Heartbeat – May 2002 Triumph of the trials Triumph of the trials: ACC 2002 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center

Heartbeat – May 2002

Triumph of the trials

Triumph of the trials: ACC 2002

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, New York

Christopher Cannon MDCardiologistBrigham and Women's HospitalBoston, Massachusetts

Christopher M O'Connor MDAssociate Professor of CardiologyDuke University Medical CenterDurham, NC

Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, New York



DANAMI-2Transferring patients for PCI

LIFELosartan for hypertension

WIZARDAntibiotics for coronary

disease

Subjects



DANAMI-2

DANish multicenter Trial in Acute Myocardial Infarction 2

1572 patients randomized to fibrinolysis (100 mg front loaded tPA)or PCI + stent

Referral hospitals: tPA or ambulance transfer to center for PCI

PCI centers: tPA or PCI

Primary endpoint: Death, reinfarction, or disabling stroke in 30 days



ST-elevation 4 mm

Symptoms 12 hrs at randomization

Transfer 3 hrs from referral hospital to cath-lab

Maximum transport distance 95 miles

Mean transport distance 35 miles

DANAMI-2: Inclusion criteria



DANAMI-2: New PCI centers

"In fact, one of the most interesting aspects of this study was that the Danish institutions didn't have PCI a few years ago, so they had to be trained."

5 PCI centers24 referral hospitals(62% of Danish population)

Fuster



DANAMI-2: Strategies of care

O'Connor

"I think this is an extremely important trial because it not only addresses an important scientific question but it also looks at strategies of care."



"They raised the bar in doing this study [in that] they geared up a system to try and extend the reach of primary angioplasty so that it would be possible to offer this for people as far away as 30 or 50 miles."

Cannon

DANAMI-2: Raising the bar



"What people forget is that even here in the United States we don't all have an interventional lab next door or around the corner. In California you might find an interventional lab in every cardiologist's backyard or garage but here in New York we don't have that at all."

Weber

DANAMI-2: Important to US



ACC 2002

DANAMI-2: Event rate

0%

2%

4%

6%

8%

10%

12%

14%

Combined Reinfarction Stroke Death

PCI Fibrinolysis

p=0.0003

p<0.0001

p=0.15

p=0.358.0

13.7

1.6

6.3

1.12.0

6.67.6



DANAMI-2: Government involvement

"How striking it is how a decision made by the government in running a trial like this […] in order to better serve people from the health point of view."

FusterDenmark



0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

Death

DANAMI-2: Mortality benefit

"[The 1% absolute benefit] is as big a difference as we saw between tPA and streptokinase a few years ago.

"This is far more compelling than I would ever have anticipated."

Weber



"This isn't casual angioplasty versus thrombolysis but in order to offer or expect the benefits of this strategy you really have to gear things up and do rapid angioplasty."

"Making a real commitment to the strategy will be the key to its success."

Cannon

DANAMI-2: Treatment strategy



DANAMI-2: Logistical problems

The great transfer success is because of an integrated system

Could the US adopt a system where a single phone call starts the system up at another hospital?

Fuster



DANAMI-2: Committing to a system

O'Connor

"If we're going to make this effective therapy […], we have to have protocols in place just like we have a protocol to do a clinical trial, we have to follow the protocol and people have to think of the care they are delivering like a clinical trial."



DANAMI-2 site

DANAMI-2: 12-hour window

0%2%4%6%8%

10%12%14%16%18%20%

Pri

mary

end p

oin

t

0-1.5 >1.5-2.5 >2.5-4 >4-12

Time to randomization (hours)

PCI Fibrinolysis



DANAMI-2: Busy cath-labs

Weber

If we accept these results, won't there be a tendency for EMS and referring doctors to bypass any hospital without PCI?

It's very likely, but with only 10-15% of hospitals having cath-labs available, it will be very busy

At least we seem to have a 12-hour window for the PCI

Fuster



DANAMI-2: Resistance

O'Connor

"In our health system, finances drive a lot of the way these patients are allocated to hospitals. And because the MI patient is a high-DRG diagnosis there is going to be some resistance, unfortunately, unless we can tie quality and outcomes to the care of these patients."



