Is there evidence to support that one anticoagulation protocol is preferred over another following head and neck free flap surgery that would reduce the risk of flap complications such as venous thrombosis, arterial thrombosis, or hematoma?

Comment by InpharmD Researcher

There does not appear to be convincing evidence to support one anticoagulation protocol over another following head and neck free flap surgery. In general, the use of anticoagulation including unfractionated heparin, low-molecular-weight heparin, or antiplatelet therapy has not been found to be beneficial and has actually been observed to increase flap complications such as thrombosis and hematoma.

Background

A 2022 meta-analysis did not find a benefit for the routine use of additional anticoagulation to reduce the risk of free flap failure in head and neck surgery. Moreover, there may be an increased risk of hematoma and bleeding complications with anticoagulation. From 8 randomized controlled and observational studies (N= 3,531) of patients undergoing head and neck surgery, the cumulative anticoagulated group reported a non-significantly increased risk ratio (RR) of 1.54 (95% confidence interval [CI] 0.73 to 3.23; p= 0.25) for flap free complications versus control while there was a significantly increased risk of hematoma and bleeding requiring intervention (RR 2.98; 95% CI 1.47 to 6.07). Based on the lack of benefit in reducing free flap failure along with a significant risk of bleeding complications, the authors recommend limiting anticoagulation to standard prophylactic use of low-molecular-weight heparin in the perioperative setting without additional anticoagulation. [1]

A multicenter, individual patient data meta-analysis investigated the effectiveness of postoperative anticoagulants to improve survival after free radial forearm flap (FRFF) in head and neck reconstruction. A total of four studies were available for meta-analysis (n= 759 FRFF procedures). Anticoagulants used in procedures included aspirin (12%), low-molecular-weight dextran (18.3%), unfractionated heparin (28.1%), low-molecular-weight heparin (49%), and prostaglandin-E1 (2.1%); there were 31% of patients who did not receive anticoagulation. Outcomes evaluated included flap failure, defined as flap failure with or without revision surgery, and flap complications including bleeding, wound infection, seroma, fistula formation, and (partial) flap failure. Pooled analysis indicated that initial flap failure occurred in 90 (12%) patients. The rate of flap failure was significantly greater with heparin (odds ratio [OR] 3.99; 95% CI 1.579 to 10.082; p= 0.003) and LMWH (OR 5.429; 95% CI 1.671 to 17.64; p= 0.005) compared to no anticoagulation. No difference in flap failure was reported between aspirin or low-molecular-weight dextran and no anticoagulation. Further, the univariate analysis determined anticoagulation use resulted in significantly more flap failure (OR 2.6; 95% CI 1.1 to 6.4; p <0.05), specifically with aspirin and heparin/LMWH, and flap complications (OR 2.2; 95% CI 1.1 to 4.1; p <0.05) compared to no anticoagulation use. [2]

A 2015 meta-analysis investigated the efficacy and safety of heparin or low-molecular-weight heparin (LMWH) along with other antithrombotics for the development of various flap complications, including flap failure and pedicle thrombosis. Heparin and LMWH were grouped together due to their comparable antithrombotic activity. Four clinical trials (N= 1,796) were analyzed which reported a non-significant but lower risk of total flap loss in the heparin and LMWH group versus comparator (relative risk [RR] 0.65; 95% CI 0.25 to 1.69). The risk of thrombosis was also not significantly lower in the heparin and LMWH group (RR 0.84; 95% CI 0.07 to 8.70). However, the risk of hematoma was significantly greater in the heparin group (4.15-fold increased risk) although limited data prevented investigation in the LMWH group. While the majority of studies were head and neck surgeries, other upper extremity sites were also included in the meta-analysis, limiting the applicability of results to the specific population. [3]

A 2018 meta-analysis that included 2,048 free-flap surgery procedures in the head and neck determined there to be no significant difference in the occurrence of flap loss (RR 1.25; 95% CI 0.85 to 1.81; p= 0.26) and thromboembolic events (RR 1.05; 95% CI 0.74 to 1.48; p= 0.79) when anticoagulation was utilized compared with no anticoagulation. Additionally, the risk of hematoma was significantly higher when anticoagulation was utilized compared to when no anticoagulation was used (RR 2.02; 95% CI 1.08 to 3.76; p= 0.03). These results indicate the lack of benefit of postoperative anticoagulation therapy for reducing the risk of flap loss and thromboembolic events in free-flap surgery in the head and neck. It should be noted that this analysis is limited due to the inclusion of only retrospective studies. [4]

