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Evidence Based Medicine
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Edward G. Hamaty Jr., D.O. FACCP, FACOI
Meta Analysis & Diagnosis
Meta Analysis
• Objectives
• The purpose of our study was to conduct an evidencebased evaluation of stress cardiac magnetic resonance
imaging (MRI) in the diagnosis of coronary artery disease
(CAD).
• Background
• Stress cardiac MRI has recently emerged as a noninvasive
method in the detection of CAD, with 2 main techniques in
use: 1) perfusion imaging; and 2) stress-induced wall
motion abnormalities imaging.
• Methods
• We examined studies from January 1990 to January 2007
using MEDLINE and EMBASE. A study was included if it: 1)
used stress MRI as a diagnostic test for CAD (≥50%
diameter stenosis); and 2) used catheter X-ray angiography
as the reference standard.
Meta Analysis
Meta Analysis
• Data extraction and quality assessment
• Two independent investigators performed data extraction. Inconsistencies
were resolved by discussion and consensus. Data were recorded, as
available, at the coronary territory level (left anterior descending, left
circumflex, and right coronary arteries) and patient level. Study quality
and applicability were assessed by a modified checklist based on the
Quality Assessment Tool for Diagnostic Accuracy guidelines by 2
independent investigators, with discrepancies solved by consensus (1).
• Data synthesis and statistical analysis
• Categorical variables from studies are presented as percentages and
continuous variables as mean values. The main analysis was performed at
the patient level, as most studies provided this level of information.
Secondary analyses were performed at the coronary territory level. We
applied the bivariate mixed-effects regression model for treatment trial
meta-analysis and modified for synthesis of diagnostic test data assuming
binomial errors distribution for sensitivity and specificity ([2] and [3]).
Between-study variability was assessed assuming correlated normally
distributed random effects for logit (sensitivity) and logit (specificity) with
the degree of correlation between studies predictive of an implicit
threshold effect. We derived summary sensitivity and specificity as
functions of the estimated model parameters with associated 95% CIs.
Meta Analysis
Meta Analysis
• Methods
• We examined studies from January 1990 to January 2007 using MEDLINE
and EMBASE. A study was included if it: 1) used stress MRI as a diagnostic
test for CAD (≥50% diameter stenosis); and 2) used catheter X-ray
angiography as the reference standard.
• Results
• Thirty-seven studies (2,191 patients) met the inclusion criteria, with 14
datasets (754 patients) using stress-induced wall motion abnormalities
imaging and 24 datasets (1,516 patients) using perfusion imaging. Stressinduced wall motion abnormalities imaging demonstrated a sensitivity of
0.83 (95% confidence interval [CI] 0.79 to 0.88) and specificity of 0.86
(95% CI 0.81 to 0.91) on a patient level (disease prevalence = 70.5%).
Perfusion imaging demonstrated a sensitivity of 0.91 (95% CI 0.88 to 0.94)
and specificity of 0.81 (95% CI 0.77 to 0.85) on a patient level (disease
prevalence = 57.4%).
• Conclusions
• In studies with high disease prevalence, stress cardiac MRI, using either
technique, demonstrates overall good sensitivity and specificity for the
diagnosis of CAD. However, limited data are available regarding use of
either technique in populations with low disease prevalence.
CAD Prevalence =
57.4%
CAD Prevalence =
70.5%
Meta Analysis
• Assessment of heterogeneity – Cochran’s Chi-Square
Test for Homegeneity (I2) vs. “Eyeball” approach
• Analysis at the patient level demonstrated moderate
heterogeneity in sensitivities between perfusion
imaging studies (I2 = 0.44, p = 0.04) and specificities
between stress-induced wall motion abnormality
studies (I2 = 0.73, p < 0.001). At the coronary territory
level, heterogeneity was present for between-study
specificities for both perfusion (I2 = 0.62, p < 0.001) and
stress-induced wall motion abnormality studies (I2 =
0.85, p < 0.001).
• The larger the I2 value, the more likely the values are
related. 0 = no hetergeneity (differences in values due
to chance) 100 = differences in values NOT due to
chance.
Meta Analysis
Meta Analysis
Diagnosis
Diagnosis
Diagnosis
• Estimate of clinical utility
• The positive likelihood ratio (LR+) measures the
likelihood that a positive (abnormal) stress MRI would
be expected in a patient with CAD, whereas the
negative LR (LR−) measures the likelihood that a
negative (normal) stress MRI would be expected in a
patient without CAD.