"How expensive is it going to be to prepare institutions to be ready for these kinds of transfers?"

Fuster

"In figuring out the real costs we have to go beyond the acute event and see what happens over the next few days and the next few weeks."

Weber

DANAMI-2: Economics



DANAMI-2: Summary

It is feasible to transfer patients in a reasonable window of time

It will require a community-wide commitment in order to make this happen

Is that commitment possible economically?

Fuster



DANAMI-2: Costs

Costs are similar for thrombolysis and PCI since many thrombolysis patients go on to get PCI later

Receiving hospitals like more patients so there is not a burden

The fear is that the referral hospitals will lose not just the ST-elevation patients but all chest pain patients

Cannon



DANAMI-2: Boston pilot study

We have to have the protocol of 12-lead ECG in field to target specifically the ST-elevation patients

We are changing the paradigm from going to the nearest acute hospital to going to the nearest primary angioplasty hospital

A 5- or 6-year process

Cannon



LIFE: Inclusion Criteria

Losartan Intervention For Endpoint reduction in hypertension• 9193 patients

• Age 55-80 years

• Previously treated or untreated hypertension

• Systolic BP 160-200 mmHg or diastolic BP 95-115 mmHg

• ECG LVH

Cornell Voltage Duration Product >2440 mm*msec (6-mm gender adjustment in women)

Sokolow-Lyon >38 mm



LIFE: Hypothesis

If two drugs lower the blood pressure equally but one causes LVH regression, is one superior in preventing CV events?

Primary composite endpoint of cardiovascular morbidity and mortality, defined as stroke, MI or cardiovascular death

Losartan vs atenolol



LIFE: Primary Composite Endpoint

6

Pro

port

ion

of

pati

en

ts w

ith

firs

t even

t (%

)

18 24 30 36 42 48 54

Losartan

Atenolol

Dahlof et al. Lancet 2002;359:995-1003

60 6600

2

4

6

8

10

12

14

16

Intention-to-Treat

12

Adjusted Risk Reduction 13·0%, p=0.021

Unadjusted Risk Reduction 14·6%, p=0.009

Study MonthLosartan (n)Atenolol (n)

4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 9014588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876



LIFE: Fatal/Nonfatal Stroke

6

Pro

port

ion

of

pati

en

ts w

ith

firs

t even

t (%

)

18 24 30 36 42 48 54

Losartan

Atenolol


60 660

Intention-to-Treat

12

Adjusted Risk Reduction 24·9%, p=0.001

Unadjusted Risk Reduction 25·8%, p=0.0006

Study Month

8

7

6

5

4

3

2

1

0



LIFE: Additional points

Blood pressure drop was the same in both groups

LVH regressed in roughly 1/3 of patients in losartan group

New onset of diabetes reduced by 25%



"The first time that, head-to-head, one anti-hypertensive drug has beaten another anti-hypertensive drug in terms of important clinical endpoints."

"Since the blood pressure reductions with the two drugs were identical, then we have to believe that blocking the renin-angiotensin system […] is critical in providing protection for these vulnerable patients."

LIFE: Head-to-head winner

Weber



LIFE: Discontinuations


02468

101214161820

Discontinuation dueto AE

Discontinuation dueto drug related AE

Discontinuation dueto serious drug

related AE

Percentage

P<0.0001

P<0.0001

P=0.006

Atenolol

Losartan



ACC 2002

LIFE: Event rate

0%

2%

4%

6%

8%

10%

12%

14%

Composite MI Stroke Death

Losartan Atenololp=0.021

p=0.491

p=0.001

p=0.206



"From a patient's point of view, these are all major cardiovascular events and so none of the three [death, MI, stroke] is any good to have."

It is hoped this will provide guidance for offering therapy a patient can comply with easily

"This could be a terrific way to offer appropriate blood pressure reduction."