A 2014 meta-analysis focused on heparin for the prevention of flap loss during head, neck, and upper extremity surgery. Data was limited to 4 studies of which were divided into two categories: heparin versus aspirin and high-dose heparin/dalteparin versus low-dose heparin/dalteparin. The two studies comparing heparin versus aspirin reported a combined OR of 2.003 (95% CI 0.976 to 4.109; p= 0.058) which was not significantly different. The high-dose versus low-dose study reported an OR of 7.810 (95% CI 1.859 to 32.808; p= 0.005) which indicates significantly greater odds of flap loss rates in patients receiving high doses of heparin and dalteparin. Individually, the single study focused on heparin reported an OR of 11.00 which significantly associates high-dose heparin with a greater flap loss rate (p= 0.011). The single dalteparin study trended towards association but was not significant (OR 4.691; p= 0.181). The findings are limited due to the limited number of studies and statistical power. [5]

A 2018 review presented the available evidence for thromboprophylaxis in otolaryngology or head and neck surgeries. Subcutaneous heparin appears to not be associated with increased adverse flap outcomes, based on individual studies. However, a cited meta-analysis reported a significantly increased risk of hematoma, despite reducing the risk of flap loss by 35%. A combination of subcutaneous heparin and aspirin is frequently reported in practice but may increase complication rates and the benefit of aspirin remains suspect. There is limited information regarding intravenous heparin in head and neck surgery, but some studies related to free tissue transfer suggest an increased risk of bleeding complications with heparin drips and continuous infusions at doses above 500 U/hour. Low-molecular-weight heparin has also demonstrated a similar and potentially lower risk of bleeding complications versus unfractionated heparin, while other studies suggest inferiority. Because of this, the use of low-molecular-weight heparin remains controversial and requires further investigation. [6]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Postoperative Management of Antithrombotic Medication in Microvascular Head and Neck Reconstruction: A Comparative Analysis of Unfractionated and Low-Molecular-Weight Heparin
Design	Single-center, retrospective analysis N= 266
Objective	To compare low-dose unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in perioperative thrombosis prophylaxis
Study Groups	UFH (n= 87) LMWH (n= 179)
Inclusion Criteria	Patients with ablative surgical procedures and microvascular flap transplantation that received postoperative therapy with either low-dose UFH (500 IU/h) or LMWH (20/40 mg daily)
Exclusion Criteria	Did not receive low-dose UFH or LMWH protocol
