CLINICAL COURSE OF VENOUS THROMBOEMBOLISM
Proximal vein thrombosis is a serious and potentially lethal condition. Untreated proximal vein thrombosis is associated with a 10 percent rate of fatal PE. Inadequately treated proximal vein thrombosis results in a 20 to 50 percent risk of recurrent VTE events.51 Prospective studies of patients with clinically suspected DVT or PE indicate that new VTE events on followup are uncommon (≤2 percent) among patients in whom proximal vein thrombosis is absent by objective testing.17,32,33,47,50 The aggregate data from diagnostic and treatment studies indicate that the presence of proximal vein thrombosis is the key prognostic marker for recurrent VTE.
Thrombosis that remains confined to the calf veins is associated with low risk (≤1 percent) of clinically important PE. Extension of thrombosis into the popliteal vein or more proximally occurs in 15 to 25 percent of patients with untreated calf vein thrombosis.1 Patients with documented calf vein thrombosis should either receive anticoagulant treatment to prevent extension or undergo monitoring for proximal extension using serial ultrasonography.
The postthrombotic syndrome is a frequent complication of DVT.52 Patients with the postthrombotic syndrome complain of pain, heaviness, swelling, cramps, and itching or tingling of the affected leg. Ulceration may occur. The symptoms usually are aggravated by standing or walking and improve with rest and elevation of the leg. A prospective study documented a 25 percent incidence of moderate-to-severe postthrombotic symptoms 2 years after the initial diagnosis of proximal vein thrombosis in patients who were treated with initial heparin and oral anticoagulants for 3 months.53 The study also demonstrated that ipsilateral recurrent venous thrombosis is strongly associated with subsequent development of moderate or severe postthrombotic symptoms. Thus, prevention of ipsilateral recurrent DVT likely reduces the incidence of the postthrombotic syndrome. Application of a properly fitted graded compression stocking, as soon after diagnosis as the patient’s symptoms will allow, can improve edema and pain in the acute stage of DVT and may also help control or relieve symptoms in patients who develop the postthrombotic syndrome. Conflicting findings have been found in randomized trials of graded compression stockings for preventing the development of the postthrombotic syndrome.54,55
Chronic Thromboembolic Pulmonary Hypertension
Chronic thromboembolic pulmonary hypertension is a serious complication of PE. Historically, thromboembolic pulmonary hypertension was believed to be relatively rare and to occur only several years after the diagnosis of PE. A prospective cohort study provides important information on the incidence and timing of thromboembolic pulmonary hypertension.56 The results indicate that thromboembolic pulmonary hypertension is more common and occurs earlier than previously thought. On prospective followup of 223 patients with documented PE, the cumulative incidence of chronic thromboembolic pulmonary hypertension was 3.8 percent at 2 years after diagnosis, despite state-of-the-art treatment for PE. The strongest independent risk factors were a history of PE (odds ratio: 19) and idiopathic PE at presentation (odds ratio: 5.7).56
OBJECTIVES AND PRINCIPLES OF ANTITHROMBOTIC TREATMENT
The objectives of treatment in patients with established VTE are to (1) prevent death from PE, and (2) prevent morbidity from recurrent DVT or PE, especially the postthrombotic syndrome and chronic pulmonary hypertension.
