Management of Venous Thromboembolism

Optimal management of venous thromboembolism (VTE) hinges upon understanding the medical, economic, and psychosocial consequences of pulmonary embolism (PE) and deep vein thrombosis (DVT). In an international registry of 23,858 patients with acute PE over 13 years, the mean length of hospital stay decreased 32% and the risk of all-cause 30-day mortality decreased from 6.6% to 4.9%. The risk-adjusted 30-day PE-related mortality decreased from 3.3% to 1.8%. Of special concern, however, is that the annual VTE event rate is increasing. The adverse effects of concomitant DVT on prognosis of PE, the association of VTE with atherosclerosis, and the late effects of VTE—postthrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) —factor into the construction of a comprehensive program for immediate treatment and secondary prevention. The best management, though not always feasible, is primary prevention of VTE.

The Nationwide Inpatient Sample data show that US hospital admissions for PE increased from 23 per 100,000 in 1993 to 65 per 100,000 in 2012. The percent of massive PE admissions decreased from 5.3% to 4.4%, even though the absolute number of admissions for massive PE increased from 1.5 to 2.8 per 100,000. The median length of hospital stay for PE was halved from 8 days to 4 days. However, adjusted hospital charges increased from $16,475 in 1993 to $25,728 in 2012. All-cause hospital mortality for PE decreased from 7.1% to 3.2%. Patients residing in zip codes with lower socioeconomic status had increased in-hospital mortality rates compared with patients residing in higher socioeconomic status zip codes. In a Dutch study that encompassed 1.4 million inhabitants, higher neighborhood socioeconomic status was associated with a lower incidence of VTE.

In an Australian study of patients hospitalized with PE, the post-discharge mortality of 8.5% per patient-year was 2.5-fold higher than that of an age- and sex-matched general population. Patients with known cardiovascular disease at baseline had a 2.2-fold greater all-cause mortality than those without cardiovascular disease; 40% of the post-discharge deaths were attributed to cardiovascular causes.

The Framingham Heart Study reported VTE incidence from 1995 to 2014. The age-adjusted incidence rate was 20.3/10,000; 40% of events were PE, and 60% were DVT. Increasing age and obesity were associated with VTE.

Management of VTE should strive to be cost-effective. In the US, treatment of an acute VTE has an incremental direct medical cost of about $12,000 to $15,000 among first-year survivors. Subsequent complications increase cumulative costs to $18,000 to $23,000 per incident case. Annual incident VTE events cost the U.S. healthcare system $7 to $10 billion per year for 375,000 to 475,000 newly diagnosed, medically treated cases.

The psychosocial impact of VTE should also be recognized. Among patients 13 to 33 years of age, the diagnosis of VTE is associated with a poorer mental health prognosis compared with non-VTE patients. In a Danish study, 20% received prescriptions for psychotropic medications such as antidepressants, anxiolytics, or sedatives. Global public awareness is lower for PE (54%) and DVT (44%) than for myocardial infarction (88%) and stroke (85%). For those stricken with VTE, they are less likely to present themselves for medical evaluation if they are not aware of the existence of VTE and its symptoms and signs ( Box 52.1 ).

Box 52.1

VTE Megatrends That Impact VTE Management

In-hospital PE mortality has declined by about 50% over the past decade.
Median length of hospital stay for PE has halved during the past decade.
Annual incident VTE events cost the US healthcare system $7–$10 billion.
VTE occurs more often in communities with lower socioeconomic status.
Global public awareness of PE and DVT is lower than of myocardial infarction and stroke.

DVT, Deep vein thrombosis; PE , pulmonary embolism; VTE , venous thromboembolism.

Pathophysiology and Risk Factors for Venous Thromboembolism

Deep Vein Thrombosis

Most venous thrombosis originates in the pelvic or deep leg veins. The clot initially is in the center of the vein. Over the ensuing days to weeks, most venous thrombi develop some fibrosis and become tethered to the vein wall. For reasons that remain uncertain, some thrombi dislodge from the vein wall and embolize to the lungs. Others never adhere to the vein wall securely and embolize to the lungs.

