acc 2006 part 2: where's the controversy?

Heartbeat – ACC 2006

ACC 2006 part 2: Where's the controversy?

Christopher Cannon MDStaff cardiologistBrigham and Women's HospitalBoston, MA

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

Melissa Walton-Shirley MDCardiologist TJ Samson Community HospitalGlasgow, KY


Four controversial studiesfrom the recent ACC meeting

ASTEROID

• A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden

UNLOAD

• Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure

BASKET-LATE

• Basel Stent Cost-Effectiveness Trial–Late Thrombotic Events

MIST

• Migraine Intervention with STARflex Technology

Valentin Fuster


ASTEROID: Study design

Between November 2002 and October 2003, 507 patients were enrolled in this intravascular ultrasound (IVUS) study

All patients were treated with 40-mg rosuvastatin daily

There was no control group

Participants were followed for 24 months, at which time they were reevaluated with IVUS

Baseline and 24-month IVUS data were available for 349 patients

Nissen SE. ACC 2006 Scientific Sessions; March 13, 2006; Atlanta, GA. Abstract 411-8.Nissen SE, et al. JAMA 2006;295:1556.

Valentin Fuster


ASTEROID:Lipid results (mean values)

Baseline

After 24months of treatment

%change*

Total cholesterol (mg/dL)

204 133.8 –33.8

LDL-C (mg/dL) 130.4 60.8 –53.2

HDL-C (mg/dL) 43.1 49.0 +14.7

Triglycerides (mg/dL) 152.2 121.2 -14.5

LDL-C/HDL-C ratio 3.2 1.3 –58.5

*p<0.001 for all comparisons between baseline and during treatment


The mean change in the percent of atheroma volume was borderline because it was of an entire vessel

•Average decrease in volume was 3.1%

Results were significant at p=0.001

Valentin Fuster

ASTEROID: Primary efficacyparameters


ASTEROID: Conclusions

It appears that 40-mg rosuvastatin daily not only prevented progression of the disease but also slightly enhanced regression

However

•The patient population was not high risk.

•There was no control group.

•The changes are minimal.

Valentin Fuster


ASTEROID: Exciting results

The results really match up nicely with everything we know

There are limitations to the study

• Not having a control group

Results show

• Intensively modifying lipids has a dramatic effect on LDL-C levels

• A trend toward a significant (15%) increase in HDL-C

For the first time in a single statin study, these factors are shown to be important in the regression of plaque

Christopher Cannon


ASTEROID: Goals of therapy

This study is not too different from the GREACE study

• Lower the LDL-C as much as possible

• Raise the HDL-C as much as possible

Rosuvastatin does just that

There is no progression of disease over 24 months, which is very attractive

Valentin FusterGREACE: Athyros VG et al. J Clin Pathol 2004;57:728.


ASTEROID: Tempered enthusiasm

Rosuvastatin is not an equal-opportunity therapy

• Many patients cannot tolerate statins at any dose

• Even more patients cannot afford statins

• Some patients are noncompliant

Will physicians subconsciously push patients who are suffering from myalgia or other side effects to stay on statins?

Future studies should include strategies aimed at improving tolerability

• Simultaneous coenzyme-Q10 use

• High-dose pulse therapy

Melissa Walton-Shirley


ASTEROID: Patient population

Issues important to the general clinician

• Patients in this study did not necessarily have significant progression

• There was no control group

• Only 13% of the patients had diabetes

• A large proportion of patients just had unstable angina

Valentin Fuster


ASTEROID: Figure 3Relationship between mean LDL-C levels and median change in percent atheroma volume for several intravascular ultrasound trials

Nissen SE, et al. JAMA 2006;295:1556.

