Thrombolytic Agents

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for thrombolytic agents. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for thrombolytic agents and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site:

IOM Citations:

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
• Chapter 1, Section 30 Drugs and Biologicals
• Chapter 15, Section 50 Drugs and Biologicals
• CMS IOM Publication 100-04, Medicare Claims Processing Manual,
• Chapter 17, Section 40 Discarded Drugs and Biologicals
• CMS IOM 100-08, Medicare Program Integrity Manual,
  • Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.

Compliance with the provisions in this policy may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

Thrombosis is the formation of a blood clot (thrombus). It is an important part of the normal hemostatic response that limits hemorrhage caused by microscopic or macroscopic vascular injury. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. Physiologic thrombosis is counterbalanced by intrinsic antithrombotic properties and fibrinolysis. Under normal conditions, a thrombus is confined to the immediate area of injury and does not obstruct flow to critical areas, unless the blood vessel lumen is already diminished, as it is in atherosclerosis.

Under pathologic conditions, a thrombus can propagate into otherwise normal vessels. A clot that breaks free and begins to travel around the body is known as an embolus. Thromboembolism is the combination of thrombosis and its main complication, embolism. A thrombus that has propagated where it is not needed can obstruct flow in critical vessels; it can also destroy valves and other structures that are essential to normal hemodynamic function.

The 3 main components of a blood clot are platelets (thrombocytes), thrombin, and fibrin; each of these components is a key therapeutic target. During thrombus formation, circulating prothrombin is activated to the active clotting factor, thrombin, by activated platelets. Fibrinogen is activated to fibrin by the newly activated thrombin. Fibrin is then formed into the fibrin matrix. All this takes place while platelets are being adhered and aggregated.

Fibrin-bound plasminogen will be converted by thrombolytic drugs to plasmin, the rate-limiting step in thrombolysis.

It should be kept in mind that the thrombolysis process works best on recently formed thrombi. Older thrombi have extensive fibrin polymerization that makes them more resistant to thrombolysis; hence, the importance of time for thrombolytic therapy.

Covered Indications:

Injection of thrombolytic agents is eligible for payment for the following indications:

1. Treatment of acute arterial thrombosis (other than coronary or intracranial).
   
   Treatment Recommendation Guidelines*:
   
   
   • Acute leg ischemia is one of the most challenging and dangerous conditions in vascular surgical practice and carries a high risk of amputation and death when left untreated. Catheter-directed thrombolysis (CDT) can be considered a complementary and not a competing technology with surgical or percutaneous revascularization, with an acceptably low complication rate.
   • Patients with limb-threatening ischemia are not candidates for local fibrinolysis, which usually takes between 6 and 72 hours to achieve clot lysis. These patients require emergency embolectomy. CDT is reserved for patients with non–life-threatening limb ischemia due to in situ thrombosis of less than 14 days’ duration. Consider that patients with thrombosis of more than 30 days’ duration are not likely to respond to local fibrinolysis.
   • In patients with acute limb ischemia due to arterial emboli or thrombosis, it is suggested to administer immediate systemic anticoagulation with unfractionated heparin over no anticoagulation; it is suggested to administer reperfusion therapy (surgery or intraarterial thrombolysis) over no reperfusion therapy; it is recommended to perform surgery over intraarterial thrombolysis. In patients undergoing intraarterial thrombolysis, it is suggested to administer recombinant tissue-type plasminogen activator (rtPA) or urokinase over streptokinase.
     
     
2. Treatment of acute ischemic stroke.
   
   Treatment Recommendation Guidelines*:
   
   
   • Intravenous Recombinant Tissue Plasminogen Activator (IV rtPA) for Acute Ischemic Stroke:
     
     
     • In patients with acute ischemic stroke in whom treatment can be initiated within 3 hours of symptom onset, it is recommended to administer IV rtPA over no IV rtPA. In patients with acute ischemic stroke in whom treatment can be initiated within 4.5 but not within 3 hours of symptom onset, it is suggested to administer IV rtPA over no IV rtPA. In patients with acute ischemic stroke in whom treatment cannot be initiated within 4.5 hours of symptom onset, recommendations are against IV rtPA.
       
