NSTEMI and antithrombotics

Part II

Dr. Gilbert Boucher

R4 Emergency Medicine

McGill

Last time:

• Review definitions of Non-ST-elevation Myocardial infraction and related items.

• Prognostic factors.

• Current therapies.

Today:

• Finish anticoagulants.– Hirudin

• Gp IIb/IIIa inhibitors.– Their indications…

• Treatment strategies.– Early vs late angio.

• Special groups.

What's New?

 

October 4 , 2001

Practice Guidelines: Atherosclerotic Cardiovascular Disease

 

September 1 , 2001

Practice Guidelines: Atrial Fibrillation

 

April 27 , 2001

Practice Guidelines: Percutaneous Coronary Intervention

 

April 27 , 2001

Expert Consensus Document: Catheterization Laboratory Standard

 

April 3 , 2001

Consensus Conference Report: Care of the Patient with Adult Congenital Heart Disease

 

April 2 , 2001

Expert Consensus Document: Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies

 

March 1, 2001

Teaching Slides: ACC/AHA Guidelines for the Management of Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction

 

January 1, 2001

Consensus Conference Report: Mechanical Cardiac Support 2000: Current Applications and Future Trial Design

 

November 1, 2000

Clinical Competence Statement: Invasive Electrophysiology Studies, Catheter Ablation, and Cardioversion

 

October 1, 2000

Clinical Competence Statement: Stress Testing

 

September 1, 2000

Practice Guidelines: Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction

September 1, 2000

Consensus Conference Report: Myocardial Infarction Redefined—A Consensus Document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction

 

July 1, 2000

Expert Consensus Document: Electron-Beam Computed Tomography for the Diagnosis and Prognosis of Coronary Artery Disease

 

June 1, 2000

Training Statement: Adult Cardiovascular Medicine (COCATS) Revised 6/00 Task Force #5: Training in Nuclear Cardiology

www.acc.org

Anticoagulants

• UFH

• LMW heparin

• Hirudin

Hirudin

• Direct thrombin inhibtor.

• For patients with HIT or history of.

• Binds directly to catalytic site of thrombin without going through antithrombin III

• TIMI 7: better than ASA alone in UA…

• Mild improvement compared to UFH but increase in bleeding, no benefit in STEMI.

• Meta-analysis shows OR of 0.90

Platelet GP IIb/IIIa Receptor Antagonists

• Activation of platelets leads to configurational change increasing affinity for fibrin and other ligands

• Necessary final step to platelets aggregation.

• Needs 80% blockade to achieve potent antithrombotic effects

GP IIb/IIIa Receptor Antagonists.

• Abciximab (reopro): non-specific binding– Unclear significance

• Eptifibatide (integrilin), tirofiban (aggrastat): very specific binding achieve >80% within 5 minutes

• Different antagonists can bind at different sites and can paradoxically activates the GPIIb/IIIa receptor– ?what is happening with the oral form.

GP IIb/IIIa Receptor Antagonists

• 4 main studies

• 2 positives

• High-risk features

• 11.7% vs 8.7%,

• 15.7% vs 14.2%

Numbers…

• PRISM:Platelet Receptor Inhibition in Ischemic Syndrome Management.– heparin (non-weight based) vs tiroban X 48hrs

ECG changes or enzymes or very strong hx of CAD

Composite end-point better at 48hr but only trend at 30 days.

MI/death: non-significant at 48 hrs but + at 30 days (3.6 vs 2.3%).

?Playing/fishing for numbers

PRISM: Lancet 1999•

                                       

   Figure 1: Adjusted hazard ratios (95% CI) for treatment with tirofiban by

troponin I quartiles

•

                             

             Figure 2: Event-rate curves

(mortality, myocardial infarction) for 30-day follow-up for patients with + troponin

I

Numbers…• Prism-plus: Platelet Receptor Inhibition in Ischemic

Syndrome Management in Patients Limited by Unstable Signs and Symptoms

• THE study

• ST changes or + enzymes

• Tiroban alone dropped due to too much mortality– 4.6% vs 1.1 and 1.5%??? (remember PRISM study)

• At 7 days, composite end-point: 17.9% vs 12.9%

• 22% CEP reduction at 30 days (absolute 3.8%)

• 19% CEP reduction at 6 months (absolute 4.4%)

                                                        Figure 10

Numbers…• PURSUIT: Eptifibatide

– Platelet Glycoprotein IIb/IIIa in Unstable Angina:Receptor Suppression Using Integrilin Therapy.

