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 tota
l occlusion of a vessel causes ST-elevation MI, whereas non-ST MI or unstable an
gina is usually caused by a severe obstruction, but not total occlusion of an ar
tery.
Definition/Classification of UA/NSTEMI
Unstable angina is defined as angina pectoris (or equivalent type of ischemic di
scomfort) with at least one of three features: – Occurring at rest (or minimal exe
rtion) and usually lasting >20 minutes (if not interrupted by nitroglycerin admi
nistration) – 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 fre
quent than previously) Of this group, 50% will have evidence of myocardial necro
sis on basis of elevated enzymes- CKMB, Trop T or I and have diagnosis of NSTEMI
Classification
Clinical Circumstances
– Primary Unstable Angina – Secondary Angina – Post-MI Unstable Angina
In the setting of extracardiac condition- anemia 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 suppo
rted 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 freq
uently visualizes thrombus in UA/NSTEMI – Coronary Angiography has demonstrated ul
ceration or irregularities suggesting a ruptured plaque and/or thrombus – Elevatio
n 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 pr
esented with prolonged rest pain and transient anterior ST elevations.
Pathophysiology
Platelet Aggregation and activation – Rupture of a plaque causing plt adhesion, ac
tivation, then aggregation – Secondary hemostasis when plasma coagulation system i
s activated, thrombin formed Coronary Vasoconstriction – Prinzmetal variant angina
– Microcirulatory Angina with constriction of small intramural coronary resistanc
e 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 – Reste
nosis after PCI or rapid cell proliferation Secondary Unstable Angina- in pts w/
prior coronary stenosis – Conditions that increase oxygen demand i.e anemia, tachy
cardia, 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, hypotensio
n
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 sub
jects and not greater than a 10% coefficient of variation (a measure of reproduc
ibility of assay). – Can be positive in other conditions such as CHF with no coron
ary 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 th
an 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 – Afte
r hospitalization and treatment started to monitor for residual ischemia and gui
de further therapy – To evaluate LV function – Estimate prognosis- those with ischem
ia 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 e
vidence from several trials has suggested pharmacological, or symptom-limited st
ress testing is safe after a period of at least 24-48 hrs of stabilization. Cont
raindications 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 ec
hocardiographic imaging has slightly more sensitivity than ECG stress testing al
one 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 ther
e 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 angi
ography
– – – – – 34% had 3-V disease 28% had 2-V disease 26% had 1-V disease 13% had no significa
nt (<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 combin
ation.
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 l
esions other than the culprit lesion responsible for the ACS event. The early mo
rtality risk in ACS is related to the extent of myocardial damage and resulting
hemodynamic compromise. In contrast, long-term outcomes—both for mortality and non
fatal events, is actually worse for patients with either UA or NSTEMI compared w
ith STEMI. This finding likely results from the older age, greater extent of cor
onary 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 sh
ows angiographic and angioscopic images of 58-year-old male with anterior myocar
dial infarction. The culprit lesion is seen in the proximal left anterior descen
ding artery at site 8. However, other segments of the artery, which appear norma
l on the coronary angiogram, demonstrate at angioscopy the presence of vulnerabl
e plaques.
Methods of Risk Stratification
Specific subgroups of patients, identified by clinical features, electrocardiogr
aphic findings and/or cardiac (or vascular) markers are at higher risk of advers
e outcomes These groups appear to derive greater benefit from aggressive antithr
ombotic and/or interventional therapies Those determined to be at highest risk s
hould be admitted to the coronary care unit, whereas those at intermediate or lo
wer risk may be admitted to a monitored bed on a cardiac stepdown 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 (secon
dary 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 b
eased troponin T or I or creatine kinase-MB Increased C-reactive protein or whit
e blood cell count Increased B-type natriuretic peptide Elevated creatinine Elev
ated glucose or hemoglobin A1C
Cardiac Markers
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 gradie
nt of risk, from 4.7 percent to 40.9 percent
– – – – – – – Age >65 years >3 risk factors for CAD Documented CAD at catheterization ST de
tion >0.5 mm >2 episodes of angina in last 24 hours ASA within prior week, Eleva
ted 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 treat
ed
with enoxaparin as compared with unfractionated heparin with a GP IIb/IIIa inhib
itor as compared with placebo with an invasive versus conservative strategy
A. Risk of death, MI, or urgent revascularization based on TIMI Score. B. TACTIC
S TIMI 18 TRIAL that used conservative vs early invasive therapy based on TIMI r
isk 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
Beta Blockers
– Inc coronary blood flow/decr myocard. O2 demand – No mortatlity benefit, but goal
is relief of pain – Reduces infarct size, reinfarction, and mortality – Should not b
e 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 b
lockers with persistent ischemia, contraindication to beta blockers, or hyperten
sion
Antithrombotic Agents
Antiplatelet – Aspirin Decreases plt aggregation at site of thrombus by blocking s
ynthesis of thromboxane A2 50% reduction in risk of death or MI in pts with UA/N
STEMI – 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, elevate
d 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 signifi
cantly reduced the rate of death or MI at 30 days.