Certain conditions seem to cause increased adherence to the vein wall, thus lessening the chance of developing PE. The best-known example is factor V Leiden, which predisposes to VTE. The “factor V Leiden paradox” is the term used to describe this observation. These patients have more DVT than expected but less PE than would be predicted. Other apparent risk factors that share this good prognostic finding include oral contraceptive use, pregnancy, minor leg injuries, and obesity. In contrast, conditions that appear to predispose to embolization of leg DVT and result in acute PE include chronic obstructive lung disease, pneumonia, and sickle cell disease.

Unresolved DVT leads to increased ambulatory venous pressure, which in turn impairs venous return, reduces calf muscle perfusion, increases tissue permeability at the microvasculature, and leads to chronic venous hypertension. The two principal mechanisms are persistent venous obstruction and valvular reflux ( Fig. 52.1 ). Inflammation delays thrombus resolution, resulting in chronic thrombosis in the vein wall and further promoting valvular reflux. Activated inflammatory cells and platelets interact at the interface of the thrombus and vein wall.

Fig. 52.1, Pathophysiology of symptoms in deep venous thrombosis.

Because of inflammation in the venous thrombus, with its associated white blood cells and activated platelets, VTE is no longer classified as a “red clot” disease. Thrombi due to PE and DVT are filled with polymorphonuclear leukocytes and activated platelets, which release procoagulant microparticles and proinflammatory mediators. Neutrophil extracellular traps (NETs) consist of DNA extruded from white blood cells. These NETs are prothrombotic and procoagulant. NETs provide the scaffold that binds erythrocytes and that promotes further platelet aggregation.

Pulmonary Embolism

The right ventricle plays a central role in the pathophysiology of PE ( Fig. 52.2A ). Increased pulmonary vascular resistance leads to right ventricular overload, which in turn can cause right ventricular dilatation and hypokinesis. Increased right ventricular systolic pressure causes deviation of the interventricular septum toward the left ventricle. In severe cases, right ventricular cardiac output decreases (see Fig. 52.2B ). Although the left ventricle remains intrinsically normal, left ventricular filling can be impaired, leading to decreased left ventricular cardiac output, with consequent decrease of systemic arterial pressure. Increased right ventricular myocardial wall tension impedes oxygen supply to the right ventricle, resulting in decreased coronary arterial perfusion, especially to the right coronary artery. The result is right ventricular ischemia and microinfarction of the right ventricle.

Right ventricular myocardial stretch leads to elevation of brain natriuretic peptide (BNP) levels. Right ventricular microinfarction leads to elevation of cardiac biomarkers such as troponin and heart-type fatty acid-binding protein.

Impaired gas exchange occurs because of: (1) increased alveolar dead space due to vascular obstruction, (2) hypoxemia from alveolar hypoventilation and right-to-left shunting, (3) impaired carbon monoxide transfer caused by loss of gas exchange surface, (4) alveolar hyperventilation caused by reflex stimulation of irritant receptors, (5) increased airway resistance due to bronchoconstriction, and (6) decreased pulmonary compliance due to lung edema, lung hemorrhage, and loss of surfactant.

The “Post-PE Syndrome” is characterized by suboptimal cardiac function, abnormal pulmonary gas exchange in combination with chronic dyspnea, exercise intolerance, chronic functional limitations, and decreased quality of life. The pathophysiology is thought most likely due to impaired endogenous fibrinolysis coupled with abnormal thrombus remodeling.

Root Causes of Venous Thromboembolism

Optimal strategies for VTE management can be facilitated by identifying root causes of PE and DVT. Virchow’s triad of stasis, hypercoagulability, and endothelial injury has served as the foundation of our understanding of VTE pathophysiology. However, contemporary concepts prioritize inflammation as possibly the most important root cause of VTE.

VTE is now considered part of a pan-vascular syndrome of thrombosis-related illnesses that include myocardial infarction, stroke, and peripheral artery disease. Classic cardiovascular risk factors for coronary artery disease serve as risk factors associated with VTE, including obesity, hypertension, diabetes mellitus, smoking, and hypercholesterolemia, as well as low HDL cholesterol levels. A more recent study only showed an association between VTE and cigarette smoking. Other inflammatory illnesses associated with VTE include psoriasis and sepsis.

