Sarah A. Spinler

Statins and liver toxicity: a meta-analysis.

Study Objective. To assess the risk of liver function test (LFT) abnormalities with the use of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) for the treatment of hyperlipidemia.

Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies.

BACKGROUND The advantages of enoxaparin over unfractionated heparin (UFH) for the treatment of patients with non-ST-segment elevation acute coronary syndromes are well established. However, no data are available about the safety and efficacy in patients who are obese and patients with severe renal impairment. METHODS A retrospective analysis of treatment effects was performed on patients who were obese and patients with severe renal impairment from the Efficacy Safety Subcutaenous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) and Thrombolysis in Myocardial Infarction (TIMI) 11B trials, in which patients were treated with enoxaparin or UFH. The primary composite end point was death, myocardial infarction (MI), and urgent revascularization (UR), and the secondary end points were major and any hemorrhage. RESULTS When compared with UFH, enoxaparin reduced the rate of the primary end point in patients who were obese (14.3% vs 18.0%, P =.05), patients who were not obese (16.1% vs 19.2%, P <.01), and patients without severe renal impairment (15.7% vs 18.4%, P <.01). There was no significant difference in major bleeding between enoxaparin and UFH in any of the 4 subgroups. There were no differences in either the primary end point (17.6% vs 16.2%, P =.39) or major hemorrhage (1.3% vs 0.8%, P =.12) in patients who were obese receiving either UFH or enoxaparin compared with patients who were not obese. Patients with severe renal impairment tended toward a higher rate of the primary end point (25.9% vs 17%, P =.09) and experienced more major hemorrhages (6.6% vs 1.1%, P <.0001). CONCLUSIONS Enoxaparin reduced the rate of the combined end point of death/MI/UR in the subgroups of patients who were obese, patients who were not obese, and patients without renal insufficiency. Obesity did not impact clinical outcomes in the combined analysis of ESSENCE and TIMI 11B. Patients with severe renal impairment have a higher risk of clinical events and major and any hemorrhages than patients without severe renal impairment, whether they are treated with UFH or enoxaparin.

Hyponatremia Associated with Selective Serotonin-Reuptake Inhibitors in Older Adults

Objective: To review the incidence, risk factors, mechanism, times of onset and resolution, and treatment of hyponatremia associated with selective serotonin-reuptake inhibitors (SSRIs). Data Sources: An English-language literature search was conducted using MEDLINE (1966–December 2005) using the search terms selective serotonin-reuptake inhibitor, hyponatremia, syndrome of inappropriate secretion of antidiuretic hormone, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. Additional references were identified by reviewing bibliographies of articles retrieved. Study Selection and Data Extraction: Relevant data were extracted from published reports, letters, and studies of humans with hyponatremia and/or syndrome of inappropriate secretion of antidiuretic hormone (SIADH) secondary to SSRIs. All articles identified from data sources were reviewed for relevant information. Applicable information was included in this review. Data Synthesis: Numerous case reports, observational studies, and case-controlled studies, as well as one prospective clinical trial, have reported hyponatremia associated with SSRI use, with the incidence varying from 0.5% to 32%. Risk factors for the development of hyponatremia with SSRIs include older age, female gender, concomitant use of diuretics, low body weight, and lower baseline serum sodium concentration. In published reports, hyponatremia developed within the first few weeks of treatment and resolved within 2 weeks after therapy was discontinued. The mechanism by which SSRIs cause hyponatremia is thought to be secondary to development of SIADH. Treatment of isovolemia hypotonic hyponatremia associated with SSRI use includes water restriction and mild diuresis with a loop diuretic. More severe cases may be treated with higher doses of loop diuretics and hypertonic saline. There have been few reports of rechallenge with the same or another SSRI or substitution of another agent from a different therapeutic class. In some, but not all, cases hyponatremia recurred. Conclusions: Practitioners should be on the alert for this potentially life-threatening adverse event, especially in older adults with other risk factors for developing hyponatremia.

Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia.

