Terrence D. Ruddy

Impaired myocardial flow reserve on rubidium-82 positron emission tomography imaging predicts adverse outcomes in patients assessed for myocardial ischemia.

OBJECTIVES We evaluated the prognostic value of myocardial flow reserve (MFR) using rubidium-82 ((82)Rb) positron emission tomography (PET) in patients assessed for ischemia. BACKGROUND The clinical value of MFR quantification using (82)Rb PET beyond relative myocardial perfusion imaging remains uncertain. METHODS We prospectively enrolled 704 consecutive patients; 677 (96%) completed follow-up (median 387 days [interquartile range: 375 to 416 days]). Patients were divided into 4 groups: I, normal summed stress score (SSS) (<4) and normal myocardial flow reserve (MFR) (>2); II, normal SSS and MFR <2; III, SSS ≥4 and MFR ≥2; IV, SSS ≥4 and MFR <2. RESULTS For patients with a normal SSS and those with an abnormal SSS, there were significant differences in outcomes for hard events (cardiac death and myocardial infarction) between patients with MFR ≥2 and those with MFR <2 (I: 1.3% vs. II: 2% [p = 0.029]; III: 1.1% vs. IV: 11.4% [p = 0.05]) and for major adverse cardiac events (MACE) (p = 0.003 and p < 0.001, respectively). In the adjusted Cox model, MFR was an independent predictor of hard events (hazard ratio: 3.3; 95% confidence interval: 1.1 to 9.5; p = 0.029) and MACE (hazard ratio: 2.4, 95% confidence interval: 1.4 to 4.4, p = 0.003). The incremental prognostic value of the MFR over the SSS was demonstrated by comparing the adjusted SSS model with and without the MFR for hard events (p = 0.0197) and MACE (p = 0.002). CONCLUSIONS MFR quantified using (82)Rb PET predicts hard cardiac events and MACE independent of the SSS and other parameters. Routine assessment of (82)Rb PET-quantified MFR could improve risk stratification for patients being investigated for ischemia.

Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making.

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.

Prognostic Value of 64-Slice Cardiac Computed Tomography: Severity of Coronary Artery Disease, Coronary Atherosclerosis, and Left Ventricular Ejection Fraction

OBJECTIVES We sought to determine the prognostic and incremental value of coronary artery disease (CAD) severity, coronary atherosclerosis, and left ventricular ejection fraction (LVEF) measured with cardiac computed tomography angiography (CTA). BACKGROUND CTA is an emerging tool used for the detection of obstructive CAD. However, there are limited data supporting the prognostic value of 64-slice CTA and its ability to predict all-cause mortality and major adverse cardiac events such as cardiac death and nonfatal myocardial infarction. METHODS Consecutive patients (without history of revascularization, heart transplantation, and congenital heart disease) were prospectively enrolled. Each CTA was evaluated for CAD severity, total plaque score, and LVEF. Patients were followed, and all events were confirmed with death certificates or hospital or physician records and reviewed by a clinical events committee. RESULTS Between February 2006 and February 2008, 2,076 consecutive patients were prospectively enrolled and followed for a mean of 16 +/- 8 months. At follow-up, a total of 31 (1.5%) patients had cardiac death or nonfatal myocardial infarction and 47 (2.3%) had all-cause mortality or nonfatal myocardial infarction. Multivariate analysis showed that CAD severity (hazard ratio [HR]: 3.02; 95% confidence interval [CI]: 1.89 to 4.83) was a predictor of major adverse cardiac events and that LVEF (HR: 1.47; 95% CI: 1.17 to 1.86) had incremental value over CAD severity. Total plaque score had incremental value over CAD severity and LVEF for all-cause mortality and nonfatal myocardial infarction (HR: 1.17; 95% CI: 1.06 to 1.29). CONCLUSIONS Using CTA, CAD severity, LVEF, and total plaque score seems to have prognostic and incremental value over routine clinical predictors. Cardiac CTA seems to be a promising noninvasive modality with prognostic value.

Comparative Efficacy of Two Angiotensin II Receptor Antagonists, Irbesartan and Losartan, in Mild-to-Moderate Hypertension