For most patients, these objectives are achieved by providing adequate anticoagulant treatment. Thrombolytic therapy is indicated in selected patients (see “Thrombolytic Therapy” below). Use of an inferior vena cava filter is indicated to prevent death from PE in patients in whom anticoagulant treatment is absolutely contraindicated and in other selected patients (see “Anticoagulant Therapy” below). These recommendations and those below are linked to the strength of the evidence from clinical trials and evidence-based guidelines.9,30,57,58
Anticoagulant therapy is the treatment of choice for most patients with proximal vein thrombosis or PE.9,57,58 Patients with proximal DVT require both adequate initial anticoagulant treatment with heparin or low-molecular-weight (LMW) heparin and adequate long-term anticoagulant therapy to prevent recurrent VTE.51,59,60 Anticoagulant therapy for at least 3 months is required to prevent a high frequency (15 to 25 percent) of symptomatic extension of thrombosis and/or recurrent venous thromboembolic events.51,60,61 Adequate anticoagulant treatment reduces the incidence of recurrence during the first 3 months after diagnosis to 5 percent or less.51,59,60,61
The absolute contraindications to anticoagulant treatment include intracranial bleeding, severe active bleeding, recent brain, eye, or spinal cord surgery, and malignant hypertension. Relative contraindications include recent major surgery, recent cerebrovascular accident, active gastrointestinal tract bleeding, severe hypertension, severe renal or hepatic failure, and severe thrombocytopenia (platelets <50 × 109/L).
Heparin and Low-Molecular-Weight Heparin Initial therapy with continuous intravenous heparin was the standard approach to treatment of VTE during the 1970s and 1980s. During the 1990s, LMW heparin given by subcutaneous injection once or twice daily was evaluated by clinical trials and shown to be as effective and safe as continuous intravenous heparin for the initial treatment of patients with proximal DVT and submassive PE.57,58,62 The advantage of LMW heparin is that it does not require anticoagulant monitoring. LMW heparin given subcutaneously once or twice daily is preferred over intravenous unfractionated heparin for the initial treatment of most patients with either DVT or PE.57,58 LMW heparin enables outpatient therapy for many patients with uncomplicated DVT and selected patients with PE. Intravenous unfractionated heparin remains a useful approach for initial anticoagulant therapy in patients with severe renal failure. Initial treatment with LMW heparin or unfractionated heparin should be continued for at least 5 days. Table 133–2 lists the specific LMW heparin regimens for the treatment of VTE.
Table 133–2.Anticoagulant Drug Regimens for Treatment of Venous Thromboembolism ||Download (.pdf) Table 133–2. Anticoagulant Drug Regimens for Treatment of Venous Thromboembolism
|Drug ||Regimen |
|LOW-MOLECULAR-WEIGHT HEPARINS |
|Enoxaparin ||1.0 mg/kg BID* |
|Dalteparin ||200 IU/kg once daily† |
|Tinzaparin ||175 IU/kg once daily‡ |
|Nadroparin || |
6150 IU BID for 50–70 kg
4100 IU BID if patient weighs <50 kg
9200 IU BID if patient weighs >70 kg
|Reviparin || |
4200 IU BID for 46–60 kg
3500 IU BID if patient weighs 35–45 kg
6300 IU BID if patient weighs >60 kg
|INDIRECT FACTOR Xa INHIBITOR |
|Fondaparinux || |
7.5 mg once daily if patient weight 50–100 kg
5.0 mg once daily if patient weight <50 kg
10.0 mg once daily if patient weight >100 kg
|DIRECT ORAL ANTICOAGULANTS |
|Dabigatran ||150 mg BID after 5 days of parenteral low-molecular-weight heparin or heparin |
|Rivaroxaban || |
15 mg BID for 21 days, then 20 mg once daily
Taken with food
|Apixaban || |
10 mg BID for 7 days, then 5 mg BID
After 6 months, 2.5 mg BID for extended therapy
|Edoxaban ||60 mg once daily after 5 days of parenteral low-molecular-weight heparin or heparin§ |
If unfractionated heparin is used for initial therapy, it is important to achieve an adequate anticoagulant effect, defined as an activated partial thromboplastin time (aPTT) above the lower limit of therapeutic range within the first 24 hours.63,64 Failure to achieve an adequate aPTT effect early during therapy is associated with a high incidence (25 percent) of recurrent VTE.63 Two-thirds of the recurrent events occur between 2 and 12 weeks after the initial diagnosis despite treatment with oral anticoagulants, and the initial management with either unfractionated heparin or LMW heparin is critical to the patient’s long-term outcome.63,64
Fondaparinux The synthetic pentasaccharide fondaparinux, which is an indirect inhibitor of factor Xa, has been evaluated by large randomized clinical trials.65,66 These studies indicate fondaparinux is as effective and safe as LMW heparin for treatment of established DVT and as effective and safe as intravenous heparin for treatment of symptomatic PE. Fondaparinux is given subcutaneously once daily at a dose of 7.5 mg for patients weighing between 50 and 100 kg (85 percent of all patients evaluated in the clinical trials), 5 mg for patients weighing less than 50 kg, and 10 mg for patients weighing more than 100 kg.65,66
Vitamin K Antagonists Oral anticoagulant treatment using a vitamin K antagonist (e.g., sodium warfarin) has been the standard approach for long-term treatment in most patients for more than 60 years. Treatment with a vitamin K antagonist is started with initial heparin or LMW heparin therapy and overlapped for 4 to 5 days.