• As a measure of test performance, the LR has
advantages over sensitivity and specificity as it changes
with disease prevalence and can be used to calculate
post-test probability. Positive likelihood ratio and LR−
are defined with the following formulas: LR+ =
sensitivity/(1 − specificity) and LR− = (1 −
sensitivity)/specificity.
Diagnosis
Diagnosis – Perfusion Data
Diagnosis – Perfusion Data
Diagnosis – Wall Motion Data
Diagnosis – Wall Motion Data
Diagnosis
Combined Curves
Individual Curves Per/Wall
Diagnosis
• Patient-level summary performance estimates
• After pooling 14 datasets (1,183 patients after exclusion of 50
patients secondary to unsuccessful MRI), perfusion imaging
demonstrated a sensitivity of 0.91 (95% CI 0.88 to 0.94) and
specificity of 0.81 (95% CI 0.77 to 0.85), compared with catheterbased X-ray angiography (Fig. 2A). The prevalence of CAD in this
group was 57.4% (679 of 1,183).
• After pooling 13 datasets (735 patients after exclusion of 5 patients
secondary to unsuccessful MRI), stress-induced wall motion
abnormalities imaging demonstrated a sensitivity of 0.83 (95% CI
0.79 to 0.88) and specificity of 0.86 (95% CI 0.81 to 0.91) for CAD at
the subject level (Fig. 2B). The prevalence of CAD in this group was
70.5% (518 of 735).
• Overall, these summary estimates show good sensitivity and
specificity for CAD at the patient level. Analysis of stress-induced
wall motion abnormalities imaging with dobutamine or exercise as
the stressor (excluding studies utilizing dipyridamole) demonstrates
an improved sensitivity of 0.85 (vs. 0.83 without) (95% CI 0.82 to
0.90) with a comparable specificity of 0.86 (95% CI 0.81 to 0.91).
Diagnosis
• Evaluating clinical utility:
• The positive LR for perfusion MRI is 5.10 (95% CI 3.92
to 6.28); the negative LR, 0.11 (95% CI 0.07 to 0.15).
• For stress-induced wall motion abnormalities imaging,
the positive LR is 5.24 (95% CI 3.28 to 7.21); the
negative LR, 0.19 (95% CI 0.15 to 0.24).
• Using the rule of thumb that for a diagnostic test to be
useful it should have a high positive LR (>5) (i.e., good
at ruling in a disease) and a low negative LR (<0.2) (i.e.,
good at ruling out disease), both methods are good at
confirming and excluding CAD.
• For each test, Figure 3 (Curves) shows the effect of a
positive or negative result on pretest probabilities.
Likelihood Ratios
• What do all these numbers mean? The Likelihood ratios indicate by how
much a given diagnostic test result will raise or lower the pretest
probability of the target disorder. A likelihood ratio of 1 means that the
posttest probability is exactly the same as the pretest probability.
Likelihood ratios >1.0 increase the probability that the target disorder is
present, and the higher the likelihood ratio, the greater is this increase.
Conversely, likelihood ratios <1.0 decrease the probability of the target
disorder, and the smaller the likelihood ratio, the greater is the decrease in
probability and the smaller is its final value.
• How big is a "big" likelihood ratio, and how small is a "small" one? Using
likelihood ratios in your day-to-day practice will lead to your own sense of
their interpretation, but consider the following a rough guide:
• Likelihood ratios of >10 or < 0.1 generate large and often conclusive
changes from pre- to posttest probability;
• Likelihood ratios of 5-10 and 0.1-0.2 generate moderate shifts in pre- to
posttest probability;
• Likelihood ratios of 2-5 and 0.5-0.2 generate small (but sometimes
important) changes in probability; and
• Likelihood ratios of 1-2 and 0.5-1 alter probability to a small (and rarely
important) degree.
Diagnosis
Diagnosis - Conclusion
• Conclusions
• In studies with high disease prevalence, stress
cardiac MRI, using either technique,
demonstrates overall good sensitivity and
specificity for the diagnosis of CAD. However,
limited data are available regarding use of
either technique in populations with low
disease prevalence.
Efficacy and Safety
Efficacy and Safety
• Objectives
• This study reports a prospectively planned analysis of patients with acute
coronary syndrome who underwent early percutaneous coronary
intervention (PCI) in the OASIS-5 (Fifth Organization to Assess Strategies in
Ischemic Syndromes) trial.
• Background
• In the OASIS-5 trial, fondaparinux was similar to enoxaparin for short-term
efficacy, but reduced major bleeding by 50% and 30-day mortality by 17%.
