Heartbeat – Sep 2002 ESC 2002 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai...

Heartbeat – Sep 2002

ESC 2002

ESC 2002

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


ESC 2002

Acute coronary syndromesMAGIC

OPTIMAALRITA-3

BNP prognostics

Off-pump surgery

Stem cells

Topics


ESC 2002

MAGIC: Trial design

MAGnesium In Coronaries (MAGIC)

PI: Elliot Antman

•6213 MI patients.

•Randomized to IV magnesium or placebo.

•Primary end point: all-cause mortality at 30 days.


ESC 2002

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

Death

Mg Placebo

MAGIC: Mortality results

No difference in 30-day mortality between magnesium and placebo.

No significant differences in any subgroup.

No benefit or harm seen in secondary outcomes.

“Magnesium is dead in the water.”

Rory Collins


ESC 2002

MAGIC: Time to move on

There were intriguing questions generated by earlier trials.

“But when you put it to the test, it doesn’t make any difference. So, let’s move on.”

Ferguson


ESC 2002

MAGIC: Rationale for the trial

Cannon

LIMIT-2: Mg started before thrombolysis.

ISIS 4: Mg started several hours after thrombolysis.

The negative results in ISIS-4 could have been due to the delay.

MAGIC went back to early administration of Mg.


ESC 2002

MAGIC: A might-have-been?

“We really don’t have any information that would allow us to make that judgment.”

Did magnesium never have a chancebecause ACE inhibitors and thrombolysis got there first?

Weber


ESC 2002

OPTIMAAL: Trial design

Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL)

PI: Kenneth Dickstein•5477 patients.•Acute MI.•Losartan 50 mg once daily vs captopril

50 mg 3 times daily mm Hg.•Primary end point: all-cause mortality

at 2.7 years follow-up.


ESC 2002

Lancet 360:752-760

OPTIMAAL: Results

0%2%4%6%8%

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

Rate

of

endpoin

t

Mortality CV death

captopril losartan

p=0.069 p=0.032


ESC 2002

OPTIMAAL: ACE vs ARB

The angiotensin axis is important, but ACE inhibitors are still superior to ARBs in the doses we’ve tested.

New tools help, but losartan is still just a good alternative therapy.

There is interest in higher doses of losartan.

Ferguson


ESC 2002

The results were known well over a year ago.

ELITE-2 also had a trend favoring captopril with the same doses.

VAL-HeFT used a genuine dose (160 mg twice a day) of valsartan and got FDA approval for heart failure.

50 mg is a nonsense dose.

Weber

OPTIMAAL: A Greek tragedy


ESC 2002

The name is ironic because OPTIMAAL tested suboptimal levels of losartan.

Dose is critical–-we haven’t tested proper doses of losartan yet.

“The whole rationale in this field is moving toward complete blockade of this axis, so to use a very low dose goes counter to the thinking of how this pathway can be best inhibited and outcomes improved.”

Cannon

OPTIMAAL: Misnamed


ESC 2002

Losartan as a replacement for captopril should use a minimum of 100 mg.

We should push the doses as high as one appropriately can because that goes after the pathophysiology of the problem.

Cannon

OPTIMAAL: Appropriate dosing


ESC 2002

Losartan should be used at 50 mg bid.

LIFE titrated patients from 50 mg a day to as much as 100 mg daily.

The advantage in LIFE was a stroke advantage, not an MI advantage.

“For all the excitement with the ARBs they’ve still got to prove themselves as having a cardioprotective effect.”

OPTIMAAL: ARBs

Weber


ESC 2002

RITA-3: Trial design

Randomized Intervention Trial of unstable Angina (RITA-3)

PI: Keith AA Fox•1810 patients with non-ST-elevation Ml

or unstable angina. •Randomized to conservative or

interventional approach.•Primary end points: death, MI, and

refractory angina at 4 months and death and MI at 1 year.


ESC 2002

RITA-3: Defining risk

Troponin is the most potent: high vs low risk (FRISC II).

ST-segment changes on the EKG also gives high vs low risk.

TIMI risk score ranges from 0 to 7, defining low-, intermediate-, and high-risk groups.

TACTICS-TIMI 18 and FRISC II both found intermediate to high risk benefitedfrom an early intervention strategy.

Cannon


ESC 2002

RITA-3: Heart failure as a risk factor

Admission with heart failure is a very important predictor of death but a less important predictor of recurrent MI or recurrent ischemia.

Markers of the burden of disease are more effective for predicting the broader impact of a therapy.

Cannon


ESC 2002

RITA-3: Moderate risk?

Patients in RITA-3 are called moderate risk but:•75% of the patients were troponin

positive.•Exclusion criteria included 2x normal CK

elevation.•The CK-negative/troponin-positive

group is at highest risk of recurrent ischemic events.


