What heparin dosing regimens should be used for indications related to peripheral artery disease?

Introduction
Peripheral artery disease (PAD) is a highly prevalent cardiovascular (CV) disease associated with increased risk of myocardial infarction (MI), stroke, amputation, death, and impaired quality of life (QOL), walking performance, and functional status.1,2 In the United States (US), there is approximately 6.5 million adults 40 years and older that have PAD, based on the definition of an ankle brachial index (ABI) <0.9.3 When individuals with borderline ABI values of 0.90 to 0.99 are included in the statistics, the prevalence increases to approximately 8.5 million adults. Risk factors for PAD include smoking, diabetes, dyslipidemia, hypertension, sedentary lifestyle, and age ≥ 60 years.3-5

PAD is primarily caused by atherosclerosis that reduces blood flow to peripheral arteries and is more common in the lower body extremities.4,5 While PAD may still occur in arteries elsewhere in the body, this FAQ applies to lower extremity PAD and its specific complications.

General treatment considerations for peripheral artery disease
There are 4 clinical presentation subsets for which patients with confirmed PAD can be categorized: Asymptomatic PAD, chronic symptomatic PAD, chronic limb-threatening ischemia (CLTI), and acute limb ischemia (ALI).1 Over time, patients may present into a different subset with the potential to progress into more severe presentations. Patients with asymptomatic PAD may not have any leg symptoms but could still have functional impairment; diagnosis would be based on a comprehensive medical history and physical examination as well as testing, inclusive of resting ABI. Chronic symptomatic PAD includes patients who present with claudication (ie, pain, aching, cramping, tired feelings in legs that occur continuously while walking) and significant functional impairment. CLTI and ALI are both severe clinical subsets of PAD with high risk for amputations and mortality. CLTI is associated with symptoms of ischemic rest pain, nonhealing wounds/ulcers, or gangrene being present for greater than 2 weeks. ALI symptoms appear over a duration of less than 2 weeks and may include pain, pallor, pulselessness, coolness, paresthesia, and potential for paralysis.

In 2024, a US multi-organization clinical practice guideline from the American College of Cardiology (ACC), American Heart Association (AHA), American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR), American Podiatric Medical Association (APMA), Association of Black Cardiologists (ABC), Society for Cardiovascular Angiography and Interventions (SCAI), Society for Vascular Medicine (SVM), Society for Vascular Nursing (SVN), Society for Vascular Surgery (SVS), Society of Interventional Radiology (SIR), and Vascular & Endovascular Surgery Society (VESS) for the management of lower extremity PAD was published.1 The European Society of Cardiology (ESC) has also published guidelines in 2024 for the management of peripheral arterial and aortic diseases.6 General medical management includes therapies to reduce the risk of major adverse cardiac events (MACE), major adverse limb events (MALE), and progression to more severe disease as well as therapy to improve symptoms, functioning, and QOL.1,2,6

To reduce the risk of MACE, the 2024 US multi-organization guideline recommends single antiplatelet therapy (SAPT) with either clopidogrel 75 mg daily or aspirin 75-325 mg in patients with symptomatic PAD.1 Low-dose rivaroxaban of 2.5 mg twice daily, combined with low-dose aspirin (81 mg daily), may also be used in symptomatic PAD to reduce the risk of MACE and MALE in patients who are not at increased risk of bleeding. Low-dose rivaroxaban and low-dose aspirin are also recommended for patients after endovascular or surgical revascularization for PAD. Other medical CV risk reduction strategies include guideline-directed lipid-lowering, antihypertensive, and diabetes treatments, as well as annual influenza vaccinations and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) vaccinations. The 2024 ESC guidelines provide similar recommendations for the use of antiplatelets; also stating the combination rivaroxaban and aspirin should be considered for patients with PAD, high ischemic risk, and non-high bleeding risk.6 High bleeding is defined by the ESC as dialysis or renal impairment glomerular filtration rate <15 mL/min/1.73 m2, acute coronary syndrome <30 days, history of intracranial hemorrhage, stroke or transient ischemia attack, or active or clinically significant bleeding. Low-dose aspirin (75-100 mg) is also recommended for primary prevention in patients with asymptomatic PAD and diabetes mellitus.

The guideline states that for the medical management of chronic leg symptoms, cilostazol is recommended to improve symptoms and increase walking distance, but should not be used in patients with PAD and congestive heart failure of any severity.1 In patients with chronic symptomatic PAD with claudication who are unresponsive to medical or other therapies (ie, structured exercise), revascularization procedures may be considered if the benefits outweigh the risks.

