A. Scott Mathis

Hypercoagulable states in renal transplant candidates: impact of anticoagulation upon incidence of renal allograft thrombosis.

INTRODUCTION Although multiple studies of demographic variables have been associated with allograft thrombosis, these results are not routinely reproducible. Are ESRD patients with hypercoagulable states (HCS) (antithrombin III deficiency, protein S or C deficiency, activated protein C resistance, and anticardiolipin antibodies) at predictably greater risk for allograft thrombosis? METHODS Between 1996 and 1999, all renal transplant candidates were screened for hypercoagulability risk factors [HRF] (multiple arteriovenous access thromboses, prior deep vein thrombosis, prior allograft thrombosis, collagen vascular disease, multiple miscarriages, diabetes, autoimmune disease, and Fabrys disease). HRF(+) candidates were then tested for HCS status. We administered preemptive posttransplant i.v. Heparin in HCS(+) patients and observed the impact of this intervention upon the incidence of allograft thrombosis. We compared demographic data and incidence of allograft thrombosis in an historic control (346 patients transplanted between June 31, 1992, and March 5, 1996) not tested for HCS and a study cohort (502 patients transplanted between March 6, 1996, and June 31, 1999) prospectively screened for HRF. HRF(+) patients who were HCS(+) in the study cohort received i.v. heparin immediately after transplant and p.o. warfarin as outpatients. RESULTS Demographic characteristics previously implicated in allograft thrombosis were equivalently distributed in both cohorts with the exceptions that more living-donor transplants (33.1% vs. 15.3%) were performed in study cohort, CIT>24 hr occurred in more control patients (37.3% vs. 22.1%) and more study patients (16.7% vs. 0%) received tacrolimus. Hypercoagulable states were found upon reevaluating five of seven controls (71.4%), who lost prior allografts to thrombosis. Hypercoagulable states were prospectively detected in 10 study patients with hypercoagulability risk factors. Most (9 of 10) study patients receiving anticoagulation have achieved long-term allograft function. Study group allograft thrombosis incidence was reduced (1.59% vs. 4.05%). Hypercoagulable states were demonstrated in most episodes of allograft thrombosis. Control patients who lost prior allografts to thrombosis were anticoagulated after retransplantation and 100% achieved long-term allograft function. CONCLUSIONS Long-term allograft function has been achieved in 90% of study patients when prophylactically anticoagulating study patients with hypercoagulable states. A 2.6-fold reduction in the expected incidence of allograft thrombosis was observed in anticoagulated patients with hypercoagulable states.

Probable case of torsades de pointes induced by fluconazole.

A 25‐year‐old woman who was hospitalized for worsening endocarditis had a prolonged QT interval at baseline and developed monomorphic ventricular arrhythmias, which were managed successfully with pacing and antiarrhythmic therapy. Several days later, the patient started receiving high‐dose fluconazole for fungemia and subsequently experienced episodes of torsades de pointes, a polymorphic ventricular arrhythmia associated with a prolonged QT interval or prominent U wave on the electrocardiogram. The arrhythmia developed in the presence of known risk factors. Clinicians should be aware of these risk factors and other relevant structural similarities with drugs that cause torsades de pointes so that they can recognize patients who may be at risk for fluconazole‐associated arrhythmia.

Levofloxacin-Associated Achilles Tendon Rupture

OBJECTIVE: To describe a case of levofloxacin-induced partial Achilles tendon rupture; this occurred in the presence of known risk factors and acute renal failure. CASE SUMMARY: A 79-year-old white man received levofloxacin for presumed pneumonia, developed acute renal failure in the setting of dehydration, and began having ankle pain on the 12th day of admission. Levofloxacin was discontinued, and magnetic resonance imaging revealed a 6-cm partial tear and degenerative changes. DISCUSSION: The Naranjo probability scale indicates a possible association between levofloxacin and tendon rupture because the event occurred in the setting of known risk factors such as steroid use, renal failure, older age, and male gender. CONCLUSIONS: Levofloxacin, like other fluoroquinolones, may cause Achilles tendon rupture, and this may be particularly likely with known risk factors.

Sex and ethnicity may chiefly influence the interaction of fluconazole with calcineurin inhibitors.

