Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer

  • Review
  • Intervention

Authors


Abstract

Background

Compared with patients without cancer, patients with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE.

Objectives

To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in patients with cancer.

Search methods

A comprehensive search for studies of anticoagulation in patients with cancer including a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and ISI Web of Science.

Selection criteria

Randomized clinical trials (RCTs) comparing LMWH, UFH, and fondaparinux in patients with cancer and objectively confirmed VTE.

Data collection and analysis

Using a standardized data form, review authors extracted data in duplicate on methodologic quality, participants, interventions, and outcomes of interest that included mortality, recurrent VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia.

Main results

Of 9559 identified citations, 16 RCTs were eligible: 13 compared LMWH with UFH, two compared fondaparinux with heparin, and one compared dalteparin with tinzaparin. Meta-analysis of 11 studies showed a statistically significant reduction in mortality at three months of follow-up with LMWH compared with UFH (risk ratio (RR) 0.71; 95% confidence interval (CI) 0.52 to 0.98). There was little change in the effect estimate after excluding studies of lower methodologic quality (RR 0.72; 95% CI 0.52 to 1.00). A meta-analysis of three studies comparing LMWH with UFH showed no statistically significant reduction in VTE recurrence (RR 0.78; 95% CI 0.29 to 2.08). The overall quality of evidence was low for LMWH versus UFH due to imprecision and likely publication bias. There were no statistically significant differences between heparin and fondaparinux for the outcomes of mortality (RR 1.27; 95% CI 0.88 to 1.84), recurrent VTE (RR 0.95; 95% CI 0.57 to 1.60), major bleeding (RR 0.79; 95% CI 0.39 to1.63), or minor bleeding (RR 1.50; 95% CI 0.87 to 2.59). The one study comparing dalteparin with tinzaparin found no statistically significant difference in mortality (RR 0.86; 95% CI 0.43 to 1.73).

Authors' conclusions

LMWH is possibly superior to UFH in the initial treatment of VTE in patients with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review.

Résumé scientifique

Anticoagulation dans le traitement initial de la thromboembolie veineuse chez les patients cancéreux

Contexte

Par rapport aux patients sans cancer, les patients cancéreux qui reçoivent un traitement par anticoagulants pour la thromboembolie veineuse (TEV) sont plus susceptibles de développer une TEV récurrente.

Objectifs

Comparer l'efficacité et l'innocuité de trois types d'anticoagulants parentéraux (c.-à-d. l'héparine de bas poids moléculaire (HBPM) à dose fixe, l'héparine non fractionnée (HNF) à dose ajustée et le fondaparinux) dans le traitement initial de la TEV chez les patients cancéreux.

Stratégie de recherche documentaire

Une recherche exhaustive d'études sur l'anticoagulation chez les patients cancéreux a été menée, dont une recherche électronique effectuée en février 2013 dans le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE, EMBASE et ISI Web of Science.

Critères de sélection

Essais cliniques randomisés (ECR) comparant l'HBPM, l'HNF et le fondaparinux chez les patients atteints de cancer et de TEV confirmée objectivement.

Recueil et analyse des données

À l'aide d'un formulaire de données standardisé, les auteurs de la revue ont extrait en duplicata les données sur la qualité méthodologique, les participants, les interventions et les critères de jugement d'intérêt, dont la mortalité, la TEV récurrente, l'hémorragie majeure, l'hémorragie mineure, le syndrome post-phlébitique, la qualité de vie et la thrombocytopénie.

Résultats principaux

Sur 9 559 citations identifiées, 16 ECR étaient éligibles : 13 comparaient l'HBPM et l'HNF, deux comparaient le fondaparinux à l'héparine et un la daltéparine à la tinzaparine. Une méta-analyse de 11 études montrait une réduction statistiquement significative de la mortalité à trois mois de suivi avec l'HBPM par rapport à l'HNF (risque relatif (RR) 0,71 ; intervalle de confiance (IC) à 95 % de 0,52 à 0,98). L'estimation de l'effet a peu changé après avoir exclu les études dont la qualité méthodologique était plus faible (RR 0,72 ; IC à 95 % de 0,52 à 1,00). Une méta-analyse de trois études comparant l'HBPM et l'HNF ne montrait aucune réduction statistiquement significative dans la récurrence de TEV (RR 0,78 ; IC à 95 % de 0,29 à 2,08). La qualité globale des preuves était faible pour l'HBPM versus l'HNF en raison de l'imprécision et de probables biais de publication. Il n'y avait aucune différence statistiquement significative entre l'héparine et le fondaparinux pour les critères de jugement de la mortalité (RR 1,27 ; IC à 95 % de 0,88 à 1,84), la TEV récurrente (RR 0,95 ; IC à 95 % de 0,57 à 1,60), l'hémorragie majeure (RR 0,79 ; IC à 95 % de 0,39 à 1,63,) ou l'hémorragie mineure (RR 1,50 ; IC à 95 % de 0,87 à 2,59). La seule étude comparant la daltéparine à la tinzaparine n'a trouvé aucune différence statistiquement significative en termes de mortalité (RR 0,86 ; IC à 95 % de 0,43 à 1,73).

Conclusions des auteurs

L'HBPM semblerait supérieure à l'HNF dans le traitement initial de la TEV chez les patients cancéreux. Des essais supplémentaires portant sur des critères de jugement importants pour le patient permettront de répondre plus précisément aux questions traitées dans cette revue.

Plain language summary

Blood thinners for the initial treatment of blood clots in patients with cancer

Background

Patients with cancer are at an increased risk of blood clots. The blood thinner (anticoagulant) administered in the first few days can consist of unfractionated heparin (infused intravenously) or low molecular weight heparin (injected subcutaneously once or twice per day). These two blood thinners may have different effectiveness and safety profiles.

Study characteristics

We searched scientific databases for clinical trials comparing different blood thinners in people with cancer with a confirmed diagnosis of a blood clot. The trials looked at death, recurrent blood clots, bleeding, postphlebitic syndrome (a complication of long-term blood clots), quality of life and levels of blood platelets (which are involved in blood clotting). The evidence is current to February 2013.

Key results

In this systematic review, data from 13 studies suggest that low molecular weight heparin is superior to unfractionated heparin in reducing mortality. However, there is not enough evidence to prove superiority in reducing recurrence of blood clots. We did not find data to compare the safety profile of these two medications.

Quality of the evidence

The overall quality of the evidence was low.

Résumé simplifié

Anticoagulants pour le traitement initial de caillots sanguins chez des patients atteints de cancer

Contexte

Les patients atteints de cancer sont exposés à un risque accru de caillots sanguins. L'anticoagulant (fluidifiant de sang) administré dans les premiers jours peut être de l'héparine non fractionnée (en perfusion intraveineuse) ou de l'héparine de bas poids moléculaire (en injection sous-cutanée une ou deux fois par jour). Ces deux anticoagulants peuvent avoir des profils d'efficacité et de tolérance différents.

Caractéristiques des études

Nous avons effectué des recherches dans des bases de données scientifiques pour les essais cliniques comparant différents anticoagulants chez les personnes atteintes de cancer ayant un diagnostic confirmé d'un caillot de sang. Les essais avaient examiné la mortalité, la récurrence de caillots sanguins, les saignements, le syndrome post-phlébitique (une complication à long terme des caillots sanguins), la qualité de vie et les niveaux de plaquettes sanguines (qui sont impliquées dans la coagulation du sang). Les preuves sont à jour en février 2013.

Résultats principaux

Dans cette revue systématique, les données issues de 13 études suggèrent que l'héparine de bas poids moléculaire réduit plus efficacement la mortalité que l'héparine non fractionnée. Cependant, les preuves ne sont pas suffisantes pour prouver sa supériorité en termes de réduction de la récurrence de caillots sanguins. Les données disponibles ne permettent pas de comparer les profils de sécurité de ces deux médicaments.

Qualité des preuves

La qualité globale des preuves était faible.

Notes de traduction

Traduit par: French Cochrane Centre
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Резюме на простом языке

Лекарства, разжижающие кровь, для стартового лечения тромбозов у больных раком

Актуальность

Больные раком имеют повышенный риск образования тромбов. Лекарство, разжижающее кровь (антикоагулянт), вводимое в первые несколько дней, может состоять из нефракционированного гепарина (который вводят путем внутривенной инфузии) или низкомолекулярного гепарина (который вводят подкожно один или два раза в день). Эти два антикоагулянта могут иметь различные профили эффективности и безопасности.

Характеристика исследований

Мы провели поиск в научных базах данных на предмет клинических испытаний, сравнивающих различные антикоагулянты у людей с раком с подтвержденным диагнозом тромбоза [образованием тромбов]. Эти клинические испытания изучали смерть, рецидивы образования тромбов [кровяных сгустков], кровотечения, постфлебитический синдром (осложнение в результате сохранения тромбов в течение длительного времени), качество жизни и уровень тромбоцитов в крови (клетки, участвующие в процессе свертывания крови). Доказательства актуальны по февраль 2013 года.

Основные результаты

В этом систематическом обзоре, данные из 13 исследований позволяют предположить, что низкомолекулярный гепарин превосходит нефракционированный гепарин в снижении смертности. Однако, недостаточно доказательств, чтобы доказать превосходство в снижении рецидивов тромбообразования [повторного образования кровяных сгустков]. Мы не нашли данных, которые бы позволили сравнить безопасность этих двух лекарств.

Качество доказательств

В целом, качество доказательств было низким.

