Jeffrey D. Lorin

Prognostic Value of Fractional Flow Reserve: Linking Physiologic Severity to Clinical Outcomes

BACKGROUND Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

Percutaneous coronary intervention versus coronary bypass graft surgery for diabetic patients with unstable angina and risk factors for adverse outcomes with bypass: Outcome of diabetic patients in the AWESOME randomized trial and registry

OBJECTIVES This study compared survival after percutaneous coronary intervention (PCI) with survival after coronary artery bypass graft surgery (CABG) among diabetics in the Veterans Affairs AWESOME (Angina With Extremely Serious Operative Mortality Evaluation) study randomized trial and registry of high-risk patients. BACKGROUND Previous studies indicate that CABG may be superior to PCI for diabetics, but no comparisons have been made for diabetics at high risk for surgery. METHODS Over five years (1995 to 2000), 2,431 patients with medically refractory myocardial ischemia and at least one of five risk factors (prior CABG, myocardial infarction within seven days, left ventricular ejection fraction <0.35, age >70 years, or an intra-aortic balloon being required to stabilize) were identified. A total of 781 were acceptable for CABG and PCI, and 454 consented to be randomized. The 1,650 patients not acceptable for both CABG and PCI constitute the physician-directed registry, and the 327 who were acceptable but refused to be randomized constitute the patient-choice registry. Diabetes prevalence was 32% (144) among randomized patients, 27% (89) in the patient-choice registry, and 32% (525) in the physician-directed registry. The CABG and PCI survival rates were compared using Kaplan-Meier curves and log-rank tests. RESULTS The respective CABG and PCI 36-month survival rates for diabetic patients were 72% and 81% for randomized patients, 85% and 89% for patient-choice registry patients, and 73% and 71% for the physician-directed registry patients. None of the differences was statistically significant. CONCLUSIONS We conclude that PCI is a relatively safe alternative to CABG for diabetic patients with medically refractory unstable angina who are at high risk for CABG.

Effect of PCI on Long-Term Survival in Patients with Stable Ischemic Heart Disease

BACKGROUND Percutaneous coronary intervention (PCI) relieves angina in patients with stable ischemic heart disease, but clinical trials have not shown that it improves survival. Between June 1999 and January 2004, we randomly assigned 2287 patients with stable ischemic heart disease to an initial management strategy of optimal medical therapy alone (medical-therapy group) or optimal medical therapy plus PCI (PCI group) and did not find a significant difference in the rate of survival during a median follow-up of 4.6 years. We now report the rate of survival among the patients who were followed for up to 15 years. METHODS We obtained permission from the patients at the Department of Veterans Affairs (VA) sites and some non-VA sites in the United States to use their Social Security numbers to track their survival after the original trial period ended. We searched the VA national Corporate Data Warehouse and the National Death Index for survival information and the dates of death from any cause. We calculated survival according to the Kaplan-Meier method and used a Cox proportional-hazards model to adjust for significant between-group differences in baseline characteristics. RESULTS Extended survival information was available for 1211 patients (53% of the original population). The median duration of follow-up for all patients was 6.2 years (range, 0 to 15); the median duration of follow-up for patients at the sites that permitted survival tracking was 11.9 years (range, 0 to 15). A total of 561 deaths (180 during the follow-up period in the original trial and 381 during the extended follow-up period) occurred: 284 deaths (25%) in the PCI group and 277 (24%) in the medical-therapy group (adjusted hazard ratio, 1.03; 95% confidence interval, 0.83 to 1.21; P=0.76). CONCLUSIONS During an extended-follow-up of up to 15 years, we did not find a difference in survival between an initial strategy of PCI plus medical therapy and medical therapy alone in patients with stable ischemic heart disease. (Funded by the VA Cooperative Studies Program and others; COURAGE ClinicalTrials.gov number, NCT00007657.).

Optimal medical therapy with or without percutaneous coronary intervention for patients with stable coronary artery disease and chronic kidney disease.