Objective: To evaluate the comparative efficacy and safety of the 4 currently available hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, fluvastatin, lovastatin, pravastatin, and simvastatin, in the treatment of primary hypercholesterolemia. Data Sources: English-language clinical studies, abstracts, and review articles identified from MEDLINE searches and bibliographies of identified articles. Unpublished data were obtained from the Food and Drug Administration in accordance with the Freedom of Information Act. Study Selection: Placebo-controlled and comparative studies of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Data Extraction: Pertinent studies were selected and the data were synthesized into a review format. Data Synthesis: The chemistry, pharmacology, and pharmacokinetics of the 4 HMG-CoA reductase inhibitors are reviewed. Clinical trials evaluating the hypocholesterolemic efficacy of the HMG-CoA reductase inhibitors are examined, and results on the comparative efficacy and safety of these agents are summarized. On a milligram-per-milligram basis, simvastatin is twice as potent as lovastatin and pravastatin. The hypocholesterolemic effects of fluvastatin appear to be approximately 30% less than that of lovastatin. In posttransplant patients receiving cyclosporine, safety has been documented for low doses of lovastatin and simvastatin, but when a higher dosage of an HMG-CoA reductase inhibitor is warranted, pravastatin should be considered the drug of choice because of a lower incidence of myopathy. Relevant data on the incidence of adverse effects are presented. Pertinent outcomes data from clinical trials evaluating the effect of HMG-CoA reductase inhibitors on atherosclerosis regression and coronary mortality, as well as published economic analyses of cholesterol-lowering agents, are summarized. Recommendations on the selection of an HMG-CoA reductase inhibitor in various clinical situations are provided. Conclusions: The literature supports the comparable safety and tolerability of all 4 currently available HMG-CoA reductase inhibitors. Therefore, the choice of an HMG-CoA reductase inhibitor should depend on the extent of cholesterol lowering needed to meet the recommended treatment goal established by the National Cholesterol Education Program. Direct comparative studies are needed to confirm the relative, long-term cost-effectiveness of the various HMG-CoA reductase inhibitors in the treatment of primary hypercholesterolemia.

Cockcroft-Gault Versus Modification of Diet in Renal Disease Importance of Glomerular Filtration Rate Formula for Classification of Chronic Kidney Disease in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes

OBJECTIVES Our purpose was to compare formulae for estimating glomerular filtration rate (GFR) in non-ST-segment elevation acute coronary syndromes (NSTE ACS) patients. BACKGROUND Assessment of GFR is important for antithrombotic dose adjustment in NSTE ACS patients. METHODS We assessed estimated glomerular filtration rate (eGFR) with Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) formulae in 46,942 NSTE ACS patients from 408 CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association Guidelines) hospitals. Formula agreement was shown continuously and by chronic kidney disease (CKD) stages. We determined in-hospital outcomes and the association between antithrombotic dose adjustment and bleeding for moderate CKD as determined by each formula. RESULTS The median (interquartile range [IQR]) eGFR was 53.2 ml/min (34.7, 75.1 ml/min) by C-G and 65.8 ml/min (47.6, 83.5 ml/min) by MDRD. The mean eGFR was higher with MDRD (approximately 9.1 ml/min), but this difference was greater in age, weight, and gender subgroups. Chronic kidney disease classification differed in 20% of the population and altered when antithrombotic dose adjustment was required by C-G versus MDRD (eptifibatide: 45.7% vs. 27.3%; enoxaparin: 19.0% vs. 9.6%). CONCLUSIONS Important CKD disagreements occur in approximately 20% of acute coronary syndrome patients, affecting dosing adjustments in those already susceptible to bleeding. Dosing based on C-G formula is preferable, particularly in the small, female, or elderly patient.

Role of P-glycoprotein in Statin Drug Interactions

Understanding the mechanisms of drug interactions with 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) has become increasingly important because of the potential for serious adverse effects, most notably myopathy. Most of the evidence supports the role of cytochrome P450 (CYP) isoenzymes in many of these drug interactions. However, P‐glycoprotein (P‐gp), an efflux protein located in the gastrointestinal tract, placenta, kidneys, brain, and liver, may also play a role. Results of several studies with in vitro models have shown that lovastatin, simvastatin, and atorvastatin are inhibitors for P‐gp and may be substrates for this transporter as well. Pravastatin and fluvastatin consistently demonstrate no significant inhibition of P‐gp. Drug interaction studies involving statins and digoxin support a role for P‐gp. Many additional drugs such as diltiazem, verapamil, itraconazole, ketoconazole, and cyclosporine, as well as dietary supplements such as St. Johns wort and grapefruit juice, interact with statins and are modulators of both CYP3A4 and P‐gp. However, the role of P‐gp in these specific drug interactions remains unclear.

Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases.

