heartbeat – acc 2006 antithrombotic therapies christopher cannon md staff cardiologist brigham and...

Heartbeat – ACC 2006

Antithrombotic therapies

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

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

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

Harlan Krumholz MDProfessor of MedicineYale University, New Haven, CT


CHARISMA

Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance

EXTRACT-TIMI 25

Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment—Thrombolysis in Myocardial Infarction 25

OASIS-6

Sixth Organization to Assess Strategies in Acute Ischemic Syndromes

Topics


• Four large trials showed clopidogrel + stenting to be beneficial

• CAPRIE trial: Clopidogrel alone "borderline better" in CVD than aspirin alone

• The question remained: What about patients with chronic CVD—are clopidogrel + aspirin better than aspirin alone?

Clopidogrel: Historical background


CHARISMAAtherothrombotic Risk and Ischemic

Stabilization Management and Avoidance


CHARISMA: Trial design

• Over 15 000 patients worldwide• Patients with evidence of CVD or

multiple risk factors• 75-mg clopidogrel daily + low-dose

aspirin vs placebo + aspirin• Median 28 months of follow-up• Primary efficacy end point: MI,

stroke, or cardiac death


• No significant differences in primary efficacy end point (6.8% vs 7.3%, p=NS)

• Second efficacy end point , adding hospitalization for ischemic events: borderline significance favoring clopidogrel + aspirin

• Severe bleeding: 1.7% in clopidogrel + aspirin vs 1.3% in aspirin + placebo group (p=0.09)

• A negative trial overall; some positivity in terms of secondary end point , but counterbalanced by bleeding

CHARISMA: Results


"We can say that clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of MI, stroke, or death from CV causes in patients with very high risk for cardiovascular disease or patients with [early] manifestations of CVD."

Fuster

CHARISMA: Messages


• Expanding the patient population using aspirin + clopidogrel is appealing, but we've seen we can't broaden too far

• No benefit and some harm in patients with no previous clinical events

• Higher-risk coronary patients, including prior MI/stroke, had a more robust benefit

Cannon

CHARISMA: Messages


"To me it shows that for longer-term use, higher-risk patients benefit from higher-intensive therapy, and we simply have to integrate that into the decisions on who continues on clopidogrel for longer than one year."

CHARISMA: Messages

Cannon


"There were some things that were very surprising and . . . some things that weren't necessarily quite such a big surprise."

• Can we extend this into a higher-risk primary-prevention group?

• Is there benefit over a longer period of time?

• What is the risk that one pays?

Ferguson

CHARISMA: Messages


"It really, in my mind, sharpens the distinction that one has to make between primary prevention in people at risk for the disease and secondary prevention in people who already have the disease."

Ferguson

CHARISMA: Messages


• The results were negative overall, with some concerns about GI bleeding

• Two groups of patients: Those with manifestations of disease

showed some favorable trends with clopidogrel + aspirin

Primary-prevention patients with high-risk profile showed opposite results

Fuster

CHARISMA: Messages


CHARISMA: Subgroup hazards

Krumholz

• Clopidogrel not effective? Or "suggestive" of benefit in certain groups?

• Secondary outcomes/subgroup analyses often promoted to the point that studies seem positive when they're not


CHARISMA: Subgroup hazards

Krumholz

• But aspects of subgroups in CHARISMA make sense clinically; help explain results

• Clinicians must decide whether to treat patients on the basis of CHARISMA subgroups


CHARISMA: Results in practice

• Are there patients in whom we should start new treatment?

No

• But we should still use this information to treat patients who are on clopidogrel for other reasons

Cannon


"I would prefer the term neutral, rather than negative."


Ferguson

• No long-term extended clopidogrel + aspirin in people at risk

• In patients on clopidogrel + aspirin for ACS indication: no push to extend use beyond one year

• New risk of people stopping clopidogrel for the wrong reasons, leading to possible explosion of subacute stent thrombosis.


• Patients at "high risk" only should not get aspirin + clopidogrel, just aspirin alone

• ACS or stent patients should get drug combination for one year

• Only patients to get combination beyond one year would be very high-risk patients, with CAD and/or stroke recurrences, but only those with no history of bleeding

Fuster



• Dangers of stopping clopidogrel—will public/press misinterpret results?

• Compounded by results from BASKET-LATE study, showing high rates of clinical events possibly related to stent thrombosis after stopping clopidogrel

• Need to get the message out about not prematurely stopping clopidogrel in DES patients

CHARISMA: Disaster pending?

Cannon


"It's really more of a lesson in not who you can stop it in but who you should not be starting it in as long-term therapy."

CHARISMA: Lessons

Ferguson


• Anybody who is within one year of stenting should continue to use clopidogrel + aspirin

• Individual with CVD with previous manifestations/recurrences, possibly affecting multiple systems, may need combination therapy

• A class IIa or IIb recommendation?

Fuster

CHARISMA: Concerns


EXTRACT-TIMI 25Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment

—Thrombolysis in Myocardial Infarction 25


• Enrolled >20 000 patients with ST-elevation AMI scheduled for fibrinolysis

• Randomized to either enoxaparin throughout hospitalization or weight-based UFH for at least 48 hours

• Primary efficacy end point: death or repeat MI within 30 days

Fuster

EXTRACT TIMI-25:Enoxaparin in STEMI


• A positive result with LMW heparin in terms of efficacy, but a concern about bleeding, although composite still favored enoxaparin

EXTRACT TIMI-25: Results

Outcome UFH Enoxaparin p

Primary end point(%)

12 9.9 <0.001

Nonfatal MI(%)Major bleeding (%)

4.5

1.4

3

2.1

<0.001

<0.001


"In patients with STEMI undergoing fibrinolytic therapy, enoxaparin appeared to be superior to UFH. . . . Despite increased bleeding, the net clinical benefit was there."

