Low Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Selection
2.1.1. Patients
2.1.2. Interventions
2.1.3. Outcomes
2.2. Data Sources and Searches
2.3. Data Extraction and Quality Assessment
2.4. Data Synthesis and Analysis
2.4.1. Assessment of Significance
2.4.2. Meta-Analysis
2.4.3. Trial Sequential Analysis
2.4.4. Assessment of Heterogeneity
2.4.5. Subgroup Analysis
2.4.6. Sensitivity Analysis
2.5. GRADE
3. Results
3.1. Characteristics of the Included Studies
3.2. Bias Risk Assessment
3.3. Co-Primary Outcomes
3.3.1. All-Cause Mortality
3.3.2. Symptomatic Venous Thromboembolism
3.3.3. Major Bleeding
3.4. Secondary Outcomes
3.4.1. Serious Adverse Events
3.4.2. Clinically Relevant Non-Major Bleeding
3.4.3. Any Venous Thromboembolism
4. Discussion
4.1. Considerations on the Optimal Prophylactic Dose
4.2. Implications for Clinical Practice
4.3. Strengths and Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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LMWH Type | A Priori Defined as Low-Dose LMWH | Dose Used in Included Trials |
---|---|---|
Bemiparin | <3500 IU | 2500 IU |
Certoparin | <5000 IU | 3000 IU |
Dalteparin | <5000 IU | 2500 IU a |
Enoxaparin | <40 mg | 20 mg |
Nadroparin | <5700 IU | 2850–3800 IU b,c |
Parnaparin | <4250 IU | 3200 IU |
Reviparin | <3436 IU | 1750 IU |
Tinzaparin | <4500 IU | 3500 IU d |
Outcome | Included Trials | Trials (Patients) | Conventional Meta-Analysis a | Primary TSA a α 2.5%; ß 90%; RRR 20%; D2 Model Variance Based | Sensitivity TSA a α 2.5%; ß 90%; RRR Based on Low Risk Trials; D2 Model Variance Based | Sensitivity TSA a α 2.5%; ß 90%; RRR 20%; D2 25% | Certainty of Evidence |
---|---|---|---|---|---|---|---|
Mortality | Low bias risk | 5 (4.960) | RR 1.03 (0.92 to 1.16) | RR 1.03 (0.88 to 1.20) | Insufficient data (<5% of DIS) | RR 1.03 (0.86 to 1.23) | Low d, e, f |
All | 23 (15.487) | RR 0.99 (0.85 to 1.14) | RR 1.02 (0.89 to 1.16) b | Insufficient data (<5% of DIS) | RR 1.02 (0.90 to 1.15) | Low d, g | |
Symptomatic VTE | Low bias risk | 5 (4.878) | RR 0.65 (0.45 to 0.94) | RR 0.67 (0.15 to 3.05) | RR 0.67 (0.32 to 1.38) | 0.67 (0.15 to 3.05) | Moderate e |
All | 25 (15.920) | RR 0.62 (0.48 to 0.81) | RR 0.62 (0.44 to 0.89) c | RR 0.62 (0.42 to 0.92) | RR 0.62 (0.20 to 1.95) | Moderate g | |
Major bleeding | Low bias risk | 5 (4.960) | RR 1.70 (0.77 to 3.74) | Insufficient data (<5% of DIS) | Insufficient data (<5% of DIS) | Insufficient data (<5% of DIS) | Moderate f |
All | 33 (13.091) | RR 1.07 (0.72 to 1.59) | RR 1.01 (0.18 to 5.73) c | RR 1.01 (0.52 to 1.93) | RR 1.09 (0.75 to 1.60) | Low e, f, g | |
SAE | Low bias risk | 1 (1.150) | RR 0.89 (0.68 to 1.17) | RR 0.89 (0.41 to 1.96) | RR 0.89 (0.27 to 2.96) | RR 0.89 (0.36 to 2.23) | Low e, f, h |
All | 8 (5.180) | RR 0.98 (0.78 to 1.25) | RR 0.98 (0.37 to 2.58) | Insufficient data (<5% of DIS) | RR 0.98 (0.77 to 1.24) | Very low d, e, f, g | |
Clinically relevant non-major bleeding | Low bias risk | 0 (0) | - | - | - | - | - |
All | 5 (3.372) | RR 1.50 (0.72 to 3.12) | Insufficient data (<5% of DIS) | Insufficient data (<5% of DIS) | Insufficient data (<5% of DIS) | Very low d, e, f, g | |
Any VTE | Low bias risk | 3 (1.254) | RR 0.57 (0.38 to 0.84) | RR 0.57 (0.11 to 2.82) | RR 0.57 (0.32 to 1.01) | Not performed (D2 >25%) | Moderate e, i, k |
All | 30 (5.849) | RR 0.61 (0.50 to 0.75) | RR 0.63 (0.49 to 0.82) | RR 0.63 (0.50 to 0.80) | Not performed (D2 >25%) | Low e, i, j, k |
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Eck, R.J.; Bult, W.; Wetterslev, J.; Gans, R.O.B.; Meijer, K.; van der Horst, I.C.C.; Keus, F. Low Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis. J. Clin. Med. 2019, 8, 2039. https://doi.org/10.3390/jcm8122039
Eck RJ, Bult W, Wetterslev J, Gans ROB, Meijer K, van der Horst ICC, Keus F. Low Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis. Journal of Clinical Medicine. 2019; 8(12):2039. https://doi.org/10.3390/jcm8122039
Chicago/Turabian StyleEck, Ruben J., Wouter Bult, Jørn Wetterslev, Reinold O. B. Gans, Karina Meijer, Iwan C.C. van der Horst, and Frederik Keus. 2019. "Low Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis" Journal of Clinical Medicine 8, no. 12: 2039. https://doi.org/10.3390/jcm8122039
APA StyleEck, R. J., Bult, W., Wetterslev, J., Gans, R. O. B., Meijer, K., van der Horst, I. C. C., & Keus, F. (2019). Low Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis. Journal of Clinical Medicine, 8(12), 2039. https://doi.org/10.3390/jcm8122039