Utility of N-acetylcysteine to prevent acute kidney injury after cardiac surgery: a randomized controlled trial.

Adabag AS, Ishani A, Koneswaran S, Johnson DJ, Kelly RF, Ward HB, McFalls EO, Bloomfield HE, Chandrashekhar Y.

Division of Cardiology, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, MN 55417, USA. adaba001@umn.edu

Abstract
BACKGROUND: Acute kidney injury (AKI) after heart surgery is associated with increased mortality. We sought to determine whether prophylactic perioperative administration of N-acetylcysteine (NAC) prevents postoperative AKI in patients with chronic kidney disease undergoing cardiac surgery (clinical trials.gov identifier NCT00211653). METHODS: In this prospective, randomized, placebo-controlled, double-blinded clinical trial, 102 patients with chronic kidney disease who underwent heart surgery at the Minneapolis Veterans Affairs Medical Center were randomized to either NAC (n = 50) 600 mg PO twice daily or placebo (n = 52) for a total of 14 doses (3 preoperative). The primary outcome was maximum change in creatinine from baseline within 7 days after surgery. Secondary outcome was AKI (ie, >0.5 mg/dL or >or=25% increase in creatinine from baseline). RESULTS: Creatinine increased in both groups (0.45 +/- 0.7 mg/dL in NAC vs 0.55 +/- 0.9 mg/dL in placebo, P = .53) and peaked on postoperative day 5. Acute kidney injury occurred in 41 patients (22 NAC vs 19 placebo, P = .44) by postoperative day 5, but persisted in only 14 (7 NAC vs 7 placebo, P = .94) by day 30. In multivariable analysis, perioperative NAC was unassociated with AKI (relative risk 1.2, 95% CI, 0.8-1.9, P = .34). Five patients (3 NAC vs 2 placebo, P = .68) underwent hemodialysis, and 5 (2 NAC vs 3 placebo, P = 1.0) died perioperatively. There was no difference in lengths of stay in the intensive care unit (4.9 +/- 7 days in NAC vs 6.5 +/- 9 days in placebo, P = .06) and the hospital (13.2 +/- 13 days in NAC vs 16.7 +/- 17 days in placebo, P = .12). CONCLUSION: Prophylactic perioperative NAC administration does not prevent AKI after cardiac surgery.

Does the prophylactic administration of N-acetylcysteine prevent acute kidney injury following cardiac surgery?
Ashworth A, Webb ST.

Department of Anaesthesia and Intensive Care, Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge CB23 3RE, UK.

Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'does prophylactic administration of N-acetylcysteine (NAC) prevent acute kidney injury (AKI) following cardiac surgery?' More than 60 papers were found using the reported search, of which 10 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The administration of NAC prior intravenous radioactive contrast has been shown to reduce the incidence of contrast-induced nephropathy. There have been two recent meta-analyses and several randomised controlled trials (RCTs) and investigating the effectiveness of prophylactic administration of NAC in the prevention of AKI following cardiac surgery. The RCTs have investigated the use of NAC to prevent AKI in low-risk patients, high-risk patients and high-risk patients with pre-existing chronic kidney disease. The meta-analyses and RCTs demonstrated that the prophylactic administration of NAC did not reduced the incidence of AKI, postoperative complications, postoperative interventions, mortality or length of ICU stay. We conclude that prophylactic administration of NAC does not prevent AKI or reduce mortality following cardiac surgery.

Acute effects of acetylsalicylic acid on blood glucose and insulin in noninsulin dependent diabetes.
Tornvall G, Allgn LG.

Abstract
Two groups of diabetic patients--one treated with diet and glipizide and the other with diet alone--volunteered in the study. After a standard meal blood glucose and insulin were followed for four hours during two separate days. On the first day the patients received their ordinary treatment, whereas on the second 1 g of acetylsalicylic acid was added before the test meal. In both groups an enhanced insulin mobilization was observed, when acetylsalicylic acid has been added. A decrease of the blood sugar level was recorded as well. The latter was however less pronounced in the group of subjects receiving only diet.

Does aspirin cause acute or chronic renal failure in experimental animals and in humans?
D'Agati V.

Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

Abstract
There are conflicting reports on the ability of aspirin as a single agent to cause acute or chronic renal failure in experimental animals. Chronic administration of aspirin alone over 18 to 68 weeks in doses of 120 to 500 mg/kg/d has been reported to cause renal papillary necrosis in rats. However, some investigators have been unable to produce renal papillary necrosis in other species or in rats given lower divided doses comparable to therapeutic doses used in humans. In a variety of rat strains, aspirin administered as a single high dose intravenously or by oral gavage produces acute tubular necrosis of proximal tubules, rarely accompanied by renal papillary necrosis in susceptible strains. Several human studies have addressed the chronic nephrotoxicity of aspirin alone or relative risk of end-stage renal disease in association with aspirin use after correction for other analgesics. With the exception of one case control study demonstrating a low, but statistically significant risk of end-stage renal disease in association with aspirin use, all other case control studies and several prospective studies have been unable to identify a significant risk of chronic renal failure in patients using aspirin alone in therapeutic doses. In healthy adults, short-term aspirin administration in therapeutic doses has no effect on creatinine clearance, urine volume, osmolar clearance, or sodium and potassium excretion. However, in predisposed individuals with glomerulonephritis, cirrhosis, and chronic renal insufficiency, and in children with congestive heart failure, short-term aspirin use in therapeutic doses may precipitate reversible acute renal failure. Acute aspirin intoxication (>300 mg/kg) frequently causes acute renal failure and doses of 500 mg/kg may be lethal. Chronic salicylate intoxication has been reported to cause reversible or irreversible acute renal failure in association with a pseudosepsis syndrome.

Blood pressure-lowering effect and duration of action of bedtime administration of doxazosin determined by home blood pressure measurement.
Gonokami K, Obara T, Kobayashi M, Katada S, Hara A, Metoki H, Asayama K, Kikuya M, Ohkubo T, Imai Y.

Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences and Medicine, Sendai, Japan.

Abstract
The effects and duration of action of bedtime administration of doxazosin 2 mg for 4 weeks on uncontrolled morning home hypertension were investigated. Morning home blood pressure (HBP) was significantly lowered by bedtime administration of doxazosin. Doxazosin significantly lowered evening HBP only in the subgroup of patients with an uncontrolled evening HBP. The evening (E)/morning (M) ratio was greater in patients with an uncontrolled evening HBP than in those with a controlled evening HBP. The results suggest that bedtime administration of doxazosin effectively suppresses morning HBP in uncontrolled morning hypertensives and lowers evening HBP in uncontrolled evening hypertensives

BENIGN PROSTATIC HYPERPLASIA 1-8 mg once daily. The initial dosage of CARDURA is 1 mg, given once daily in the a.m. or p.m. Depending on the individual patient's urodynamics and BPH symptomatology, dosage may then be increased to 2 mg and thereafter to 4 mg and 8 mg once daily, the maximum recommended dose for BPH. The recommended titration interval is 1-2 weeks. Blood pressure should be evaluated routinely in these patient

Administration-Time-Dependent Effects of Doxazosin GITS on Ambulatory Blood Pressure of Hypertensive Subjects

Read More: http://informahealthcare.com/doi/abs/10.1081/CBI-120037772

1

Bioengineering & Chronobiology Laboratories, University of Vigo, Campus Universitario, Vigo, Spain Hypertension and Vascular Risk Unit, Hospital Clnico Universitario, Santiago de Compostela, Spain Correspondence: Ramn C. Hermida, Director, Bioengineering and Chronobiology Labs., E.T.S.I.

Telecomunicacin, Campus Universitario, Vigo (Pontevedra) 36200, Spain, 34-986-812116 rhermida@tsc.uvigo.es

