have to be very careful about monitoring safety here."
Weber
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: History
Two problems evolved with hirudin when it was first introduced
•Bleeding issues•Rebound: when you stop the drug,
all the events begin to occur
We should not forget the history of the field as we move forward
Fuster
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Bleeding
Warfarin's variability in anticoagulation intensity may be a source of bleeding problems and these may be avoided by oral antithrombins
Ferguson
In the 9 trials with antithrombins in the past 2 years, none were stopped for bleeding, which is good news
Fuster
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Expenses
New drugs are very impressive advances in prevention and therapy
•ACE inhibitors•Statins•Clopidogrel•Oral antithrombins
Is the expense too much for most of the world?
Fuster
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Cost
Ferguson
The costs related to oral antithrombin therapy are not just the costs of the drug but of all the monitoring and adjustments that warfarin required
"Yes, we're going to have to deal with the cost issues, but I think that the total effect on the healthcare system is going to be beneficial."
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Real world use
SPORTIF III had superb control of INR that you do not see in real-world practice
The benefit may be even greater in the real world because the warfarin is less effectively controlled and more bleeding is likely
Cannon
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: Trial design aspects
Two bold aspects of this trial are worth noting
•Had a per-protocol analysis in addition to intention to treat
•Prospective, randomized, open-label blinded end points
These trials are easier, safer, and less expensive, and it is good to see them accepted
Weber
Heartbeat – Apr 2003
ACC 2003
SPORTIF III: SPORTIF V
Ferguson
SPORTIF V will be a blinded trial in the same sorts of patients
"If that turns out to be positive as well, and there's no reason to think that it shouldn't be, that is really going to nail it."
Heartbeat – Apr 2003
ACC 2003
ASCOT: Trial design
Lipid-lowering arm of ASCOT trial in hypertension patients
• 10 305 hypertensive patients with at least 3 other cardiovascular risk factors and with total cholesterol below 6.5 mmol/L (250 mg/dL)
• Randomized to 10-mg atorvastatin or placebo
• Primary end point: fatal CHD/nonfatal MI with planned 5-year follow-up
• Secondary end points: fatal and nonfatal stroke, total cardiovascular events, and total coronary events
Heartbeat – Apr 2003
ACC 2003
Lancet 2003; 361:1149-1158
ASCOT: Results
0.01.02.03.04.05.06.07.08.09.0
10.0
Even
ts (
%)
Primary endpoint
Total coronaryevents
Total CVevents
Atorvastatin Placebo
Heartbeat – Apr 2003
ACC 2003
Lancet 2003; 361:1149-1158
ASCOT: Cholesterol levels
0.0
1.0
2.0
3.0
4.0
5.0
6.0
To
tal
ch
ole
ste
rol
(m
mo
l/L)
6months
1 year 2 years 3 years End offollow-
up
Atorvastatin Placebo
Heartbeat – Apr 2003
ACC 2003
ASCOT: Primary prevention
Like a primary prevention trial:
•Original cholesterol levels were fairly normal
•Patients with multiple risk factors
"You put a statin on top of hypertension and other risk factors and you end up with these very significant and positive results."
Fuster
Heartbeat – Apr 2003
ACC 2003
ASCOT: Beyond the guidelines
This provides very strong data that lipid-lowering and statin therapy has use beyond current guidelines
"Many of these patients are at lower risk for long-term development of cardiovascular disease than are in the current guidelines. So this is a mega result."
Cannon
Heartbeat – Apr 2003
ACC 2003
ASCOT: One-size fits all
Ferguson
There was substantial relative benefit, but the absolute benefit was small in terms of number of primary events
•100 in atorvastatin group•154 in the placebo group
"This is one-size-fits-all therapy that appears to provide benefit."
Heartbeat – Apr 2003
ACC 2003
ASCOT: Absolute vs relative risk
Absolute risk reduction in primary event:
•3.4/1000 patient years
In primary prevention, the number of events will be relatively small
Strong relative benefit in these patients will not translate into a strong reduction of absolute events
Fuster
Heartbeat – Apr 2003
ACC 2003
ASCOT: Ease of statins
A strange reluctance for people to use statins despite their proven ease of use
Hopefully the demonstrated benefit for
lower-risk patients will help convince higher-risk patients to go on statins
Risk stratification for these types of patients will have to determined
Cannon
Heartbeat – Apr 2003
ACC 2003
ASCOT: Extends the application
Ferguson
All prespecified subgroups benefited from atorvastatin
"This extends the potential world of the application of statin therapy. Rather than putting statins in everybody's drinking water right now--that would be great if we could do that but somebody's got to pay for it. "
Heartbeat – Apr 2003
ACC 2003
ASCOT: WHO
World Health Organization issued a statement in October, 2002 saying the most immediate improvement in CV health would involve getting aspirin and statins to everyone at risk
Made possible by generics in statins, bringing cost of the drug combination would cost less than US$14 to treat each person annually
Cannon
Heartbeat – Apr 2003
ACC 2003
ASCOT: HPS study
20 000 patients at increased risk of CHD death due to prior disease
•Myocardial infarction or other coronary heart disease
•Occlusive disease of noncoronary arteries; or
•Diabetes mellitus or treated hypertension
Fuster
Heartbeat – Apr 2003
ACC 2003
ASCOT: HPS results
0
2
4
6
8
10
12
14
16
Event
rate
(%
)
All-cause mortality Vascular death
Simvastatin Placebo
Lancet 2002; 360:7-22
Heartbeat – Apr 2003
ACC 2003
ASCOT: Global risk
These patients were also being aggressively treated for their other risk factors
•May explain low event rates
Interesting that the cholesterol was low enough to justify a placebo
Weber
Heartbeat – Apr 2003
ACC 2003
ASCOT: ALLHAT Trial design
•10 355 patients age >55 with hypertension and 1 additional risk factor and moderate hypercholesterolemia
•Randomized to:
pravastatin (40 mg/day, n=15 255)
usual care
•Primary end point: all-cause mortality
Heartbeat – Apr 2003
ACC 2003
ASCOT: ALLHAT Primary results
0
2
4
6
8
10
12
14
16
6-y
ear
even
t ra
te/
100 p
ati
en
ts
Mortality CHD and nonfatal MI
Pravastatin Usual care
JAMA 2002; 288:2998-3007
Heartbeat – Apr 2003
ACC 2003
ASCOT: Hypertension plus
Ferguson
ASCOT is hypertension plus additional risk factors while ALLHAT-LLT was not
"There is your risk stratification right there."
