Heartbeat – AHA 2006 AHA 2006: Occluded arteries, NSAIDs, and D2B Christopher Cannon MD Staff cardiologist Brigham and Women's Hospital, Boston, MA Valentin

Heartbeat – AHA 2006

AHA 2006: Occluded arteries, NSAIDs, and D2B

Christopher Cannon MDStaff cardiologistBrigham and Women's Hospital, Boston, MA

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical Center, New York, NY

James "Terry" Ferguson MDAssociate Director, CardiologyTexas Heart Institute, Houston, TX

Harlan Krumholz MDYale University School of MedicineNew Haven, CT


TOSCA 2: The Total OcclusionStudy of Canada

International study looking at the effects of percutaneous coronary intervention (PCI) on late artery patency and left ventricular (LV) function

Enrollment: May 2000 to July 2005

Population: 381 patients with an occluded native artery leading to MI

Dzavik V et al. Circulation 2006; published online before print Nov 14, 2006.

Fuster


TOSCA 2

Patients were randomized between three and 28 days to either

•PCI with stenting•Optimal medical therapy alone

Coronary and LV angiography was performed one year after randomization

Primary end points•Patency of the infarct-related artery•Change in LV ejection fraction (LVEF)

Fuster


TOSCA 2: Results

PCI was successful in 92% of the cases

At one-year follow-up, the artery was open in •83% of PCI patients•25% of the medically treated patients

At one-year follow-up, LVEF was completely unchanged in the PCI group, in spite of the significant improvement in patency

In both groups, EF increased slightly •~4.2% in the PCI group•~3.5% in the medically treated group

Fuster


TOSCA 2: Conclusions

PCI with stenting of a persistently occluded infarct-related artery in the subacute phase of an MI (between three and 28 days) maintains long-term patency but has no effect on LVEF

PCI is therefore not recommended for stable patients with a persistently occluded infarct-related artery after MI

Fuster


Results not surprising

A clear randomized trial is very helpful in sorting such questions out

If an infarct is completed and there's no ischemia, it's an anatomic change

Cannon


Value of retrospective studies

Retrospective ad hoc analyses have suggested that opening an artery late after an MI benefits patients

Animal models have suggested that there is a viable zone surrounding the infarct, which can, over a period of time, become necrotic if the artery is not opened

Can retrospective studies lead us in wrong direction?

Fuster


Issues with retrospective trials

Retrospectively, we sometimes emphasize things that reinforce our beliefs and we discard or don't pursue things that don't, leading to a certain publication bias

TOSCA 2 is about surrogate outcomes

•They tried to spin some of this positively by talking about LV size, but there really isn't much that reinforces positive ideas

Krumholz


Fibrinolytic trials

In the fibrinolytic trials, there's an early separation in risk

•You see benefit up to 35 days

In the 10-year data, the lines become parallel

You save lives early, but the lines don't continue to separate

Of the survivors at 35 days, those who got fibrinolytic therapy must have been more likely to have open arteries than thosewho didn't, yet the lines are completely parallel after that

Krumholz


Retrospective trials

Retrospective studies suggest that opening arteries late in life is beneficial

However, the grades of evidence used must be considered

Krumholz


Everybody dies

In every study, the curves become parallel at the end—everybody dies

How long does it take for the curves to becomes closer together?

•Here, it's very soon (three to 28 days)

"My hypothesis is that the medically treated patients were so well treated with ACE inhibitors and beta blockers that the whole concept of remodeling was taken care of by pharmacological therapy."

•Whether the artery is opened or not is irrelevant; we are treating our patients today much better medically

Fuster


No reason to intervene

Presumably, the same medical therapy was undertaken in the people that were intervened upon

It's just not beneficial to open occluded arteries when the infarct is completed and it's a simple infarct

Pharmacological therapies to stabilize atherosclerotic plaque and reduce the likelihood of events are substantial right now

Ferguson


Aggressive treatment helps everyone

It is becoming more and more clear that the more aggressively you treat the patient medically, the better the results in the so-called control group

In the OAT study, we look at the function of the ventricle

•It appears that the ventricle is the same in both groups because they are both treated very well

Fuster


OAT: The Occluded Artery Trial

Worldwide study of 2166 stable patients who had•Total occlusion of the infarct-related artery three to 28

days after MI•Relatively low EF (<50%)

Patients were randomized to either•Routine PCI and stenting with optimal medical therapy•Optimal medical therapy alone

Primary end point at three-year follow-up•Composite of death, MI, or NYHA class 4

heart failure

Fuster

Hochman JS et al. N Engl J Med 2006; published online before print Nov 14, 2006.