Заметки по переводу

Перевод: Раззакова Чинара Маратовна. Редактирование: Юдина Екатерина Викторовна. Координация проекта по переводу на русский язык: Казанский федеральный университет - аффилированный центр в Татарстане Северного Кокрейновского Центра. По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

Summary of findings(Explanation)

Summary of findings for the main comparison. Low molecular weight heparin compared with unfractionated heparin for the initial treatment of venous thromboembolism in patients with cancer
  1. 1 Of the 11 studies, 10 clearly concealed allocation; 1 blinded patients, providers, or data collectors; 11 blinded outcome adjudicators; and 10 used intention to treat (ITT). We did not downgrade for risk of bias.
    2 We downgraded for imprecision due to wide CIs; likely to be an overestimate in the context of publication bias that informs our judgment about optimal information size (lower estimate than the 29%).
    3 We downgraded for due to publication bias: we excluded 11 studies from the systematic review because the data for the cancer subgroup analysis was not reported. An analysis of the same question not restricted to patients with cancer, demonstrated a likely publication bias in favor of LMWH (separate footnote for VTE).
    4 Of the 13 included studies, only 3 reported on the recurrence VTE outcome.

    5 Of the 3 studies, 2 clearly concealed allocation; none blinded patients, providers, or data collectors; 3 blinded outcome adjudicators; and 2 used ITT.
    6 We downgraded for imprecision with a CI that includes values suggesting benefit and values suggesting harm.

Low molecular weight heparin compared with unfractionated heparin for the initial treatment of venous thromboembolism in patients with cancer
Patient or population: patients with cancer with the initial treatment of VTE
Settings: inpatient or outpatient
Intervention: LMWH
Comparison: UFH
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
UFH LMWH
Mortality at 3 months
Follow-up: median 3 months
189 per 1000 134 per 1000
(98 to 185)
RR 0.71
(0.52 to 0.98)
801
(11 studies)
⊕⊕⊝⊝
low 1,2,3
-
Recurrent VTE
Follow-up: median 3 months
96 per 1000 75 per 1000
(28 to 200)
RR 0.78
(0.29 to 2.08)
371
(3 studies)
⊕⊕⊝⊝
low 4,5,6
-
Major bleeding - not reported--Not estimable--There is indirect evidence that both LMWH and UFH increase the risk of major bleeding compared with no anticoagulation
Postphlebitic syndrome - not reported--Not estimable---
Quality of life - not reported--Not estimable---
Thrombocytopenia - not reported--Not estimable---
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; LMWH: low molecular weight heparin; RR: risk ratio; UFH: unfractionated heparin; VTE: venous thromboembolism.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Fondaparinux compared with heparin for the initial treatment of venous thromboembolism in patients with cancer

Summary of findings 2. Fondaparinux compared with heparin for the initial treatment of venous thromboembolism in patients with cancer
  1. 1 Of the 2 studies, both concealed allocation; 1 blinded patients, providers, data collectors, and outcome adjudicators; both used ITT and none was stopped early for benefit.
    2 CI includes values suggesting benefit and values suggesting harm.
    3 Unexplained heterogeneity with I2 = 85%.
    4 I2 = 38%.

Fondaparinux compared with heparin for the initial treatment of venous thromboembolism in patients with cancer
Patient or population: patients with cancer with the initial treatment of VTESettings: inpatient or outpatient
Intervention: fondaparinux
Comparison: heparin
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Heparin Fondaparinux
Mortality
Follow-up: median 3 months
Study population RR 1.27
(0.88 to 1.84)
477
(2 studies)
⊕⊕⊕⊝
moderate 1,2
-
172 per 1000 218 per 1000
(151 to 316)
Medium-risk population
170 per 1000 216 per 1000
(150 to 313)
Recurrent VTE
Follow-up: median 3 months
Study population RR 0.95
(0.57 to 1.6)
477
(2 studies)
⊕⊕⊝⊝
low 1,2,3
-
117 per 1000 111 per 1000
(67 to 187)
Medium-risk population
113 per 1000 107 per 1000
(64 to 181)
Major bleeding
Follow-up: median 3 months
Study population RR 0.79
(0.39 to 1.63)
477
(2 studies)
⊕⊕⊕⊝
moderate 1,3
There is indirect evidence that both fondaparinux and heparin increase the risk of bleeding compared with no anticoagulation
67 per 1000 53 per 1000
(26 to 109)
Medium-risk population
67 per 1000 53 per 1000
(26 to 109)
Minor bleeding
Follow-up: median 3 months
Study population RR 1.5
(0.87 to 2.59)
477
(2 studies)
⊕⊕⊕⊝
moderate 2,4
There is indirect evidence that both fondaparinux and heparin increase the risk of bleeding compared with no anticoagulation
79 per 1000 119 per 1000
(69 to 205)
Medium-risk population
81 per 1000 122 per 1000
(70 to 210)
Postphlebitic syndrome - not reportedSee commentSee commentNot estimable-See comment-
Quality of life - not reportedSee commentSee commentNot estimable-See comment-
Thrombocytopenia - not reportedSee commentSee commentNot estimable-See comment-
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; VTE: venous thromboembolism.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Table 1 lists a glossary of terms.

Table 1. Glossary
TermDefinition
A prioriMade before or without exam; not supported by factual study
Adjuvant therapyAssisting in the amelioration, or cure of disease
AnticoagulationThe process of hindering the clotting of blood especially by treatment with an anticoagulant
AntithromboticUsed against or tending to prevent thrombosis (clotting)
CoagulationClotting
Deep vein thrombosis (DVT)A condition marked by the formation of a thrombus within a deep vein (as of the leg or pelvis) that may be asymptomatic or be accompanied by symptoms (as swelling and pain) and that is potentially life threatening if dislodgment of the thrombus results in pulmonary embolism
FondaparinuxAn anticoagulant medication
Hemostatic systemThe system that shortens the clotting time of blood and stops bleeding
HeparinAn enzyme occurring especially in the liver and lungs that prolongs the clotting time of blood by preventing the formation of fibrin. 2 forms of heparin that are used as anticoagulant medications are: unfractionated heparin (UFH) and low molecular weight heparins (LMWH)
HeterogeneityThe quality or state of being heterogeneous, i.e. incongruous. This is a statistical technique to check whether study results are consistent
Hypercoagulable stateA state of excessive affinity to clotting
Impedance plethysmographyA technique that measures the change in blood volume (venous blood volume as well as the pulsation of the arteries) for a specific body segment
Kappa statisticA measure of degree of nonrandom agreement between observers, measurements of a specific categorical variable, or both
MetastasisThe spread of a cancer cells from the initial or primary site of disease to another part of the body
Parenteral nutritionThe practice of feeding a patient intravenously, circumventing the gastrointestinal tract
Pulmonary embolism (PE)Embolism of a pulmonary artery or 1 of its branches that is produced by foreign matter and most often a blood clot originating in a vein of the leg or pelvis and that is marked by labored breathing, chest pain, fainting, rapid heart rate, cyanosis, shock, and sometimes death
ThrombocytopeniaPersistent decrease in the number of blood platelets that is often associated with hemorrhagic conditions
ThrombosisThe formation or presence of a blood clot within a blood vessel
Vitamin K antagonistsAnticoagulant medications that are used for anticoagulation. Warfarin is a vitamin K antagonist
WarfarinAn anticoagulant medication that is a vitamin K antagonist that is used for anticoagulation
XimelagatranAn anticoagulant medication

Description of the condition

Cancer status by itself increases the risk of venous thromboembolism (VTE) by four- to six-fold (Heit 2000). In addition, therapeutic interventions such as chemotherapy, hormonal therapy, and indwelling central venous catheters increase the risk of VTE in these patients (Heit 2000). Similarly, patients undergoing surgery for cancer have a higher risk of VTE than patients undergoing surgery for benign diseases (Gallus 1997; Kakkar 1970). Patients with cancer and VTE have a higher risk of death than patients with cancer alone or VTE alone (Levitan 1999; Sorensen 2002).

This heightened hypercoagulable state might alter the response to anticoagulant treatment and the risk of bleeding. Compared with patients without cancer, patients with cancer who receive anticoagulant treatment for VTE are more likely to develop recurrent VTE with an annual risk of 21% to 27%, a two- to three-fold risk increase (Hutten 2000; Prandoni 2002). These patients are also more likely to develop major bleeding with an annual risk of 12% to 13%, a two- to six-fold risk increase (Hutten 2000; Prandoni 2002).

Description of the intervention

Heparin, low molecular weight heparins (LMWHs), fondaparinux, and danaparoid do not have intrinsic anticoagulant activity but potentiate the activity of antithrombin III in inhibiting activated coagulation factors. These agents constitute indirect anticoagulants as their activity is mediated by plasma cofactors. Recombinant hirudin, bivalirudin, and argatroban directly inhibit thrombin and are classified as direct anticoagulants (Hirsh 2008). Heparin and its low molecular weight derivatives are not absorbed orally and must be administered parenterally by intravenous infusion or subcutaneous injection (Hirsh 1993).

How the intervention might work

In the initial treatment of VTE, LMWHs and unfractionated heparin (UFH) might have a different comparative efficacy in patients with cancer than in patients without cancer. Subgroup analyses of one Cochrane systematic review showed that in patients without cancer there was no statistically significant difference between the effects of LMWH and UFH on overall mortality (odds ratio (OR) 0.97; 95% confidence interval (CI) 0.61 to 1.56) (van Dongen 2007). However, in patients with cancer, LMWH resulted in a lower overall mortality compared with UFH (OR 0.53; 95% CI 0.33 to 0.85).

Why it is important to do this review

No systematic review has focused on the initial treatment of VTE in patients with cancer. While the above-mentioned Cochrane review subgroup analysis compared the efficacy of these two drug classes, it did not report on the safety of LMWH and UFH in this patient group. Furthermore, The Cochrane Collaboration has recognized that addressing all important outcomes including harm is of great importance to make evidence-based healthcare decisions. In addition, an analysis that includes an evaluation of direct comparative trials and subgroup analysis could prevent the potential pitfalls of subgroup analysis (Oxman 2002). A subgroup refers to a segment of the studied population with a specific characteristic that is relevant to the question under consideration (e.g. a subgroup of patients with cancer with advanced disease).

Objectives

To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose LMWH, adjusted-dose UFH, and fondaparinux) for the initial treatment of VTE in patients with cancer.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs).

