OFFICIAL COMMUNICATION OF THE SSC
Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children
Lesley G. Mitchell, Stollery Children’s Hospital, Department of Pediatrics, University of Alberta, Dentistry Pharmacy Centre, 11304-89 Avenue, Edmonton, AB T6G 2C7, Canada.
Tel.: +1 780 492 3137; fax: +1 780 492 3350.
The incidence of venous thromboembolism (VTE), defined as deep venous thrombosis (DVT) and/or pulmonary embolism (PE), has increased in recent years, with VTE now diagnosed in approximately 1/200 hospitalized children . Few pediatric interventional VTE trials have been completed and treatment recommendations in children remain largely extrapolated from adult trial evidence. Numerous new antithrombotic agents are currently under clinical investigation in adults, and with national/international directives that such agents be evaluated in children, an increasing number of pediatric VTE trials are anticipated. In order to permit comparisons across studies and interventions in pediatric VTE, standardized outcome measures must be defined and employed.
Definitions of outcomes are based on presentations/discussions at the Perinatal and Paediatric Haemostasis Subcommittee meetings during the 56th–58th Scientific and Standardization Committee (SSC) Meetings of the ISTH. Input was also provided via email from the SSC and by teleconference involving the working group (L. Mitchell [Chair], U. Nowak-Göttl, C. Male and N.A. Goldenberg [2010–11]). Guidelines were developed via a review of sources and were revised following the aforementioned input and consensus process.
Source materials reviewed were:
- 1 Pediatric trials literature: a literature search for pediatric interventional studies of VTE treatment and prevention was performed using PubMed search term ‘anticoagulants or fibrinolytics’ and limits of ‘all child, clinical trial, abstract/title’; studies with defined outcomes were reviewed [2–8].
- 2 Literature on outcome guidelines for adult interventional VTE studies: the ISTH/SSC on Control of Anticoagulation published position papers defining major bleeding in non-surgical patients and surgical patients [9,10].
- 3 Regulatory guidelines: no guidelines for outcomes for pediatric VTE studies were available from either the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA). No guidelines from the FDA for adult studies were available; however, three online guidelines from the EMA are available [11–13]. The review was expanded to include adult trials literature via a PubMed search by term ‘antithrombotic’ and limits of ‘clinical trial’ and ‘2005–present’.
For the position paper, we have restricted definitions of qualifying VTE to DVT affecting venous drainage from limbs (including caval thrombosis), right atrial thrombosis and PE. While treatment indications for thrombosis at other venous sites (e.g. cerebral sinovenous thrombosis, renal vein thrombosis and portal vein thrombosis) are not addressed, such events are considered among possible outcomes, as well as arterial ischemic stroke (AIS) from paradoxical embolism.
Treatment studies Treatment studies in VTE also comprise secondary prevention. While overlap exists with outcomes employed historically in adult VTE trials, there are significant differences.
Primary endpoints include a composite of time-dependent risks of all recurrent VTE and VTE-related mortality. ‘All recurrent VTE’ is defined as any radiologically proven new thrombosis (whether non-contiguous new thrombus or contiguous progression of previously defined thrombus) of any component of the venous or pulmonary arterial circulations, intracardiac thrombosis, or occurrence of paradoxical embolism, including both asymptomatic and symptomatic events. In contrast to adult recommendations, the inclusion of asymptomatic events reflects experience that acutely asymptomatic VTE in children not uncommonly presents with functional sequelae (e.g. PTS). Inclusion of asymptomatic VTE in the primary efficacy endpoint is most valid for study designs in which the frequency and time intervals of surveillance (i.e., asymptomatic) radiological imaging are prescribed by the protocol in order to avoid observational bias.
‘VTE progression’ is defined as either an increase in longitudinal extent of thrombosis or a change from non-occlusive to occlusive. The exact criteria for determination of an increase in longitudinal extent of thrombosis will need to be determined a priori in each study, reflecting limitations of the imaging modality.
Given the relative infrequency of VTE recurrence, progression and specific mortality and yet their independent clinical importance, we recommend that the primary endpoint should typically consist of composites. However, when it is feasible to power a trial to separately evaluate recurrent VTE, this should be considered as the primary efficacy endpoint. Post-thrombotic syndrome (PTS) is recognized as an important secondary outcome of interest. Until such a time that specific recommendations on a standardized technique for assessing PTS in children are reported from the SSC, use of one of the two published scores is required for studies [14,15].
Recommended outcome definitions:
- 1 Primary outcome. A composite of: (i) all recurrent VTE defined as either contiguous progression or non-contiguous new thrombus and including DVT, PE and paradoxical embolism and (ii) VTE-related mortality.