In a registry of 991 acute VTE patients, independent predictors of all-cause mortality included age, active cancer, diabetes mellitus, sedentary lifestyle, and polypharmacy. In a meta-analysis of seven PE cohorts with 7868 participants, the presence of concomitant DVT almost doubled the 30-day mortality rate compared to PE patients without DVT (6.2% versus 3.8%, respectively). Another adverse prognostic factor is the “weekend effect,” with a risk-adjusted 17% increased PE mortality rate compared with weekdays.

Thrombophilia

The two most common inherited thrombophilias are factor V Leiden and the prothrombin gene mutation. A single point mutation in the factor V gene, designated factor V Leiden, causes resistance to the endogenous anticoagulant, activated protein C. A single point mutation in the prothrombin gene increases the levels of prothrombin and doubles the risk of VTE. Clinical characteristics suggesting an inherited thrombophilia include thrombosis at a young age in association with unprovoked VTE or weak provoking factors, a strong family history of VTE, recurrent VTE especially at a young age, or VTE in unusual sites, such as splanchnic or cerebral veins.

Thrombophilia can impact women’s contraceptive therapy, fertility, and pregnancy. Use of estrogen-containing contraceptive pills can triple the risk of VTE and, in the presence of thrombophilia such as factor V Leiden, can increase the VTE risk by at least 30-fold. Thrombophilia may manifest as difficulty with conception, recurrent pregnancy loss, or both. Thrombophilia also increases the risk of pregnancy-related complications such as preeclampsia and placental abruption.

The antiphospholipid syndrome is an acquired prothrombotic disorder that can affect both the venous and arterial circulations. The deep leg veins and the cerebral arterial circulation are the most common sites of thromboses. Catastrophic antiphospholipid syndrome is characterized by thrombi in multiple small vascular beds. It can cause multisystem organ failure. The syndrome is also associated with obstetrical complications such as otherwise unexplained miscarriages and premature birth before the 34th week of gestation, often in the setting of eclampsia or severe preeclampsia.

Anticoagulation

Parenteral Anticoagulants: Unfractionated Heparin, Low-Molecular-Weight Heparins, Fondaparinux, and Direct Thrombin Inhibitors

Anticoagulation comprises the foundation of therapy for VTE. There are three fundamental anticoagulation strategies for treatment of acute PE or DVT: (1) parenteral monotherapy, (2) parenteral anticoagulation either overlapping or abruptly switching to oral anticoagulation, and (3) oral anticoagulation alone, without parenteral therapy. At times, ill patients with acute VTE are initiated on continuous intravenous unfractionated heparin (UFH), followed by a switch to low-molecular-weight heparin (LMWH) as they become more clinically stable, followed by initiation of oral anticoagulation.

Unfractionated Heparin

UFH is a partially purified, highly sulfated glycosaminoglycan that is most often obtained from pig intestinal mucosa. Heparin binds to the protein, antithrombin, and changes the conformation of antithrombin so that its activity is markedly accelerated. Antithrombin, in turn, inhibits coagulation factors XII, XI, X, IX, and II (thrombin) and thus prevents additional thrombus formation. Although heparin itself does not dissolve thrombus, endogenous fibrinolytic mechanisms often lyse some of the clot that has already formed.

Inflammation contributes critically to the development of thrombosis, principally through disruption of endothelial functions, local leukocyte recruitment, and promotion of a pro-coagulant milieu. Heparin has a biological basis as a modulator of inflammation. Heparin inhibits the activation and function of neutrophils. It interacts with the vascular endothelium to prevent expression of inflammatory mediators which initiate activation of the innate immune system. Heparin also inhibits proliferation of the vascular smooth muscle cell. The anti-inflammatory effect of LMWH is at least as strong as that of UFH.