Types of participants

Patients with cancer and a confirmed diagnosis of VTE (acute deep venous thrombosis or pulmonary embolism). Patients could have been of any age group (including children) with either solid or hematologic cancer and at any stage of their cancer irrespective of the type of cancer therapy.

To include patients, deep venous thrombosis should have been diagnosed using one the following objective diagnostic tests: venography, 125I-fibrinogen uptake test, impedance plethysmography, or Doppler ultrasound. Pulmonary embolism should have been diagnosed using one the following objective diagnostic tests: pulmonary perfusion or ventilation scans, computed tomography, or pulmonary angiography.

Types of interventions

We considered comparisons of the following agents used in initial parenteral anticoagulation (typically the first five to 10 days): LMWH, UFH, or fondaparinux. We excluded studies in which thrombolytic therapy (e.g. streptokinase) was part of the intervention. The protocol should have planned to provide all other co-interventions (e.g. chemotherapy) similarly.

Types of outcome measures

Primary outcomes
  • All-cause mortality.

Secondary outcomes
  • Symptomatic recurrent deep venous thrombosis; events had to be diagnosed using one of the following objective diagnostic tests: venography, 125I-fibrinogen uptake test, impedance plethysmography, or Doppler ultrasound.

  • Symptomatic recurrent pulmonary embolism; events had to be diagnosed using one of the following objective diagnostic tests: pulmonary perfusion or ventilation scans, computed tomography, pulmonary angiography, or autopsy.

  • Major bleeding.

  • Minor bleeding.

  • Postphlebitic syndrome.

  • Quality of life.

  • Thrombocytopenia.

We accepted the study authors' definitions of major bleeding, minor bleeding, thrombocytopenia, and postphlebitic syndrome as long as they were standardized.

Search methods for identification of studies

Electronic searches

The search was part of a comprehensive search for studies of anticoagulation in patients with cancer. We electronically searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, 2012), MEDLINE (1966 to February 2013; accessed via Ovid), EMBASE (1980 to February 2013; accessed via Ovid), and ISI Web of Science (February 2010). The search strategies combined terms relating to the anticoagulants, cancer, and study design. We listed the search strategies in Appendix 1.

Searching other resources

We handsearched the conference proceedings of the American Society of Clinical Oncology (ASCO) (starting with its first volume, 1982) and American Society of Hematology (ASH) (starting with its 2003 issue). We reviewed the reference lists of papers included in this review and of other relevant systematic reviews (Dolovich 2000; Gould 1999; Hettiarachchi 1999; Quinlan 2004; Siragusa 1996; van Dongen 2007). We used the 'related article' feature in PubMed to identify additional articles. We did not use language restrictions.

Data collection and analysis

Selection of studies

Two review authors independently screened the title and abstract of identified article citations for potential eligibility. We retrieved the full text of articles judged potentially eligible by at least one review author. Two review authors then independently screened the full-text article for eligibility using a standardized form with explicit inclusion and exclusion criteria (as detailed in the Criteria for considering studies for this review section). The two review authors resolved any disagreements about which articles were eligible by discussion or by consulting a third review author.

Data extraction and management

We developed a data extraction form and pilot tested it. For English articles, two review authors independently extracted the data from each study and resolved their disagreements by discussion or by consulting a third review author. For non-English articles, one review author extracted data. The collected data related to the following.

Participants
  • Demographic characteristics (e.g. age, sex).

  • Cancer characteristics (e.g. type, location, stage, time since diagnosis, estimated life expectancy, current cancer treatments, performance status).

  • Whether participants had deep venous thrombosis, pulmonary embolism, or both.

  • Number of patients in each treatment arm.

Interventions
  • Type, dosage, and administration schedule of LMWH.

  • Dosage and administrative schedule of UFH.

  • Dosage schedule of fondaparinux.

  • Duration of initial parenteral therapy.

  • Type (oral anticoagulant versus LMWH) and duration of long-term anticoagulation.

Outcomes

We attempted to extract both time to event data (for the survival outcome) and categorical data (for all outcomes). However, none of the studies reported time to event data for patients with cancer. For categorical data, we extracted the reported outcome data necessary to conduct intention-to-treat (ITT) analyses. Outcome event rates were collected whenever they were reported in a trial. When the study authors did not report and could not provide the number of events at specific time points, two biostatisticians estimated these numbers independently and in duplicate from survival curves, if available.

We attempted to contact study authors for incompletely reported data. We decided a priori to consider abstracts only if study authors supplied us with full reports of their methods and results.

Assessment of risk of bias in included studies

First, we assessed risk of bias at the study level using The Cochrane Collaboration's 'Risk of bias' tool. Two review authors independently assessed the methodologic quality of each included study and resolved their disagreements by discussion. Methodologic criteria included the following.

  • Adequate sequence generation.

  • Allocation concealment.

  • Patient blinding.

  • Provider blinding.

  • Data collector blinding.

  • Outcome assessor blinding.

  • Analyst blinding.

  • Percentage followed up and whether incomplete outcome data were addressed.

  • Whether the study was free of selective outcome reporting.

  • Whether the study was stopped early for benefit.

  • Whether the analysis followed the ITT principle.

Second, we assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Higgins 2012).

Measures of treatment effect

We collected and analyzed risk ratios (RRs) for dichotomous data. None of the outcomes of interest were meta-analyzed as a continuous variable.

Unit of analysis issues

The unit of analysis was the individual participant.

Dealing with missing data

All but two included studies reported 100% follow-up. We analyzed the available data assuming that any data that could be missing were missing at random.

Assessment of heterogeneity

We assessed heterogeneity between trials by visual inspection of forest plots, estimation of the percentage heterogeneity between trials that could not be ascribed to sampling variation (I2 statistic) (Higgins 2003), and by a formal statistical test of the significance of the heterogeneity. If there was evidence of substantial heterogeneity, we investigated and reported the possible reasons for this.

Assessment of reporting biases

We assessed reporting bias by try to identify whether the study was included in a trial registry, whether a protocol was available, and whether the methods section provided a list of outcomes (to assess selective outcome reporting bias). We compared the list of outcomes from those sources to the outcomes reported in the published paper.

We assessed publication bias by creating an inverted funnel plot for the primary outcome of survival. We used the trim and fill technique to evaluate the existence of publication bias statistically (Duval 2000). We did not create funnel plots for the other outcomes due to the low number of included trials for each outcome.

Data synthesis

We calculated the agreement between the two independent review authors for the assessment of eligibility using the kappa statistic.

For dichotomous data, we calculated the RR separately for each study and the 95% confidence interval We then pooled the results of the different studies using a random-effects model

Subgroup analysis and investigation of heterogeneity

We planned subgroup analyses based on characteristics of participants but did not conduct them as the data were not available.

Sensitivity analysis

We conducted sensitivity analysis by excluding studies with small and unbalanced arms.

Results

Description of studies

Results of the search

The February 2013 search strategy identified 9559 citations from which we removed the results of our February 2010 search. Figure 1 shows the study flow. The title and abstract screening of the 9559 unique citations identified 59 as potentially eligible for this review. We included 16 studies and excluded the remaining 43. The February 2013 search strategy identified no new eligible study. Agreement between review authors for study eligibility was excellent (kappa = 0.94).

Figure 1.

Study flow diagram.

Included studies

In all of the 16 included studies, patients with cancer constituted subgroups. Of these 16 studies, four studies reported data for the cancer subgroups (Prandoni 1992; Simonneau 1993; van Doormaal 2009a; van Doormaal 2009b), and three studies (Breddin 2001; Hull 1992; Merli 2001) had follow-up publications reporting the cancer subgroup data (Green 1992; Kakkar 2000; Pineo 1997; Rodgers 1999). For two studies, we obtained the cancer subgroup data from the study authors (Galilei 2004; Wells 2005). Seven studies did not report cancer subgroup data (Columbus 1997; Duroux 1991; Koopman 1996; Levine 1996; Lindmarker 1994; Lopaciuk 1992; Simonneau 1997), so we used the data as reported in two published systematic reviews (Hettiarachchi 1999; van Dongen 2007).

Of the 16 studies, 13 compared a LMWH to UFH (1016 participants), one compared dalteparin to tinzaparin (Wells 2005), one compared fondaparinux to enoxaparin (van Doormaal 2009a), and one compared fondaparinux to UFH (van Doormaal 2009b). None of the studies specified the types of cancer of the participants. In 15 of the 16 studies, the initial parenteral anticoagulation was followed by oral anticoagulation for at least three months. In Duroux 1991, the long-term anticoagulation was either UFH subcutaneously or oral anticoagulation depending on the usual regimen of the participating center (Duroux 1991).

Excluded studies

Of the 43 excluded studies, in 11 studies patients with cancer constituted study subgroups but their outcome data were not available (Albada 1989; Belcaro 1999; Bratt 1990; Buller 2004; Fiessinger 1996; Harenberg 1990; Harenberg 2000; Holm 1986; Hull 2000; Luomanmaki 1996; Riess 2003). We excluded the remaining 32 studies for the following reasons: review (11 studies), case report or series (four studies), letter to the editor or editorial (four studies), cohort study (three studies), no patients with cancer included (three studies), retrospective study (two studies), no relevant outcome (two studies), different long-term management (one study), not randomized (one study), and survey (one study).

Risk of bias in included studies

Allocation

Allocation was adequately concealed in 14 studies; it was not clear whether it was adequately concealed in two studies (Breddin 2001; Duroux 1991).

Blinding

All studies blinded outcome assessors. Only two studies blinded data analysts (Galilei 2004; Wells 2005), and only three studies blinded patients and caregivers (Hull 1992; van Doormaal 2009a; Wells 2005).

Incomplete outcome data

Follow-up was 89% for Breddin 2001, 92% for Duroux 1991, and 100% for the remaining studies.

