Randomized, pilot study of intermittent pneumatic compression devices plus dalteparin versus intermittent pneumatic compression devices plus heparin for prevention of venous thromboembolism in patients undergoing craniotomy

doi:10.1016/S0090-3019(03)00111-3

Surgical Neurology

Volume 59, Issue 5, May 2003, Pages 362-371

https://doi.org/10.1016/S0090-3019(03)00111-3 Get rights and content

Abstract

Background

Unfractionated heparin and the low molecular weight heparin, dalteparin, are used for prophylaxis against venous thromboembolism in patients undergoing craniotomy. These drugs were compared in a randomized, prospective pilot study comparing intermittent pneumatic compression devices plus dalteparin to intermittent pneumatic compression devices plus heparin.

Methods

One hundred patients undergoing craniotomy were randomly allocated to receive perioperative prophylaxis with subcutaneous (SC heparin, 5000 units every 12 hours, or dalteparin, 2,500 units once a day, begun at induction of anesthesia and continued for 7 days or until the patient was ambulating. Entry criteria were age over 18 years, no deep vein thrombosis (DVT) preoperatively as judged by lower limb duplex ultrasound and no clinical evidence of pulmonary embolism preoperatively. Patients with hypersensitivity to heparin, penetrating head injury or who refused informed consent were excluded. Patients underwent a duplex study 1 week after surgery and 1 month clinical follow-up. All patients were treated with lower limb intermittent pneumatic compression devices.

Results

There were no differences between groups in age, gender, and risk factors for venous thromboembolism. There were no differences between groups in intraoperative blood loss, transfusion requirements or postoperative platelet counts. Two patients receiving dalteparin developed DVT (one symptomatic and one asymptomatic). No patient treated with heparin developed DVT and no patient in either group developed pulmonary embolism. There were two hemorrhages that did not require repeat craniotomy in patients receiving dalteparin and one that did require surgical evacuation in a patient treated with heparin. Drug was stopped in two patients treated with dalteparin because of thrombocytopenia. None of these differences were statistically significant.

Conclusion

There was no significant difference in postoperative hemorrhage, venous thromboembolism or thrombocytopenia between heparin and dalteparin. The results suggest that, given the small sample size of this trial, both drugs appear to be safe and the incidence of venous thromboembolism by postoperative screening duplex ultrasound appears to be low when these agents are used in combination with intermittent pneumatic compression devices.

Section snippets

Protocol

One hundred consecutive patients who met entry criteria were allocated by blinded, block randomization to receive heparin, 5000 U SC twice daily or dalteparin, 2500 U factor Xa activity SC once daily, starting at the time of surgery and continued for 1 week postoperatively (Figure 1). Randomization was by computer-generated blocks of four. When a patient gave informed consent, the pharmacy was notified and a pharmacist not otherwise involved in the study opened an envelope containing the group

Results

Patients were entered between September, 1998 and December, 1999. During this time, an additional 106 patients were screened and excluded for the following reasons: no informed consent [84], preoperative abnormal coagulation parameters [10], preoperative treatment with anticoagulants [2], preoperative DVT [4], pregnancy [2], and attending surgeon preference [4]. Four patients were excluded because they had preoperative DVT at some time in the past. One was a 69-year-old man who presented with

Discussion

This pilot study found no major differences in safety, assessed by risk of postoperative intracranial hemorrhage and efficacy assessed by venous thromboembolism, between low-dose unfractionated heparin and dalteparin. While we did not detect differences, the rates of venous thromboembolism, thrombocytopenia and intracranial hemorrhage were low. Power calculations suggest that to detect what would be an important 50% reduction from 3 to 1.5%, 5,000 patients would have to be randomized. The rate

Conclusions

The results of this trial, which has only a small sample size, suggest that both drugs appear to be safe and the incidence of venous thromboembolism by postoperative screening duplex ultrasound appears to be low when these agents are used in combination with intermittent pneumatic compression devices. Additional randomized studies are needed to address duration of prophylaxis and to study the effects of combined mechanical and pharmacological prophylaxis and of heparin versus low molecular

Acknowledgments

The study was supported by a grant from Pharmacia-Upjohn.

