Armin Koch

Peginterferon plus Adefovir versus Either Drug Alone for Hepatitis Delta

BACKGROUND Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in the most severe form of viral hepatitis. There is no currently approved treatment. We investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone, and adefovir dipivoxil alone. METHODS We conducted a randomized trial in which 31 patients with HDV infection received treatment with 180 μg of peginterferon alfa-2a weekly plus 10 mg of adefovir daily, 29 received 180 μg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional 24 weeks. Efficacy end points included clearance of HDV RNA, normalization of alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen (HBsAg). RESULTS The primary end point--normalization of alanine aminotransferase levels and clearance of HDV RNA at week 48--was achieved in two patients in the group receiving peginterferon alfa-2a plus adefovir and two patients in the group receiving peginterferon alfa-2a plus placebo but in none of the patients in the group receiving adefovir alone. At week 48, the test for HDV RNA was negative in 23% of patients in the first group, 24% of patients in the second, and none of those in the third (P = 0.006 for the comparison of the first and third groups; P = 0.004 for the comparison of the second and third). The efficacy of peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of the patients receiving peginterferon alfa-2a plus adefovir or peginterferon alfa-2a alone having negative results on HDV-RNA tests; none of the patients receiving adefovir alone had negative results. A decline in HBsAg levels of more than 1 log(10) IU per milliliter from baseline to week 48 was observed in 10 patients in the first group, 2 in the second, and none in the third (P<0.001 for the comparison of the first and third groups and P = 0.01 for the comparison of the first and second). CONCLUSIONS Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustained HDV RNA clearance in about one quarter of patients with HDV infection. (Current Controlled Trials number, ISRCTN83587695.).

Possible Role of Acetaldehyde in Ethanol-Related Rectal Cocarcinogenesis in the Rat

Prospective epidemiologic studies have reported an increased risk of rectal cancer following chronic ethanol ingestion. The effect of ethanol on chemically induced colorectal carcinogenesis is controversial depending on the experimental conditions. In the present study the effect of chronic ethanol administration on acetoxymethylmethylnitrosamine-induced rectal cancer and the possible role of acetaldehyde in this process were investigated. Chronic ethanol administration resulted in an earlier occurrence of rectal tumors in this animal model. Because the concomitant administration of cyanamide, a potent acetaldehyde dehydrogenase inhibitor, showed a positive trend toward increased incidences of tumors, acetaldehyde could be involved in the ethanol-associated carcinogenesis. To measure colonic acetaldehyde, 12 chronically ethanol-fed and control rats received an acute dose of ethanol (2.5 g/kg body wt). The mucosal concentration of acetaldehyde was significantly higher in the rectum compared with the cecum (198 +/- 23 vs. 120 +/- 23 nmoles.g colon-1, p less than 0.05), but was not affected by chronic ethanol feeding. Furthermore, 6 germ-free rats had significantly lower acetaldehyde concentrations in the rectum (84 +/- 11 vs. 234 +/- 33 nmoles.g colon-1, p less than 0.01) and in the cecum (59 +/- 13 vs. 121 +/- 33 nmoles.g colon-1, p less than 0.05) compared with 6 conventional animals, and this was paralleled by the number of fecal bacteria in the 2 intestinal segments. In addition, to determine the effect of chronic ethanol feeding on colorectal cell turnover, 30 animals were pair-fed liquid diets. Using the metaphase-arrest technique, alcohol feeding induced rectal (19.1 +/- 2.0 vs. 9.1 +/- 1.8 cells.crypt-1.h-1, p less than 0.01), but not cecal (18.9 +/- 1.3 vs. 22.2 +/- 3.3 cells.crypt-1.h-1, p greater than 0.05) hyperregeneration. This was accompanied by an increase in the crypt proliferative compartment and increased mucosal ornithine decarboxylase activity (63 +/- 18 vs. 22 +/- 6 pmoles.hr-1.mg protein-1, p less than 0.05). The data show that chronic ethanol ingestion accelerates chemically induced rectal carcinogenesis and raise the possibility that acetaldehyde probably generated through bacterial ethanol oxidation may be involved in this process. The secondary hyperregeneration of the mucosa, observed after alcohol feeding, could by itself favour carcinogenesis.

Personalized medicine using DNA biomarkers: a review

Biomarkers are of increasing importance for personalized medicine, with applications including diagnosis, prognosis, and selection of targeted therapies. Their use is extremely diverse, ranging from pharmacodynamics to treatment monitoring. Following a concise review of terminology, we provide examples and current applications of three broad categories of biomarkers—DNA biomarkers, DNA tumor biomarkers, and other general biomarkers. We outline clinical trial phases for identifying and validating diagnostic and prognostic biomarkers. Predictive biomarkers, more generally termed companion diagnostic tests predict treatment response in terms of efficacy and/or safety. We consider suitability of clinical trial designs for predictive biomarkers, including a detailed discussion of validation study designs, with emphasis on interpretation of study results. We specifically discuss the interpretability of treatment effects if a large set of DNA biomarker profiles is available and the number of therapies is identical to the number of different profiles.

Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis: meta-analysis based on original patient data.

A meta-analysis (MA) based on original patient data has been performed comparing low molecular weight heparins (LMWH) with unfractionated heparin (UFH) in thrombosis prophylaxis after major surgical interventions. The analyses have been done for the following prespecified groups of studies: all studies, studies in orthopaedic surgery (OS) and studies in general surgery (GS, with further separation into low-dose studies [GS-LD] and high-dose studies [GS-HD]). Deep vein thrombosis (DVT, all locations) and wound haematoma were used as primary endpoints for efficacy and safety, respectively. The analysis confirms the results of previous publication-based meta-analyses. In GS there is no relevant difference between LMWH and UFH regarding efficacy; the safety results strongly depend on the dosage: under low-dose LMWH the risk of wound haematoma is significantly lower, under high-dose LMWH it is significantly higher than under UFH. However, most of the studies in the last group used regimens of LMWH that are not considered appropriate any more. In OS there is a trend towards a better efficacy and safety of LMWH. In addition, LMWHs are superior to UFH, in OS, with respect to the secondary endpoints proximal DVT and pulmonary embolism. The rates of proximal DVT and pulmonary embolism, respectively, are consistently lower under LMWH than under UFH, whereas slightly smaller rates of distal DVT are observed under UFH.

Regulation of matrix metalloproteinases and their inhibitors in uterine endometrial cells of patients with and without endometriosis

OBJECTIVE To determine whether alterations in the secretion and regulation of matrix metalloproteinases (MMPs) and their inhibitors are present in uterine endometrial cells from endometriosis patients. STUDY DESIGN In an in vitro study, uterine endometrial cells from 19 regularly cycling women with and 32 without endometriosis were treated with diethyl stilbestrol, promegestone (R5020), interleukin-1 (IL-1) and tumor necrosis factor a (TNF-alpha). Culture supernatants were assayed for MMPs 1, 2, 3, and 9, and for tissue inhibitors of MMP (TIMP-1 and TIMP-2) by ELISA. RESULTS MMP-3 was secreted in high concentrations, moderate concentrations were seen for MMP-1 and MMP-2, and very low concentrations for MMP-9. Substantially more TIMP-1 than TIMP-2 was secreted. MMP-1 and MMP-3 were uniformly attenuated by R5020, while MMP-2 was not influenced by hormone treatment. MMP-3 was upregulated by TNF-alpha in all samples while IL-1 only increased secretion in cells from endometriosis patients. CONCLUSION The upregulation of MMP-3 by IL-1 may contribute to an increased invasiveness of uterine endometrial fragments in endometriosis patients.

Meta-analysis macros for SAS

This paper presents a collection of macros for The SAS System to perform meta-analyses of clinical trials where the results of a single trial can be displayed in a fourfold-table. These macros provide the diagnostic plots most of which can be found in almost every meta-analysis publication (Funnel-Plot, confidence interval plot, Galbraith-Plot, Sensitivity-Plot by Thompson) as well as the computation of the different estimators of the treatment effect along with their summary estimators. Results from a meta-analysis on the comparison of low-molecular weight heparin and standard heparin for the prophylaxis of thromboembolic events are used for illustrative purposes.

Delayed versus immediate treatment for patients with acute hepatitis C: a randomised controlled non-inferiority trial