Background. Calcineurin inhibitors (CNI) and azole antifungal agents have been reported to interact in a disparate manner. The azole dose and route and the level of involvement of the liver and intestines have been implicated, although data are limited. A significant interaction may result in CNI toxicity, and withdrawal of the azole may result in subtherapeutic CNI concentrations. Fluconazole, available in both intravenous and oral formulations, is commonly used in transplant recipients and is ideal for determining the presence of a disparate effect on CNI concentrations. We retrospectively investigated the interaction of CNIs with fluconazole, evaluating CNI blood troughs corrected for daily CNI dose, the factors influencing the interaction, and the effect on clinical outcomes in renal and simultaneous pancreas kidney transplant recipients. Methods. Twenty-eight patients received a CNI and fluconazole during the calendar year 1999, but only 19 patients had documented CNI blood troughs and outpatient follow-up. There were 25 episodes of use in the 19 included patients. CNI blood troughs were evaluated for changes induced by fluconazole, given by both routes, and clinical outcomes were tracked. Results. Data demonstrated both intravenous and oral fluconazole alter CNI blood concentrations. Two metabolic patterns were observed, and we termed these convergent and divergent. Divergent metabolizers did not have significant interaction (n=5), and convergent metabolizers did have a significant interaction (n=15). One patient had a divergent episode after a previous convergent episode. The main contributors to the lack of interaction appeared to be female sex and African American ethnicity. Additionally, tacrolimus levels were significantly more affected than cyclosporine, during and after fluconazole administration. No patient experienced nephrotoxicity or cellular rejection related to antifungal therapy. Conclusions. Oral and intravenous fluconazole appear to increase oral CNI trough concentrations to a similar extent even after adjusting for daily calcineurin dose. These interactions appear to be chiefly influenced by sex and ethnicity. Further prospective study is necessary to clarify this issue.

Bleeding and Thrombosis in High-Risk Renal Transplantation Candidates Using Heparin

BACKGROUND Heparin can reduce the risk of renal artery/vein thrombosis in renal transplant patients with hypercoagulable states (HCS), but is associated with a high bleeding risk. Little is known about risk factors for this bleeding risk or the optimal anticoagulation target. OBJECTIVE To determine factors associated with this bleeding risk and determine the optimal partial thromboplastin time (PTT) ratio. METHODS We retrospectively reviewed medical records of consecutive adult renal transplant recipients administered heparin for perioperative renal thrombosis prevention (1998–2002). RESULTS Twenty-eight (3.86%) of 725 consecutive renal transplant recipients received heparin to prevent renal thrombosis. Eighteen patients (64.3%) had clinically important bleeding (14 major bleeding). Patients with and without bleeding were similar in baseline demographic characteristics and overall mean PTT. Bleeding occurred at a mean PTT ratio of 2.5 ± 1, higher than the overall mean in bleeders and nonbleeders (p = 0.001). Among postoperative characteristics, higher maximum PTT (p = 0.052) and prolonged surgical antibiotic prophylaxis (p = 0.053), particularly with cefotetan (p = 0.091), trended toward a significant association with bleeding. Two renal thrombotic episodes occurred, both at PTT ratios <1.5. A PTT ratio of 1.5–1.9 resulted in no thrombosis and ≤4.2% bleeding. CONCLUSIONS The benefits and risks of therapeutic heparin anticoagulation in renal transplant patients with HCSs were confirmed. Higher PTTs and cefotetan antibiotic surgical prophylaxis could contribute to bleeding. The optimal PTT ratio appeared to be 1.5–1.9 to prevent thrombosis and limit bleeding risk.

Prescribing patterns and outcomes of enoxaparin for anticoagulation of atrial fibrillation

Study Objective. To determine prescribing patterns and clinical outcomes of enoxaparin for anticoagulation of atrial fibrillation.

Percutaneous Coronary Intervention–Related Bleeding Risk Factors in Current Practice

BACKGROUND: Bleeding is a common and costly complication of percutaneous coronary intervention (PCI). Little is known about the risk factors for bleeding complications. Objective: To report our PCI-related observations from a single institution and use the information to establish risk factors for short-term bleeding complications, with special focus on examining the importance of renal function. METHODS: A retrospective record review was conducted of the admission of 300 patients grouped according to antithrombotic regimen: unfractionated heparin alone (n = 187), bivalirudin (n = 26), and glycoprotein IIb/IIIa antagonist plus heparin (n = 103). Bleeding and ischemic outcomes were tracked. A model was constructed to predict independent bleeding risk factors. RESULTS: Treatment groups differed significantly regarding any bleeding (p = 0.001), minor bleeding (p < 0.001), and length of stay (p = 0.01). Multivariate predictors of any bleeding included antithrombotic regimen, creatinine clearance (Cl cr ) <30 mL/min, and hypertension. Any bleeding was associated with prolonged length of stay. Major bleeding was predicted by Cl cr <30 mL/min and was associated with prolonged length of stay and death. Minor bleeding was predicted only by choice of antithrombotic regimen. CONCLUSIONS: The major influences on bleeding risk appeared to be Cl cr <30 mL/min and choice of antithrombotic regimen. It is important to note that other markers of renal function, including serum creatinine value and serum creatinine at a cutoff level of 1.5 mg/dL, did not predict bleeding events.