• Methods
• The OASIS-5 trial was a double-blind, randomized comparison of
fondaparinux and enoxaparin in 20,078 patients with acute coronary
syndrome. A total of 12,715 patients underwent heart catheterization
during the initial hospitalization, and 6,238 patients underwent PCI. In the
fondaparinux group, intravenous fondaparinux was given for PCI. In the
enoxaparin group, no additional anticoagulant was given if PCI was <6 h
from last subcutaneous dose, and additional intravenous unfractionated
heparin (UFH) was given if PCI was >6 h.
Efficacy and Safety
• Results
• Fondaparinux compared with enoxaparin reduced major bleeding by more
than one-half (2.4% vs. 5.1%, hazard ratio [HR] 0.46, p < 0.00001) at day 9,
with similar rates of ischemic events, resulting in superior net clinical
benefit (death, myocardial infarction, stroke, major bleeding: 8.2% vs.
10.4%, HR 0.78, p = 0.004). Fondaparinux reduced major bleeding 48 h
after PCI irrespective of whether PCI was performed <6 h of the last
enoxaparin dose (1.6% vs. 3.8%, HR 0.42, p < 0.0001) or >6 h when UFH
was given (1.3% vs. 3.4%, HR 0.39, p < 0.0001). Catheter thrombus was
more common in patients receiving fondaparinux (0.9%) than enoxaparin
alone (0.4%), but was largely prevented by using UFH at the time of PCI,
without any increase in bleeding.
• Conclusions
• Upstream therapy with fondaparinux compared with upstream enoxaparin
substantially reduces major bleeding while maintaining efficacy, resulting
in superior net clinical benefit. The use of standard UFH in place of
fondaparinux at the time of PCI seems to prevent angiographic
complications, including catheter thrombus, without compromising the
benefits of upstream fondaparinux.
Efficacy and Safety
• Briefly, patients with unstable angina or non–ST-segment elevation
MI were randomized, in a double-blind, double-dummy fashion, to
receive either subcutaneous fondaparinux 2.5 mg once daily or
subcutaneous enoxaparin 1 mg/kg twice daily (dose reduced to 1
mg/kg once daily in patients with creatinine clearance <30 ml/min).
• Patients were eligible for inclusion in the OASIS-5 trial if they met at
least 2 of the following criteria: age ≥60 years, positive cardiac
biomarkers, or electrocardiographic changes compatible with
ischemia.
• Key exclusion criteria were any contraindication to low-molecularweight heparin, hemorrhagic stroke within the last 12 months, an
indication for anticoagulation other than ACS, revascularization
procedure already performed for the qualifying event, and severe
renal insufficiency (i.e., serum creatinine ≥3 mg/dl or 265 μmol/l).
• Patients could be treated with study drug for a maximum of 8 days
after randomization. However, the median duration of therapy in
patients undergoing PCI was only 2.5 days. Study drug was stopped
because of either clinical stabilization, a revascularization
procedure, or discharge home from hospital.
Protocol
The administration of study drugs during PCI maintained
the double-dummy, double-blind design (Fig. 1) (10).
The dose of study drug administered at PCI was
determined by the time that had elapsed since
administration of the last subcutaneous injection of
study drug, and by whether concurrent glycoprotein
(GP) IIb/IIIa inhibitors were to be used (Fig. 1).
Monitoring of the activated clotting time (ACT) during
PCI was not recommended because standard doses of
unfractionated heparin (UFH) were used, but the ACT
could be measured at the discretion of the investigator,
particularly if a clinical need arose.
Centers had the option of continuing study drug after a
revascularization procedure, but this was not mandated
by the study protocol.
Sheaths could be removed immediately after PCI if a
vascular closure device was used or a radial artery
procedure was performed or >6 h after the last injection
of fondaparinux or enoxaparin.
Efficacy and Safety
Efficacy and Safety
Efficacy and Safety
Efficacy and Safety
• Conclusions
• Upstream therapy with fondaparinux compared
with upstream enoxaparin substantially reduces
major bleeding while maintaining efficacy,
resulting in superior net clinical benefit.
• The use of standard UFH in place of fondaparinux
at the time of PCI seems to prevent angiographic
complications, including catheter thrombus,
without compromising the benefits of upstream
fondaparinux.
