Evidence Based MedicineEvidence Based MedicineExamplesExamples

Edward G. Hamaty Jr., D.O. FACCP, FACOIEdward G. Hamaty Jr., D.O. FACCP, FACOI

Meta Analysis & DiagnosisMeta Analysis & Diagnosis

Meta AnalysisMeta Analysis• Objectives• The purpose of our study was to conduct an evidence-

based 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 AnalysisMeta Analysis

Meta AnalysisMeta 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 AnalysisMeta Analysis

Meta AnalysisMeta 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. Stress-induced 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%57.4%).

• Conclusions• In studies with highhigh 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 = 70.5%

CAD Prevalence = 57.4%

Meta AnalysisMeta 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 AnalysisMeta Analysis

Meta AnalysisMeta Analysis

DiagnosisDiagnosis

DiagnosisDiagnosis

DiagnosisDiagnosis• 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.

DiagnosisDiagnosis

Diagnosis – Perfusion DataDiagnosis – Perfusion Data

Diagnosis – Perfusion DataDiagnosis – Perfusion Data

Diagnosis – Wall Motion DataDiagnosis – Wall Motion Data

Diagnosis – Wall Motion DataDiagnosis – Wall Motion Data

DiagnosisDiagnosis

Combined Curves Individual Curves Per/Wall

DiagnosisDiagnosis• 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 catheter-based 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).

DiagnosisDiagnosis• 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 RatiosLikelihood Ratios• What do all these numbers mean? The Likelihood ratios 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.

DiagnosisDiagnosis

Diagnosis - ConclusionDiagnosis - 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 SafetyEfficacy and Safety

Efficacy and SafetyEfficacy 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 SafetyEfficacy 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 SafetyEfficacy 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-molecular-weight 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.

ProtocolThe 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 SafetyEfficacy and Safety

Efficacy and SafetyEfficacy and Safety

Efficacy and SafetyEfficacy and Safety

Efficacy and SafetyEfficacy 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 SafetyEfficacy and Safety

Efficacy and SafetyEfficacy and Safety

Hazard RatioHazard Ratio

Hazard RatioHazard Ratio

Hazard RatioHazard Ratio

Hazard RatioHazard 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%)

PrognosisPrognosis

PrognosisPrognosis• 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.

PrognosisPrognosis• 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).

PrognosisPrognosis

• Conclusions• Dipyridamole stress CMR is useful for

predicting the outcome of patients with known or suspected coronary artery disease.

BackgroundBackground• 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

PrognosisPrognosis• 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.

PrognosisPrognosis• 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”.)

PrognosisPrognosis

PrognosisPrognosis

PrognosisPrognosis• 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).

PrognosisPrognosis• 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).

PrognosisPrognosis• 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.

PrognosisPrognosis• 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.

PrognosisPrognosis• 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

PrognosisPrognosis• 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.

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• 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.

PrognosisPrognosis