Anticoagulation for the long‐term treatment of venous thromboembolism in people with cancer

Abstract

Background

Cancer increases the risk of thromboembolic events, especially in people receiving anticoagulation treatments.

Objectives

To compare the efficacy and safety of low molecular weight heparins (LMWHs), direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) for the long‐term treatment of venous thromboembolism (VTE) in people with cancer.

Search methods

We conducted a literature search including a major electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE (Ovid), and Embase (Ovid); handsearching conference proceedings; checking references of included studies; use of the 'related citation' feature in PubMed and a search for ongoing studies in trial registries. As part of the living systematic review approach, we run searches continually, incorporating new evidence after it is identified. Last search date 14 May 2018.

Selection criteria

Randomized controlled trials (RCTs) assessing the benefits and harms of long‐term treatment with LMWHs, DOACs or VKAs in people with cancer and symptomatic VTE.

Data collection and analysis

We extracted data in duplicate on study characteristics and risk of bias. Outcomes included: all‐cause mortality, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and health‐related quality of life (QoL). We assessed the certainty of the evidence at the outcome level following the GRADE approach (GRADE handbook).

Main results

Of 15,785 citations, including 7602 unique citations, 16 RCTs fulfilled the eligibility criteria. These trials enrolled 5167 people with cancer and VTE.

Low molecular weight heparins versus vitamin K antagonists
 Eight studies enrolling 2327 participants compared LMWHs with VKAs. Meta‐analysis of five studies probably did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on mortality up to 12 months of follow‐up (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.13; risk difference (RD) 0 fewer per 1000, 95% CI 45 fewer to 48 more; moderate‐certainty evidence). Meta‐analysis of four studies did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on major bleeding (RR 1.09, 95% CI 0.55 to 2.12; RD 4 more per 1000, 95% CI 19 fewer to 48 more, moderate‐certainty evidence) or minor bleeding (RR 0.78, 95% CI 0.47 to 1.27; RD 38 fewer per 1000, 95% CI 92 fewer to 47 more; low‐certainty evidence), or thrombocytopenia (RR 0.94, 95% CI 0.52 to 1.69). Meta‐analysis of five studies showed that LMWHs probably reduced the recurrence of VTE compared to VKAs (RR 0.58, 95% CI 0.43 to 0.77; RD 53 fewer per 1000, 95% CI 29 fewer to 72 fewer, moderate‐certainty evidence).

Direct oral anticoagulants versus vitamin K antagonists
 Five studies enrolling 982 participants compared DOACs with VKAs. Meta‐analysis of four studies may not rule out a beneficial or harmful effect of DOACs compared to VKAs on mortality (RR 0.93, 95% CI 0.71 to 1.21; RD 12 fewer per 1000, 95% CI 51 fewer to 37 more; low‐certainty evidence), recurrent VTE (RR 0.66, 95% CI 0.33 to 1.31; RD 14 fewer per 1000, 95% CI 27 fewer to 12 more; low‐certainty evidence), major bleeding (RR 0.77, 95% CI 0.38 to 1.57, RD 8 fewer per 1000, 95% CI 22 fewer to 20 more; low‐certainty evidence), or minor bleeding (RR 0.84, 95% CI 0.58 to 1.22; RD 21 fewer per 1000, 95% CI 54 fewer to 28 more; low‐certainty evidence). One study reporting on DOAC versus VKA was published as abstract so is not included in the main analysis.

