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PubMed1988

Improving the quality of data in randomized clinical trials: the COMPACT computer package. COMPACT Steering Committee.

One crucial component for a successful clinical trial is that the data gathered have a high level of reliability and completeness. This paper reviews some problems of data management and describes the computer package COMPACT which has been developed to deal with such problems. The package allows range and consistency checks and can monitor complex follow-up schedules. A unique feature of the package is a PROBLEMS file which has use both for identification of queries about the data and of patients with particular characteristics of interest. The ability to monitor drug dosages and to signal deviations from the protocol is of particular value. COMPACT has the syntax necessary to create a 'flat' file for transfer to statistical packages for analysis, and the variable description files for SAS, SPSS and MINITAB. The package is written in standard FORTRAN which enables transfer to different types of mini and micro computer systems.

Clinical Trials as Topic↗

PubMed1994

The early termination of clinical trials: causes, consequences, and control. With special reference to trials in the field of arrhythmias and sudden death. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology.

The early termination of clinical trials, for either benefit or harm, often generates undue enthusiasm or alarm. The enhanced publicity attending early termination of a trial promotes inappropriate interpretations that are favored by the inherent difficulty of prompt and comprehensive data review. Furthermore, the process of monitoring the accumulating outcome data for early evidence of treatment benefit or harm is fraught with many statistical and methodological difficulties. This report from a task force convened by the Working Group on Arrhythmias of the European Society of Cardiology incorporates first, a series of trials terminated appropriately or inappropriately for benefit or harm and used as examples to illustrate the importance of suitable trial design and of proper stopping rules; second, a description of the committee structure of a clinical trial; third, an analysis of the general design issues; fourth, a review of the main issues in interim analysis with special reference to main strategies for reducing the rate of false-positive claims that could result from early trial termination; and finally, a series of specific recommendations concerning the design, structure, analysis, interpretation, and presentation of a clinical trial.

Arrhythmias, Cardiac↗

PubMed2005

Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol.

AIMS/HYPOTHESIS: Studies suggest that in addition to blood glucose concentrations, thiazolidinediones such as rosiglitazone improve some cardiovascular (CV) risk factors and surrogate markers, that are abnormal in type 2 diabetes. However, fluid retention might lead to cardiac failure in a minority of people. The aim of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study is to evaluate the long-term impact of these effects on CV outcomes, as well as on long-term glycaemic control, in people with type 2 diabetes. MATERIALS AND METHODS: RECORD is a 6-year, randomised, open-label study in type 2 diabetic patients with inadequate blood glucose control (HbA1c 7.1-9.0%) on metformin or sulphonylurea alone. The study is being performed in 327 centres in Europe and Australasia. After a 4-week run-in, participants were randomised by current treatment stratum to add-on rosiglitazone, metformin or sulphonylurea, with dose titration to a target HbA1c of < or = 7.0%. If confirmed HbA1c rises to > or = 8.5%, either a third glucose-lowering drug is added (rosiglitazone-treated group) or insulin is started (non-rosiglitazone group). The same criterion for failure of triple oral drug therapy in the rosiglitazone-treated group is used for starting insulin in this group. The primary endpoint is the time to first CV hospitalisation or death, blindly adjudicated by a central endpoints committee. The study aim is to evaluate non-inferiority of the rosiglitazone group vs the non-rosiglitazone group with respect to CV outcomes. Safety, tolerability and study conduct are monitored by an independent board. All CV endpoint and safety data are held and analysed by a clinical trials organisation, and are not available to the study investigators while data collection is open. RESULTS: Over a 2-year period a total of 7,428 people were screened in 25 countries. Of these, 4,458 were randomised; 2,228 on background metformin, 2,230 on background sulphonylurea. Approximately half of the participants are male (52%) and almost all are Caucasian (99%). CONCLUSIONS/INTERPRETATION: The RECORD study should provide robust data on the extent to which rosiglitazone, in combination with metformin or sulphonylurea therapy, affects CV outcomes and progression of diabetes in the long term.