Fuster

EXTRACT TIMI-25: Results


• Past studies suggested that LMWH provides more reliable anticoagulation at a small but real bleeding price

• Larger questions raised about event curves at 48 hours, when heparin was discontinued—possible benefits of prolonging antithrombotic duration following fibrinolysis

• Also notable that LMWH dose was adjusted in elderly

EXTRACT TIMI-25: Implications

Ferguson


"The real question for any clinician is: How do I do the math to figure out if this is the right strategy?"

EXTRACT TIMI-25:Benefits vs bleeding risks

Krumholz


• A 2.2% absolute difference in death/MI/nonfatal disabling stroke favoring enoxaparin

• Factor in major bleeding, favoring UFH at 1.7% absolute difference

• Composite score=1.5% absolute fewer patients having any one of those events with enoxaparin: a net clinicalbenefit


Cannon


• Does the fact that UFH was given for only two days and enoxaparin for seven days explain the differences in efficacy and bleeding?


Fuster


• Direct comparison at 48 hours favors enoxaparin

• Added advantage of continuing longer

"Compared with what we're doing now, longer duration of antithrombin therapy . . . was better than the shorter duration."


Cannon


• Longer-duration UFH not possible in this setting

• Extended duration is an advantage of other compounds

• Discontinuing UFH may have been problematic

EXTRACT TIMI-25: Duration of treatment

Ferguson


• Patients who went on to PCI stayed on enoxaparin and did well, with fewer bleeding complications—a useful finding

• Enoxaparin easier to use than UFH• In the guidelines, use of enoxaparin would

be a class I indication for STEMI• Costs: $50–$60 per day, but fewer lab

tests—relatively inexpensive

EXTRACT TIMI-25:Other benefits


• Enoxaparin compares favorably with UFH in STEMI

• Some questions/caution about bleeding• Enoxaparin appears to be a class I

indication for STEMI, as compared with UFH

EXTRACT TIMI-25:Conclusions

Fuster


OASIS-6Sixth Organization to Assess Strategies in

Acute Ischemic Syndromes


• A synthetic pentasaccharide• A selective factor Xa inhibitor• Not a direct antithrombin• Does not affect platelet adhesion• Penetrates into factor Xa in the clot

Fondaparinux:Theoretical advantages

Fuster


• 20 000 patients with NSTE-ACS randomized to fondaparinux 2.5 mg daily or enoxaparin for a mean of six days

• Fondaparinux noninferior for primary outcome of death, MI, or refractory ischemia at nine days

• Significantly lower rate of secondary outcome—major bleeding at nine days

• Less bleeding translated into superior performance of fondaparinux at30 days and six months

OASIS 5: Published in NEJM


• OASIS 5 reminds us of need to avoid bleeding, potentially improving efficacy and reducing mortality

-Cannon

• Questions remain re: bleeding definitions, dosing, and problems related to PCI in OASIS 5

-Ferguson

• Fondaparinux concept has always "made sense" and looks promising

-Krumholz

OASIS 5: Published in NEJM


"The good news is, there's a lot of things that work; the bad news is, there's a lot of things that work. And now we've got to make some decisions."

Anticoagulants:A multitude of choices

Ferguson


"We may need to get a lot of people together to update the guidelines soon, because the confusion is going to lead to paralysis: people aren't going to know what to do."

Krumholz

Anticoagulants:A multitude of choices


"In OASIS 6, my enthusiasm dial is not quite as high."

• An overall benefit, but clear subsets didn't benefit: Patients heading to PCI Patients in whom UFH, not

placebo, was the control"I have real questions as to what exactly this has really shown us."

OASIS 6: Fondaparinux in STEMI

Ferguson


• Vast majority of patients got no antithrombin as control

• Very different from EXTRACT, which compared therapy with guideline-recommended treatment

• More evidence that longer therapy may be beneficial



• OASIS 6 will not have major impact on MI world

-Ferguson

• Our enthusiasm should be circumspect-

Krumholz

• You need some type of antithrombin in the cath lab

-Cannon



Recommendations: CHARISMA

• Clopidogrel + aspirin for one year is "a must" poststenting and for AMI patients: a class I indication

• Beyond one year, or in nonstented patients/non-ACS patients, evidence is less clear for clopidogrel + aspirin


Recommendations:EXTRACT-TIMI 25 and OASIS 5, 6

• EXTRACT-TIMI 25: Enoxaparin moving toward a class I indication in STEMI

• OASIS 5: Fondaparinux in NSTE-ACS: likely a class I indication

• OASIS 6: Fondaparinux in STEMI appeared to be superior, but the trial was complex: possibly a IIa or IIb level of evidence

Fuster


• Many exciting new options for antithrombotic therapy in various types of ACS

"We all need to revisit our pathways to sort out: do we have the mix right for what's available and what our practice is in our hospitals?"

Conclusions

Cannon


• Concerns about fondaparinux in NSTE-ACS due to invasive management pathway and catheter thrombosis in OASIS 5

• CHARISMA: Don't use combination therapy on the basis of individual risk, or beyond one year except in rare circumstances

Conclusions

Ferguson


• EXTRACT TIMI 25: Rethink LMWH as fibrinolytic therapy in STEMI; possible need for longer-duration fibrinolysis

• OASIS 5, 6: How can we integrate fondaparinux intoguidelines, practice?

Conclusions

Ferguson


"The avalanche of information that's coming out of these meetings is a challenge. [We have] to try to help doctors sort through this and to figure out how we're going to create faster ways to adapt the right technology."

Krumholz

Conclusions

heartbeat – acc 2006 antithrombotic therapies christopher cannon md staff cardiologist brigham and...

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