Braunwald Lecture Series

CHAPTER 53 – Unstable
Angina and Non-ST Elevation
Myocardial Infarction
 Unstable Angina and Non-ST
Elevation MI
1.3 million pts each year have unstable
angina or Non-ST elevation MI
Acute total occlusion of a vessel causes
ST-elevation MI, whereas non-ST MI or
unstable angina is usually caused by a
severe obstruction, but not total occlusion
of an artery.
 Definition/Classification of
UA/NSTEMI
Unstable angina is defined as angina pectoris (or
equivalent type of ischemic discomfort) with at least one
of three features:
– Occurring at rest (or minimal exertion) and usually
lasting >20 minutes (if not interrupted by nitroglycerin
administration)
– Being severe and described as frank pain, and of new
onset (within 1 month)
– Occurring with a crescendo pattern (i.e., more
severe, prolonged, or frequent than previously)
Of this group, 50% will have evidence of myocardial
necrosis on basis of elevated enzymes- CKMB, Trop T or
I and have diagnosis of NSTEMI
 Classification
Clinical Circumstances
– Primary Unstable Angina
– Secondary Angina
In the setting of extracardiac condition- anemia
– Post-MI Unstable Angina
Develops within 2 weeks of MI
Severity
– Class I- new onset of severe, accelerated angina, no
rest pain
– Class II- angina at rest within past month, but not
within past 48 hrs
– Class III- angina at rest within 48 hrs
 Five pathophysiological
processes may contribute to the
development of UA/NSTEMI
 A multimarker strategy for
evaluation of the etiology and
prognosis of UA/NSTEMI
 Thrombosis
Central role of coronary artery thrombosis in pathogenesis
of UA/NSTEMI is supported by 6 sets of observations:
– At autopsy, thrombi localize at site of ruptured coronary
plaque
– Coronary atherectomy specimens demonstrate a high
incidence of thrombotic lesions as compare to pts with
stable angina
– Coronary angioscopy frequently visualizes thrombus in
UA/NSTEMI
– Coronary Angiography has demonstrated ulceration or
irregularities suggesting a ruptured plaque and/or
thrombus
– Elevation of several markers of platelet activity and
fibrin formation supports ongoing thrombosis
– Improvement in clinical outcomes by antithrombotic
therapy
Pathophysiology of UA/NSTEMI
Progressive process of atherothrombosis
Coronary artery thrombus in a patient with unstable angina. A 60-year-old
man presented with prolonged rest pain and transient anterior ST
elevations.
 Pathophysiology
Platelet Aggregation and activation
– Rupture of a plaque causing plt adhesion, activation, then
aggregation
– Secondary hemostasis when plasma coagulation system is
activated, thrombin formed
Coronary Vasoconstriction
– Prinzmetal variant angina
– Microcirulatory Angina with constriction of small intramural coronary
resistance vessels
– Local vasoconstrictors from platelets, thromboxane A2, serotonin,
and thrombin
– Miscellaneous- dysfunctional coronary endothelium, adrenergic
stimuli, cold immersion, cocaine or metal stress
Progressive mechanical obstruction
– Restenosis after PCI or rapid cell proliferation
Secondary Unstable Angina- in pts w/prior coronary stenosis
– Conditions that increase oxygen demand i.e anemia, tachycardia,
thyrotoxicosis, fever, hypoxia, hypo/hypertension
 Primary Hemostasis- platelet
adhesion/activation/aggregation
Clinical Presentation of Patients
with UA/NSTEMI
Physical exam
– Diaphoresis, pale/cool skin, tachycardia, 3rd/4th
heart sound, rales, hypotension
ECG
– ST depressions, transient elevations, or T
wave changes in 50% of pts
Continuous ECG
– Monitor for arrythmias, further ST changes
Example of T wave changes in
UA/NSTEMI
 Labs/Testing
Troponin, CKMB
– Elevated Troponin used to distinguish those pts with
NSTEMI which is associated with worse prognosis
– Most labs use 99th percentile of a normal population of
subjects and not greater than a 10% coefficient of
variation (a measure of reproducibility of assay).