Blood Glucose↗

PubMed1991

Operational aspects of terminating randomization in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) is a randomized clinical trial sponsored by the National Eye Institute (NEI) designed to test whether cryotherapy applied to eyes of premature infants with a specified extent of stage 3+ ROP significantly decreases the incidence of an unfavorable outcome. An unfavorable outcome is defined as either retinal detachment or a retinal fold and was determined at 3 months posttreatment by the use of a masked photographic system. Enrollment into the trial was terminated on recommendation of the Data and Safety Monitoring Committee 9 months before the scheduled closing date for enrollment because of demonstrated treatment benefit. The purpose of this article is to discuss the operations involved in the orderly termination of enrollment and dissemination of results from this trial. These activities included preparation of trial participants and staff, release of trial information, continuing patient care, data collection and coding, and publication of trial results.

Blindness↗

PubMed1995

Guidelines for clinical trials in systemic sclerosis (scleroderma). I. Disease-modifying interventions. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis.

OBJECTIVE: To develop guidelines for therapeutic trials designed to improve the overall course of systemic sclerosis (SSc), that is, to reduce the development of significant organ damage or death. METHODS: A committee developed general guidelines for patient inclusion and exclusion criteria, randomization, blinding of patients and physicians, controls, duration of the trial, investigator training, responses, samples size, study dropouts, statistical analyses, data management, and safety monitoring. Delphi and nominal group techniques were used. RESULTS: Briefly, patients with diffuse cutaneous SSc of less than 24 months' duration should be included because they are at greatest risk for the development of severe organ damage and death. Patients should be excluded if they have other connective tissue diseases, SSc-like illnesses related to exposures or ingestions, severe existing internal organ damage, an unacceptable risk of side effects, or concurrent therapies that might independently influence the outcome. Randomized, double-blind, placebo-controlled trials are preferred. The treatment and followup period must be long enough to permit observation of any disease modification, which is likely to require 18-36 months, unless an extraordinarily effective therapy is identified. Responses selected should be quantitative, consistently and accurately reflect activity of SSc in major target organs (not solely the skin), be sensitive to change, and be standardized, with limited variability. An example of a set of responses is given. Surrogate responses are desirable, but none have been validated as correlating with organ damage. CONCLUSION: Guidelines have been established for trials of disease-modifying interventions in SSc. These guidelines will need to be altered as additional information becomes available. Any given protocol will be individualized based on the nature of the intervention and objectives of the study. Nonetheless, each study team should develop a protocol that meets the spirit of these guidelines.

Clinical Protocols↗

PubMed1991

Statistical considerations in terminating randomization in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) was a randomized trial designed to test whether cryotherapy applied to the retina significantly decreased the incidence of retinal detachment, retinal fold, or retrolental "mass." Randomization into the trial was terminated on recommendation of the Data and Safety Monitoring Committee 9 months before the scheduled end of the intake period. At the time of the decision, a favorable outcome at 3 months posttreatment occurred more frequently in eyes treated with cryotherapy (78%) as compared to untreated eyes (57%) (chi 2 = 20.5). The basic statistical method used in monitoring the results was conditional power (or stochastic curtailment). Several other issues were considered in deciding to terminate the trial, including the examination of results across subgroups and clinical centers, the completeness of follow-up, clinical assessment of outcome, and long-term consequences of the treatment.

Bias↗

PubMed2002

Position paper on therapeutic drug monitoring of antiretroviral agents.

Monitoring drug concentrations in humans to optimize efficacy and reduce toxicity is not a new concept in clinical pharmacology. It has been successfully applied to many different classes of drugs. As a result of considerable concentration and response data, the concept of therapeutic drug monitoring (TDM) has been expanded to certain antiretroviral compounds. In particular, protease inhibitors and nonnucleoside reverse transcriptase inhibitors may be viable candidates for TDM, and limited clinical trial data suggest monitoring plasma concentrations of these agents may indeed clinically benefit patients with HIV infection. A primary distinction between TDM of antiretroviral drugs compared with other drugs is that multiple agents are concomitantly used to treat HIV infection. As with all illnesses that require self-administered drug therapy, poor adherence is a major impediment to success. However, in the treatment of HIV infection, inadequate drug concentrations will result in the appearance or evolution of drug resistance mutations that can endanger present and future drug treatment options. Procedures for sample collection, cross-validation of analytical procedures, and interpretation of assay results should be standardized. More clinical data are needed to confirm this approach and methods of implementing TDM should be further explored. This position paper offers guidelines to aid clinicians who choose to incorporate TDM into the routine care of their patients.