Methods	The operating surgeon decided whether to administer either low-dose UFH or subcutaneous LMWH after surgery. Intravenous low-dose UFH was given as a 500 IU/h infusion. LMWH was given per standard protocol with enoxaparin. Each individual's risk of thrombosis was assessed and those with low peri- and postoperative thrombosis risk received 20 mg of enoxaparin once a day. Patients with medium to high thrombosis risk (e.g., obesity) received 40 mg of enoxaparin once a day. Other anticoagulants that would influence the coagulation time were not administered.
Duration	Antithrombotic therapy: 5 days postoperation Average follow-up: 65.4 ± 42.3 months Procedure completed: January 2004 to July 2017
Outcome Measures	Primary: total frequency of transplant thrombosis and number of flap failures Secondary: occurrence of peri- and postoperative complications (minor complications defined as treatable with sufficient conservative therapy; major complications defined as requiring surgical revision)
Baseline Characteristics		UFH (n= 87)	LMWH (n= 179)	p-value
	Age, years	57.9 ± 11.2	59.7 ± 10.5	0.202
	Male	72 (82.8%)	138 (77.1%)	0.288
	Location of Primary Oral Cavity Oropharynx Hypopharynx Larynx Other	16 (18.4%) 41 (47.1%) 16 (18.4%) 3 (3.4%) 11 (12.6%)	27 (15.1%) 95 (53.1%) 24 (13.4%) 14 (7.8%) 19 (10.6%)	0.443
	Tumor Stage T1 T2 T3 T4	n= 82 11 (13.4%) 23 (28.1%) 28 (34.1%) 20 (24.4%)	n= 174 16 (9.2%) 68 (39%) 49 (28.2%) 41 (23.6%)	0.317
	Peripheral artery occlusive disease Fontaine 1 Fontaine 2 Fontaine 3	3 (3.5%) 0 1 (1.1%)	3 (1.7%) 1 (0.6%) 1 (0.6%)	0.797
	Coronary heart disease	10 (11.5%)	14 (7.8%)	0.298
	Activated partial thromboplastin time (APTT)	31.1 ± 4.4	32.1 ± 7.3	0.261
	Prothrombin time (PT)	91.2 ± 10.4	94.4 ± 9.5	0.095
Results	Endpoint	UFH (n= 87)	LMWH (n= 179)	p-value
	Flap thrombosis Total rate Arterial Venous	8 (9.2%) 3 (3.5%) 5 (5.7%)	17 (9.5%) 2 (1.1%) 15 (8.4%)	0.767 0.040 0.445
	Time to thrombosis, hours	29.8 ± 66.5	63.9 ± 100.7	0.227
	Total flap loss	3 (3.4%)	12 (6.7%)	0.280
	Partial flap loss	5 (5.7%)	4 (2.2%)	0.134
	Postoperative Bleeding Minor Major	3 (3.4%) 4 (4.6%)	8 (4.5%) 12 (6.7%)	0.688 0.498
	Hematoma formation Minor Major	12 (13.8%) 4 (4.6%)	22 (12.3%) 7 (3.9%)	0.731 0.792
	Salivary fistula Minor Major	9 (10.3%) 4 (4.6%)	22 (12.3%) 12 (6.7%)	0.632 0.498
	Overall revision rate	18 (20.7%)	36 (20.1%)	0.912
	Pulmonary artery embolism	1 (1.1%)	0 (0%)	--
	5-year overall survival	66.7%	70.1%	0.420
	There were no cases of deep vein thrombosis or heparin-induced thrombocytopenia reported.
Adverse Events	Common Adverse Events: Not Disclosed
	Serious Adverse Events: Not Disclosed
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	The free-flap survival rate using low-dose UFH seems to be equivalent to LMWH regimens without compromising the postoperative outcome. Consequently, for risk-adapted thrombosis prophylaxis, either LMWH or UFH can be administrated.
InpharmD Researcher Critique	This study did not prove any statistically significant difference between UFH and LMWH; both groups had similar outcomes with regard to thrombosis, flap loss, hematoma, and fistula formation. This study is limited by its retrospective, single-center design, which lowers external validity and generalizability of the results.

