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Antithrombotic Therapy

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Antithrombotic Therapy: Cost-Effective Approaches


Rodger L. Bick, MD, PhD, FACP

Abstract


Thrombosis accounts for extraordinary morbidity and mortality, as well as high medical care costs. The condition, which presents multidisciplinary medical problems, can be treated cost-effectively, and preventive steps can also be taken.

Introduction


Thrombosis is the most common cause of death in the US. Over 2 million people die each year from an arterial or venous thrombosis or their consequences.[1] By contrast, about 550,000 will die this year from cancer; thus, fatal thrombosis is about 4 times as prevalent as fatality from malignancy.[1] Over 2 million people also suffer from nonfatal thrombosis, such as deep vein thrombosis (DVT), nonfatal pulmonary embolus, nonfatal cerebrovascular thrombosis (CVT), cerebral transient ischemic attack (TIA) (40% of these will have a fatal or nonfatal CVT within 1 year),[2] nonfatal coronary artery thrombosis, and retinal vascular thrombosis (RVT). Many, if not most, episodes of thrombosis can be prevented by appropriate primary antithrombotic therapy, and almost all instances of recurrence can be prevented by appropriate secondary therapy.[3]

About 80% to 90% of all unexplained episodes of venous thrombosis (nontraumatic and nonsurgical) and about 65% of arterial thrombosis events are associated with a blood coagulation protein or platelet defect.[3,4] Of these, about 50% harbor a congenital defect and about 50% harbor an acquired blood coagulation protein or platelet defect which caused the thrombotic event.[1,3]

The following statistics highlight the scope of the problem: The incidence of DVT in the US is about 159 per 100,000, or about 450,000 a year. The overall incidence of pulmonary embolism (PE) in the US is about 139 per 100,000 or about 355,000 cases a year; the incidence of fatal PE in the US is 94 per 100,000 or about 240,000 deaths (Table 1).[5-7]

The etiologies of hypercoagulability and overt thrombosis are becoming clearer and, with enhanced knowledge of hemostasis and the development of testing systems for evaluating patients with thrombotic and thromboembolic disorders, the etiologies often become definitive.[8] Using these test systems in conjunction with careful clinical assessment of patients, 80% to 90% of patients with thrombosis will have a defined etiology.[1,3,4] Many of these will have an obvious clinical condition leading to thrombosis and at least 50% to 80% will have an underlying hereditary or acquired blood protein/platelet defect causing thrombosis.

Many clinical conditions are associated with an increased risk of arterial or venous thrombosis and thromboembolism; the more common of these are summarized in Table 2.[1] In many instances, though, a clinical situation associated with thrombosis serves to unmask a congenital or acquired blood coagulation protein/platelet defect harbored by the patient.

Effective management of thrombosis, with the goal of reducing morbidity and mortality and containing costs, centers around 3 interrelated areas: clear definition of the etiology of thrombosis; secondary prevention (prevention of recurrence); and primary (prophylactic) therapy for first events.

Etiology of Thrombosis


Most instances of arterial and venous thrombosis are unexplained -- that is, they are not associated with surgery, trauma, cardiac emboli, or other specific events. Most instances of first-event thrombosis are expensive; national average costs for DVT/PE and CVT/TIA per episode (admission) are presented in Table 3.[9] An appreciation of these per-episode costs of care allows one to appreciate cost savings per patient and per type of thrombosis for each potentially preventable primary or recurrent episode.

Both the common and rarer blood coagulation protein/platelet defects leading to thrombosis are summarized in Table 4. When viewing this table, remember that a clinical etiology has not been identified in most instances of thrombosis, and often a clinical event associated with thrombosis is simply unmasking an underlying blood coagulation protein/platelet defect harbored by the patient.

