Tamir Bental

Long-Term Stabilizing Effect of Angiotensin-Converting Enzyme Inhibition on Plasma Creatinine and on Proteinuria in Normotensive Type II Diabetic Patients

Diabetic nephropathy is the single most important cause of end-stage renal failure in the western world. It accounts for 15% to 25% of all renal failure in patients receiving chronic dialysis [1]. About 40% of type I and 20% of type II diabetics develop clinically important nephropathy [2-4]. However, the ratio of type II to type I diabetics is 10 to 1, and the number of patients with chronic renal failure due to type II disease exceeds that of type I [4-6]. Therefore, an obvious need exists to evaluate treatments that may delay the progress of nephropathy in type II diabetes. However, most studies of diabetic renal disease have hitherto focused on type I diabetes. Available data suggest that effective antihypertensive treatment is the best inhibitor of diabetic nephropathy [7-10]. Angiotensin-converting enzyme inhibitors have been found more effective than placebo and -adrenergic blocking agents in hypertensive as well as in normotensive diabetics with early and advanced nephropathy [11-15]. Some classes of calcium antagonists effectively decrease urinary protein excretion and may preserve renal function. However, analysis of several studies shows that, although the effects of angiotensin-converting enzyme inhibitors are consistent, those of calcium antagonists vary [16-18]. Short-term studies showed a clear antiproteinuric effect of captopril and of enalapril on the diabetic kidney, probably independent of the antihypertensive effect of these agents [14, 15, 19]. However, the outcome of long-term intervention and the possibility of a true alteration of the natural course of the disease were unknown. We did a relatively long-term, 5-year study of the effect of the angiotensin-converting enzyme inhibitor, enalapril, on the course of diabetic nephropathy in normotensive, type II diabetic patients with microalbuminuria and normal renal function. Our report describes a randomized, placebo-controlled, double-blind study on 94 diabetic patients. Methods Patients A total of 108 patients with type II diabetes mellitus, diagnosed according to World Health Organization criteria [20] who attended six clinics in the Tel Aviv area were recruited during 1986 and gave informed consent to participate in the study. The inclusion criteria were as follows: age less than 50 years; duration of diabetes mellitus of less than 10 years with no evidence of systemic, renal, cardiac, or hepatic diseases; body mass index less than 27 kg/m2; normal blood pressure values on two consecutive examinations (systolic, 140 mm Hg; diastolic, 90 mm Hg; mean blood pressure < 107 mm Hg); serum creatinine, < 123 mol/L (1.4 mg/dL); and microalbuminuria (urinary protein excretion of 30 to 300 mg/24 h) on two consecutive visits without evidence of urinary tract infection. Initially, there were 49 men and 59 women, ages 34 to 49 years (mean age [SD], 44 4 years). The duration of diabetes was 0.5 to 9.1 years (mean duration [SD], 6.7 1.6 years). Sixteen patients received insulin, 43 were taking oral hypoglycemic agents, and 49 were using diet to control their diabetes. Protocol The protocol was approved by the hospital review board. After a 2-month pretreatment period, the patients were randomly allocated to receive either 10 mg enalapril (Teva Pharmaceutical Industries, Ltd., Petach Tikwa, Israel) daily or placebo in a double-blind manner. The placebo tablets were similar but not identical to enalapril. Randomization was done using a table of random numbers [21]. The follow-up period was terminated, for each patient, exactly 5 years after his or her randomization, and the data were submitted for evaluation. The patients were seen by their family physicians approximately every 3 to 4 months. On these visits, fasting blood glucose, glycosylated hemoglobin, serum creatinine, serum electrolyte levels, and albuminuria in 24-hour urine samples were determined. Blood pressure was measured by mercury sphygmomanometers with the patients sitting after a 5-minute rest; the average of two determinations was recorded. The diastolic pressure was determined at Korotkoff phase V. If systolic blood pressure values of 145 mm Hg, or diastolic values of 95 mm Hg, were found on two consecutive occasions, treatment with long-acting nifedipine (Pressolate, Agis Industries Ltd., Yeruham, Israel) was initiated. Funduscopy was done yearly by an ophthalmologist, and the presence of diabetic retinopathy was recorded. Measurements Glucose and creatinine levels were determined by routine automated methods. Glycosylated hemoglobin levels were measured by affinity chromatography with a commercial kit (Isolab, Biochemical Methodology, Drower 4350, Akron, Ohio). The albumin excretion rate was measured on 24-hour urine samples by an automated immunoturbidimetric assay [22]. Sixteen to 20 fasting blood glucose determinations and 15 to 20 glycosylated hemoglobin values were available for each patient. For each patient, the correlation coefficients between fasting blood glucose