Chronic kidney disease (CKD) is a risk factor for poor outcomes in patients with coronary artery disease (CAD), but it is unknown whether CKD influences the efficacy of alternative CAD treatment strategies. Thus, we compared outcomes in stable CAD patients with and without CKD randomized to percutaneous coronary intervention (PCI) and optimal medical therapy (OMT) or OMT alone in a post hoc analysis of the 2,287 patient COURAGE study. At baseline, 320 patients (14%) had CKD defined as a glomerular filtration rate of <60 mL/min/1.73 m(2), as estimated by the abbreviated 4-variable Modification of Diet in Renal Disease equation. The patients with CKD were older (68 +/- 9 vs 61 +/- 10 years; p <0.001) and more often had diabetes mellitus (42% vs 33%; p = 0.002), hypertension (81% vs 65%; p <0.03), heart failure (13% vs 3.4%; p <001), and three-vessel CAD (37% vs 29%, p = 0.01). After adjustment for these differences, CKD remained an independent predictor of death or nonfatal myocardial infarction (hazard ratio 1.48, 95% confidence interval 1.15 to 1.90). PCI had no effect on these outcomes. Furthermore, at 36 months, a similar percentage of patients with CKD treated with OMT (70%) and PCI plus OMT (76%) were angina free compared to patients without CKD. In conclusion, CKD is an important determinant of clinical outcomes in patients with stable CAD, regardless of the treatment strategy. Although PCI did not reduce the risk of death or myocardial infarction when added to OMT for patients with CKD, it also was not associated with worse outcomes in this high-risk group.

Rapid thrombectomy for treatment of macroembolization during percutaneous coronary intervention in the setting of acute myocardial infarction

We report the use of the Export catheter as an urgent modality to aspirate thrombus that embolized down the left anterior descending artery during acute myocardial infarction. Cathet Cardiovasc Intervent 2003;59:219–222. Published 2003 Wiley‐Liss, Inc.

Revascularization Strategies in Patients with Diabetes Mellitus and Acute Coronary Syndrome

Patients with diabetes mellitus (DM) have more severe CAD and higher mortality in acute coronary syndrome (ACS) than patients without DM. The optimal mode of revascularization—coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI)—remains controversial in this setting. For patients with DM and ST-segment elevation myocardial infarction, prompt revascularization of the culprit artery via PCI is generally preferable. In non-ST-elevation ACS, the decision on mode of revascularization is more challenging. Trials comparing CABG with percutaneous transluminal coronary angioplasty, bare metal stents, and first-generation drug-eluting stents in DM patients with multivessel have demonstrated decreased mortality in those receiving CABG. On the other hand, trials and retrospective analyses comparing CABG to PCI with second-generation drug-eluting stents have not shown a statistically significant mortality benefit favoring CABG. This potentially narrowed that gap between CABG and PCI requires further investigation.

Comparison of platelet activity measurements by use of arterial and venous blood sampling

