Incidence Of Alanine Aminotransferase Elevations Research Articles

Incidence and Pattern of Aminotransferase Elevation During Anti-Hypertensive Therapy With Angiotensin-II Receptor Blockers

BackgroundAngiotensin type II receptor blockers (ARBs) are the most widely used anti-hypertensive drugs. This study aimed to elucidate the likelihood and pattern of ARB-induced liver injury in a hospital-based cohort.MethodsData of patients receiving fimasartan (n = 5,543), candesartan (n = 6,406), valsartan (n = 6,040), and losartan (n = 9,126) were retrieved from the clinical data warehouse of two tertiary hospitals. Patients with alanine aminotransferase (ALT) levels > 5 times the upper normal limit were assessed according to the Roussel Uclaf Causality Assessment Method (RUCAM).ResultsA total of 27,115 patients were enrolled, including 14,630 (54.0%) men, with a mean age of 64.6 years (standard deviation, 13.6). During 31,717 person-years of ARB therapy, serum ALT levels > 120 IU/L were found in 558 (2.1%) person-years, and levels > 200 IU/L were found in 155 (0.6%) person-years. The incidence of ALT elevation > 120 IU/L per 106 cumulative defined daily doses was 6.6, 3.6, 3.9, and 4.0 in the fimasartan, candesartan, valsartan, and losartan groups, respectively (P = 0.002). An ALT level > 200 IU/L with RUCAM score ≥ 6 was found in 20 patients, suggesting probable drug-induced liver injury for 11 (0.2%) patients receiving fimasartan, five (0.1%) receiving candesartan, four (0.1%) receiving valsartan, and none receiving losartan (P < 0.001).ConclusionApproximately 2% of patients receiving ARB therapy had significant ALT elevation (4.24/106 cumulative defined daily doses [cDDDs]), which was associated with probable ARB-related liver injury in 0.07% of patients (0.15/106 cDDDs). Elevation of ALT was more commonly associated with fimasartan than the other ARBs. Clinicians should be aware of the possibility of ARB-related ALT elevation in patients with unexplained chronic abnormal ALT.

Epidemiological and clinical characteristics of COVID-19 patients in Hengyang, Hunan Province, China.

BACKGROUNDIn December 2019, an ongoing outbreak of coronavirus disease 2019 (COVID-19) was first identified in Wuhan, China. The characteristics of COVID-19 patients treated in local hospitals in Wuhan are not fully representative of patients outside Wuhan. Therefore, it is highly essential to analyze the epidemiological and clinical characteristics of COVID-19 in areas outside Wuhan or Hubei Province. To date, a limited number of studies have concentrated on the epidemiological and clinical characteristics of COVID-19 patients with different genders, clinical classification, and with or without basic diseases.AIMTo study the epidemiological and clinical characteristics of COVID-19 patients in Hengyang (China) and provide a reliable reference for the prevention and control of COVID-19.METHODSFrom January 16 to March 2, 2020, a total of 48 confirmed cases of COVID-19 were reported in Hengyang, and those cases were included in this study. The diagnostic criteria, clinical classification, and discharge standard related to COVID-19 were in line with the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) released by National Health Commission and National Administration of Traditional Chinese Medicine. The presence of SARS-CoV-2 in pharyngeal swab specimens was detected by quantitative reverse transcription polymerase chain reaction. All the data were imported into the excel worksheet and statistically analyzed by using SPSS 25.0 software.RESULTSA total of 48 cases of COVID-19 were collected, of which 1 was mild, 38 were moderate, and 9 were severe. It was unveiled that there were 31 (64.6%) male patients and 17 (35.4%) female patients, with a female-to-male ratio of 1.82:1. The range of age of patients with COVID-19 was dominantly 30-49 years old [25 (52.1%) of 48], followed by those aged over 60 years old [11 (22.9%)]. Besides, 29.2% (14 of 48) of patients had basic diseases, and 57.2% (8 of 14) of patients with basic diseases were aged over 60 years old. The occupations of 48 COVID-19 patients were mainly farmers working in agricultural production [15 (31.5%) of 48], rural migrant workers from Hengyang to Wuhan [15 (31.5%)], and service workers operating in the service sector [8 (16.7%)]. The mean latent period was 6.86 ± 3.57 d, and the median was 7 [interquartile range (IQR): 4-9] d. The mean time from onset of symptoms to the first physician visit was 3.38 ± 2.98 (95%CI: 2.58-9.18) d, with a median of 2 (IQR: 1-5) d, and the mean time from hospital admission to confirmed diagnosis was 2.29 ± 2.11 (95%CI: 1.18-6.42) d, with a median of 2 (IQR: 1-3) d. The main symptoms were fever [43 (89.6%) of 48], cough and expectoration [41 (85.4%)], fatigue [22 (45.8%)], and chills [22 (45.8%)]. Other symptoms included poor appetite [13 (27.1%)], sore throat [9 (18.8%)], dyspnea [9 (18.8%)], diarrhea [7 (14.6%)], dizziness [5 (10.4%)], headache [5 (10.4%)], muscle pain [5 (10.4%)], nausea and vomiting [4 (8.3%)], hemoptysis [4 (8.3%)], and runny nose [1 (2.1%)]. The numbers of peripheral blood leukocytes, lymphocytes, and eosinophils were significantly reduced in the majority of the patients. The levels of C-reactive protein, fibrinogen, blood glucose, lactate dehydrogenase, D-dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (γ-GT), myoglobin (MB), and creatine kinase (CK) were increased in 64.6%, 44.7%, 43.2%, 37.0%, 29.5%, 22.9%,20.8%, 21.6%, 13.6%, and 12.8% of patients, respectively. The incidence of ALT elevation in male patients was remarkably higher than that in females (P < 0.01), while the incidences of AST, CK, and blood glucose elevations in severe patients were remarkably higher than those in moderate patients (P < 0.05, respectively). Except for the mild patients, chest computed tomography showed characteristic pulmonary lesions. All the patients received antiviral drugs, 38 (79.2%) accepted traditional Chinese medicine, and 2 (4.2%) received treatment of human umbilical-cord mesenchymal stem cells. On March 2, 2020, 48 patients with COVID-19 were all cured and discharged.CONCLUSIONBased on our results, patients with COVID-19 often have multiple organ dysfunction or damage. The incidences of ALT elevation in males, and AST, CK, and blood glucose elevations in severe patients are remarkably higher.

Association between Alanine Aminotransferase and Growth Hormone: A Retrospective Cohort Study of Short Children and Adolescents.

Objective This study aimed to examine the relationship between serum alanine aminotransferase (ALT) and growth hormone (GH) in children and adolescents with short stature. Methods In this retrospective cohort study, 670 Chinese children and adolescents with short stature were included, and 253 of them received recombinant human GH (rhGH) therapy. Anthropometric and biochemical indicators were measured. GH peak levels were assessed after provocation tests with L-dopa and insulin. The subjects were divided into 3 groups according to the GH peak level. The association between the GH peak and ALT was analyzed. The change of ALT during rhGH therapy was assessed by a generalized additive mixed model. Results Serum ALT and incidence of ALT elevation were both decreased across the GH tertiles (P = 0.002, 0.012, respectively). A univariate analysis showed that the GH peak was negatively associated with ALT (β: -0.12; 95%CI: -0.22, -0.02; P = 0.023). Furthermore, multiple linear stepwise regression analysis demonstrated that the GH peak was independently related to ALT after adjusting for other confounding variables (β: -0.12; 95%CI: -0.24, -0.00; P = 0.042). Besides, mean values of the change in ALT from baseline displayed that, during the early stages of rhGH treatment, serum ALT level indicated a temporary upward trend, but it subsequently gradually decreased (β: -0.16; 95%CI: -0.23, -0.09; P < 0.001). ConclusionsGH secretion level was strongly negatively correlated with ALT in short children and adolescents. And rhGH therapy could reduce ALT level over time.

Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience

Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns. The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug. The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n=5359, fasiglifam group), fasiglifam and sitagliptin (n=123), or a comparator agent (n=3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations>3×upper limit of normal (ULN), 5×ULN, and 10×ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations>3×ULN for fasiglifam were 2.7% compared with 0.8 and 0.5% for the active comparators and placebo. There did not appear to be a clear dose response in incidence of ALT elevations between patients receiving 25 or 50mg daily. The cumulative incidence of elevations in serum ALT>3×ULN was higher in the first 6months of treatment with fasiglifam compared with both placebo and the active comparators, but the rate of new ALT elevations appeared to be similar across all treatment groups thereafter. No demographic or baseline patient characteristics were identified to predict elevations exceeding ALT>3×ULN in fasiglifam-treated patients. The pattern of liver injury with fasiglifam was hepatocellular, and there were no reports of liver-related deaths, liver failure or life-threatening liver injury. Most fasiglifam-associated ALT elevations were asymptomatic and resolved promptly upon discontinuing treatment, but in two patients the recovery was prolonged. Importantly, three important serious liver injury cases were identified among fasiglifam-treated patients; one case was adjudicated to be a clear Hy's Law case and the two remaining cases were considered to closely approximate Hy's Law cases. Although the incidence of overall AEs, SAEs, and deaths was similar between fasiglifam and placebo, a liver signal was identified based primarily on the difference in liver chemistry values in the fasiglifam group compared with the placebo and active comparator groups. Three serious liver injuries were attributed to fasiglifam treatment. Clinical development of fasiglifam was halted due to these liver safety concerns.

Telbivudine for prevention of perinatal transmission in pregnant women infected with hepatitis B virus in immune-tolerant phase: a study of efficacy and safety of drug withdrawal

To observe the success rate of telbivudine (LdT) for the prevention of perinatal transmission of hepatitis B virus (HBV) and the incidence of alanine aminotransferase (ALT) elevation during LdT treatment and after LdT withdrawal in HBV-infected pregnant woman with high viremia in immune-tolerant phase and receiving LdT treatment at the end of pregnancy, and to evaluate the efficacy of LdT in the prevention of perinatal transmission and the safety for pregnant women. Pregnant women infected with HBV in immune-tolerant phase who had normal ALT levels (≤40 U/L) and high viremia (HBV DNA ≥6 log10 IU/ml) with positive HBeAg were enrolled as subjects. All pregnant women received antiviral treatment with LdT at the end of pregnancy to prevent perinatal transmission of HBV. All infants received standard combined immunoprophylaxis. Failure for prevention of perinatal transmission of HBV was defined as positive HBsAg or HBV DNA in infants 7 months of age (or at one month after the third injection of hepatitis B vaccine). Liver function, HBV DNA, and HBV serological markers were evaluated at baseline, after 1 month of treatment, before childbirth, and 1, 3, and 6 months after drug withdrawal. SPSS 16.0 software was used to analyze the data. Between-group comparison of continuous data was made by t test, and comparison of categorical data was made by chi-square test. One hundred and four pregnant women (treatment group) received oral administration of 600 mg LdT once a day, and 25 pregnant women (observation group) did not receive any antiviral therapy. The success rate for the prevention of perinatal transmission was significantly higher in the treatment group than in the observation group (100% vs 89.47%, χ (2) = 9.862, P = 0.028). There was no significant difference in the incidence of ALT elevation during treatment and within 6 months after drug withdrawal between the treatment group and the observation group (4.81% (5/104) vs 4.00% (1/25), χ (2) = 0.030, P = 1.000). In the treatment group, the mean HBV DNA at baseline was significantly higher than that before childbirth (8.20±0.78 vs 3.98±0.90 log10IU/ml, t = 6.979, P < 0.001). One hundred patients with drug withdrawal had HBV DNA increased to 8.11±0.80 log10 IU/ml at one month after childbirth. LdT treatment at the end of pregnancy can effectively reduce the incidence of perinatal transmission of HBV in pregnant women with high viremia in immune-tolerant phase. The immediate drug withdrawal after childbirth is safe for the mother. The incidence of hepatitis is low after drug withdrawal.

A pre-marketing ALT signal predicts post-marketing liver safety

Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an “ALT signal”. We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hepatotoxicity. Incidence of ALT elevations (ALT⩾3 times upper limits normal [× ULN]) for drug and placebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05⩾2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT⩾3× ULN in treated versus placebo) was examined. An ALT signal of⩾1.2% was significantly associated with a post-marketing liver safety signal (p⩽0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT⩾3× ULN in treated versus placebo groups provides an easily calculated method for predicting post-marketing liver safety.

Aminotransferase Levels in Relation to Short-Term use of Acetaminophen Four Grams Daily in Postoperative Cardiothoracic Patients in the Intensive Care Unit

A volunteer study suggested that taking paracetamol 4 g daily could result in elevated alanine aminotransferase plasma levels in a substantial proportion of healthy volunteers. The safety of this dose of paracetamol for acute postoperative pain remains controversial. This study aimed to examine the incidence of alanine aminotransferase elevations after short-term use of paracetamol 4 g daily, as part of the standard pain management protocol, for 93 consecutive patients after cardiothoracic surgery. Alanine aminotransferase levels and other liver function tests were measured preoperatively as baseline and once daily after surgery during the intensive care unit stay. Preoperative alanine aminotransferase levels of more than one time the upper limit of normal (ULN >40 U/l) was observed in 11% (n=10) of the patients but none of these baseline alanine aminotransferase levels exceeded three times the ULN (>3 x ULN). The average daily dose of paracetamol administered was 50 mg/kg (SD=16) after surgery. Postoperative alanine aminotransferase levels of >1 x ULN was observed in 17% (n=16), and 4% (n=4) exceeded >3 x ULN The other liver function tests of the latter four patients, including aspartate aminotransferase (range 173 to 5590 U/l), gamma-glutamyltransferase (range 56 to 103 U/l), lactate dehydrogenase (range 376 to 3518 U/l) and the International Normalised Ratio (range 2.0 to 6.6), were all abnormal. These four patients all had right ventricular failure or cardiogenic shock during the postoperative period which could explain the significant rises in alanine aminotransferase after surgery. In conclusion, the incidence of significant alanine aminotransferase elevations after using daily paracetamol as an analgesic agent for cardiac surgery, at a dose of 4 g per day, was low and mostly due to complications after surgery. Our results, albeit still very limited, provided some reassurance about the safety of paracetamol 4 g daily, as a supplementary analgesic agent for adult patients undergoing cardiac surgery.

Response by Sex to Statin and Ezetimibe Versus Statin Monotherapy: Pooled Analysis from 22,913 Hyperlipidemic Patients

Synopsis: Coronary heart disease (CHD) remains the leading cause of mortality in women, highlighting the importance of preventive interventions in women. Purpose: To assess sex-related efficacy of statin + ezetimibe (EZ) vs statin in a broad, pooled database. Methods: Data were pooled from 27 double-blind, active, or placebo-controlled studies that randomized adult patients with hypercholesterolemia to statin alone or statin + EZ. Consistency of treatment effect among sexes was tested with ANCOVA with terms for treatment, first/second-line therapy status (FSLT), race, sex, CHD, statin potency, age, body mass index, baseline (BL) low-density lipoprotein cholesterol, BL high-density lipoprotein cholesterol (HDL-C), BL triglycerides, BL response variable, diabetes, trial within FSLT, treatment by FSLT, and treatment by sex interactions. Results: BL lipids and high-sensitivity C-reactive protein (hs-CRP) were generally greater in women than men. Both therapies significantly reduced low-density lipoprotein cholesterol, non-HDL-C, TG, apoB, TC, and hs-CRP, with significantly greater reductions seen with statin + EZ vs statin for prespecified dose comparisons. In general, treatment group differences for women were slightly smaller. HDL-C increased more for women than men in both treatment groups. There were no between-group differences in adverse events or creatine kinase elevations in the overall population. A greater incidence of alanine aminotransferase elevations was seen in statin + EZ vs statin patients in the overall population (0.6% vs 0.3%). Some minor differences, although not clinically relevant, were noted between sexes in the incidence of some AEs. Conclusions: This pooled database describes a large clinical experience with statin + EZ for women in which significantly greater changes in lipid and hs-CRP levels were seen with statin + EZ vs statin in both sexes, although women experienced smaller reductions than men for some lipids. Both treatments were generally well tolerated without major sex-related safety issues. ErratumJournal of Clinical LipidologyVol. 4Issue 4PreviewIn the June 2010 issue (4/3) of Journal of Clinical Lipidology, in the section titled “Scientific Poster Abstracts Selected for the National Lipid Association 2010 Annual Scientific Sessions” (2010;4:198-231), changes were made post-submission as noted below. Full-Text PDF

Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study

Background:The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis.Objective:To evaluate through the AMBITION study the efficacy and safety of tocilizumab...

