Thomas B. Wiegmann

Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy

Context Previously published results of this randomized, double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy. Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine. Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks. Cautions The trial had limited power to detect important differences between groups in mortality or strokes, and most patients received several antihypertensive agents. The Editors Patients with diabetes have an increased risk for cardiovascular complications and death (1). Studies that analyzed the effects of inhibition of the reninangiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes (2-5) or were done exclusively in patients with diabetes (6-8). The meta-analysis of these studies (9), the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation (HOPE) study (2), and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial (5) demonstrated that angiotensin-converting enzyme (ACE) inhibitors (2, 9) and angiotensin-receptor blockers (5) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events. These studies randomly assigned few patients with renal involvement and overt proteinuria. Overt proteinuria occurred in fewer than 20% of the 470 patients in the Appropriate Blood Pressure Control in Diabetes (ABCD) trial (6), and only 11% of the 1195 patients in the LIFE trial (5). The Captopril Prevention Project (CAPP) (3) and the Swedish Trial in Old Patients with Hypertension-2 (STOP Hypertension-2) (4) did not state the number of patients with diabetes and overt proteinuria. There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) (7), and patients with dipstick-positive albuminuria were excluded from the HOPE trial (2). Since proteinuria is an independent risk factor for cardiovascular disease (10, 11), the data obtained in the aforementioned trials cannot be extrapolated to patients with type 2 diabetes and overt nephropathy. Trials performed in such patients have reported a blood pressureindependent effect of two different angiotensin-receptor blocker agents to protect against nephropathy (12, 13) without a change in all-cause mortality. Apart from studies in heart failure, few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers. We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial (IDNT) (12) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents. Methods Patients The IDNT was a randomized, double-blind study on the effect of treatment with irbesartan or amlodipine compared with placebo in patients with type 2 diabetic nephropathy. The protocol of this study has been published (12, 14). Entry criteria required that patients be between 30 and 70 years of age and have type 2 diabetes mellitus and overt nephropathy, as evidenced by current treatment for hypertension or by a protein excretion rate of 900 mg/d or greater, serum creatinine level of 89 mol/L (1.0 mg/dL) to 266 mol/L (3.0 mg/dL) in women or of 106 mol/L (1.2 mg/dL) to 266 mol/L (3.0 mg/dL) in men, and baseline seated blood pressure greater than 135/85 mm Hg. The institutional review boards of each center approved the protocol. All patients gave written informed consent. Treatment and Randomization Patients were randomly assigned centrally by computer to receive treatment with irbesartan, 300 mg/d (Avapro, Bristol-Myers Squibb, Princeton, New Jersey); amlodipine, 10 mg/d (Norvasc, Pfizer, New York); or matched placebo. To minimize any center effect, randomization was blocked by center. All patients had blood pressure controlled to the same blood pressure goal of less than 135/85 mm Hg by using antihypertensive agents other than ACE inhibitors, angiotensin II receptor blocking agents, or calcium-channel blockers. For the analysis of cardiovascular end points, patients were followed to initiation of treatment for end-stage renal failure (dialysis or renal transplantation), reaching a serum creatinine level of 530.4 mol/L (6.0 mg/dL) or higher, death, or administrative censoring in December 2000. Outcomes We prospectively established cardiovascular outcomes, defined in the Appendix Table. Appendix Table. Classification for Fatal and Nonfatal Cardiovascular Events Ascertainment of Cardiovascular Events Information about hospitalizations and adverse events were screened at Bristol-Myers Squibb, Princeton, New Jersey, by trained, blinded clinical research associates to identify potential cardiovascular events. Investigators used study forms to report and characterize all cardiovascular outcomes. For all potential events, records, including laboratory values, electrocardiograms, and