The preferred intensity of the anticoagulant effect of treatment with a vitamin K antagonist has been established by clinical trials.69,70,71,72 The dose of vitamin K antagonist should be adjusted to maintain the international normalized ratio (INR) between 2.0 and 3.0. High-intensity vitamin K antagonist treatment (INR 3.0 to 4.0) should not be used because it has not improved effectiveness in patients with the antiphospholipid syndrome and recurrent thrombosis71 and has caused more bleeding.72 Low-intensity therapy (INR 1.5 to 1.9) is not recommended because it is less effective than standard-intensity treatment (INR 2.0 to 3.0) and does not reduce bleeding complications.70
Long-term treatment with LMW heparin is indicated for select patients in whom vitamin K antagonists are contraindicated (e.g., pregnant women), and in patients with concurrent cancer for whom LMW heparin regimens are more effective.67,68
Direct Oral Anticoagulants Oral anticoagulants that bind directly to the target coagulation enzyme of either thrombin or factor Xa have been evaluated in phase III clinical trials for the treatment of patients with VTE (Chap. 25).73,74,75,76,77,78 The advantages of these drugs are: (1) they can be administered orally once or twice daily without the need for anticoagulant monitoring and dose titration; (2) they have fewer clinically relevant drug interactions; (3) because of a fast onset of anticoagulant action, similar to that of LMW heparin, they can simplify treatment for many patients by replacing the standard approach of a parenteral drug (heparin, LMW heparin or fondaparinux) followed by an oral vitamin K antagonist with a single drug given for both initial and long-term therapy; and (4) they result in less clinically important bleeding. Table 133-2 lists the direct-acting oral anticoagulant (DOAC) regimens that have been evaluated by clinical trials for the treatment of established VTE.
Six phase III clinical trials evaluating the DOACs for the treatment of acute VTE have been completed and published.73,74,75,76,77,78 Table 133–3 outlines the design features of these trials and the efficacy and bleeding results. Each of these trials met the prespecified criteria for noninferiority of the efficacy of the DOAC for preventing recurrent VTE.
Table 133–3.Clinical trials of direct oral anticoagulants for treatment of venous thromboembolism ||Download (.pdf) Table 133–3. Clinical trials of direct oral anticoagulants for treatment of venous thromboembolism
The six trials included more than 27,000 patients with acute VTE, and meta-analyses of these studies has been done.79 The meta-analyses provide added clinically useful information regarding specific major bleeding outcomes (intracranial bleeding and fatal bleeding), and regarding the risk-to-benefit profile in key patient subgroups commonly encountered by the clinician. These subgroups are patients presenting with symptomatic PE or symptomatic DVT, the elderly (age ≥75 years), the obese, patients with moderate renal impairment (creatinine clearance 30 to 49 mL/min), and patients with cancer. The DOACs were associated with clinically important reductions in major bleeding (relative risk [RR] 0.61), intracranial bleeding (RR 0.37), and fatal bleeding (RR 0.36).79 For each of these outcomes, the results are consistent among the trials; none of the trials have a point estimate for these outcomes in favor of the vitamin K antagonists (supplementary data online79). The number of patients who would need to be treated with a DOAC rather than a vitamin K antagonist to avoid one event of intracranial bleeding is 588, and for fatal bleeding is 1250. In view of the large number of VTE patients each year, and the devastating nature of these bleeding events, these are important impacts on population health. The results of cost-effectiveness studies have shown the DOACs to be cost-effective.