The primary objectives of this double-blind study were to compare the antihypertensive efficacy and tolerability of irbesartan and losartan, two angiotensin II (AT1 subtype) receptor antagonists with different pharmacokinetic profiles in patients with mild-to-moderate hypertension. Both drugs are approved for once-daily use (although losartan may also be prescribed twice-daily). After a placebo lead-in, 567 patients were randomized (1:1:1:1) to once-daily therapy with placebo, 100 mg losartan, 150 mg irbesartan, or 300 mg irbesartan for 8 weeks. Treatment groups had comparable demographic and baseline characteristics. After 8 weeks of treatment, reductions from baseline in trough seated diastolic blood pressure (SeDBP) and trough seated systolic blood pressure (SeSBP) with 300 mg irbesartan were greater than with 100 mg losartan (P < .01 for both comparisons), by 3.0 and 5.1 mm Hg, respectively; larger reductions were also demonstrated at weeks 1 and 4 (P < .01 and P = .017, respectively, for SeDBP). Throughout the study, the antihypertensive effect of 150 mg irbesartan did not differ significantly from that of 100 mg losartan. All therapies were well tolerated. The 300 mg dose of irbesartan was associated with the lowest incidence of adverse events (AE) and discontinuations because of AE. This study demonstrates that the maximally effective once-daily doses of two different AT1 receptor antagonists may result in clinically significant differences in blood pressure reductions, and therefore highlights the potential importance of the pharmacokinetic and pharmacodynamic differences between these two members of this class.The primary objectives of this double-blind study were to compare the antihypertensive efficacy and tolerability of irbesartan and losartan, two angiotensin II (AT1 subtype) receptor antagonists with different pharmacokinetic profiles in patients with mild-to-moderate hypertension. Both drugs are approved for once-daily use (although losartan may also be prescribed twice-daily). After a placebo lead-in, 567 patients were randomized (1:1:1:1) to once-daily therapy with placebo, 100 mg losartan, 150 mg irbesartan, or 300 mg irbesartan for 8 weeks. Treatment groups had comparable demographic and baseline characteristics. After 8 weeks of treatment, reductions from baseline in trough seated diastolic blood pressure (SeDBP) and trough seated systolic blood pressure (SeSBP) with 300 mg irbesartan were greater than with 100 mg losartan (P < .01 for both comparisons), by 3.0 and 5.1 mm Hg, respectively; larger reductions were also demonstrated at weeks 1 and 4 (P < .01 and P = .017, respectively, for SeDBP). Throughout the study, the antihypertensive effect of 150 mg irbesartan did not differ significantly from that of 100 mg losartan. All therapies were well tolerated. The 300 mg dose of irbesartan was associated with the lowest incidence of adverse events (AE) and discontinuations because of AE. This study demonstrates that the maximally effective once-daily doses of two different AT1 receptor antagonists may result in clinically significant differences in blood pressure reductions, and therefore highlights the potential importance of the pharmacokinetic and pharmacodynamic differences between these two members of this class.

Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.

OBJECTIVES The aim of this study was to determine whether the extent of viability or scar is important in the amount of recovery of left ventricular (LV) function, and to develop a model for predicting recovery after revascularization that could be tested in a randomized trial. BACKGROUND F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is used to define viable myocardium in patients with coronary artery disease (CAD) and severe LV dysfunction and to guide revascularization decisions. Whether this approach improves clinical outcomes has not been tested in a randomized trial. Before doing so, an objective model for prediction of recovery is required. METHODS A total of 82 patients with CAD and an ejection fraction (EF) < or =35% had FDG PET perfusion imaging before revascularization. Complete follow-up was available on 70 patients (86%). Patients had radionuclide angiograms at baseline and three months post-revascularization. RESULTS Diabetes (p = 0.029), time to operation (p = 0.008), and scar score (p = 0.001) were significant independent predictors of the change in EF. Previous coronary artery bypass graft confounded the effect of age. There was a significant interaction between the perfusion tracer used and mismatch score (p = 0.02). The multivariable prediction model incorporating PET and clinical variables had a goodness of fit with p = 0.001. Across tertiles of scar scores (I, small: 0% to 16%; II, moderate: 16% to 27.5%; III, large: 27.5% to 47%), the changes in EFs were 9.0 +/- 1.9%, 3.7 +/- 1.6%, and 1.3 +/- 1.5% (p = 0.003: I vs. III), respectively. CONCLUSIONS In patients with severe LV dysfunction, the amount of scar was a significant independent predictor of LV function recovery after revascularization. A combination of PET and clinical parameters predicts the degree of recovery. This model is being applied in a large randomized controlled trial to determine the effectiveness of therapy guided by FDG PET.

Potential Clinical and Economic Consequences of Noncardiac Incidental Findings on Cardiac Computed Tomography

OBJECTIVES We sought to determine the incidence, clinical significance, and potential financial impact of noncardiac incidental findings (IF) identified with cardiac computed tomography (CT). BACKGROUND Cardiac CT is gaining acceptance and may lead to the frequent discovery of extracardiac IF. METHODS Consecutive patients undergoing cardiac CT had noncardiac structures evaluated after full field of view (32 to 50 cm) reconstruction. IF were categorized as clinically significant (CS), indeterminate, or clinically insignificant. Patient follow-up was performed by telephone, and verified with hospital records and/or communication with physicians. RESULTS Of 966 patients (58 +/- 16 years of age, 55.4% men, >98% outpatients), 401 (41.5%) patients had noncardiac IF. A total of 12 (1.2%) patients had CS findings, and 68 (7.0%) patients had indeterminate findings. At follow-up (18.4 +/- 7.6 months), none of the indeterminate findings became CS. Although 3 patients with indeterminate findings were diagnosed with malignant lesions, they were unrelated to the IF. After adjusting for age, IF were not an independent predictor of noncardiac death. Noncardiac death and cancer death in patients with and without IF were not statistically different. One patient suffered a major complication related to the investigation of an IF. The total direct cost associated with investigating IF was Canadian

Diagnostic accuracy and impact of computed tomographic coronary angiography on utilization of invasive coronary angiography.