LIFE: Patient's view

Cannon



It is hoped this will point toward research into the effect of the renin-angiotensin system on stroke

A patient with a prior MI should be on a beta-blocker, and this suggests you should add angiotensin II inhibition as well

LIFE: Combination therapy

Cannon



LIFE: HOPE results

Endpoint ramipril placebo p value

Mortality 10.4% 12.2% 0.005

CV Death 6.1% 8.1% <0.001

Stroke 3.3% 4.9% <0.001

MI 9.9% 12.3% <0.001

HOPE Investigators. N Engl J Med 2000; 342: 145-53



HOPE compared ACE-inhibitor vs placebo

"The HOPE study was bedeviled by the fact that there were blood-pressure changes. Some people are even arguing that much of the benefit of the ACE inhibitor in HOPE could be explained by the fact that it lowered blood pressure pretty effectively."

LIFE: Differences with HOPE

Weber



"You can make an argument right now […] that for any reasonably high-risk hypertensive who came into your office that an angiotensin-receptor blocker might have to be your number-one preferred drug to start the treatment […] because it has gone out and beaten the drug that is currently recommended as the first step in treatment."

LIFE: New first-choice therapy

Weber



LIFE: Future trials

Antihypertensive Lipid Lowering Heart Attack Trial – (ALLHAT)

doxazosin vs chlorthalidone

Valsartan Antihypertensive Long-term Use Evaluation - (VALUE)

valsartan vs amlodipine



"All these hundreds of millions of dollars and years and years of effort will be wasted, or at least greatly diluted, if indeed we don't have equal blood pressure effects so we can really look at what goes beyond the blood pressure."

LIFE: Matching blood pressure

Weber



WIZARD: C pneumoniae in MI

4-5 years ago we believed that infections are important in CVD

• C pneumoniae inside the arteries

• C pneumoniae inside the monocytes

• Small retrospective studies seemed to support this idea

Fuster



WIZARD: ACADEMIC

Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia

302 patients with CAD and positive serology for C pneumoniae randomized to receive either placebo or azithromycin

No significant difference in primary endpoint: CV death, non-fatal MI, or unplanned revascularization

Circulation 2000; 102(15):1755-60



WIZARD: CLARIFY

Clarithromycin in Acute Coronary Syndrome Patients in Finland (CLARIFY)

148 patients randomized to placebo or clarithromycin for 3 months

Patients were followed for up to 3 years

51% relative risk reduction in CV events

Circulation 2002; 105(13): 1555-60



WIZARD: Infectious burden

German study links the number of infections to severity of atherosclerosis

Circulation 2002; 105(1):15-21

"Where Framingham said risk factors are important, now we are going to say the number of infections are important but you have to accumulate a number of them to really have an impact."

Fuster



WIZARD: Trial design

Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders

7747 patients with were randomized to 12 weeks of either azithromycin or placebo

Inclusion criteria> 6 weeks post-MI C pneumoniae 1:16



WIZARD: Change in enrollment

O'Connor

WIZARD was originally powered to enroll 3000 patients and detect a 25% difference

Pfizer got feedback saying that a 15-20% event reduction would be acceptable, and so expanded and extended the trial

"It was very courageous of a sponsor because you don't see this often."



WIZARD: Trial design

Primary composite endpoint:MortalityReinfarctionHospitalization for unstable anginaRevascularization

Trial concluded in Feb 2002 with >1000 adjudicated events



0 6 12 18 24 30 36 42 48 540

5

10

15

20

25

30

WIZARD: Primary Endpoint%

of

pat

ien

ts w

ith

eve

nt

Time from Treatment Start (Months)

Risk Reduction = 7%95% CI = (-5, 17)P-value = 0.23

AzithPlacebo

O'Connor – ACC2002



WIZARD: Length of treatment

CLARIFY saw benefit appear after long treatment and long follow-up, do you think we will see the same with WIZARD?

When the study was planned, the issues around duration of therapy were toxicology issues

A decision was made to go ahead and not wait for the toxicology studies

O'Connor



0 0.5 1 1.5

WIZARD:Treatment Effect by Time

0 0.5 1 1.5

Composite Endpoint Death/MI

Cen

sori

ng

Tim

e (y

ears

)

.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Hazard Ratio (95% CI)O'Connor – ACC2002



WIZARD: Duration is critical

O'Connor

"I think duration is critical, and therefore I think there is still hope."