Cost Containment


Individuals harboring these defects should be defined in order to: (1) allow appropriate antithrombotic therapy and decrease risks of recurrence; (2) determine the length of time the patient must remain on therapy for secondary prevention; and (3) allow for testing and primary prevention for family members of those harboring a hereditary blood coagulation protein or platelet defect (about 50% of all coagulation and platelet defects mentioned above). The known prevalence of coagulation protein/platelet defects in common thrombotic disorders is shown in Table 5; this prevalence will increase as additional studies and discoveries of new defects are reported.[3,4,10]

In addition to mortality, significant additional morbidity occurs as a result of both arterial or venous thrombotic events, including but not limited to paralysis (nonfatal thrombotic stroke), cardiac disability (repeated coronary events), loss of vision, RVT, and fetal wastage syndrome (placental vascular thrombosis), stasis ulcers, and other manifestations of post-phlebitic syndrome (recurrent DVT).

A diagnosis of thrombosis is similar to a diagnosis of "anemia" in that it is generic; however, approaching the diagnosis in this manner probably accounts for many treatment failures as well as confusing and conflicting results of clinical trials. Failure to make a specific diagnosis accounts for enhanced morbidity and mortality, and exorbitant and unnecessary medical costs for recurrent episodes -- most of which are easily prevented. One must therefore ask, what is the etiology? As is the case with anemia, the specific and appropriate therapy for thrombosis is highly dependent on defining the etiology.

Most clinicians and most investigators who conduct clinical trials that treat thrombosis as a disease subject to generic diagnosis fail to note that outcomes for a heterogeneous population will depend on designing therapy specific for a given etiology. For example, it would not make sense to treat a patient with thrombosis who has sticky platelet syndrome (SPS) with heparin or warfarin when he or she actually needs aspirin (ASA),[11,12] nor would it make sense to treat a patient with thrombosis who has antiphospholipid syndrome with aspirin (no response) or warfarin (65% failure rate)[4,13] when heparin is the preferred treatment.[4,13,14] Defining the defect and instituting appropriate therapy will save a minimum of $2,900,000 per 1000 patients with DVT and a minimum of $350,000 per 100 patients with CVT.[3,15] The cost of defining the common blood coagulation protein defects in these patients is $1000-$1500 per patient.[3,15] Thus, a cost of $1100 x 1000 DVT patients ($1,100,000) will save a minimum of $2,900,000. A cost of $1100 per 100 CVT patients ($110,000) will save a minimum of $350,000.[3,15-17] This does not account for additional savings, such as those related to rehabilitation, long-term care, and the savings in morbidity, all of which contribute greatly to a reduction in cost. Two examples follow to further illustrate cost benefits: DVT/PE and CVT/TIA.

DVT


The incidence of DVT in the US is about 159 per 100,000, or about 450,000 cases per year.[5,6] A definable etiology can be found in 80% to 90% of these patients; this allows effective therapy to be delivered and allows for the other advantages of defining the blood coagulation protein or platelet defects to be instituted. For example, about 28% of these patients will have antiphospholipid syndrome, and if treated with oral anticoagulants, about 65% will fail (re-thrombose).[4] Each of these failures will be readmitted at a cost of about $6000-$7000, with an average hospital length of stay (LOS) of about 6-7 days. Also, about 30% to 50% of these patients will have coagulation protein or platelet defects that are congenital; family members should therefore be assessed and spared a first event by instituting appropriate therapy at appropriate times, depending on the clinical status of the patient. Pertinent information includes whether the patient is taking oral contraceptives or hormone replacement therapy, facing impending surgery, or recovering from a trauma.[3] Antithrombotic therapy for the afflicted patient should, of course, be long-term.[17]

The cost of an evaluation for the common blood coagulation protein/platelet defects is about $1100-$1500; this is not expensive when you consider that approximately 28% of patients with DVT/PE have antiphospholipid syndrome; of those, 65% will fail warfarin or antiplatelet therapy, but only 1% will fail subcutaneous porcine heparin every 12 hours or subcutaneous low molecular weight heparin (LMWH) every 24 hours. Also, about 14% of DVT/PE patients will harbor SPS and almost all will fail warfarin or heparin/LMWH -- but less than 1% will fail (ASA) at 81mg/day.[11,12]