and glycosylated hemoglobin levels were between 0.60 and 0.84. The mean blood pressure values were calculated for each patient (mean pressure defined as diastolic value plus one third of the pulse pressure). The reciprocal creatinine value (100/creatinine value) was calculated for each visit [23], and the decline in renal function was expressed as a percentage of the initial value. The course of renal function, of the mean blood pressure, and of urinary protein excretion were plotted against time (separately) for the enalapril and the placebo groups. Statistical Analysis All data were expressed as mean (SD) and ranges. Significance was defined as P < 0.05. To test for adequate randomization, the enalapril and placebo groups were compared with respect to mean age, mean duration of diabetes, as well as mean baseline values of albuminuria, serum creatinine, glycosylated hemoglobin, and mean blood pressure using pooled variance Student t-tests for independent groups as well as one-way analysis of variance. To compare the annual means of the various measurements between the two groups and within each group, one between-group factor and one repeated measures factor were used in analysis of variance. The rate of decrease of reciprocal creatinine levels and the rate of increase of albuminuria were calculated by linear regression analysis. Results Five patients, 2 taking enalapril and 3 taking placebo left the study during the first year. Six patients (4 taking enalapril and 2 taking placebo) developed a disturbing cough, and the treatment was discontinued. Three patients (1 on enalapril and 2 on placebo) were lost to follow-up during the third and fourth years. The final analysis was therefore done on 94 patients, of whom 49 received enalapril and 45 received placebo. Age, male/female ratio, duration of diabetes, and the other baseline data of the two groups are shown in Table 1. No statistically significant differences existed between the initial characteristics of the enalapril and the placebo groups. Table 1. Baseline Data from 94 Type II Diabetic Patients with Microalbuminuria* During the first year of treatment, the urinary albumin excretion in the enalapril group decreased from an initial mean of 143 mg/24 h to an annual mean of 122 mg/24 h. Values greater than 300 mg/24 h were recorded in only two patients. Subsequently, a minimal but steady increase occurred in mean daily albumin excretion of these patients, with a fourth-year mean of 136 mg/24 h and a fifth-year mean of 140 mg/24 h. In six patients, albuminuria exceeded 300 mg/24 h. In contrast, among the placebo-treated patients, a steady, gradual increase occurred in mean daily albuminuria. The initial albumin value was 123 mg/24 h, the first-year mean was 134 mg/24 h, and the fifth-year value was 310 mg/24 h. Albumin values were greater than 300 mg/24 h in 19 patients and greater than 1 mg/24 h in three patients. The difference between the mean values of daily albuminuria in the two groups became statistically significant after the first year. However, the difference in the rate of change in proteinuria from baseline was statistically significant at the end of the first year (P < 0.05). These data are shown in Figure 1 and are numerically detailed in the Appendix Table. If the development of overt proteinuria ( 300 mg/24 h) is considered clinically important, the risk for developing this degree of proteinuria within 5 years of follow-up was 19/45 (42%) in the placebo group compared with 6/49 (12%) in the enalapril group. Therefore, enalapril treatment resulted in an absolute risk reduction of 30 percentage points for the development of overt proteinuria (95% CI, 15% to 45%; P < 0.001) for a 5-year period. Appendix Table. Initial and Annual Averages of Blood Chemistry Values for the 5-Year Follow-up in the Enalapril- and Placebo-Treated Groups* Figure 1. Proteinuria during 5-year follow-up in diabetics treated with enalapril or placebo. P P P Renal function, expressed as reciprocal creatinine (100/cr) remained unchanged in the enalapril group during the first 2 years of follow-up. From the third year onward, a small, nonsignificant but systematic decrease was recorded. The decrease was 1% of the initial value during the 5 years. In the placebo-treated group, a gradual, steady decrease of about 2% occurred in renal function each year. The difference between the initial and mean fifth-year values was 13% (P < 0.05). The difference between the mean rate of decrease of reciprocal creatinine among the enalapril- and the placebo-treated groups became significant after the second year. These data are shown in Figure 2 and are outlined in the Appendix Table. Figure 2. Reciprocal creatinine (100/cr) levels expressed as percentage of initial value, during 5 years of follow-up in placebo-and enalapril-treated type II diabetics. P P The mean blood pressure in the enalapril-treated patients decreased slightly from an initial value of 99 mm Hg to 96 mm Hg during the first year

Intermittent dobutamine treatment in patients with chronic refractory congestive heart failure: a randomized, double-blind, placebo-controlled study.

