Effects of extended-release niacin/laropiprant on correlations between apolipoprotein B, LDL-cholesterol and non-HDL-cholesterol in patients with type 2 diabetes.

BACKGROUND: LDL-C, non-HDL-C and ApoB levels are inter-correlated and all predict risk of atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes mellitus (T2DM) and/or high TG. These levels are lowered by extended-release niacin (ERN), and changes in the ratios of these levels may affect ASCVD risk. This analysis examined the effects of extended-release niacin/laropiprant (ERN/LRPT) on the relationships between apoB:LDL-C and apoB:non-HDL-C in patients with T2DM. METHODS: T2DM patients (n = 796) had LDL-C ≥1.55 and <2.97 mmol/L and TG <5.65 mmol/L following a 4-week, lipid-modifying run-in (~78 % taking statins). ApoB:LDL-C and apoB:non-HDL-C correlations were assessed after randomized (4:3), double-blind ERN/LRPT or placebo for 12 weeks. Pearson correlation coefficients between apoB:LDL-C and apoB:non-HDL-C were computed and simple linear regression models were fitted for apoB:LDL-C and apoB:non-HDL-C at baseline and Week 12, and the correlations between measured apoB and measured vs predicted values of LDL-C and non-HDL-C were studied. RESULTS: LDL-C and especially non-HDL-C were well correlated with apoB at baseline, and treatment with ERN/LRPT increased these correlations, especially between LDL-C and apoB. Despite the tighter correlations, many patients who achieved non-HDL-C goal, and especially LDL-C goal, remained above apoB goal. There was a trend towards greater increases in these correlations in the higher TG subgroup, non-significant possibly due to the small number of subjects. CONCLUSIONS: ERN/LRPT treatment increased association of apoB with LDL-C and non-HDL-C in patients with T2DM. Lowering LDL-C, non-HDL-C and apoB with niacin has the potential to reduce coronary risk in patients with T2DM.

Extended-release niacin/laropiprant significantly improves lipid levels in type 2 diabetes mellitus irrespective of baseline glycemic control.

BACKGROUND: The degree of glycemic control in patients with type 2 diabetes mellitus (T2DM) may alter lipid levels and may alter the efficacy of lipid-modifying agents. OBJECTIVE: Evaluate the lipid-modifying efficacy of extended-release niacin/laropiprant (ERN/LRPT) in subgroups of patients with T2DM with better or poorer glycemic control. METHODS: Post hoc analysis of clinical trial data from patients with T2DM who were randomized 4:3 to double-blind ERN/LRPT or placebo (n=796), examining the lipid-modifying effects of ERN/LRPT in patients with glycosylated hemoglobin or fasting plasma glucose levels above and below median baseline levels. RESULTS: At Week 12 of treatment, ERN/LRPT significantly improved low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol, triglycerides, and lipoprotein (a), compared with placebo, with equal efficacy in patients above or below median baseline glycemic control. Compared with placebo, over 36 weeks of treatment more patients treated with ERN/LRPT had worsening of their diabetes and required intensification of antihyperglycemic medication, irrespective of baseline glycemic control. Incidences of other adverse experiences were generally low in all treatment groups. CONCLUSION: The lipid-modifying effects of ERN/LRPT are independent of the degree of baseline glycemic control in patients with T2DM (NCT00485758).

Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression.

Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D2, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.

Extended-release niacin/laropiprant lowers serum phosphorus concentrations in patients with type 2 diabetes.

BACKGROUND: Niacin compounds lower serum phosphorus concentrations in patients with end-stage renal disease. METHODOLOGY: We evaluated the impact of extended release niacin, given in fixed-dose combination with laropiprant, a specific inhibitor of prostaglandin-mediated, niacin-induced flushing, versus placebo, on serum phosphorus concentrations measured serially (at weeks 0, 4, 8, 12, 18, 24, 30, and 36) during a 36-week randomized, controlled trial. All subjects had a confirmed diagnosis of type 2 diabetes (n = 446 niacin/laropiprant; n = 339 placebo). Estimated glomerular filtration rate ranged from 36 to 184 mL/min/1.73 m(2), with n = 111 (14.1%) having a value <60 mL/min/1.73 m(2). Subjects received one tablet daily of extended-release niacin/laropiprant (1g niacin/ 20 mg laropiprant) for the first 4 weeks, and 2 tablets once daily, thereafter, or matched placebo. Niacin lowered serum phosphorus concentrations by 0.36 mg/dL (95% CI: -0.40, -0.31; P < .001), relative to placebo, from baseline values of 3.57 and 3.56 mg/dL in the niacin and placebo groups, respectively. Subgroup analyses revealed no evidence for phosphorus-lowering effect modification by these baseline variables: glomerular filtration rate <60 (n = 111;14.1%) vs ≥60 mL/min/m(2) (n = 674; 85.9%); phosphorus ≤3.5 mg/dL (n = 392; 49.9%) vs >3.5 mg/dL (n = 393; 50.1%); or prior statin use (n = 618; 78.7%) vs nonuse (n = 167; 21.3%). CONCLUSIONS AND IMPLICATIONS: These data confirm that niacin's phosphorus-lowering effects-which may have therapeutic implications for the management of hyperphosphatemia and possible prevention of cardiorenal outcomes in renal disease-extend across a broad spectrum of renal function in type 2 diabetics without stage 4 or 5 chronic kidney disease (a glomerular filtration rate ≥30 mL/min/1.73 m(2)).