As the only oral anticoagulation option available in the United States, warfarin use remains widespread. However, concerns of safety remain a substantial issue. Additional anticoagulation options include unfractionated heparin, low‐molecular‐weight heparins (e.g., enoxaparin, dalteparin, and tinzaparin), and the indirect‐acting factor Xa inhibitor, fondaparinux. Direct thrombin inhibitors represent a newer class of anticoagulants used primarily in the treatment of heparin‐induced thrombocytopenia and percutaneous coronary interventions. Three intravenous agents are currently available—lepirudin, bivalirudin, and argatroban—with an oral agent, dabigatran etexilate, undergoing clinical investigation. Dabigatran etexilate offers a rapid onset of action after oral administration, reaching peak plasma concentrations and onset of anticoagulant effect within 0.5–2 hours after administration. Studies have demonstrated linear pharmacokinetics, a linear relationship between ecarin clotting time and international normalized ratio, and no known clinically significant drug or food interactions. Dabigatran etexilate has been studied in clinical trials as prophylaxis for venous thromboembolism in patients undergoing total knee replacement or total hip replacement surgeries, as well as for stroke prevention in patients with atrial fibrillation. Dabigatran etexilate has demonstrated superiority and noninferiority to enoxaparin as prophylaxis for venous thromboembolism in patients undergoing orthopedic surgery, with the most frequent adverse effects being gastrointestinal complaints. Elevations in alanine aminotransferase concentrations were noted in small percentages of patients in both the dabigatran etexilate and enoxaparin groups, with no observed dose association. The overall rates of major bleeding were low, with minor bleeding commonly noted, often at surgical sites. Clinical trials of dabigatran etexilate in patients with atrial fibrillation are ongoing. Results of short‐term efficacy and safety appear promising. Further research is needed regarding long‐term safety and efficacy for other anticoagulation indications.

Clinical ResearchRenal Function in Acute Coronary SyndromeCockcroft-Gault Versus Modification of Diet in Renal Disease: Importance of Glomerular Filtration Rate Formula for Classification of Chronic Kidney Disease in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes

OBJECTIVES Our purpose was to compare formulae for estimating glomerular filtration rate (GFR) in non-ST-segment elevation acute coronary syndromes (NSTE ACS) patients. BACKGROUND Assessment of GFR is important for antithrombotic dose adjustment in NSTE ACS patients. METHODS We assessed estimated glomerular filtration rate (eGFR) with Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) formulae in 46,942 NSTE ACS patients from 408 CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association Guidelines) hospitals. Formula agreement was shown continuously and by chronic kidney disease (CKD) stages. We determined in-hospital outcomes and the association between antithrombotic dose adjustment and bleeding for moderate CKD as determined by each formula. RESULTS The median (interquartile range [IQR]) eGFR was 53.2 ml/min (34.7, 75.1 ml/min) by C-G and 65.8 ml/min (47.6, 83.5 ml/min) by MDRD. The mean eGFR was higher with MDRD (approximately 9.1 ml/min), but this difference was greater in age, weight, and gender subgroups. Chronic kidney disease classification differed in 20% of the population and altered when antithrombotic dose adjustment was required by C-G versus MDRD (eptifibatide: 45.7% vs. 27.3%; enoxaparin: 19.0% vs. 9.6%). CONCLUSIONS Important CKD disagreements occur in approximately 20% of acute coronary syndrome patients, affecting dosing adjustments in those already susceptible to bleeding. Dosing based on C-G formula is preferable, particularly in the small, female, or elderly patient.

Predictive Performance of Ten Equations for Estimating Creatinine Clearance in Cardiac Patients

OBJECTIVE: The predictive performance of 10 equations used to estimate creatinine clearance (Clcr) was assessed retrospectively from data collected on 420 patients. DESIGN: This study is a retrospective data analysis of information collected on hemodynamically stable patients awaiting coronary angiography during the Iohexol Cooperative Study. SETTING: The Iohexol Cooperative Study was a multicenter study that compared nephrotoxicity of high- and low-osmolar contrast media in patients undergoing coronary angiography. Data used for this analysis were preangiography 24-hour urine collections that were primarily collected in hospitalized patients. PATIENTS: Patients selected from the Iohexol Cooperative Study database for analysis were participants categorized into one or more of six subgroups: elderly (n = 222), hypoalbuminemic (n = 25), chronic renal insufficiency (n = 128), low serum creatinine (n = 115), obese (n = 208), and diabetic (n = 191) who had baseline urine collections of at least 24 hours. OUTCOME MEASURES: Predictive performance was assessed using bias, precision, slopes, and y-intercepts. RESULTS: The Salazar–Corcoran equation was unbiased in the entire group as well as in five of the subgroups. The Cockcroft–Gault equation was unbiased in three of the subgroups. All other equations were biased in predicting Clcr in the entire group as well as in at least four of the subgroups. Precision was generally poor. All slopes were significantly different than one and all y-intercepts were significantly different than zero (p < 0.01). Correlation coefficients were between 0.63 and 0.79 with the exceptions of the low serum creatinine subgroup (r values 0.35–0.64) and the Davis–Chandler equation (r values 0.35–0.71 across groups). CONCLUSIONS: Of the equations studied, Salazar–Corcoran and Cockcroft–Gault appear to be the best for predicting Clcr.

Conversion of Recent-Onset Atrial Fibrillation with Intravenous Amiodarone: A Meta-Analysis of Randomized Controlled Trials

Study Objective. To evaluate efficacy and safety of intravenous amiodarone for conversion of recent‐onset atrial fibrillation.