Selective reporting

We did not suspect selective reporting of outcomes for any of the studies. The cancer subgroup data were missing for a large number of studies.

Other potential sources of bias

Thirteen studies clearly used ITT analysis (Duroux 1991; Galilei 2004; Hull 1992; Koopman 1996; Levine 1996; Lindmarker 1994; Lopaciuk 1992; Merli 2001; Prandoni 1992; Simonneau 1997; van Doormaal 2009a; van Doormaal 2009b; Wells 2005). None of the studies were stopped early for benefit.

Effects of interventions

See: Summary of findings for the main comparison Low molecular weight heparin compared with unfractionated heparin for the initial treatment of venous thromboembolism in patients with cancer; Summary of findings 2 Fondaparinux compared with heparin for the initial treatment of venous thromboembolism in patients with cancer

Low molecular weight heparin versus unfractionated heparin

Mortality

The number of fatal events was available for 11 studies (801 patients) at three months' follow-up (Columbus 1997; Duroux 1991; Galilei 2004; Hull 1992; Koopman 1996; Levine 1996; Lindmarker 1994; Lopaciuk 1992; Prandoni 1992; Simonneau 1993; Simonneau 1997). The pooled analysis showed a statistically significant mortality reduction in patients treated with LMWH compared with patients treated with UFH (RR 0.71; 95% CI 0.52 to 0.98) (Figure 2). No heterogeneity was present (I2 = 0%). After excluding the three studies with small and imbalanced arms (Duroux 1991; Lopaciuk 1992; Simonneau 1993), the benefit remained borderline statistically significant (RR 0.72; 95% CI 0.52 to 1.00). Figure 3 shows the inverted funnel plot for the outcome of death. The trim and fill technique did not suggest publication bias but we still suspected it because 11 studies did not report cancer subgroup data. Figure 4 summarizes the risk of bias for studies assessing this outcome. The quality of the body of evidence for mortality was low due to imprecision and likely publication bias (Summary of findings for the main comparison).

Figure 2.

Forest plot of comparison: 1 Low molecular weight heparin (LMWH) versus unfractionated heparin (UFH), outcome: 1.1 Mortality at 3 months.

Figure 3.

Inverted funnel plot for studies comparing the effect on mortality of low molecular weight heparin (LMWH) and unfractionated heparin (UFH) as the initial anticoagulation in patients with cancer with venous thromboembolism.

Figure 4.

Risk of bias summary: review authors' judgments about each risk of bias item for included studies assessing mortality (low molecular weight heparin (LMWH) versus unfractionated heparin (UFH)).

Recurrent venous thromboembolism

No data were available for deep venous thrombosis or pulmonary embolism events separately. The data for recurrent VTE events were available for three studies (Breddin 2001; Galilei 2004; Merli 2001). The pooled analysis failed to show or to exclude a beneficial effect or detrimental of LMWH over UFH (RR 0.78; 95% CI 0.29 to 2.08) with low heterogeneity (I2 = 32.4%) (Figure 5). Figure 6 summarizes the risk of bias for studies assessing this outcome. The quality of the body of evidence for recurrent VTE was low due to imprecision and likely publication bias (Summary of findings for the main comparison).

Figure 5.

Forest plot of comparison: 1 low molecular weight heparin (LMWH) versus unfractionated heparin (UFH), outcome: 1.2 Recurrent venous thromboembolism.

Figure 6.

Risk of bias summary: review authors' judgments about each risk of bias item for included studies assessing recurrent venous thromboembolism (low molecular weight heparin (LMWH) versus unfractionated heparin (UFH)).

No data were available for bleeding outcomes, thrombocytopenia, postphlebitic syndrome, or quality of life.

Fondaparinux versus heparin

The pooled results of the two studies comparing fondaparinux with heparin showed no statistically significant difference between the two agents for the outcomes of mortality (RR 1.27; 95% CI 0.88 to 1.84), recurrent VTE (RR 0.95; 95% CI 0.57 to 1.60), major bleeding (RR 0.79; 95% CI 0.39 to1.63), or minor bleeding (RR 1.50; 95% CI 0.87 to 2.59) (van Doormaal 2009a; van Doormaal 2009b). Figure 7 summarizes the risk of bias for these two studies. The quality of the body of evidence was moderate for mortality, major bleeding, and minor bleeding due to imprecision; and low for recurrent VTE due to inconsistency and imprecision (Summary of findings 2).

Figure 7.

Risk of bias summary: review authors' judgments about each risk of bias item for included studies (fondaparinux versus heparin).

No data were available for thrombocytopenia, postphlebitic syndrome, or quality of life.

Dalteparin versus tinzaparin

The study comparing dalteparin with tinzaparin found no statistically significant difference for the outcomes of mortality (RR 0.86; 95% CI 0.43 to 1.73), VTE recurrence (RR 0.44; 95% CI 0.09 to 2.16), major bleeding (RR 2.19; 95% CI 0.20 to 23.42), or minor bleeding (RR 0.82; 95% CI 0.30 to 2.21). Figure 8 summarizes the risk of bias for this study. The overall quality of evidence was moderate, due to imprecision.

Figure 8.

Risk of bias summary: review authors' judgments about each risk of bias item for the included study (dalteparin versus tinzaparin).

Discussion

Summary of main results

This systematic review found a patient important and statistically significant mortality reduction with the use of LMWH compared with UFH in the initial treatment of VTE in patients with cancer. The comparative effect on the incidence of VTE was not statistically significant. There were no statistically significant differences between fondaparinux and heparin or between dalteparin and tinzaparin in the effects on the outcomes of interest.

Overall completeness and applicability of evidence

The completeness of the data is a major concern in this systematic review. First, of a total of 24 potentially eligible studies we did not include 11 because the study authors did not report the needed subgroup data for patients with cancer. These 11 studies would have contributed 340 additional participants to the meta-analysis (801 are currently included). If the treatment effect from those studies was different from the reported effect, their exclusion from the meta-analysis could have biased our results. Moreover, only three of the included studies reported cancer subgroup data for VTE recurrence and none reported cancer subgroup data for the bleeding outcomes.

Second, there is evidence of publication bias in favor of LMWH even when considering all studies comparing subcutaneous UFH with LMWH in the initial management of VTE for any patient (with or without cancer) (see Figure 9; Figure 10; and Figure 11 from an unpublished analysis). This affects our confidence in the results of the current analysis suggesting superiority of LMWH over UFH.

Figure 9.

Funnel plot for mortality outcome for low molecular weight heparin (LMWH) versus subcutaneous unfractionated heparin (UFH) in all patients (unpublished).

Figure 10.

Funnel plot for recurrent venous thromboembolism outcome for low molecular weight heparin (LMWH) versus subcutaneous unfractionated heparin (UFH) in all patients (unpublished).

Figure 11.

Funnel plot for major bleeding outcome for low molecular weight heparin (LMWH) versus subcutaneous unfractionated heparin (UFH) in all patients (unpublished).

Quality of the evidence

For the LMWH versus UFH comparison, the methodologic quality for mortality and recurrent VTE outcomes was low due to imprecision and likely publication bias. For the fondaparinux versus heparin comparison, the quality of evidence was low for recurrent VTE (due to imprecision and inconsistency) and moderate for mortality and bleeding outcomes (due to imprecision). For the dalteparin versus tinzaparin comparison, the quality of evidence was also moderate for the outcomes of interest due to imprecision.

Potential biases in the review process

A potential bias of our review might be the limitation of the electronic search strategy to patients with cancer, while the data needed for this review came from studies not restricted to this subgroup. However, we consider that the supplemental search strategies that we used (in addition to the electronic search) were effective. In fact, our search strategy did not miss any of the studies reported in earlier systematic reviews on the topic.

Agreements and disagreements with other studies or reviews

Three previous systematic reviews compared the effects of LMWH and UFH on mortality in patients with cancer and with VTE. A 1999 review by Hettiarachchi et al. included nine studies and 629 patients and resulted in an OR of 0.61 (95% CI 0.40 to 0.93) (Hettiarachchi 1999). A review by Gould et al. included 279 patients and resulted in an OR of 0.57 (95% CI 0.31 to 1.03) (Gould 1999). Van Dongen et al. conducted, in a Cochrane review, a subgroup analysis for patients with cancer and included six studies and 446 patients; it showed an OR of 0.53 (95% CI 0.33 to 0.85) (van Dongen 2007). While the current review includes more studies and patients (11 studies and 801 patients) than the three previous reviews, the resulting effect is consistent.

The two reviews by Hettiarachchi et al. and van Dongen et al. assessed the comparative efficacy of LMWH and UFH separately in patients with and without cancer (Hettiarachchi 1999; van Dongen 2007). While LMWH was superior to UFH in patients with cancer, as noted above, they were statistically equivalent in patients without cancer, with respective ORs of 0.94 (95% CI 0.60 to 1.47) and 0.97 (95% CI 0.61 to 1.56). However, the authors did not report testing statistically for subgroup effect.

Authors' conclusions

Implications for practice

Low molecular weight heparin (LMWH) is possibly superior to unfractionated heparin (UFH) in reducing mortality in the initial treatment of venous thromboembolism (VTE) in patients with cancer. The confidence in this effect is reduced by both the risk of bias in included studies and the likelihood of publication bias. However, there are additional advantages of LMWH related to subcutaneous administration and outpatient management (O'Brien 1999; Othieno 2007).

Implications for research

There is a need to conduct trials comparing anticoagulants in the initial treatment of VTE that are restricted to patients with cancer. Researchers should consider making the raw data of randomized controlled trials available for individual patient data meta-analysis. In addition, as recognized by The Cochrane Collaboration, addressing all important outcomes including harm is of great importance in making evidence-based healthcare decisions.

Acknowledgements

We thank Dr. Merli, Dr. Prandoni, Dr. Siragusa, and Dr. Wells for providing us with data. We thank Ms. Ann Grifasi for her administrative support. We thank Dr. Srinivasa Rao Vasireddi and Dr. Sameer Gunukula for their contributions to previous versions of this systematic review.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group.