Efficacy and Safety
Efficacy and Safety
Hazard Ratio
Hazard Ratio
Hazard Ratio
Hazard Ratio
• Hazard Ratio for Major Bleeding at 9 days =
0.46
• HR = odds = P/(1 – P)
• P = HR/(1 + HR)
• P = 0.46/(1 + 0.46)
• P = 0.315 = a chance of bleeding of only 31.5%
with Fondaparinux vs Enoxaparin, or 1/0.315 =
3.17 x increased risk of major bleed with Enox
vs Fond at Day 9. (317%)
Prognosis
Prognosis
• Objectives
• We evaluated the prognostic value of dipyridamole stress
cardiovascular magnetic resonance imaging (CMR) in patients with
chest pain and known or suspected coronary artery disease.
• Background
• Stress perfusion CMR has been incorporated in daily practice. Data
on its prognostic value are preliminary.
• Methods
• Dipyridamole stress CMR was performed in 420 patients with chest
pain and known or suspected coronary artery disease. The extent
(number of segments according to the 17-segment model) of
abnormal wall motion at rest (AWM-rest), abnormal wall motion
with dipyridamole (AWM-D), perfusion deficit (at stress first-pass
perfusion imaging), and delayed enhancement (at late
enhancement imaging) were analyzed.
Prognosis
• Results
• During a median follow-up of 420 days, 41 major adverse cardiac
events (MACE), including 9 cardiac deaths, 14 nonfatal myocardial
infarctions, and 18 readmissions for unstable angina with
documented abnormal angiography, were documented.
• The MACE were more frequent in patients with significant (>1
segment) AWM-rest (22% vs. 5%), AWM-D (21% vs. 4%), perfusion
deficit (17% vs. 5%), and delayed enhancement (20% vs. 6%; p
<0.0001 in all cases).
• In a multivariate analysis adjusted for baseline characteristics, the
extent of AWM-D was independently related to MACE (hazard ratio
[HR] 1.15 [95% confidence interval (CI) 1.06 to 1.24] per segment; p
= 0.0006) and to major events (cardiac death or nonfatal myocardial
infarction; HR 1.15 [95% CI 1.05 to 1.26] per segment; p = 0.002).
Prognosis
• Conclusions
• Dipyridamole stress CMR is useful for
predicting the outcome of patients with
known or suspected coronary artery disease.
Background
• In patients with known or suspected myocardial ischemia,
noninvasive techniques are necessary not only to establish
or exclude the presence of coronary artery disease but also
to define management and prognosis ([1] and [2]).
Cardiovascular magnetic resonance imaging (CMR) is
becoming an integral part of the diagnostic workup of
patients with ischemic heart disease (1).
• So far, the usefulness of vasodilator stress CMR for
predicting clinical events has not been proven. The purpose
of the present study was to determine the prognostic value
of dipyridamole stress CMR in patients with known or
suspected ischemic heart disease
Prognosis
• Methods
• Study group
• The study population was represented by 420 consecutive patients
with chest pain of possible coronary origin who underwent
dipyridamole stress CMR between January 2003 and January 2006
owing to inconclusive exercise testing (18%), altered
electrocardiogram (22%), inability to exercise (23%), evaluation of
the severity of intermediate lesions (10%), and first choice (27%).
• Exclusion criteria were a history of myocardial infarction or
coronary revascularization within the last 3 months, hemodynamic
instability, asthma, and a follow-up duration of <6 months.
• All data were prospectively recorded. The study protocol was
approved by an ethics committee, and all subjects gave informed
consent.
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Prognosis
CMR data analysis
Cardiovascular magnetic resonance studies were analyzed by an experienced
observer blinded to all patient data and using customized software (Syngo,
Siemens). The 17-segment model was applied (3). We evaluated 4 dipyridamole
stress CMR-derived indexes (Fig. 1, Online Video 1):
1 Wall motion at rest (AWM-rest): number of segments showing hypokinesis,
akinesis, or dyskinesis at baseline.
2 Wall motion with dipyridamole (AWM-D): number of segments showing
hypokinesis, akinesis, or dyskinesis at stress.
3 Perfusion deficit with dipyridamole: number of segments showing persistent
delay (in at least 3 consecutive temporal images) in the visual analysis of
enhancement pattern during the first pass of contrast through the myocardium
(4).
4 Delayed enhancement: number of segments showing enhancement in late
enhancement imaging.
The AWM, AWM-D, perfusion deficit, and delayed enhancement were categorized
according to the best cut-off value in receiver-operating characteristic curves (0 to
1 segment vs. >1 segment in all cases) to predict major adverse cardiac events
(MACE) during follow-up. In our laboratory, interobserver agreement concerning
these 4 CMR indexes is >90%. (But no Chi Square published…”faith statement”.)