– Can be positive in other conditions such as CHF with
no coronary stenosis, but these pts also have poor
prognosis.
CXR- pulmonary edema
Lipid panel
– Should be measured at time of initial presentation as
LDL can be 30-40% lower than baseline 24 hrs
following a STEMI or UA/NSTEMI
 Labs/Testing
Non-invasive testing
– Used at initial presentation to distinguish
presence of CAD in low risk pts
– After hospitalization and treatment started to
monitor for residual ischemia and guide
further therapy
– To evaluate LV function
– Estimate prognosis- those with ischemia on
stress testing or decreased LV function are at
higher risk
 Labs/Testing
The safety of early stress testing in pts with UA/NSTEMI
has been debated, but evidence from several trials has
suggested pharmacological, or symptom-limited stress
testing is safe after a period of at least 24-48 hrs of
stabilization.
Contraindications to stress testing are a recent
recurrence of rest pain, especially if it is associated with
ECG changes or other signs of instability (hemodynamic
or arrhythmic).
Stress myocardial perfusion imaging with sestamibi or
stress echocardiographic imaging has slightly more
sensitivity than ECG stress testing alone and has shown
greater prognostic value, only cost effective in high risk
pts.
Must individualize choice based on pt and what tests are
available and if there are ST changes present on ECG.
 Coronary Arteriographic
Findings in UA/NSTEMI
TACTICS-TIMI 18 Study, those pts enrolled in
the invasive arm who underwent angiography
– 34% had 3-V disease
– 28% had 2-V disease
– 26% had 1-V disease
– 13% had no significant (<50%) stenosis
– 5-10% had 50% L main stenosis
Culprit lesion was usually eccentric w/scalloped
or overhanging edges and narrow neck which
may represent disrupted atherosclerotic plaque,
thrombosis or combination.
 Risk Stratifcation
An important concept that has emerged regarding the
long-term outcome following an ACS event is that the
risk of recurrent ischemic events links to multifocal
lesions other than the culprit lesion responsible for the
ACS event.
The early mortality risk in ACS is related to the extent of
myocardial damage and resulting hemodynamic
compromise.
In contrast, long-term outcomes—both for mortality and
nonfatal events, is actually worse for patients with either
UA or NSTEMI compared with STEMI.
This finding likely results from the older age, greater
extent of coronary disease, and prior MI and
comorbidities—such as diabetes and impaired renal
function—in patients with UA/NSTEMI versus STEMI.
 Evidence of multiple “vulnerable” plaques in acute coronary syndrome. This
figure shows angiographic and angioscopic images of 58-year-old male with
anterior myocardial infarction. The culprit lesion is seen in the proximal left
anterior descending artery at site 8. However, other segments of the artery,
which appear normal on the coronary angiogram, demonstrate at angioscopy
the presence of vulnerable plaques.