Anti-HIV Agents↗

PubMed2025

DigiNet: Optimizing personalized care for patients with stage IV non-small cell lung cancer (NSCLC) through a digitally connected provider network-analysis plan of a prospective multicenter cohort trial.

PURPOSE: The German sector-based healthcare system poses a major challenge to continuous patient monitoring and long-term follow-up, both essential for generating high-quality, longitudinal real-world data. The national Network for Genomic Medicine (nNGM) bridges the inpatient and outpatient care sectors to provide comprehensive molecular diagnostics and personalized treatment for non-small cell lung cancer (NSCLC) patients in Germany. Building on the established nNGM infrastructure, the DigiNet study aims to evaluate the impact of digitally integrated, personalized care on overall survival (OS) and the optimization of treatment pathways, compared to routine care. METHODS: DigiNet is a prospective, controlled, non-randomized multicenter cohort study including patients with stage IV NSCLC in two study regions (East and West) in Germany. The results of molecular diagnostics and clinical information, along with the entire treatment data are documented in a shared database. A board of lung cancer specialists monitors critical events. Patients digitally complete quality of life questionnaires, with results visualized for physicians. To assess the impact of this personalized digital care, a population-based control group will be identified by matching cohorts within the involved cancer registries. The primary endpoint is OS, and secondary endpoints comprise time on first-line treatment and hospitalization rates. Furthermore, a health economic and business economic evaluation will be conducted. Qualitative interviews with patients and physicians will be performed to assess barriers and facilitating factors for implementing the DigiNet intervention. ETHICS: The study protocol was reviewed and approved by the Ethics Committee of the University Hospital of Cologne (21-1521). TRIAL REGISTRATION: NCT05818449, registered retrospectively on December 12, 2022.

Humans↗

PubMed2000

Screening, endpoint classification, and safety monitoring in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).

The MERIT-HF study was designed to investigate the effect of once-daily dosing of metoprolol succinate CR/XL added to standard therapy in patients with chronic heart failure. A screening programme, aiming at identifying eligible patients for the study was used by 231 out of 313 sites, resulting in 8912 screened patients. These patients were older, more often women, had marginally higher ejection fraction and were more often in NYHA class IV compared to the finally randomised patients. There was a positive correlation between the number of screened and randomised patients and due to the high inclusion rate the number of randomised patients was increased from 3200 to 3991 patients. The clinical events were defined by a manual and were based on identical classifications made independently by two members of an Independent Endpoint Committee. Data from the case report form and the classifications made by the Endpoint Committee were in accordance for hospitalisation due to worsening heart failure on 722 occasions. On 207 occasions the data from the case report forms and the classification made by the committee differed regarding this clinical event. The Independent Safety Committee monitored safety aspects of the study by using asymmetric group sequential procedures. The study was stopped early on recommendation from the Independent Safety Committee, when the second pre-specified interim analysis (50% of total number of expected deaths) showed that the criterion for stopping due to benefit had been met and exceeded. In conclusion, a screening programme facilitated patient recruitment and showed the characteristics of the background population, the event classification was improved by using an independent endpoint committee, and the safety monitoring allowed an early closure of the study due to mortality benefit, without jeopardising the final analyses of the results.

Adrenergic beta-Antagonists↗

PubMed2004

A randomized controlled trial of intravenous N-acetylcysteine for the prevention of contrast-induced nephropathy after cardiac catheterization: lack of effect.