radiographic reports were obtained for clarification. Since myocardial infarctions may go unrecognized, a central electrocardiogram reading center was established at Brigham and Womens Hospital, Boston, Massachusetts, where two cardiologists reviewed every electrocardiogram. Electrocardiography was performed at baseline, 6 months, 12 months, and annually thereafter. A total of 5698 electrocardiograms were reviewed at the center. When a new Q-wave infarction was found, the cardiologists asked whether a clinical myocardial infarction was reported. Even when myocardial infarctions were not clinically reported, these Q-wave infarctions were adjudicated as myocardial infarctions. Adjudication of Cardiovascular Events Investigators at each center reported cardiovascular events, defined in the Appendix Table. The information on all potential events was referred to one member of the Outcomes Confirmation and Classification Committee (Appendix). If the committee member agreed with the judgment of the center investigator, their combined judgment was accepted. If the center investigator and the committee member differed, the case material was reviewed by the membership of the committee, whose decision was accepted. Deaths were adjudicated by a Mortality Committee (Appendix). Each death was reviewed by two members of the committee and presented to the membership, whose decision was accepted as final. Statistical Analysis For graphical presentation (Figure) and overall testing for statistically significant differences among the three treatment groups, time to the first occurrence of either a specific cardiovascular outcome or one of the composite outcomes was analyzed by product-limit survival curves and the log-rank test (15). We used proportional hazards modeling to determine hazard ratios. For the cardiovascular death outcome, which could occur only once, we used the standard proportional hazards model (16), with treatment assignment as the only independent covariate. For other cardiovascular outcomes, which could occur more than once, we used the AndersonGill formulation of the proportional hazards model (17), in which patients are considered at risk for the first event from randomization to the first event, at risk for the second event from the day following the first event to the second event, and so forth, permitting use of all the data. In accordance with the method of Lee and colleagues (18), we used a robust variance estimate that accounts for the possibility of correlation of risk for several events within a patient. We believed that occurrence of a first event of a given type increases the likelihood of a subsequent similar event. Therefore, both treatment assignment and a time-dependent covariate indicating whether the event was the first of its type or a subsequent event were included in these analyses. The time-dependent covariate was statistically significant in each case, confirming the above assumption. There was no statistically significant interaction between treatment and the time-dependent covariatethe effects of treatment assignment were similar for first and subsequent eventsand inclusion of the time-dependent covariate did not change either the estimates of the treatment effect or their statistical significances. Figure. Time to first cardiovascular composite event as a function of treatment assignment. P Data management and computations were done by using SAS software for Windows, version 8 (SAS Institute, Inc., Cary, North Carolina), or S-Plus for Windows, version 6.0 (Insightful Corp., Seattle, Washington). Statistical tests were two sided. A P value of 0.05 or less, unadjusted for the multiple comparisons, was considered statistically significant. Role of the Funding Sources The funding sources were involved in the data collection but not in the analysis or interpretation or the decision to submit the manuscript for publication. Results The baseline characteristics of the three groups are shown in Table 1. A flow diagram of the study is shown in the Appendix Figure. Table 1. Baseline Characteristics Appendix Figure. Flow diagram for the Irbesartan Diabetic Nephropathy Trial. Clinical Management During the study, the blood pressure decreased from the baseline values to 140/77 mm Hg in the irbesartan group, 141/77 mm Hg in the amlodipine group, and 144/80 mm Hg in the placebo group. Blood pressure in the two active treatment groups did not differ; values in both groups were statistically significantly lower than in the placebo group (P = 0.001). The distribution of nonstudy drugs used to achieve the target blood pressure was similar i

Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial.

Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP <85 mmHg was associated with a trend to increase in all-cause mortality, significant increase in MI, but decreased risk for strokes. Increased pulse pressure predicted increased all-cause mortality, CV mortality, MI, and CHF. It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients. BP < or =120/85 may be associated with an increase in CV events.

Regional Citrate Anticoagulation for Hemodialysis in the Patient at High Risk for Bleeding

CONVENTIONAL hemodialysis requires heparin anticoagulation to prevent clotting in the dialysis assembly. Hemodialysis of the patient who is at high risk for hemorrhage is complicated by a 10 to 30 ...

Sulodexide Fails to Demonstrate Renoprotection in Overt Type 2 Diabetic Nephropathy

Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has been reported to reduce albuminuria in patients with diabetes, but it is unknown whether it is renoprotective. This study reports the results from the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (>900 mg/d) already receiving maximal therapy with angiotensin II receptor blockers. The primary end point was a composite of a doubling of baseline serum creatinine, development of ESRD, or serum creatinine ≥6.0 mg/dl. We planned to enroll 2240 patients over approximately 24 months but terminated the study after enrolling 1248 patients. After 1029 person-years of follow-up, we did not detect any significant differences between sulodexide and placebo; the primary composite end point occurred in 26 and 30 patients in the sulodexide and placebo groups, respectively. Side effect profiles were similar for both groups. In conclusion, these data do not suggest a renoprotective benefit of sulodexide in patients with type 2 diabetes, renal impairment, and macroalbuminuria.

Ambulatory Blood Pressure in Type I Diabetes Mellitus: Comparison to Presence of Incipient Nephropathy in Adolescents and Young Adults

AMBP measurements were obtained at 20-min intervals during the day and at 60-min intervals during the night in 38 adolescents and young adults (12–25 yr old) with type I diabetes, and in 36 healthy, nondiabetic control subjects of comparable age. The group of patients with elevated AER (>15 μg/min) had higher mean 24-h sBP, dBP, and BPB (defined as the prevalence of systolic readings >130 mm Hg or diastolic readings >85 mm Hg) compared with both the group of patients with type I diabetes and AER<15, and the control group. The normal diurnal variation in BP and BPB was observed in the control group and the group with type I diabetes and AER<15, whereas the nocturnal decrease observed in the group with type I diabetes and AER>15 was not statistically significant. Elevations in AMBP of the patient group with AER>15 were reflected in random BP measurements. Even though the mean random BP measurements of all groups were within the normal range for age, the mean random sBP and dBP of the type I diabetes patients with AER>15 was higher than both the control group and the group with type I diabetes and AER<15. The GFR, determined by the clearance of 99Tc-DTPA, was associated negatively with measures of AMBP and AER in the group with AER>15. The mean 24-h sAMBP, dAMBP, and BPB of the type I diabetes patients with AER<15 were elevated compared with the control group. The mean random sBP of the type I patients with AER<15 was not significantly different from the control group, whereas the mean random dBP of this group was significantly greater than the control group. Significant overlap in the BPs and BPBs occurred among the groups, but the mean 24-h sBP and BPBs were above the 90th percentile for control subjects in most type I diabetes patients with AER<15 and in ∼50% of type I diabetes patients with AER<15. The three groups separated across the age range (12–25 yr old) for the different measures of AMBP. We conclude that AMBP measurement is useful in detecting abnormalities in BP that are not apparent in random BP measurement in patients with onset of type I diabetes before puberty and no evidence of early diabetic nephropathy. These findings may be important in identifying individuals who either are susceptible to the development of diabetic nephropathy or have early renovascular dysfunction not apparent in AER>15. AMBP measurement may be useful in monitoring interventions designed to prevent or delay the development of diabetic nephropathy.

Recognition of Hypertension and Abnormal Blood Pressure Burden With Ambulatory Blood Pressure Recordings in Type I Diabetes Mellitus

Ambulatory blood pressure (AMBP) measurements were obtained at 20-min intervals for 24 h in 25 subjects with insulin-dependent (type I) diabetes mellitus and 21 control subjects. The diabetic patients had normal kidney function (glomerular filtration rate 112.1 ± 7.2 ml · min−1 · 1.73 m−2, renal plasma flow 459.0 ± 23.4 ml · min−1 · 1.73 m−2) and were normotensive according to standard sphygmomanometer examinations. Mean ± SE AMBP (systolic/diastolic in mmHg) measurements in diabetic patients (24 h, 131.7/77.2 ± 2.9/1.8; 0600–2200, 132.3/78.4 ± 2.9/3.4; 2200–0600, 125.1/75.7 ± 3.9/3.4) significantly exceeded control values during all times (24 h, 121.8/70.3 ± 2.9/1.9; 0600–2200, 120.7/71.8 ± 2.6/2.0; 2200–0600, 108.2/61.5 ± 6.6/2.7). Mean 24-h AMBP exceeded 135/85 mmHg in 49% of diabetic patients. The same threshold of 135/85 mmHg was used to determine the prevalence of abnormal measurements per time period (pressure burden). Pressure burden was increased twofold in diabetic patients compared with control subjects. Mean AMBP was significantly reduced at night in control subjects but not in diabetic patients. Changes in blood pressure were not related to kidney function in diabetic patients. AMBP recordings uncovered an increased prevalence of abnormal mean blood pressure, increased pressure burden, and a lack of diurnal variation of blood pressure in subjects with type I diabetes mellitus. These findings have important implications for early intervention strategies in diabetes mellitus because AMBP recordings correlate well with end-organ damage.