Low-Molecular-Weight Heparins

UFH has an average molecular weight of about 15,000 Da, whereas LMWH has an average molecular weight of about 5000 Da. LMWH is manufactured by depolymerizing UFH using chemical or enzymatic processes. LMWH potently inhibits activated clotting factor X. It has greater bioavailability with a more predictable dose response and longer half-life than UFH. LMWH is dosed by weight in patients with normal renal function. However, because it is metabolized by the kidneys, dose reductions are required in patients with impaired renal function. Whether LMWH should be titrated using anti-Xa levels, particularly in special populations such as obese or pregnant patients, remains uncertain. When used for low-dose primary VTE prophylaxis, the typical regimen for enoxaparin is 40 mg once daily. LMWH in full dose as monotherapy is the guideline-recommended treatment for cancer patients with VTE.

Heparin-induced thrombocytopenia (HIT) and thrombosis-associated HIT occur less often with LMWH than with UFH. One hospital reduced the hospital burden of HIT by switching from UFH to LMWH.

Fondaparinux

Fondaparinux is a synthetically manufactured pentasaccharide that binds to and potentiates the effect of antithrombin III in blocking activated clotting factor X. It has a long half-life, approximately 17 hours. It is metabolized by the kidney and must be downward dose-adjusted in patients with renal dysfunction. Fondaparinux has no reliable reversal agent ( Box 52.2 ). It is often used off-label in patients with suspected or proven HIT.

Box 52.2

Parenteral Anticoagulants for Acute Venous Thromboembolism

Intravenous unfractionated heparin: 80 U/kg loading dose; 18 U/kg/h
Subcutaneous enoxaparin: 1 mg/kg twice daily—with normal renal function
Subcutaneous fondaparinux: 7.5 mg once daily for weight 50–100 kg; 10 mg for weight > 100 kg; 5 mg for weight < 50 kg—with normal renal function

Direct Thrombin Inhibitors

Bivalirudin, metabolized by the kidney, and argatroban, metabolized by the liver, are the two direct thrombin inhibitors available in the United States. Argatroban is FDA approved for treatment of HIT-associated thrombosis. Bivalirudin is FDA approved for use during percutaneous coronary intervention in patients with acute or previous HIT and in patients with HIT-associated thrombosis. Overall, bivalirudin is frequently used off-label for anticoagulation of any patient with suspected or proven HIT.

Oral Anticoagulation With Warfarin and Other Vitamin K Antagonists

Warfarin is the most widely used vitamin K antagonist. It prevents gamma-carboxylation of clotting factors II, VII, IX, and X. Attaining its full effect requires 5 to 7 days, and therefore, most patients are initially “bridged” with UFH, LMWH, or fondaparinux. Warfarin is usually dosed to achieve a target International Normalized Ratio (INR) between 2.0 and 3.0. Three large randomized trials of pharmacogenetic- guided versus routine clinical dosing of vitamin K antagonists showed either no usefulness with the pharmacogenetic approach or, at best, marginal utility. The pharmacogenetic approach was also expensive and inconvenient for patients and practitioners.

In a meta-analysis of individual patient data, self-monitoring and self-management of warfarin were found to be safe options suitable for patients of all ages. In 11 trials with data for 6417 participants and 12,800 person-years of follow-up, there was a 49% reduction in thromboembolic events in the self-monitoring group. However, the 12% reduction in major hemorrhagic events with self-monitoring did not achieve statistical significance.

Warfarin remains a potentially dangerous drug that can be difficult to dose and regulate, even by experienced clinicians. In a study of emergency hospitalizations for adverse drug events in older Americans, warfarin was the most frequent drug causing adverse events (33%) followed by insulin (14%), oral antiplatelet agents (13%), and oral hypoglycemic agents (11%). In Denmark, increased antithrombotic drug use, especially vitamin K antagonists, was associated with a higher risk of subdural hematoma. The highest odds of subdural hematoma occurred with the combination of a vitamin K antagonist and an antiplatelet drug. Almost half of intracranial hemorrhages in warfarin-treated patients occur with INRs in the desired target range of 2.0 to 3.0.