ESC 2002

ESC 2002

RITA-3: Event rate

0%

2%

4%

6%

8%

10%

12%

14%

16%

Rate

of

endpoin

t

4 months 1 year

Interventional Conservative

p=0.001

p=0.589.6

14.5

7.6

8.3


ESC 2002

ESC 2002

RITA-3: Trial comparison

0%

5%

10%

15%

20%

25%

Death

or

MI

in 1

year

VANQWISH T-T 18 FRISC I I RITA-3



ESC 2002

RITA-3: More cath labs

RITA-3 and TACTICS-TIMI used an early invasive approach, FRISC II a little later.

“The hope is that this will really spur Canada and the European countries to start building some more cath labs and start talking with their health authorities to say this is way we can improve outcomes for a large group of patients.”

Cannon


ESC 2002

RITA-3: So many patients

We should see cath rates in the 80% to 85% range if we follow evidence-based medicine:•Between 2/3 and 3/4 UA/NSTEMI

patients are moderate to high risk.•Three million estimated UA/NSTEMI

patients in Europe and the US.•Even in clinical trials, half the

conservative therapy group goes on to cath eventually.

Cannon


ESC 2002

RITA-3: Angina

0

20

40

60

80

100

120

Indiv

idual endpoin

t at

1 y

ear

Death MI Refractoryangina


Lancet 360:743-751


ESC 2002

Lancet 360:743-751

RITA-3: MI using standard definition

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Death

or

MI a

t 1 y

r

Death MI Death or MI



ESC 2002

RITA-3: Inadequate resources

“Even in this country we do have a great inadequacy of resources.”

Most of the hospitals in Brooklyn do not have the resources to get quickly to a cath lab and to provide the appropriate intervention.

“This is a big problem over here as well.”

Weber


ESC 2002

RITA-3: Summary

RITA-3 adds to the thinking that acute coronary syndromes fall more and more into the interventional arena.

What will the economics of this mean to poorer countries?

Fuster


ESC 2002

BNP prognostics: Trial design

BNP as a prognostic for sudden death in HF

PI: Rudolf Berger

•452 ambulatory patients with LVEF ≤ 35%.

•Primary end point: sudden death over 3 years.


ESC 2002

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

Death

<2.11 2.11+

BNP: Mortality results

A log BNP ≥ 2.11 was the only independent predictor of sudden death

This could discriminate who is a candidate for an ICD


ESC 2002

BNP: Prognostic tool

The study is fascinating because this takes BNP from a diagnostic to a prognostic tool.

Maybe we have to start monitoring BNP in our heart failure patients.

Patients with so-called mild heart failure may be the people for whom this test would be particularly helpful.

Weber


ESC 2002

BNP: Screening patients

With a 20% total mortality rate, it’s hard to say how “mild” the heart failure really is.

The predictive nature of BNP is really intriguing because we are all looking for ways to stratify patients for ICD.

“I’d like to see this extended and confirmed.”

Ferguson


ESC 2002

BNP: Questions about ICDs

Patients with MI and low EF should receive ICDs, but we are still looking at ways to screen the patients who will most benefit.

For cardiac failure not related to coronary artery disease, do we know if ICDs are even useful?

Fuster


ESC 2002

BNP: We need risk stratification

We need tools to pick out the patients who would most benefit from ICDs, because the costs could be prohibitive.

Risk stratification is the right strategy, as it was with ACS.

I’m hoping BNP can be measured in MADIT II and in upcoming trials.

Cannon


ESC 2002

BNP: Two patients

Myocardial infarction

EF = 35%

Dilated cardiomyopathy

EF = 35%


ESC 2002

Monitor the cardiomyopathy patient, maybe measure BNP levels, look for an indication to use an ICD.

I don’t think this particular information really speaks to patients with AMI. It’s not clear what the proper approach should be.

BNP: Two patients

Weber


ESC 2002

BNP will rise in the first 8 to 12 hours to a peak and then gradually descend with treatment.

Maybe we need to treat patients differently, depending on how recent their MI.

“[BNP] is now the new CRP for heart failure and I think we’ll have much more information in the next 6 to 12 months.”

BNP: AMI

Cannon


ESC 2002

BNP: Physiology matters

“It brings us back to the issue that physiology matters.”

The metabolic pathways underlying this process is important.

“We just don’t quite understand enough about it to figure out exactly what’s going on yet.”

Ferguson


ESC 2002

Off-pump CABG: Trial design

Patency of Off-Pump CABG

PI: Brompton group

•103 patients.

•54 off-pump, 49 conventional CABG.

•Primary end point: graft patency at 3-months.


ESC 2002

0%

20%

40%

60%

80%

100%

Patancy

Off-pump On-pump

Off-pump CABG: Patency results

Not a significant finding

If the grafts are more occluded, are all the advantages of off-pump surgery irrelevant?