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The rate of DVT was almost as prevalent as SCITI 2003 study. A study by Macdonald et al. investigate the use of dalteparin + IPC vs. heparin + IPC in patients undergoing craniotomy, in this study, both drugs were found to be safe [19]. The rate of VTE in the aforementioned study was 2 % (both were DVT) [19] similar to the pooled DVT incidence in IPC group of this meta-analysis.
The incidence of venous thromboembolism (VTE) remains high despite the use of low-molecular weight heparin (LMWH) and compression stocking (CS). We aimed to evaluate the use of IPC as VTE prophylaxis in neurosurgical patients.
We conducted meta-analysis to assess the use of IPC as VTE prophylaxis in neurosurgical patients from several databases.
There was a total of 7.515 subjects from 5 studies. Reduction in VTE incidence was demonstrated by the IPC group (OR 0.40 [0.31, 0.52], p < 0.001; I²: 44 %). IPC was shown to reduce the incidence of deep venous thrombosis (DVT) (OR 0.43 [0.32, 0.57], p < 0.001; I²: 0 %) compared to the control group. Incidence of pulmonary embolism (PE) was lower (OR 0.42 [0.25, 0.70], p < 0.001; I²: 80 %) in IPC. Upon sensitivity analysis, PE was significantly lower in IPC (OR 0.24 [0.13, 0.45], p < 0.001; I²: 0 %). Subgroup analysis on patients undergoing neurosurgical intervention (operation) and receiving LMWH + CS shows a markedly reduced incidence of VTE (OR 0.37 [0.28, 0.50], p < 0.001; I²: 3 %), DVT (OR 0.39 [0.28, 0.54], p < 0.001; I²: 0 %), and PE (OR 0.22 [0.11, 0.43], p < 0.001; I²: 0 %) in IPC.
Intermittent pneumatic compression was associated with less VTE in neurosurgical patients, especially in those who received neurosurgical interventions, however, the certainty of evidence remained inadequate for creating a strong recommendation and further randomized controlled trials are needed before drawing a definite conclusion.
American Society of Hematology 2019 guidelines for management of venous thromboembolism: Prevention of venous thromboembolism in surgical hospitalized patients
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Background: Venous thromboembolism (VTE) is a common source of perioperative morbidity and mortality.
Objective: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about preventing VTE in patients undergoing surgery.
Methods: ASH formed a multidisciplinary guideline panel balanced to minimize bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic reviews. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment.
Results: The panel agreed on 30 recommendations, including for major surgery in general (n = 8), orthopedic surgery (n = 7), major general surgery (n = 3), major neurosurgical procedures (n = 2), urological surgery (n = 4), cardiac surgery and major vascular surgery (n = 2), major trauma (n = 2), and major gynecological surgery (n = 2).
Conclusions: For patients undergoing major surgery in general, the panel made conditional recommendations for mechanical prophylaxis over no prophylaxis, for pneumatic compression prophylaxis over graduated compression stockings, and against inferior vena cava filters. In patients undergoing total hip or total knee arthroplasty, conditional recommendations included using either aspirin or anticoagulants, as well as for a direct oral anticoagulant over low-molecular-weight heparin (LMWH). For major general surgery, the panel suggested pharmacological prophylaxis over no prophylaxis, using LMWH or unfractionated heparin. For major neurosurgery, transurethral resection of the prostate, or radical prostatectomy, the panel suggested against pharmacological prophylaxis. For major trauma surgery or major gynecological surgery, the panel suggested pharmacological prophylaxis over no prophylaxis.
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While prophylaxis with intravenous unfractionated heparin (UFH) can effectively prevent venous thromboembolism (VTE) during the neurocritical care of patients with severe aneurysmal subarachnoid hemorrhage (aSAH), the risk for intracranial bleeding complications might increase. Owing to this therapeutic dilemma, the UFH administration regimen in this critical patient population remains highly controversial.
We performed a retrospective analysis of patients with severe aSAH (Fisher grade 3-4) receiving either low-dose (activated partial thromboplastin time [aPTT] <40 seconds) or therapeutic range (aPTT 50–60 seconds) UFH during intensive care unit (ICU) treatment after complete surgical/endovascular aneurysm occlusion. The primary outcome was the rate of bleeding/VTE complications and the investigation of potential risk factors.
This study series comprised 410 patients with aneurysmal SAH (aSAH), with a mean age of 54.7 ± 12.6 years, a male:female ratio of 1:2.2, and aSAH-associated intracerebral hemorrhage (ICH) in 33.2%. After complete aneurysm occlusion, 112 patients (27.3%) received therapeutic dose UFH and 298 patients (72.7%) received low-dose UFH. VTE events occurred in 5.4% of the low-dose UFH cohort and in 6.3% of the therapeutic dose UFH cohort, with no significant differences in the rate and severity of VTE events. However, an increase in initial SAH-associated ICH was significantly (P = 0.007) more frequent in the therapeutic dose cohort (18.8% vs. 3.4%). Heparin-induced thrombocytopenia (HIT) was the sole risk factor for VTE (P < 0.001), and both an aPTT ≥50 seconds under UFH administration (P = 0.007) and the initial presence of SAH-associated ICH (P = 0.035) were significant risk factors for intracranial bleeding complications.
Even in high-risk neurocritical patients with severe SAH and prolonged ICU treatment, low-dose UFH-administration for VTE prophylaxis is equally effective as therapeutic UFH administration and carries a lower risk of bleeding complications.
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Also the neurosurgical literature has documented a reduction in the incidence of DVT with heparin use, although concerns regarding the increased propensity for hemorrhage have limited uniform and widespread application of the drug [7,9,18,24,26,41,60,66]. In fact, whereas mechanical prophylaxis with IPC used intra-operatively and postoperatively poses little to no risk in neurosurgical patients, the risk of hemorrhagic complications related to low-dose subcutaneous UFH or LMWH regimens may prove devastating in preventing the neurosurgical community to reach a formal agreement [39]. In a neurosurgical series (cranial and spinal) published more than 20 years ago by Frim et al. [18], the efficacy of mechanical compression alone or plus low-dose subcutaneous UFH/LMWH prophylaxis was prospectively analyzed.
To analytically discuss some protocols in Deep vein thrombosis (DVT)/pulmonary Embolism (PE) prophylaxis currently use in Neurosurgical Departments around the world.
Analysis of the prophylaxis protocols in the English literature: An analytical and narrative review of literature concerning DVT prophylaxis protocols in Neurosurgery have been conducted by a PubMed search (back to 1978).
80 abstracts were reviewed, and 74 articles were extracted.
The majority of DVT seems to develop within the first week after a neurosurgical procedure, and a linear correlation between the duration of surgery and DVT occurrence has been highlighted. The incidence of DVT seems greater for cranial (7.7%) than spinal procedures (1.5%). Although intermittent pneumatic compression (IPC) devices provided adequate reduction of DVT/PE in some cranial and combined cranial/spinal series, low-dose subcutaneous unfractionated heparin (UFH) or low molecular-weight heparin (LMWH) further reduced the incidence, not always of DVT, but of PE. Nevertheless, low-dose heparin-based prophylaxis in cranial and spinal series risks minor and major postoperative haemorrhages: 2–4% in cranial series, 3.4% minor and 3.4% major haemorrhages in combined cranial/spinal series, and a 0.7% incidence of major/minor haemorrhages in spinal series.
This analysis showed that currently most of the articles are represented by case series and case reports. As long as clear guidelines will not be defined and universally applied to this diverse group of patients, any prophylaxis for DVT and PE should be tailored to the individual patient with cautious assessment of benefits versus risks.

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Surgery complicationsRandomized, pilot study of intermittent pneumatic compression devices plus dalteparin versus intermittent pneumatic compression devices plus heparin for prevention of venous thromboembolism in patients undergoing craniotomy

Abstract

Background

Methods

Results

Conclusion

Section snippets

Protocol

Results

Discussion

Conclusions

Acknowledgments

Thromb Res

Chest

Med Clin North Am

Chest

Lancet

Thromb Res

Thromb Res

Med Clin North Am

Surg Neurol

Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery

N Engl J Med

Safety of mini-dose heparin administration for neurosurgical patients

J Neurosurg

Experience with external pneumatic calf compression in neurology and neurosurgery

Neurosurgery

External pneumatic calf compression reduces deep venous thrombosis in patients with ruptured intracranial aneurysms

Neurosurgery

Post-operative thromboembolism in neurosurgery. A study on the prophylactic effect of calf muscle stimulation plus dextran compared to low-dose heparin

Acta Neurochir

Does peroperative external pneumatic leg muscle compression prevent post-operative venous thrombosis in neurosurgery?

Acta Neurochir

Deep vein thrombosis and low-dose heparin prophylaxis in neurosurgical patients

J Neurosurg

Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparinoverview of results of randomized clinical trials in general, orthopedic, and urologic surgery

N Engl J Med

Safety of perioperative minidose heparin in patients undergoing brain tumor surgerya prospective, randomized, double-blind study

J Neurosurg

Enoxaparin increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors

Neurosurgery

Postoperative low-dose heparin decreases thromboembolic complications in neurosurgical patients

Neurosurgery

Venous thromboembolism prophylaxis in the craniotomy patientan editorial

Surg Neurol

Surgery complications
Randomized, pilot study of intermittent pneumatic compression devices plus dalteparin versus intermittent pneumatic compression devices plus heparin for prevention of venous thromboembolism in patients undergoing craniotomy