In addition to hemorrhage, warfarin is associated with an increase in coronary and peripheral vascular calcification. This is due to inhibition of the enzyme matrix gamma-carboxyglutamate Gla Protein (MGP). In women undergoing routine mammography, breast arterial calcification may correlate with calcification of peripheral arteries. The clinical ramifications of warfarin-associated vascular calcification remain undefined.

Warfarin’s anticoagulant effect can be most effectively reversed with 4-factor prothrombin complex concentrates, administered in conjunction with intravenous vitamin K. In a systematic review and meta-analysis, prothrombin complex concentrates compared with fresh frozen plasma reversed warfarin with a significant reduction in all-cause mortality, more rapid INR reduction, and less volume overload, without an increased risk of thromboembolic events.

Efficacy and Safety of Direct Oral Anticoagulants (Non–vitamin K Oral Anticoagulants) for Treatment of Venous Thromboembolism

Direct oral anticoagulants (DOACs) have become the predominant anticoagulants to manage VTE. Six randomized controlled pivotal trials recruited more than 27,000 patients and led to approval of dabigatran, rivaroxaban, apixaban, and edoxaban for the treatment of PE and DVT. There are about 200,000 patients who have been studied with DOACs versus warfarin in observational cohort studies. Thus far, there is no contradiction between results from the randomized trials compared with the observational clinical practice trials. In general, DOACs should be avoided in patients with a creatinine clearance less than 30 mL/min because this was an exclusion criterion in the randomized controlled pivotal VTE trials.

The DOACs have noninferior efficacy but superior safety compared to warfarin for VTE treatment. When meta-analyzing the six pivotal acute VTE trials of DOACs versus warfarin, DOACs show a nonsignificant 10% reduction in recurrent VTE or VTE-related death. Regarding specific VTE subgroups, patients 75 years of age or older had a significant 44% reduction in recurrent VTE, and patients with cancer had a significant 43% reduction in recurrent VTE. In these same trials, DOACs exhibit a highly significant 39% reduction in major bleeding compared to warfarin. There was a 64% reduction in fatal bleeding and a 63% reduction in intracranial bleeding.

Dabigatran

Dabigatran is an oral direct thrombin inhibitor that is about 80% metabolized by the kidneys. Its half-life is about 12 to 17 hours. Dabigatran should be taken on a full stomach to minimize the possibility of gastrointestinal upset. It should not be administered if the creatinine clearance is less than 30 mL per minute.

For anticoagulation of acute VTE, the FDA has approved dabigatran in a dose of 150 mg twice daily, after a 5-day course of UFH, LMWH, or fondaparinux. This approval is based upon two pivotal randomized controlled trials, RE-COVER and RE-COVER II, comparing dabigatran to warfarin. The pooled analysis of these two trials, comprising 5107 subjects, showed that dabigatran was noninferior to warfarin for preventing recurrent VTE and that dabigatran reduced the rate of any bleeding by 30% compared with warfarin.

Among dabigatran-treated elderly patients, as renal function worsened, recurrent VTE/VTE-related death decreased, from 3.1% with normal renal function to 1.9% for mild renal impairment, and to 0.0% with moderate renal impairment. This is probably because plasma dabigatran levels increased with worsening renal function. For warfarin-treated patients, the recurrent VTE rates were 2.6%, 1.6%, and 4.1%, respectively. Major bleeding increased with increasing renal impairment and with increasing age, with no apparent difference between dabigatran and warfarin patients.

When analyzing the subset of patients who presented with symptomatic PE (with or without DVT) as the index event, dabigatran was noninferior to warfarin with respect to efficacy. Regarding major bleeding events in symptomatic PE patients, there was a significant 40% reduction in major bleeding with dabigatran compared with warfarin.

Two pivotal extension studies were undertaken with dabigatran in patients who had completed at least 3 months of anticoagulation for VTE. The active control study, RE-MEDY, tested dabigatran against warfarin for 6 to 36 months in 2866 patients. In RE-MEDY, dabigatran was noninferior to warfarin with respect to efficacy and showed a significant 46% reduction in major or clinically relevant bleeding. The placebo control study, RE-SONATE, tested dabigatran against placebo for 6 months in 1353 patients. In RE-SONATE, there was a significant 92% reduction in recurrent VTE in the dabigatran group and a 3-fold increase in major or clinically relevant bleeding compared with placebo.