Complications of percutaneous endoscopic and fluoroscopic gastrostomy tube insertion procedures in 378 patients.

Gastrostomy tubes are used for primary and supplemental feeding and gastric decompression. The purpose of the study was to compare the complication rate of gastrostomy tube placement by either endoscopic or fluoroscopic technique. Between 1996 and 2004, the surgical and radiological services at a Level I trauma hospital placed gastrostomy tubes in 378 patients (endoscopy=268, fluoroscopy=110). The percutaneous gastrostomy group comprised 71% of the cohort with a mean age of 51+/-21 (range: 1-93 years of age), and the percutaneous radiographic gastrostomy group comprised the remaining cohort (29%) with a mean age of 57+/-19 (range: 17-95 years of age). Fifty-eight percent of the percutaneous gastrostomy group were female (n=155) and 42% were male (n=113), whereas the gender distribution for the percutaneous radiographic gastrostomy group was 33% female (n=36) and 67% male (n=74). There was an overall complication rate of 36% (22% and 70% for the endoscopic and fluoroscopic methods, respectively). The most frequent complication in both types of techniques was tube dislodgement (endoscopic=32% [19/268]; fluoroscopic=27% [21/110]). There were very few serious complications. Women had a higher rate of postprocedure complications than did men, at 35% versus 27%. We conclude that gastrostomy tube placement by either endoscopic or fluoroscopic methods results in a number of complications, though most of them are minor. Patients must therefore be informed that this is not a complication-free procedure.

Complications of endovascular repair of abdominal aortic aneurysms: a review.

The endovascular procedure for repair of abdominal aortic aneurysms has had an enormous impact on the treatment of this challenging disease. Complications, however, do occur and it is important to have a thorough understanding of the array of complications and appropriate management strategies. In this review of endovascular complications, we describe early and late complications paying particular attention to preventive, treatment and surveillance strategies.

Novel computed tomography scan scoring system predicts the need for intervention after splenic injury.

BACKGROUND: The purpose of this study was to develop a computed tomography (CT) scan screening test to predict the need for intervention in patients with splenic injury. METHODS: CT scans of 20 patients with blunt injury to the spleen were reviewed to identify findings that correlated with the need for intervention (surgery or embolization). A screening test was created and then validated in CT scans from 56 consecutive patients. RESULTS: Three findings correlated with the need for intervention: 1) devascularization or laceration involving 50% or more of the splenic parenchyma, 2) contrast blush greater than one centimeter in diameter (from active extravasation of intravenous contrast material or pseudoaneurysm formation), and 3) a large hemoperitoneum. The sensitivity of the screening test was 100%, specificity was 88%, and overall accuracy was 93%. CONCLUSIONS: These CT scan grading criteria appears to reliably predict the need for invasive management in patients with blunt injury to the spleen.

Devastating consequences of subway accidents: traumatic amputations.

The efficiencies of the subway system are tempered by the occurrence of accidents, some with devastating injuries. The purpose of this study is to examine our experience with traumatic amputations after subway accidents. A retrospective trauma registry review (1989-2003) of 41 patients who presented to Bellevue Hospital, New York City, with amputations from subway accidents was undertaken to examine the following end points: age, sex, Injury Severity Score, time and mechanism of accident, history of psychiatric disorders and alcohol use, admission vital signs, Glasgow Coma Scale score, amputation type, associated injuries, limb salvage rate, operative procedures, mortality, and disposition. Elevated alcohol levels and prior psychiatric diagnoses were present in 39 per cent and 17 per cent of the patients, respectively. Patients were stable on admission with a mean systolic blood pressure of 114 mmHg, hematocrit of 32, and Glasgow Coma Scale score range of 13 to 15. The most common amputation was below knee, and patients underwent an average of three operative procedures. Limb salvage was attempted in eight patients with no successes. Amputation wound infection rate was 32 per cent and mortality rate was 5 per cent. Victims of subway trauma who arrive at the hospital with devastating amputations have an excellent chance of surviving to discharge.

