What is the evidence for the use of low, fixed-dose heparin or "subtherapeutic" dose heparin in patients with acute limb ischemia? Is this dosing strategy used in other indications?

Comment by InpharmD Researcher

Use of low-dose heparin or subtherapeutic heparin in patients with acute limb ischemia is seldom reported in clinical literature. Studies published in the 1990s report have evaluated use of intra-arterial subtherapeutic/low-dose heparin in combination with thrombolytics in acute limb ischemia and peripheral arterial occlusion, but comparisons between subtherapeutic/low-dose heparin and standard dose heparin do not appear to have been conducted; thus, limited conclusions regarding the efficacy or safety of heparin in this setting can be drawn. Fixed, low-dose heparin is also utilized in venous thromboembolism prophylaxis and has also been studied in various settings, including acute MI, general surgery, and trauma, but its efficacy in these settings is limited.

Background

The 2016 American Heart Association and the American College of Cardiology (AHA/ACC) guideline on the management of patients with lower extremity peripheral artery disease recommends that in patients with acute limb ischemia, systemic anticoagulation with heparin should be administered unless contraindicated (class of recommendation: I). The panel did not further discuss the use of a subtherapeutic or low-dose heparin regimen for patients with acute limb ischemia. [1]

A quality improvement guideline discusses that published literature has evaluated varying doses of heparin in thrombolytic infusions in the setting of acute lower-extremity ischemia, with no dose identified to predict adverse bleeding outcomes. Heparin is recommended to be utilized carefully during thrombolytic infusions due to the risk of bleeding. Subtherapeutic doses of heparin may be acceptable when used in combination with thrombolytic therapy. However, when used in combination with urokinase infusion treatment, therapeutic doses are recommended. In a randomized study published in 1998, therapeutic doses of heparin were initially associated with an intracranial hemorrhage rate of 4.8% when used along with urokinase. This led to a protocol change in which the heparin dose was reduced to a subtherapeutic dose (specific dose not specified) and administered through the arterial sheath instead of intravenously in order to prevent pericatheter thrombosis. Heparin was given concurrently with urokinase, leading to recanalization in 196 out of 246 patients (79.7%). Other instances where subtherapeutic heparin may be appropriate are not discussed. [2], [3]

A 2001 statement from the AHA discusses use of fixed, low-dose heparin (5,000 units subcutaneously [SC] every 8 or 12 hours) in various settings. For prophylaxis of venous thromboembolism (VTE), low-dose heparin has been found to reduce the risk of venous thrombosis and fatal pulmonary embolism. Additionally, low-dose heparin has been found to prevent VTE in patients with myocardial infarction (MI). Low-dose heparin has been compared to moderate-dose heparin (12,500 units SC every 12 hours) in the setting of acute MI, but moderate-dose heparin was found to be more effective for reducing the incidence of mural thrombosis. Low-dose heparin has also been utilized in the setting of general surgery and orthopedic surgery, with minimal differences identified for prophylaxis compared to low-molecular-weight heparin (LMWH). In the multiple trauma setting, low-dose heparin has also been compared to LMWH, but significant differences in the incidence of venous thrombosis have been observed in favor of LMWH. [4]

References:

[1] Writing Committee Members, Gerhard-Herman MD, Gornik HL, et al. 2016 AHA/ACC Guideline on the Management of Patients with Lower Extremity Peripheral Artery Disease: Executive Summary. Vasc Med. 2017;22(3):NP1-NP43. doi:10.1177/1358863X17701592
[2] Patel NH, Krishnamurthy VN, Kim S, et al. Quality improvement guidelines for percutaneous management of acute lower-extremity ischemia. J Vasc Interv Radiol. 2013;24(1):3-15. doi:10.1016/j.jvir.2012.09.026
[3] Ouriel K, Veith FJ, Sasahara AA. A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators. N Engl J Med. 1998;338(16):1105-1111. doi:10.1056/NEJM199804163381603
[4] Hirsh J, Anand SS, Halperin JL, Fuster V; American Heart Association. AHA Scientific Statement: Guide to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association. Arterioscler Thromb Vasc Biol. 2001;21(7):E9. doi:10.1161/hq0701.093520
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence for the use of low, fixed-dose heparin or "subtherapeutic" dose heparin in patients with acute limb ischemia? Is this dosing strategy used in other indications?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-2 for your response.

