Acute Coronary Syndrome

1
Acute Coronary Syndrome
2
Worldwide Statistics

• Each year
• gt 4 million patients are admitted with unstable
  angina and acute MI
• gt 900,000 patients undergo PTCA with or without
  stent

3
Myocardial Ischemia

• Spectrum of presentation
• silent ischemia
• exertion-induced angina
• unstable angina
• acute myocardial infarction

4
Cumulative 6-month mortality from ischemic heart
disease
25
N 21,761 1985-1992 Diagnosis on adm to hosp
20
15
Deaths / 100 pts / month
Acute MIUnstable anginaStable angina
10
5
0
0 1 2 3
4 5 6
Months after hospital admission
Duke Cardiovascular Database
5
Ischemic Heart Diseaseevaluation

• Based on the patients
• history / physical exam
• electrocardiogram
• Patients are categorized into 3 groups
• non-cardiac chest pain
• unstable angina
• myocardial infarction

6
Acute Coronary Syndrome
HistoryPhysical Exam
Ischemic DiscomfortUnstable Symptoms
No ST-segmentelevation
ST-segmentelevation
ECG
Unstable Non-Q Q-Waveangina AMI AMI
AcuteReperfusion
7
Acute Coronary Syndrome

• The spectrum of clinical conditions ranging from
• unstable angina
• non-Q wave MI
• Q-wave MI
• characterized by the common pathophysiology of a
  disrupted atheroslerotic plaque

8
Unstable Angina - Definition

• angina at rest (gt 20 minutes)
• new-onset (lt 2 months) exertional angina (at
  least CCSC III in severity)
• recent (lt 2 months) acceleration of angina
  (increase in severity of at least one CCSC class
  to at least CCSC class III)

Canadian Cardiovascular Society Classification
Agency for Health Care Policy Research - 1994
9
Unstable AnginaLikelihood of CAD

• Previous history of CAD
• presence of risk factors
• older age
• ST-T wave ischemic ECG changes

Agency for Health Care Policy Research - 1994
10
Unstable Anginaprecipitating factors

• Inappropriate tachycardia
• anemia, fever, hypoxia, tachyarrhythmias,
  thyrotoxicosis
• High afterload
• aortic valve stenosis, LVH
• High preload
• high cardiac output, chamber dilatation
• Inotropic state
• sympathomimetic drugs, cocaine intoxication

11
Unstable Anginaprognostic indicators

• Presence of ST-T-wave changes with pain
• Hemodynamic deterioration
• pulmonary edema, new mitral regurgitation,
• 3rd heart sound, hypotension
• Other predictors
• left ventricular dysfunction, extensive CAD, age,
  comorbid conditions (diabetes mellitus,
  obstructive pulmonary disease, renal failure,
  malignancy)

12
Unstable Anginapathogenesis

• Plaque disruption
• Acute thrombosis
• Vasoconstriction

13
Unstable Anginapathogenesis

• Plaque disruption
• Passive plaque disruptionsoft plaque with high
  concentration of cholesteryl esters and a thin
  fibrous cap
• Active plaque disruptionmacrophage-rich area
  with enzymes that may degrade and weaken the
  fibrous cap predisposing it to rupture

14
Unstable Anginapathogenesis

• Acute Thrombosis
• Vulnerable plaque
• disrupted plaque with ulceration
• occurring in 2/3 of unstable patients
• the exposed lipid-rich core abundant in
  cholesteryl ester is highly thrombogenic
• Systemic Hypercoagulable State
• disrupted plaque with erosion
• occurring in 1/3 of unstable patients

15
Unstable Anginapathogenesis

• Vasoconstriction
• the culprit lesion in response to deep arterial
  damage or plaque disruption
• area of dysfunctional endothelium near the
  culprit lesion
• platelet-dependent and thrombin-dependent
  vasoconstriction, mediated by serotonin and
  thromboxane A2

16
Acute Coronary Syndrome

• Process of resolution
• spontaneous thrombolysis
• vasoconstriction resolution
• presence of collateral circulation
• Delayed or absence of resolution may lead to
  non-Q-wave or Q-wave myocardial infarction