Intravenous dobutamine administration improves short‐term hemodynamics in patients with severe congestive heart failure (CHF). However, the clinical benefit of periodic administration remains controversial.

Response to Prasugrel and Levels of Circulating Reticulated Platelets in Patients With ST-Segment Elevation Myocardial Infarction

OBJECTIVES The aim of this study was to determine whether response to prasugrel is associated with the proportion of circulating reticulated platelets (RPs) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Despite better pharmacodynamic properties and clinical efficacy of prasugrel compared with clopidogrel, antiplatelet responses to prasugrel are not uniform. The mechanism of this variability in response is not clear. RPs, young hyperactive forms, are increased during situations of enhanced platelet turnover. METHODS Patients with STEMI treated with primary percutaneous intervention (PCI) and prasugrel were tested for platelet reactivity using purinergic receptor P₂Y, G-protein coupled, 12 (P₂Y₁₂) assay and multiple electrode aggregometry (MEA). RP levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2 to 4 days and 30 days post-PCI. Platelet function was compared by varying levels of RPs, analyzed as continuous (regression analysis) and categorical (tertiles) variables. RESULTS Sixty-two patients were included (mean age: 57.5 ± 8 years; 21.2% women; 27.7% diabetes). At the early time point, RP levels were strongly correlated with platelet reactivity when evaluated by the P₂Y₁₂ assay (Spearmans correlation coefficient: 0.55 for P₂Y₁₂ reaction units, -0.49 for percent inhibition) and MEA (Spearmans: 0.50). The upper tertile of RPs displayed higher platelet reactivity compared with the middle and lower tertiles, according to P₂Y₁₂ assay and MEA. Similar results with strong correlations between RP and platelet reactivity were noted at 30 days post-PCI. CONCLUSIONS The proportion of circulating RPs strongly correlates with response to prasugrel in patients with STEMI treated with PCI. High levels of RPs are associated with increased platelet reactivity despite prasugrel treatment.

The ratio of contrast volume to glomerular filtration rate predicts outcomes after percutaneous coronary intervention for ST-segment elevation acute myocardial infarction†

Objective: To assess the value of the ratio between contrast medium volume and glomerular filtration rate (CMGFRr) for prediction of development of contrast‐induced nephropathy (CIN) and mortality in patients with ST‐segment elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Background: Renal function is a strong predictor of outcome in patients with STEMI. CIN may complicate the course of primary PCI in these patients. Methods: The study population included all 871 consecutive patients with STEMI without cardiogenic shock who underwent primary PCI at our center from January 1, 2001, to October 30, 2006. CIN was defined as an absolute increase in serum creatinine > 0.5 mg/dL or a relative increase >25% within 48 hr after PCI. Results: In‐hospital CIN developed in 72 (8.3%) patients. On linear regression analysis, the following variables were independently associated with CIN: male sex (odds ratio [OR] = 0.42, 95% confidence interval [CI], 0.18–0.97, P = 0.04), GFR < 60 (OR = 3.6, 95% CI, 2.79–4.78, P < 0.0001), multivessel coronary artery disease (OR = 1.67, 95% CI, 1.08–2.58, P = 0.02), CMGFRr (OR = 1.53, 95% CI, 1.01–2.31, P = 0.04, for upper tertile vs. lower two tertiles), and Killip class > 1 (OR = 1.35, 95% CI, 1.03–1.76, P = 0.03). CMGFRr > 3.7 was a strong independent predictor of CIN (OR = 3.87, 95% CI, 1.72–8.68, P = 0.001). Twenty‐six (2.9%) patients died at 1 month after PCI. The following variables were independently predictive of 1‐month mortality: CMGFRr > 3.7 (OR = 3.3, 95% CI, 1.22–9.04, P = 0.018) and multivessel coronary artery disease (OR = 2.3, 95% CI, 1.28–4.07, P = 0.005). Conclusion: The contrast medium‐to‐GFR ratio is a strong predictor of CIN and of 1‐month mortality in patients undergoing primary PCI for STEMI.