BACKGROUND Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa monotherapy is very effective, with cure rates of greater than 85%. However, spontaneous clearance of HCV occurs in 10-50% of cases. We aimed to assess an alternative treatment strategy of delayed antiviral therapy in patients who do not eliminate the virus spontaneously compared with immediate treatment. METHODS In our open-label phase 3 non-inferiority trial, we enrolled adults (≥18 years) with acute hepatitis C but no HIV or hepatitis B co-infection at 72 centres in Germany. We randomly allocated patients with symptomatic acute hepatitis C (1:1) to receive immediate pegylated interferon alfa-2b treatment for 24 weeks or delayed treatment with pegylated interferon alfa-2b plus ribavirin (for 24 weeks) starting 12 weeks after randomisation if HCV RNA remained positive. We used a computer-generated randomisation sequence and block sizes of eight, stratified by bilirubin concentration. We assigned all asymptomatic patients to immediate treatment with pegylated interferon alfa-2b for 24 weeks. The primary endpoint was sustained HCV RNA negativity in all randomly allocated participants who completed screening (intention-to-treat analysis), with a non-inferiority margin of 10%. For the primary analysis, we calculated the virological response of patients in the immediate and delayed treatment groups and an absolute risk difference stratified by bilirubin status. The trial was stopped early on advice from the study advisory committee because of slow recruitment of participants. This study is registered, number ISRCTN88729946. FINDINGS Between April, 2004, and February, 2010, we recruited 107 symptomatic and 25 asymptomatic patients. 37 (67%) of 55 symptomatic patients randomly allocated to receive immediate treatment and 28 (54%) of 52 symptomatic patients randomly allocated to receive delayed treatment had a sustained virological response (difference 13·7%, 95% CI -4·6 to 32·0; p=0·071). 18 (72%) of 25 asymptomatic patients had a sustained virological response. 22 (42%) of 52 symptomatic patients allocated to receive delayed treatment did not complete follow-up compared with 20 (25%) of 80 symptomatic or asymptomatic patients assigned immediate treatment (p=0·037). 11 symptomatic patients (21%) assigned delayed treatment had spontaneous HCV clearance. 14 patients who received delayed pegylated interferon alfa-2b plus ribavirin treatment and completed follow-up achieved sustained virological response. INTERPRETATION Delayed treatment is effective although not of equal efficacy to immediate treatment; coupled with the rate of spontaneous clearance it can reduce unnecessary treatment in closely monitored populations. Immediate treatment seems preferable in populations where loss to follow-up is great. FUNDING German Network of Competence on Viral Hepatitis (HepNet, funded by the German Federal Ministry of Education and Research, grants 01KI0102, 01KI0401, and 01KI0601), MSD, Schering-Plough.

Hypothesis testing in the "gold standard" design for proving the efficacy of an experimental treatment relative to placebo and a reference.

Abstract This article reviews the most important reasons to include a placebo and a reference treatment group in a study to investigate the efficacy of a new experimental treatment. We argue that as a general rule the regulatory requirement is the proven superiority of the experimental treatment over placebo and the proven noninferiority of the experimental treatment as compared to the reference treatment. Whether or not the reference treatment can be shown to be superior to placebo may impact the formulation of the indication but should not, per se, question the usefulness of the experimental treatment or the credibility of the principal proof of efficacy. We argue that a mandatory requirement for the reference treatment to be superior to placebo is ill founded and especially difficult to justify in the situation where the experimental treatment can also prove its superiority over the reference treatment. For this latter situation, it is shown that no adjustment for multiple hypothesis testing is needed, if at the same time superiority of the reference over placebo and superiority of the experimental treatment over the reference are investigated.

Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study

Acquired hemophilia A (AHA) is caused by autoantibodies against factor VIII (FVIII). Immunosuppressive treatment (IST) results in remission of disease in 60% to 80% of patients over a period of days to months. IST is associated with frequent adverse events, including infections as a leading cause of death. Predictors of time to remission could help guide IST intensity but have not been established. We analyzed prognostic factors in 102 prospectively enrolled patients treated with a uniform IST protocol. Partial remission (PR; defined as no active bleeding, FVIII restored >50 IU/dL, hemostatic treatment stopped >24 hours) was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with ≥1 IU/dL (89%, 24 days). After adjustment for other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within ≤21 days was more common in patients with FVIII ≥1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival. In conclusion, presenting FVIII and inhibitor concentration are potentially useful to tailor IST in AHA.

Frühbehandlung des akuten Myokardinfarktes: Umsetzung von Therapierichtlinien in den klinischen Alltag, MITRA-Pilotphase