Opinion is divided on the optimal timing of GP IIb/IIIa inhibition, with some ad
vocating use of GP IIb/IIIa inhibition at the time of presentation, whereas othe
rs reserve it for use during PCI. The ACC/AHA Guidelines note that either strate
gy is acceptable
A. CAPTURE Trial- Use of Abciximab in setting of + vs – troponin T in refractory u
nstable angina treated with angioplasty. B. ISAR-REACT 2 Benefit of abciximab ve
rsus 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 U
FH plus aspirin versus aspirin alone. – ACC/AHA Guidelines recommend a weight adju
sted dosing of UFH with a target range of APTT between 1.52X control or approx.
50-70 seconds. – Adverse events of bleeding and HIT. – 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
Low-Molecular-Weight Heparin
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 isc
hemia throughout the first 9 days were similar with fondaparinux and enoxaparin
(5.9 percent versus 5.8 percent), meeting the prespecified hypothesis of noninfe
riority – 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 significant
ly 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 tha
n a 3X increased risk of catheter-related thrombi, something also observed in pa
tients with STEMI treated with fondaparinux. – Supplemental UFH at the time of cat
h 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 ind
ication for lepirudin and argatroban is for anticoagulation in patients with hep
arin-induced thrombocytopenia (HIT) and associated thromboembolic disease. – ACUIT
Y trial randomized 13,819 patients with UA/NSTEMI to one of three treatments: UF
H or enoxaparin plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inh
ibitor, or bivalirudin alone – Substitution of bivalirudin as the anticoagulant am
ong patients receiving supplemental GP IIb/IIIa inhibitors did not change effica
cy 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 o
r 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 th
e next 24 hours – Other high-risk indicators, such as recurrent ischemia or eviden
ce of congestive heart failure – Cardiogenic shock – Those who present with UA/NSTEM
I 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 randomi
zation to cath of only 2 hrs, compared with a delayed invasive strategy (avg tim
e to cath, 4 days) A second study compared an immediate invasive approach (but w
ithout GP IIb/IIIa inhibition) with a strategy that included early GP IIb/IIIa i
nhibition 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 catheteri
zation 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.
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 sub
stituted for ACE inhibitors based on the VALIANT trial, that showed equivalent o
utcomes in post MI patients between captopril and valsartan. Lipid Lowering/Stat
in Therapy – In the Long-Term Intervention with Pravastatin in Ischemic Disease (L
IPID) 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 catheter
ization, or those identified to have very high-risk coronary anatomy (e.g., left
main stenosis) as a bridge to PCI or CABG.
Other therapies
Summary of Tx for UA/NSTEMI
Prinzmetal Variant Angina
n 1959, Prinzmetal and colleagues described a syndrome of ischemic pain that occ
urred at rest and not with exertion, accompanied by ST segment elevation. This s
yndrome, known as Prinzmetal or “variant” angina, may be associated with acute MI, v
entricular tachycardia, or fibrillation, as well as with sudden death.
Systemic alteration in nitric oxide production or an imbalance between endotheli
um-derived relaxing and contracting factors Enhanced phospholipase C (PLC) activ
ity has also been documented. Because PLC (through activating the inositol triph
osphate pathway) mobilizes Ca2+ from intracellular stores, it may enhance contra
ction of smooth muscle cells. An inflammatory etiology –elevated CRP Polymorphisms
of the alpha2 presynaptic and the postsynaptic beta2 receptor Histological find
ings in pts undergoing coronary atherectomy suggest that repetitive coronary vas
ospasm may provoke vascular injury and lead to the formation of neointimal hyper
plasia at the initial site of spasm, leading to rapid progression of coronary st
enosis in some patients.
Prinzmetal Variant Angina Mechanisms
Clinical/Lab Findings
ECG- episodic ST elevation w/pain Exercise testing w/variable responses Coronary
arteriography- spasom of proximal coronary artery w/resultant transmural ischem
ia and abnormalities in LV function are diagnostic hallmarks. Medicines used to
provoke PVAergonovine, acetylcholine
Management of PVA
STOP SMOKING Calcium channel blockers +/- nitrates Differences between PVA and U
nstable 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 prost
acyclin, coronary vasodilator) – PCI or CABG sometimes helps PVA, but spasm may de
velop in other locations – Ischemia associated V-fib who with continued ischemia o
n 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 episod
es of angina and cardiac events during the first 6 months after diagnosis. In a
series of 277 patients with a median followup 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 ar
rhythmias (VTach, Vfib, high-degree AV block, or asystole) develop during sponta
neous episodes of pain have a higher risk of sudden death.