Methods of Risk Stratification
Specific subgroups of patients, identified by
clinical features, electrocardiographic findings
and/or cardiac (or vascular) markers are at
higher risk of adverse outcomes
These groups appear to derive greater benefit
from aggressive antithrombotic and/or
interventional therapies
Those determined to be at highest risk should be
admitted to the coronary care unit, whereas
those at intermediate or lower risk may be
admitted to a monitored bed on a cardiac step-
down unit
 Risk Stratification/Clinical
Indicators of Increased Risk in
UA/NSTEMI
History
– Advanced Age (>70 yrs old)
– DM
– Post-MI Angina
– Prior PVD
– Prior CVA
 Risk Stratification/Clinical
Indicators of Increased Risk in
UA/NSTEMI
Clinical Presentation
– Braunwald class II or III (acute or subacute
rest pain)
– Braunwald class B (secondary unstable
angina)
– Heart failure/hypotension
– Multiple episodes of pain within 24 hr
Risk Stratification/Clinical Indicators
of Increased Risk in UA/NSTEMI
ECG
– ST segment deviation ≥0.05 mV
– T wave inversion ≥0.3 mV
– Left bundle branch block
Cardiac Markers
– Increased troponin T or I or creatine kinase-MB
– Increased C-reactive protein or white blood cell count
– Increased B-type natriuretic peptide
– Elevated creatinine
– Elevated glucose or hemoglobin A1C
Risk Stratification/Clinical Indicators
of Increased Risk in UA/NSTEMI
Angiogram
– Thrombus
– Multivessel disease
– Left ventricular dysfunction
 TIMI Risk Score
Seven independent risk factors to risk-stratify
patients across a 10-fold gradient of risk, from
4.7 percent to 40.9 percent
– Age >65 years
– >3 risk factors for CAD
– Documented CAD at catheterization
– ST deviation >0.5 mm
– >2 episodes of angina in last 24 hours
– ASA within prior week,
– Elevated cardiac markers
 TIMI Risk Score
This risk score predicts the response to
several of the therapies in UA/NSTEMI:
– Pts with higher TIMI risk scores had
significant reductions in events when treated
with enoxaparin as compared with unfractionated
heparin
with a GP IIb/IIIa inhibitor as compared with
placebo
with an invasive versus conservative strategy
A. Risk of death, MI, or urgent revascularization based on TIMI Score.
B. TACTICS TIMI 18 TRIAL that used conservative vs early
invasive therapy based on TIMI risk score
Number of elevated biomarkers to predict 30-day mortality
in UA/NSTEMI Troponin I, CRP, BNP
Medical Therapy for UA/NSTEMI
Oxygen if pulse ox < 92%
Morphine- relief of pain/venodilatory effects
Nitrates
– Inc coronary blood flow/decr myocard. O2 demand
– No mortatlity benefit, but goal is relief of pain
Beta Blockers
– Reduces infarct size, reinfarction, and mortality
– Should not be used in decompensated CHF
Calcium Channel Blockers- vasodilatory effects
and lower BP
– diltazem or verapamil (HR slowing)
– Only used after full dose nitrates and beta blockers
with persistent ischemia, contraindication to beta
blockers, or hypertension
 Antithrombotic Agents
Antiplatelet
– Aspirin
Decreases plt aggregation at site of thrombus by
blocking synthesis of thromboxane A2
50% reduction in risk of death or MI in pts with
UA/NSTEMI
– Plavix
Inhibits plt aggregation by inhibiting ADP action on plt
receptors
In the CURE Trial-the combination of plavix plus
aspirin conferred a 20 percent reduction in
cardiovascular death, MI, or stroke compared with
aspirin alone, in both low- and high-risk patients with
UA/NSTEMI .
Aspirin vs Placebo in UA/NSTEMI
Benefit of Aspirin and Plavix vs
Aspirin and Placebo
 Antithrombotic Agents
Glycoprotein IIB/IIA Inhibitors
– Greatest benefit in high risk pts- ST segment changes on ECG,
diabetics, elevated troponins
– Tirofiban plus heparin and aspirin significantly reduced the rate of
death, MI, or refractory ischemia at 7 days compared with heparin
plus aspirin. Death or MI at 30 days also fell significantly by 30
percent, from 11.9 percent to 8.7 percent.
– In a trial involving 10,948 patients, eptifibatide also significantly
reduced the rate of death or MI at 30 days.
Opinion is divided on the optimal timing of GP IIb/IIIa
inhibition, with some advocating use of GP IIb/IIIa inhibition
at the time of presentation, whereas others reserve it for use
during PCI.
The ACC/AHA Guidelines note that either strategy is
acceptable
A. CAPTURE Trial- Use of Abciximab in setting of + vs – troponin T in
refractory unstable angina treated with angioplasty.