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health

Data and analyses

Download statistical data

Comparison 1. Low molecular weight heparin (LMWH) versus unfractionated heparin (UFH)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality at 3 months11801Risk Ratio (M-H, Random, 95% CI)0.71 [0.52, 0.98]
2 Recurrent venous thromboembolism3371Risk Ratio (M-H, Random, 95% CI)0.78 [0.29, 2.08]
Analysis 1.1.

Comparison 1 Low molecular weight heparin (LMWH) versus unfractionated heparin (UFH), Outcome 1 Mortality at 3 months.

Analysis 1.2.

Comparison 1 Low molecular weight heparin (LMWH) versus unfractionated heparin (UFH), Outcome 2 Recurrent venous thromboembolism.

Comparison 2. Fondaparinux versus heparin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality2477Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.88, 1.84]
2 Recurrent venous thromboembolism2477Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.57, 1.60]
3 Major bleeding2477Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.39, 1.63]
4 Minor bleeding2477Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.87, 2.59]
Analysis 2.1.

Comparison 2 Fondaparinux versus heparin, Outcome 1 Mortality.

Analysis 2.2.

Comparison 2 Fondaparinux versus heparin, Outcome 2 Recurrent venous thromboembolism.

Analysis 2.3.

Comparison 2 Fondaparinux versus heparin, Outcome 3 Major bleeding.

Analysis 2.4.

Comparison 2 Fondaparinux versus heparin, Outcome 4 Minor bleeding.

Appendices

Appendix 1. Full search strategies for the electronic databases - update 2010

DatabaseStrategy
CENTRAL (latest issue, 2010)

#1 heparin OR low molecular weight heparin OR LMWH OR low-molecular-weight-heparin OR nadroparin OR fraxiparin OR enoxaparin OR clexane OR lovenox OR dalteparin OR fragmin OR ardeparin OR normiflo OR tinzaparin OR logiparin OR innohep OR certoparin OR sandoparin OR reviparin OR clivarin OR danaproid OR orgaran
#2 Coumarins OR Warfarin OR coumadin OR acenocumarol OR phenprocumon OR 4-hydroxicoumarins OR oral anticoagulant OR vitamin K antagonist OR VKA
#3 fondaparinux OR Arixtra
#4 ximelagatran OR Exanta
#5 Pradaxa or Dabigatran or rivaroxaban or Xarelto or apixaban

#6 1 OR 2 OR 3 OR 4 OR 5
#7 malignan$ OR neoplasm$ OR cancer OR carcinoma$ OR adenocarcinoma OR tumour OR tumor
#8 6 AND 7

MEDLINE

#1 Heparin/
#2 Heparin.tw
#3 Heparin, Low-Molecular-Weight/
#4 (LMWH OR low molecular weight heparin OR nadroparin OR fraxiparin OR enoxaparin OR clexane OR lovenox OR dalteparin OR fragmin OR ardeparin OR normiflo OR tinzaparin OR logiparin OR innohep OR certoparin OR sandoparin OR reviparin OR clivarin OR danaproid OR orgaran).tw
#5 1 OR 2 OR 3 OR 4
#6 Coumarins/
#7 Warfarin/
#8 (warfarin OR coumadin OR acenocumarol OR phenprocumon OR 4-hydroxicoumarins OR oral anticoagulant OR vitamin K antagonist OR VKA).tw
#9 6 OR 7 OR 8
#10 (fondaparinux OR Arixtra).tw
#11 (ximelagatran OR Exanta).tw

#12 (Pradaxa or Dabigatran or rivaroxaban or Xarelto or apixaban).tw.
#13 5 OR 9 OR 10 OR 11 OR 12
#14 Neoplasms/
#15 (malignan$ OR neoplasm$ OR cancer OR carcinoma$ OR adenocarcinoma OR tumour OR tumor).tw
#16 14 OR 15
#17 clinical trial.pt. OR random:.tw. OR tu.xs.
#18 animals/ NOT human/
#19 17 NOT 18
#20 13 AND 16 AND 19

EMBASE

#1 Heparin/
#2 heparin.tw
#3 Low Molecular Weight Heparin/
#4 (LMWH OR low molecular weight heparin OR nadroparin OR fraxiparin OR enoxaparin OR clexane OR lovenox OR dalteparin OR fragmin OR ardeparin OR normiflo OR tinzaparin OR logiparin OR innohep OR certoparin OR sandoparin OR reviparin OR clivarin OR danaproid OR orgaran).tw
#5 1 OR 2 OR 3 OR 4
#6 Coumarin derivative/
#7 Warfarin/
#8 (warfarin OR coumadin OR acenocumarol OR phenprocumon OR 4-hydroxicoumarins OR oral anticoagulant OR vitamin K antagonist OR VKA).tw
#9 6 OR 7 OR 8
#10 fondaparinux/
#11 (fondaparinux OR Arixtra).tw
#12 ximelagatran/
#13 (ximelagatran OR Exanta).tw

#14 (Pradaxa OR Dabigatran OR rivaroxaban OR Xarelto OR apixaban).tw.
#15 5 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14
#16 Neoplasm/
#17 (malignan$ OR neoplasm$ OR cancer OR carcinoma$ OR adenocarcinoma OR tumour OR tumor).tw
#18 16 OR 17
#19 Random:.tw. OR clinical trial:.mp. OR exp health care quality
#20 animals/ NOT human/
#21 19 NOT 20
#22 15 AND 18 AND 21

ISI (International Scientific Information) the Web of Science

#1 heparin OR low molecular weight heparin OR LMWH OR low-molecular-weight-heparin OR nadroparin OR fraxiparin OR enoxaparin OR clexane OR lovenox OR dalteparin OR fragmin OR ardeparin OR normiflo OR tinzaparin OR logiparin OR innohep OR certoparin OR sandoparin OR reviparin OR clivarin OR danaproid OR orgaran
#2 Coumarins OR Warfarin OR coumadin OR acenocumarol OR phenprocumon OR 4-hydroxicoumarins OR oral anticoagulant OR vitamin K antagonist OR VKA
#3 fondaparinux OR Arixtra
#4 ximelagatran OR Exanta

# 5 Pradaxa OR Dabigatran OR rivaroxaban OR Xarelto OR apixaban
#6 1 OR 2 OR 3 OR 4 OR 5
#7 malignan$ OR neoplasm$ OR cancer OR carcinoma$ OR adenocarcinoma OR tumour OR tumor
#8 random$ OR placebo$ OR versus OR vs OR double blind OR double-blind OR compar$ OR controlled
#9 6 AND 7 AND 8

Appendix 2. Full search strategies for the electronic databases - update 2013

DatabaseStrategy
CENTRAL (Issue 12, 2012)

#1 MeSH descriptor: [Heparin] explode all trees

#2 (LMWH or heparin or nadroparin or fraxiparin or enoxaparin or clexane or lovenox or dalteparin or fragmin or ardeparin or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin or danaproid or orgaran or bemiparin or hibor, badyket, semuloparin, parnaparin, fluxum)

#3 MeSH descriptor: [Coumarins] explode all trees

#4 (warfarin or coumadin or acenocumarol or phenprocumon or 4-hydroxicoumarins or oral anticoagulant or vitamin K antagonist or VKA)

#5 (fondaparinux or arixtra)

#6 (ximelagatran or exanta)

#7 (pradaxa or dabigatran or rivaroxaban or xarelto or apixaban or eliquis or edoxaban or lixiana or betrixaban or edoxaban or otamixaban)

#8 #1 or #2 or #3 or #4 or #5 or #6 or #7

#9 MeSH descriptor: [Neoplasms] explode all trees

#10 (malignan* or neoplasm* or cancer* or carcinoma* or adenocarcinoma* or tumour* or tumor*)

#11 #9 or #10

#12 #8 and #10

MEDLINE

#1 exp Heparin/

#2 (LMWH or heparin or nadroparin or fraxiparin or enoxaparin or clexane or lovenox or dalteparin or fragmin or ardeparin or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin or danaproid or orgaran or bemiparin or hibor, badyket, semuloparin, parnaparin, fluxum).tw.

#3 exp Coumarins/

#4 (warfarin or coumadin or acenocumarol or phenprocumon or 4-hydroxicoumarins or oral anticoagulant or vitamin K antagonist or VKA).tw.

#5 (fondaparinux or arixtra).tw.

#6 (ximelagatran or exanta).tw.

#7 (pradaxa or dabigatran or rivaroxaban or xarelto or apixaban or eliquis or edoxaban or lixiana or betrixaban or edoxaban or otamixaban).tw.

#8 1 or 2 or 3 or 4 or 5 or 6 or 7

#9 exp Neoplasms/

#10 (malignan* or neoplasm* or cancer* or carcinoma* or adenocarcinoma* or tumour* or tumor*).tw.

#11 9 or 10

#12 8 and 11

#13 randomized controlled trial.pt.

#14 controlled clinical trial.pt.

#15 randomized.ab.

#16 placebo.ab.

#17 drug therapy.fs.

#18 randomly.ab.

#19 trial.ab.

#20 groups.ab.

#21 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20

#22 12 and 21

#23 exp animals/ not humans.sh.

#24 22 not 23

EMBASE

#1 heparin/

#2 exp low molecular weight heparin/

#3 (LMWH or heparin or nadroparin or fraxiparin or enoxaparin or clexane or lovenox or dalteparin or fragmin or ardeparin or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin or danaproid or orgaran or bemiparin or hibor, badyket, semuloparin, parnaparin, fluxum).tw.

#4 exp coumarin derivative/

#5 (warfarin or coumadin or acenocumarol or phenprocumon or 4-hydroxicoumarins or oral anticoagulant or vitamin K antagonist or VKA).tw.

#6 (fondaparinux or arixtra).tw.

#7 (ximelagatran or exanta).tw.