17
Non-Q-Wave MIclues to diagnosis

• Prolonged chest pain
• Associated symptoms from the autonomic nervous
  system
• nausea, vomiting, diaphoresis
• Persistent ST-segment depression after resolution
  of chest pain

18
Prinzmetals Anginaclues to diagnosis

• Transient ST-segment elevation during chest pain
• Intermittent chest pain
• often repetitive
• usually at rest
• typically in the early morning hours
• rapidly relieved by nitroglycerine
• Syncope (rare), Raynauds, migraine

19
Unstable AnginaRisk Stratification

• Low Risk
• new-onset exertional angina
• minor chest pain during exercise
• pain relieved promptly by nitroglycerine
• Management
• can be managed safely as an outpatient (assuming
  close follow-up and rapid investigation)

20
Unstable AnginaRisk Stratification

• Intermediate Risk
• prolonged chest pain
• diagnosis of rule-out MI
• Management
• observe in the ER or Chest Pain Unit
• monitor clinical status and ECG
• obtain cardiac enzymes (troponin T or I) every 8
  to 12 hours

21
Unstable AnginaRisk Stratification

• High Risk
• recurrent chest pain
• ST-segment change
• hemodynamic compromise
• elevation in cardiac enzymes
• Management
• monitor in the Coronary Care Unit

22
Risk Stratification by ECG

• The risk of death or MI at 30 days is strongly
  related to the ECG at the time of chest pain.
• ST depression 10
• T-wave inversion 5
• No ECG changes 1-2

23
Unstable AnginaTherapeutic Goals

• Therapeutic Goals
• Reduce myocardial ischemia
• Control of symptoms
• Prevention of MI and death
• Medical Management
• Anti-ischemic therapy
• Anti-thrombotic therapy

24
Unstable AnginaMedical Therapy

• Anti-ischemic therapy
• nitrates, beta blockers, calcium antagonists
• Anti-thrombotic therapy
• Anti-platelet therapy
• aspirin, ticlopidine, clopidogrel, GP IIb/IIIa
  inhibitors
• Anti-coagulant therapy
• heparin, low molecular weight heparin (LMWH),
  warfarin, hirudin, hirulog

25
Unstable AnginaAnti-ischemic Therapy

• restrict activities
• morphine
• oxygen
• nitroglycerine
• pain relief, prevent silent ischemia, control
  hypertension, improve ventricular dysfunction
• nitrate free period recommended after the first
  24-48 hours

26
Unstable AnginaAnti-ischemic Therapy

• beta-blockers
• lowering angina threshold
• prevent ischemia and death after MI
• particularly useful during high sympathetic tone
• calcium antagonists
• particularly the rate-limiting agents
• nifedipine is not recommended without concomitant
  ß-blockade

27
Unstable AnginaAnti-thrombotic Therapy

• Thrombolytics are not indicated
• lytic agents may stimulate the thrombogenic
  process and result in paradoxical aggravation of
  ischemia and myocardial infarction

TIMI IIIB InvestigatorsCirculation 1994
891545-1556
28
Platelets in Acute Coronary Syndromes

• Platelets play a key role in ACS
• Sources of platelet activation (triggers)
• thromboxane A2 (TXA2)
• ADP
• epinephrine
• collagen
• thrombin

29
Unstable AnginaAnti-platelet Therapy

• aspirin is the gold standard
• irreversible inhibition of the cyclooxygenase
  pathway in platelets, blocking formation of
  thromboxane A2, and platelet aggregation
• in AMI, ASA reduced the risk of death by 20-25
• in UA, ASA reduced the risk of fatal or nonfatal
  MI by 71 during the acute phase, 60 at 3
  months, and 52 at 2 years
• bolus dose of 160-325 mg, followed by maintenance
  dose of 80-160 mg/d

30
GP IIb/IIIa ReceptorFinal Pathway to Platelet
Aggregation

• Platelet activation and aggregation are early
  events in the development of coronary thrombosis
• GP IIb/IIIa receptors on activated platelets
  undergo a conformational change allowing
  recognition and binding of fibrinogen
• Fibrinogen acts like glue, bridging GP IIb/IIIa
  receptors on adjacent platelets, leading to
  platelet aggregation