If there had been more patients in ALLHAT maybe you would have seen a result teased out
Heartbeat – Apr 2003
ACC 2003
ALLHAT-LLT: Statin use
0
10
20
30
40
50
60
70
80
90
% o
n s
tati
n
2 years 4 years 6 years
Statin arm Usual-care arm
JAMA 2002; 288:2998-3007
Heartbeat – Apr 2003
ACC 2003
ASCOT: Diverging curves
The Kaplan-Meier curves separate almost immediately in this study
Previously, the curves in long-term populations studies of statins separated after a year
"I don't know what the explanation for that very early separation is, but it's encouraging that we're getting an essentially immediate effect." Cannon
Heartbeat – Apr 2003
ACC 2003
ASCOT: All-cause mortality
Ferguson
The all cause mortality curves don't separate throughout the trial
The stroke curves diverge over time
"To make the leap and say that there's something unique about this population where we get instantaneous benefit, I think you need to look at the endpoints that you're looking at."
Heartbeat – Apr 2003
ACC 2003
Summary: SPORTIF III
Oral antithrombins at a fixed dose are of at least equal benefit as warfarin, with possibly fewer side effects
There may be a liver enzyme issue; so far it seems transient and reversible
Must wait for SPORTIF V
Fuster
Heartbeat – Apr 2003
ACC 2003
Summary: ASCOT
Hypertension patients with other risk factors randomized to atorvastatin or placebo
Strikingly positive results favoring the statin group
The use of statin appears to be meaningful in patients with multiple risk factors without an event
Similar to HPS
Fuster
Heartbeat – Apr 2003
ACC 2003
EPHESUS
0
5
10
15
20
25
30
Even
ts (
%)
Mortality CV mortality CV mortalityor CV hospital
Eplerenone Placebo
N Engl J Med 2003; 348:1309-1321
Heartbeat – Apr 2003
ACC 2003
Coated stents: TAXUS II
Ferguson
Long-term results with the paclitaxel stents in TAXUS II were very good
% MACE at 12 monthsBare stent--21.7Slow-release coated stent--10.9Moderate-release coated stent--9.9
"We may have another player emerging into the marketplace in the not-too-distant future."
Heartbeat – Apr 2003
ACC 2003
Coated stents:SIRIUS cost analysis
Cost Sirolimus ($)
Control ($)
Difference ($)
p
Index procedure
7252 4395 2856 <0.001
Initial hospital costs
11 345 8464 2880 <0.001
Discharge to1 year
5468 8040 -2571 <0.001
Total 1 year 16 813 16 504 309 NS
Cohen DJ. ACC 2003
Heartbeat – Apr 2003
ACC 2003
Coated stents: Cost effectiveness
Coated stents seem essentially cost-neutral, you pay more up front but you recoup that by avoiding expensive hospitalizations down the line
This should be very reassuring to all of us that this is a therapy whose early costs are offset by the lack of late costs
Cannon
Heartbeat – Apr 2003
ACC 2003
Final word: Weber
I'll be a lot more aggressive in the use of statins
• Is it worth measuring cholesterol now in high-risk patients?
Antithrombins will become a dominant force
We need to explain to our administrators the wisdom of an up-front investment in drug-eluting stents Weber
Heartbeat – Apr 2003
ACC 2003
Final word: Cannon
We didn't discuss higher-dose clopidogrel loading that seemed to obviate the need for GP IIb/IIIa inhibition in low-risk patients
"We thought we had maxed out on [antithrombotic] treatment but we're still making advances."
Cannon
Heartbeat – Apr 2003
ACC 2003
Final word: Ferguson
We have better ways of doing things and easier ways of doing them
"What you're watching in the meetings is the relentless progress of medical care as we're ultimately targeting improving patient outcomes."
Ferguson
Heartbeat – Apr 2003
ACC 2003
Final word: Fuster
"When you go back even 5 years, I don't see any other area in medicine where so many advances have been made in respect to therapies and prevention."
Fuster
Heartbeat – Apr 2003
ACC 2003
Next program
ACC 2003 Part 2
Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, NY
Christopher Cannon MDCardiologistBrigham and Women's HospitalBoston, MA
Robert Harrington MDProfessor, CardiologyDuke University Medical CenterDurham, NC
Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, NY
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