Regarding the key patient subgroups evaluated, the noninferior efficacy of the DOACs was consistent across all subgroups, with possibly superior efficacy in the elderly and in cancer patients.79 The safety advantage of reduced major bleeding was also consistent across the subgroups, except possibly in cancer patients, in whom the pooled estimate of a 33 percent risk reduction did not achieve statistical significance.
The DOACs are preferred over vitamin K antagonists in most new patients commencing anticoagulant treatment for VTE. The exceptions are patients with severe renal impairment (creatinine clearance <30 mL/min), because they were not included in the clinical trials, and cancer patients, because only relatively small numbers of selected cancer patients were included, and because clinical trials comparing DOACs to the currently recommended standard therapy with LMW heparin have not been performed. For patients already taking long-term vitamin K antagonist therapy who are well controlled with a high proportion of time in therapeutic range, and for whom regular anticoagulant monitoring is not a burden, switching treatment to a DOAC is not indicated unless a clinical reason develops.
Some practical issues remain incompletely resolved. Rivaroxaban and apixaban can be used as a single-drug approach, whereas dabigatran and edoxaban are preceded by at least 5 days of heparin or LMW heparin treatment. Whether DOAC monotherapy is sufficient for the full spectrum of VTE severity, or whether “lead-in” heparin treatment is preferred in some patients, such as those with PE who have right ventricular dysfunction,78 remains uncertain. The DOACs currently lack a specific reversal agent. In general, this should not be a reason to withhold from most patients the benefit of significantly reduced risks of major bleeding, intracranial bleeding and fatal bleeding with the DOACs. For the near term, vitamin K antagonists may be preferred in patients in whom prompt and measurable reversal of the anticoagulant effect will be required because of planned surgery or invasive procedures. Multiple rapid reversal agents for the DOACs are currently in development. Because the DOACs do not require laboratory monitoring, patients receiving DOACs may have less-frequent contact with their physician or anticoagulation clinic, and nonadherence to the prescribed therapy may not be detected as readily. Physicians and health systems should employ evidence-based strategies to enhance adherence and should evaluate patients at intervals to assess if ongoing anticoagulant therapy is appropriate and adhered to. The effectiveness and safety of the DOACs compared with LMW heparin treatment in cancer patients with VTE has not been evaluated, and LMW heparin remains indicated for these patients.
Duration of Anticoagulant Therapy
Anticoagulant treatment should be continued for at least 3 months in all patients with VTE.9,57,58,80 Stopping treatment at 4 to 6 weeks resulted in an increased incidence of recurrent VTE during the following 6 months (absolute risk increase: 8 percent).57,80,81,82 In contrast, treatment for 3 to 6 months resulted in a low rate of recurrence during the following 1 to 2 years (annual incidence 3 percent).80,81,82
The decision to stop anticoagulant therapy, or continue treatment after 3 months is influenced mainly by the patient’s clinical presentation of thromboembolism as either “provoked,” which refers to VTE occurring in association with known risk factors, or “unprovoked,” in which identifiable risk factors for VTE are absent. Approximately 20 to 40 percent of all symptomatic patients present as unprovoked VTE.