       
   • Intraarterial (IA) Thrombolysis in Acute Ischemic Stroke:
     
     
     • In patients with acute ischemic stroke due to proximal cerebral artery occlusions (i.e., internal carotid artery, middle cerebral artery [MCA], vertebral artery, and basilar artery) who do not meet eligibility criteria for treatment with IV rtPA, it is suggested to administer IA rtPA initiated within 6 hours of symptom onset over no IA rtPA.
     • In patients with acute ischemic stroke it is suggested to administer IV rtPA over the combination IV/IA rtPA.
   
   
   
3. Treatment of acute pulmonary thromboembolism.
   
   Treatment Recommendation Guidelines*:
   
   
   • In patients with acute pulmonary embolism (PE) associated with hypotension (e.g., systolic BP less than 90 mm Hg) who do not have a high bleeding risk, it is suggested to provide systemically administered thrombolytic therapy over no such therapy.
   • In most patients with acute PE not associated with hypotension, it is recommended against systemically administered thrombolytic therapy.
   • In selected patients with acute PE not associated with hypotension and with a low bleeding risk whose initial clinical presentation, or clinical course after starting anticoagulant therapy, suggests a high risk of developing hypotension, it is suggested to administer thrombolytic therapy.
   • In selected patients with acute PE associated with hypotension in a high bleeding risk patient, (for example, acute post op status of major surgery, recent trauma with surgery, recent ischemic stroke, recent GI bleed) catheter directed therapy with thrombolytics may be used if the appropriate expertise and resources are available.
   • In patients with acute PE, when a thrombolytic agent is used, it is suggested to provide short infusion times (e.g., a 2-hour infusion) over prolonged infusion times (e.g., a 24-hour infusion).
   • In patients with acute PE when a thrombolytic agent is used, it is suggested to provide administration through a peripheral vein over a pulmonary artery catheter unless special circumstances as above are noted.
     
     
4. Treatment of thrombosed vascular prosthetic devices, implants, and grafts.
   
   
5. Treatment of Ileofemoral deep vein thrombosis.
   
   Treatment Recommendation Guidelines*:
   
   
• In patients with acute proximal deep vein thrombosis (DVT) of the leg, it is suggested to administer anticoagulant therapy alone over systemic thrombolysis.
• It is believed that systemic thrombolysis should be considered only in patients who meet all of the following criteria:
  
  
  • Iliofemoral DVT, symptoms for less than 14 days, good functional status, life expectancy greater than or equal to 1 year, and low risk of bleeding. Based on low-quality evidence of greater effectiveness and less bleeding, if resources and expertise are available to perform CDT, it is considered the preferable approach. Because the balance of risks and benefits with systemic thrombolysis is uncertain, and particularly because of concerns about major bleeding, anticoagulant therapy alone is an acceptable alternative to systemic thrombolysis in all patients with acute DVT who do not have impending venous gangrene
    
    
6. Treatment of acute ST segment elevation myocardial infarction (STEMI).
   
   Treatment Recommendation Guidelines*:
   
   
6. In the absence of contraindications, fibrinolytic therapy should be administered to patients with STEMI at non–percutaneous coronary intervention (PCI)-capable hospitals when the anticipated First Medical Contact (FMC)-to-device time at a PCI-capable hospital exceeds 120 minutes because of unavoidable delays.
7. When fibrinolytic therapy is indicated or chosen as the primary reperfusion strategy, it should be administered within 30 minutes of hospital arrival.
8. Reperfusion therapy is reasonable for patients with STEMI and symptom onset within the prior 12 to 24 hours who have clinical and/or ECG evidence of ongoing ischemia. Primary PCI is the preferred strategy in this population.

CLASS I

• In the absence of contraindications, fibrinolytic therapy should be given to patients with STEMI and onset of ischemic symptoms within the previous 12 hours when it is anticipated that primary PCI cannot be performed within 120 minutes of FMC.