Previous studies have shown that a single nighttime dose of standard doxazosin, an -adrenergic antagonist, reduces blood pressure (BP) throughout the 24 h. We investigated the administration-timedependent effects of the new doxazosin gastrointestinal therapeutic system (GITS) formulation. We studied 91 subjects (49 men and 42 women), 56.7 11.2 (mean SD) yrs of age with grade 12 essential hypertension; 39 patients had been previously untreated, and the remaining 52 had been treated with two antihypertensive medications with inadequate control of their hypertension. The subjects of the two groups, the monotherapy and polytherapy groups, respectively, were randomly assigned to receive the single daily dose of doxazosin GITS (4 mg/day) either upon awakening or at bedtime. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours just before and after 3 months of treatment. After 3 months of doxazosin GITS therapy upon awakening, there was a small and nonstatistically significant reduction in BP (1.8 and 3.2 mm Hg in the 24 h mean of systolic and diastolic BP in monotherapy; 2.2 and 1.9 mm Hg in polytherapy), mainly because of absence of any effect on nocturnal BP. The 24 h mean BP reduction was larger and statistically significant (6.9 and 5.9 mm for systolic and diastolic BP, respectively, in monotherapy; 5.3 and 4.5 mm Hg in polytherapy) when doxazosin GITS was scheduled at bedtime. This BP-lowering effect was similar during both the day and nighttime hours. Doxazosin GITS ingested daily on awakening failed to provide full 24 h therapeutic coverage. Bedtime dosing with doxazosin GITS, however, significantly reduced BP throughout the 24 h both when used as a monotherapy and when used in combination with other antihypertensive pharmacotherapy. Knowledge of the chronopharmacology of doxazosin GITS is key to optimizing the efficiency of its BPlowering effect, and this must be taken into consideration when prescribing this medication to patients.

Read More: http://informahealthcare.com/doi/abs/10.1081/CBI-120037772

The Bedtime Administration of Doxazosin Controls Morning Hypertension and Albuminuria in Patients with Type-2 Diabetes: Evaluation Using Home-Based Blood Pressure Measurements

Read More: http://informahealthcare.com/doi/abs/10.1081/CEH-57438

1

Department of Medicine, Nagaoka Red Cross Hospital, Nagaoka, Niigata, 940-2085, Japan

Correspondence: Dr.Kyuzi Kamoi, Department of Medicine, Nagaoka Red Cross Hospital, Nagaoka,

Niigata, 940-2085, Japan, + 81 0258-28-9000 kkam-int@echigo.ne.jp

The control of high blood pressure (BP) after awakening in the morning (morning hypertension) as determined by home BP (HBP), as well as BP control throughout the day, may prevent diabetic vascular complications. We examined the effect of an -adrenergic blocker (doxazosin) on BP measurements taken by HBP after awakening and during clinic visits (CBP) in 50 patients with type-2 diabetes and morning hypertension. We evaluated the urinary albumin excretion rate as an indicator of nephropathy. Doxazosin was taken orally once at bedtime for 1 to 3 months. The mean ( SD) dose was 2.9 2.1 mg/day (1 to 8 mg/day). The BP was measured monthly at the clinic during the day and at home after awakening in the morning. In this short-term trial (2.8 0.4 months), the systolic HBP decreased significantly from 164 17 mmHg before treatment to 146 19 mmHg after treatment, and the diastolic HBP decreased significantly from 85 14 mmHg before treatment to 80 9 mmHg after treatment. The systolic, but not the diastolic CBP, decreased significantly after treatment. There was no significant difference in the systolic or diastolic values between the HBP and the CBP after treatment. The percentage change in the systolic HBP after treatment was three times greater than for the systolic CBP. The median (interquartile) urinary albumin excretion rate decreased significantly (P < 0.001) from 62 (25203) mg/g creatinine before treatment to 19 (976) mg/g creatinine after treatment. On multiple regression analysis, the decrease in the systolic HBP with treatment positively correlated with the reduction in urinary excretion of albumin. The control of morning hypertension reduced the albuminuria found in both untreated and treated hypertensive patients with type-2 diabetes. Bedtime administration of doxazosin appears to be safe and effective in reducing morning hypertension as measured by HBP. This finding also demonstrates that HBP taken in the morning has a stronger predictive power for the albuminuria level than does CBP.