- 2 Secondary outcomes. (i) Each individual component of primary outcome; (ii) all-cause mortality; (iii) new symptomatic DVT (including DVT progression); (iv) new symptomatic PE; (v) new paradoxical embolism; (vi) new asymptomatic DVT (including DVT progression); and (vii) PTS.
Prophylaxis studies For VTE prevention trials, primary endpoints include incident VTE and VTE-related death. Incident VTE includes symptomatic and asymptomatic events. Qualifying asymptomatic VTE will be radiologically defined as adherent to the vessel wall and obstructing ≥ 1/3 of the venous segment diameter. Similar considerations apply as in treatment trials regarding the use of composite vs. individualized primary endpoints.
- 1 Primary Outcome. A composite of: (i) all incident VTE including DVT, PE and paradoxical embolism and (ii) VTE-related mortality.
- 2 Secondary outcomes. (i) Each individual component of primary outcome and (ii) all-cause mortality.
Pediatric safety endpoints reflect instances where there is a clear rationale to depart from recommendations in adult VTE trials. A category ‘clinically-relevant, non-major bleeding’ is used given that: (i) need for blood-product transfusion or for non/minimally-invasive medical or surgical intervention are each less clinically significant in potential morbidity and/or mortality than bleeding at critical sites; (ii) pediatric transfusion practise is highly variable; and (iii) need for blood-product transfusion or non/minimally-invasive medical or surgical intervention to restore hemostasis is clinically relevant, and more burdensome for the patient and health care system than bleeding episodes that are routinely managed at home.
Recommended outcome definitions:
- 1 Primary outcome. Major bleeding, a composite of: (i) fatal bleeding; (ii) clinically overt bleeding associated with a decrease in Hgb of at least 20 g L−1 (2 g dL−1) in a 24-h period; (iii) bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the central nervous system; and (iv) bleeding that requires surgical intervention in an operating suite.
- 2 Secondary outcomes.
- • Clinically relevant non-major bleeding, a composite of: (i) overt bleeding for which a blood product is administered and which is not directly attributable to the patient’s underlying medical condition and (ii) bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating suite.
- • Minor bleeding: any overt or macroscopic evidence of bleeding that does not fulfill the above criteria for either major bleeding or clinically relevant, non-major bleeding. Menstrual bleeding resulting in a medical consultation and/or intervention will be classified as a minor bleeding event.
The present recommendations are made in an effort to improve standardization of outcomes in pediatric VTE clinical trials and are directed by principles and judgments of the international pediatric thrombosis scientific community.
Although study design and analytic methodology were not in the purview of this working group (and are the subject of a separate subcommittee working group), they are intimately related to the outcomes. Use of a blinded central adjudication committee is recommended in order to enhance objectivity and standardization of outcome determinations in pediatric multicenter VTE clinical trials. For studies in which central radiology adjudication may not be feasible, the committee recommends radiologic outcome determination according to a predetermined standardized protocol at each center by two blinded radiologists experienced in venous imaging.
We acknowledge that after determination of primary and secondary outcomes, there may be other tertiary outcomes of some clinical interest. Cost effectiveness could be highly relevant, given costs of new interventions over standard anticoagulation. Health-related or disease-specific quality of life may be important, especially where the burden of injectable vs. oral therapies, or blood monitoring, may impact on acceptability of the treatment to children. Until disease-specific HR-QoL measurements for children with VTE are developed and validated, we recommend use of internationally validated generic HR-Qol instruments such as the KINDL questionnaire . The subcommittee suggests assessing these outcomes as appropriate on a study to study basis.
The endpoints recommended and their primary or secondary prioritization are most applicable to VTE clinical anticoagulation trials evaluating safety and efficacy. Trials designed to address other objectives (e.g. pharmacodynamic studies) or studying specific subpopulations (e.g. cancer patients) or indications (e.g. devices) within pediatric VTE, may warrant different endpoints and/or prioritizations. Furthermore, present recommendations will require updates as data from clinical studies become available. Nevertheless, it is hoped that regulatory agencies such as the FDA and EMA will adopt the present recommendations, in order to facilitate the conduct of (and comparisons among) pediatric VTE clinical trials.
The research was supported by the Canadian Institutes of Health Research, Grant #114981 (L.G. Mitchell). N.A. Goldenberg is funded in part by a Career Development Award from the National Institutes of Health, National Heart, Lung, and Blood Institute. U. Nowak-Göttl is supported by a university research award (IZKF) and ‘Förderverein Schlaganfall und Trombosen e.V.’. The authors thank M.J. Manco-Johnson and W.R. Hiatt for insightful comments on the manuscript.
Disclosure of Conflicts of Interest
The authors state that they have no conflict of interest.