BACKGROUND: Contrast-induced nephropathy (CIN) after cardiac catheterization is common in patients with preexisting renal dysfunction. Studies of oral acetylcysteine to prevent CIN have produced conflicting results. Intravenous N-acetylcysteine (NAC) has logistic advantages in this setting. The objective of this study was to evaluate, in a blinded, randomized, placebo-controlled fashion, whether intravenous NAC reduced CIN in the setting of cardiac catheterization in patients with preexisting renal insufficiency. METHODS: Patients with renal dysfunction undergoing cardiac catheterization were randomly assigned to intravenous NAC 500 mg immediately before the procedure or placebo. All patients received isotonic saline (200 mL) beforehand, followed by 1.5 mL/kg per hour for 6 hours, unless contraindicated. Exclusion criteria included acute renal failure, creatinine >400 micromol/L, concurrent dialysis, unstable clinical status, and prior NAC use. Baseline creatinine was obtained immediately before the procedure and repeated 2 to 8 days later. The primary end point was the occurrence of CIN defined as a reduction in creatinine clearance from baseline of >5 mL/min (Cockcroft-Gault formula). RESULTS: The study was terminated early because of a determination of futility by the Data Safety Monitoring Committee after enrollment of 487 patients. The median baseline creatinine clearance was 44 mL/min (interquartile range, 33, 55). Median contrast received was 120 mL (interquartile range, 80, 175). Baseline characteristics were similar in the two groups. Altogether, 98 (22.0%) subjects had the primary end point: 23.3% in the NAC group and 20.7% in the placebo arm (P =.57). CONCLUSIONS: In this large, randomized trial, enrolling a high-risk group of patients with impaired renal function, intravenous NAC was ineffective in preventing CIN.

Acetylcysteine↗

PubMed1995

Use of cumulative meta-analysis in the design, monitoring, and final analysis of a clinical trial: a case study.

From 1983 to 1987, the Department of Veterans Affairs (DVA) Cooperative Studies Program (CSP) conducted a multicenter clinical trial (CSP #207) to determine whether four different antiplatelet regimens compared to placebo could prevent the occlusion of grafts following coronary artery bypass surgery. The study showed that all of the active regimens tended to be better than placebo and that the three regimens containing aspirin were statistically significantly better. A cumulative meta-analysis of 12 trials performed shortly before the end of CSP #207 raised the issue as to whether the meta-analysis, if done earlier, would have changed the conduct of the trial. At the start of the planning period, one trail of size n = 37 had been published with a nonsignificant odds ratio (OR) of 0.74 (95% CI: 0.18, 3.12). At the time that CSP # 207 was approved by the DVA Cooperative Studies Evaluation Committee, two trials had been published (cumulative n = 150, OR = 0.44, 95% CI 0.19, 0.99). At the time patient intake started, five trials showed cumulative n = 769, OR = 0.42, 95% CI = 0.26, 0.68. Although the first 6-month CSP #207 progress report showed no treatment effect, by the time of the 12-month review by the Data Monitoring Board (DMB) a trend was developing in favor of active treatment. If the results of the meta-analysis had been available to the DMB at that time, conceivably the Board would have recommended stopping the placebo arm because of a convincing treatment effect based on the totality of the evidence. Cumulative meta-analysis could be useful as an adjunct in the planning, conduct, and final analysis of a clinical trial. It could also be used as one piece of evidence in the monitoring of the ongoing phase of a trial.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1998

Clinical trials and treatment effects monitoring.

Treatment effects monitoring is the act of reviewing accumulated data by treatment group to determine whether a trial should continue unaltered. That monitoring is required for any trial where there is a risk of an aggregate form of harm for subjects because of continued use of an inferior treatment or because of failure to use a superior treatment. Institutional review boards (IRBs), in deciding whether to approve such research, require that (when appropriate) there is adequate provision for monitoring the data collected to ensure the safety of subjects. The focus here is on the conditions necessary to satisfy this requirement. The conditions discussed are timeliness of the monitoring, completeness of data for monitoring, competency of monitors, and freedom of monitors to act and recommend as they deem necessary, regardless of the wishes, desires, or dictates of sponsors.

Clinical Trials as Topic↗

PubMed2001

A clinical trial in type 2 diabetic nephropathy.