31
GP IIb/IIIa ReceptorKVGFFGR

• There are approximately 50,000 GP IIb/IIIa
  receptors on each platelet
• KVGFFGR is a specific region within GP IIb/IIIa
  receptor that is thought to be involved in
  platelet activation

32
Incidence of Ischemic Events
Incidence of death and MI
16
12
9
No aspirin(early 1980s)
Aspirin
Aspirin Heparin
33
Unstable AnginaAnti-platelet Therapy

• Thienopyridines
• ticlopidine (Ticlid Hoffmann-La Roche)
• clopidogrel (Plavix Bristol-Myers Squibb)
• block platelet aggregation induced by ADP and
  the transformation of GP IIb/IIIa into its high
  affinity state

34
Unstable AnginaAnti-platelet Therapy

• Ticlopidine
• in an open-label, randomized study in patients
  with unstable angina
• ticlopidine 250 mg bid vs. placebo reduced the
  risk of fatal or nonfatal MI by 46 at 6 months
• benefit not seen at 7 days, but became apparent
  after 10 days of therapy (the time required for
  full antiplatelet activity)
• an alternative for patient with aspirin
  intolerance

Circulation 19908217-26
35
Unstable AnginaAnti-platelet Therapy

• Clopidogrel
• CAPRIE (Clopidogrel versus Aspirin in Patients at
  Risk of Ischemic Events)
• 19,000 patients randomly assigned to clopidogrel
  (75 mg/d) or to aspirin (325 mg/d)
• there was an 8.7 reduction in the combined
  incidence of stroke, MI, or death (P.043)
• patients with MI did better with aspirin
• patients with PVD or stroke did better with
  clopidogrel

Lancet 19963481329-1339Circulation 1998971107
36
Unstable AnginaAnti-platelet Therapy

• GP IIb/IIIa inhibitors
• abciximab (monoclonal antibody)
• eptifibatide (peptidic inhibitor)
• lamifiban and tirofiban (non-peptides)
• direct occupancy of the GP IIb/IIIa receptor by
  a monoclonal antibody or by synthetic compounds
  mimicking the RGD sequence for fibrinogen binding
  prevents platelet aggregation

37
Unstable AnginaAnti-platelet Therapy

• Abciximab (Reo-Pro)
• EPIC Trialeffective in preventing death, MI, and
  abrupt closure associated with coronary
  angioplasty (see also EPIC slides)
• EPISTENT Trial(unpublished - see MedSlides News)

38
Unstable AnginaAnti-platelet Therapy

• Abciximab (Reo-Pro)
• CAPTURE (Chimeric 7E3 Antiplatelet in Unstable
  Angina Refractory to Standard Treatment)
• 1,000 patients with angiographically documented
  unstable angina, not responding to ASA, nitrates,
  heparin,and other anti-anginals, received either
  abciximab or placebo within 18-24 hours

Lancet 19973491429-1435
39
Unstable AnginaAnti-platelet Therapy

• Abciximab (ReoPro Centocor)
• CAPTURE
• At 30 days, there was a 29 reduction in the
  primary composite endpoint of death, MI, or
  urgent revascularization in the abciximab group
• At 6 months, this benefit was not evident

Lancet 19973491429-1435
40
Unstable AnginaAnti-platelet Therapy

• Lamifiban
• PARAGON (Platelet IIb/IIIa Antagonist for the
  Reduction of Acute Coronary Syndrome Events in a
  Global Organization Network)
• 2000 patients received two different doses of
  lamifiban compared with placebo heparin
• at 6 months, there was a lower event rate (12.6
  vs 17.9) with low dose lamifiban

41
Unstable AnginaAnti-platelet Therapy

• Tirofiban (Aggrastat Merk Co.)
• PRISM (Platelet Receptor Inhibition for Ischemic
  Syndrome Management)
• 3,200 patients with unstable angina were treated
  with either heparin or tirofiban
• At 48 hours, there was significant risk reduction
  (5.9 to 3.6) in the rate of death, MI, or
  refractory ischemia. The benefit was lost at 30
  days.

