David Weismantel, MD

Evidence summary

Because of a lack of uniformity in the definition of shoulder disorders and a wide variation in outcomes assessed in clinical trials, there is limited opportunity to compare and pool the results of individual trials. Even when studies define the disorders and outcomes similarly, the heterogeneity of the interventions, timing of outcome assessment, inadequate reporting of results, and small sample sizes limit the inference of specific therapeutic recommendations for shoulder pain.

A recent Cochrane Review concluded that there is little evidence to either support or refute the efficacy of most common interventions for shoulder pain.¹ The pooled analyses of 2 studies of rotator cuff tendinitis suggested that NSAIDs may be superior to placebo in improving the range of abduction, but there was no significant weighted difference between pain scores.^2,3 Another randomized controlled trial⁴ found 14-day treatment with oral NSAIDs superior to placebo for relieving acute shoulder pain (86% vs 56%; absolute risk reduction 30%; 95% confidence interval, 10%-50%).

A randomized single-blind study of primary care patients reported superiority of manipulative therapy over classic physiotherapy in the treatment of shoulder pain (70% vs 10% cure rate at 5 weeks).⁵ Manipulative therapy as performed by general practitioners or physiotherapists included mobilization and manipulation of the upper spine and ribs, acromioclavicular joint, and the glenohumeral joint. Classic physiotherapy as performed by physiotherapists included only exercise therapy, massage, and physical applications. For the patients with synovial pain, intra-articular corticosteroid injection was superior to both manipulative therapy and classic physiotherapy (cure rates of 75% vs 40% and 20%, respectively, at 5 weeks), yet many primary care physicians may not have enough experience to specifically diagnose synovial pain.

Recommendations from others

We identified no other published recommendations or guidelines from professional organizations.

Evidence summary

Because of a lack of uniformity in the definition of shoulder disorders and a wide variation in outcomes assessed in clinical trials, there is limited opportunity to compare and pool the results of individual trials. Even when studies define the disorders and outcomes similarly, the heterogeneity of the interventions, timing of outcome assessment, inadequate reporting of results, and small sample sizes limit the inference of specific therapeutic recommendations for shoulder pain.

A recent Cochrane Review concluded that there is little evidence to either support or refute the efficacy of most common interventions for shoulder pain.¹ The pooled analyses of 2 studies of rotator cuff tendinitis suggested that NSAIDs may be superior to placebo in improving the range of abduction, but there was no significant weighted difference between pain scores.^2,3 Another randomized controlled trial⁴ found 14-day treatment with oral NSAIDs superior to placebo for relieving acute shoulder pain (86% vs 56%; absolute risk reduction 30%; 95% confidence interval, 10%-50%).

A randomized single-blind study of primary care patients reported superiority of manipulative therapy over classic physiotherapy in the treatment of shoulder pain (70% vs 10% cure rate at 5 weeks).⁵ Manipulative therapy as performed by general practitioners or physiotherapists included mobilization and manipulation of the upper spine and ribs, acromioclavicular joint, and the glenohumeral joint. Classic physiotherapy as performed by physiotherapists included only exercise therapy, massage, and physical applications. For the patients with synovial pain, intra-articular corticosteroid injection was superior to both manipulative therapy and classic physiotherapy (cure rates of 75% vs 40% and 20%, respectively, at 5 weeks), yet many primary care physicians may not have enough experience to specifically diagnose synovial pain.

Recommendations from others

We identified no other published recommendations or guidelines from professional organizations.

Evidence summary

Because of a lack of uniformity in the definition of shoulder disorders and a wide variation in outcomes assessed in clinical trials, there is limited opportunity to compare and pool the results of individual trials. Even when studies define the disorders and outcomes similarly, the heterogeneity of the interventions, timing of outcome assessment, inadequate reporting of results, and small sample sizes limit the inference of specific therapeutic recommendations for shoulder pain.

A recent Cochrane Review concluded that there is little evidence to either support or refute the efficacy of most common interventions for shoulder pain.¹ The pooled analyses of 2 studies of rotator cuff tendinitis suggested that NSAIDs may be superior to placebo in improving the range of abduction, but there was no significant weighted difference between pain scores.^2,3 Another randomized controlled trial⁴ found 14-day treatment with oral NSAIDs superior to placebo for relieving acute shoulder pain (86% vs 56%; absolute risk reduction 30%; 95% confidence interval, 10%-50%).