Read More: http://informahealthcare.com/doi/abs/10.1081/CEH-57438

Coronary Artery Disease

Prior aspirin use predicts worse outcomes in patients with nonST-elevation acute coronary syndromes1
Abstract
Aspirin is beneficial in the prevention and treatment of cardiovascular events, but patients who have events while taking aspirin may have worse outcomes than those not on aspirin. We investigated the association between prior aspirin use and clinical outcomes in 9,461 patients with nonST-elevation acute coronary syndromes enrolled in the Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, before and after adjustment for baseline factors. We also examined whether eptifibatide has a differential treatment effect in prior aspirin users. Prior aspirin users

were less likely to have an enrollment myocardial infarction (MI) (vs unstable angina) (43.9% vs 48.8%, p = 0.001) but more likely to have death or MI at 30 days (16.1% vs 13.0%, p = 0.001) and at 6 months (19.9% vs 15.9%, p = 0.001). After adjustment, prior aspirin users remained less likely to have an enrollment MI (odds ratio 0.88, 95% confidence interval 0.79 to 0.97) and more likely to have death or MI at 30 days (odds ratio 1.16, 95% confidence interval 1.00 to 1.33) but not at 6 months (odds ratio 1.14, 95% confidence interval 0.98 to 1.33). In a multivariable model, eptifibatide did not have a different treatment effect in prior aspirin users compared with nonusers (p = 0.534). Prior aspirin users had fewer enrollment

Adherence with once daily versus twice daily carvedilol in patients with heart failure: the Compliance And Quality of Life Study Comparing Once-Daily Controlled-Release Carvedilol CR and Twice-Daily Immediate-Release Carvedilol IR in Patients with Heart Failure (CASPER) Trial.
MIs but worse longUdelson JE, Pressler SJ, Sackner-Bernstein J, Massaro J, Ordronneau P, Lukas MA, Hauptman PJ.

Division of Cardiology, Tufts Medical Center, Boston, Massachusetts 02111, USA. JUdelson@tuftsmedicalcenter.org

Abstract
BACKGROUND: Suboptimal compliance in taking guideline-based pharmacotherapy in patients with chronic heart failure (HF) potentially increases the burden of hospitalizations and diminishes quality of life. By simplifying the medical regimen, once-daily dosing can potentially improve compliance. The Compliance And Quality of Life Study Comparing Once-Daily Controlled-Release Carvedilol CR and Twice-Daily Immediate-Release Carvedilol IR in Patients with Heart Failure (CASPER) Trial was designed to measure differential compliance, satisfaction, and quality of life in chronic HF patients taking carvedilol immediate release (IR) twice daily versus the bioequivalent carvedilol controlled-release (CR) once daily.

METHODS AND RESULTS: CASPER was a prospective multicenter, 3-arm, parallel-group, randomized clinical trial for a 5-month period. The primary objective of the study was to evaluate and compare compliance with carvedilol IR twice daily (BID) and carvedilol phosphate CR once daily (QD) in patients with chronic HF who were taking carvedilol IR. Secondary objectives included comparisons of quality of life (Kansas City Cardiomyopathy Questionnaire), satisfaction with medication, and brain natriuretic peptide levels between subjects taking the two formulations. A total of 405 patients with chronic HF and left ventricular dysfunction were randomized to: (A) carvedilol IR twice daily, given double blind; (B) carvedilol CR taken in the morning and placebo in the afternoon, given double blind; or (C) carvedilol CR once daily, open label. Compliance was measured using the medication event monitoring system that captures time of bottle opening. The primary end point was a comparison of taking compliance (doses taken divided by total number of prescribed doses over the actual duration of the study) between the double-blind carvedilol IR BID versus the open-label carvedilol CR QD groups. Sample size

estimates were based on assumptions of 75% compliance with BID dosing and 90% compliance with QD dosing. Mean compliance with carvedilol IR BID was 89.3% compared with 88.2% for carvedilol CR QD, and differential mean compliance was 1.1% (95% CI -4.4%, 6.6%; ie, not significant). There were no statistically significant differences in compliance between any of the 3 groups, nor differences in quality of life, treatment satisfaction, or physiologic measures among the 3 study arms. There were also no significant differences in adverse events or side effects among patients switching from carvedilol IR to carvedilol CR in arms B or C over the 5-month study duration compared with patients remaining on carvedilol IR.

CONCLUSIONS: Compliance among chronic HF patients in the CASPER trial was high at baseline and unaffected by QD versus BID dosing. Over the 5-month follow-up period, there were no differences in adverse events among patients switching from carvedilol IR to CR. term outcomes than nonusers. We found no evidence for a different treatment effect of eptifibatide in prior aspirin users.