57,596 (U.S.

Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial.

83,035). CONCLUSIONS Although noncardiac IF are common, clinically significant or indeterminate IF are less prevalent. Rates of death were similar in patients with and without IF, and IF was not an independent predictor of noncardiac death. The investigation of IF is not without cost or risk. Larger studies are required to assess the potential mortality benefit of identifying IF.

Half-Time SPECT Myocardial Perfusion Imaging with Attenuation Correction

Background—Computed tomographic coronary angiography (CTA), given its high negative predictive value, is a potential gatekeeper for invasive coronary angiography (ICA). Before CTA can be further accepted into clinical practice, its impact on healthcare resources needs to be better understood. We sought to determine the clinical impact of CTA on ICA referrals, CTA accuracy, and normalcy rate. Methods and Results—To determine the impact of CTA, consecutive patients (n=7017) undergoing ICA before and after implementing a dedicated cardiac CT program were reviewed and compared with 3 other centers (n=11 508). To determine CTA accuracy, we evaluated consecutive CTA patients who underwent ICA. For normalcy rate, we identified patients with a low pretest probability for obstructive coronary artery disease. With the implementation of a cardiac CT program, the frequency of normal ICA decreased from 31.5% (1114 of 3538 patients) to 26.8% (932 of 3479 patients) (P<0.001). These findings were significantly different (P=0.003) from the 3 centers, in which normal ICAs were unchanged (30.0% [1870 of 6224 patients] to 31.0% [1642 of 5284 patients]). CTA had excellent per-patient sensitivity (99% [CI, 95% to 100%]), positive predictive value (92% [CI, 86% to 96%]) and negative predictive value (95% [CI, 72% to 100%]). Because of referral bias, specificity (64% [CI, 44% to 81%]) was low; however, the normalcy rate of CTA was 94% (CI, 90% to 97%). After adjusting for referral bias, the adjusted sensitivity was 90% (CI, 89% to 91%), and the adjusted specificity was 95% (CI, 94% to 96%), with positive and negative predictive values of 92% (CI, 91% to 93%) and 93% (CI, 92% to 94%), respectively. Conclusion—The clinical implementation of CTA appears to positively impact ICA by reducing the frequency of normal ICA. The operating characteristics of CTA support its potential role as a tool useful in ruling out obstructive coronary artery disease.

Effects of indoor, outdoor, and personal exposure to particulate air pollution on cardiovascular physiology and systemic mediators in seniors.

OBJECTIVES We sought to determine: 1) whether F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) parameters identify high-risk patients who gain benefit from revascularization; 2) whether there is a cut point for such benefit; and 3) predictors of outcome in patients with severe left ventricular (LV) dysfunction due to coronary artery disease. BACKGROUND Patients with ischemic LV dysfunction might benefit from revascularization but not without risk. The FDG PET imaging can detect viable myocardium that recovers after revascularization. In the PARR-2 (PET and Recovery Following Revascularization-2) trial, FDG PET imaging showed a nonsignificant trend for improved outcome compared with standard care. Understanding the predictors of outcome from this prospective trial should help better identify patients at risk and which patients most benefit from revascularization. METHODS This post hoc analysis included 182 patients with left ventricular ejection fraction (LVEF) <35% and coronary artery disease, being considered for revascularization work-up, and randomized to the PET arm of PARR-2. The primary outcome was a composite of cardiac death, myocardial infarction, or cardiac repeat hospital stay at 1 year. RESULTS There is an interaction between PET mismatch and protocol revascularization such that higher mismatch, when combined with revascularization, yields fewer primary outcome events (p = 0.02). On the basis of adjusted Cox modeling, with reduced mismatch (<7%), the risk is not significantly different with or without revascularization. As mismatch increases above this mark, risk is reduced with revascularization. Increasing creatinine (for a 10-mumol/l increase: hazard ratio: 1.03, 95% confidence interval: 1.01 to 1.06, p = 0.010) is also associated with increased risk, whereas decreasing LVEF (for a 2% decrease: hazard ratio: 1.08, 95% confidence interval: 0.99 to 1.18, p = 0.087) trends toward an association with increased risk. CONCLUSIONS In this post hoc analysis, patients with ischemic cardiomyopathy with larger amounts of mismatch have improved outcome with revascularization. Renal function was also an independent predictor of outcome. The FDG PET seems to define high-risk patients that gain benefit from revascularization. (PET and Recovery Following Revascularization [PARR 2]; NCT00385242).