Mean LDL-C (mg/dL)

–1.2

–0.6

0

0.6

1.2

1.8

50 70 80 90 100 110 120

Mean

ch

an

ge in

perc

en

tath

ero

ma v

olu

me,

%

60

CAMELOTplacebo

A-Plusplacebo

REVERSALatorvastatin

REVERSALpravastatin

ASTEROIDrosuvastatin

r2=0.97p<0.001


ASTEROID: Limitations

The different duration of this trial makes comparison difficult

• ASTEROID was 24 months

• Previous IVUS studies done by Nissen et al were 18 months

Measuring atherosclerosis in different patient populations makes comparisons difficult to interpret

• People with not-too-severe atherosclerosis

• Higher-risk patients

Although this trial has limitations, the results seem to fit with everything we know about intensive statin therapy

Christopher Cannon


ASTEROID: Data needed

REVERSAL used IVUS to show that lowering LDL-C significantly with atorvastatin stopped the progression of disease in a relatively high-risk population

PROVE IT–TIMI 22 showed that there were significantly fewer cardiovascular events with atorvastatin

ASTEROID showed that rosuvastatin is very effective in modifying lipid profiles and in preventing progression of disease and maybe some regression

• However, there are no clinical data correlating rosuvastatin and IVUS

REVERSAL: Nissen SE et al. JAMA 2004; 291:1071. Valentin Fuster


JUPITER trial

Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial

• More than 9000 patients enrolled

• Lower-risk population

• A primary-prevention trial

• Positive C-reactive protein (CRP) as an entry criterion

JUPITER results are probably two years away, but clinical data are coming

Ridker PM et al. Circulation 2003;108:2292-2297

Christopher Cannon


Rosuvastatin: Side effects?

A few months ago, there was a lot of discussion about whether rosuvastatin caused side effects

•What was reported

•What was not reported

Valentin Fuster


The trouble with statins

Simvastatin becomes generic in late 2006

We don't know whether data from simvastatin translate or extrapolate to other statins

Patients are still reluctant to take statins

• It's up to the practitioner to convince patients that statins are safe as long as they monitor side effects and communicate with their practitioner



ASTEROID: Summary

There are many people who should be taking statins that are not

• We must look for strategies to increase their use

ASTEROID trial

• 40 mg rosuvastatin daily proves that lower LDL-C and higher HDL-C is better

• Some degree of regression was shown over 24 months

Valentin Fuster


ASTEROID: Key message

In five years, our LDL-C target in a high-risk population will probably be around 50 mg/dL

One of the messages from ASTEROID is that lower is better

Christopher Cannon


LDL-C target in five years

Prediction

•An LDL-C of 50 mg/dL in a high-risk population

•An LDL-C of 75 mg/dL in a lower-risk population

Valentin Fuster


UNLOAD: Study design

200 patients with acute decompensated heart failure at 28 institutions

Randomized to either • Peripheral ultrafiltration using a commercially

available system • Standardized IV diuretic therapy

Patients were evaluated at 48 hours and at 90 days

Patients required up to two sessions of ultrafiltration over a period of a couple of days• 4 L of fluid were removed in each eight-hour

session • A total of 8 L of fluid were removed altogether

Costanzo MR et al. ACC 2006 Scientific Sessions; March 14, 2006; Atlanta, GA. Abstract 418-7.

Valentin Fuster


UNLOAD: Results

Fewer patients in the ultrafiltration group than in the diuretic-treated group subsequently required vasoactive drugs at 90-day follow-up

The ultrafiltration group did better

• More fluid lost in the first 48 hours.

• Potassium levels were more stable.

• No increase in creatinine levels.

Valentin Fuster


UNLOAD: Results at 90 days

Rehospitalization at 90 days:

• 18% of the ultrafiltration group.

• 32% of the diuretic-treated group.

Number of rehospitalization days:

• 1.4 days in the ultrafiltration group.

• 3.8 days in the diuretic-treated group.

Emergency-room visits:

• 21% in the ultrafiltration group.

• 44% in the diuretic-treated group.

Valentin Fuster


UNLOAD: Questions

Do all these patients need ultrafiltration?

Were diuretics used appropriately in UNLOAD?