Incidence and prevalence of abnormal liver associated enzymes in patients with atrial fibrillation in a routine clinical care population

The prevalence of elevated liver enzymes has not been described in patients with atrial fibrillation (AF) who may be more likely to develop these abnormalities due to comorbidities and medications. As signals of liver injury lead to termination of drug development programs, an attempt to better define the background prevalence would aid in interpreting these elevations in the setting of exposure to a new drug. The aim of this study was to estimate the prevalence and incidence of alanine aminotransferase (ALT) elevations in a cohort with AF. Retrospective cohort of patients with AF using the outpatient medical record of the University of Pennsylvania Health System (UPHS). Primary outcomes were prevalence and incidence of ALT elevations (>40 U/L). We also examined the prevalence of risk factors for ALT elevations. Liver enzymes were measured at least once in 1630 of 2151 patients (76%). The prevalence of ALT >40 U/L was 27.6% (95%CI 25.7-29.5%). The incidence of new ALT elevations was 14.5/100 person-years (95%CI 13.0-16.1) for ALT > 40 U/L and 2.1/100 person-years (95%CI 1.6-2.8) for ALT elevations above twice the upper limit of normal (ULN). New persistent ALT elevations above twice the ULN were identified in 0.2% of patients. Elevated ALT is common among patients with AF, although new and persistent elevation greater than twice the ULN is uncommon. In the setting of a new drug, these factors make it difficult to delineate drug-induced liver injury from incident elevations due to comorbidities.

