Post on 17-Dec-2015
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
Heartbeat – Sep 2002
ESC 2002
Acute coronary syndromesMAGIC
OPTIMAALRITA-3
BNP prognostics
Off-pump surgery
Stem cells
Topics
Heartbeat – Sep 2002
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.
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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.
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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.
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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.
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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.
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Interventional Conservative
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
ESC 2002
RITA-3: Angina
0
20
40
60
80
100
120
Indiv
idual endpoin
t at
1 y
ear
Death MI Refractoryangina
Interventional Conservative
Lancet 360:743-751
Heartbeat – Sep 2002
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
Interventional Conservative
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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.
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
ESC 2002
BNP: Two patients
Myocardial infarction
EF = 35%
Dilated cardiomyopathy
EF = 35%
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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.
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
ESC 2002
Stem cells: Mode of delivery
SYLVAIN’s PIC
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
ESC 2002
Stem cells: New cardiomyocytes
Bone marrow Pluripotent cells
Stromal-mesenchymalpathway
Skeletal muscle, cardiomyocytes
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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
Heartbeat – Sep 2002
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