 

Randomized trial of intra-arterial recombinant tissue plasminogen activator, intravenous recombinant tissue plasminogen activator and intra-arterial streptokinase in peripheral arterial thrombolysis

Design

Randomized parallel group observational study

N= 60

Objective

To compare intra-arterial (IA) streptokinase, IA recombinant tissue plasminogen activator (rt-PA), and intravenous (IV) rt-PA for peripheral arterial thrombolysis

Study Groups

IA streptokinase (n= 20)

IA rt-PA (n= 20)

IV rt-PA (n= 20)

Inclusion Criteria

Sudden onset or deterioration of peripheral limb ischemia less than 30 days duration sufficient to cause critical ischemia

Exclusion Criteria

Ischemia severe enough to cause neurosensory deficit, clinically obvious embolic source, proximal emboli of less than 2 days duration, childbearing potential, recent major trauma or surgery (< 10 days), known bleeding diathesis, added risk of bleeding, cerebrovascular accident within previous 2 months, arterial thrombosis causing severe ischemia with good run-off

Methods

Patients were randomized to receive IA streptokinase (5,000 units/h with 250 units/h sodium heparin), IA rt-PA (0.5 mg/h with 250 units/h sodium heparin), or IV rt-PA (1, 2, 5, or 10 mg/h for a maximum of 100 mg). Following completion of lysis, with or without angioplasty, the catheter was withdrawn, and heparin therapy was given at 1,000 units/h after hemostasis had been achieved in the groin. Following a check on the full clotting screen after 12 h, heparin was then increased to achieve an activated partial thromboplastin time (APTT) of approximately 2-3 times the control value.

Duration

Intervention: until lysis achieved, patient deteriorated, or no further discernible lysis occurred after a 12-hour period

Follow-up: 30 days and 3 months after the end of lysis

Outcome Measures

Radiological success, angioplasty, clinical improvement, change in ankle:brachial pressure index (ABPI), outcomes at 30 days and 3 months after thrombolysis, complications of thrombolysis

Baseline Characteristics

  

IA streptokinase (n= 20)

IA rt-PA (n= 20)

IV rt-PA (n= 20)

Age, years

 70 70 72

Weight, kg

 68 72 67

History, n

Previous cerebrovascular accident

Previous myocardial infarction

Angina/congestive heart failure

Diabetes

Smoker


4

5

3

6

11


1

5

2

3

14


3

2

3

2

10

Duration of history, days

 16 14 12

Length of occlusion, cm

 19 21 18

Occlusion > 25 cm, n

 6 9 5

Ankle:brachial pressure index

 0.10 0.13 0.14

Results

Endpoint

IA streptokinase (n= 20)

IA rt-PA (n= 20)

IV rt-PA (n= 20)

Radiological success, n

Complete

Partial

Total


16

0

80%


17

3

100%*


6

3

45%

Angioplasty, n

4

8

1

Clinical improvement, n

16

20

11

Median increase in ABPI (range)

0.24 (0 to 0.57)

0.57 (0.33 to 0.82)**

0.18 (0 to 0.41)

30-day limb salvage, n

Asymptomatic

Critical ischemia

Amputation

Death

Reconstructed

IA lysis


12

0

7

1 (pneumonia)

0

0


16

0

1

3 (1 pneumonia, 2 MI)

0

0


9

5

0

3 (2 pneumonia, 1 MI)

2

1

3-month limb salvage

Asymptomatic

Critical ischemia

Patency

Amputation

Death

Reconstructed

IA lysis


12

0

11

6

2

0

0


15

0

14

1

4

0

0


10

1

7

1

5

2

1

*0.01< p< 0.04; **p< 0.001 vs. the other two groups

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: cerebrovascular accident (1 event in IV rt-PA group), major hemorrhage (3 events in IA streptokinase group and 3 events in IV rt-PA group), perforation (1 event in IA rt-PA group), re-thrombosis (4 events in IA streptokinase group and 2 events in IA rt-PA group), embolization (1 event in IA rt-PA group)

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

IA rt-PA provides a more effective, safer fibrinolytic regimen than conventional therapy with streptokinase. IV rt-PA has not been as successful and carries a significantly higher risk of hemorrhagic complications.

InpharmD Researcher Critique

It is difficult to draw conclusions regarding the use of low-dose heparin in this study as both groups receiving IA fibrinolysis also received concomitant low-dose heparin.