• Resistance to diuretics such as Lasix [furosemide] can develop

Is ultrafiltration necessary, or could diuretics, which are much cheaper, be used more effectively?

Valentin Fuster


UNLOAD: Effect on therapy

Of all the data that were presented at ACC 2006, the UNLOAD findings have the greatest potential to affect acute hospital-based therapy

From a clinical standpoint, ultrafiltration allows patients to fit into their shoes and to go home with the same creatinine levels they came in with

This was a natural next step for cardiologists dealing with CHF

• It is nearly impossible to motivate nephrologists to manage fluid in the nonuremic patient



UNLOAD: Cost effectiveness

Reducing the cost of DRG 127 [heart failure and cardiac shock] is the holy grail of CHF management

The $19 000 this device costs is a pittance compared with other technology purchases hospitals make

Shortening the length of hospital stay and preventing readmission of just two patients pays for the device



UNLOAD: Cost of ultrafiltration

Each ultrafiltration session costs close to $1000

Decreasing the number of hospital days and the number of visits to the emergency room saves money

Despite being somewhat expensive, is ultrafiltration cost effective?

Valentin Fuster


UNLOAD: Cost effective

We have to be careful not to buy into the "just-plug-them-into-a-machine" mentality

Ultrafiltration should not replace good dietary instruction and fluid restriction

We should take a hard look at the medical regimen of volume-overloaded patients • Are we doing anything to offend them?• Are we keeping them on dihydropyridine calcium-

channel blockers? • Do we have them on glitazones (which, for some

patients, means a 40-lb weight gain)?

We must carefully select which patients are offered ultrafiltration



UNLOAD: Diuretic resistance

When I see a patient on a dose of Lasix over 300 mg, I drop the dose and prescribe Zaroxolyn [metolazone]

• In general, there is a significant change in the diuresis of these patients

Ultrafiltration is a significant move forward, but I'm not convinced that most of the patients we see on a daily basis need this device

Valentin Fuster


UNLOAD: Heart failure

As coronary disease is treated successfully in more and more patients, more and more patients are left with heart failure

Diuresis takes an enormous amount of time

Ultrafiltration offers another option to people on high doses of Lasix who are still fluid-overloaded

• The savings in length of hospital stays and rehospitalizations leads to an overall cost benefit

A formal cost-effectiveness analysis is still needed

Christopher Cannon


UNLOAD: Chemistry

Why does all the chemistry continue to be fantastic, even after 8 L of fluid is removed?

Valentin Fuster


UNLOAD: Chemistry explained

The fluid that's removed is isotonic, so there's no activation of the renin angiotensin system

There was not a lot of hypotension in UNLOAD patients so, unfortunately, patients left the hospital feeling about the same, with shortness of breath

• However, they could wear their clothing and had significant weight loss, which is really the goal for these patients

The reason for the lack of improvement in dyspnea is unclear



UNLOAD: A significant advance

Ultrafiltration is a significant advance for patients with significant cardiac failure and volume load

Valentin Fuster


UNLOAD: Nesiritide alternative

Ultrafiltration is a perfect solution for patients excluded by the nesiritide-clinic situation

Our nesiritide clinic, which ran for several months, was closed when the controversy began

Patients who no longer have access to the nesiritide clinic on a weekly basis are looking forward to trying this device



BASKET LATE: Study design

The original BASKET trial randomized a relatively complex patient group to a bare-metal stent or to a drug-eluting stent, either paclitaxel (Taxus) or sirolimus (Cypher)

BASKET LATE followed 746 BASKET patients who were free of major adverse coronary events (MACE) at six months for an additional 12 months

Pfisterer ME et al. ACC 2006 Scientific Sessions;March 14, 2006; Atlanta, GA. Abstract 422-11.