OAT: Results

Cumulative primary event rate

•17.2% in the PCI group

•15.6% in the medical-therapy group

Fatal or nonfatal rates of MI

•7% in the PCI group

•5.3% in the in the medical-therapy group

Nonfatal MIs

•6.9% in the PCI group

•5% in the in the medical-therapy group

Fuster


OAT: Conclusions

PCI did not reduce the occurrence of death, reinfarction, or heart failure

There was a trend toward excess reinfarction during the four-year follow-up in stable patients with occlusion of the infarct-related artery three to 28 days after MI

Fuster


Financial considerations?

"Is this an issue of knowing an answer to thescientific question, or was it a case of putting thepocketbook, the ability to reap financial rewards fromdoing the procedures, over the interests of patientsbeing given the opportunity to participate in a clinicaltrial that would answer a very important question?"

— Rob Califftheheart.org, Nov 14, 2006

Many cardiologists are enamored by the open-artery hypothesis

"I'm not sure this was driven so much by finances as by a strong conceptual model that opening the arteries is a good thing to do for patients."

Krumholz


Who were the OAT patients?

Were people that physicians felt would benefit most from opening the artery not directed to the study?

Were those that were directed toward the study the ones that physicians felt could do without intervention?

Does this population represent all the people who met the eligibility criteria?

"This is another nail in the coffin for doing PCI electively for stable patients, especially those without symptoms."

Krumholz


A definitive answerto the trial question

The question this trial asked was answered definitively

•We must be careful not to go beyond it

The points that Rob Califf made during the discussion about the pathetic enrollment numbers in the US are valid

What led to such a slow and difficult enrollment in the US?

Does this mean that there are actually very few of these patients in the US?

Ferguson


OAT patients

OAT participants were very stable patients that physicians felt were appropriate for the trial

•The upcoming COURAGE trial will study patients with a positive stress test, not an occluded artery, to determine whether intervention is necessary in otherwise-stable patients

The OAT data distinguish the use of PCI in stable patients from its use in either acute MI as primary intervention or in patients with recurrent ischemia where intervention is clearly indicated

Cannon


Too much angioplasty

The OAT data were well presented

However, the lines have gotten blurred, and once again there's too much angioplasty being done

Ferguson


Eligible vs enrolled patients

How are patients screened for enrollment into trials?

We see recommendations about registries, but they are expensive

Most trials don't explain the patients who met the eligibility criteria but who don't get into the trial

Krumholz


Registries: Useful when selecting certain types of patients

In the acute ST-elevation-MI setting, the population is generally representative

•Those not enrolled tend to be those with clearly documented comorbidities

The SAVE trial of ACE inhibitors post MI •25 000-person registry•2000 people enrolled in the trial

We can learn a lot from registries•For the initial trial •For sorting out what unmet needs there

are in the populations not enrolled

Cannon


Prospective trials: The real world

FREEDOM •Multivessel diabetic patients with significant

risk-factor profiles•All the risk factors were treated very

aggressively

The NHANES data are completely different from the registry data, in which there is compliance in risk-factor profile in more than 70% of patients

Prospective studies seem to be conveying that strong medical therapy can be a winner in many of the interventional studies, particularly in stable patients

Fuster


Compliance is important

The testing of a new intervention should be done on a background of doing all the things we know we should be doing

For the trial, it's appropriate to have excellent background therapy, because then we know that changes are incremental

Compliance in the real world is amazingly low

This should be impetus for us to find new strategies to make the real world better

Cannon


Reinforcing compliance

The structure of trials tends to reinforce compliance and adherence

What can we learn about the things we do in trials that we can apply to everyday practice?

There might be inexpensive strategies that would allow the treatment patterns seen in trials to be reflected in real-world populations

Krumholz


Wasting time

During the acute phase of MI, a patient can spend two hours in the ER before the artery is finally opened

Why is so much time wasted?