Treatment for patients CLTI requires a multispecialty team, inclusive of vascular medical and surgical specialists.1,2 Proper wound care and management of infection, pressure offloading, revascularization, and therapies to reduce risk of MACE and MALE are also recommended.1,2,6 When feasible, surgical, endovascular, or hybrid revascularization techniques may be recommended. In some cases, amputation may be needed to remove necrotic tissue.

Acute limb ischemia is an emergency situation that requires prompt recognition and treatment to maximize the probability of salvaging the limb.1,6 Patients should be treated by clinicians with sufficient experience and resources; patient transfer to an appropriate facility may need to be considered. Revascularization is indicated for patients with ALI and a salvageable limb. All patients with ALI should be administered systemic anticoagulation with unfractionated heparin (UFH) on diagnosis unless there is a contraindication per the US multi-organization guideline.1 A direct thrombin inhibitor may be used instead of heparin for patients with a history of heparin-induced thrombocytopenia (HIT). The 2024 ESC guidelines recommend anticoagulation with either UFH or low molecular weight heparin (LMWH).6 The dosing recommendation provided by the ESC for UFH is a bolus dose of 5000 IU or 70-100 IU/kg body weight, followed by continuous infusion with dose adjustment based on patient response, monitored by activated clotting time (ACT) or activated partial thromboplastin time (aPTT). Enoxaparin, a LMWH, is dosed at 1 mg/kg per body weight twice daily as a subcutaneous injection. Additional therapies recommended for patients with ALI include appropriate analgesia, intravenous (IV) fluids, and treatment for acidosis and hyperkalemia as necessary.

Note that the guideline recommendations made in regards to use of heparin for ALI have been rated as a level of evidence of C, due to the lack of randomized clinical trials of heparin for this indication.1,6 Despite this level of evidence, the US multi-organization guideline provides a strong recommendation for its use as the benefits greatly outweigh the risks.1 The ESC guideline states that heparin may be considered.6

Overview of UFH
Unfractionated heparin is an anticoagulant with several US Food and Drug Administration (FDA) and off-label indications.1,7-10 These indications are listed in Table 1; general dosing and administration recommendations for adult patients per the FDA labeling of UFH are listed in Table 2. Across any of its indications, the most common therapeutic continuous dose of UFH is a bolus IV injection of 80 units/kg followed by an initial continuous infusion rate of 18 units/kg/hour.7 However, dosing may differ depending on the indication. As an example, the dosing for non-ST-elevation myocardial infarction (NSTEMI) is lower with an initial guideline recommended loading dose of 60 IU/kg and initial infusion rate of 12 IU/kg/hour.8

UFH is a drug product made up of a heterogenous mixture of glycosaminoglycans, which are straight-chain anionic mucopolysaccharides.9 The glycosaminoglycans have anticoagulant properties. UFH is derived from porcine intestinal mucosa, which is standardized for its anticoagulant activity. As an anticoagulant, UFH works by inducing a conformation change in the plasma protein antithrombin III, which thereby inhibits clotting factors in the clotting cascade. The primary factors UFH inhibits are Factor IIa (thrombin) and, to a smaller degree, Factor Xa.

The pharmacokinetics and pharmacodynamics of UFH may vary widely between patients and therefore, close monitoring is needed to maintain therapeutic effectiveness while reducing the risk for bleeding.10,11 Laboratory tests for therapeutic monitoring of UFH include aPTT, ACT, and anti-factor Xa levels.7 A 2017 literature review was conducted by the University of Illinois at Chicago Drug Information Group on the therapeutic monitoring of UFH using anti-factor Xa levels versus aPTT, which can be accessed here.11 Per the FDA approved labeling, the UFH dosage is considered adequate when aPTT is 1.5 to 2 times normal.9 The American College of Chest Physicians (ACCP) list a therapeutic aPTT range between 1.5 to 2.5 times control to reduce the risk of recurrent venous thromboembolism (VTE) based on a retrospective study.12 However, this range may vary depending on reagents and instruments used. Therefore, therapeutic aPTT ranges need to be established by individual institutions based on their specific laboratory equipment and reagents utilized.