A Replacement for Warfarin

HomeCirculationVol. 116, No. 2A Replacement for Warfarin Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBA Replacement for WarfarinThe Search Continues John W. Eikelboom, MD and Jeffrey I. Weitz, MD John W. EikelboomJohn W. Eikelboom From the Departments of Medicine (J.W.E., J.I.W.) and Biochemistry and Biomedical Sciences (J.I.W.), McMaster University and Henderson Research Centre, Hamilton, Ontario, Canada. Search for more papers by this author and Jeffrey I. WeitzJeffrey I. Weitz From the Departments of Medicine (J.W.E., J.I.W.) and Biochemistry and Biomedical Sciences (J.I.W.), McMaster University and Henderson Research Centre, Hamilton, Ontario, Canada. Search for more papers by this author Originally published18 Jun 2007https://doi.org/10.1161/CIRCULATIONAHA.107.712349Circulation. 2007;116:131–133Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 18, 2007: Previous Version 1 Vitamin K antagonists (VKAs) such as warfarin are the only oral anticoagulants currently available for clinical use. Warfarin has numerous limitations, including slow onset and offset of action, a narrow therapeutic window, and a metabolism that is affected by diet, drugs, and genetic polymorphisms.1 Because of its unpredictable dose response, warfarin requires careful coagulation monitoring to ensure that a therapeutic anticoagulant effect is achieved.2 Variable dose requirements, concern about the risk of bleeding, and the need for frequent coagulation monitoring have prompted the development of new oral anticoagulants to replace warfarin. With a predictable anticoagulant response and little potential for food or drug interactions, these new agents have been designed to be administered in fixed doses without coagulation monitoring. Consequently, these drugs have the potential to simplify long-term anticoagulant therapy.Article p 180The features of the new oral anticoagulants in the most advanced stages of clinical development are listed in the Table and are compared with those of warfarin. Unlike warfarin, which reduces the functional levels of factors II (prothrombin), VII, IX, and X, these novel agents are directed against the active site of factor Xa or thrombin, the enzymes responsible for thrombin generation and fibrin formation, respectively (see the Figure). Rivaroxaban and apixaban target factor Xa, whereas dabigatran etexilate inhibits thrombin. Comparison of Warfarin to New Oral Anticoagulants in Advanced Stages of Clinical DevelopmentDrugTargetDosingCoagulation MonitoringHalf-Life, hRenal Clearance, %InteractionsIndicationsAF indicates atrial fibrillation.*Includes ketoconazole, macrolides (eg, clarithromycin), and protease inhibitors (eg, atanazavir).†Moderately reduces absorption.RivaroxabanFactor XaFixed, once dailyNo965Potent CYP3A4 inhibitors*VTE prevention and treatment, stroke prevention in AF, acute coronary syndromesApixabanFactor XaFixed, twice dailyNo9–1425Potent CYP3A4 inhibitors*VTE prevention and treatment, stroke prevention in AF, acute coronary syndromesDabigatran etexilateFactor IIa (thrombin)Fixed, twice dailyNo14–17100Proton pump inhibitors†VTE prevention and treatment, stroke prevention in AF, acute coronary syndromesWarfarinVitamin K epoxide reductaseVariable, once dailyYes400Multiple drugs, dietary vitamin KVTE prevention and treatment, stroke prevention in AF, secondary prevention after myocardial infarction, mechanical heart valvesDownload figureDownload PowerPointTargets of new oral anticoagulant drugs. Oral factor Xa inhibitors (rivaroxaban, apixaban) bind directly to factor Xa and prevent thrombin generation. Dabigatran etexilate, an orally active direct thrombin inhibitor, undergoes metabolic activation to dabigatran, which binds to the active site of thrombin (factor IIa) and blocks its capacity to convert fibrinogen to fibrin, to activate platelets, and to amplify its own generation by activating factors V, VIII, and XI. By blocking the active site of thrombin, dabigatran also blocks the activation of protein C and thrombin-activatable fibrinolysis inhibitor by the thrombin/thrombomodulin complex. TF indicates tissue factor.Rivaroxaban is a small molecule directed against the active site of factor Xa. After oral administration, it is absorbed in the stomach and small intestine with a bioavailability of 60% to 80%. Peak plasma levels are achieved in 3 hours, and the drug circulates with a half-life of 9 hours. Rivaroxaban is cleared via 2 pathways: ≈65% is excreted unchanged in the urine, and the remainder is eliminated through the biliary/fecal route. Because of the predominance of the renal pathway of excretion, the half-life of rivaroxaban is prolonged in the elderly and in patients with renal impairment.3 Apixaban has properties similar to those of rivaroxaban except that the clearance of apixaban is mainly via the biliary/fecal route. Therefore, apixaban is less likely to accumulate in patients with renal insufficiency than is rivaroxaban.4As direct inhibitors of factor Xa, rivaroxaban and apixaban inactivate free factor Xa and factor Xa incorporated within the prothrombinase complex equally well. In contrast, indirect factor Xa inhibitors such as fondaparinux have reduced capacity to inhibit factor Xa when it is incorporated within the prothrombinase complex. Whether inhibition of platelet-bound factor Xa endows direct factor Xa inhibitors with an advantage over indirect inhibitors remains to be established.The clinical development of rivaroxaban is more advanced than that of apixaban.3 Favorable early results with rivaroxaban for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery5–7 prompted its recent evaluation in phase II clinical trials for the treatment of patients with acute symptomatic VTE. In the present issue of Circulation, Agnelli and colleagues8 report the results of the Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis (ODIXa-DVT) study, a phase II randomized trial of rivaroxaban for the treatment of DVT. In that trial, 613 patients with symptomatic proximal DVT who did not have pulmonary embolism were randomized to receive fixed-dose oral rivaroxaban (at doses of 10, 20, or 30 mg twice daily or 40 mg once daily) or subcutaneous enoxaparin (at a dose of 1 mg/kg twice daily), followed by a VKA. Allocation to rivaroxaban or enoxaparin/VKA treatment was open label, but patients and investigators were blinded to the dose of rivaroxaban, and all outcomes were adjudicated centrally without knowledge of treatment allocation. The primary efficacy outcome was improvement in thrombotic burden (assessed by repeating the compression ultrasound and comparing the test results with those done at baseline) without recurrent symptomatic VTE or VTE-related death. The primary efficacy outcome occurred in 44% to 59% of patients receiving rivaroxaban and in 46% of those randomized to enoxaparin/VKA. There was no indication of a dose–efficacy relationship with rivaroxaban, but the incidence of bleeding (major plus minor) was higher with increasing doses of rivaroxaban, ranging from 5.0% to 11.6%, compared with a rate of 6.3% in patients treated with enoxaparin/VKA. Symptomatic VTE or death occurred in 2.1% of patients treated with rivaroxaban and in 0.9% of those given enoxaparin/VKA.The ODIXa-DVT study is one of a pair of phase II trials evaluating the efficacy and safety of rivaroxaban for the treatment of DVT. Its companion study, the as-yet unpublished EINSTEIN-DVT trial,9 was of similar design but compared once-daily rivaroxaban (in doses of 20, 30, or 40 mg) with a heparin (either unfractionated heparin or low-molecular-weight heparin), followed by a VKA, in 543 patients with symptomatic DVT without associated symptomatic pulmonary embolism. The primary efficacy outcome was deterioration in thrombotic burden (assessed by repeating the compression ultrasound and perfusion lung scan at 12 weeks and comparing the results with those obtained at baseline) or symptomatic recurrent VTE. This outcome occurred in 5.4% to 6.6% of patients randomized to rivaroxaban and in 9.9% of those given heparin/VKA. Again, there was no evidence of a dose–efficacy relationship with rivaroxaban, but in contrast to the results of the ODIXa-DVT trial, there was no dose response for bleeding. Clinically relevant bleeding occurred in 2.9% to 7.5% of patients randomized to rivaroxaban and in 8.8% of those treated with heparin/VKA.The lack of a dose–efficacy response for rivaroxaban in the ODIXa-DVT trial, which evaluated total daily rivaroxaban doses ranging from 20 to 60 mg, and in the EINSTEIN-DVT trial,9 which examined daily doses ranging from 20 to 40 mg, suggests that there is a plateau for efficacy in this dose range. The significant dose relationship for bleeding with twice-daily administration, but not with once-daily dosing, raises the possibility that dose frequency might influence bleeding risk independently of dose intensity. This could occur if the sustained drug levels achieved with twice-daily dosing confer a greater bleeding risk than the high peak levels obtained with once-daily drug administration. However, comparison across these trials is potentially confounded by differences in the comparators, cointerventions, and outcome definitions. In the ODIXa-DVT trial, the major bleeding rates with 40 mg rivaroxaban once daily or 20 mg twice daily were both 1.7%, whereas the minor bleeding rates were 9.9% and 7.7% with once-daily and twice-daily dosing, respectively. These findings suggest that if dose frequency does influence the bleeding risk, its effect is likely to be minor.The results of the ODIXa-DVT and EINSTEIN-DVT trials provide proof of principle for the efficacy and safety of rivaroxaban for the treatment of DVT. On the basis of these trials, the 20-mg once-daily dose of rivaroxaban has been chosen for evaluation in phase III randomized trials of rivaroxaban for the treatment of VTE and for the prevention of stroke in atrial fibrillation.3 However, has the optimal dose been identified in these phase II trials? The lack of a dose–efficacy response with daily rivaroxaban doses ranging from 20 to 60 mg suggests that lower doses also may be effective. For example, it is possible that the 10-mg once-daily dose that is currently being evaluated in phase III studies for the prevention of VTE in major orthopedic surgery3 would maintain efficacy for treatment of VTE while reducing the risk of bleeding. Support for the concept that lower anticoagulant doses may reduce bleeding without compromising antithrombotic efficacy is provided by the results of the Organization to Assess Strategies for Ischemic Syndromes 5 (OASIS-5) trial.10 In this study, the dose of fondaparinux used for VTE prophylaxis11 was as effective as conventional treatment doses of enoxaparin at preventing recurrent ischemia in patients with non–ST-elevation acute coronary syndromes. However, this low-dose fondaparinux regimen was associated with a 50% reduction in the risk of major and minor bleeding. These observations raise the possibility that more work should be done to determine the optimal dose of rivaroxaban to carry forward into the phase III program.The composite primary efficacy outcomes in the ODIXa-DVT and EINSTEIN-DVT trials were driven primarily by changes in thrombotic burden as assessed by repeated compression ultrasonography and perfusion lung scanning. Previous studies have shown that venographic assessment of thrombus burden using the Marder score is a valid surrogate for recurrent DVT.12 Compression ultrasonography has largely replaced venography because compression ultrasonography is noninvasive and obviates the need for injection of contrast dye. In the ODIXa-DVT trial, changes in compression ultrasound findings were quantified with an adapted Marder score. Although this is a logical approach, such an ultrasound scoring system has never been directly compared with its venographic counterpart. Nonetheless, assessment of thrombus burden with repeated compression ultrasound examinations has been used successfully in phase II dose-finding studies with other anticoagulants.13,14Unexpected hepatotoxicity during recent randomized evaluation of ximelagatran, the first oral direct thrombin inhibitor, has prompted intense scrutiny of the potential hepatic side effects of new