MITRA (Maximale Individuelle TheRapie beim Akuten Myokardinfarkt) ist eine Anwendungsbeobachtung für den stationären und poststationären Verlauf eines nicht selektierten Patientenkollektivs mit akutem transmuralem Infarkt. Es sollen die Praktikabilität, der optimale Einsatz und die Sicherheit einer „individuell optimierten” Infarkttherapie untersucht werden. Zusätzlich soll die Qualität der Infarkttherapie in bezug auf jeden einzelnen Therapiebaustein abgeschätzt werden. An der multizentrischen Studie beteiligen sich fast flächendeckend 54 Kliniken einer umschriebenen Region im Südwesten Deutschlands. In der Pilotphase wurden konsekutiv 1303 Patienten mit akutem transmuralem Infarkt eingeschlossen. Im Median betrug das Alter 66 Jahre, ⅔ waren Männer. Die Prähospitalzeit war 2,7 Stunden, 64% erreichten die Klinik innerhalb der ersten 4 Stunden nach Symptombeginn. Bei 47% bestand ein Vorderwandinfarkt. In den Subgruppen der Patienten, die keine absolute Kontraindikationen hatten, erhielten: 53,4% das Thrombolytikum, 87,6% ASS, 37,1% den Betablocker und 17,4% der Patienten den ACE-Hemmer. In einer gesonderten Betrachtung wurden Patienten als „optimal behandelt” definiert, wenn sie in der Akutphase Thrombolyse, ASS und Betablocker nur dann erhielten, wenn sie absolute Kontraindikationen hatten. Bekamen die Patienten mindestens eines dieser drei Therapeutika nicht, obwohl absolute Kontraindikationen nicht vorlagen, wurden sie als „suboptimal behandelt” klassifiziert. Nur 29% (n = 383) der Patienten wurden „optimal”, während 71% (n = 775) suboptimal behandelt wurden. Die univariate Analyse ergab, daß die optimal therapierten Patienten jünger waren, sie hatten häufiger ein eindeutiges EKG oder einen Linksschenkelblock, einen Vorderwandinfarkt, eine manifeste Herzinsuffizienz, AV-Block, Bradykardie oder eine fortgeschrittene COLD. Die Prähospitalzeit war häufiger verfügbar. Im optimal behandelten Kollektiv betrug die 48-h-Mortalität 5,0% vs. 9,3% im suboptimal behandelten Kollektiv und die Krankenhausmortalität 10,9% vs. 17,7%. Die multivariate Analyse zeigte, daß die Variable „optimale Therapie” ein unabhängiger Prädiktor sowohl für die Früh- als auch für die Krankenhausmortalität ist. Intrahospitale Komplikationen traten auf: Apoplex 2,8%, Reinfarkt 12,9%, Herzinsuffizienz 21,5%, kardiogener Schock 10,4% und Krankenhaussterblichkeit 18,1% (Letalität < 48 h 9,5%). Zwischen den Erkenntnissen und Empfehlungen aus großen randomisierten Therapiestudien und der klinischen Praxis besteht zum jetzigen Zeitpunkt eine deutliche Diskrepanz. Nach den vorliegenden Daten sollte die Qualität der derzeitigen medikamentösen Infarkttherapie noch deutlich verbessert werden, denn „optimale Therapie” ist ein günstiger Prädiktor für die Früh- und Klinikmortalität. The prognostic value of thrombolytics, aspirin, beta-blockers and ACE-inhibitors has been well documented in large clinical trials, but the application of these drugs in clinical practice is not known. MITRA is a multicenter study of 54 hospitals in a defined region in southwest Germany. The aim is to document actual clinical practice (pilot phase) and to establish an individually optimised prognostic therapy for acute myocardial infarction, considering only the absolute contraindications for each drug. In the pilot phase, 1303 consecutive patients with acute transmural myocardial infarction were enrolled. The median age was 66 years, the prehospital time was 2.7 hours. 47 % had an anterior infarction. In the subgroup of patients without absolute contraindications, only 53.4% were treated with thrombolytics, 87.6% with aspirin, 37.1% with beta-blocker, and 17.4% with ACE-inhibitor. Out of these, patients were classified as “optimally treated” if they received thrombolysis, aspirin as well as beta-blocker. Patients were also included if any of these medications was withheld in the presence of absolute contraindications. Treatment was defined suboptimal, if the patients did not receive any of these three medications despite the absence of absolute contraindications. Only 29% (n = 383) received an optimal postinfarction therapy and 71% (n = 775) a suboptimal treatment. The univariate analysis revealed 10 variables influencing optimal therapy. In this subgroup patients were younger, they more often had clear ECG-findings or left bundle branch block, an anterior infarction, acute cardiac failure, AV-block, bradycardia, recent trauma or surgery (less then 2 weeks) and a severe chronic obstructive lung disease. The prehospital time was more often available. Early mortality after 2 days was 5.0% versus 9.3% in the suboptimal treated patients (OR: 0.5, CI: 0.30–0.86) the total inhospital mortality was 10.9% in the optimal versus 17.7% in the suboptimal group (OR: 0.6, CI: 0.38–0.84). In a multivariate analysis the parameter “optimal treatment” was found to be an independent predictor of the early (OR = 0.4; CI: 0.20–0.69) and the inhospital mortality (OR = 0.4; CI: 0.25–0.64). The following in-hospital events occurred: stroke 2.8%, reinfarction 12.9%, cardiac failure 21.5%, cardiogenic shock 10.4% and in-hospital mortality 18.1% (2-days mortality 9.5%). Pharmacological therapy for acute myocardial infarction is inconsistent with the recommendations suggested in recent clinical trials and needs to be individually optimised. Optimal treatment is an independent predictor of early and inhospital mortality.