Pathological and clinical studies consistently demonstrate that platelets play a significant role in the pathophysiology of atherothrombosis, and measurement of platelet activity can identify individuals at increased cardiovascular risk. While light transmission aggregation is the historical “gold standard” for platelet activity measurement, the large sample volume and significant sampling time preclude this measurement from being widely used. Other more convenient markers of platelet activity are increasingly being investigated as data demonstrating their association with clinical outcomes emerge [1]. Monocyte (MPA) and leukocyte platelet aggregates (LPA) are robust markers of platelet adhesion and activation measured by flow cytometry, the advantages of which include the use of low sample volumes, standardization of technique, and allowance for whole blood to be immediately fixed and processed at a more suitable time [2–3]. Mean platelet volume (MPV), measured on routine automated hemograms, reflects platelet size. Larger platelets are metabolically and enzymatically more active, with greater prothrombotic potential, and associated with clinical outcomes [4–5]. Finally, soluble markers of activation, such as p-selectin, can be evaluated anytime from stored frozen plasma [6]. Collectively, these data make it pertinent for us to understand these markers of platelet activity, including the effect of blood source sampling on their measurements. In this study, we aim to assess the relationship between arterial and venous sources of different markers of platelet activity. Patients in this study were part of the platelet substudy of a randomized trial evaluating effects of glucose-lowering medications in patients with diabetes mellitus, which included non-diabetic controls [7]. All patients underwent coronary angiography at the Manhattan Veterans Affairs Hospital. Of the 75 patients enrolled in this substudy measuring markers of platelet activity on procedural access, 70 had simultaneous measurements from arterial and venous blood sources. All patients signed informed consent, and the institutional review board approved the study. At the time of coronary angiography, blood samples were collected after an initial 2cc discard simultaneously from the antecubital vein using a minimum 21-guage needle and the radial (n=7) or femoral (n=63) artery using a minimum 5 french sheath. Blood was collected in a 7.2mg K2 ethylenediaminetetraacetic (EDTA) acid tube (BD Vacutainer 4.0mL, BD Franklin Lakes, NJ, USA) and processed within 60 minutes on a Sysmex XE-2100 hematology analyzer (Mundelein, Illinois, USA) for platelet count (reported coefficient of variation (CV) <4.0%), MPV (CV <3.0%), and immature platelet fraction (IPF) (CV not reported) measurements. Additional blood was collected in a 3.2% (0.109 moles/L) sodium citrate tube (BD Vacutainer 2.7mL, BD Franklin Lakes, NJ, USA) and processed within 25 minutes for measurement of MPA, LPA, and sP-selectin (sP-selectin) levels. MPA and LPA were measured via an Accuri C6 flow cytometer using directly conjugated CD14-PE or CD45-PE and CD42a-FITC antibodies. Citrate-anticoagulated blood was centrifuged at 8°C for 10 min at 2500×g, plasma was stored at −80°C, and measurements of sP-selectin were made using commercial enzyme-linked immunosorbent assay (ELISA) (eBioscience, CV 7.8%). Measures of platelet activity are presented as median [interquartile range] given their skewed distribution (Shapiro-Wilk). Reproducibility and agreement of each platelet measure between the arterial and venous source was assessed by intraclass correlation coefficient (ICC) and the Bland-Altman analysis of agreement, respectively. ICC was defined as a variance ratio (ρ=σb2σb2+σw2), the proportion of between subject variation, which was estimated using the differences of between subject variance and within subject variance over the total variation (Sb2−Sw2Sb2+Sw2), where Sb2 represents the between subject variance and Sw2 represents within subjects variance [8]. The corresponding variance components were estimated in the framework of one-way ANOVA model. Plots are presented with 95% limits of agreement (precision ± 2 standard deviations) and bias (mean difference) [9]. Correlation of platelet measures between the arterial and venous source was performed using the Spearman’s test [10]. Statistical analysis was conducted using the R program for Scientific Computing (available at www.r-project.org). The median age (n=70) was 65 years (interquartile range 63−72), 99% male, and 80% White. Medical history was significant for known coronary artery disease in 59%, diabetes mellitus in 69%, peripheral artery disease in 14%, and tobacco use in 76%. Measures of platelet activity using an arterial versus venous blood source were reproducible by varying degrees (Table 1). The limits of agreement for arterial versus venous measurement of MPV, IPF, MPA, LPA, and sP-selectin were 0.38 fL to −0.59 fL, 2.0% to −2.39%, −19.0% to −22.2%, 5.7% to −6.5%, and 36.5 ng/mL to −56.6 ng/mL, respectively (Figure S1). The bias for the hematology analysis markers ranged from −0.11 to −0.17, the flow cytometric markers ranged from −0.4% to −1.6%, and sP-selectin was −10.1 ng/mL. Table 1 Markers of platelet activity measured using arterial and venous blood sources Platelet activity is increasingly investigated as a surrogate end-point in the setting of percutaneous coronary intervention (PCI) [11]. Arterial access obtained during PCI provides for a convenient source of blood sampling, whereas venous sampling is more convenient outside the procedural time period. Therefore, when there is a need to compare time-related changes in platelet activity in the PCI population, it is necessary to understand whether venous samples obtained pre- or post-procedure can be compared with arterial samples obtained during the procedure. In the current study, markers of platelet size and activity measured on an automated hematology analyzer and using flow cytometry demonstrated excellent to good agreement between arterial and venous samples, while plasma markers measured by ELISA less so. Jaumdally and colleagues demonstrated no difference in sP-selectin levels from the coronary ostium, aorta, coronary sinus and right femoral vein [12]. They did note a difference in MPV measurements between the coronary ostium and coronary sinus or femoral vein. However, the flow patterns between the aorta and the coronary ostium are markedly different, and the difference in MPV measurements was attenuated when those from the aorta and femoral vein were compared. Furthermore, the study did not provide measures of reliability. Similarly, Chen and colleagues demonstrated significantly higher levels of sP-selectin in the left atrium of 16 patients compared with levels from the right atrium, femoral vein and femoral artery, but similar levels between the femoral vein and artery [13]. In both studies, arterial and venous samples were collected from introducer sheaths, whereas in our study, venous samples were collected from the antecubital vein, a common source of blood sampling post-procedure. Some of the limitations of the current study include the predominately male cohort and small sample size, although this cohort represents one of the larger studies published and is one of the very few studies to evaluate the agreement and correlation between samples obtained via an arterial versus venous blood source.