oral anticoagulants, including rivaroxaban. During the first 3 weeks of treatment in the ODIXa-DVT trial, the incidence of alanine aminotransferase elevations >3 times the upper limit of normal was significantly lower in patients treated with rivaroxaban than it was in those given enoxaparin/VKA. This is not surprising because enoxaparin is known to transiently increase the levels of transaminases. After 3 weeks, the incidences of alanine aminotransferase elevations were low with both treatments. No patients in the enoxaparin/VKA group stopped treatment because of elevated liver enzymes, whereas 3 patients stopped treatment early in the rivaroxaban group, 2 of whom died soon thereafter of unrelated hepatic causes (metastatic malignancy and acute hepatitis B, respectively). There has been no suggestion of adverse hepatic effects with rivaroxaban in phase II trials for VTE prevention,5–7 but more long-term data are needed.While the studies with rivaroxaban are well underway, apixaban and dabigatran etexilate are being evaluated in parallel development programs. Building on data from phase II trials for the prevention and treatment of VTE, apixaban has entered phase III evaluation for the prevention of VTE after major orthopedic surgery, for VTE prevention in medical patients, and for stroke prevention in atrial fibrillation. In contrast to rivaroxaban, a twice-daily regimen is being evaluated for these indications.Of the new oral anticoagulants, dabigatran etexilate is the drug in the most advanced stages of development. An oral direct thrombin inhibitor, dabigatran etexilate is a double prodrug that undergoes esterase-mediated conversion to dabigatran, a small molecule that targets the active site of thrombin. A phase III trial comparing 2 different doses of once-daily oral dabigatran etexilate with subcutaneous dalteparin for VTE prophylaxis after knee replacement surgery revealed similar efficacy and safety.15 Other phase III orthopedic trials have been completed, and phase III studies evaluating dabigatran etexilate for VTE treatment and for stroke prevention in atrial fibrillation are ongoing.Which is the better target, factor Xa or thrombin? Head-to-head trials of oral direct factor Xa and thrombin inhibitors are needed to address this question. Nonetheless, with the results of these clinical trials beginning to unfold, we are coming closer to finding a safer and more convenient replacement for warfarin.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.DisclosuresDr Weitz is a consultant for Bayer and served as a member of the independent central adjudication committee for ODIXa-DVT. Dr Eikelboom has received consulting fees and/or research funding from companies that are developing new anticoagulants (Bristol-Myers Squibb, Boehringer Ingelheim, Johnson & Johnson, Pfizer, and Sanofi-Aventis).FootnotesCorrespondence to Dr Jeffrey Weitz, Henderson Research Centre, 711 Concession St, Hamilton, Ontario, L8V 1C3, Canada. E-mail [email protected] References 1 Hirsh J. Oral anticoagulant drugs. N Engl J Med. 1991; 324: 1865–1875.CrossrefMedlineGoogle Scholar2 Bates SM, Weitz JI. The status of new anticoagulants. Br J Haematol. 2006; 134: 3–19.CrossrefMedlineGoogle Scholar3 Weitz JI. Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost. 2006; 96: 274–284.CrossrefMedlineGoogle Scholar4 Turpie AG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007; 27: 1238–1247.LinkGoogle Scholar5 Turpie AG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kalebo P, Misselwitz F, Gent M, for the ODIXa-Knee Study Group. BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement: a phase II dose-ranging study. J Thromb Haemost. 2005; 3: 2479–2486.CrossrefMedlineGoogle Scholar6 Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, Misselwitz F, Kalebo P, for the ODIXa-HIP Study Investigators. Oral, direct factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost. 2006; 4: 121–128.CrossrefMedlineGoogle Scholar7 Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, Muehlhofer E, Dierig C, Misselwitz F, Kalebo P, for the ODIXa-HIP Study Investigators. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation. 2006; 114: 2374–2381.LinkGoogle Scholar8 Agnelli G, Gallus A, Goldhaber SZ, Haas S, Huisman MV, Hull RD, Kakkar AK, Misselwitz F, Schellong S, for the ODIXa-DVT Study Investigators. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation. 2007; 116: 180–187.LinkGoogle Scholar9 Buller HR, for the EISTEIN-DVT Study Group. Once daily treatment with an oral, direct factor Xa inhibitor—rivaroxaban (BAY 59-7939)—in patients with acute, symptomatic deep vein thrombosis: the EINSTEIN-DVT dose-ranging study. Eur Heart J. 2006; 27: 761. Abstract.CrossrefMedlineGoogle Scholar10 Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, Budaj A, Peters RJ, Bassand JP, Wallentin L, Joyner C, Fox KA, for the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006; 354: 1464–1476.CrossrefMedlineGoogle Scholar11 Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002; 162: 1833–1840.CrossrefMedlineGoogle Scholar12 Hull RD, Marder VJ, Mah AF, Biel RK, Brant RF. Quantitative assessment of thrombus burden predicts the outcome of treatment for venous thrombosis: a systematic review. Am J Med. 2005; 118: 456–464.CrossrefMedlineGoogle Scholar13 Rembrandt Investigators. Treatment of proximal deep vein thrombosis with a novel synthetic compound (SR90107A/ORG31540) with pure anti-factor Xa activity: a phase II evaluation. Circulation. 2000; 102: 2726–2731.CrossrefMedlineGoogle Scholar14 PERSIST Investigators. A novel long-acting synthetic factor Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis: a phase II evaluation. J Thromb Haemost. 2004; 2: 47–53.CrossrefMedlineGoogle Scholar15 Eriksson BI, Dahl OE, van Dijk CN, Frostick SP, Kurth AA, Rosencher N, Schnee J, Hettiarachchi R, Christiansen AY, Hantel S, Büller HR. A new oral anticoagulant, dabigatran etexilate, is effective and safe in preventing venous thromboembolism after total knee replacement surgery (the RE-MODEL Trial). Blood. 2006; 108: 573. Abstract.CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bauersachs R (2016) Non-vitamin K antagonist oral anticoagulants for the prevention of recurrent venous thromboembolism, Thrombosis Research, 10.1016/j.thromres.2016.05.022, 144, (12-20), Online publication date: 1-Aug-2016. Ogata K, Shimizu T, Masumoto H, Oguma T, Sugiyama N and Kunitada S (2015) Clinical Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Novel Factor Xa Inhibitor DY-807f in Healthy Volunteers, Thrombosis Research, 10.1016/j.thromres.2014.12.028, 135:4, (594-601), Online publication date: 1-Apr-2015. Bollati M, Moretti C, Sciuto F, Omedè P, Marra W, Morello M, Grimaldi R, Rabbia C, Zoccai G and Sheiban I (2015) Postpartum valve thrombosis, Journal of Cardiovascular Medicine, 10.2459/JCM.0b013e328341033d, 16, (S49-S50), Online publication date: 1-Jan-2015. Eriksson B, Agnelli G, Gallus A, Lassen M, Prins M, Renfurm R, Kashiwa M and Turpie A (2017) Darexaban (YM150) versus enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a randomised phase IIb dose confirmation study (ONYX-3), Thrombosis and Haemostasis, 10.1160/TH13-04-0296, 111:02, (213-225), . Groenendaal D, Strabach G, Garcia-Hernandez A, Kadokura T, Heeringa M, Mol R, Eltink C and Onkels H (2013) The pharmacokinetics of darexaban are not affected to a clinically relevant degree by rifampicin, a strong inducer of P-glycoprotein and CYP3A4, British Journal of Clinical Pharmacology, 10.1111/j.1365-2125.2012.04346.x, 75:2, (440-449), Online publication date: 1-Feb-2013. Obonska K, Navarese E, Lansky A, Tarantini G, Rossini R, Kozinski M, Musumeci G, Di Pasquale G, Górny B, Szczesniak A, Kowalewski M, Gurbel P and Kubica J (2013) Low-dose of oral factor Xa inhibitors in patients with a recent acute coronary syndrome: A systematic review and meta-analysis of randomized trials, Atherosclerosis, 10.1016/j.atherosclerosis.2013.04.022, 229:2, (482-488), Online publication date: 1-Aug-2013. Wilkinson P (2012) New oral anticoagulants: an alternative to warfarin, British Journal of Hospital Medicine, 10.12968/hmed.2012.73.9.498, 73:9, (498-501), Online publication date: 1-Sep-2012. Deitelzweig S, Lin J and Lin G (2011) Preventing Venous Thromboembolism Following Orthopedic Surgery in the United States, Clinical and Applied Thrombosis/Hemostasis, 10.1177/1076029611404215, 17:6, (640-650), Online publication date: 1-Nov-2011. Steg P, Mehta S, Jukema J, Lip G, Gibson C, Kovar F, Kala P, Garcia-Hernandez A, Renfurm R and Granger C (2011) RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome, European Heart Journal, 10.1093/eurheartj/ehr334, 32:20, (2541-2554), Online publication date: 1-Oct-2011., Online publication date: 1-Oct-2011. Huo M (2017) New oral anticoagulants in venous thromboembolism prophylaxis in orthopaedic patients: Are they really better?, Thrombosis and Haemostasis, 10.1160/TH10-10-0653, 106:07, (45-57), . Eikelboom J, O'Donnell M, Yusuf S, Diaz R, Flaker G, Hart R, Hohnloser S, Joyner C, Lawrence J, Pais P, Pogue J, Synhorst D and Connolly S (2010) Rationale and design of AVERROES: Apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment, American Heart Journal, 10.1016/j.ahj.2009.08.026, 159:3, (348-353.e1), Online publication date: 1-Mar-2010. Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M and Kunitada S (2013) Clinical Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Factor Xa Inhibitor Edoxaban in Healthy Volunteers, The Journal of Clinical Pharmacology, 10.1177/0091270009351883, 50:7, (743-753), Online publication date: 1-Jul-2010. Halley C and Klein A (2010) Antithrombotic Therapy for Atrial Fibrillation and Cardioversion Antithrombotic Drug Therapy in Cardiovascular Disease, 10.1007/978-1-60327-235-3_20, (389-403), . Torella M, Torella D, Chiodini P, Franciulli M, Romano G, De Santo L, De Feo M, Amarelli C, Sasso F, Salvatore T, Ellison G, Indolfi C, Cotrufo M and Nappi G (2010) LOWERing the INtensity of oral anticoaGulant Therapy in patients with bileaflet mechanical aortic valve replacement: Results from the “LOWERING-IT” Trial, American Heart Journal, 10.1016/j.ahj.2010.05.005, 160:1, (171-178), Online publication date: 1-Jul-2010. Maegdefessel L, Linde T, Krapiec F, Hamilton K, Steinseifer U, van Ryn J, Raaz U, Buerke M, Werdan K and Schlitt A (2010) In vitro comparison of dabigatran, unfractionated heparin, and low-molecular-weight heparin in preventing thrombus formation on mechanical heart valves, Thrombosis Research, 10.1016/j.thromres.2010.06.011, 126:3, (e196-e200), Online publication date: 1-Sep-2010. Levy J and Azran M (2010) Anesthetic concerns for patients with coagulopathy, Current Opinion in Anaesthesiology, 10.1097/ACO.0b013e328339480a, 23:3, (400-405), Online publication date: 1-Jun-2010. Turpie A (2009) Thromboprophylaxis After Major Orthopaedic Surgery: State of the Art European Instructional Lectures, 10.1007/978-3-642-00966-2_4, (29-38), . Hlinomaz O (2009) Antithrombotic therapy after acute myocardial infarction, Cor et Vasa, 10.33678/cor.2009.028, 51:2, (112-117), Online publication date: 1-Feb-2009. Hughes S and Messerly S (2009) Progress in Prevention, Journal of Cardiovascular Nursing, 10.1097/JCN.0b013e318197b5c5, 24:2, (171-173), Online publication date: 1-Mar-2009. Stewart R (2009) Clinical trials in heart valve disease, Current Opinion in Cardiology, 10.1097/HCO.0b013e32832b40e1, 24:4, (279-287), Online publication date: 1-Jul-2009. Eikelboom J and Weitz J (2008) Selective factor Xa inhibition for thromboprophylaxis, The Lancet, 10.1016/S0140-6736(08)60879-X, 372:9632, (6-8), Online publication date: 1-Jul-2008. Janjigian M and Muhs B (2008) Current Treatment of Acute Lower Extremity Deep Venous Thrombosis, The International Journal of Lower Extremity Wounds, 10.1177/1534734608314566, 7:1, (15-20), Online publication date: 1-Mar-2008. Harenberg J (2008) Indirect and direct anticoagulants predominantly inhibiting factor Xa, Therapy, 10.2217/14750708.5.2.177, 5:2, (177-192), Online publication date: 1-Mar-2008. July 10, 2007Vol 116, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.107.712349PMID: 17576860 Originally publishedJune 18, 2007 KeywordsanticoagulantsEditorialsthrombosisPDF download Advertisement SubjectsAnticoagulantsPlatelets