Table 1. Indications of unfractionated heparin.1,7-10
FDA approved9Off-label indications1,7,8,10
Prophylaxis and treatment of venous thrombosis and PE

Prevention of postoperative DVT and PE in patients undergoing major abdominothoracic surgery at risk of developing thromboembolic disease

Atrial fibrillation with embolization

Treatment of acute and chronic consumptive coagulopathies

Prevention of clotting in cardiac and arterial surgery

Use as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures		ACS (including unstable angina, NSTEMI and STEMI)

PCI

ALI

As a bridge to warfarin for mechanical and bioprosthetic valves
Abbreviations: ACS=acute coronary syndrome; ALI=acute limb ischemia; DVT=deep vein thrombosis; FDA=Food and Drug Administration; NSTEMI=non-ST-elevation myocardial infarction; PCI=percutaneous coronary intervention; PE=pulmonary embolism; STEMI=ST-elevation myocardial infarction.
Table 2. General FDA approved dosing and administration recommendations.a,9
RoutesDosing and frequencyMonitoring frequency
Deep SCInitial: 5000 units by IV, followed by 10,000 to 20,000 units of concentrated solution, SCBest drawn 4 to 6 hours after injection
Every 8 hours:
8,000 to 10,000 units of concentrated solution

Or

Every 8 hours:
15,000 to 20,000 units of concentrated solution
Intermittent IVInitial: 10,000 units, either undiluted or in 50 to 100% mL of 0.9% sodium chloride injection solutionBefore each injection during initiation of treatment and appropriate intervals thereafter
Every 4 to 6 hours: 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% sodium chloride injection solution
Continuous IVInitial: 5000 units by IV injectionAt initiation, every 4 hours, and then at appropriate intervals thereafter
Continuous: 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% sodium chloride or other compatible injection solution for infusion
Abbreviations: FDA=Food and Drug Administration; IV=intravenous; SC=subcutaneous.
aPer FDA approved labeling for therapeutic anticoagulant effect with full-dose heparin in adult patients based on a 68 kg patient; the manufacturer labeling states that the dosages must be adjusted for the individual patient according to applicable lab results; dosage schedule presented may be used as guidelines and are based on clinical experience.

Heparin dosing for peripheral arterial disease-specific indications
A literature search was conducted to identify sources that provided dosing information for the use of UFH in PAD-related indications. Studies discussing the use of UFH for VTE prophylaxis and treatment, as well as its other indications, were excluded from the search. No randomized controlled trials were identified. The literature that was found that identified specific dosing information are listed in Table 3. In addition to the ESC guidelines, dosing information was found in 9 other publications consisting of a systematic review, a survey of hospital institutional practices, 4 observational studies, and 3 reviews with a case report, a case series, and expert opinion.6,13-21 Uses of UFH included continuous infusion for patients with ALI, including as part of regimens for catheter-direct therapy (CDT), and intermittent dosing for patients undergoing endovascular or other procedures for PAD.

Table 3. Literature found with specified doses of heparin for PAD6,13-21
CitationLiterature type Specified use(s)UFH dosing informationa
Clinical practice guidelines
Mazzolai et al 20246ESC GuidelinesALIBolus of 5000 IU or 70-100 IU/kg, followed by continuous infusion with adjustment based on aPTT or ACT
Systematic reviews and survey studies
Qureshi et al 202013Systematic reviewEndovascular interventions for PADDosage varied across the 94 total studies in review

UFH used peri-procedurally in 57% of studies

Range: 2500-7500 IU
Mode: 5000 IU (21 trials)
Leenstra et al 201914Survey of SOPsCDT for acute arterial occlusions of the lower extremities34 total SOPs collected from institutions across the Netherlands

In 13 SOPs, UFH administered via the catheter sheath at doses of 2500 IU/hour, 3000 IU/hour, or 5000 IU/hour; 5000 IU/hour was most common

In 26 SOPs, continuous IV UFH doses ranged from 200 IU/hour to 1000 IU/hour; 13 also had UFH bolus of 2500 IU or 5000 IU
Observational studies
Roosendaal et al 202315Retrospective chart reviewIntraoperative doses in interventions for PAD (ie, NCAP)Group 1:
Bolus of 5000 IU

Group 2:
Bolus of 100 IU/kg, followed by intermittent doses based on ACT values to target of 200 to 250 seconds, as needed until end of procedure

44% of patients in group 1 reached peak ACT > 200 seconds vs 95% of patients in group 2

Bleeding complication rates were higher in group 2
Nissborg and Wahlgren 201916Prospective pilot with retrospective quality reviewElective endovascular intervention for arterial insufficiency in lower extremitiesIntra-arterial dose of 5000 IU without adjustment for weight or monitoring during procedure