In patients with a first episode of DVT or PE provoked by a reversible risk factor (e.g., surgery), treatment for 3 months is usually sufficient if the risk factor(s) is no longer present. If the risk factor(s) persist, for example prolonged immobility or cancer, treatment should be continued until the risk factor is reversed. It has been a customary practice to treat patients with PE for 6 months rather than 3 months, but the clinical trials indicate there is little to no added benefit of doing so, with a small but additional risk of bleeding.80 Thus, for patients with DVT or PE provoked by a risk factor that has reversed, 3 months is sufficient and recommended over longer therapy.57
Patients with a first episode of unprovoked VTE should be considered for indefinite anticoagulant therapy.57,58 The term “indefinite” refers to continued treatment without a scheduled stopping date; treatment may be stopped in the future if the patient’s risk-to-benefit profile or preference for continued treatment changes. The decision to stop or continue anticoagulation after 3 months in patients with a first episode of unprovoked VTE should take into consideration the risk of recurrent VTE, the risk of bleeding, and patient preference. If indefinite anticoagulant treatment is chosen, the risks and benefits of continuing such treatment should be reassessed at periodic intervals.57
There has been significant research to develop strategies to aid the clinician in assessing the risk of recurrent VTE in patients with unprovoked VTE. The presence of residual DVT assessed by compression ultrasonography,83 elevated levels of plasma D-dimer after discontinuing anticoagulant treatment,84 and male gender85 are associated with an increased incidence of recurrent thromboembolism. The challenge, however, has been to identify the subgroup of patients with a sufficiently low annual risk of recurrence to warrant stopping anticoagulant therapy. Palaretti and colleagues evaluated an approach for patients with a first episode of unprovoked VTE or VTE associated with a minor risk factor (e.g., estrogens, pregnancy, or travel related thrombosis) which combined evaluation of the presence or absence of residual thrombosis by ultrasonography with serial D-dimer measurement to guide the decision to stop or continue anticoagulant therapy.86 Patients in whom residual vein thrombosis was absent after 3 months of treatment, or in those with residual vein thrombosis who had been treated for at least 1 year, and who had serially negative D-dimer measurements for 3 months after stopping vitamin K antagonist treatment, had an annual rate of recurrent VTE of 3 percent during followup off anticoagulant therapy; this compared to 0.7 percent per year in 373 patients who resumed anticoagulation because of an elevated D-dimer measurement, and 8.8 percent per year among the 109 patients with elevated D-dimer who did not continue anticoagulant therapy.86 An annual risk of recurrent VTE of 3 percent may be low enough to discontinue therapy in patients in whom the annual risk of bleeding, especially major bleeding, is similar or higher. However, if the risk of major bleeding is low, for example 1 percent per year or lower, then the annual risk of recurrent VTE of 3 percent may not be sufficiently low to stop anticoagulation, especially if the patient’s preference is on avoiding further recurrent VTE events.
A variety of thrombophilic conditions have been identified and can be evaluated in the laboratory. These include deficiencies of the naturally occurring inhibitors of coagulation such as antithrombin, protein C, and protein S; specific gene mutations including factor V Leiden and prothrombin 20210A; elevated levels of coagulation factor VIII; and the presence of antiphospholipid antibodies (Chap. 131). The role of the presence or absence of thrombophilia in guiding decisions about duration of therapy has been controversial and is incompletely resolved. Indefinite anticoagulant treatment should be considered in patients with a first episode of VTE and antiphospholipid antibodies or the presence of one or a combination of the more potent thrombophilias (deficiency of antithrombin, protein C or protein S, homozygous factor V Leiden, or prothrombin 20210A gene mutation, or one of these with a family history of VTE). Again, patient preference is important to the decision.
The DOACs have been evaluated by randomized trials for the extended treatment of patients with VTE who have completed an initial course of 6 months of anticoagulant therapy.75,87,88,89 Most of the patients in these trials had unprovoked VTE at their initial presentation and all had clinical equipoise about the benefit to risk tradeoff of receiving extended anticoagulant therapy. The results of the trials are consistent. The DOACs produced 80 percent or greater reductions in the annual incidence of recurrent VTE of 7 to 9 percent per year in patients receiving placebo to approximately 2 percent per year in those given DOACs.75,87,88,89 The rates of major bleeding were 0.1 to 0.7 percent. Clinically relevant nonmajor bleeding occurred in 3 to 4 percent of patients.75,87,88,89 In the AMPLIFY Extension trial,89 the rate of major bleeding for the 2.5 mg apixaban regimen was 0.2 percent per year, compared with 0.5 percent for placebo. The low rates of major bleeding, coupled with the advantage of not requiring laboratory monitoring of the anticoagulant effect, will likely tip the balance in favor of extended treatment for more patients with unprovoked VTE.