CLASS IIa

• In the absence of contraindications and when PCI is not available, fibrinolytic therapy is reasonable for patients with STEMI if there is clinical and/or ECG evidence of ongoing ischemia within 12 to 24 hours of symptom onset and a large area of myocardium at risk or hemodynamic instability.

CLASS III: HARM

• Fibrinolytic therapy should not be administered to patients with ST depression except when a true posterior (inferobasal) MI is suspected or when associated with ST elevation in lead aVR. 

*NOTE: The treatment recommendation guidelines are mentioned to serve as references to all providers of these services as to the level of care that is expected and to serve as an educational tool to all those involved in billing, review, and handling these types of services. Medicare realizes that practice guidelines may change or be updated. Future changes or updates to guidelines may result in a change in the coverage criteria including a possible denial of services. We shall make every attempt to keep abreast of these changes. However, we encourage our providers, beneficiaries, and other stakeholders to notify us of guideline changes.

Medicare will cover thrombolytic treatment via transcatheter, intracoronary, and intracranial infusion when reasonable and necessary per the indications section only in the setting of a hospital, as an inpatient. Thrombolytic treatment via intravenous infusion may be covered in the setting of a hospital, as an inpatient; or in an emergency room; or critical access hospital. There is no limitation on setting for thrombolytic treatment of thrombosed implanted vascular access device or catheter. Please refer to the limitations section for specific criteria.

*Note: The use of thrombolytic agents specific to hemodialysis arteriovenous (AV) fistula including percutaneous thrombectomy and intra-graft thrombolysis of an AV fistula is not addressed by this LCD. Please follow correct coding guidelines per AMA CPT for reporting these services.

Coding Guidelines and Drug Wastage

Please refer to the Local Coverage Article: Billing and Coding: Thrombolytic Agents (A55237) for information on drug wastage and coding guidelines for thrombolytic agents.

Limitations

The thrombolytic agent Urokinase is only to be reported for the use of declotting of implanted vascular access device or catheter. All other uses are considered not reasonable and necessary. Please refer to ICD-10 Code group 1 in the related billing and coding article A55237 for covered indications.

Place of Service (POS)

NOTE: Thrombolytic treatment via transcatheter, intracoronary, and intracranial infusion will be considered reasonable and necessary per the indications section only when performed in facility based care.

Thrombolytic treatment via intravenous infusion will be considered reasonable and necessary per the indications section only when performed in facility based care setting, such as inpatient; an emergency room; observation or critical access hospital.

Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this policy, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.

The redetermination process may be utilized for consideration of services performed outside of the reasonable and necessary requirements in this LCD.

A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (PE)

This is a single arm study from multiple centers where massive and submassive pulmonary emboli were treated with small catheters and direct infusions of thrombolytic agents. Physiologic parameters for inclusion criteria include dilated right ventricular (RV) with a RV-to-left ventricular (LV) ratio of .9 by a chest computed tomography (CT) scan.¹ Safety outcome of bleeding was assessed. Within 48 hours, the ratio of RV:LV improved. Short-term outcomes were discussed, but long term results and clinical outcomes were not available. The authors concluded this technique decreased RV dilatation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage in these clinical settings.

Catheter Directed Therapy (CDT) in Acute Pulmonary Embolism with Right Ventricular Dysfunction: A promising Modality to Provide Early Hemodynamic Recovery

Small retrospective review of 15 patients who had acute PE, massive or submassive and underwent catheter directed therapy. Review of hemodynamic changes (RV dilatation, hypokinetic RV on Echo), outcomes was noted. Clinical situations in which this was done were noted. All procedures were done with the same interventional radiologist. Clinical situations in which this technique was done include: recent major surgery, trauma with recent surgery, central nervous system (CNS) neoplasm, recent gastrointestinal (GI) bleed, recent ischemic stroke and refractory hypotension. It was felt massive vs submassive PE were equivalent on outcomes. Deaths did occur in both types of PE. RV dysfunction was not defined other than those parameters listed above. The authors concluded that CDT was appropriate when there was RV dysfunction and a risk of bleeding.²