Effect of Angiotensin-Converting Enzyme Inhibition on Renal Function and Albuminuria in Normotensive Type I Diabetic Patients

Normotensive patients with insulin-dependent (type l) diabetes mellitus (n = 18) were given 25 mg captopril (b.i.d.) and placebo for 3 mo in a randomized double-blind crossover study. Patients had normal renal function, and none had retinopathy. Albuminuria was <20 μg/min in 12 patients and between 20 and 200 μg/min in the other 6. Patients were examined at the end of the placebo and captopril phases. Captopril caused little reduction in blood pressure obtainedby 24-h ambulatory monitoring (systolic 126.0 ± 2.7 to 123.9 ± 2.4 mmHg, P< 0.08; diastolic 74.2 ± 1.9 to 72.1 ± 1.9 mmHg, P < 0.09). Captopril lowered glomerular filtration rate from 99.5 ± 7.7 to 71.0 ± 5.5 ml · min−1 · 1.73 m−2(P < 0.01), whereas renal plasma flow (443.9 ± 15.2 ml.min−1. 1.73 m−2) remained unchanged. Filtration fraction was reduced from 22.4 ± 1.4 to 17.4 ± 1.4% (P < 0.01). Urinary albumin excretion was reduced from 59.1 ± 0.15 to 27.7 ± 13.9 μg/min (P < 0.1). Reduction was relatedto the extent of initial albuminuria (r = 0.997, P < 0.001), a relationship that remained significant after logarithmic transformation (r = 0.540, P < 0.02). Dextran clearance was used to determine glomerular capillary function. Angiotensin inhibition caused reduction in effective glomerular pore size and also reduced flow via the nondiscriminatory shunt. Angiotensin inhibition in normotensive patients with type I diabetes was well tolerated. Reduction in albuminuria is mediated by a combination of hemodynamic changes and alterations in glomerular capillary function.

Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study.

Insulin resistance underlies most glucose disorders in adults and is associated with an increased risk of cardiovascular disease. Alpha blockers decrease insulin resistance, whereas diuretics increase insulin resistance.

Renal structural-functional relationships in early diabetes mellitus

Abstract.  To define the earliest renal morphological changes in patients with type I diabetes, we studied renal function and morphometric analysis of renal biopsies in 59 patients with diabetes for 5 – 12 years and normal blood pressure, normal creatinine clearance (CCr), and negative dipstick urinary protein. Arteriolar hyalinization and intimal fibrous thickening were noted in 43%. Glomerular basement membrane thickness and fractional mesangial volume were increased in 51% and 56%, respectively. The pre-pubertal and post-pubertal years of diabetes were associated with similar degrees of renal structural changes, but during the pre-pubertal years normal urinary albumin excretion (UAE) was seen. Principal factor analysis of morphometric structural parameters yielded four clusters of variables: “glomerular size” correlated with patient age, CCr, and UAE; “peripheral capillary decrease” correlated with glycosylated hemoglobin, diastolic blood pressure, glomerular filtration rate, and UAE; “mesangial increase” correlated with UAE; and “interstitial scarring” correlated with diastolic blood pressure. This study provides unique documentation of renal structural abnormalities which precede clinically evident renal functional abnormalities and documents that these early structural abnormalities are present in the pre-pubertal years of diabetes as well as postpuberty, and are associated with each other in constellations that correspond to postulated mechanisms in diabetic nephropathy.

Peritonitis Due to Drechslera spicifera Complicating Continuous Ambulatory Peritoneal Dialysis

Excerpt Most organisms causing peritonitis in continuous ambulatory peritoneal dialysis are gram-positive bacteria (1). The frequency of isolating gram-negative bacteria increases with the number o...