A randomized single-blind study of primary care patients reported superiority of manipulative therapy over classic physiotherapy in the treatment of shoulder pain (70% vs 10% cure rate at 5 weeks).⁵ Manipulative therapy as performed by general practitioners or physiotherapists included mobilization and manipulation of the upper spine and ribs, acromioclavicular joint, and the glenohumeral joint. Classic physiotherapy as performed by physiotherapists included only exercise therapy, massage, and physical applications. For the patients with synovial pain, intra-articular corticosteroid injection was superior to both manipulative therapy and classic physiotherapy (cure rates of 75% vs 40% and 20%, respectively, at 5 weeks), yet many primary care physicians may not have enough experience to specifically diagnose synovial pain.

Recommendations from others

We identified no other published recommendations or guidelines from professional organizations.

Evidence summary

The current expert recommendations are apparently based on the 0.5% to 3% occurrence of a persistent elevation in aminotransferases (greater than 3 times the upper limit of normal occurring on 2 or more occasions) noted in clinical studies of statins. The incidence of this asymptomatic abnormality increases in a dose-dependent fashion and usually occurs within the first 3 months of therapy. A decreased dose or discontinuation of statin therapy typically results in normalization of aminotransferase values. Yet at least 2 placebo-controlled randomized trials demonstrated no significant difference in the incidence of persistently elevated aminotransferases between statin and placebo treatment.^1,2 Since there has been no study of the natural history and prognosis of persistently elevated aminotransferase values secondary to statin therapy, it is impossible to accurately estimate the need or value of screening for this complication. Gemfibrozil only rarely causes persistently elevated aminotransferase levels.

Myopathy, defined as generalized myalgia with a serum creatine kinase (CK) level greater than 10 times the upper limit of normal is rare (<0.1%), but less so when the statins are used concomitantly with medications such as gemfibrozil, nicotinic acid, antifungal azoles, macrolide antibiotics, and cyclosporine. The myalgia and CK elevation typically resolves after prompt discontinuation from treatment; several fatal cases of rhabdomyolysis, however, have been reported. Remaining alert for the symptoms of myopathy appears to be the best approach to minimize morbidity. The routine determination of serum CK during either statin or gemfibrozil monotherapy is not recommended.

Recommendations from others

For each of the currently approved statins, the US Food and Drug Administration approved labeling information generally includes liver function testing before, and at 12 weeks following, the initiation of therapy, and at any elevation of dose and periodically thereafter. Periodic liver function monitoring is also recommended for treatment with the fibric acid derivative gemfibrozil.

The Washington Manual of Medical Therapeutics³ recommends liver function testing every 6 weeks for the first 3 months, then every 6 months afterward. The National Cholesterol Education Program guidelines do not address the appropriateness or frequency of liver function testing.⁴

Evidence summary

The current expert recommendations are apparently based on the 0.5% to 3% occurrence of a persistent elevation in aminotransferases (greater than 3 times the upper limit of normal occurring on 2 or more occasions) noted in clinical studies of statins. The incidence of this asymptomatic abnormality increases in a dose-dependent fashion and usually occurs within the first 3 months of therapy. A decreased dose or discontinuation of statin therapy typically results in normalization of aminotransferase values. Yet at least 2 placebo-controlled randomized trials demonstrated no significant difference in the incidence of persistently elevated aminotransferases between statin and placebo treatment.^1,2 Since there has been no study of the natural history and prognosis of persistently elevated aminotransferase values secondary to statin therapy, it is impossible to accurately estimate the need or value of screening for this complication. Gemfibrozil only rarely causes persistently elevated aminotransferase levels.

Myopathy, defined as generalized myalgia with a serum creatine kinase (CK) level greater than 10 times the upper limit of normal is rare (<0.1%), but less so when the statins are used concomitantly with medications such as gemfibrozil, nicotinic acid, antifungal azoles, macrolide antibiotics, and cyclosporine. The myalgia and CK elevation typically resolves after prompt discontinuation from treatment; several fatal cases of rhabdomyolysis, however, have been reported. Remaining alert for the symptoms of myopathy appears to be the best approach to minimize morbidity. The routine determination of serum CK during either statin or gemfibrozil monotherapy is not recommended.

Recommendations from others

For each of the currently approved statins, the US Food and Drug Administration approved labeling information generally includes liver function testing before, and at 12 weeks following, the initiation of therapy, and at any elevation of dose and periodically thereafter. Periodic liver function monitoring is also recommended for treatment with the fibric acid derivative gemfibrozil.

