heartbeat – apr 2003 acc 2003 acc 2003: sportif iii and ascot valentin fuster md director,...

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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."


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


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


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


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


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."


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


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


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."


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


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


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


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


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


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."


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


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


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. "


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


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


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


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


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


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


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


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


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


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."


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


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


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


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."


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


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


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


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


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


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


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

heartbeat – apr 2003 acc 2003 acc 2003: sportif iii and ascot valentin fuster md director,...

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