The risk of cardiac complications following noncardiac surgery in patients with drug eluting stents implanted at least six months before surgery.

Aims: Given the anecdotal reports and case series suggesting that drug‐eluting coronary stents [DES] may be still vulnerable to coronary thrombosis after six months, we sought to assess this risk in patients undergoing non‐cardiac surgery six months after stenting. Methods and Results: Linking the Rabin Medical Centre interventional cardiology database with its non‐cardiac surgical database, we identified 78 patients who underwent DES placement and subsequently [after six months] had noncardiac surgery [15‐vascular, 37‐ abdominal and genitourinary and 26‐others, excluding ophthalmic surgery]. Outcome measures included 30‐day rate of postoperative myocardial infarction (MI), DES‐related thrombosis, and cardiac mortality. Major adverse cardiac events [death and non‐fatal MI] occurred in 6 (7.7%) patients including 2 cardiac deaths (2.6%), 4 (5.1%) non‐fatal myocardial infarctions (MIs). Two patients (2.6%) sustained stent thrombosis [one patient had ‘definite’ and one ‘probable’ stent thrombosis]. All MIs [including stent thrombosis] occurred in the vascular and abdominal surgery group. Two of the MIs events occurred while the patients were on dual antiplatelet agents. In conclusions: Perioperative cardiac events during non cardiac surgery after six months of DES deployment still occur. These cardiac complications [not entirely prevented by continued dual antiplatelet agents] remain a matter of diagnostic and therapeutic challenge and concern.

Long-Term Outcomes for Patients With Severe Symptomatic Aortic Stenosis Treated With Transcatheter Aortic Valve Implantation.

Transcatheter aortic valve implantation (TAVI) is an emerging technique for the treatment of severe symptomatic aortic stenosis. Little has been reported about the use of different devices and multiple catheter-based options and anesthetic techniques in the same institution. We report the long-term clinical experience in treating patients with severe symptomatic aortic stenosis using TAVI. We analyzed the outcomes of 153 TAVI-treated patients who were followed for ≤2 years. All patients were at very high risk of surgical valve replacement. The Medtronic-CoreValve device was used in 59.5% and the Edwards-SAPIEN device in 40.5% of the patients. The primary end point was death from any cause during follow-up. The mean ± SD patient age was 81.1 ± 6 years, and 62% of the patients were women. The procedural success rate was 97.4%. At 30 days of follow-up, the all-cause mortality was 3.9%. Two-year follow-up data were obtained for 108 patients, with 85.5% survival of treated patients. The 30-day stroke rate was 3.9%. No significant differences in mortality were found when angioplasty was performed before or during TAVI compared with TAVI alone. Multivariate analysis showed that increased baseline creatinine (hazard ratio 1.55, 95% confidence interval 1.01 to 2.42, p = 0.049) and increased logistic European System for Cardiac Operative Risk Evaluation score (hazard ratio 1.03, 95% confidence interval 1.01 to 1.06, p = 0.048) predicted all-cause mortality. In conclusion, the clinical outcome of TAVI is favorable. The use of both procedural devices and multiple techniques in the same institution is feasible and potentially desirable.

Circulating endothelial progenitor cell levels and function in patients who experienced late coronary stent thrombosis