The Washington Manual of Medical Therapeutics³ recommends liver function testing every 6 weeks for the first 3 months, then every 6 months afterward. The National Cholesterol Education Program guidelines do not address the appropriateness or frequency of liver function testing.⁴

Evidence summary

The current expert recommendations are apparently based on the 0.5% to 3% occurrence of a persistent elevation in aminotransferases (greater than 3 times the upper limit of normal occurring on 2 or more occasions) noted in clinical studies of statins. The incidence of this asymptomatic abnormality increases in a dose-dependent fashion and usually occurs within the first 3 months of therapy. A decreased dose or discontinuation of statin therapy typically results in normalization of aminotransferase values. Yet at least 2 placebo-controlled randomized trials demonstrated no significant difference in the incidence of persistently elevated aminotransferases between statin and placebo treatment.^1,2 Since there has been no study of the natural history and prognosis of persistently elevated aminotransferase values secondary to statin therapy, it is impossible to accurately estimate the need or value of screening for this complication. Gemfibrozil only rarely causes persistently elevated aminotransferase levels.

Myopathy, defined as generalized myalgia with a serum creatine kinase (CK) level greater than 10 times the upper limit of normal is rare (<0.1%), but less so when the statins are used concomitantly with medications such as gemfibrozil, nicotinic acid, antifungal azoles, macrolide antibiotics, and cyclosporine. The myalgia and CK elevation typically resolves after prompt discontinuation from treatment; several fatal cases of rhabdomyolysis, however, have been reported. Remaining alert for the symptoms of myopathy appears to be the best approach to minimize morbidity. The routine determination of serum CK during either statin or gemfibrozil monotherapy is not recommended.

Recommendations from others

For each of the currently approved statins, the US Food and Drug Administration approved labeling information generally includes liver function testing before, and at 12 weeks following, the initiation of therapy, and at any elevation of dose and periodically thereafter. Periodic liver function monitoring is also recommended for treatment with the fibric acid derivative gemfibrozil.

The Washington Manual of Medical Therapeutics³ recommends liver function testing every 6 weeks for the first 3 months, then every 6 months afterward. The National Cholesterol Education Program guidelines do not address the appropriateness or frequency of liver function testing.⁴

Deep vein thrombosis (DVT), defined as a partial or complete occlusion of a deep vein by thrombus, is a relatively uncommon yet important diagnosis in primary care practice. Population-based studies have estimated the age-adjusted incidence of DVT at 48 per 100,000 persons per year, with age-specific rates increasing steadily as the patient grows older.^1,2 A typical family physician could expect to diagnose 1 or 2 patients with DVT each year. In addition to age, other personal risk factors for the development of DVT include previous thromboembolism, pregnancy and the postpartum period, malignancy, inherited thrombophilias, and exogenous estrogen therapy. Environmental risk factors include immobility, trauma, surgery, and intensive care. The classic Virchow triad (stasis, vascular damage, and hypercoagulability) describes the basic pathophysiologic factors that alone or more commonly in combination promote the development of thrombosis.

The previous article in this series described the evaluation of the patient with suspected DVT. In this article I will outline an evidence-based approach to treating a patient with a confirmed diagnosis of DVT Figure 1. Special attention will be given to the selection of cost-effective interventions that minimize the likelihood of acute or long-term complications.

Initial Therapy

Prompt anticoagulation with heparin is the first priority in treating the patient with DVT by preventing the local extension, embolization, and recurrence of venous thromboembolic disease. Heparin acts immediately to catalyze the inhibition of several activated coagulation factors and leads to the stabilization of the intravascular thrombus. Heparinization is typically continued for 3 to 5 days until a stable and therapeutic international normalized ratio (INR) is established with oral warfarin therapy. There are 2 approved approaches available for the acute anticoagulant treatment of DVT: intravenous unfractionated heparin (UH) and subcutaneous low-molecular-weight heparin (LMWH). In the case of a significant contraindication to anticoagulation or a recurrent thromboembolic event despite adequate anticoagulation, an inferior vena caval filter is the treatment of choice.

Unfractionated Heparin

Traditionally the initial treatment of DVT has been anticoagulation with intravenous UH; the goal of this therapy is the prompt establishment of an activated partial thromboplastin time (APTT) of 1.5 to 2.5 times the control.³ The failure to achieve a therapeutic APTT within 24 hours has been associated with an increased likelihood of recurrent thromboembolism (23% vs 5%, absolute risk reduction [ARR]=18%; number needed to treat [NNT]=5.5; level of evidence [LOE]=1b).^4,5 Several protocols for managing UH therapy have been shown to achieve therapeutic anticoagulation more rapidly than traditional approaches. Figure 2 summarizes a weight-based heparin dosing nomogram that has been proved effective, safe, and superior to standard therapy in a randomized controlled trial; this particular protocol achieved therapeutic anticoagulation in 97% of patients within 24 hours (LOE=1b).⁶ Patients treated with UH should remain hospitalized until therapeutically anticoagulated with oral warfarin.