Direct oral anticoagulants versus low molecular weight heparins
 Two studies enrolling 1455 participants compared DOAC with LMWH. The study by Raskob did not rule out a beneficial or harmful effect of DOACs compared to LMWH on mortality up to 12 months of follow‐up (RR 1.07, 95% CI 0.92 to 1.25; RD 27 more per 1000, 95% CI 30 fewer to 95 more; low‐certainty evidence). The data also showed that DOACs may have shown a likely reduction in VTE recurrence up to 12 months of follow‐up compared to LMWH (RR 0.69, 95% CI 0.47 to 1.01; RD 36 fewer per 1000, 95% CI 62 fewer to 1 more; low‐certainty evidence). DOAC may have increased major bleeding at 12 months of follow‐up compared to LMWH (RR 1.71, 95% CI 1.01 to 2.88; RD 29 more per 1000, 95% CI 0 fewer to 78 more; low‐certainty evidence) and likely increased minor bleeding up to 12 months of follow‐up compared to LMWH (RR 1.31, 95% CI 0.95 to 1.80; RD 35 more per 1000, 95% CI 6 fewer to 92 more; low‐certainty evidence). The second study on DOAC versus LMWH was published as an abstract and is not included in the main analysis.

Idraparinux versus vitamin K antagonists
 One RCT with 284 participants compared once‐weekly subcutaneous injection of idraparinux versus standard treatment (parenteral anticoagulation followed by warfarin or acenocoumarol) for three or six months. The data probably did not rule out a beneficial or harmful effect of idraparinux compared to VKAs on mortality at six months (RR 1.11, 95% CI 0.78 to 1.59; RD 31 more per 1000, 95% CI 62 fewer to 167 more; moderate‐certainty evidence), VTE recurrence at six months (RR 0.46, 95% CI 0.16 to 1.32; RD 42 fewer per 1000, 95% CI 65 fewer to 25 more; low‐certainty evidence) or major bleeding (RR 1.11, 95% CI 0.35 to 3.56; RD 4 more per 1000, 95% CI 25 fewer to 98 more; low‐certainty evidence).

Authors' conclusions

For the long‐term treatment of VTE in people with cancer, evidence shows that LMWHs compared to VKAs probably produces an important reduction in VTE and DOACs compared to LMWH, may likely reduce VTE but may increase risk of major bleeding. Decisions for a person with cancer and VTE to start long‐term LMWHs versus oral anticoagulation should balance benefits and harms and integrate the person's values and preferences for the important outcomes and alternative management strategies.

Editorial note: this is a living systematic review (LSR). LSRs offer new approaches to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Plain language summary

Blood thinners for the long‐term treatment of blood clots in people with cancer

Background
 People with cancer are at an increased risk of developing blood clots and might respond differently to different types of blood thinners (anticoagulants).

Study characteristics
 We searched scientific databases for clinical trials looking at the effects of long‐term treatment with different blood thinners on blood clot recurrence in people with cancer with a confirmed diagnosis of deep venous thrombosis (a blood clot in the limbs) or pulmonary embolism (a blood clot in the lungs). We included trials with any type of cancer, and irrespective of the type of cancer treatment. The trials looked at survival, recurrent blood clot, bleeding and blood platelet levels (which are involved in blood clotting). The evidence was current to May 2018.

Key results
 We found 16 trials enrolling 5167 participants with cancer and blood clots. The studies found that low molecular weight heparins (LMWHs; a type of blood thinner that is injected into a vein) were superior to vitamin K antagonists (VKAs; a type of blood thinner taken by mouth (oral)) in reducing the recurrence of blood clots. The available data did not provide a clear answer about the effects of these drugs on death and the side effect of bleeding. The studies also found that direct oral anticoagulants (DOACs; another type of blood thinner taken by mouth) might decrease the recurrence of blood clots compared to LMWH while increasing the risk of bleeding. There was no clear answer when comparing DOACs (a newer type of oral blood thinner) and VKAs (an older type of oral blood thinner) for death, blood clot recurrence and bleeding.

Reliability of the evidence
 When comparing LMWHs to VKAs, we judged the certainty of the evidence to be moderate for recurrent blood clots, death at one year and major bleeding, and low for minor bleeding.

When comparing DOACs to VKAs, we judged the certainty of the evidence to be low for death, recurrent blood clots and bleeding complications.

Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.