Additional dose administered per preference of surgeon, without additional monitoring; doses ranged from 2000-2500 IU

5% of patients had ACT <200 seconds and 21.7% had ACT ≥350 seconds 10 minutes after UFH administration; 17.2% had ACT <200 seconds and 20.7% had ACT ≥350 seconds by end of procedure

Mean body weight dose based on patients in study was 70 IU/kg

A significant difference was identified between ACT levels 10 minutes after administration with analysis based on body weight dose; the mean body weight dose for ACT <200 seconds was 54 IU/kg, the mean body weight for ACT ≥350 seconds was 82 IU/kg

Authors found a mean dose of 70 IU/kg to be appropriate to reach target ACT goal between 200-350 seconds
Lukasiewicz et al 201617Prospective, observational studyALI, treated with CDT protocolsBolus of 50 IU/kg, followed by continuous infusion at rate of 1000 IU/hour, with adjustment to maintain aPTT 1.5 to 2.5 times baseline
Marotti et al 201518Retrospective chart reviewTIA, stroke, ALI, postoperative revascularizationGroup 1:
Bolus of 60 units/kg, followed by initial infusion rate of 12 units/kg/hour

Group 2:
Bolus of 80 units/kg, followed by initial infusion rate of 18 units/kg/hour

Both groups had doses adjusted to achieve a therapeutic aPTT range of 65-110 seconds

Group 2 was more likely to achieve a therapeutic aPTT at 6 hours after initiation of therapy, but more likely to have supratherapeutic aPTT

Authors suggest a loading dose of 70 units/kg may be appropriate
Case series, case reports, reviews, and expert opinions
Santistevan 201719Review, expert opinionALIBolus of 80-150 units/kg IV, followed by 18 units/kg/hour, adjusted to target aPTT of 2 to 2.5 times baseline
Braun and Lin 201620Case report and reviewALI with CDTCase study:
Bolus of 10,000 units used followed by continuous infusion at 1000 units/hour in ED, followed by 600 units/hour during procedure/hospitalization

Patient discharged to home on hospital day 4

Other dosage discussed in literature review for patients undergoing intra-arterial thrombolytic infusions:
Bolus of 2500 units, followed by continuous infusion of 500 units/hour to maintain PTT between 1.25 and 1.5 times control
Henke 200921Case series and literature reviewALIBolus of 100 to 150 units/kg, followed by continuous infusion to maintain aPTT of 2 to 2.5 times baseline
Abbreviations: ACT=activated clotting time; ALI=acute limb ischemia; aPTT=activated partial thromboplastin time(s); CDT=catheter-direct thrombolysis; ED=emergency department; ESC=European Society of Cardiology; IV=intravenous; NCAP=noncardiac arterial procedures; PAD=peripheral arterial disease; PTT=partial thromboplastin time; SOPs=standard operating procedures; TIA=transient ischemic attack; UFH=unfractionated heparin.
aUnits of measurement (ie, IU vs units) reported out based on how described in each publication.

Discussion
There is a limited amount of evidence on specific dosing regimens for UFH for PAD-related indications. Of the literature identified, dosage protocols ranged based on the specific indication (ie, peripheral endovascular interventions vs ALI) and not all studies assessed for target therapeutic monitoring levels.6,13-21 Intermittent dosing of UFH is utilized for endovascular interventions of the lower extremities for patients without ALI.13,15,16 The most common dosage identified for this use, regardless of study type, was 5000 IU. However, two observational studies suggested weight-based dosing may allow for more patients to reach target therapeutic aPTT or ACT levels.15,16 For presentation of ALI, with or without CDT, dosages included a bolus of either 5000 IU or a range of 50 IU/kg to as high as 150 IU/kg.6,14,17-21 The continuous infusion rates included doses of 500 to 1000 IU/hour and 60 to 80 IU/kg/hour. There were also ranges of values for the therapeutic monitoring of UFH with either ACT or aPTT. Note that these variabilities may have been due for several reasons including potential concomitant procedures and medications. For example, patients receiving thrombolytics would use lower dosing protocols to reduce the risk of bleeding events. Other concomitant medications that may increase the risk of bleeding (ie, aspirin or clopidogrel) should also be accounted for. Differences in laboratory assays and equipment would mean the potential for differences in target ACT and aPTT values. All these considerations underscore the importance of health institutions developing protocols specific to their patient populations, procedures, and laboratory environments, and that there is not one specific universal dosing protocol of UFH for all PAD-related indications.