AIMS The pathogenesis of late coronary stent thrombosis may be related to impaired arterial healing. Endothelial progenitor cells (EPCs) have been shown to play an important role in repair and re-endothelialization following vascular injury. We hypothesized that patients who develop late stent thrombosis may have reduced or dysfunctional EPCs, and aimed to compare EPC level and function in patients who experienced stent thrombosis vs. matched controls. METHODS AND RESULTS Patients who developed late (> 30 days) stent thrombosis within the past 3 years were compared with matched patients who underwent stenting and did not develop stent thrombosis. All patients had blood samples taken ≥ 3 months from the stent thrombosis or index procedure. The proportion of peripheral mononuclear cells (PMNCs) expressing vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34 was evaluated by flow cytometry. Endothelial progenitor cell colony forming units (CFUs) were grown from PMNCs, characterized and counted following 7 days of culture. The two groups (n = 30 each) were well-matched (93.3% men, mean age 60-62 years, 33.3% diabetes, 73-80% DESs). The proportion of cells co-expressing VEGFR-2, CD133, and CD34 was lower in the stent thrombosis group compared with the control [VEGFR-2(+)CD133(+): 0.18% (0.03-0.41%) vs. 0.47% (0.16-0.66%), P = 0.01; VEGFR-2(+)CD34(+): 0.32% (0.22-0.70%) vs. 0.66% (0.24-1.1%), P = 0.03]. The number of EPC CFUs was also lower in the stent thrombosis group [3.9% (3.2-5.5%) vs. 8.3% (6.5-13.4%) colonies/well, respectively, P < 0.0001]. CONCLUSION Patients who suffered late coronary stent thrombosis appear to have reduced levels of circulating EPCs and impaired functional properties of the cells. These findings require validation by further studies, but may contribute to understanding the pathogenesis of late stent thrombosis.

Gender-related differences in hospitalized heart failure patients.

The burden of heart failure (HF)‐related hospitalization and mortality of female patients with HF is substantial. Currently, several gender‐specific distinctions have been recognized amongst HF patients, but their relationships to outcomes have not been fully elucidated. Accordingly, in the current work, we aimed to explore gender‐specific clinical and echocardiographic measures and to assess their potential impact on outcome.

A comparative analysis of major clinical outcomes with drug-eluting stents versus bare metal stents in male versus female patients.

AIMS To conduct a risk-adjusted gender-based analysis of clinical outcomes following drug-eluting stent (DES) versus bare metal stent (BMS) implantation in patients with coronary artery disease. METHODS AND RESULTS We compared risk-adjusted total mortality rate, myocardial infarction, and event-free survival (defined as freedom from death, myocardial infarction and/or repeat revascularisation) in a consecutive cohort of 7,662 patients undergoing percutaneous coronary intervention at our institution, including 1,835 (25.4%) women. Follow-up was six months to 6.2 years (mean: 3.5 years; median: 3.6 years). The women were older than men and more likely to suffer from diabetes, hypertension or congestive heart failure. Smokers were more often men, and men were more likely to have had prior coronary bypass surgery compared to women. A DES was used in 39.9% of males and 39.5% of females. Both genders derived a significant long-term clinical benefit from DES compared to BMS; advantages were observed for mortality (men: HR=0.78, 95% CI: 0.64-0.96, p=0.016; women: HR=0.62, 95% CI: 0.45-0.85, p=0.003) and major adverse cardiac events (men: HR=0.73, 95% CI: 0.63-0.84, p<0.001; women: HR=0.76, 95% CI: 0.52-0.84, p=0.001). Among BMS-treated patients, women had worse cumulative clinical outcomes than men. DES eliminated the gender differences in cardiac prognosis. CONCLUSIONS Our analysis indicated a profound prognostic advantage for DES versus BMS among both genders, though female patients appeared to derive the greatest benefit.

Long-term outcome of patients with antiphospholipid syndrome who undergo percutaneous coronary intervention.

Objectives: Patients with antiphospholipid antibody syndrome (APS) have an increased risk of atherothrombotic complications. There are limited data regarding the outcome of patients with APS who undergo percutaneous coronary intervention (PCI). Accordingly, we aimed to assess the long-term outcomes of these patients. Methods: Nineteen APS patients who underwent PCI between the years 2003 and 2008 were compared to 380 patients who had undergone PCI during the same period (PCI group) and were matched by age (±5 years), gender, diabetes and hypertension. In addition, APS patients were compared to 1,458 patients with ST segment elevation myocardial infarction (MI) who were treated with PCI during the same period. Six-month to 4-year clinical outcomes were evaluated. Results: The indication for PCI in the APS group was acute coronary syndrome in 52.6% of patients. After 1 year of follow-up, patients with APS had higher rates of target vessel revascularization than the other two groups, which translated to higher rates of major adverse cardiac events. There were no differences in MI or mortality rates between the groups. Conclusions: Patients with APS who undergo PCI have worse long-term clinical outcomes, driven by higher rates of revascularization, than other patients undergoing PCI. Further study is warranted to examine the mechanisms underlying these findings.