– 11 000 pts

– + ECG changes or enzymes rise

• Death or MI at 30 days: 15.7% vs 14.2%– 9.1% vs 7.6% at 4 days

– 11.6% vs 10.1% at 7 days

– Major bleed increased by 1.5%

• Cath rate overall: 60%

Real Numbers!

• GUSTO IV:Lancet June 2001

• Abciximab: 7800 pts without PCI

• Same mortality at 30 days: 8-9%

– Despite all sorts of subgroup analysis…

Antithrombotics:1, 2 or 3 agents???

•  

Cardiogenic shock… BAD!!!

• Circulation 1999: GUSTO IIb

• 200 pts with NSTEMI and shock– Incidence of 2.5%

• 73% mortality

• But median time to shock 76 hrs…– 9.6 hrs in STEMI

Last words:

• Journal of Emergency Medicine

October 2000:

– “The effect of early ED treatment with GPIIb/IIIa inhibitors has never been formally studied until now”.

– EARLY trial will compare early ED, vs late CCU vs catheterization laboratory

TIMI score• JAMA, August 16, 2000

• Databases of ESSENCE and TIMI11B

• 12 variables, 7 significants– Age > 65yo

– 3 risk factors for CAD

– Prior coronary stenosis of > 50%

– St deviation

– Severe angina symptoms

– ASA use within 7 days

– Elevated serum cardiac markers

        

                               

 Figure 1. TIMI Risk Score Rates of all-cause mortality, myocardial infarction, and severe recurrent ischemia prompting urgent revascularization through 14 days after randomization were calculated for various patient subgroups based on the number of risk factors present in the test cohort (the unfractionated heparin group in the Thrombolysis in Myocardial Infarction [TIMI] 11B trial; n = 1957) (see Table 1). Event rates increased significantly as the TIMI risk score increased (P<.001 by  

2 for trend).

•GP IIb/IIIa inh for score 5 or above???

                                  

                                                      

 Figure 2. Validation of TIMI Risk Score and Assessment of Treatment Effect According to Score Rates of all-cause mortality, myocardial infarction, and severe recurrent ischemia prompting urgent revascularization through 14 days after randomization were calculated for the enoxaparin and unfractionated heparin groups in the Thrombolysis in Myocardial Infarction (TIMI) 11B trial and the Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI trial (ESSENCE), based on the TIMI risk score. The pattern of increasing event rates with increasing TIMI risk score was confirmed in all 3 validation cohorts (P<.001 by  

2 for trend). C statistics were 0.65 for the unfractionated heparin group and 0.61 for the enoxaparin group in TIMI 11B; and 0.65 for the unfractionated heparin group and 0.59 for the enoxaparin group in ESSENCE. The rate of increase in events as more risk factors were present was significantly lower in the enoxaparin group in both studies (for TIMI 11B, P = .01; for ESSENCE, P = .03). Positive values for absolute risk difference (ARD) and number needed to treat to prevent 1 event (NNT) indicate calculations favoring enoxaparin, while negative values indicate calculations favoring unfractionated heparin.

As Dr. Lang would said…

• Auto-validation on its own cohort

• Retrospective

• Specific (but large) group

• That would make it a level…4 if we want to use it as a Clinical decision rule to know whether or not to use GP IIb/IIIa inhibitors.

TIMI Risk Calculator For Unstable Angina

In the blue column, please enter the patient's age, and then answer each clinical question with a Y (for yes) or an N (for no).  The patient's risk appears at the bottom of the blue column.