Prognosis
Prognosis
Prognosis
• Results
• All patients were followed up for at least 6 months (495 ±
309 days, range 184 to 1,372 days, median 420 days); 41
MACE including 23 major events (9 cardiac deaths and 14
nonfatal myocardial infarctions) and 18 readmissions for
unstable angina were detected. The baseline characteristics
are shown in Table 1 and Table 2.
• MACE
• Patients with MACE had a worse clinical profile (Table 1). In
the univariate analysis, all dipyridamole stress CMR indexes
evaluated were related to MACE (Table 2, Figure 2 and
Figure 3).
Prognosis
• In the multivariate analysis, the extent of AWM-D was the only
dipyridamole stress CMR index independently related to MACE (Table 5).
• Major events
• Patients with major events had a worse clinical profile (Table 3) and a
larger extent of AWM-rest, AWM-D, perfusion deficit, and delayed
enhancement (Table 4, Fig. 2).
• In the multivariate analysis, the extent of AWM-D was the only
dipyridamole stress CMR index independently related to major events
(Table 5).
• The C-statistic (the measure of the discriminative power of the logistic
equation) of the model with baseline characteristics included in Table 3
(0.779) was improved by the addition of CMR data included in Table 4
(0.836).
• Nonrevascularized patients
• In the 340 nonrevascularized patients, we detected 32 MACE, including 8
cardiac deaths, 11 nonfatal myocardial infarctions, and 13 readmissions
for unstable angina.
• Similarly to the whole group, the extent of AWM-D was the only
dipyridamole stress CMR index independently related to MACE and major
events (Fig. 3, Table 5).
Prognosis
• Combination of CMR indexes
• We created a 5-step score (from 0 to 4 indexes)
according to the number of abnormal CMR
indexes detected. The percentage of MACE (2%CMR = 0, 10%, 17%, 16%, and 24%-CMR = 4); p <
0.0001 for the trend) and of major events (2%,
6%, 9%, 8%, and 11%; p = 0.06 for the trend)
increased with the number of abnormal CMR
indexes detected. In the multivariate analysis this
score was not selected as an independent
variable.
Prognosis
• Discussion
• The main finding of the present study is that dipyridamole stress
CMR provides independent information for predicting cardiac
events in patients with chest pain and known or suspected ischemic
heart disease.
• Stress CMR and prognosis of coronary artery disease
• Stress CMR is likely to be useful for establishing the prognosis in
patients with chest pain and known or suspected ischemic heart
disease. However, so far, only dobutamine stress CMR ([5] and [6])
has been proven to be useful. Data concerning the prognostic value
of vasodilator stress CMR are scarce (7). The present study is the
first to assess the usefulness of vasodilator stress CMR for
predicting spontaneous clinical events.
• Cardiovascular magnetic resonance imaging allows a
comprehensive evaluation of coronary patients (8). In fact, all 4
CMR indexes assessed—AWM-rest, AWM-D, perfusion deficit, and
delayed enhancement—related to prognosis.
Prognosis
• Wall motion at stress
• Only AWM-D afforded independent information: each
additional dysfunctional segment increased the risk of
events by 15%.
• Abnormal wall motion at peak stress integrates the
information provided by systolic function at rest plus
stress-induced systolic function. This observation is in
accordance with studies using nuclear imaging
techniques (2), stress echocardiography (9), and
dobutamine CMR ([5] and [6]), suggesting that wall
motion at peak stress is the most significant predictor
of cardiac events
Prognosis
• Perfusion imaging
• Quantitative assessment of perfusion is possible but it is
time consuming. Moreover, TrueFISP sequences with high
dose of contrast offer high image quality, but occasionally
transitory artifacts make quantitative assessment difficult.
The accuracy of visual analysis, as we did, has been
encouraging ([1] and [4]).
• The prognostic value of perfusion deficit was weaker than
that of AWM-D. Revascularization guided by perfusion
deficit might partially attenuate the deleterious effect of
this finding. However, results were identical after censoring
those 80 patients who underwent a CMR study-related
revascularization procedure. This reinforces the value of
wall motion at stress in relation to the spontaneous
evolution of patients.
Prognosis
Prognosis
Prognosis
Prognosis
• Conclusions
• In patients with chest pain and known or
suspected ischemic heart disease,
dipyridamole stress CMR predicts clinical
events over the subsequent months. The
extent of abnormal wall motion at stress is the
CMR index most closely related to outcome.
Prognosis