Bivalirudin in peripheral interventions.

The discovery of heparin and its eventual incorporation into many therapeutic and diagnostic procedures has made this agent ubiquitous in the fields of cardiac and vascular medicine. Heparin however does have a significant complication and side-effect profile that includes both bleeding as well as vessel thrombosis through the development of heparin-induced thrombocytopenia. The recent addition of direct thrombin inhibitors, for example, bivalirudin, to the anticoagulation armaterium has produced favorable outcomes. Most of the experience with bivalirudin has been in coronary interventions and only recently have more interventionalists been turning to this agent as the sole anticoagulant for peripheral interventions even in patients who could tolerate heparin. In this review, we describe our experience with bivalirudin in peripheral interventions emphasizing how we dose and monitor this drug. In addition, this article discusses the findings in existing clinical trials involving bivalirudin.

A clinically relevant liver injury grading system by CT, preliminary report.

Current computed tomography (CT) grading scales are anatomic and do not reliably identify those liver injuries requiring intervention (surgery or angioembolization). We propose a clinically relevant CT grading system that could predict need for intervention. CT scans of 11 patients with hepatic injury were reviewed to establish criteria that correspond with intervention. Five features were identified that were associated with intervention: laceration in greater than or equal to three segments, laceration extending into the hilum, hemoperitoneum, active extravasation, and sentinel clot. Radiologists then evaluated the predictability of these criteria by analyzing 24 CT scans. Inter-observer agreement of the American Association for the Surgery of Trauma (AAST) grading system was compared to this new system. In the analysis of 24 CT scans, active extravasation and sentinel clot demonstrated the highest specificity for intervention. This new grading system had superior inter-observer agreement (k=0.56) as compared to the AAST grading system (k=0.47). Active extravasation and the presence of sentinel clot should form the foundation of a new liver grading system.

Retrograde migration of an abdominal aortic aneurysm endograft leading to postoperative renal failure.

The phenomenon of antegrade (distal) endograft migration is an extensively documented complication after endovascular abdominal aortic aneurysm repair. This case report describes the finding of postoperative abdominal aortic aneurysm endograft retrograde (proximal) migration occluding bilateral renal arteries and leading to dialysis-dependent renal failure.

Bivalirudin as an anticoagulation agent: safety and efficacy in peripheral interventions.

PURPOSE: Traditionally, unfractionated heparin is used to prevent thrombotic complications in peripheral interventions. The purpose of this study is to evaluate the use of bivalirudin as the anticoagulant agent for peripheral interventions. MATERIALS AND METHODS: A retrospective analysis of 108 patients who underwent 110 peripheral interventions between January 2002 and January 2004 and received bivalirudin as the sole anticoagulation agent was conducted at Baptist Cardiac and Vascular Institute. Interventions were performed in the following areas: iliac, femoropopliteal, and distal (n = 55), carotid (n = 31), vertebral (n = 1), renal (n = 14), aorta (n = 7), and subclavian (n = 2). The following procedural and clinical endpoints were examined: death, requirement of urgent surgery or surgery during the same admission, urgent percutaneous revascularization in the same treated vessel, thrombotic or embolic events, bleeding events, and groin complications. RESULTS: A total of 266 lesions were dilated in 185 arteries. There were no procedural mortalities, procedural success was 99.1%, and the complication rate was 3.6%. There was one embolic stroke (0.9%), one thrombosis (0.9%), and two groin hematomas (1.8%). No patient required urgent surgery or reintervention in the same treated vessel. No complications were noted at 7 days after the procedure. There were two interventions by postprocedure day 30: toe amputation and groin debridement. CONCLUSION: Bivalirudin is a safe alternative to unfractionated heparin as the anticoagulation agent in peripheral interventions. This study shows that the complication profile is comparable to other bivalirudin studies. Bivalirudin is effective, easy to use, and is associated with few bleeding complications.

Complications of acute fatty liver of pregnancy treated with activated protein C.

INTRODUCTION: Acute fatty liver (AFL) of pregnancy is a difficult and challenging diagnosis. The treatment plan is usually supportive. CASE REPORT: We present a case of a patient with AFL of pregnancy and Gram-negative endomyometritis and sepsis. Our treatment plan included the use of activated protein C (APC). CONCLUSION: This is the first case report of the use of APC in a post-partum patient with AFL and sepsis.

Past, present, and future endograft devices.

Since the original descriptions of endovascular grafts for treatment of aneurysms, a number of devices and approaches have been developed. The following is a discussion summarizing the number of devices which have been developed and used in patients, as well as chosen the directions of this technology. The diversity of approach from an engineering and materials point of view speaks of the fact that opportunity exists for continued development in the future.