Do we need to look deeper into what is happening with off-pump CABG?

Fuster


ESC 2002

The most important thing is graft patency.

“If it were me or my family member, I’d definitely go for the real thing.”

“I suppose it’s a replay of the PCI story, that suboptimal stent deployment leads to suboptimal results.”

Off-pump CABG: Suboptimal patency

Cannon


ESC 2002

Off-pump CABG:Tweaking the technique

We improved adjunctive therapy with PCI over time, we can do the same here.

“I think that off-pump is here to stay. I think we may just need to tweak it and may need to do the larger-scale trials looking closely at patency but also making an effort to optimize the adjunctive therapy.”

Ferguson


ESC 2002

Two or 3 patients made all the difference in this trial.

These results must be very dependent on the skill and experience of the surgeons. We might see no difference between off-pump and on-pump patency in 5 or 6 years

“But I suspect that in a handful of years we’re going to see much more shift to the off-pump method.”

Off-pump CABG: Experience

Weber


ESC 2002

Stem cells: Mode of delivery

SYLVAIN’s PIC


ESC 2002

Strauer BE et al. Circulation 2002

Stem cells: Ventricular function

Function parameterBefore cell therapy

3-monthfollow-up

p

Infarct region as functional defect* (%)

30+13 12+7 0.005

Infarct region as perfusion defect (cm2)

174+99 128+71 0.016

Stroke volume index (mL/m2)

49+7 56+7 0.010

Infarction wall movement velocity (mm/s)

2.0+1.1 4.0+2.6 0.028

*Percentage of hypokinetic, akinetic, or dyskinetic regions


ESC 2002

Stem cells: New cardiomyocytes

Bone marrow Pluripotent cells

Stromal-mesenchymalpathway

Skeletal muscle, cardiomyocytes


ESC 2002

Stem cells: Arrhythmia

There are concerns about increased risk of arrhythmias with this technique.

We need studies with more patients.

“As we look at heart failure, as we look at acute myocardial infarction, I think [stem cell therapy] is an area that we’re going to be seeing an awful lot more from. ”

Ferguson


ESC 2002

“The whole field of acute MI has revolved around the need for early salvage because you can’t get the heart cells back. But if in fact you can repair the heart then it’s just a wonderful new hope.”

Stem cells: A new hope

Cannon


ESC 2002

Summary: MAGIC

Randomized MI patients to IV magnesium or placebo.

Absolutely no effect on mortality at 30 days.

“We have to forget about magnesium, at least for the next 25 years.”

Fuster


ESC 2002

Summary: OPTIMAAL

Losartan 50 mg once daily vs captopril 50 mg 3 times daily.

Trend favored captopril, but questions remain because the dose of losartan was so low.

“The issue is not closed.”

Fuster


ESC 2002

Summary: RITA-3

NSTEMI/UA patients randomized to conservative or interventional approach.

Intervention is much better than conservative therapy.

“This really moves the field of acute coronary syndromes more and more toward the interventional area.”

Fuster


ESC 2002

Summary: BNP

BNP was a predictor of sudden death in patients with chronic cardiac failure.

This opens the possibility of screening patients for ICD use.

The data don’t translate into AMI patients, where BNP levels are highly variable.

Fuster


ESC 2002

Summary: Off-pump surgery

We all think off-pump surgery lets patients go home early and has fewer bleeding complications.

Graft patency was better in the on-pump CABG patients.

We need to follow this new technology closely.

Fuster


ESC 2002

Summary: Stem cells

Injection of pluripotent bone-marrow cells into myocardium post-MI.

No inflammatory response, potential improvement in ventricular function, but a possible increase in arrhythmia.

Fuster


ESC 2002

Patients in the original SOLVD trial got 8 to 9 months of increased life expectancy from aggressive ACE inhibitor treatment.

It just emphasizes how the newer modalities we talked about today may be the ones that will make a real difference for people with heart failure.

Final word: SOLVD

Weber


ESC 2002

In the ACS arena, the invasive strategy has held up as the best management strategy.

“Hopefully we’ll start to see a move toward more patients being referred appropriately for cardiac catheterization and probably a need for more cath labs.”

Final word: Interventional strategy

Cannon


ESC 2002

“The dose of a given drug is almost as important as the drug itself.”

We need to make sure we are dosing appropriately in our practice. It’s not just enough to be on the right drug, the dose must be the right dose.

Final word: Dose

Cannon


ESC 2002

Final word: 3 lessons

1: We need clinical trials:more and more important at meetings.

2: If you do trials, you need to do them right:

dosing, logistics, understand the biology.

3: Care moves forward: We have a responsibility to take the information and apply it to real-world practice.

Ferguson


ESC 2002

ESC 2002: End

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 – Sep 2002 ESC 2002 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai...

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Transcript of Heartbeat – Sep 2002 ESC 2002 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai...