valentin fuster md director, cardiovascular institute mount sinai medical center new york, ny

Heartbeat – May 2003

ACC 2003

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

ACC 2003: Biomarkers and devices


ACC 2003

BiomarkersCalcium scoreLp-PLA2

Dual-chamber pacemakersCOMPANION trial

Drug-eluting stentsTAXUS II and SIRIUS

Topics


ACC 2003

EBCT: St Francis Heart Study

Assessment of prognostic accuracy of EBCT

• Prospective, longitudinal, population-based study, scanning 5585 asymptomatic men and women aged 50 to 70 years of age and with no prior history of CV disease

• Risk factors for CV disease were measured in 1817 patients.

• High calcium scores: >80th percentile for age and gender and were compared with controls (<80th)

• Follow-up 4.3 years


ACC 2003

EBCT:Calcium score threshold

Guerci AD. ACC 2003

Calcium score

Positive predictive value (%)

Specificity (%)

Sensitivity (%)

95% CI

>0 3.2 36 91 3.0-11.6

>100 8.6 82 71 7.1-16.3

>200 10.5 89 54 6.1-12.9

>600 14.1 96 26 5.3-12.1

RR of CV event for calcium score >100 vs <100 = 9.5


ACC 2003

EBCT: What do you do with it?

26% sensitivity is not very high

What to do with patients with high calcium score?

•Asymptomatic patients

•High calcium score only leads back to treating known risk factors

Weber


ACC 2003

EBCT: What for?

What are we using the test for?

•Not very effective for screening a population

Standard risk factors are still cheaper and easier to evaluate

Harrington


ACC 2003

EBCT: Reacting to a high score

Do you take a high-calcium-score patient to get an angiogram?

Do you revascularize patients based on anatomy?

What do we want to use this test for?

Start with classical risk factors and maybe look at other, cheaper biomarkers

Harrington


ACC 2003

EBCT: Beyond the evidence

Cannon

Patient with a score of >600 means there may be a problem, but you go back to traditional approaches

A potential use of EBCT is to convince someone with risk factors that there really is a problem

"To go beyond doing risk-factor modification goes way beyond the data."


ACC 2003

EBCT: A warning sign

A high calcium score is like having diabetes

•Once identified, you aggressively approach all the risk factors

"It puts people on alert that perhaps you have to be much more aggressive in the approach to the patient."

Fuster


ACC 2003

EBCT: Reacting to a low score

A calcium score of zero implies no anatomical disease at that moment

"It shouldn't give you carte blanche to go out and ignore the other conventional risk factors."

A good sign, but it doesn't negate the fact you should monitor traditional risk factors

Harrington


ACC 2003

Lp-PLA2: WOSCOPS

Lipoprotein-associated phospholipase A2: enzyme that hydrolyzes phospholipids

•WOSCOPS found Lp-PLA2 to be an important predictor of nonfatal MI, death from cardiac causes, or revascularization as a first event

Fuster


ACC 2003

Lp-PLA2: ARIC

ACC 2003

Outcome Second tertile of Lp-PLA2

(310-420 μg/L)

Third tertile ofLp-PLA2

(>420 μg/L)

LDL <130 mg/dL (without CRP adjustment)

1.81 (1.10-2.97) 2.02 (1.19-3.44)

LDL <130 mg/dL (with CRP adjustment

1.81 (1.08-3.01) 2.12 (1.22-3.69)

CHD risk ratio by Lp-PLA2 tertiles in ARIC

(lowest tertile is reference)


ACC 2003

Lp-PLA2: Biomarkers

Marker approach to risk-stratification is "taking off"

Risk markers in ACS are expanding, here we have some in a stable population

Inexpensive tests that refine and expand identification of high-risk patients

"This is a very promising area in general."

Cannon


ACC 2003

Lp-PLA2: What do you do?

Promising—but unclear what to do with a result

"What do we do if we know someone has an elevated Lp-PLA2? What are we going to treat? What are we going to do to make these patients better?"

We are increasing our awareness of risk, and maybe motivating the patient, but we aren't sure how to treat this

Weber


ACC 2003

Lp-PLA2: Exciting times

Biomarker approach is expanding our diagnostic and prognostic capabilities

"We are at the cusp of a very exciting time to be able to offer more and more for this population of patients, but clearly a lot of work needs to be done."

Harrington


ACC 2003

Lp-PLA2: Active elements

Perhaps in the future this will be computerized, where the assembly of factors are analyzed at once

We will need to determine which are active and which are just markers

Fuster


ACC 2003

Lp-PLA2: Applications

Biomarkers started to gain traction with troponin but became popular only when linked to a treatment strategy

"When you can link up doing something differently based on a new marker, this is when people find it very useful and it will get into guidelines."

Cannon


ACC 2003

COMPANION: Trial design

Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure

• 1600 patients with QRS >120 ms, P-R interval >150 ms, class 3 or 4 heart failure, and hospitalization for HF in past 12 months

•Randomized to optimal medical therapy, cardiac resynchronization, or resynchronization with an ICD

•Primary end point: all-cause mortality and all-cause hospitalization


ACC 2003

ACC 2003

COMPANION: Results

05

1015202530354045

Reducti

on in e

vents

(%

)

Mortality andhospitalization

All-cause mortality

CRT CRT+ICD


ACC 2003

COMPANION: Very preliminary data

The total number of events were relatively small

There wasn't a real difference between CRT and CRT+ICD, so do you need both?

This was a highly selected population and those selection criteria might be used to decide who gets these devices

Weber


ACC 2003

COMPANION: When to present data?

With modern technology, we can present data to practicing clinicians in many ways

"When you have preliminary data, which are not fully complete, when you have data that are complicated . . . it takes a bit more to digest it and to determine if these are the kind of data that ought to impact practice."

Harrington


ACC 2003

COMPANION: Too soon

We don't have enough information yet

• Not all rehospitalizations were counted as part of the end point

We need to see the final trial results

These are complicated data and there are huge financial-resources issues here

Harrington


ACC 2003

COMPANION: A new avenue

Devices in HF have advanced while neurohormonal inhibition seems to be leveling off

"Cardiac synchronization is for real."

Novel data suggesting ICD in nonischemic cardiomyopathy

Cannon


ACC 2003

COMPANION: CRT ineffective?

The ICD data were consistent with the known ICD story

The CRT mortality reduction was not statistically significant

The combined end point in CRT was driven by the rehospitalizations, but which rehospitalizations were includedwas unclear

Harrington


ACC 2003

COMPANION: Trend on mortality

Trend on mortality for CRT

"That says that the benefits that have been seen in each of the studies in terms of improving symptoms and reducing hospitalizations may have an even broader impact."

Cannon


ACC 2003

COMPANION: Two questions

If life is prolonged, how many months or years?

• In a high-risk patient, how much real gain do you get?

Improvement of symptoms

•Stress testing•Oxygen consumption

Fuster


ACC 2003

COMPANION: Additional lifespan

We don't have the data in yet

•SOLVD and CONSENSUS showed ACE inhibitors added 3 to 6 months

• I expect an increase of less than 3 to 6 months lifespan for these devices

Weber


ACC 2003

COMPANION: Cost effectiveness

Given the costs, it is even more important to get the cost-effectiveness analysis done

"What is the actual cost per life-year saved?"

Industry and investigators should work to include these analyses as part of evaluation of these therapies

Harrington


ACC 2003

COMPANION: Optimism

"One important thing here is that we are seeing mortality benefits that are pretty dramatic."

This is the highest risk of the heart-failure group

"This can be a great therapy to offer to the patients where you've done everything and yet they're still not living a livable life really."

Cannon


ACC 2003

COMPANION: Significant advance

We need the cost-effectiveness data

Hopefully wide use of these devices will bring the cost down

"It’s the constant drum beat—each of these two different devices, and it looks like both together, have been a significant advance."

Cannon


ACC 2003

COMPANION: Mechanical interventions

Mechanical interventions have had a significant impact on CV health

•CABG•PCI•Transplantations•Pacemakers•Defibrillators

Fuster


ACC 2003

ACC 2003

TAXUS II: 12-month results

0

5

10

15

20

25

Events

l (%

)

MACE TVR TLR

Controls Slow-release stents Moderate-release stents


ACC 2003

TAXUS II: Encouraging

Not that much new between 6 and 12 months

Clinical end point for TVR has gradually moved to 9 months since 6 months doesn't allow long enough follow-up

How does it stack up to sirolimus? Trial-to-trial comparisons are hard

Cannon


ACC 2003

TAXUS II: Winning technology

The technology works on both:

•The biology (TVR)•The clinical aspect (MACE)

Patients have been mainly low- or moderate-risk patients

We need randomized head-to-head comparisons

Harrington


ACC 2003

TAXUS II: Risk

These were patients mainly with single-vessel disease

Against historical controls, even bare-metal stents in this trial did reasonably well

It would be interesting to see the results in a high-risk group

Weber


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

"The good news is, we're not going to bankrupt the healthcare system."

Hospitals will pay more up front and get fewer admissions

HMOs will benefit by fewer repeat procedures

Cannon


ACC 2003

Coated stents: Perspective

"From a national perspective, this looks to be a good thing. Yes, it's an expensive technology up front but it does reduce some serious outcomes that are both important to patients and expensive."

Individual health systems will need to grapple with how to deal with this

Harrington


ACC 2003

Coated stents: Other patients

How do we apply the data for patients not yet studied?

•Multivessel disease•Diffuse disease•Very small-vessel disease•Chronic total occlusion•Graft disease

Still work to be done on how to incorporate it into practice

Harrington


ACC 2003

Coated stents: Cost issues

"You can't look at this from the point of view of hospital costs or pharmacy costs, but you have to look at it as a total integrated concept."

With more approvals, that should drive down costs

Federal authorities are getting hostile to new technologies that raise initial cost

Weber


ACC 2003

Summary: EBCT

Calcium score does seem to have predictive value

Calcium score may add to Framingham risk

Calcium score should not lead to treatments we wouldn't otherwise do for patients with high-risk factor profiles

Fuster


ACC 2003

Summary: Lp-PLA2

ACC 2003

Outcome Second tertile of Lp-PLA2

(310-420 μg/L)

Third tertile ofLp-PLA2

(>420 μg/L)

LDL <130 mg/dL 1.81 (1.10-2.97) 2.02 (1.19-3.44)

LDL <130 mg/dL 1.81 (1.08-3.01) 2.12 (1.22-3.69)

CHD risk ratio by Lp-PLA2 tertiles in ARIC

(lowest tertile is reference)


ACC 2003

Summary: COMPANION

CRT with or without ICD for patients with severe heart failure

May have meaningful use for a small but very sick group of patients

ICDs may be effective in patients with dilated cardiomyopathy

Results are still very preliminary

Fuster


ACC 2003

Summary: Drug-eluting stents

Results continue to be positive and impressive

Should we have a trial comparing paclitaxel vs sirolimus?

The sirolimus stents appear to be cost-effective over time when compared with conventional stents

Fuster


ACC 2003

Final word: Cannon

Devices are advancing tremendously

"There has been a lot of talk about all the various medical therapies, but now in CHF these two different technologies both seem to be very helpful."

Cannon


ACC 2003

Final word: Weber

Drug-eluting stents are the way of the future and CRT and ICDs are promising

"We can talk about high cost and all the difficulties of selecting the right patients but I think deep down we all know that if we had patients who would fit those criteria we wouldn't hesitate to make this sort of technology available to them."

Weber


ACC 2003

Final word: Harrington

"Our beginning discussion on markers really tells me that we are here in an era of proteomics."

We need to learn how to use biomarkers to improve:

•diagnosing patients•risk-stratifying patients•selecting therapies

Harrington


ACC 2003

Final word: Fuster

We are entering an era of merging physicists and biologists

"This field is evolving like NASA, where all the different people have something to offer."

Fuster

valentin fuster md director, cardiovascular institute mount sinai medical center new york, ny

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