Aspirin has also been evaluated for the extended treatment of patients with a first episode of unprovoked VTE who have received a course of 6 months or more of anticoagulant therapy.90.91 Aspirin produced a statistically significant 42 percent RR reduction in recurrent VTE in one study (from 11.2 percent to 6.6 percent per year),90 and a nonsignificant (p = 0.09) 26 percent RR reduction in the second study (from 6.5 percent to 4.8 percent per year).91 The rates of major bleeding for aspirin (0.5 to 0.6 percent per year) were similar to placebo. Although intuitive to the clinician, there is no data to indicate that aspirin causes less major bleeding than the DOACs, although it is likely that the efficacy for preventing recurrent VTE is significantly less (only about half as effective as the DOACs).
Oral anticoagulant treatment should be given indefinitely for most patients with a second episode of unprovoked VTE,57,58,92 because stopping treatment at 3 to 6 months in these patients results in a high incidence (21 percent) of recurrent VTE during the following 4 years.92 The risk of recurrent thromboembolism during 4-year followup was reduced by 87 percent (from 21 percent to 3 percent) by continuing anticoagulant treatment92; this benefit is partially offset by the risk of bleeding.
Anticoagulant Therapy of Venous Thromboembolism in Cancer Patients
Use of LMW heparin for long-term treatment of VTE has been evaluated in clinical trials.67,68 The studies indicate that long-term treatment with subcutaneous LMW heparin for 3 to 6 months is at least as effective as, and in cancer patients is more effective than, an oral vitamin K antagonist adjusted to maintain the INR between 2.0 and 3.0. Therefore, patients with VTE associated with concurrent cancer should be treated with LMW heparin for the first 3 to 6 months of long-term treatment.9,57,58 The patients then should receive anticoagulation indefinitely or until the cancer resolves. The regimens of LMW heparin that are established as effective for long-term treatment are dalteparin 200 U/kg once daily for 1 month, followed by 150 U/kg daily thereafter, or tinzaparin 175 U/kg once daily.
Anticoagulant Therapy During Pregnancy
LMW heparin or adjusted-dose subcutaneous heparin are the options for anticoagulant therapy of pregnant patients with VTE.94,95,96 LMW heparin is preferred because it has the safety advantages of causing less thrombocytopenia and probably less osteoporosis than unfractionated heparin An additional advantage is that LMW heparin is effective when given once daily, whereas unfractionated heparin requires twice-daily injection. A study indicates no major change in the peak anti–factor Xa levels over the course of pregnancy in most patients treated with a once-daily therapeutic LMW heparin regimen (tinzaparin 175 U/kg).96 Measurement of the anti–factor Xa level may provide reassurance that major drug accumulation is not occurring. However, the appropriate dose adjustments in response to a decreased anti–factor Xa level are uncertain. The DOACs have not been evaluated in pregnant patients. Evidence-based guidelines for antithrombotic therapy during pregnancy are available.94
Side Effects of Anticoagulant Therapy
Bleeding Bleeding is the most common side effect of anticoagulant therapy. Bleeding can be classified as major or clinically relevant nonmajor according to standardized international criteria. Major bleeding is defined as clinically overt bleeding resulting in a decline of hemoglobin of at least 2 g/dL, transfusion of at least 2 U of packed red cells, or bleeding that is retroperitoneal or intracranial, or occurs into other critical spaces. The rates of major bleeding in contemporary clinical trials of initial therapy with intravenous heparin, LMW heparin, or fondaparinux are 1 to 2 percent.65,66,73,74,75,76,77,78 Patients at increased risk of major bleeding are those who have undergone surgery or experienced trauma within the previous 14 days; those with a history of gastrointestinal or intracranial bleeding, peptic ulcer disease, or genitourinary bleeding; and those with miscellaneous conditions predisposing to bleeding, such as thrombocytopenia, liver disease, and multiple invasive lines.