References:

Berridge DC, Gregson RH, Hopkinson BR, Makin GS. Randomized trial of intra-arterial recombinant tissue plasminogen activator, intravenous recombinant tissue plasminogen activator and intra-arterial streptokinase in peripheral arterial thrombolysis. Br J Surg. 1991;78(8):988-995. doi:10.1002/bjs.1800780831

 

Comparison of tissue plasminogen activator and urokinase in the local infiltration thrombolysis of peripheral arterial occlusions

Design

Prospective randomized study 

N= 120

Objective

 To establish whether there is any difference between urokinase and tissue plasminogen activator (rt-PA) in the short- and long-term outcome of local fibrinolytic therapy for the treatment of peripheral arterial occlusive disease

Study Groups

Urokinase (n= 60)

rt-PA (n= 60)

Inclusion Criteria

 Suffering from occlusions of the femoral artery, the popliteal artery, or the biarterial trunk

Exclusion Criteria

N/A

Methods

Before thrombolysis, all patients received heparin 5,000 IU intra-arterially. During thrombolysis, patients were randomized to receive either heparin 700 IU/h (total 50,000 IU in 50 mL physiological saline, via an infusion pump) and urokinase 60,000 IU/h (total 500,000 IU in 500 mL complete electrolyte solution, via infusion pump) or a 5-mg bolus of rt-PA dissolved in 20 mL saline, administered over 10 min, followed by 5 mg/h (total 15 mg in 50 mL physiological saline via an infusion pump) and heparin 750 IU/h (total 50,000 IU in 50 mL physiological saline via infusion pump), both directly to the thrombus. 

Postoperatively, patients received heparin 20,000 IU/24 h for 5 days, administered via infusion pump, along with the transition to oral anticoagulation with a target INR of 2.5 to 3.5. 

Duration

Between October 1993 and July 1995

Follow-up: 6 months 

Outcome Measures

Short- and long-term outcomes of intra-arterial local lysis 

Baseline Characteristics

  

Urokinase (n= 60)

rt-PA (n= 60)

  

Age, years

Male 

Female

 

65

67

 

64.2

66.3

  

Female

40% 43%  

Duration of symptoms, days 

 16 17  

Length of occlusion, cm

 6.5 6.7  

Doppler pressure of the ankle arteries

 0.57 0.56  

Site of occlusion

Femoral artery

Femoral and popliteal artery

Popliteal artery

Popliteal artery and trifurcation

 

18.3%

28.3%

8.3%

45.1%

 

16.6%

26.6%

13.3%

43.5%

  

Results

Endpoint

Urokinase (n= 60)

rt-PA (n= 60)

p-value

Initially successful recanalization

Femoral artery

Femoral and popliteal artery

Popliteal artery

Popliteal artery and trifurcation

 

81.8%

82.3%

80.0%

63.9%

 

90.0%

87.5%

87.5%

80.7%



< 0.05

-

-

-

Long-term at 6-month follow-up 

Successful recanalization

Femoral artery

Femoral and popliteal artery

Popliteal artery

Popliteal artery and trifurcation

n= 50

-

74.2%

62.8%

74.2%

42.8%

n= 52

-

80.4%

70.7%

78.0%

60.9%

 < 0.05

Long-term clinical outcomes 

Loss of limb

Partial ambutation

Dceased 

 

4.0%

6.0%

2.0%

 

1.9%

3.8%

1.9%

Not significant

Adverse Events

Common Adverse Events: short-term complications local hematomas (8.3% vs. 15%), systemic nose bleeds (0 vs. 1.6%), bleeding from gum (0 vs. 1.6%)

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

 This study shows that local lysis with rt-PA yields better results than urokinase, not only in the short term but also 6 months later.

InpharmD Researcher Critique

While the study does not specifically evaluate the safety and efficacy of low-dose heparin infusion for the treatment of peripheral arterial occlusive disease, it demonstrated the clinical applicability of concurrent use of intra-arterial heparin in addition to local thrombolysis, without major safety concerns. 



References:

Schweizer J, Altmann E, Stösslein F, Florek HJ, Kaulen R. Comparison of tissue plasminogen activator and urokinase in the local infiltration thrombolysis of peripheral arterial occlusions. Eur J Radiol. 1996;22(2):129-132. doi:10.1016/0720-048x(96)00742-5