Guidelines recommend that the time from a patient entering the ER to balloon inflation should be no more than 90 minutes

Fuster


Study of door-to-balloon time

This study looked at the effect that 28 specific strategies had on door-to-balloon time in 365 hospitals in the US

In a large number of hospitals in the US, the time from door to balloon is longer than 90 minutes

Bradley EH et al. N Engl J Med 2006; published online before print Nov 13, 2006.

Fuster


Reducing door-to-balloontime in acute MI

Strategies for reducing door-to-balloon time •Have an emergency-medicine physician on site

to activate the cardiac cath lab immediately •Require only a single call to a central page

operator to activate the cath lab •Activate the cath lab while the patient is en

route to the hospital and an EKG is being transmitted and interpreted

•Have an attending cardiologist around the ER

Are these strategies feasible or are they going to be expensive and difficult to implement?

Fuster


A beautiful analysis

This is a fabulous example of a new approach to sorting out quality of care

•Each step was identified and assessed, and then it was determined which steps worked

It's a very scientific approach to practical commonsense type things, to see what's actually working at different places

"It's a beautiful analysis that helps us focus on the things that can work."

Cannon


Small things make a big difference

This is the sort of thing we need to be doing if we're going to improve care

We establish goals and targets, but we are completely unsuccessful in reaching them

The strategies identified were not frequently applied in the 365 hospitals surveyed

• <4% of the institutions had a cardiologist in the hospital, which saved about 15 minutes

• No strategy was present in more than half the institutions

This is an opportunity to tangibly begin reducing door-to-balloon times

Ferguson


Menu of strategies

This provides a menu of strategies that work from which hospitals can choose

Having the cath lab located on the same floor as the ER wasn't associated with any benefit in time, so hospitals don't have to spend millions of dollars relocating their cath labs

Hospitals can direct resources toward things that have worked in other hospitals

It's very helpful to have this laid out scientifically

Cannon


Focus not on what to dobut on how to do it

The 28 strategies tested came from site visits to hospitals around the country that were performing extraordinarily well

•We visited these places•We took field notes•We interviewed people•We tried to understand what they were doing

right

We then were able to correlate practicesand times

Krumholz


"Door to Balloon: An Alliancefor Quality" campaign

When we were finishing our report, we recognized that we should put our results into action

We launched a campaign to disseminate information to hospitals, so that they could

•Pick the easiest strategies and implement them immediately•Make a commitment to change practice

Four of the six strategies are organizational; they don't cost anything

We're trying to get hospitals to adopt the easy ones now so that they can improve their performance immediately

Krumholz


What about liability?

What if door-to-balloon time for a patient is 120 rather than 60 minutes?

Does the hospital become legally liable?

Fuster


The downside of guidelines

Even with guidelines you increase liability; any treatment that doesn't comply with the guidelines is susceptible to legal action

We have to continue to do the right thing, to do our best, to commit ourselves to the interest of the patient

We can't defend ourselves against people who want to take advantage of a system that doesn't always work

Setting standards opens us up to the risk of not meeting those standards

Krumholz


Delivering the best possible care

This is exactly the kind of effort and undertaking that physicians need to be doing to make sure that we deliver the best possible care

These strategies are not complicated or difficult

"The logistics of getting a cath-lab team within 20 minutes and the logistics of having a physician on site are a little bit daunting, but if you really want to get better and you really want to be a heart-referral center for acute MI, those are the things you have to do."

Ferguson


There's work to be done

This will help for the in-hospital phase of treatment

Probably a bigger issue to tackle is the transfer component of door-to-balloon time

•A similar analysis could identify what kind of things will help speed up transfer from outside hospitals

Cannon


COX-2 inhibitors

Selective COX-2 inhibitors predispose a patient to an increased risk of thrombotic events by inhibiting a defense mechanism against thrombosis (prostacyclin)

Nonspecific COX inhibitors (eg, aspirin) block such inhibitors, which is bad news, but they also block thromboxane

This study looked at the selective COX-2 inhibitor etoricoxib

Fuster• Cannon CP et al. Lancet 2006; 368(9549): 1771-1781.