Activated protein C resistance, protein C, S, and antithrombin deficiency, and prothrombin 20210A mutation are probably best treated with warfarin unless recurrence happens, in which case heparin/LMWH is preferred. The other, rarer defects mentioned in Table 5 are probably best treated with warfarin, but more studies are needed to define the ideal therapy for many of them. Thus, the cost of effective therapy is minuscule when compared with the cost and associated morbidity of recurrence. In addition, if "generic therapy" is offered -- usually in the form of initial inpatient heparin for 5-7 days, followed by outpatient warfarin for 6 weeks to 6 months -- re-thrombosis will occur in 40% of patients with blood coagulation protein/platelet defects refractory to warfarin, and 40% of these will subsequently develop chronic venous insufficiency (post-phlebitic syndrome). The sequelae of post-phlebitic syndrome is well known to all and consists of a life-long experience of recurrent DVT/PE requiring many admissions and the development of stasis ulcers that require vigorous wound care, long-term expensive antibiotics, and other supportive therapy.[18,19] The costs of allowing unnecessary recurrence and development of chronic venous insufficiency are exorbitant; moreover, the associated morbidity and potential mortality can have devastating consequences.

Cerebral Ischemic Events (CVT/TIAs)


CVT occurs in more than 1,500,000 individuals yearly in the US; of these, 66% suffer severe permanent paralysis or die.[1,3] Up to 90% of those with CVT harbor blood coagulation protein/platelet defects associated with thrombosis. Also, 40% of patients (if not treated appropriately) will suffer a recurrent CVT within 1 year. Up to 80% of patients who have experienced TIAs harbor blood coagulation protein/platelet defects associated with thrombosis.[16] Thirty percent of patients with TIAs will sustain a CVT within 1 year of diagnosis. As with the disorders discussed above, including DVT/PE, the need to define the presence or absence and type of defect is of obvious importance to prevent recurrence or, in the case of TIA patients, to prevent the first event of CVT. The cost of each CVT is about $12,000, with a LOS of 6-7 days; the cost of care for TIAs is about $7,500, with a LOS of 4 days.[9]

The scenario for CVT and TIA is the same as that outlined for DVT/PE: Patients with antiphospholipid syndrome (about 65% of patients with CVT and about 28% of patients with TIAs) will fail warfarin or antiplatelet therapy in about 65% of cases, but only 1% will fail subcutaneous porcine heparin every 12 hours or subcutaneous LMWH every 24 hours. Also, about 19% of CVT patients and about 30% of TIA patients will harbor SPS and almost all will fail warfarin or heparin/LMWH, but less than 1% will fail ASA, 81mg/day. The cost reductions resulting from appropriate definition of the precise etiology (blood coagulation protein/platelet defect) in DVT/PE and CVT/TIA patients is summarized in Table 6. The costs of heparin, LMWH, warfarin, and ASA therapy are summarized in Table 7.[20,21]

Cost-effective Treatment of DVT/PE


DVT is a common event that accounts for significant morbidity and moderate mortality through development of PE, and it is associated with high costs of care. This section discusses cost-effective inpatient care for DVT +/- PE versus "early discharge"/outpatient care for DVT. There is not yet enough information to establish guidelines for outpatient management of PE. As a general principle, calf vein thrombosis should be treated in the same manner as proximal vein thrombosis.[22] Calf vein thrombosis has been treated by many clinicians with ASA, anti-inflammatory, and local supportive measures; this treatment is inappropriate and not cost-effective. Although the majority of PEs arise from proximal vein thrombosis, about 25% of PEs arise from isolated calf vein thrombosis.[3,23] Additional problems with calf vein thrombosis include propagation to proximal deep veins (30% of calf thrombi), destruction or damage to venous valves, and late sequelae of chronic venous insufficiency.[24,25]