N Engl J Med 19983381498-505
42
Unstable AnginaAnti-platelet Therapy

• Tirofiban
• PRISM -PLUS (Platelet Receptor Inhibition for
  Ischemic Syndrome Management in Patients Limited
  by Unstable Signs and Symptoms)
• randomized 1,915 patients with UA and non-Q-MI to
  tirofiban alone, heparin alone, or a combination
  of the two (all received aspirin)

N Engl J Med 19983381488-97
43
Unstable AnginaAnti-platelet Therapy

• Tirofiban
• PRISM -PLUS
• angiography was performed after 48 hr of initial
  medical therapy
• combination therapy (tirofiban, aspirin, and
  heparin) reduced the risk of death and MI at 48
  hr from 2.6 to 0.9, and at 30 days from 11.9
  to 8.7

N Engl J Med 19983381488-97
44
Unstable AnginaAnti-platelet Therapy

• Tirofiban
• RESTORE (Randomized Efficacy Study of Tirfiban
  for Outcomes and Restenosis)
• evaluate the impact of tirofiban on angioplasty
  for acute coronary syndromes
• tirofiban reduced the frequency of events
  associated with intervention in ACS

45
Unstable AnginaAnti-platelet Therapy

• Eptifibatide (Integrilin Cor/Schering)
• PURSUIT (Platelet IIb/IIIa Underpinning the
  Receptor for Suppression of Unstable Ischemia
  Trial)
• 11,000 patients admitted with unstable angina or
  non-Q-wave myocardial infarction
• a broad-based trial encompassing a variety of
  clinical practices and practice styles

NEJM 1998339436-443
46
Unstable AnginaAnti-platelet Therapy

• Eptifibatide (Integrilin Cor/Schering)
• PURSUIT
• randomized to eptifibatide or placebo all
  patients received aspirin and heparin
• significantly reduced the risk of death and MI at
  30 days from 15.7 to 14.2, a 9 risk reduction

NEJM 1998339436-443
47
Platelet Inhibition and Bleeding Time

• IMPACT II PURSUIT
• 135 / 0.5 180 / 2.0
• Inhibition of platelet aggregation
• 15 minutes after bolus 69 84
• at steady state 40-50 gt90
• 4h after infusion discontinuation lt30
  lt50
• Bleeding-time prolongation
• at steady state lt5x lt5x
• 6h after infusion discontinuation 1x
  1.4x

48
Fibanincidence of intracranial bleeding

• Treatment ()
• Study Compound Placebo Active Heparin
• RESTORE Tirofiban 0.3 0.1
• EPIC Abciximab 0.3 0.1
• 0.4
• EPILOG Abciximab 0.0 0.1
• IMPACT II Integrelin 0.07
  0.07 0.15

Bolus
Bolus Infusion
Low dose
High dose
The EXCITE Trial Investigators
49
Unstable AnginaAnti-platelet Therapy

• Summary
• the four P trials (PRISM, PRISM-PLUS, PARAGON,
  PURSUIT)
• all show reduction of death rate between1.3 and
  3.4 - in addition to the benefit of aspirin
• useful in the management of patients with
  unstable angina and MI without ST elevation

50
Unstable AnginaAnti-platelet Therapy

• Summary
• The question is no longerIs there a reason to
  use GP IIb/IIIa inhibitors? but Is there a
  reason not to use them?
• Eric Topol, MD

51
Unstable AnginaAnti-coagulant Therapy

• Heparin
• recommendation is based on documented efficacy in
  many trials of moderate size
• meta-analyses (1,2) of six trials showed a 33
  risk reduction in MI and death, but with a two
  fold increase in major bleeding
• titrate PTT to 2x the upper limits of normal

1. Circulation 19948981-88 2. JAMA
1996276811-815
52
Unstable AnginaAnti-coagulant Therapy

• Low-molecular-weight heparinadvantages over
  heparin
• better bio-availability
• higher ratio (31) of anti-Xa to anti-IIa
  activity
• longer anti-Xa activity, avoid rebound
• induces less platelet activation
• ease of use (subcutaneous - qd or bid)
• no need for monitoring