Valentin Fuster


BASKET LATE: Study design

Thrombosis-related events in the two groups (bare-metal or drug-eluting stents) were compared

• Thrombosis-related events comprised angiographically confirmed stent thrombosis, sudden cardiac death, and target-vessel myocardial infarction

Pfisterer ME et al. ACC 2006 Scientific Sessions;March 14, 2006; Atlanta, GA. Abstract 422-11.

Valentin Fuster


BASKET LATE: Results

MACE rates were no different between the bare-metal and drug-eluting stent groups

The rates of nonfatal MI plus cardiac death and of nonfatal MI alone were significantly higher with drug-eluting stents than with bare-metal stents

• Nonfatal MI: 4.1% in the drug-eluting-stent group vs 1.3% in the bare-metal-stent group

• Cardiac death and nonfatal MI: 4.9% in the drug-eluting-stent group vs 1.3% in the bare-metal-stent group

Valentin Fuster


BASKET LATE: Surprising results

The design of BASKET LATE led to a unique opportunity to look at planned discontinuation of clopidogrel six months after stent placement

The dramatic findings have immediate implications

• They aren't definitive because only ~100 patients were studied, but the data are compelling

Christopher Cannon


BASKET LATE and clopidogrel

What does the fact that most of the BASKET LATE patients stopped taking clopidogrel at

six months tell us?

Valentin Fuster


BASKET LATE: Clopidogrel debate

This study shows that discontinuation of clopidogrel six months after drug-eluting-stent placement is not a good idea

Package-insert information, based on the elective single-vessel stenting that earned these stents initial approval:• Taxus stent: Clopidogrel for six months• Cypher stent: Clopidogrel for three months

The BASKET LATE population comprised high-risk patients at high risk for recurrent events

Many interventionalists are considering two years of clopidogrel to prevent stent thrombosis related to drug-eluting stents

This study will extend the duration of clopidogrel treatment after drug-eluting-stent placement

Christopher Cannon


BASKET LATE: The trade-off

In 100 patients with drug-eluting stents:

• Five restenotic phenomena will be prevented.

• There will be 3.3 late deaths from MI.

Valentin Fuster


BASKET LATE: Implications

After seeing a couple of case reports in the literature of late and ultralate thrombosis (one of which was 18 months out), I started advising patients who have received drug-eluting stents to stay on clopidogrel indefinitely

These results are concerning because many patients cannot afford a year's worth of clopidogrel

At our facility, 100% of the patients who are implanted are STEMI patients, who are at higher risk



BASKET LATE: Choosing a stent

It's not the up-front cost of the stent anymore that determines which stent will be used, it's the ability of the patient to pay for the long-term Plavix prescription and the expectation of compliance by the patient

We need to do a better job of taking a good general medical review of systems before stent implantation • Many patients are coming back within three months

of implant needing a cholecystectomy or with gut bleeding

We need to do a better job of defining who should and who should not get a drug-eluting stent• A patient who knew he was facing a biopsy for a

chest mass received a drug-eluting stent when he underwent PCI



BASKET LATE:Appropriate use of clopidogrel

Based on this study, perhaps we should prescribe clopidogrel for 18 to 24 months

The significant drop in the rate of restenosis means we should not discount drug-eluting stents

• Perhaps the appropriate use of clopidogrel over a longer period of time is required

Valentin Fuster


BASKET LATE:Clopidogrel and surgery

The preprinted letter that comes from the surgeon advising patients to stop all anticlotting drugs for 10 days before surgery must be carefully considered

We may need to time clopidogrel more like warfarin

• New data suggest discontinuing clopidogrel three days before surgery and then monitoring the level of platelet inhibition so that people are not putting themselves at risk for thrombotic events by discontinuing clopidogrel

Christopher Cannon


MIST: Study design

147 migraine patients, between 18 and 60 years, previously found to have a patent foramen ovale (PFO)

All patients were refractory to at least two classes of migraine medications and had a one-year history of migraine

All patients had contrast transthoracic echocardiography to establish shunt size

• Half were treated with a PFO closure device implantation, the STARflex septal-repair implant

• Half underwent a sham procedure consisting of general anesthesia and a groin incision

All patients were prescribed aspirin and clopidogrel for three months

Taaffe M. ACC 2006 Scientific Sessions;March 12, 2006; Atlanta, GA. Abstract 945-109.