The goals of therapy for DVT are to arrest thrombus growth, prevent recurrence, limit swelling (which can lead to compartmental compression syndrome with resultant obstruction of venous and arterial flow and subsequent gangrene/loss of limbs), and prevent embolization (which can lead to significant morbidity or mortality).[22] The mainstay of initial treatment of DVT/PE is heparin/LMWH in some form.[23] Thrombolytic therapy may be indicated for extensive or recurrent DVT/PE, as it clearly is associated with reduction in incidence of chronic venous insufficiency.[26] However, costs and hemorrhagic complications limit indications for thrombolysis. Indications for thrombolysis have been reviewed.[24,25]

  • Inpatient management of acute DVT/PE. In general, the initial therapy for inpatient care of DVT/PE is porcine mucosal unfractionated heparin (UFH) or fixed-dose LMWH. UFH may be given intravenously or via a dose-adjusted subcutaneous route; the dose-adjusted subcutaneous route has clearly been shown to be equal to or better than the IV route.[4,27-30] Intravenous UFH is given by IV bolus, followed by infusion to maintain an activated partial thromboplastin time (aPTT) prolongation, which is equivalent to a therapeutic range of 0.30-0.70 anti-Xa units.[22,30] Reliance on simple prolongation of the aPTT to 1.5-2.0 times baseline is no longer valid with today's hypersensitive reagents and inconsistencies between collection in 3.2% versus 3.8% citrate; thus, all laboratories must calibrate the particular aPTT reagents to a therapeutic anti-Xa range, as defined above.[31]
  • Warfarin is started at the same time as IV UFH; UFH is continued for at least 5 days, and stopped when the International Normalized Ratio (INR) is a2.0 for at least 48 hours.[32] Dose-adjusted subcutaneous UFH injection is given every 12 hours, aiming for the same aPTT as mentioned above and initiating warfarin therapy as defined above. It should be noted that if using IV or dose-adjusted UFH for initial therapy for DVT/PE, it is imperative to reach a therapeutic range (as defined above) within 24 hours; if this is not achieved, the chance of late recurrence is markedly increased.[33]

DVT/PE may also be treated by LMWH; in such cases the dose is fixed and given every 12 hours or every 24 hours and the aPTT is not used to assess therapy.[21] Thus, an aPTT is not needed. In general, heparin assays by anti-Xa assay are also unnecessary unless clinical changes suggest too much (hemorrhage) or too little (recurrence) LMWH, or if the patient is unusually obese or small. With both modes of therapy (UFH and LMWH), frequent platelet counts are required to assure quick detection of heparin-induced thrombocytopenia, a rare complication of UFH or LMWH therapy and much less common with LMWH than with UFH.[29]

There have been 13 well-controlled, double-blind, randomized trials comparing UFH (IV or dose-adjusted subcutaneous) with LMWH for treatment of active DVT/PE.[34-46] In all such trials, objective methods were used for initial diagnosis and confirmation of recurrence. These trials have used a variety of LMWH preparations given once or twice a day, depending on the brand. The results of these trials are summarized in Table 8. A meta-analysis of these trials demonstrates clear superiority of LMWH over UFH for treatment of active DVT.[47] LMWH demonstrated significantly reduced recurrence rates, significantly fewer major hemorrhagic events (defined as intracranial bleed, retroperitoneal, required transfusions, forced disruption of therapy, necessitated surgery, or fatality), and significantly reduced mortality. Since some of the studies included patients with PE and others excluded PE, risk reduction of PE cannot be assessed in analysis of these trials. The magnitude of risk reductions in the 4354 patients assessed in these 13 trials is summarized in Table 8. The cost savings in risk reduction of recurrence is depicted as savings per 1000 patients. The cost reduction in preventing major hemorrhage or development of chronic venous insufficiency is extraordinary and incalculable.