MEDAL: Etoricoxib vs diclofenac

Researchers compared, in 34 701 patients, etoricoxib with diclofenac, an NSAID that is not as pure as the selective COX-2 inhibitors

Some NSAIDs block thromboxane better than others

Diclofenac is widely used in patients with rheumatoid arthritis and osteoarthritis

The study pooled data from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomized to the selective COX-2 inhibitor etoricoxib or to diclofenac

Fuster


MEDAL: Results

Thrombotic cardiovascular events•320 in the etoricoxib-treated group, a rate of

1.24% a year•323 in the diclofenac-treated group, a rate of

1.3% per year

The rate of complicated upper-gastrointestinal events was similar in the two groups

Results with the very selective inhibitor of COX-2, etoricoxib, are similar to those with diclofenac, the less-selective NSAID, which is believed to also block the thromboxane pathway

Fuster


COX-2 inhibition:One question answered

A population of almost 35 000 is very impressive

MEDAL answered one question, which had to do with the selectivity of COX-2 inhibition and its effect on cardiovascular events

• It leaves other questions unanswered

Diclofenac also has some COX-2 effects; it might be the worst of the NSAIDs

"The COX-2 issue is the tip of the iceberg that relates to the entire nonsteroidal field, or at least the vast majority of the nonsteroidal field."

Ferguson


Questions remain

MEDAL provides information about COX-2 inhibition and cardiovascular events as it compares with an NSAID

But what are the risks?

COX-2 inhibitors and NSAIDs are not going away

Studies like this will tell us more about how we can use these drugs and who should be using them

Ferguson


The spectrum of selectivityfor COX inhibition

Grosser T, Fries S, FitzGerald GA. J Clin Invest 2006;116:4-15.

COX-1 IC50 (μM)

CO

X-2

IC

50 (

μM

)

100.00

10.00

1.00

0.10

0.010.01 0.10 1.00 10.0 100.0

naproxenibuprofen

indomethacin

acetaminophen

meloxicam

nimesulideetoricoxib

lumiracoxib

rofecoxibvaldecoxib

celecoxib

diclofenac

Krumholz

equivalent COX-1 and COX-2 inhibition

less potent more potent


EDGE trial

Three years ago the FDA asked for some one-year data on outcomes

EDGE trial: 7500 patients

To get definitive answers, we pooled that as part of the overall program to get long-term (out to three years) data

CannonHerbert SB et al. Arthritis Rheum 2004; 50(9, suppl):S346.


What is COX-2 selectivity?

The COX-2 level of inhibition is similar across all of the agents

The difference is the amount of COX-1 inhibition, so an agent is more selective for COX-2 if there's less COX-1 inhibition

Cannon


COX-1 inhibition = thromboxane inhibition

The COX-2-selective agents have almost no COX-1 inhibition•Celecoxib, etoricoxib, rofecoxib, and lumiracoxib, at the

doses used, have essentially no COX-1 inhibition

Diclofenac is intermediate•At a peak of ~60%, platelet inhibition is reversible

Ibuprofen can reach 90% inhibition for about two hours in a dosing interval, which is why ibuprofen is not used as a substitute for aspirin in cardiac patients

Naproxen, at a high dose, has a longer half-life and has constant platelet inhibition (~90%-95%)

Cannon


Diclofenac vs COX-2 inhibitors

Diclofenac is in the middle range and the closest in the spectrum when the IC50, or the concentration of a drug that would block the receptor, is used as the metric of selectivity

Diclofenac is different in the amount of COX-1 and platelet inhibition it has

Diclofenac has COX-1 inhibition; the COX-2 inhibitors don't

In MEDAL, the shift from some COX-1 inhibition to no COX-1 inhibition didn't increase the risk of thrombotic events

Cannon


Complete COX-1 inhibitionwith platelet inhibition

High-dose naproxen has been shown to be much better in terms of MI than rofecoxib

"This has pushed a little bit further the idea that the level of platelet inhibition might be driving the beneficial effects that have been seen to date with the high-dose naproxen."

Cannon


Low event rates

When you pool patients with rheumatoid arthritis and osteoarthritis together, COX-2 appears to be a disaster

However, the event rate is very low: 1.24% per year

That's what you'd get in the general population >50 years not taking a COX-2 inhibitor

Fuster


Event rates as anticipatedIn MEDAL, the average age was ~63 years

There were a spectrum of risks • ~1% of the population had no known disease or risk

factors• ~3% of the population per year had known prior MI or

stroke (similar to that in CHARISMA)

Event rates are much lower than in PROVE-IT, in the post-ACS setting, where the patients were very unstable

"The absolute differences in risk that we're talking about are in the one-per-1000 range, so it's micro differences, but obviously still important to sort out ."