#8 (pradaxa or dabigatran or rivaroxaban or xarelto or apixaban or eliquis or edoxaban or lixiana or betrixaban or edoxaban or otamixaban).tw.

#9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

#10 exp neoplasm/

#11 (malignan* or neoplasm* or cancer* or carcinoma* or adenocarcinoma* or tumour* or tumor*).tw.

#12 10 or 11

#13 9 and 12

#14 crossover procedure/

#15 double-blind procedure/

#16 randomized controlled trial/

#17 single-blind procedure/

#18 random*.mp.

#19 factorial*.mp.

#20 (crossover* or cross over* or cross-over*).mp.

#21 placebo*.mp.

#22 (double* adj blind*).mp.

#23 (singl* adj blind*).mp.

#24 assign*.mp.

#25 allocat*.mp.

#26 volunteer*.mp.

#27 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26

#28 13 and 27

#29 (exp animal/ or nonhuman/ or exp animal experiment/) not human/

#30 28 not 29

Feedback

Cochrane Editorial Unit's report on feedback on anticoagulants reviews, 15 February 2011

Summary

Feedback received on this review, and other reviews and protocols on anticoagulants, is available on the Cochrane Editorial Unit website at editorial-unit.cochrane.org/anticoagulants-feedback.

Reply

N/A

Contributors

N/A

What's new

DateEventDescription
11 February 2015AmendedContact details updated.

History

Protocol first published: Issue 3, 2007
Review first published: Issue 1, 2008

DateEventDescription
3 June 2014New citation required but conclusions have not changedReview updated
9 February 2013New search has been performedSearch updated
13 January 2011New citation required but conclusions have not changedUpdated search (February 2010)

Contributions of authors

EAA: protocol development, search for trials, screening, data extraction, data analysis, manuscript drafting, review coordination.LK: screening, data extraction.IN: screening.MB: screening, data extraction.FS: screening, data extraction.IT: screening, data extraction.PM: data analysis, methodologic advice.HJS: protocol development, search for trials, data extraction, data analysis, methodologic advice.

Declarations of interest

None

Sources of support

Internal sources

  • State University of New York at Buffalo, Department of Medicine, USA.

  • Italian National Cancer Institute Regina Elena Rome, Italy.

External sources

  • Research Grants, Other.

    H Schünemann: no personal payments from for-profit sponsors. Research grants and honoraria were received by research accounts or received by a research group that he belongs to from AstraZeneca, Amgen, Chiesi Foundation, Lily, and Pfizer, Roche and UnitedBioSource for development or consulting regarding quality of life instruments for chronic respiratory diseases and as lecture fees related to the methodology of evidence-based practice guideline development and research methodology. Institutions or organizations that he is affiliated with likely receive funding from for-profit sponsors that are supporting infrastructure and research that may serve his work.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Breddin 2001

MethodsRandomized controlled open-label trial
Participants74 cancer patients with DVT but not PE (study subgroup); minimum age 18 years
Interventions

Intervention: reviparin weight based SC twice daily

Control: UFH IV (continuous infusion of 1250 IU/hour) x 5-7 days
Vitamin K antagonist (target INR > 2) started on day 1 x 90 days
A third group received reviparin SC once daily x 28 days and vitamin K antagonist on days 21-90

OutcomesMortality, symptomatic DVT (not clear whether asymptomatic events included), PE, major bleeding
Notes

Funding: Knoll, Germany

Follow-up: 90 days

Radiologic surveillance: venography surveillance for DVT conducted at day 21

Setting: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Patients were randomly assigned to one of three groups, stratified according to site"
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of patients?High risk

Quote: "open-label trial"

Comment: definitely no

Blinding of providers?High risk

Quote: "open-label trial"

Comment: definitely no

Blinding of data collectors?High risk

Quote: "open-label trial"

Comment: probably no

Blinding of outcome adjudicators?Low risk

Quote: "The venogram were assessed by two members of an independent committee who were unaware of the patients' treatment assignments and of whether the venograms were obtained before or after treatment"

Comment: definitely yes

Blinding of data analysts?Unclear risk

Not reported

Comment: definitely no

Incomplete outcome data addressed?Low risk89% follow-up rate for VTE recurrence
Intention-to-treat analysis?Unclear riskNot reported
Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section reported on
Free of other bias?Low riskStudy not stopped early for benefit

Columbus 1997

MethodsRandomized controlled trial, subgroup of a large study
Participants232 patients with cancer with proximal or distal DVT, PE, or both; minimum age 18 years
Interventions

Intervention: reviparin weight based SC twice daily at home

Control: UFH IV (target aPTT 1.5-2.5) in the hospital x 5 days. Coumarin derivative (target INR > 2) started on 1st or 2nd day x 12 weeks

OutcomesMortality, recurrent symptomatic VTE, bleeding
Notes

Funding: Knoll AG

Follow-up: 12 weeks

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: patients could be treated at home, but the decision to do so was left to the treating physician

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Randomization was performed with a computer algorithm"
Allocation concealment (selection bias)Low riskQuote: "Randomization was performed with a computer algorithm and the use of a central 24-hour telephone service that recorded information on the patient before the treatment assignment was disclosed"
Blinding of patients?High risk

Quote: "open international, randomized clinical trial"

Comment: definitely not

Blinding of providers?High risk

Quote: "open international, randomized clinical trial"

Comment: probably not

Blinding of data collectors?High risk

Quote: "open international, randomized clinical trial"

Comment: probably not

Blinding of outcome adjudicators?Low risk

Quote: "Information on all suspected outcome events and deaths was reviewed and classified by a central adjudication committee whose members were unaware of the treatment assignments"

Comment: definitely yes

Blinding of data analysts?Unclear riskUnclear
Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Unclear riskNot reported
Free of selective reporting?Low riskStudy not registered. No published protocol. All relevant outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Duroux 1991

MethodsRandomized controlled trial
Participants18 patients with cancer with proximal DVT but no PE; minimum age 18 years
Interventions

Intervention: CY216 (fraxiparin) 255 antiXa U/kg twice daily x 10 days

Control: UFH IV (target aPTT 1.5-2) x10 days
After day 10 each center continued its usual anticoagulant regimen either by SC UFH at adjusted doses or by oral anticoagulants x 12 weeks

OutcomesMortality, VTE (venogram detected DVT), bleeding
Notes

Funding: Sanofi-Choay

Follow-up: 12 weeks

Radiologic surveillance: venography surveillance for DVT conducted at day 10

Setting: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Study was a randomized parallel group trial"
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of patients?High riskQuote: "Treatment could not be given double-blinded because of the different methods of administration and primarily the need for dose adjustment in the UFH group"
Comment: probably not
Blinding of providers?High risk

Quote: "Treatment could not be given double-blinded because of the different methods of administration and primarily the need for dose adjustment in the UFH group"

Comment: probably not

Blinding of data collectors?High risk

Quote: "Treatment could not be given double-blinded because of the different methods of administration and primarily the need for dose adjustment in the UFH group"

Comment: probably not

Blinding of outcome adjudicators?Low riskQuote: "Principal judgement criterion was evaluated blinded by two independent radiologists(coded films)"
Comment: definitely yes
Blinding of data analysts?High risk

Quote: "Treatment could not be given double-blinded because of the different methods of administration and primarily the need for dose adjustment in the UFH group"

Comment: probably not

Incomplete outcome data addressed?Low risk92% follow-up rate.
Intention-to-treat analysis?Low risk

Quote: "An intention-to-treat analysis including patients with premature cessation of treatment but in whom there was a D10 venogram was also undertaken"

Comment: probably yes

Free of selective reporting?Low riskStudy not registered. No published protocol. All relevant outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Galilei 2004

MethodsRandomized controlled trial
Participants156 patients with cancer (study subgroup) with DVT of lower extremities, PE, or both; minimum age18 years; minimum life expectancy 3 months
Interventions

Intervention: nadroparin 80 U/kg twice daily

Control: UFH 1st dose weight adjusted IV, subsequent doses SC twice daily (target aPTT 50-90 s) x 5 days warfarin (target INR 2-3) started the first 2 days x 12 weeks

OutcomesMortality, symptomatic recurrent VTE, major bleeding, heparin-induced thrombocytopenia
Notes

Funding: Gentium SpA, Como, Italy

Follow-up: 3 months

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Randomization was performed with a computer algorithm"
Allocation concealment (selection bias)Low riskQuote: "Randomization was performed with a computer algorithm and the use of a 24 hour telephone service that recorded patient information before disclosure of the treatment assigned"
Blinding of patients?High risk

Quote: "open multicenter clinical trial"

Comment: probably not

Blinding of providers?High risk

Quote: "open multicenter clinical trial"

Comment: probably not

Blinding of data collectors?High risk

Quote: "open multicenter clinical trial"

Comment: probably not

Blinding of outcome adjudicators?Low risk

Quote: "Information on all suspected outcome events and deaths was reviewed and classified by a central adjudication committee blinded to treatment assignment"

Comment: definitely yes

Blinding of data analysts?Low risk

Quote: "open multicenter clinical trial"

Comment: probably not

Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low risk

Quote: "Both analyses were performed on an intention-to-treat basis and included all patients who were randomly assigned to either strategy"

Comment: definitely yes

Free of selective reporting?Low riskStudy not registered. No published protocol. All relevant outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Hull 1992

MethodsRandomized controlled trial
Participants95 patients with cancer with proximal DVT (study subgroup); minimum age 18 years
Interventions

Intervention: tinzaparin 175 antiXa U/kg SC once daily

Control: UFH IV (target aPTT 1.5-2.5) x 6 days
Warfarin (target INR 2-3) started on day 2 for 3 months