References:

Sievert M, Goncalves M, Tamse R, et al. Postoperative management of antithrombotic medication in microvascular head and neck reconstruction: a comparative analysis of unfractionated and low-molecular-weight heparin. Eur Arch Otorhinolaryngol. 2021;278(5):1567-1575. doi:10.1007/s00405-020-06219-w

Aspirin, Heparin, and Ischemia Time in Microvascular Free Flap Surgery - Their Influence and an Optimal Anticoagulation Protocol
Design	Retrospective, observational, quasirandomized cohort study N= 178
Objective	To develop and optimize a new anticoagulation protocol using aspirin (ASA) and unfractionated heparin (UH) for intraoperative and immediate postoperative administration in the intensive care unit (ICU)
Study Groups	Group I (n= 42) Group II (n= 44) Group IIIa: free soft tissue flaps (n= 32) Group IIIb: free bone flaps (n= 26) Group IV (n= 34)
Inclusion Criteria	All microvascular free flap surgeries performed at a single center in Germany between 2013 and 2018
Exclusion Criteria	N/A
Methods	This was a single-center study from a German hospital that stratified groups based on the time the microvascular free flap surgery was conducted. These time frames correspond to different anticoagulation protocols at the institution. Group I consisted of surgeries prior to 2015 with random anticoagulation. Group II comprised of surgeries from January 2015-August 2016. At that time, the anticoagulation protocol included an intraoperative bolus of UFH 5,000 IU followed by continuous UFH with a goal activated partial thromboplastin time (aPTT) of 60-80 seconds. Groups IIIa and IIIb consisted of surgeries from September 2016-May 2018. Both groups were given an intraoperative UFH 5,000 IU bolus. However, Group IIIa (free soft tissue flaps) followed with UFH 1 mL/hr with no target aPTT while Group IIIb (free bone flaps) followed with continuous UFH and a target aPTT of 60-80 seconds. Group IV comprised of surgeries from May 2018-December 2018. The anticoagulation protocol called for an intraoperative bolus of ASA 300 mg and UFH 20 IU/kg followed by UFH 1 mL/hr with no target aPTT and ASA 100 mg/day. Once patients were transferred to the floor, UFH was replaced with enoxaparin 40-60 mg once daily and ASA was continued at 100 mg/day until discharge. Notably, patients who received two or more flaps at different time points were listed multiple times.
Duration	2013 to 2018
Outcome Measures	Rate of flap loss; complications rates including bleeding, hematoma, and problems with anastomosis; important blood values within patient groups
Baseline Characteristics		Group 1 (n= 42)	Group 2 (n= 44)	Group IIIa (n= 32)	Group IIIb (n= 26)	Group IV (n= 34)
	Age, years	59.3 ± 14.1	64.5 ± 11.3	65.3 ± 13.7	61.5 ± 14.1	66.9 ± 9.7
	Flap performed Radial forearm flap Latissimus dorsi flap Free fibula flap Iliaic crest flap Scapula Anterolateral thigh (ALT)	59.5% 23.8% 16.7% 2.3% - -	23.9% 10.9% 10.9% 23.9% 28.2% 2.2%	65.6% 25% - - - 9.4%	6.1% 15.2% 21.2% 39.4% 18.1% -	36.9% 13.1% - 36.9% 10.5% 2.6%
	Arterial anastomosis Superior thyroid artery Facial artery Lingual artery Others	76.7% 9.3% 7% 7%	51.1% 35.6% 8.9% 4.4%	40.6% 37.5% 12.5% 9.4%	10.7% 57.1% 14.3% 17.9%	35.3% 52.9% 5.9% 5.9%
	Venous anastomosis Jugular vein Facial vein Others	90.5% 7.1% 2.4%	68.2% 27.3% 4.5%	50% 34.4% 15.6%	46.4% 39.3% 14.3%	56.8% 43.2% -
	Of the total (N= 178) patients, 41% of patients were female and the average ischemia time was 129.2 ± 65.1 minutes.
Results		Group 1 (n= 42)	Group 2 (n= 44)	Group IIIa (n= 32)	Group IIIb (n=26)	Group IV (n= 34)
	Loss of free flap	14.3%	9.1%	6.23%	15.4%	5.9%
	Bleeding	2.4%	11.4%	18.8%	3.9%	11.8%
	Hematoma	2.4%	20.5%	18.8%	23.1%	5.9%
	Problems with anastomosis	16.7%	13.6%	12.5%	27%	14.7%
	Hemoglobin, g/dL Preoperative Postoperative	13.3 ± 2 10.1 ± 1.6	12.9 ± 1.6 9.1 ± 1.8	12.9 ± 2 10.1 ± 1.6	12.7 ± 1.5 8.9 ± 0.8	13.1 ± 1.8 9.1 ± 1.3
	aPTT at ICU, s	38.4 ± 12.2	49.5 ± 13.8	46.6 ± 16.3	55.7 ± 11.8	44.12 ± 10
Study Author Conclusions	Complication rates in free flap surgery can be influenced by the intra- and postoperative anticoagulation regime used. While prolonged administration of ASA increases the complication rate, short-term administration of ASA seems to be beneficial. Concomitant administration of unfractionated heparin helps to reduce the incidence of flap loss as long as the dose administered is not too high (< 500 IU/h). A combined anticoagulation regimen consisting of an intraoperative bolus of ASA 300 mg and a bolus UFH (20 IU/kg) followed by ASA 100 mg/d and UFH 1 mL/h (25.000 IU/50 mL) with no target value for aPTT is a promising anticoagulation regimen that we recommend for the first postoperative days after microvascular free flap surgery.
InpharmD Researcher Critique	Limitations of this study include the small sample size, retrospective design (that may include confounding variables), and location at a single-center in Germany. Additionally, there was no significance found in the correlation between ischemia time and complication rates.

