What does the evidence say about the efficacy and safety of milvexian versus enoxaparin for venous thromboembolism and bleeding in patients undergoing elective knee arthroplasty?

The American Society of Hematology recommends the use of of direct oral anticoagulants (DOACs) as first-line treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE). Therapy with DOACs is preferred over vitamin K antagonists (VKAs) for most patients without severe renal insufficiency (creatinine clearance <30 ml/min), moderate-severe liver disease, or antiphospholipid antibody syndrome.

For patients with DVT and/or PE, the ASH guideline panel does not suggest one DOAC over another. Factors, such as a requirement for lead-in parenteral anticoagulation, once- vs twice-daily dosing, and out-of-pocket cost may drive the selection of specific DOACs. [1]

A critical analysis review assessing venous thromboembolism chemoprophylaxis in total hip and knee arthroplasty (TKA) found that warfarin had the highest rate of pulmonary embolism (PE). Aspirin had the lowest rate of PE, however the evidence grade for the recommendation was lower (grade B). The authors concluded that there was no single agent preferred. Warfarin was effective but had varied patient responses. Low-dose heparin was effective, but had the potential to cause compliance concerns given its subcutaneous administration. Oral Factor-Xa inhibitors are effective but could cause bleeding, and may lack reversal agents. Ultimately, clinicians should consider multiple factors, including timing to first dose, duration of prophylaxis, and more when choosing an appropriate agent. [2]

No review articles or commentaries were found regarding the role of milvexian for patients with knee arthroplasty.

A meta-analysis assessing safety and efficacy of anticoagulants in hip and knee arthroplasty patients reviewed 18 different randomized, double-blinded, controlled trials. The primary efficacy outcome was incidence of venous thromboembolism (VTE) and the primary safety outcome was a composite of major bleeding. The researchers concluded that compared to enoxaparin 40 mg daily, apixaban, rivaroxaban, fondaparinux, and edoxaban reduced the rate of VTE after arthroplasty. Fondaparinux proved superior to enoxaparin 30 mg twice daily. With the exception of apixaban, which reduced major/clinically relevant bleeding, the newer anticoagulants that lowered the risk of post-operative VTE increased bleeding. [3]

Milvexian for the Prevention of Venous Thromboembolism

Design

Open-label, randomized, parallel-group, adaptive design with blinded outcome adjudication

N= 1242

Objective

To compare the efficacy and safety of milvexian and enoxaparin in patients undergoing elective knee arthroplasty.

Study Groups

Milvexian Twice Daily:

25 mg (n= 129)

50 mg (n= 124)

100 mg (n= 134)

200 mg (n- 131)

Milvexian Once Daily:

25 mg (n= 28)

50 mg (n = 127)

200 mg (n= 123)

Enoxaparin (n= 252)

Inclusion Criteria

50 years of age or older, had a medically stable condition, and were appropriate candidates for anticoagulant prophylaxis

Exclusion Criteria

contraindications to enoxaparin (creatinine clearance, <30 ml per minute), a history of severe hepatic impairment or previous venous thromboembolism, the use of long-term antithrombotic therapy other than aspirin (≤100 mg per day), or the inability to undergo venography

Methods

In this study, a total of 1242 patients underwent randomization at 118 centers in 18 countries.

Patients were randomly assigned, in a 1:1:1:1:1:1:2 ratio, to one of seven post-operative, parallel treatment groups with milvexian, or 40 mg of enoxaparin once daily.

The seven treatment groups included:

milvexian 25 mg twice daily

milvexian 50 mg twice daily

milvexian 100 mg twice daily

milvexian 200 mg twice daily

milvexian 25 mg once daily

milvexian 200 mg once daily

Patients in the milvexian groups were asked to take a total of four capsules (active drug or matching placebo) per day, two capsules in the morning and two capsules in the evening. In the enoxaparin group, the drug was administered subcutaneously at a dose of 40 mg once daily.

Trial medication was started 12-24 hours after surgery, and treatment with milvexian or enoxaparin was given for 10 to 14 days after surgery.

During ad hoc analysis, 25 mg of milvexian once daily was stopped because the point estimate for the incidence of venous thromboembolism was 25%, meeting the prespecified criteria for insufficient efficacy. A regimen of 50 mg of milvexian once daily was then added.

Duration

All patients were followed for 30 days.

Outcome Measures

The primary efficacy outcome was venous thromboembolism, which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause.

The principal safety outcome was bleeding of any severity, which was defined as the composite of major bleeding, clinically relevant nonmajor bleeding, and minimal bleeding.