Major bleeding occurs in approximately 1 to 2 percent of patients during the first 3 months of oral anticoagulant treatment using a vitamin K antagonist and in 1 to 3 percent per year of treatment thereafter.97 A meta-analysis suggests the clinical impact of major bleeding during long-term oral vitamin K antagonist treatment is greater than widely appreciated.97 The estimated case fatality rate for this major bleeding is 13 percent, and the rate of intracranial bleeding was 1.15 per 100 patient-years. These risks are important considerations in the decision about extended or indefinite anticoagulant therapy in patients with VTE. As noted above, clinical trials of the DOACs and meta-analysis indicate clinically important lower rates of bleeding, including major, intracranial, and fatal bleeding than the vitamin K antagonists.73,74,75,76,77,78,79
Heparin-Induced Thrombocytopenia (See also Chap. 118.) Heparin or LMW heparin may cause thrombocytopenia. In large clinical studies of acute VTE treatment, thrombocytopenia occurred in less than 1 percent of more than 2000 patients treated with unfractionated heparin or LMW heparin.66 Nevertheless, heparin-induced thrombocytopenia can be a serious complication when accompanied by extension or recurrence of VTE or the development of arterial thrombosis. Such complications may precede or coincide with the fall in platelet count and are associated with a high rate of limb loss and a high mortality. Heparin in all forms should be discontinued when the diagnosis of heparin-induced thrombocytopenia is made on clinical grounds, and treatment with an alternative anticoagulant, such as danaparoid, bivalirudin, or argatroban, should be initiated. The DOACs have potential to be useful for anticoagulant therapy in patients with heparin-induced thrombocytopenia, but their use has not been evaluated by clinical trials in this patient group.
Heparin-Induced Osteoporosis Osteoporosis may occur as a result of long-term treatment with heparin or LMW heparin (usually after more than 3 months). The earliest clinical manifestation of heparin-associated osteoporosis usually is nonspecific low back pain primarily involving the vertebrae or the ribs. Patients also may present with spontaneous fractures. Up to one-third of patients treated with long-term heparin may have subclinical reduction in bone density. Whether these patients are predisposed to future fractures is not known. The incidence of symptomatic osteoporosis in clinical trials of LMW heparin treatment for 3 to 6 months was very low and are not increased compared to warfarin treatment. Patients with osteoporosis or fractures often had other risk factors such as bone metastases.
Other Side Effects of Heparin Heparin or LMW heparin may cause elevated liver transaminase levels. These elevations are of unknown clinical significance and usually return to normal after the heparin or LMW heparin is discontinued. Awareness of this biochemical effect is important so as to avoid unnecessary interruption of heparin therapy and unnecessary liver biopsies in patients who may develop elevated transaminase levels during heparin or LMW heparin therapy. Additional rare side effects of heparin include hypersensitivity and skin reactions, such as skin necrosis, alopecia, and hyperkalemia occurring as a result of hypoaldosteronism.
Thrombolytic therapy is indicated for patients with PE who present with hypotension or shock, and for select patients with PE who have evidence of right ventricular dysfunction and are at high risk of hemodynamic collapse.30 Thrombolytic therapy provides more rapid lysis of pulmonary emboli and more rapid restoration of right ventricular function and pulmonary perfusion than does anticoagulant treatment.30,98,99 Effective regimens are 100 mg of recombinant tissue plasminogen activator by intravenous infusion over 2 hours (50 mg/h), or 30 to 50 mg (depending on body weight) of tenecteplase given as a single bolus injection.98,99 Heparin then is given by continuous infusion once the thrombin time or aPTT is less than twice the control value.98,99 The starting infusion dose is 1000 U/h. Chapters 25 and 135 provide further details of thrombolytic therapy.