Cannon


COX-2 conundrum

Has the issue of COX-2 been overblown?

Fuster


Importance of event ratesEvent rates are very dependent on the population that's enrolled

• For rofecoxib, there's evidence that the event rate doubles

• In VIGOR, the event rate quintupled

In absolute numbers, the number of heart attacks was small

In a real-world group that has real-world rates, do the relative increases hold steady?

If there's no interaction between underlyingrisks and the relative increase in risk, these become important

Krumholz


Absolute vs relative increases

The reason there are small absolute differences is because the underlying risk in the study population is low

The question is whether the relative increases we see are going to be bigger, smaller, or the same as in a higher-risk population

If the event rates are taken at face value, then in any sort of real-world population, there is concern about additional events

Absolute increases in risk from clinical-trial populations cannot be extrapolated to lower-risk populations

Krumholz


MEDAL: Representative population

In MEDAL, we enrolled 34 700 patients in 18 months

This is a pretty representative population

There are undoubtedly people at higher risk who were not enrolled, but it is a pretty broad group

Cannon


No cause for alarm

The point is not to be alarmist about some of these results, but patients must be informed

Sometimes an increase in the relative reduction in a population that has a relatively low absolute rate is not that big a deal

Patients should know what they're getting into

Krumholz


Is some of the problem our fault?

Sometimes we report results with significant p values, the press gets involved, and then everybody gets frightened

We have to learn how to transmit data to the public

Fuster


Context matters

Huge relative increases have to be taken in the context of the absolute numbers that we're talking about

Ferguson


Summing up: Opening arteries

"I learned something that we knew for a long time: the earlier you open an artery in MI, the better the results."

Harlan Krumholz's group came up with a strategy to do that in the hospital

•We now need strategies that apply outside the hospital and education for the public

In two studies, opening an artery three to 28 days after MI in what appears to be a stable group of patients doesn't make a difference in terms of EF at one year or clinical events at three to four years

Fuster


Summing up: COX-2 inhibitors

COX-2 inhibitors have been a problem when it comes to thrombotic events, because they do not inhibit platelets but they do inhibit an inhibitor of platelets (prostacyclin), which leads to thrombotic events

A comparison of a pure COX-2 inhibitor and an intermediate COX-2 inhibitor found that there was no difference in event rates

A question about relative and absolute risk was raised

Do we talk too much about results with p values that have little impact,thereby frightening the public?

Fuster


The importance of randomized trials

One theme that emerged is the value of randomized trials

We intuitively thought opening an artery would be great but learned from two randomized trials that the anticipated benefit wasn't there

Many thought there would be a dramatic increase in cardiovascular events with selective COX-2 inhibitors, but a large randomized trial showed that this wasn't the case

Large randomized trials help us get at the real answer so that we can make reasoned decisions

Cannon


You can't fool Mother Nature, we need to do what's right, and we

don't know it all "There's stuff that we thought we knew that was wrong, there's stuff that we thought we knew that was right, and stuff that we still don't know."

The stuff we thought we knew that was wrong is that all these arteries should be opened

The stuff we knew that was right is that, in acute MIs, we need to open the arteries up as soon as possible

The stuff we still don't know about hasto do with the COX world

Ferguson


www.d2balliance.org

I urge listeners to encourage their hospitals to become part of the "D2B: An Alliance for Quality" campaign

The closed artery studies were very useful•They should make us think twice about

intervening when we have no clear evidence of benefit

The COX-2 study adds to the literature, but many questions remain

Krumholz


Final comments

What we do in the ER and in hospitals should be simplified

When medical therapy is done well in the stable patient, it is going to prevent a significant number of interventions

In two of the studies that we discussed today, the best medical therapy was used and the patients did well

Fuster

Documents

Heartbeat – AHA 2006 AHA 2006: Occluded arteries, NSAIDs, and D2B Christopher Cannon MD Staff cardiologist Brigham and Women's Hospital, Boston, MA Valentin