A prospective, randomized, three-armed, double-blind, placebo-controlled clinical trial has been completed in 210 sites worldwide to determine whether the angiotensin II receptor blocker irbesartan or the calcium channel blocker amlodipine has a renoprotective effect in patients with overt type 2 diabetic nephropathy. A total of 1,715 subjects randomized during a 3-year period were followed a minimum of 2 years. The goal for all treatment groups was to achieve equivalent blood pressure control, with the blinded study drug (irbesartan, amlodipine, or placebo) as primary therapy with additional antihypertensive drugs, excluding angiotensin-converting enzyme inhibitors, calcium antagonists, and angiotensin II receptor antagonists, to achieve seated systolic blood pressure less than 135 mm Hg and diastolic blood pressure less than 85 mm Hg. The primary outcome was the combined endpoint of time to doubling of entry serum creatinine, end-stage renal disease, or death. Secondary outcomes included fatal and nonfatal cardiovascular events. A Clinical Management Committee monitored the conduct of the study. An Outcome Confirmation Committee classified all study outcome events in blinded fashion. An external Data Safety Monitoring Committee monitored unblinded data for interim safety and efficacy analyses of the study. Eligibility criteria included informed consent, age 30 to 70 years, adult-onset diabetes, hypertension, urine protein excretion greater than 900 mg/24 hours, and serum creatinine values of 90 to 265 micromol/L in women and 110 to 265 micromol/L in men. Baseline characteristics were age, 59 +/- 8 years; body mass index, 31 +/- 7 kg/m(2); 67% male; 73% white, 14% black, and 13% other; duration of diabetes, 15 +/- 9 years; retinopathy, 66%; neuropathy, 48%; congestive heart failure, 7.5%; screening seated systolic blood pressure, 156 +/- 18 mm Hg, and diastolic blood pressure, 85 +/- 11 mm Hg; urine protein excretion, 4.0 +/- 3.5 g/24 hours; serum creatinine, 150 +/- 53 micromol/L; serum potassium, 4.6 +/- 0.5 mEq/L; total cholesterol, 229 +/- 58 mg/dL; and hemoglobin A(1c), 8.1 +/- 1.7%. This large-scale international trial should help define the clinical course and standards of care for hypertensive adults with type 2 diabetes mellitus and nephropathy. Results available on May 19, 2001, will help in defining the current controversy of the risks and benefits of blockade of the renin-angiotensin system versus calcium channel blockade versus standard antihypertensive therapy in this large patient population.

Adult↗

PubMed2005

Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer.

PURPOSE: The objective of this study was to determine whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase pathologic complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2) -positive disease. PATIENTS AND METHODS: Forty-two patients with HER2-positive disease with operable breast cancer were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. The primary objective was to demonstrate a 20% improvement in pCR (assumed 21% to 41%) with the addition of trastuzumab to chemotherapy. The planned sample size was 164 patients. RESULTS: Prognostic factors were similar in the two groups. After 34 patients had completed therapy, the trial's Data Monitoring Committee stopped the trial because of superiority of trastuzumab plus chemotherapy. pCR rates were 25% and 66.7% for chemotherapy (n = 16) and trastuzumab plus chemotherapy (n = 18), respectively (P = .02). The decision was based on the calculation that, if study continued to 164 patients, there was a 95% probability that trastuzumab plus chemotherapy would be superior. Of the 42 randomized patients, 26% in the chemotherapy arm achieved pCR compared with 65.2% in the trastuzumab plus chemotherapy arm (P = .016). The safety of this approach is not established, although no clinical congestive heart failure was observed. A more than 10% decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms, respectively. CONCLUSION: Despite the small sample size, these data indicate that adding trastuzumab to chemotherapy, as used in this trial, significantly increased pCR without clinical congestive heart failure.

Adult↗

PubMed1993

Monitoring of clinical trials: issues and recommendations.

Interim analyses of randomized trials enable investigators to make more efficient use of limited research resources and to satisfy ethical requirements that a regimen be discontinued as soon as it has been established to have an inferior efficacy/toxicity profile. Unfortunately, the integrity and credibility of these trials can be compromised if inappropriate procedures are used in monitoring interim data. In this paper we discuss how group sequential designs provide useful guidelines that enable one to satisfy the valid objectives of interim monitoring while avoiding undesirable consequences, and we consider how flexible one can be in the way such designs are implemented. We also provide motivation for the role of data-monitoring committees in preserving study integrity and credibility in either government- or industry-sponsored trials. In our view, these committees should have multidisciplinary representation and membership limited to individuals free of apparent significant conflict of interest, and ideally should be the only individuals to whom the data analysis center provides interim results on relative efficacy of treatment regimens. Finally, we discuss some important practical issues such as estimation following group sequential testing, analysis of secondary outcomes after using a group sequential design applied to a primary outcome, early stopping of negative trials, and the role of administrative analyses.