Abdominal wall necrotizing fasciitis from dislodged percutaneous endoscopic gastrostomy tubes: a case series.

We report three cases of abdominal wall necrotizing fasciitis that occurred as a result of leakage from displaced percutaneous endoscopic gastrostomy tubes. This is the first report of such a series. Patients underwent extensive operative excisions of their abdominal walls down to their posterior fascia. All patients tolerated their initial surgery, however, two patients ultimately expired from respiratory complications. The surviving patient underwent multiple repeat debridements and reconstructive abdominal wall surgery. We review the epidemiology of patients at risk for this complication and discuss its presentation, as well as the appropriate workup and management. We also address the issues of closure of large abdominal wall defects and future alimentation in this patient group. Finally, abdominal wall necrotizing faciitis from gastrostomy tube leakage is a devastating complication, and the development of preventative strategies for patients at risk is of paramount importance.

Interleukin 10 gene transfection of donor lungs ameliorates posttransplant cell death by a switch from cellular necrosis to apoptosis.

BACKGROUND: We have previously shown that cell death is a pathophysiologic consequence of ischemia-reperfusion and that interleukin-10 gene therapy improves the function of transplanted lungs. Interleukin-10 downregulates the inflammatory response and can inhibit apoptosis. The objective was to determine whether donor lung transfection with the interleukin-10 gene ameliorates lung dysfunction by decreasing cell death after transplantation. METHODS: Single lung transplants were performed in 3 groups of rats (n = 5 each): AdhIL-10, transtracheal administration of Ad5E1RSVhIL-10 (5 x 10(9) pfu); EV, empty vector; and VD, vector diluent (3% sucrose). After in vivo transfection, donor lungs were excised, stored at 4 degrees C for 24 hours, and then transplanted. After 2 hours of reperfusion, lungs were flushed with trypan blue and fixed. TUNEL staining was used for the detection of apoptosis. This combined staining technique allows one to determine the mode of cell death by distinguishing apoptotic dead cells from necrotic dead cells. RESULTS: Lung function was superior in the interleukin-10 group (P =.0001) vs the EV and VD group (Pao(2): 240 +/- 31 mm Hg vs 98 +/- 17 mm Hg vs 129 +/- 11 mm Hg, respectively). Although the total number of dead cells (as percent of total cells) was similar in all groups (32.7% +/- 3.2%, 30.2% +/- 2.5%, and 30.3% +/- 3.8%), interestingly, apoptosis was highest in interleukin-10 lungs (9.7 +/- 1.9 vs 2 +/- 1.9 and 1.8 +/- 2, P =.0001), and necrosis was lowest in the interleukin-10 group (20.6 +/- 5.7 vs 28.3 +/- 3.1 and 30.3 +/- 4.2, P =.01). CONCLUSIONS: AdhIL-10 gene transfection improves function of transplanted lungs. Although the total number of cells dying as a result of the transplant process did not change, the mode of cell death appears to have been modified. It is possible that AdhIL-10, by decreasing proinflammatory cytokine production, ameliorates the overall injury and preserves the ability of damaged cells to undergo a more quiescent and less tissue-damaging mode of cell death-apoptosis, rather than necrosis.

Soluble transforming growth factor-beta type III receptor gene transfection inhibits fibrous airway obliteration in a rat model of Bronchiolitis obliterans.

Post-transplant bronchiolitis obliterans (BO) is characterized by fibroproliferation and fibrous obliteration of distal airways in chronically rejected lungs. In this study, using a rat heterotopic allogeneic tracheal transplant model of BO, we evaluated the expression of transforming growth factor-beta (TGFbeta) during the development of airway fibrous obliteration. Immunohistochemical analysis revealed TGFbeta staining in infiltrating mononuclear cells at Days 2 and 7, and in the fibrous tissues until Day 21. Soluble TGFbeta receptor type III (TGFBIIIR), by blocking TGFbeta binding to its membrane receptors, functions as a TGFbeta antagonist. To study the role of TGFbeta in the development of BO, adenoviral-mediated soluble TGFBIIIR gene transfection (5 x 10(9) particles) was performed topically at the site of transplant on Day 5 after transplantation, which leads to inhibition of fibrous airway obliteration. In contrast, empty vector gene delivered through intramuscular injection, or given locally at Days 0 or 10 after tracheal transplantation had no significant effect. These results suggest that TGFbeta expressed in the allografts plays a pivotal role in the pathogenesis of BO. Soluble TGFBIIIR may competitively inhibit TGFbeta activity locally. Adenoviral-mediated soluble TGFBIIIR gene transfection should be further explored as a potential therapeutic modality for BO and other conditions involving chronic fibrosis.