References:

Rothweiler R, Gerlach V, Voss P, et al. Aspirin, heparin and ischemia time in microvascular free flap surgery - their influence and an optimal anticoagulation protocol. J Stomatol Oral Maxillofac Surg. 2022;123(5):e556-e562. doi:10.1016/j.jormas.2022.03.001

Intraoperative Heparin Bolus and Postoperative Anticoagulation with Low Molecular Weight Heparin Increase Reliability of Microsurgical Free Flaps for Upper Extremity Reconstruction
Design	Retrospective, single-center, observational study N= 169
Objective	To evaluate the impact of perioperative anticoagulation and antiplatelet therapy in microsurgical upper extremity reconstruction
Study Groups	All patients (N= 169) Eligible free flaps (n= 183)
Inclusion Criteria	Patients who received a free flap for microsurgical upper extremity defect coverage
Exclusion Criteria	Free toe transfers, lymph node flaps, free vascularized bone grafts (including periosteal flaps) without soft tissue components, free functional muscle transfers, and flow-through venous flaps
Methods	Anticoagulation and antiplatelet therapy for the upper extremity was chosen at the discretion of the operating surgeon. Patients were evaluated on the basis of intraoperative anticoagulation (no heparin, different bolus levels of unfractionated heparin [UFH] intravenous, low-molecular-weight heparin [LMWH] subcutaneously, or continuous intravenous application of UFH), intraoperative antiplatelet therapy (aspirin and/or clopidogrel), postoperative anticoagulation (LMWH subcutaneously once a day, LMWH subcutaneously twice a day, or continuous targeted UFH therapy intravenously), and postoperative antiplatelet therapy (with or without aspirin and/or clopidogrel).
Duration	Treated with microsurgical upper extremity reconstruction: January 2000 to July 2014
Outcome Measures	All major complications (e.g., total flap loss, arterial and venous thrombosis) and minor complications
Baseline Characteristics		All patients (N= 169)
	Age, years (range)	46.3 (7 to 88)
	Most frequently applied flap Anterior lateral thigh flap Latissimus dorsi Parascapular flap	35.5% 17.5% 15.8%
	Main defect causes Trauma Infection Tumor	38.5% 23.1% 11.2%
Results		Eligible free flaps (n= 183)
	Major complications Total flap losses Arterial thrombosis Venous thrombosis	23 (12.6%) 11 (6.0%) 11 (6.0%) 9 (4.9%)
	Minor complications	55 (30.1%)
	Intraoperative: No use of heparin intraoperatively was associated with major complications (34.8%; p= 0.001) and total flap loss (45.5%; p= 0.004). No dose of intraoperative bolus administration of UFH intravenously showed significant superiority; however, there were numerically fewer complications in the group that received 501 to 1,000 units of heparin bolus intraoperatively (8.7%; p= 0.058). A continuous dose of UFH intravenously or LMWH subcutaneously intraoperatively was demonstrated to be a potential risk factor for more major complications (p= 0.044). Additionally, intraoperative administration of antiplatelet therapy with aspirin had no significant effect on the development of major complications. Postoperative: Use of continuous UFH intravenously postoperatively was significantly associated with major complications (60.9%; p= 0.12), total flap loss (72.7%; p= 0.02), and arterial thrombosis (72.7%; p= 0.02). Administration of antiplatelet therapy (aspirin and/or clopidogrel) was significantly correlated with a higher rate of total flap loss (27.3%; p= 0.027). None of the different intraoperative or postoperative regimens had a significant effect on the rate of hematoma/bleeding complications.
Adverse Events	N/A
Study Author Conclusions	The results of the present study favor the administration of 501 to 1,000 units of UFH intravenously as an intraoperative bolus (e.g., 750 units of UFH intravenously). Postoperative low molecular weight heparin subcutaneous application in a prophylactic dose given once or twice a day was associated with fewer complications compared with continuous infusion of UFH, although continuously applied UFH may reflect an increased risk profile.
InpharmD Researcher Critique	Despite some of the results indicating significance, a prospective, interventional study with randomized groups of the respective protocols are necessary to clarify the observations seen in this study.

References:

Kallenberger AK, Xiong L, Gazyakan E, et al. Intraoperative Heparin Bolus and Postoperative Anticoagulation with Low Molecular Weight Heparin Increase Reliability of Microsurgical Free Flaps for Upper Extremity Reconstruction [published online ahead of print, 2022 Aug 11]. J Reconstr Microsurg. 2022;10.1055/s-0042-1755264. doi:10.1055/s-0042-1755264