Valentin Fuster


MIST: Results

Three patients in each arm achieved the primary end point—complete cessation of headaches

More PFO-closure than sham patients had a 50% or greater reduction in headache days • 42% of PFO-closure patients vs 23% of sham

patients achieved a 50% reduction in headache days

More PFO-closure than sham patients had a reduction in headache burden (calculated as headache frequency × duration)

PFO closure might help headaches by preventing platelets from releasing serotonin, which causes headaches

Valentin Fuster


MIST: Jury still out

I sent a patient two years ago for PFO closure who presented with a transient neurologic deficit; she happened to also have a history of severe migraines • She was 100% migraine free immediately after the

procedure and continues to be two years later

The presenters have not yet finished the calculations for the shunt data, and therein might lie the explanation• These patients had exceptionally large

communications; if the closures were not complete, improvement would not be expected

Any migraine sufferer would jump at the chance for a 50% reduction in the number of headaches or the number of trips to the emergency room

It would be nice if the primary end point in MIST II were the reduction in migraines instead of a cure



MIST: Cause of headaches

Are platelets crossing the PFO and getting into the head and releasing serotonin, which causes the headaches?

Valentin Fuster


MIST: More data needed

The pathophysiology explaining this is unclear

If data from MIST II are consistent, then the two trials together would show this benefit

One concern about PFO or atrial septal-defect closure is with fractured parts of the devices causing strokes

• Is this device different than atrial septal-defect closure devices?

We need to see all the safety data, beyond half of 147 patients

Christopher Cannon


MIST: Course of action

If a patient presents tomorrow with constant headaches and a PFO, would you close it?

Valentin Fuster


MIST: Go with PFO closure

Patients who are completely incapacitated by headaches and who are refractory to two or three different therapies would jump at any chance for relief

Because safety data for the closure device are good, I'd recommend the procedure



Summary: ASTEROID

ASTEROID

• 40-mg rosuvastatin daily

• LDL-C reaching an average of 60 mg/dL

• HDL-C increase of 15%

• No progression seen with IVUS

• Possibly some regression

A great study moving us toward lower LDL-C

In the future, in the high-risk population, LDL-C targets may be as low as 50 mg/dL

Valentin Fuster


Summary: UNLOAD

UNLOAD: Ultrafiltration vs diuretics in patients with decompensated heart failure

• Great chemistry

• No decrease in potassium

• No change in creatinine

• Fewer rehospitalizations

Ultrafiltration is cost effective

• It is worth it to pay $1000 for each of two ultrafiltration sessions because of the reduction in length of hospital stay and in rehospitalizations

Valentin Fuster


Summary: BASKET LATE

In BASKET LATE, there was a higher incidence of MI and sudden death related to thrombosis with a drug-eluting stent than with a bare-metal stent

When drug-eluting stents are used, continuing clopidogrel for more than six months should be considered

• Clopidogrel should probably be taken for 18 to 24 months

Valentin Fuster


Summary: MIST

In patients with recurrent headaches and a PFO, closing the PFO decreases by 50% the headache burden of these patients

Valentin Fuster


UNLOAD and CHF patients

More patients with congestive heart failure than with acute MI present every day to emergency rooms around the country

The UNLOAD data will likely affect the largest number of patients



Four good studies

ASTEROID reinforces the benefit of intensive statin treatment

BASKET LATE reinforces the duration of clopidogrel treatment of at least one year in ACS or PCI patients

UNLOAD provides a terrific new option for the large number of patients with severe heart failure

Data from the closure of PFOs look intriguing; we await the data from MIST II to see whether they support the results from MIST

Christopher Cannon

acc 2006 part 2: where's the controversy?

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