53
Unstable Angina Anti-coagulant Therapy

• Low-molecular-weight heparin
• ESSENCE Trial (Efficacy and Safety of
  Subcutaneous Enoxaparin in non-Q-Wave Coronary
  Events Study)
• at 30days, there was a relative risk reduction of
  15 -16 in the rate of death, MI, or refractory
  ischemia as compared to standard heparin

N Eng J Med 1997337447-452
54
ESSENCE Trialincidence of death, MI, or
recurrent angina
Day 14
Day 30
23.3
19.8
19.8 P0.016
16.6 P0.019
n1564 n1607
n1564 n1607
heparin Lovenox
heparin Lovenox
N Eng J Med 1997337447-452
55
Unstable Angina Coronary Interventions

• TIMI 3B
• early intervention vs conservative
  strategy(coronary angiography within 24-48 hrs,
  followed by angioplasty or bypass surgery)
• 1473 patients with UA or non-Q-wave MI were
  randomized, there were no difference between the
  groups in the rates of death or MI at 1 year

Circulation 1994891545-1556
56
Unstable Angina Coronary Interventions

• VANQWISH (Veteran Affairs non-Q-Wave Infarction
  Strategies in Hospital)
• better outcome with initial conservative therapy
  with lower rates of death and MI medical inva
  siveHosp discharge 3 8One year
  18.5 24

NEJM 19983381785-1792
57
Unstable Angina role of non-ionic contrast

• Ionic contrast media seem to perform better in
  ACS
• prospective, randomized control trial of 211
  patient
• a much greater need for CABG was seen in the
  non-ionic contrast medium group

J Am Col Cardiol 1996 261381-6
58
Trials Underway

• GUSTO-IV (abciximab vs placebo)
• EXCITE ( Eval of Oral Xemilofiban in Controlling
  Thrombotic Events)
• OPUS (Orofiban in Patients with Unstable Coronary
  Syndromes)
• SYMPHONY (Sibrafiban vs Aspirin to Yield Maximum
  Protection from Ischemic Events Post ACS)

59
References

• Acute Coronary Syndromes Unstable angina and
  Non-Q-wave MI. Pierre Theroux and Valentin
  Fuster. Circulation 1998971195-1206
• Aspirin, heparin, or both to treat acute unstable
  angina.TherouxP, et al. N Eng J Med.
  19883191105-1111.
• Risk of myocardial infarction and death during
  treatment with low dose aspirin and intravenous
  heparin in men with unstable coronary disease.
  The RISC Group. Lancet 1990336827-830.
• Protective effects of aspirin against myocardial
  infarction and death in men with unstable
  angina.Lewis HD, et al. N Eng J Med.
  1983309396-403.
• Aspirin, sulfinpyrazone, or both in unstable
  angina.Cairns JA, et al. N Eng J Med.
  19853131369-1375.

60
References

• Antiplatelet treatment with ticlopidine in
  unstable angina a controlled multicenter
  clinical trial. Balsano F, et al. Circulation
  19908217-26.
• A randomized, blinded, trial of clopidogrel
  versus aspirin in patients at risk of ischemic
  events.CAPRIE Steering Committee. Lancet
  19963481329-1339.
• Combination antithrombotic therapy in unstable
  rest angina and non-Q-wave infarction in nonprior
  aspirin users.Antithrombotic Therapy in Acute
  Coronary Syndromes Research Group. Circulation
  19948981-88
• Adding heparin to aspirin reduces the incidence
  of myocardial infarction and death in patient s
  with unstable angina.Oler S, et al. JAMA
  1996276811-815

61
References

• Low molecular weight heparin versus
  unfractionated heparin for unstable angina and
  non-Q wave myocardial infarction. Efficacy and
  Safety of Subcutaneous Enoxaparin in non-Q-Wave
  Coronary Events Study Group. N Engl J Med
  1997337447-452.
• A comparison of aspirin plus tirofiban with
  aspirin plus heparin for unstable angina. PRISM -
  The Platelet Receptor Inhibition in Ischemic
  Syndrome Management Study Invistigators N Engl J
  Med 19983381498-505