When the efficacy of dabigatran versus warfarin in acute VTE patients with thrombophilia was studied, results were pooled from RE-COVER, RE-COVER II, and RE-MEDY. The efficacy and safety of dabigatran were not significantly affected by the presence of thrombophilia or the antiphospholipid antibody syndrome.

Dabigatran administered for 6 months is currently being tested after a 72-hour course of parenteral heparin anticoagulation for acute submassive PE in a European study called PEITHO-2. The target enrollment is 700 patients.

Rivaroxaban

Rivaroxaban is an oral direct anti-Xa anticoagulant that is about 35% metabolized by the kidneys. Its half-life is about 5 to 9 hours. To maximize its half-life, rivaroxaban should be taken on a full stomach. The loading dose is 15 mg twice daily for 3 weeks. The maintenance dose with normal renal function is 20 mg once daily with the dinner meal. Rivaroxaban should not be administered if the creatinine clearance is less than 30 mL per minute.

In a pivotal randomized trial, EINSTEIN-DVT, of 3449 acute DVT patients allocated to rivaroxaban or to warfarin, rivaroxaban was noninferior to warfarin with respect to efficacy and safety. DVT patients, regardless of their participation in EINSTEIN-DVT, who had completed at least 6 months of anticoagulation, were eligible to participate in the EINSTEIN-Extension trial. These latter patients were randomized to rivaroxaban 20 mg daily versus placebo and were treated for 1 year. The rivaroxaban patients had an 82% reduction in recurrent VTE compared with placebo-treated patients. There was no significant difference in major bleeding complications between rivaroxaban and placebo, 0.7% versus 0.0%, respectively.

In a “real world” observational study of rivaroxaban versus standard anticoagulation of acute DVT patients, XALIA, the rivaroxaban- treated patients had a lower risk profile at baseline than those treated with standard anticoagulation. Propensity score-adjusted results showed that rivaroxaban was a safe and effective alternative to standard anticoagulation in a broad range of patients.

In another large, observational study of 13,609 rivaroxaban patients compared with 32,244 warfarin patients being treated for VTE, rivaroxaban patients had a 19% reduction in recurrent VTE and 21% reduction in major bleeding compared with warfarin patients. Rivaroxaban patients had a 60% reduction in intracranial hemorrhage and a 28% reduction in gastrointestinal bleeding compared with warfarin patients.

Apixaban

Apixaban is a direct oral anti-Xa anticoagulant that is about 25% metabolized by the kidneys. Its half-life is about 12 hours. The loading dose is 10 mg twice daily for 1 week. The maintenance dose is 5 mg twice daily. Apixaban should not be administered if the creatinine clearance is less than 25 ml per minute.

The pivotal AMPLIFY Trial enrolled 5395 acute VTE patients. They were randomized to apixaban versus warfarin for a 6-month treatment course. Apixaban was noninferior to warfarin with respect to efficacy and resulted in a 69% reduction in major bleeding compared with warfarin.

A 12-month extension study was undertaken in acute VTE patients who had completed 6 to 12 months of anticoagulation. Two doses of apixaban, 2.5 mg twice daily and 5 mg twice daily, were compared against placebo. The primary efficacy outcome was recurrent VTE or death from any cause. There was a highly significant 64% reduction in the primary efficacy outcome for apixaban 5 mg twice daily versus placebo and 67% reduction in the primary efficacy endpoint for apixaban 2.5 mg twice daily versus placebo. The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5 mg twice daily apixaban group, and 0.1% in the 5 mg twice daily apixaban group.

In a substudy of AMPLIFY, the clinical presentation of bleeding events and the clinical course of bleeding events were analyzed. Of the major bleeds, there was a more severe clinical presentation in the warfarin patients (45%) compared with the apixaban patients (28%). The clinical course of major bleeds was similar.

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