The recently reported PEITHO trial99 evaluated the effectiveness and safety of thrombolysis with tenecteplase followed by anticoagulant therapy compared with anticoagulant therapy alone in 1006 patients with PE and evidence of both right ventricular dysfunction by echocardiography or CT scan, and evidence of myocardial injury by the results of troponin I or troponin T measurement. The primary outcome of death or hemodynamic compensation (or collapse) within 7 days occurred in 13 of 506 patients (2.6 percent) given thrombolysis, compared with 28 of 499 (5.6 percent) receiving anticoagulant therapy alone (p = 0.02).99 Stroke occurred in 12 patients (2.4 percent) in the thrombolysis group, compared with one (0.2 percent) in the anticoagulant alone group (p = 0.003). Extracranial bleeding occurred in 32 patients (6.3 percent) given thrombolysis, and in six patients (1.2 percent) receiving anticoagulant therapy alone (p <0.001). At day 7, death had occurred in six patients (1.2 percent) given thrombolysis and in nine patients (1.8 percent) given anticoagulant therapy alone; the corresponding rates at day 30 were 2.4 percent and 3.2 percent, respectively.99 The findings indicate thrombolytic therapy prevented hemodynamic decompensation, but increased the risk of major bleeding and stroke. The study was not large enough to resolve the key question of whether thrombolysis will improve survival. At present, the risk of thrombolysis outweighs the benefit for most patients with PE who do not have hypotension but who do have evidence of right ventricular dysfunction. Further trials are needed in this group of patients.
The role of thrombolytic therapy in patients with DVT is limited. Thrombolytic therapy may be indicated in patients with acute massive proximal vein thrombosis (phlegmasia cerulea dolens with impending venous gangrene) or in occasional patients with extensive iliofemoral vein thrombosis who have severe symptoms because of venous outflow obstruction. Thrombolytic therapy can be given by systemic infusion or catheter-directed infusion. Catheter-directed thrombolysis (CDT) is probably effective for reducing the incidence of the postphlebitic syndrome.100 Although it was hoped that the catheter-directed approach might be associated with a lower risk of major bleeding, particularly intracranial bleeding, than systemic injection, comparative effectiveness research data suggest the risks of bleeding still outweigh the benefits of this approach.101 From a national database of more than 90,000 patients with a principal diagnosis of proximal DVT or thrombosis involving the vena cava, the outcomes of the 3600 patients who received CDT with a similar number of propensity-matched patients treated with anticoagulation alone were compared. The CDT patients were more likely to have intracranial bleeding (0.9 percent vs. 0.3 percent), and transfusion (11.1 percent vs. 6.5 percent), and more likely to have filter placement (34.8 percent vs. 15.6 percent) and to experience PE (17.9 percent vs. 11.4 percent).101 The important message from this analysis of CDT use in practice is that the rate of intracranial bleeding is appreciable (0.9 percent) and not sufficiently low to recommend the use of CDT for DVT, other than exceptional circumstances such as threatened limb viability.
INFERIOR VENA CAVA FILTER
Insertion of an inferior vena cava filter is indicated for patients with acute VTE and an absolute contraindication to anticoagulant therapy and also indicated for the rare patients who have objectively documented recurrent VTE during adequate anticoagulant therapy.
Insertion of a vena cava filter is effective for preventing PE. However, use of a permanent filter results in an increased incidence of recurrent DVT 1 to 2 years after insertion (increase in cumulative incidence at 2 years increases from 12 percent to 21 percent).102 Therefore, if the indication for filter placement is transient, such as a contraindication to anticoagulation as the result of a temporary high risk of bleeding, a retrievable vena cava filter should be used. A retrievable filter can then be removed in the several weeks to months later, once the filter is no longer required. If a permanent filter is placed, long-term anticoagulant treatment should be given as soon as safely possible to prevent morbidity from recurrent DVT.