Antithrombotic Therapy for VTE Disease

This is a compellation of reviews of various clinical scenarios for this use of thrombolytic therapy. It is done by experts for the American College of Chest Physicians. It represents practice guidelines based on the clinical reviews. In regard to the initial use of a catheter based therapy the guidelines state the following in patients with acute PE associated with hypotension and who have a high bleeding risk, failed systemic thrombolysis, or shock that is likely to cause death before systemic thrombolysis can take effect (e.g. within hours), if appropriate expertise and resources are available, we suggest catheter –assisted thrombus removal over no such intervention.³

The analysis of the information concluded that CDT was appropriate when there was RV dysfunction and a risk of bleeding. The treatment with small catheters and direct infusions of thrombolytic agents technique decreased RV dilatation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage in these clinical settings.

Refer to the Local Coverage Article: Billing and Coding: Thrombolytic Agents, A55237 for all coding information.

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Other Contractor Policies

Contractor Medical Directors

1. Piazza, G, Hohlfelder, B. et al: A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism. The American College of Cardiology Foundation. 2015 Aug;10(8): 1382-92
2. Dilektasli, A. G., Demirdogen Cetinoglu, E., Acet, N. A., Erdogan, C., Ursavas, A., Ozkaya, G.,Ege, E. (2016). Catheter-Directed Therapy in Acute Pulmonary Embolism with Right Ventricular Dysfunction: A Promising Modality to Provide Early Hemodynamic Recovery. Medical science monitor: international medical journal of experimental and clinical research, 22, 1265–1273. doi:10.12659/msm.897617
3. Kearon, C et al. Antithrombotic Therapy for VTE Disease. Chest 2016; 149(2): 315-352.
4. Aggarwal V, Nicolais CD, Lee A, et al. American College of Cardiology. Acute Management of Pulmonary Embolism. October 24, 2017. Accessed at https://www.acc.org/latest-in-cardiology/articles/2017/10/23/12/12/acute-management-of-pulmonary-embolism.
5. Alonso-Coello P, Bellmunt S, McGorrian C, et al. Antithrombotic Therapy in Peripheral Artery Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e669S-90S. doi: 10.1378/chest.11-2307.
6. Arcasoy SM, Kreit JW. Thrombolytic Therapy of Pulmonary Embolism: A Comprehensive Review of Current Evidence. Chest. 1999 Jun;115(6):1695-1707.
7. Bander SJ, Schwab SJ, Woo K. Central catheters for acute and chronic hemodialysis access. UpToDate®. Last updated June 25, 2015. www.uptodate.com.
8. Beathard GA. Thrombosis associated with chronic hemodialysis vascular catheters. UpToDate®. Last updated May 12, 2015. www.uptodate.com.
9. Beliaev AN, Pavelkin AG, Rodin AN. Intra-arterial thrombolytic therapy of ischaemic complications of lower-limb diabetic angiopathy. Angiol Sosud Khir. 2012;18(3):13-7.
10. Braaten JV, Goss RA, Francis CW. Ultrasound Reversibly Disaggregates Fibrin Fibers. Thromb Haemost. 1997 Sep;78(3):1063-8.
11. Cathflo® Activase® (alteplase) for Catheter Occlusions. www.cathflo.com.
12. Delewi R, Zijlstra F, Piek JJ. Left ventricular thrombus formation after acute myocardial infarction. Heart 2012;98:1743-1749 doi:10.1136/heartjnl-2012-301962.
13. Fiumara K, Kucher N, Fanikos J, et al. Predictors of Major Hemorrhage Following Fibrinolysis for Acute Pulmonary Embolism. Am J Cardiol. 2006 Jan 1;97(1):127-129.