B. ISAR-REACT 2 Benefit of abciximab versus placebo even after
patients undergoing percutaneous coronary intervention (PCI) were
pretreated with clopidogrel
 Anticoagulants
Heparin
– A meta-analysis showed a trend toward a 33% reduction
in death or MI comparing UFH plus aspirin versus aspirin
alone.
– ACC/AHA Guidelines recommend a weight adjusted
dosing of UFH with a target range of APTT between 1.5-
2X control or approx. 50-70 seconds.
– Adverse events of bleeding and HIT.
Low-Molecular-Weight Heparin
– Combine factor IIa and factor Xa inhibition and thus
inhibit both the action and generation of thrombin.
– LMWH (+ ASA) has proved effective compared with ASA
alone, leading to a 66% red. in the odds of death or MI.
– In the two most recent trials, enoxaparin was found to be
noninferior to UFH
– Must be adjusted for renal fxn, reversed with protamine
 Anticoagulants Continued
Fondaparinux
– Indirect Xa inhibitor
– OASIS-5 trial compared fondaparinux with enoxaparin in 20,078
patients with high-risk UA/NSTEMI. The rates of death, MI, or refractory
ischemia throughout the first 9 days were similar with fondaparinux and
enoxaparin (5.9 percent versus 5.8 percent), meeting the prespecified
hypothesis of noninferiority
– The rate of major bleeding was almost 50% lower in the fondaparinux
arm (2.2 percent versus 4.1 percent, p<0.001).
– By 30 days, mortality was significantly lower in the fondaparinux arm
(2.9 percent versus 3.5 percent, p = 0.02).
– In the subset of patients undergoing PCI, fondaparinux was associated
with more than a 3X increased risk of catheter-related thrombi,
something also observed in patients with STEMI treated with
fondaparinux.
– Supplemental UFH at the time of cath appeared to minimize the risk of
this complication.
 Anticoagulants Continued
Direct Thrombin Inhibitors
– Don’t require antithrombin and can inhibit clot-bound thrombin, don’t
interact with plasma proteins, don’t cause thrombocytopenia
– The only current U.S. FDA–approved indication for lepirudin and
argatroban is for anticoagulation in patients with heparin-induced
thrombocytopenia (HIT) and associated thromboembolic disease.
– ACUITY trial randomized 13,819 patients with UA/NSTEMI to one of
three treatments: UFH or enoxaparin plus a GP IIb/IIIa inhibitor,
bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone
– Substitution of bivalirudin as the anticoagulant among patients
receiving supplemental GP IIb/IIIa inhibitors did not change efficacy or
safety outcomes, but the strategy of bivalirudin alone was associated
with less bleeding than the combination of a GP IIb/IIIa inhibitor with
either UFH or enoxaparin.

No benefit of Fibrinolytic therapy in UA/NSTEMI

 Indications for Invasive vs.
Conservative Management
Strategies
Early Invasive strategy indicated in
– ST segment changes and/or positive troponin on
admission or that evolves over the next 24 hours
– Other high-risk indicators, such as recurrent ischemia
or evidence of congestive heart failure
– Cardiogenic shock
– Those who present with UA/NSTEMI within 6 months
of a prior PCI, in whom restenosis may be frequent
– Prior CABG
 Timing of Invasive Strategy
Intracoronary Stenting with Antithrombotic Regimen
Cooling-Off (ISAR-COOL) trial found a benefit of an
immediate invasive strategy with an avg time from
randomization to cath of only 2 hrs, compared with a
delayed invasive strategy (avg time to cath, 4 days)
A second study compared an immediate invasive approach
(but without GP IIb/IIIa inhibition) with a strategy that
included early GP IIb/IIIa inhibition followed by
catheterization within 24 to 48 hours.
– This study did not find an improvement in the immediate
invasive approach as compared with an early invasive
strategy.
Timing of Invasive Strategy Cont.
