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Most blood clot treatments demonstrate similar efficacy, safety
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Clinicians and patients have several anticoagulant options in the treatment of venous thromboembolism, and results from a Canadian study showed there are no significant differences in clinical and safety outcomes among most of them.
Marc Carrier, MD, MSc, physician and scientist at The Ottawa Hospital and associate professor at the University of Ottawa, and colleagues conducted a systematic review and meta-analysis of eight anticoagulation options to compare their efficacy and safety outcomes for the treatment of VTE.
The options reviewed were unfractionated heparin (UFH), low–molecular-weight heparin (LMWH), fondaparinux combined with vitamin K antagonists, LMWH with dabigatran (Pradaxa, Boehringer Ingelheim), LMWH with edoxaban (Savaysa, Daiichi Sankyo), LMWH with rivaroxaban (Xarelto, Janssen), LMWH with apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and LMWH alone.
Using meta-analytic pooling, the researchers found no statistically significant differences for safety and efficacy of most treatment strategies when compared with the LMWH–vitamin K antagonist combination. However, the findings suggested that the UFH–vitamin K antagonist combination is associated with the least effective strategy and that rivaroxaban and apixaban may be associated with the lowest risk for bleeding.
The investigators identified 1,197 eligible studies that were randomized trials reporting rates of recurrent VTE and major bleeding in patients with acute VTE. From that population, 45 trials that included 44,989 patients were used for the analysis.
The primary outcome measure was recurrent VTE and major bleeding episodes. Secondary outcomes included fatal recurrent VTE and fatal bleeding episodes.
The included studies had sample sizes ranging from 60 to 8,240 patients, with a median sample size of 298. The median follow-up was 3 months (range, 3-8.2).
In comparison with the LMWH–vitamin K antagonist combination, all treatment strategies except the UFH–vitamin K antagonist combination were associated with a lower rate of recurrent VTE events.
The UFH–vitamin K antagonist combination was associated with an increased rate of recurrent VTE (HR=1.42; 95% CI, 1.15-1.79). When the UFH–vitamin K antagonist combination was used as a comparator, the LMWH alone and the LMWH–vitamin K antagonist combination were associated with a reduction in recurrent VTE rates. There were no significant differences in all other treatment strategies.
The LMWH–edoxaban combination and apixaban were associated with the greatest probability of being the best therapy among all treatment strategies evaluated, at 33.1% and 31.6%, respectively.
The UFH–vitamin K antagonist combination was associated with a higher percentage of patients experiencing recurrent VTE during 3 months of treatment (1.84%; 95% CI, 1.33-2.51) than patients taking the LMWH–vitamin K antagonist combination (1.3%; 95% CI, 1.02-1.62).
It also was associated with the lowest efficacy and was associated with an increased risk for recurrent VTE (HR=1.74; 95% CI, 1.27-2.44).
Compared with the LMWH–vitamin K antagonist combination, rivaroxaban (HR=0.55; 95% CI, 0.35-0.89) and apixaban (HR=0.31; 95% CI, 0.15-0.62) were associated with the lowest bleeding risks.
Apixaban was associated with the greatest probability of being the least harmful therapy (88.9%) among all treatment regimens assessed.
Fatal events were rare, with 0.37% experiencing fatal recurrent VTE and 0.14% experiencing fatal bleeding events.
"To our knowledge, this network meta-analysis is the largest review, including nearly 45,000 patients, assessing the clinical outcomes and safety associated with different anticoagulation strategies for the treatment of acute venous thromboembolism,” Carrier and colleagues wrote. “We provide estimates on symptomatic recurrent venous thromboembolism and major bleeding outcomes (both patient-important outcomes), which are clinically relevant and are what clinical practice guideline recommendations are based on.”
Disclosure: The researchers report research support from, as well as payment for lecture fees or other speakers’ roles from, Bayer, bioMèrieux, Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma, Pfizer and Sanofi.
Perspective
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Kenneth A. Bauer, MD
Treatment of symptomatic venous thromboembolism with anticoagulation is highly effective in reducing morbidity and mortality. Clinical trials have evaluated the efficacy and safety of treating proximal deep venous thrombosis and pulmonary emboli with various parenteral agents (either unfractionated heparin, low–molecular-weight heparin or fondaparinux) followed by a vitamin K antagonist. More recently, several target-specific oral anticoagulants were evaluated in comparison with low–molecular-weight heparin in combination with warfarin.Castellucci and colleagues carried out a meta-analysis of clinical trials to compare the various anticoagulation strategies. They found that most regimens were similar in efficacy and safety. However, the use of unfractionated heparin as initial treatment was associated with a higher on-treatment recurrence rate at 3 months compared with low–molecular weight heparin (HR = 1.42; 95% CI, 1.15-1.79). They also found that the oral Factor Xa inhibitors rivaroxaban and apixaban, administered alone for initial therapy of venous thromboembolism, were associated with a significantly reduced risk for major bleeding at 3 months compared with the combination of low–molecular weight heparin and warfarin (HR = 0.49; 95% CI, 0.29-0.85).
This study provides further support for a safety advantage with respect to bleeding for several of the target-specific oral anticoagulants, excluding patients with active cancer or significant renal impairment (ie, creatinine clearance <30 mL/min). Decisions with regard to using target-specific anticoagulants for initial treatment or long-term secondary prevention of venous thromboembolism, however, need to be individualized. Other patient-specific factors that need to be considered include adherence, preference, out-of-pocket costs, extremes of body weight, clot burden at diagnosis and presence of some types of hypercoagulable states (eg, antiphospholipid antibody syndrome).
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