14. Francis CW, Blinc A, Lee S, et al. Ultrasound Accelerates Transport of Recombinant Tissue Plasminogen Activator Into Clots. Ultrasound Med Biol. 1995;21(3): 419-424.
15. Fremont B, Pacouret G, Jacobi D, et al. Prognostic Value of Echocardiographic Right/Left Ventricular End-Diastolic Diameter Ratio in Patients With Acute Pulmonary Embolism: Results From a Monocenter Registry of 1, 416 Patients. Chest. 2008 Feb;133(2):358-362.
16. Hilleman D, Campbell J. Efficacy, safety, and cost of thrombolytic agents for the management of dysfunctional hemodialysis catheters: a systematic review. Pharmacotherapy. 2011 Oct;31(10):1031-40.
17. Interventional Radiology Grand Rounds: Topic: New Treatment Option for DVT. Society of Interventional Radiology. 2004. www.SIRweb.org.
18. Lansberg MG, O'Donnell MJ, Khatri P, et al. American College of Chest Physicians. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e601S-36S. doi: 10.1378/chest.11-2302.
19. Lee CH, Chen CC, Chern MS. Thrombolytic therapy for acute left atrial thrombus formation in one patient with heart failure and atrial fibrillation. Circ J. 2007 Apr;71(4):604-7.
20. Lin PH, Annambhotla S, Bechara CF, et al. Comparison of Percutaneous Ultrasound-Accelerated thrombolysis versus Catheter-Directed Thrombolysis in Patients with Acute Massive Pulmonary Embolism. Vascular. 2009; 17(3): S137-S147.
21. Manning WJ. Embolism from aortic plaque: Thromboembolism. UpToDate®. Last updated: Feb 12, 2015 http://www.uptodate.com/contents/embolism-from-aortic-plaque-thromboembolism.
22. Marshall RS, Progress in Intravenous Thrombolytic Therapy for Acute Stroke. JAMA Neurol. 2015;72(8):928-934.
23. Micromedex Consumer Medication Information: Urokinase (Injection) published October 1, 2015.
24. Nykamp M, VandenHull A, Remund T, et al. Nykamp & Laurich Study, Safety and efficacy of ultrasound-accelerated catheter-directed lytic therapy in acute pulmonary embolism with and without hemodynamic instability. J Vasc Surg: Venous and Lymphatic Disorders. 2015; 3(3): 251-257. doi: 10.1016/j.jvsv.2015.03.001.
25. O'Gara P, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. Journal of the American College of Cardiology. 2013;61(4):e78-e140. doi:10.1016/j.jacc.2012.11.019.
26. Pelage JP, El Hajjam M, Lagrange C, et al. Pulmonary artery interventions: an overview. Radiographics. 2005 Nov-Dec;25(6):1653-67.
27. Sobhy E, Alamaldine T, Al Sabti H. Successful Treatment of Right-Sided Heart Thrombus with Pulmonary Embolism with Thrombolytic Therapy. Journal of Cardiovascular Diseases & Diagnosis. 2013, 1:4.
28. Vedantham S, Thorpe PE, Cardella JF, et al. Quality Improvement Guidelines for the Treatment of Lower Extremity Deep Vein Thrombosis with Use of Endovascular Thrombus Removal. J Vasc Interv Radiol. 2006; 17: 435-448.
29. Kearon C, et al. Antithrombolitic Therapy for VTE Disease. Chest. 2016; 149(2): 315-352.
30. Kuo WT, Gould MK, Louie JD, Rosenberg JK, SZE DY, Hofmann LV. Catheter-directed Therapy for the Treatment of Massive Pulmonary Embolism: Systematic Review and Meta-analysis of Modern Techniques. JVIR. November 2009: 1431-1440.
31. Wang L, Xu Y, Zhang W, Lu W, Chen M, Luo J. Early interventional therapy for acute massive pulmonary embolism guided by minimally invasive hemodynamic monitoring. J Clin Exp Med. 2015;8(8):14011-14017.
32. Pelliccia F, Schiariti M, Terzano C, et al. Treatment of Acute Pulmonary Embolism: Update on Newer Pharmacologic and Interventional Strategies. BioMed Research International. 2014:1-6.