References

  1. Gornik HL, Aronow HD, Goodney PP, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(24):e1313-e1410. doi:10.1161/CIR.0000000000001251
  2. Bates KJ, Moore MM, Cibotti-Sun M. 2024 lower extremity peripheral artery disease guideline-at-a-glance. J Am Coll Cardiol. 2024;83(24):2605-2609. doi:10.1016/j.jacc.2024.04.003
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  4. National Heart, Lung, and Blood Institute (NHLBI). What is peripheral artery disease? NHLBI website. Updated March 24, 2022. Accessed November 21, 2024. https://www.nhlbi.nih.gov/health/peripheral-artery-disease
  5. Centers for Disease Control and Prevention (CDC). About peripheral arterial disease (PAD). CDC website. Updated May 15, 2024. Accessed November 21, 2024. https://www.cdc.gov/heart-disease/about/peripheral-arterial-disease.html
  6. Mazzolai L, Teixido-Tura G, Lanzi S, et al. 2024 ESC Guidelines for the management of peripheral arterial and aortic diseases. Eur Heart J. 2024;45(36):3538-3700. doi:10.1093/eurheartj/ehae179
  7. Warnock LB, Huang D. Heparin. In: StatPearls [Internet]. StatPearls Publishing. Updated July 10, 2023. Accessed November 22, 2024. https://www.ncbi.nlm.nih.gov/books/NBK538247/
  8. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(25):e344-e426. doi:10.1161/CIR.0000000000000134
  9. Heparin sodium. Package insert. Hikma Pharmaceuticals USA Inc; 2024.
  10. 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
  11. What evidence is available to support the use of anti-factor Xa levels instead of activated partial thromboplastin time for monitoring of intravenous unfractionated heparin therapy in adults? UIC Drug Information Group website. Published July 2017. Accessed November 21, 2024. https://dig.pharmacy.uic.edu/faqs/2017-2/july-2017-faqs/
  12. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e24S-e43S. doi:10.1378/chest.11-2291
  13. Qureshi MI, Li HL, Ambler GK, et al. Antiplatelet and anticoagulant use in randomised trials of patients undergoing endovascular intervention for peripheral arterial disease: systematic review and narrative synthesis. Eur J Vasc Endovasc Surg. 2020;60(1):77-87. doi:10.1016/j.ejvs.2020.03.010
  14. Leenstra BS, van Ginkel DJ, Hazenberg CEVB, Vonken EPA, de Borst GJ. Heterogeneity in standard operating procedures for catheter directed thrombolysis for peripheral arterial occlusions in the Netherlands: a nationwide overview. Eur J Vasc Endovasc Surg. 2019;58(4):564-569. doi:10.1016/j.ejvs.2019.02.028
  15. Roosendaal LC, Radović M, Hoebink M, Wiersema AM, Blankensteijn JD, Jongkind V. The additional value of activated clotting time-guided heparinization during interventions for peripheral arterial disease. J Endovasc Ther. 2023. doi:10.1177/15266028231213611
  16. Nissborg E, Wahlgren CM. Anticoagulant effect of standard dose heparin during peripheral endovascular intervention. Ann Vasc Surg. 2019;60:286-292. doi:10.1016/j.avsg.2019.02.033
  17. Lukasiewicz A, Lichota W, Thews M. Outcomes of accelerated catheter-directed thrombolysis in patients with acute arterial thrombosis. Vasc Med. 2016;21(5):453-458. doi:10.1177/1358863X16635291
  18. Marotti SB, Barras M, Kirkpatrick C. Comparison of 2 weight-based heparin dosing nomograms in neurology and vascular surgical patients. Ther Drug Monit. 2015;37(1):33-39. doi:10.1097/FTD.0000000000000099
  19. Santistevan JR. Acute limb ischemia: an emergency medicine approach. Emerg Med Clin North Am. 2017;35(4):889-909. doi:10.1016/j.emc.2017.07.006
  20. Braun R, Lin M. Acute limb ischemia: a case report and literature review. The Journal of emergency medicine. 2015 Dec 1;49(6):1011-7.
  21. Henke PK. Contemporary management of acute limb ischemia: factors associated with amputation and in-hospital mortality. Semin Vasc Surg. 2009;22(1):34-40. doi:10.1053/j.semvascsurg.2009.01.002

Prepared by:
Jacqueline Wasynczuk, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

December 2024

The information presented is current as of November 20, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.