Baseline characteristics

Characteristics	Milvexian Twice Daily				Milvexian Once Daily			Enoxaparin
Characteristics	25 mg	50 mg	100 mg	200 mg	25 mg	50 mg	200 mg	Enoxaparin
Modified intention-to-treat population:
No. of patients	129	124	134	131	28	127	123	252
Median age - yr	69	68	67	69	67	68	68	68
Female sex – no. (%)	92 (71)	89 (72)	88 (66)	89 (68)	18 (64)	92 (72)	88 (72)	171 (68)
Race– no. (%)
White	112 (87)	107 (86)	117 (87)	116 (89)	28 (100)	103 (81)	105 (85)	216 (86)
Asian	16 (12)	15 (12)	14 (10)	14 (11)	0	21 (17)	15 (12)	29 (12)
Black	1 (1)	1 (1)	3 (2)	1 (1)	0	0	0	3 (1)
Other	0	1 (1)	0	0	0	0	3 (2)	2 (1)
Median weight - kg	83	79	85	84	82	80	82	81
Baseline median creatinine clearance – ml/min	86	92	90	94	95	88	91	92
Preoperative enoxaparin – no. (%)	8 (6)	9 (7)	8 (6)	7 (5)	2 (7)	10 (8)	11 (9)	28 (11)
Type of anesthesia – no. (%)
General	29 (22)	25 (20)	31 (23)	34 (26)	5 (18)	29 (23)	26 (21)	57 (23)
Spinal	99 (77)	99 (80)	102 (76)	96 (73)	23 (82)	101 (80)	99 (80)	194 (77)
Epidural	4 (3)	5 (4)	5 (4)	4 (3)	0	6 (5)	3 (2)	7 (3)
Regional	20 (16)	33 (27)	42 (31)	33 (25)	6 (21)	33 (26)	29 (24)	58 (23)
Other	2 (2)	4 (3)	3 (2)	4 (3)	0	1 (1)	4 (3)	9 (4)
Median duration of surgery – hr	1.3	1.4	1.4	1.4	1.4	1.4	1.4	1.4
Tourniquet use – no. (%)	89 (69)	88 (71)	98 (73)	84 (64)	20 (71)	93 (73)	84 (68)	188 (75)
Time after surgery to ambulation – days	1	1	1	1	1	1	1	1
Median baseline factor XI clotting activity – %	109	107	104	110	107	100	102	114
Median baseline activated partial thromboplastin time – sec	26	27	26	26	26	26	26	26
Safety population:
No. of patients	148	148	149	148	33	150	147	296
Median time after surgery to milvexian or enoxaparin administration -hr	22	22	22	22	22	22	23	22
Median duration of milvexian or enoxaparin treatment	12	12	12	12	12	13	12	12

Results

outcomes	Milvexian Twice Daily				Milvexian Once Daily			Enoxaparin (N= 252)
outcomes	25 mg (N= 129)	50 mg (N= 124)	100 mg (N=134)	200 mg (N= 131)	25 mg (N= 28)	50 mg (N= 127)	200 mg (N= 123)
Primary efficacy outcome: venous thromboembolism
Any event – no. (%)	27 (21)	14 (11)	12 (9)	10 (8)	7 (25)	30 (24)	8 (7)	54 (21)
Relative risk vs. enoxaparin (95%CI)	0.97 (0.65–1.45)	0.53 (0.31–0.90)	0.42 (0.23–-0.76)	0.37 (0.19–0.69)	1.00 (051–1.97)	1.15 (0.78–1.70)	0.30 (0.15–0.62)	–
Components of the primary efficacy outcome – no.
Death from any cause	0	0	0	0	0	0	0	1
Nonfatal pulmonary embolism	0	1	1	0	0	0	0	1
Symptomatic distal deep-vein thrombosis	0	0	1	0	0	2	0	0
Asymptomatic proximal deep-vein thrombosis	1	0	1	0	0	2	0	2
Asymptomatic distal deep-vein thrombosis	26	13	9	10	7	26	8	50

Safety

outcomes	Milvexian Twice Daily				Milvexian Once Daily				Enoxaparin (N= 296)
outcomes	25 mg (N= 148)	50 mg (N= 148)	100 mg (N=149)	200 mg (N= 148)	25 mg (N= 33)	50 mg (N= 150)	200 mg (N= 147)
Any bleeding — no. (%)	2 (1)	7 (5)	7 (5)	5 (3)	0	8 (5)	9 (6)	12 (4)
Relative risk vs. enoxaparin (95% CI)	0.33 (0.08–1.43)	1.15 (0.47–2.82)	1.14 (0.47–2.80)	0.81 (0.29–2.24)	0	1.17 (0.50–2.72)	1.51 (0.66–3.43)	–
Major bleeding or clinically relevant nonmajor bleeding — no. (%)	0	2 (1)	1 (1)	1 (1)	0	2 (1)	1 (1)	5 (2)
Relative risk vs. enoxaparin (95% CI)	0	0.79 (0.16–3.96)	0.39 (0.05–3.30)	0.39 (0.05–3.28)	0	0.68 (0.14–3.39)	0.40 (0.05–3.34)	–
Major bleeding — no. (%)	0	0	0	0	0	0	0	1 (<1)
Clinically relevant nonmajor bleeding — no. (%)	0	2 (1)	1 (1)	1 (1)	0	2 (1)	1 (1)	4 (1)
Serious adverse event — no. (%)	5 (3)	5 (3)	5 (3)	2(1)	1 (3)	2 (1)	2 (1)	11 (4)
At least one adverse event — no. (%)	56 (38)	67 (45)	51 (34)	54 (36)	7 (21)	58 (39)	65 (44)	113 (38)
Adverse event leading to discontinuation of treatment — no. (%)	2 (1)	7 (5)	2 (1)	4 (3)	0	4 (3)	6 (4)	8 (3)

Study Author Conclusions

Oral milvexian reduced the risk of postoperative thromboembolism among patients undergoing knee arthroplasty in a dose-dependent manner without increasing the risk of bleeding as compared with enoxaparin.

InpharmD^TM Researcher

Critique

A potential bias in favor of enoxaparin or the trial drug could exist given the open label design. Additionally, while the results were positive, further study is needed to determine whether this regimen could be good for clinical practice. An oral agent versus a subcutaneous agent could have advantages. However, comparison to other oral agents will also be necessary before this conclusion can be met.

References:
[1] Weitz JI, Strony J, Ageno W, Gailani D, Hylek EM, Lassen MR, Mahaffey KW, Notani RS, Roberts R, Segers A, Raskob GE; AXIOMATIC-TKR Investigators. Milvexian for the Prevention of Venous Thromboembolism. N Engl J Med. 2021 Dec 2;385(23):2161-2172. doi:10.1056/NEJMoa2113194. Epub 2021 Nov 15. PMID: 34780683.