Therapeutic Doses of Acetaminophen Frequently Cause Elevated Aminotransferases in Healthy Volunteers: Is it Significant?

Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC (Department of Medicine, University of North Carolina, Chapel Hill). Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006;296:87–93.Acetaminophen (N-acetyl-para-aminophenol [APAP]) is commonly used for its analgesic and antipyretic properties. Acetaminophen is relatively devoid of side effects at therapeutic doses, and lacks significant gastric irritant or antiplatelet effects, which have historically been associated with aspirin and other NSAIDs. Acetaminophen is available as a single agent or in combination with other medications like opioids and antihistamines. The analgesic ladder proposed by the cancer unit of the World Health Organization recommends that APAP can be combined with adjuvant analgesic or opioids to provide adequate pain relief (AHCPR Pub. No. 92-0032. Rockville, MD; 1992). This has led to the availability of numerous opioids and acetaminophen combination preparations in the United States.Although APAP has a clear safety record when used within the maximum recommended daily dose of 4 g in adults, acetaminophen-induced acute liver failure has long been recognized in the United Kingdom as a common etiology for acute hepatic failure for more than 30 years (Gut 1975;16:144–149). Prospective data obtained over a 6-year period by the United States observed that APAP overdose was the most common (42%) cause of acute liver failure (Hepatology 2005;42:1364–1372). Unintentional overdoses accounted for 48% of the cases occurring likely due to failure to comply with dosing limitation or lack of realization that APAP was part of different proprietary preparations. The majority of the unintentional cases in this study occurred when using a narcotic combination excessively for several days before the onset of liver injury, suggesting an addiction to the narcotic component. Several researchers thus have questioned the rationale of combining a highly addictive drug (opiate) with a dose-dependent hepatotoxin (acetaminophen; Hepatology 2004;40:1021–1022; Hepatology 2004;40:6–9; Hepatology 2004;40:23–26).Pooled data from 7 studies composed of 1,039 patient receiving APAP for osteoarthritis for a range of 4 weeks to 12 months was evaluated. Serum alanine aminotransferase (ALT) levels were measured at baseline and after initiating the therapy showed that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). None of the patients had ALT >3 times the upper limit of normal (ULN) while on APAP. Few cases of hepatotoxicity occurring with therapeutic doses of APAP have been reported with or without the presence of risk factors such as chronic alcohol, tobacco, opiate consumption, malnutrition, illness-induced starvation, HIV infection, and HCV infection (Clin Ther 2006;28:755–760; J Intern Med 2003;253:240–243; J Intern Med 2003;253:95–98).Watkins et al performed a randomized, parallel-group, placebo-controlled longitudinal study where 145 healthy adults were blinded to receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids or placebo. They characterized the incidence and magnitude of liver test elevations and compared them with participants treated with placebo. All participants stayed in house at the research facility for the entire duration of the study, and received the same standardized, whole food meals. To our knowledge, this is the first study that systematically looked at (1) the incidence and magnitude of liver tests abnormalities during the administration of therapeutic doses of acetaminophen and (2) the role of concomitant administration of opioids in acetaminophen toxicity.Participants in the study were healthy volunteers aged 18–45 years and not on concomitant medications. All patients underwent screening physical examination and comprehensive blood work that included hepatitis B surface antigen and hepatitis C antibody. They were then randomized to receive 1 of the 5 treatment regimens and administered medication orally every 6 hours for up to 14 days. The protocol required discontinuation of treatment for any participant with ALT or aspartate aminotransferase (AST) concentrations >120 U/L (3 times the ULN). The specific treatment regimens were as follows.•Treatment 1: Percocet, 2 tablets (7.5 mg of oxycodone/500 mg of APAP) plus 2 placebo tablets;•Treatment 2: Dilaudid, 2 tablets (2 mg of hydromorphone) plus Extra Strength Tylenol, 2 caplets (500 mg of APAP);•Treatment 3: Two morphine tablets (15 mg), plus Extra Strength Tylenol, 2 caplets (500 mg of APAP);•Treatment 4: Two placebo tablets plus Extra Strength Tylenol, 2 caplets (500 mg of APAP); and•Treatment 5: Two placebo tablets plus 2 placebo tablets.Routine liver tests (bilirubin, AST, ALT, and alkaline phosphatase) and serum α-glutathione S-transferase (α-GST), a measure of hepatocellular injury, were measured daily through day 8. After day 8, chemistries were measured on alternate days or daily in participants with any liver test elevations. Monitoring for adverse events was performed during the study period, and plasma APAP concentrations were measured daily in all participants at morning trough as well as over a single 6-hour dosing interval on day 3 of therapy (48–54 hours on therapy). The participants’ APAP concentration time series was then used to estimate the area under the concentration curve (AUC at 48–54 hours) and time to peak concentration (at 48–54 hours). Adverse events were monitored during the entire study period.All treatment groups had similar baseline demographic characteristics, including body mass index. Although only 1 of 39 participant (3%) taking placebo experienced ALT >2 times ULN at any time during the study, no placebo participants experienced ALT >3 times ULN. In contrast, >19% of participants experienced ALT >5 times ULN in each of the 4 active treatment groups. It is likely that the subjects with higher baseline may have had higher ALT levels; however, a similar pattern of ALT elevations by treatment is noted when participants’ peak ALT elevations were normalized by their baseline ALT values. The incidence of ALT elevations >3 times ULN, >5 times ULN, and >8 times ULN were 38%, 23%, and 4%, respectively, in the group receiving treatment with APAP only. Meaningful differences in the magnitude and incidence of ALT elevations were not detected among the active treatment regimens. The temporal pattern of ALT elevations was similar in all the active treatment groups, including the acetaminophen-alone group. Elevation of ALT to >3 times ULN (120 U/L) was not observed before day 3 in any treatment groups. After discontinuation of dosing owing to ALT elevations to >3 times ULN, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times ULN for a median of 6.5 days. The median of peak ALT values for the active treatments were 2.6–3.1 times higher than the placebo value. However, there were no statistically different median of peak ALT values among the active treatment groups. Peak ALT and peak α-GST values were highly correlated and suggestive of hepatocellular injury.AST elevations were generally smaller than those of ALT, but followed a similar time course. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase and all participants with ALT elevations were asymptomatic. The relative risk of maximum ALT >3 times ULN for Hispanic Americans versus non-Hispanic was 1.9 (95% confidence interval, 1.1–3.3). Mean AUC and peak concentration of APAP across all active treatment groups were similar. Although the data was not provided in the study, the authors comment that no difference was detected in mean APAP trough levels, peak concentrations, or AUC between those participants exhibiting ALT elevation and those who did not. The APAP concentrations fell quickly when dosing was stopped and as a result, it was often not detected while ALT remained elevated.CommentThis well-conducted study makes several important observations with regard to frequency, magnitude, and temporal patterns of ALT elevations in APAP alone and APAP/opioid combination groups. It is not very clear why a 2-week duration was chosen for APAP exposure in this study. Some of their findings are not entirely novel. For example, previous osteoporosis trials evaluating the safety of APAP have shown that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). The incidence of ALT elevations >3 times ULN was 38% in the group receiving treatment with APAP only. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase. The authors acknowledge the relatively high incidence of ALT elevations and attribute it to the high proportion of Hispanic subjects in the study. They speculate variability in APAP pharmacokinetics owing to ethnic and racial differences leading to ALT elevations. However striking the ALT elevations may be, elevations in liver enzymes without concurrently elevated serum bilirubin are generally thought to be benign. In contrast, the late Dr Hyman Zimmerman observed that elevations in transaminases in combination with jaundice signal serious liver injury and carry a significant fatality rate. AST and/or ALT >3 times the ULN or alkaline phosphatase >1.5 times the ULN in combination with an elevated bilirubin (>3 times the ULN) at any time after starting a new drug indicates serious liver injury carrying >10% mortality rate (Hy’s law). Thus, it is not likely that isolated elevations in aminotransferases observed in this study are of any clinical significance. Although the authors acknowledge that these aminotransferase elevations may have resolved with continued administration of APAP (adaptation), study protocol required discontinuation of treatment when aminotransferases increased >120 U/L (>3 times ULN). Despite wide usage of this cutoff in the drug development, there is nothing magical about it, especially when one considers wide variability in the ULN itself across various clinical laboratories. Because most subjects in this trial do not appear to be routine users of APAP, it is not clear if these data can be extrapolated to patients with chronic exposure.In this study, ALT levels >3 times the ULN were not observed before day 3 in any of the treatment groups. Upon discontinuation of APAP therapy, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times the ULN for 1–11 days (median, 6.5 days). Of note, the APAP concentrations fell quickly when dosing was stopped, and as a result, it was often not detected while ALT remained elevated. It is for this reason that measurement of acetaminophen–protein adducts holds a promising role in the diagnostic evaluation of patients with acute liver failure of unclear etiology (Gastroenterology 2006;130:687–694). If sera are available from this study, measuring acetaminophen–protein adducts may provide an opportunity to examine if isolated ALT elevations in this setting reflect gross hepatocellular damage. Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC (Department of Medicine, University of North Carolina, Chapel Hill). Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006;296:87–93. Acetaminophen (N-acetyl-para-aminophenol [APAP]) is commonly used for its analgesic and antipyretic properties. Acetaminophen is relatively devoid of side effects at therapeutic doses, and lacks significant gastric irritant or antiplatelet effects, which have historically been associated with aspirin and other NSAIDs. Acetaminophen is available as a single agent or in combination with other medications like opioids and antihistamines. The analgesic ladder proposed by the cancer unit of the World Health Organization recommends that APAP can be combined with adjuvant analgesic or opioids to provide adequate pain relief (AHCPR Pub. No. 92-0032. Rockville, MD; 1992). This has led to the availability of numerous opioids and acetaminophen combination preparations in the United States. Although APAP has a clear safety record when used within the maximum recommended daily dose of 4 g in adults, acetaminophen-induced acute liver failure has long been recognized in the United Kingdom as a common etiology for acute hepatic failure for more than 30 years (Gut 1975;16:144–149). Prospective data obtained over a 6-year period by the United States observed that APAP overdose was the most common (42%) cause of acute liver failure (Hepatology 2005;42:1364–1372). Unintentional overdoses accounted for 48% of the cases occurring likely due to failure to comply with dosing limitation or lack of realization that APAP was part of different proprietary preparations. The majority of the unintentional cases in this study occurred when using a narcotic combination excessively for several days before the onset of liver injury, suggesting an addiction to the narcotic component. Several researchers thus have questioned the rationale of combining a highly addictive drug (opiate) with a dose-dependent hepatotoxin (acetaminophen; Hepatology 2004;40:1021–1022; Hepatology 2004;40:6–9; Hepatology 2004;40:23–26). Pooled data from 7 studies composed of 1,039 patient receiving APAP for osteoarthritis for a range of 4 weeks to 12 months was evaluated. Serum alanine aminotransferase (ALT) levels were measured at baseline and after initiating the therapy showed that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). None of the patients had ALT >3 times the upper limit of normal (ULN) while on APAP. Few cases of hepatotoxicity occurring with therapeutic doses of APAP have been reported with or without the presence of risk factors such as chronic alcohol, tobacco, opiate consumption, malnutrition, illness-induced starvation, HIV infection, and HCV infection (Clin Ther 2006;28:755–760; J Intern Med 2003;253:240–243; J Intern Med 2003;253:95–98). Watkins et al performed a randomized, parallel-group, placebo-controlled longitudinal study where 145 healthy adults were blinded to receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids or placebo. They characterized the incidence and magnitude of liver test elevations and compared them with participants treated with placebo. All participants stayed in house at the research facility for the entire duration of the study, and received the same standardized, whole food meals. To our knowledge, this is the first study that systematically looked at (1) the incidence and magnitude of liver tests abnormalities during the administration of therapeutic doses of acetaminophen and (2) the role of concomitant administration of opioids in acetaminophen toxicity. Participants in the study were healthy volunteers aged 18–45 years and not on concomitant medications. All patients underwent screening physical examination and comprehensive blood work that included hepatitis B surface antigen and hepatitis C antibody. They were then randomized to receive 1 of the 5 treatment regimens and administered medication orally every 6 hours for up to 14 days. The protocol required discontinuation of treatment for any participant with ALT or aspartate aminotransferase (AST) concentrations >120 U/L (3 times the ULN). The specific treatment regimens were as follows.•Treatment 1: Percocet, 2 tablets (7.5 mg of oxycodone/500 mg of APAP) plus 2 placebo tablets;•Treatment 2: Dilaudid, 2 tablets (2 mg of hydromorphone) plus Extra Strength Tylenol, 2 caplets (500 mg of APAP);•Treatment 3: Two morphine tablets (15 mg), plus Extra Strength Tylenol, 2 caplets (500 mg of APAP);•Treatment 4: Two placebo tablets plus Extra Strength Tylenol, 2 caplets (500 mg of APAP); and•Treatment 5: Two placebo tablets plus 2 placebo tablets. Routine liver tests (bilirubin, AST, ALT, and alkaline phosphatase) and serum α-glutathione S-transferase (α-GST), a measure of hepatocellular injury, were measured daily through day 8. After day 8, chemistries were measured on alternate days or daily in participants with any liver test elevations. Monitoring for adverse events was performed during the study period, and plasma APAP concentrations were measured daily in all participants at morning trough as well as over a single 6-hour dosing interval on day 3 of therapy (48–54 hours on therapy). The participants’ APAP concentration time series was then used to estimate the area under the concentration curve (AUC at 48–54 hours) and time to peak concentration (at 48–54 hours). Adverse events were monitored during the entire study period. All treatment groups had similar baseline demographic characteristics, including body mass index. Although only 1 of 39 participant (3%) taking placebo experienced ALT >2 times ULN at any time during the study, no placebo participants experienced ALT >3 times ULN. In contrast, >19% of participants experienced ALT >5 times ULN in each of the 4 active treatment groups. It is likely that the subjects with higher baseline may have had higher ALT levels; however, a similar pattern of ALT elevations by treatment is noted when participants’ peak ALT elevations were normalized by their baseline ALT values. The incidence of ALT elevations >3 times ULN, >5 times ULN, and >8 times ULN were 38%, 23%, and 4%, respectively, in the group receiving treatment with APAP only. Meaningful differences in the magnitude and incidence of ALT elevations were not detected among the active treatment regimens. The temporal pattern of ALT elevations was similar in all the active treatment groups, including the acetaminophen-alone group. Elevation of ALT to >3 times ULN (120 U/L) was not observed before day 3 in any treatment groups. After discontinuation of dosing owing to ALT elevations to >3 times ULN, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times ULN for a median of 6.5 days. The median of peak ALT values for the active treatments were 2.6–3.1 times higher than the placebo value. However, there were no statistically different median of peak ALT values among the active treatment groups. Peak ALT and peak α-GST values were highly correlated and suggestive of hepatocellular injury. AST elevations were generally smaller than those of ALT, but followed a similar time course. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase and all participants with ALT elevations were asymptomatic. The relative risk of maximum ALT >3 times ULN for Hispanic Americans versus non-Hispanic was 1.9 (95% confidence interval, 1.1–3.3). Mean AUC and peak concentration of APAP across all active treatment groups were similar. Although the data was not provided in the study, the authors comment that no difference was detected in mean APAP trough levels, peak concentrations, or AUC between those participants exhibiting ALT elevation and those who did not. The APAP concentrations fell quickly when dosing was stopped and as a result, it was often not detected while ALT remained elevated. CommentThis well-conducted study makes several important observations with regard to frequency, magnitude, and temporal patterns of ALT elevations in APAP alone and APAP/opioid combination groups. It is not very clear why a 2-week duration was chosen for APAP exposure in this study. Some of their findings are not entirely novel. For example, previous osteoporosis trials evaluating the safety of APAP have shown that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). The incidence of ALT elevations >3 times ULN was 38% in the group receiving treatment with APAP only. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase. The authors acknowledge the relatively high incidence of ALT elevations and attribute it to the high proportion of Hispanic subjects in the study. They speculate variability in APAP pharmacokinetics owing to ethnic and racial differences leading to ALT elevations. However striking the ALT elevations may be, elevations in liver enzymes without concurrently elevated serum bilirubin are generally thought to be benign. In contrast, the late Dr Hyman Zimmerman observed that elevations in transaminases in combination with jaundice signal serious liver injury and carry a significant fatality rate. AST and/or ALT >3 times the ULN or alkaline phosphatase >1.5 times the ULN in combination with an elevated bilirubin (>3 times the ULN) at any time after starting a new drug indicates serious liver injury carrying >10% mortality rate (Hy’s law). Thus, it is not likely that isolated elevations in aminotransferases observed in this study are of any clinical significance. Although the authors acknowledge that these aminotransferase elevations may have resolved with continued administration of APAP (adaptation), study protocol required discontinuation of treatment when aminotransferases increased >120 U/L (>3 times ULN). Despite wide usage of this cutoff in the drug development, there is nothing magical about it, especially when one considers wide variability in the ULN itself across various clinical laboratories. Because most subjects in this trial do not appear to be routine users of APAP, it is not clear if these data can be extrapolated to patients with chronic exposure.In this study, ALT levels >3 times the ULN were not observed before day 3 in any of the treatment groups. Upon discontinuation of APAP therapy, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times the ULN for 1–11 days (median, 6.5 days). Of note, the APAP concentrations fell quickly when dosing was stopped, and as a result, it was often not detected while ALT remained elevated. It is for this reason that measurement of acetaminophen–protein adducts holds a promising role in the diagnostic evaluation of patients with acute liver failure of unclear etiology (Gastroenterology 2006;130:687–694). If sera are available from this study, measuring acetaminophen–protein adducts may provide an opportunity to examine if isolated ALT elevations in this setting reflect gross hepatocellular damage. This well-conducted study makes several important observations with regard to frequency, magnitude, and temporal patterns of ALT elevations in APAP alone and APAP/opioid combination groups. It is not very clear why a 2-week duration was chosen for APAP exposure in this study. Some of their findings are not entirely novel. For example, previous osteoporosis trials evaluating the safety of APAP have shown that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). The incidence of ALT elevations >3 times ULN was 38% in the group receiving treatment with APAP only. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase. The authors acknowledge the relatively high incidence of ALT elevations and attribute it to the high proportion of Hispanic subjects in the study. They speculate variability in APAP pharmacokinetics owing to ethnic and racial differences leading to ALT elevations. However striking the ALT elevations may be, elevations in liver enzymes without concurrently elevated serum bilirubin are generally thought to be benign. In contrast, the late Dr Hyman Zimmerman observed that elevations in transaminases in combination with jaundice signal serious liver injury and carry a significant fatality rate. AST and/or ALT >3 times the ULN or alkaline phosphatase >1.5 times the ULN in combination with an elevated bilirubin (>3 times the ULN) at any time after starting a new drug indicates serious liver injury carrying >10% mortality rate (Hy’s law). Thus, it is not likely that isolated elevations in aminotransferases observed in this study are of any clinical significance. Although the authors acknowledge that these aminotransferase elevations may have resolved with continued administration of APAP (adaptation), study protocol required discontinuation of treatment when aminotransferases increased >120 U/L (>3 times ULN). Despite wide usage of this cutoff in the drug development, there is nothing magical about it, especially when one considers wide variability in the ULN itself across various clinical laboratories. Because most subjects in this trial do not appear to be routine users of APAP, it is not clear if these data can be extrapolated to patients with chronic exposure. In this study, ALT levels >3 times the ULN were not observed before day 3 in any of the treatment groups. Upon discontinuation of APAP therapy, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times the ULN for 1–11 days (median, 6.5 days). Of note, the APAP concentrations fell quickly when dosing was stopped, and as a result, it was often not detected while ALT remained elevated. It is for this reason that measurement of acetaminophen–protein adducts holds a promising role in the diagnostic evaluation of patients with acute liver failure of unclear etiology (Gastroenterology 2006;130:687–694). If sera are available from this study, measuring acetaminophen–protein adducts may provide an opportunity to examine if isolated ALT elevations in this setting reflect gross hepatocellular damage.

Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials

ABSTRACTBackground: In two recent osteoarthritis trials, alanine aminotransferase (ALT) elevations were observed more frequently in patients receiving acetaminophen 3.9 g daily than in patients receiving placebo, and the rates were higher than aminotransferase values observed in some previous osteoarthritis studies with acetaminophen.Objective: To retrospectively analyze ALT data from McNeil osteoarthritis clinical studies involving acetaminophen in order to assess the frequency and magnitude of ALT elevations and rate of ALT resolution while patients remained on acetaminophen treatment. A review of the literature revealed a few reports of isolated aminotransferase elevations occurring during acetaminophen therapy, but these reports were not included in the analysis because they did not include enough information to evaluate the frequency, magnitude, and rate of ALT elevations while patients remained on acetaminophen treatment.Research design and methods: Nine controlled clinical trials were identified in which at least one of the treatments was acetaminophen alone. Studies were included if patients had ALT and aspartate aminotransferase (AST) values obtained at baseline and an ALT value at an additional visit after initiating therapy. Seven studies met these criteria and were included in this analysis. In these studies, patients received acetaminophen 1950–4000 mg/day for 4 weeks up to 12 months. Laboratory testing was performed at weeks 0 and 4 in the three 4‐week studies; at weeks 0, 2, 4, 8, and 12 in the two 12‐week studies; at weeks 0, 1, 2, 4, 6, 8, and 13 in the 13‐week study; and at months 0, 1, 3, 6, 9, and 12 in the 12‐month study. The pooled data set consisted of patient demographics, dosing records, aminotransferase and bilirubin laboratory values, and adverse events.Results: There were no reports of hepatotoxicity or hepatic failure in any acetaminophen-treated patient (n = 1530). In the seven studies, 1039 patients had both baseline AST and ALT activity ≤ upper limit of the reference range and an on-treatment ALT measurement. While on long-term acetaminophen treatment, 181 of 1039 (17.4%) patients had an ALT value that exceeded the upper limit of the reference range. None of the 1039 patients had an on-treatment ALT level > 3 times upper limit of the reference range in conjunction with a serum bilirubin > upper limit of the reference range, and no patient had an ALT level > 10 times upper limit of the reference range. Of the 1039 patients, 44 (4.2%) had an on-treatment ALT level > 1.5 times upper limit of the reference range, and 31 of the 44 patients had a subsequent measurement of ALT. Of these 31 patients, 29 (93.5%) had documented resolution or decreasing ALT while on treatment. An ALT level > 1.5 times upper limit of the reference range was not associated with a higher frequency of symptoms potentially related to hepatic origin.Limitations: The studies included in this analysis were limited to McNeil studies, none of which were designed to specifically evaluate the patterns of ALT activity. Thus, the incidence of ALT elevations after any specific duration of dosing, and the temporal pattern of ALT elevations, cannot be accurately determined. In addition, methodological differences existed across the studies.Conclusion: This analysis involving > 1000 acetaminophen-treated patients shows that low-level, transient ALT elevations usually resolve or decrease with continued acetaminophen treatment, are unaccompanied by signs or symptoms of liver injury, and, as such, appear to be clinically insignificant. Maximum recommended daily doses of acetaminophen did not cause liver failure or dysfunction.