A dual wire approach to severe ostial bifurcating renal artery stenosis.

Percutaneous intervention with balloon expandable stents has proven to be an effective measure to enhance renal blood flow and control blood pressure in subjects with severe ostial renal artery lesions. A small cohort of these subjects have an ostial bifurcation, which complicates the approach to revascularization. In these cases there is a concern of creating a total side‐branch occlusion during balloon expansion. We report two cases of an ostial lesion at a renal artery bifurcation revascularized by employing a sequential dilatation double guidewire technique. Using a single 7F sheath in each case, both renal artery branches were wired, and each branch was predilated and stented in a sequential fashion. Excellent angiographic results were obtained in both cases. Published 2006 Wiley‐Liss., Inc.

Effect of rosiglitazone on survival in patients with diabetes mellitus treated for coronary artery disease.

ObjectivesThe purpose of this study was to assess the impact of rosiglitazone on survival in patients with diabetes mellitus (DM) and coronary artery disease (CAD). MethodsWe carried out a drug-exposure analysis in 801 patients with DM and CAD in a cardiac catheterization laboratory registry (490 patients treated with a percutaneous coronary intervention, 224 patients treated with coronary artery bypass grafting, and 87 patients treated with medication alone). ResultsA total of 193 patients (24.1%) were exposed to rosiglitazone. The median survival from the date of cardiac catheterization in the rosiglitazone group was 146.7 months versus 109.1 months in the unexposed group (P<0.001). At 5 years, the unadjusted survival was 82% in the rosiglitazone-exposed group versus 69% in the unexposed group (P<0.001). There was no difference in survival between rosiglitazone-exposed and rosiglitazone-unexposed patients in the groups treated with coronary artery bypass grafting or medical therapy (P=0.37 and 0.11, respectively). In a multivariable model, rosiglitazone exposure had no effect on mortality (hazard ratio=0.737; 95% confidence interval: 0.521–1.044, P=0.86). ConclusionWe conclude that exposure to rosiglitazone is not associated with increased mortality in diabetics who are treated for CAD. These findings support the notion that insulin sensitization with a thiazolidinedione is safe in carefully selected and treated patients with DM and CAD.

Metabolic syndrome does not impact survival in patients treated for coronary artery disease.

ObjectivesWe evaluated the effect of metabolic syndrome (a risk factor for the development of coronary artery disease) on survival in patients with established coronary artery disease. MethodsSurvival was determined for 2886 patients with coronary artery disease diagnosed by cardiac catheterization performed between 1990 and 2005 at a Department of Veterans Affairs hospital. Variables obtained from the computerized medical record were evaluated in multivariate analysis by Cox regression. The analysis was performed for the entire population; separate analyses were performed for patient cohorts treated with percutaneous coronary intervention and medication (n=1274), coronary artery bypass grafting and medication (n=1096), or medication alone (n=516). ResultsAlthough age (odds ratio 0.948; P<0.000), left ventricular function (odds ratio 0.701; P<0.000), serum creatinine (odds ratio 0.841; P<0.000), and smoking (odds ratio 0.873; P=0.019) were all strong predictors of mortality. Metabolic syndrome had no independent effect irrespective of diabetic status. ConclusionMetabolic syndrome does not impact survival patients with coronary artery disease treated by revascularization and/or medical therapy.