OutcomesMortality, symptomatic VTE, bleeding
Notes

Funding: Heart and Stroke Foundation of Alberta and Novo Nordisk

Follow-up: 3 months

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: inpatient

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "A randomized, computer-derived treatment schedule was used to assign the patients to receive intravenous heparin or subcutaneous low molecular-weight heparin"
Allocation concealment (selection bias)Low riskQuote: "Before randomization, patients were stratified into groups according to a randomized, computer-derived treatment schedule was used to assign the patients to receive intravenous heparin or subcutaneous low molecular-weight heparin"
Blinding of patients?Low risk

Quote: "double blinded clinical trial"

Comment: probably yes

Blinding of providers?Low risk

Quote: "double blinded clinical trial"

Comment: probably yes

Blinding of data collectors?Low risk

Quote: "double blinded clinical trial"

Comment: probably yes

Blinding of outcome adjudicators?Low risk

Quote: "Central adjudication committee was made by two committee members not involved in the patient's care, and disputes were resolved independently by a third"

Comment: definitely yes

Blinding of data analysts?High risk

Quote: "double blinded clinical trial"

Comment: probably not

Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low riskNo loss to follow-up and all patients randomized included in the analyses of outcomes
Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Koopman 1996

MethodsRandomized controlled trial
Participants70 patients with cancer with proximal DVT without PE (study subgroup); minimum age 18 years; minimum life expectancy 6 months
Interventions

Intervention: nadroparin weight based SC twice daily at home

Control: UFH IV (target aPTT 1.5-2) x 5 days
Oral anticoagulation (target INR 2-3) started x 3 months

OutcomesMortality, recurrent symptomatic VTE, major bleeding
Notes

Funding: Sanofi Winthrop

Follow-up: 6 months

No scheduled radiologic surveillance for VTE was conducted

Setting: standard heparin was administered at the hospital and patients receiving LMWH were allowed to be treated at home

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "After the patients gave informed consent, randomization (stratified according to center) was achieved by means of a central 24 hour telephone service"
Allocation concealment (selection bias)Low riskQuote: "After the patients gave informed consent, randomization (stratified according to center) was achieved by means of a central 24 hour telephone service"
Blinding of patients?High riskQuote: "This was an unblinded study"
Blinding of providers?High riskQuote: "This was an unblinded study"
Blinding of data collectors?High riskQuote: "This was an unblinded study"
Blinding of outcome adjudicators?Low riskQuote: "Documentation of all potential outcome events, including deaths, was submitted to an independent adjudication committee whose members were unaware of the treatment assignments"
Blinding of data analysts?High riskQuote: "This was an unblinded study"
Incomplete outcome data addressed?Low risk99% follow-up rate
Intention-to-treat analysis?Low riskQuote: "The analyses were performed on an intention to treat basis"
Free of selective reporting?Low riskStudy not registered. No published protocol. All the outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Levine 1996

MethodsRandomized controlled trial
Participants103 patients with cancer with proximal or distal DVT without PE (study subgroup)
Interventions

Intervention: enoxaparin 1 mg/kg SC twice daily at home

Control: UFH IV (target aPTT 60-85 s) x 5 days
Warfarin (target INR 2-3) started on evening of 2nd day for at least 3 months

OutcomesMortality, recurrent symptomatic VTE, bleeding
Notes

Funding: not reported

Follow-up: 90 days

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: LMWH given as outpatient (mean hospital stay 1.1 ± 2.9 days); UFH given as inpatient (mean hospital stay 2.2 ± 3.8 days)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Patients were assigned to treatment through randomization over the telephone from a central line"
Allocation concealment (selection bias)Low riskQuote: "Patients were assigned to treatment through randomization over the telephone from a central line"
Blinding of patients?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of providers?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of data collectors?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of outcome adjudicators?Low risk

Quote: "All reported outcome events were reviewed by a central adjudication committee whose members were unaware of the treatment assignments"

Comment: definitely yes

Blinding of data analysts?High riskComment: probably not as no mention of blinding
Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low riskNo clear mention of ITT analysis. However, probably yes as no patients were lost to follow-up and there was no mention of cross-over
Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Lindmarker 1994

MethodsRandomized controlled trial
Participants16 patients with cancer with DVT (below the inguinal ligament) but no PE (study subgroup); minimum age 18 years
Interventions

Intervention: fragmin 200 IU/kg SC once daily

Control: UFH IV (target aPTT 1.5-3) x 5 days
Warfarin (target INR 2-3) x 3 months

OutcomesMortality, symptomatic PE, bleeding
Notes

Funding: Pharmacia AB

Follow-up: 6 months

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Randomization was organized centrally using sealed envelopes stratified for each center in a block size of 20"
Allocation concealment (selection bias)Low riskQuote: "Randomization was organized centrally using sealed envelopes stratified for each center in a block size of 20"
Blinding of patients?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of providers?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of data collectors?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of outcome adjudicators?Low riskQuote: "All venograms were interpreted by a radiologist who did not know which of the treatments the patient had received or in which order the venogram has been performed"
Blinding of data analysts?High riskComment: probably not as no mention of blinding
Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?High risk"Of the 204 patients, 14 treated with UFH and 10 with Fragmin were excluded from the efficacy analysis"
Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Lopaciuk 1992

MethodsRandomized controlled trial
Participants9 patients with cancer with proximal or calf DVT without PE (study subgroup)
Interventions

Intervention: nadroparin 92 antiXa U/kg twice daily

Control: UFH 1st dose IV, subsequent dose SC twice daily (target aPTT 1.5-2.5) x 10 days
Acenocoumarol (target INR 2-3) started the 7th day x at least 3 months

OutcomesMortality, symptomatic PE, recurrent DVT, bleeding
Notes

Funding: Sanofi

Follow-up: 3 months

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Study was a prospective, open, stratified, and randomized multicenter trial with a blind evaluation of phlebographic results"
Allocation concealment (selection bias)Low risk

Quote: "they were randomly allocated by using a sealed envelope to either Fraxiparine or UFH group"

Comment: no mention of sequential numbering and opacity

Blinding of patients?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of providers?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of data collectors?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of outcome adjudicators?Low risk

Quote: "blind evaluation of phlebographic results"

Comment: yes for evaluation of DVT events

Blinding of data analysts?High riskComment: probably not as no mention of blinding
Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low riskNo clear mention of ITT analysis. However, probably yes as no patients were lost to follow-up and there was no mention of cross-over
Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Merli 2001

MethodsRandomized controlled trial
Participants141 patients with cancer with DVT or PE (study subgroup); minimum age 18 years
Interventions

Intervention: enoxaparin 1 mg/kg SC twice daily or 1.5 mg/kg SC once daily

Control: UFH IV (target aPTT 55-80 s) x 5 days
Warfarin (target INR 2-3) started within 72 hours x 3 months

OutcomesMortality, symptomatic recurrent VTE, bleeding, drug-induced thrombocytopenia
Notes

Funding: Aventis

Follow-up: 3 months

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Patients were randomly assigned"
Allocation concealment (selection bias)Low riskQuote: "Randomization numbers were affixed to sealed treatment kits that contained study medication and were provided by the study sponsor"
Blinding of patients?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of providers?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of data collectors?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of outcome adjudicators?Low riskQuote: "Outcome adjudication committee, which provided blinded outcome assignments for incidence outcomes"
Blinding of data analysts?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low risk

Quote: "The efficacy analysis was performed on two study samples: all treated patients, who received at least one dose of study medication, and evaluable patients, which excluded all patients who met at least one of the criteria for non evaluability"

Comment: the first analysis is ITT

Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Prandoni 1992

MethodsRandomized controlled trial
Participants33 patients with cancer with proximal DVT (study subgroup), minimum age 18 years
Interventions

Intervention: fraxiparin weight based SC twice daily

Control: UFH IV (target aPTT 1.5-2.0) x 10 days
Coumarin (target INR 2-3) started on day 7 for at least 3 months

OutcomesMortality, symptomatic recurrent DVT, symptomatic PE
Notes

Funding: not reported

Follow-up: 1, 3, and 6 months

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Patients were allocated treatment by a prescribed randomisation schedule"
Allocation concealment (selection bias)Low riskQuote: "Treatment was allocated by the sealed envelop method"
Blinding of patients?High risk

Quote: "Because the two regimens were given by different routes and because dose adjustments were necessary in the standard heparin group, we could not use a double blind design"

Comment: probably not

Blinding of providers?High risk

Quote: "Because the two regimens were given by different routes and because dose adjustments were necessary in the standard heparin group, we could not use a double blind design"

Comment: probably not

Blinding of data collectors?High risk

Quote: "Because the two regimens were given by different routes and because dose adjustments were necessary in the standard heparin group, we could not use a double blind design"

Comment: probably not

Blinding of outcome adjudicators?Low risk

Quote: "All clinical endpoints were reviewed by an adjudication committee from the coordinating center, unaware of treatment allocation or other details of patients."