Two observational studies of the timing of
angiography failed to find any major differences
in outcomes among patients who underwent
protocol-mandated catheterization within the first
12 hours versus 12 to 24 versus 24 to 48 hours
Based on available information the optimal
timing appears to be within the first 48 hours of
presentation.
 Meta-analysis of the benefit of a routine invasive versus
“selective” invasive (i.e., conservative) strategy for patients
with unstable angina or NSTEMI on the rate of death, MI or
rehospitalization through follow-up.
 Other therapies
ACE Inhibitors/ARBs
– Three large trials showed a 0.5 % absolute mortality benefit
of early (within 24 hrs) ACE inhibitor tx in pts with acute MI.
– ARBs can be substituted for ACE inhibitors based on the
VALIANT trial, that showed equivalent outcomes in post MI
patients between captopril and valsartan.
Lipid Lowering/Statin Therapy
– In the Long-Term Intervention with Pravastatin in Ischemic
Disease (LIPID) trial, a prespecified subgroup of more than
3200 UA patients, pravastatin therapy led to a significant 26
percent reduction in total mortality (p = 0.004)
IABP
– Reserved for patients with UA/NSTEMI who are refractory to
maximal medical therapy and those with hemodynamic
compromise who are awaiting cardiac catheterization, or
those identified to have very high-risk coronary anatomy
(e.g., left main stenosis) as a bridge to PCI or CABG.
Summary of Tx for UA/NSTEMI
 Prinzmetal Variant Angina
n 1959, Prinzmetal and colleagues
described a syndrome of ischemic pain
that occurred at rest and not with exertion,
accompanied by ST segment elevation.
This syndrome, known as Prinzmetal or
“variant” angina, may be associated with
acute MI, ventricular tachycardia, or
fibrillation, as well as with sudden death.
 Prinzmetal Variant Angina
Mechanisms
Systemic alteration in nitric oxide production or an
imbalance between endothelium-derived relaxing and
contracting factors
Enhanced phospholipase C (PLC) activity has also been
documented.
Because PLC (through activating the inositol triphosphate
pathway) mobilizes Ca2+ from intracellular stores, it may
enhance contraction of smooth muscle cells.
An inflammatory etiology –elevated CRP
Polymorphisms of the alpha2 presynaptic and the
postsynaptic beta2 receptor
Histological findings in pts undergoing coronary atherectomy
suggest that repetitive coronary vasospasm may provoke
vascular injury and lead to the formation of neointimal
hyperplasia at the initial site of spasm, leading to rapid
progression of coronary stenosis in some patients.
 Clinical/Lab Findings
ECG- episodic ST elevation w/pain
Exercise testing w/variable responses
Coronary arteriography- spasom of
proximal coronary artery w/resultant
transmural ischemia and abnormalities in
LV function are diagnostic hallmarks.
Medicines used to provoke PVA-
ergonovine, acetylcholine
 Management of PVA
STOP SMOKING
Calcium channel blockers +/- nitrates
Differences between PVA and Unstable or Stable
Angina
– Both respond to nitrates, PVA responds more to Ca
channel blockers
– Beta blockers may help or hurt PVA
– Prazosin may help PVA
– Aspirin may worsen PVA (blocks prostacyclin, coronary
vasodilator)
– PCI or CABG sometimes helps PVA, but spasm may
develop in other locations
– Ischemia associated V-fib who with continued ischemia
on maximum med tx should receive and AICD.
39 y/o man with Prinzmetal Angina
 Prognosis of PVA
Many patients with PVA pass through an acute,
active phase, with frequent episodes of angina
and cardiac events during the first 6 months
after diagnosis.
In a series of 277 patients with a median follow-
up of 7.5 years, recurrent angina was common
(39%), but cardiac death and MI were relatively
infrequent and occurred in 3.5 and 6.5 % of
patients, respectively.
Patients with PVA in whom serious arrhythmias
(VTach, Vfib, high-degree AV block, or asystole)
develop during spontaneous episodes of pain
have a higher risk of sudden death.