In summary, major cost containment and a major impact on quality of life through reductions in recurrence, bleeds, and development of chronic venous insufficiency can be achieved by using LMWH for inpatients with DVT +/- PE. Further cost containment is achieved by choosing appropriate long-term therapy for patients who harbor hereditary or acquired blood coagulation protein/platelet defects causing DVT +/-PE. It is unjustified and wasteful to place DVT/PE patients on long-term warfarin after initial UFH or LMWH if they harbor a causative defect that is refractory to warfarin (eg, antiphospholipid syndrome, SPS).

  • Outpatient/"early discharge" management of acute DVT/PE. Recent studies have opened the door to another key question -- perhaps the primary question of the next decade: What is the role of outpatient management for DVT? Where cost containment (often driven by managed care) is of primary concern and clinicians are under increasing pressure to decrease hospital admissions, there is a great deal of interest in recent studies of LMWH involving randomized trials that demonstrate the clear safety and efficacy of home treatment or "early discharge" management of DVT.[48-52] These studies are too recent to have been considered in consensus conferences, and firm guidelines haven't been established.

There have been 3 well-designed, randomized trials assessing inpatient treatment of DVT/PE with UFH versus outpatient management of DVT/PE with LMWH.[50-52] These trials have included a total of 1104 patients: 550 treated in the outpatient LMWH group and 554 in the inpatient group. There were 32 recurrences (5.8%) in the outpatient group and 37 recurrences (6.6%) in the inpatient group, representing a nonsignificant risk reduction of 12.2%. All bleeding was minor: There were 10 minor bleeds (1.8%) in the outpatient group and 9 (1.6%) in the inpatient group. Unfortunately, 2 of the outpatient LMWH bleeds were accidental, the result of a miscalculated 2.5 x increased dose of LMWH and an intramuscular dose of LMWH.

When assessing the trials and DVT patients in general, only about 70% of DVT patients can realistically be treated on an outpatient basis; the remaining 30% must be admitted because of comorbid conditions requiring hospitalization, or must be admitted for 12-24 hours to initiate the items needed for successful outpatient management (discussed below); in this instance, patients arriving late in the day at the physician's office or hospital often need short-term admission in order to institute appropriate measures for successful outpatient therapy. If 70% of patients with DVT can be managed as outpatients, a cost savings of about $4,900,000 per 1000 DVT patients will be realized. See Suggested Guidelines for the Outpatient or "Early Discharge" Management of DVT for general principles of outpatient or "early discharge" management of DVT that can be instituted, pending future results of randomized trials and consensus-driven recommendations based on additional information.

Ancillary Measures for Management of DVT


Several ancillary measures should generally be instituted for all patients with DVT of the extremities: use of medium-compression pantyhose during waking hours for patients with lower-extremity DVT, medium-compression arm hose for those with upper-extremity DVT, and demonstration of antiembolic exercises and correct body positioning, as summarized below. These modalities are of minimal cost and can aid in preventing recurrence.[31]

Antiembolic leg exercises. The patient should be instructed in antiembolic leg exercises, to be performed 4 to 6 times a day, consisting of dorsi-plantar flexion of each foot (1 at a time), with the leg supported at the foot and extended straight out at an elevation of approximately 7 to 10 degrees above the hip. This should be continued for 3 to 5 minutes or until the calf muscle group is fatigued and causes pain; then, the other leg is to be exercised in a likewise manner. The patient also should be instructed not to bend the thighs and knees for more than 20 minutes at a time without straightening the legs through brief ambulation or leg-stretching for a few minutes.
Antiembolic arm exercises. The patient should be instructed in antiembolic arm exercises, to be performed 4 to 6 times a day, consisting of palmar "squeezing" of each hand (1 at a time) with the arm elevated and straightened above the head. Squeezing a tennis ball with 1 hand is excellent for this exercise. The patient should continue this for 3 to 5 minutes, or until the arm muscles are fatigued and the onset of muscle pain occurs. The other arm should be exercised in a similar manner. The patient also should be instructed not to keep the arms tightly bent at the elbow or shoulder for more than 20 minutes at a time without stretching the arms straight for a few minutes.
Recent studies have demonstrated that home therapy can easily be accomplished by 80% of patients with both safety and efficacy, and that a high level of patient satisfaction is associated with home care of DVT.[53,54]