Clinical Trials as Topic↗

PubMed1993

Branched-chain amino acids and amyotrophic lateral sclerosis: a treatment failure? The Italian ALS Study Group.

We initiated a double-blind, placebo-controlled trial to test the efficacy and safety of branched-chain amino acids (BCAA) (L-leucine 12 g, L-isoleucine 6 g, and L-valine 6 g daily) in amyotrophic lateral sclerosis (ALS) patients. There was an excess mortality in subjects randomized to active treatment (24 BCAA, 13 placebo) when a total of 126 ALS patients had been recruited. This finding, associated with the lack of efficacy of BCAA (measured by comparing the disability scales in the two treatment groups), led the Data Monitoring Committee to require cessation of the trial.

Amino Acids, Branched-Chain↗

PubMed2001

Monitoring a clinical trial conducted under the Food and Drug Administration regulations allowing a waiver of prospective informed consent: the diaspirin cross-linked hemoglobin traumatic hemorrhagic shock efficacy trial.

In 1996, the US Food and Drug Administration (FDA) enacted Rule 21 CFR section 50.24, which allows a narrow exception to the requirement for prospective informed consent from human research subjects in clinical trials investigating potentially beneficial therapies for acute, life-threatening conditions. The first clinical trial to be conducted under this rule was sponsored by Baxter Healthcare Corporation and approved by the FDA on November 21, 1996. This large, multicenter, randomized clinical trial was designed to compare the addition of diaspirin cross-linked hemoglobin (DCLHb) with standard care in the initial resuscitation of adults experiencing severe, uncompensated, traumatic hemorrhagic shock. Before the first planned interim analysis of the data, review of fatal adverse events revealed an imbalance in mortality between the 2 treatment groups. The Data Monitoring Committee (DMC) recommended suspension of patient enrollment 24 days later. Additional data collection and analyses confirmed the excess number of deaths in patients treated with DCLHb but failed to reveal the cause of these deaths. The trial was formally terminated after only 112 of the planned 850 patients had been enrolled. We review the events leading up to and the rationale behind the DMC recommendations for suspension of patient enrollment and trial termination. Although the DCLHb trial was unsuccessful in achieving its goals, the monitoring process worked well. Emergency research was facilitated by DMC oversight, and the interests of research subjects were protected by the actions of the DMC.

Aspirin↗

PubMed2006

Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding--a European perspective.

INTRODUCTION: Our aim was to develop consensus guidelines for use of recombinant activated factor VII (rFVIIa) in massive hemorrhage. METHODS: A guidelines committee derived the recommendations using clinical trial and case series data identified through searches of available databases. Guidelines were graded on a scale of A-E according to the strength of evidence available. Consensus was sought among the committee for each recommendation. RESULTS: A recommendation for use of rFVIIa in blunt trauma was made (grade B). rFVIIa might also be beneficial in post-partum hemorrhage (grade E), uncontrolled bleeding in surgical patients (grade E) and bleeding following cardiac surgery (grade D). rFVIIa could not be recommended for use: in penetrating trauma (grade B); prophylactically in elective surgery (grade A) or liver surgery (grade B); or in bleeding episodes in patients with Child-Pugh A cirrhosis (grade B). Efficacy of rFVIIa was considered uncertain in bleeding episodes in patients with Child-Pugh B and C cirrhosis (grade C). Monitoring of rFVIIa efficacy should be performed visually and by assessment of transfusion requirements (grade E), while thromboembolic adverse events are a cause for concern. rFVIIa should not be administered to patients considered unsalvageable by the treating medical team. CONCLUSIONS: There is a rationale for using rFVIIa to treat massive bleeding in certain indications; however, only adjunctively to the surgical control of bleeding once conventional therapies have failed. Lack of data from randomized, controlled clinical trials, and possible publication bias of the case series data, limits the strength of the recommendations that can be made.

Blood Substitutes↗