Venous Thromboembolism Prevention in Acutely Ill Nonsurgical Patients

OBJECTIVE To review recent advances in the prevention of venous thromboembolism (VTE) in acutely ill nonsurgical inpatients. DATA SOURCES A MEDLINE search (1966–March 2005) was done to identify relevant articles relating to prevention of VTE in acutely ill nonsurgical inpatients. STUDY SELECTION AND DATA EXTRACTION Four major prophylaxis trials, one registry, one guideline, and supporting articles representative of the subject matter from the last few years were included. DATA SYNTHESIS Enoxaparin, dalteparin, fondaparinux, and unfractionated heparin 5000 units every 8 hours are effective in reducing the risk of VTE in acutely ill medical patients, but such prophylaxis is currently underused. Barriers to be overcome include recognition of the importance of VTE in this population, definition of the optimal strategy to assess risks, optimal timing of the risk assessment, optimal prophylactic regimen for a given level of risk or disease state, and optimal duration of prophylaxis. We recommend that acutely ill medical inpatients should be risk-stratified early in their hospitalization. At this time, the specific risk-assessment protocol should be derived from the trial(s) of the available formulary agent(s). Decisions about providing prophylaxis must also be made considering anticoagulant contraindications and renal function. Mechanical methods of prophylaxis should be considered as monotherapy only if an anticoagulant contraindication exists. The optimal duration of prophylaxis is not known, but 14 days was used in recent studies. CONCLUSIONS Prophylaxis of VTE in acutely ill medical inpatients is underused. Data provide some guidance for increasing awareness and optimizing patient care.

Do Sex and Ethnicity Influence Drug Pharmacokinetics in Solid Organ Transplantation

A number of reports have identified differences in drug pharmacokinetics and pharmacodynamics between males and females, and between patients of different ethnicity. These differences are observed in both solid organ transplant recipients and in nontransplant patients. This review summarizes the pharmacokinetic differences thought to be dependent on sex and ethnicity noted with immunosuppressive agents commonly used in transplantation. This manuscript also touches on how these differences may translate into observed drug interactions. Furthermore, potential factors underlying the sex and ethnicity differences are evaluated. Current evidence points to differences in drug-metabolizing enzymes, transporters, cytokines, and environmental influences to account for the observed heterogeneity in drug response. Many of these factors seem to be under genetic control, and thus areas for further research are suggested.

Newer Antithrombotic Strategies in the Initial Management of Non–ST-Segment Elevation Acute Coronary Syndromes

OBJECTIVE: To review the place in therapy of currently available antithrombotic agents in the non–ST-segment elevation acute coronary syndromes, that is, unstable angina and non–Q-wave myocardial infarction (MI). Recommendations are made based on currently available data. DATA SOURCE: English-language clinical studies, position statements, and review articles pertaining to the management of unstable angina and non–Q-wave MI with currently available products. STUDY SELECTION: Selection of prospective clinical studies was limited to those focusing on the management of the non–ST-segment elevation acute coronary syndromes, unstable angina, and non–Q-wave MI. DATA SYNTHESIS: It has yet to be determined which combination of agents (dalteparin, enoxaparin, lepirudin, clopidogrel, ticlopidine, abciximab, eptifibatide, tirofiban) and procedural strategies most significantly reduces mortality and serious events in these patients. The relevant pathophysiology, diagnostic criteria, and risk-stratifying procedures are reviewed in context with information from clinical studies regarding currently available agents for the management of non–ST-segment elevation acute coronary syndromes. CONCLUSIONS: A large number of new therapeutic classes and agents are available for the treatment of unstable angina and non–Q-wave MI. Although the diagnoses of unstable angina or non–Q-wave MI identify risk, treatment decisions are often based on the presence or absence of ST-segment elevations. Limited prospective evidence delineates the proper utilization of resources to best manage these patients. Efforts should be aimed at identifying particular patients who will best benefit from recently available therapies.