Conclusion


The keys to cost containment in management of DVT/PE are to: (1) define the etiology (blood coagulation protein/platelet defect) and institute appropriate long-term therapy, being sure to assess appropriate family members if a hereditary defect is found; and (2) use LMWH for inpatient management, which saves 17 lives per 1000 patients and reduces the exorbitant costs associated with care of patients with chronic venous insufficiency (ie, a minimum of $210,000 per 1000 patients is saved simply through preventing recurrence).

The use of outpatient LMWH will save $4,900,000 per 1000 patients if applied to the 70% of patients with DVT who have no comorbid condition requiring hospitalization and receive a diagnosis early enough to be sent home or hospitalized for no more than 24 hours. Simply defining the defects that have caused unexplained thrombosis will add another $3,000,000 in savings per 1000 patients with DVT and about $350,000 per 100 patients with thrombotic stroke. In patients with TIAs, defining the defect and instituting appropriate antithrombotic therapy potentially prevents the development of thrombotic stroke in about 30%, thereby saving approximately $350,500 (30% of $1,168,500) per 100 patients.

Suggested Guidelines for the Outpatient or "Early Discharge" Management of DVT


1.  Admit for 24 hours if no comorbid condition exists, or treat as outpatient if no comorbid condition exists and all of the following items can be accomplished.
2.  Obtain CBC/platelet count on admission.
3.  Assess prothrombin time (PT) and aPTT on admission.
4.  Teach patient applicable antiembolic exercises on admission (see below).
5.  Start subcutaneous LMWH as:
     a.  Fragmin (dalteparin) @ 200 units/kg every 24 hours (available as 2500 units/0.2mL or 5000 units/0.2 mL or multidose vials of 95,000 units/9.5mL) Lindmarker Regimen.[41]
     b.  Lovenox (enoxaparin) @ 1mg/kg every 12 hours (=100 units kg every 12 hours) (30mg or 40mg AMPS: Levine Regimen).[40]
6.  Instruct patient in self-injection of subcutaneous LMWH in anterior/lateral thighs or anterior abdominal wall (thighs preferred; use rotating injection sites).
7.  Measure for medium-compression pantyhose or upper-extremity hose for use during waking hours only.
8.  Start warfarin @ 5mg/day if <70kg total body weight or 10mg/day if >70kg total body weight (see #17 below for exceptions).
9.  Discharge at 24 hours if no comorbid conditions present, or discharge as soon as comorbid condition (not DVT) allows.
10.  Arrange home health care if patient/family cannot self-inject LMWH.
11.  Arrange outpatient PT/INR and CBC/platelet count at home on day 3.
12.  Evaluate patient clinically (in office/clinic) on day 7; obtain PT and CBC/platelet count on days 5 and 7; stop LMWH when INR is approximately 2.0 and then adjust warfarin dose accordingly.
13.  See patient weekly until stable on long-term antithrombotic therapy.
14.  If patient is 60 years of age or younger and has unexplained DVT, consider evaluation for blood coagulation protein(s)/platelet defects leading to thrombosis (Table 4).
15.  When patient is in hospital bed, raise foot of bed straight, with patient's feet elevated 7-10 degrees above hips; never put pillow(s) under popliteal fossae.
16.  Depending on clinical parameters (eg, thrombophilia, platelet defects), alternatives to oral anticoagulants may be indicated.

Adapted from Bick,[15] Bick and Haas.[31]

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