TIMI Risk Score for UA/NSTEMI Entry ScoreAge 1History of Hypertension (Y or N) 0History of Diabetes (Y or N) 0Current Smoker (Y or N) 0Hypercholesterolemia (Y or N) 0Family history of Coronary Artery Disease (Y or N) 0Prior angiographic stenosis >50% (Y or N) 0Severe anginal symptoms (>= 2 episodes rest pain in past 24 hrs) (Y or N) 0Use of aspirin within the last 7 days (Y or N) 0Elevated cardiac markers (either CKMB or cardiac troponin) (Y or N) 0ST deviation (horizontal ST depression or transient ST elevation >= 1 mm) (Y or N) 0Total Risk Score (0-7) 1

Risk of Death/MI/Urgent Revascularization by 14 Days (%) 4.70%

Cost $$$$

• Tiroban: 950$/3 days

• Abciximab: 2000$/treatment

– But how come we are almost never using streptokinase anymore… are we reasonable???

What about:Plavix vs GP IIb/IIIa?18.8% vs 16.5%

17.9 vs 12.9%

JUST a thought …

But back to standard of care…The classics: How do we do?

• In-hospital drugs treatment (%), 1998

USA Canada World

Intravenous heparin 79 88 73

Aspirin 91 92 92

B-blockers 57 73 63

Calcium antagonists 59 53 53

Intravenous nitrates 68 40 51

Angio: stat or later• TACTICS: N Engl J Med 2001; 344:1879-1887, Jun 21, 2001

2220 patients, within 48 hours vs selectively

all got ASA, heparin, GPIIb/IIIa inh

15.9% vs 19.4% at 6 months

6% more CABG, 520 extra caths/1100 pts

MI: 4.8% vs 6.9%

• Pre GPIIb/IIIa inhibitors: TIMI3b (1995)

• Early 18.1% vs 16.2% late

• Decr length of stay

• VANQWISH Investigators: 920 pts

• Early 7.8% vs 3.3% late at hospital discharge

More does not equal better

• Lancet 1998; 352: 507–14

• 8 000 pts, various countries (Brazil, USA, Canada, Australia, Hungary, Poland)– 59% vs 21% angio rate

– Same overall MI/death rate: 4.7% at 7 days

• Late angio: decreased rate of overall cardiovascular event (including stroke) despite higher recurrent angina

What do we find anyway on angio…

• Typically shows the following profile: – 1) no severe epicardial stenosis in 10%

to 20%

– 2) 1-vessel stenosis in 30% to 35%

– 3) multivessel stenosis in 40% to 50%

– 4) significant (.50%) left main stenosis in 4% to 10%.

Next: early statin???!!!…

• Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL)

• JAMA April 2001

• 2000 pts

• Atorvastatin 80mg/d between 24 and 96hrs of admission.

• 17.4% vs 14.8% at 4 months, mostly recurrent symptomatic ischemia requiring rehospitalization.

Risk stratification

Noninvasive stress testing in low-risk patients who have been free of ischemia at rest or with low-level activity and of CHF for a minimum of 12 to 24 h. (Level of Evidence: C)

Risk stratification

• Stress test only if free of:– ST-segment abnormalities

– bundle-branch block

– LV hypertrophy

– Intraventricular conduction defect

– Paced rhythm

– Preexcitation

– Digoxin effect.

Otherwise need imaging: echo or thallium…

Special groups

• Women: more atypical symptoms

– ?better outcome in UA then men

• Elderly: More disease

• Diabetics: Increased risk for any ACS

• Post-CABG: low threshold angio

• All same protocols and numbers…

Cocaine users

• Coronary vasospasms– Worsen by minimal atherosclerosis

– Reversed by CCB

– ST-changes in 38% of pts in detox centers

• Detoxify by cholinesterase in liver and plasma– Less available in infants or elderly

• Increased platelets sensibility

• Decrease antithrombin III and protein C

Cocaine users as per AHA

• NTG and CCB for ST changes

• Angio if persistent ST elevation or if thrombus found

– Thrombolysis if not available

• B-blockers if sBp > 150 or HR > 100

– Labetolol preferred

B-blockers for cocaine users???

Annals of Internal Medicine. Jun 1990

30 volunteers

• In cath lab

• Cocaine followed by propranolol

• No change in Hr or BP but:– 50% incr in coronary resistance with 20% decr in flow

No mention of benzos???????

Conclusion

• Troponemia is a bad sign.

• Lots of studies/numbers out there

• Stratification is probably the way to go to target selected population but can we rely on present evidences…

Questions?