Comment: definitely yes

Blinding of data analysts?High risk

Quote: "Because the two regimens were given by different routes and because dose adjustments were necessary in the standard heparin group, we could not use a double blind design"

Comment: probably not

Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low riskQuote: "intention to treat analysis was used"
Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Simonneau 1993

MethodsRandomized controlled trial
Participants9 patients with cancer with proximal DVT (study subgroup); minimum age 18 years
Interventions

Intervention: enoxaparin 1 mg/kg SC twice daily

Control: UFH IV (target aPTT 1.5-2.5) x 10 days
Oral anticoagulation (target INR 2-3) started on day 10 for at least 3 months

OutcomesMortality, recurrent symptomatic VTE, bleeding
Notes

Funding: not reported

Follow-up: 3 months

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "The randomization code was drafted by means of a standard random number table randomizing in blocks of four"
Allocation concealment (selection bias)Low riskQuote: "The patients' treatment assignments were taken from sealed envelopes"
Blinding of patients?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of providers?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of data collectors?High riskComment: probably not as no mention of blinding and the compared drugs administered using 2 different routes
Blinding of outcome adjudicators?Low risk

Quote: "Venograms, perfusion lung scans, and pulmonary angiograms were subsequently reviewed by a central independent panel of two consultant specialists unaware of the treatment allocation"

Comment: definitely yes

Blinding of data analysts?High riskComment: probably not as no mention of blinding
Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low riskNo clear mention of ITT analysis. However, probably yes as no patients were lost to follow-up and there was no mention of cross-over
Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Simonneau 1997

MethodsRandomized controlled trial
Participants60 patients with cancer with PE (study subgroup); minimum age 18 years; minimum life expectancy 3 months
Interventions

Intervention: tinzaparin 175 antiXa U/kg SC once daily

Control: UFH IV (target aPTT 2-3) x 5 days
Oral anticoagulation (target INR 2-3) started on 1st to 3rd day x at least 3 months

OutcomesMortality, symptomatic recurrent VTE, major bleeding
Notes

Funding: Leo Pharmaceuticals

Follow-up: 90 days

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: the mean duration of anticoagulant treatment at a therapeutic dose before randomization was 18 ± 6 hours in the patients assigned to UFH and 18 ± 7hours in the patients assigned to LMWH

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "central randomization was performed"
Allocation concealment (selection bias)Low riskQuote: "central randomization was performed with the use of a 24 hour computer service"
Blinding of patients?High risk

Quote: "unblinded trial"

Comment: probably not

Blinding of providers?High risk

Quote: "unblinded trial"

Comment: probably not

Blinding of data collectors?High risk

Quote: "unblinded trial"

Comment: probably not

Blinding of outcome adjudicators?Low risk

Quote: "All the scans were reviewed independently and scored accordingly to this method by two readers, each unaware of the patient's treatment assignment"

Comment: definitely yes

Blinding of data analysts?High risk

Quote: "unblinded trial"

Comment: probably not

Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low risk

Quote: "The primary analysis was performed on an intention to treat basis"

Comment: definitely yes

Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

van Doormaal 2009a

MethodsRandomized controlled trial
Participants237 patients with cancer with DVT, minimum age 18 years
Interventions

Intervention: fondaparinux SC once daily in fixed dose (5 mg if patients weighed < 50 kg, or 7.5 mg if they weighed 50-100 kg, or 10 mg if they weighed > 100 kg) and twice daily SC injections of placebo that appeared identical to enoxaparin

Control: enoxaparin SC twice daily 1 mg/kg of body weight and a once daily SC injection of placebo that appeared identical to fondaparinux

In all patients, vitamin K antagonist therapy was begun as soon as possible but not later than 72 hours after commencing initial therapy

OutcomesMortality, symptomatic recurrent VTE, bleeding
Notes

Funding: Sanofi/Organon

Follow-up: 90 days

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: drug has administered by a home care service for home treatment

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Patients were randomly assigned by a computerized interactive voice response system"
Allocation concealment (selection bias)Low riskQuote: "Patients were randomly assigned by a computerized interactive voice response system"
Blinding of patients?Low risk

Quote: "double-blinded, placebo controlled study"

Comment: probably yes

Blinding of providers?Low risk

Quote: "double-blinded, placebo controlled study"

Comment: probably yes

Blinding of data collectors?Low risk

Quote: "double-blinded, placebo controlled study"

Comment: probably yes

Blinding of outcome adjudicators?Low risk

Quote: "The study used central adjudication for all clinical outcome events"

Comment: definitely yes

Blinding of data analysts?High risk

Quote: "double-blinded, placebo controlled study"

Comment: probably not

Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low risk

Quote: "The analyses were calculated in the intention to treat populations"

Comment: definitely yes

Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in methods section are reported on in the results section. All outcomes of interest, except for quality of life, reported
Free of other bias?Low riskStudy not reported as stopped early for benefit

van Doormaal 2009b

MethodsRandomized controlled trial
Participants240 patients with cancer with acute symptomatic PE, with or without associated DVT, minimum age 18 years
Interventions

Intervention: fondaparinux SC once daily in fixed dose (5 mg if patient weighed < 50 kg, or 7.5 mg if they weighed 50-100 kg, or 10 mg if they weighed > 100 kg) for 5-10 days

Control: UFH received an initial IV bolus of at least 5000 IU, followed by at least 2500 IU/hour, administered as a continuous IV infusion. The infusion was adjusted to maintain the aPTT at 1.52.5 times control value

In all patients, vitamin K antagonist therapy was begun as soon as possible but not later than 72 hours after commencing initial therapy and continued for at least 3 months

OutcomesMortality, symptomatic recurrent VTE, bleeding
Notes

Funding: Sanofi/Organon

Follow-up: 90 days

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: 14.5% of fondaparinux group received treatment on an outpatient basis

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Randomization was performed at a central location with the use of a computerized, interactive voice response system that recorded information about the patient before his or her treatment assignment"
Allocation concealment (selection bias)Low riskQuote: "Randomization was performed at a central location with the use of a computerized, interactive voice response system that recorded information about the patient before his or her treatment assignment"
Blinding of patients?High riskQuote: "was conducted on an open-label basis"
Comment: not blinded
Blinding of providers?High riskQuote: "was conducted on an open-label basis"
Comment: not blinded
Blinding of data collectors?High riskQuote: "was conducted on an open-label basis"
Comment: not blinded
Blinding of outcome adjudicators?Low risk

Quote: "All suspected outcome events were reviewed and classified by a central adjudication committee whose members were unaware of the treatment assignment"

Comment: definitely yes

Blinding of data analysts?High riskQuote: "was conducted on an open-label basis"
Comment: not blinded
Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low risk

Quote: "Efficacy analyses were based on data from all the patients who had been randomly assigned to a study group, whereas safety analyses were based on data from all the patients who actually received treatment"

Comment: yes for efficacy outcomes

Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in methods section are reported on in the results section. All outcomes of interest, except for quality of life, reported
Free of other bias?Low riskStudy not reported as stopped early for benefit

Wells 2005

  1. a

    aPTT: activated partial thromboplastin time; DVT: deep venous thrombosis; INR: international normalized ratio; ITT: intention to treat; IU: international units; IV: intravenous; LMWH: low molecular weight heparin; PE: pulmonary embolism; s: second; SC: subcutaneous; U: unit; UFH: unfractionated heparin; VTE: venous thromboembolism.

MethodsRandomized controlled trial, single blinded
Participants113 patients with cancer with upper or lower extremity, minimum age 18 years
Interventions

Intervention: tinzaparin 175 IU/kg SC once daily

Control: dalteparin SC 200 IU/kg once daily. Patients had to receive therapy on an outpatient basis

OutcomesMortality, symptomatic recurrent VTE, major bleeding, minor bleeding
Notes

Funding: Canada Research Chair from the Canadian Research Chair Program, Ottawa, Ontario (Dr. PS Wells); a research scholarship from Dalhousie University, Halifax, Nova Scotia (Dr. Anderson); an internal scholarship from the Department of Medicine, University of Western Ontario, Lon- don (Dr. Kovacs); and the Maureen Andrew New Investigator Award from the Heart and Stroke Foundation of Ontario, London (Dr. Rodger)

Follow-up: 3 months

Radiologic surveillance: no scheduled radiologic surveillance for VTE was conducted

Setting: patients had receive therapy on outpatient basis

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Randomization was performed in a computer generated blocks, with the block size unknown to the investigators"
Allocation concealment (selection bias)Low riskQuote: "Randomization assignments were concealed in opaque envelopes. Envelopes were opened sequentially and only after patient consent form was signed"
Blinding of patients?Low riskBased on personal communication with author
Blinding of providers?Low risk

Quote: "All physicians and nurses who were involved in the patient's care were blinded except for the nurse who provided the initial care to the patient"

Comment: probably yes

Blinding of data collectors?Low risk

Quote: "All physicians and nurses who were involved in the patient's care were blinded except for the nurse who provided the initial care to the patient"

Comment: probably yes

Blinding of outcome adjudicators?Low risk

Quote: "All physicians and nurses who were involved in the patient's care were blinded except for the nurse who provided the initial care to the patient"

Comment: definitely yes

Blinding of data analysts?Low riskBased on personal communication with author
Incomplete outcome data addressed?Low risk100% follow-up rate
Intention-to-treat analysis?Low risk

Quote: "The primary analysis was intention to treat"

Comment: definitely yes

Free of selective reporting?Low riskStudy not registered. No published protocol. All outcomes listed in the methods section were reported on
Free of other bias?Low riskStudy not stopped early for benefit

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Albada 1989Data for cancer subgroup not available
Altundag 2005Letter to editor
Anton 2001Review
Bauer 2000Editorial
Belcaro 1999Data for cancer subgroup not available
Bick 2003Review
Booth 1981Case report
Bratt 1985No relevant clinical outcomes
Bratt 1990Data for cancer subgroup not available
Brooks 1969Case report
Buller 2004Data for cancer subgroup not available
Dolovich 2004Review
Douketis 2000Cohort study
Eikelboom 1998Case series
Elly 1969Case report
Fiessinger 1996Data for cancer subgroup not available
Gould 1999Review
Green 1992Letter to editor
Haage 2002Review
Handeland 1990No patients with cancer in the study
Harenberg 2000Data for cancer subgroup not available
Harenberg 1990Data for cancer subgroup not available
Hettiarachchi 1998Review
Holm 1986Data for cancer subgroup not available
Holmstrom 1999Review
Hull 2000Data for cancer subgroup not available
Hull 2006Different long-term management: low molecular weight heparin in intervention arm and vitamin K antagonists in control arm
Jahanzeb 2005Review
Leizorovicz 1994Review
Levine 2001Review
Luomanmaki 1996Data for cancer subgroup not available
Martin-Carbonero 2002Cohort study
Menzoian 1983Retrospective study
Naschitz 1994Review
Prandoni 1988No control group
Prandoni 1990No cancer patients in the study
Prandoni 2005Review
Riess 2003Data for cancer subgroup not available
Sakuragi 2003Retrospective study
Siragusa 2005Not randomized
Turchetti 2003Cohort study
Warkentin 1995No relevant outcome
Wong 2003Survey

Ancillary