"You just have to treat this longer."



WIZARD: PROVE-IT

PROVE-IT: Pravastatin or Atorvastatin Evaluation and Infection Therapy

Patients will be randomized to pravastatin or atorvastatin and to gatifloxacin or placebo

Patients will receive gatifloxacin treatment throughout the trial (minimum 18 months, expected mean 24 months) for 10 days of every month



"Until we do have some sort of toxicology data and some sort of sense of what we're doing to our whole flora, I really wouldn't know what to predict would be the effect of giving an antibiotic for that long and I would be very nervous about that."

Weber

WIZARD: Toxicology



WIZARD: Multiple infections

Are we too focused on one microorganism?

It could be like giving a statin to a hypertensive patient or an anti-hypertensive to someone with high cholesterol

Maybe there are multiple microorganisms we need to target with different drugs

Fuster



WIZARD: Multiple targets

We didn't make progress against Hodgkin's disease until we began using multiple agents

There is evidence for multiple organisms in CVD

"It's tricky when you're talking about duration of therapy."

O'Connor



"A lot of it is driven by what agents we have. If we had an agent that could effectively treat CMV without a lot of toxicity that would certainly be worth testing, but we just have easy antibiotics that we used against chlamydia."

Cannon

WIZARD: Use the drugs we have



WIZARD: Monitoring for superinfection

PROVE-IT is being monitored in a blinded fashion

•previous trials found fewer infections in the antibiotic groups

•multiple classes of agents allow us to evade resistance

Both ACES and PROVE-IT should be out in about 2 years

Cannon



ICDs for post-MI patients with low EF

Economic factors are enormous

Should still do some kind of EPS study to risk-stratify

patients

Summary: MADIT II



We didn't get the quality of life information we wanted

Mortality is not different between rate or rhythm control

Summary: Atrial fibrillation



FIM study showed 0% restenosis

RAVEL also shows 0% restenosis in eluting-stent arm

Summary: Coated stents



Maybe it is time for patients to be moved to PCI centers

Must have a system prepared to use this

The economic impact of this needs to be studied

Summary: DANAMI-2



Similar drop in blood pressure with losartan but significant benefits over atenelol, especially in stroke

This may shift what we use as first-line therapy in

hypertension

Summary: LIFE



We have much to learn about the microorganisms affecting the vascular system

WIZARD was disappointing, showing no significant effect of antibiotics

Summary: WIZARD



It is exciting that we have the kinds of studies that can change practice

"I think in particular DANAMI-2 and LIFE will change the way I practice personally and the way we recommend practices to change in our healthcare system in North Carolina."

Conclusions: O'Connor

O'Connor



Conclusions: Weber

Weber

DANAMI-2

"There seems to be a different time clock for the biology of what happens to a thrombus and what happens to the myocardium following an acute MI. Clearly, after 4-6 hours its too late to do anything about the thrombus, even so apparently the myocardium may still be very viable."



0.5 1 1.5Favors L Favors A

Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)

Composite

CV Death

Stroke

MI

Total Mortality

Endpoint

242

99

116

91

167

# ofEventsEventsEvents

LIFE: Patients with Diabetes

L H Lindholm et al. Lancet 2002;359:1004-1010



Conclusions: Weber

Weber

WIZARD

The presence of inflammatory markers does not necessarily indicate infection

Angiotensin and aldosterone can stimulate inflammatory reactions

Other mechanisms may be causing the rise of inflammatory markers



Conclusions: Cannon

Cannon

To have so many good trials guiding therapy is good for cardiology

"We all have lots of things we can change so it keeps the field very fresh and good for patients."



Triumph of the trials: ACC 2002

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, New York

Christopher Cannon MDCardiologistBrigham and Women's HospitalBoston, Massachusetts

Christopher M O'Connor MDAssociate Professor of CardiologyDuke University Medical CenterDurham, NC

Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, New York

Documents

Heartbeat – May 2002 Triumph of the trials Triumph of the trials: ACC 2002 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center