Low-Molecular-Weight Heparin

After the approval of enoxaparin for the treatment of DVT in 1998, acute outpatient management of DVT with LMWH became possible. The advantages of LMWH include fixed dosing, a subcutaneous route of administration, and a more predictable anticoagulant response. Laboratory monitoring is unnecessary except in patients with renal insufficiency, as a result of better bioavailability, longer half-life, and dose-independent clearance. If monitoring of LMWH is necessary, an anti-Xa level of 0.4 to 0.7 U per mL is the goal of therapy.⁷ The only LMWHs currently approved and labeled by the United States Food and Drug Administration for the treatment of acute DVT are enoxaparin at a dosage of 1 mg per kg administered subcutaneously twice daily or 1.5 mg per kg once daily (inpatient therapy only) and tinzaparin at a dosage of 175 anti-Xa IU per kg administered subcutaneously once daily.

The safety and effectiveness of LMWH therapy for acute DVT were demonstrated in a recent meta-analysis of 11 randomized controlled trials with a total of 3674 patients. In comparison with unfractionated heparin, LMWH significantly reduced the risk of death over 3 to 6 months. A trend toward a reduction in recurrent thromboembolic events was also observed. It was concluded that more than 5 negative trials would have to be published in the future and included in a metaanalysis to negate this mortality advantage of LMWH. A summary of this metaanalysis is provided in Table 1 (LOE=1a).⁸ A subsequent meta-analysis of 13 randomized controlled trials with a total of 4447 patients with venous thromboembolism (DVT or pulmonary embolism) found a similar statistically significant reduction in mortality (ARR=1.6%; NNT=60) yet only a trend toward reduction in the risk of recurrent thromboembolism and major bleeding (LOE=1a).⁹ From this information it is apparent that LMWH is at least as safe and effective as UH in the treatment of DVT and that 1 death is prevented for every 60 patients treated with LMWH instead of UH.

Several studies have demonstrated the efficacy and safety of administering LMWH at home. One study of 400 patients with DVT compared home therapy with LMWH with inpatient UH and failed to demonstrate any significant difference in risk of recurrent thromboembolism or major bleeding (LOE=1b).¹⁰ Additionally, no difference in these clinical outcomes was found in another prospective study comparing patient self-injection with injection by home care nurse (LOE=2b).¹¹ Patients are both capable and willing to participate in this treatment regimen; 91% were pleased with home therapy, and 70% felt comfortable with self-injection of LMWH (LOE=2c).¹²

A cost-effectiveness analysis published in 1999 studied the economic viability of universal treatment of acute DVT with LMWH. The cost of initial care was higher in hospitalized patients receiving LMWH, but this was partly offset by the reduced costs for early complications. Treatment with LMWH increased the quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient LMWH treatment was $7820 per additional quality-adjusted life-year. Sensitivity analysis demonstrated that LMWH was cost saving when at least 8% of the patients were treated at home or if late complications were assumed to occur 25% less frequently in patients receiving LMWH. It was concluded that LMWH is highly cost-effective and is the preferred treatment for DVT (LOE=1b).¹³

Because using LMWH to treat outpatients with DVT has the potential to reduce health care costs, several organizations have published recommendations or guidelines suggesting an outpatient alternative for uncomplicated DVT.^3,14,15 It is generally agreed that patients with an uncomplicated DVT, good cardiopulmonary reserve, no excessive bleeding risk, and normal renal function can safely be treated with LMWH at home. Those with the comorbidities or the possible contraindications to anticoagulation noted in Table 2 should typically be hospitalized for initial management. Also, the home therapy patient will require education on the correct dosage and administration of LMWH, recognition of adverse events, and available resources to address problems or questions during the treatment course. Although there is limited evidence to support these specific recommendations, current expert opinion favors a conservative approach in the selection of patients for home treatment of DVT (LOE=5).

Whether patients are treated in the hospital or at home, LMWH should be considered the primary standard treatment for DVT. The relative safety, tolerability, efficacy, and cost-effectiveness of LMWH make it the obvious and preferred therapeutic alternative.

Vena Caval Filter Placement

Placement of an inferior vena caval filter is reserved for patients with a contraindication to anticoagulation, a serious complication of anticoagulation, or recurrent thromboembolism despite adequate anticoagulation. To date there have been no randomized or cohort studies directly comparing inferior vena caval interruption with standard anticoagulation therapy. However, a recent clinical trial of vena caval filter placement in 400 anticoagulated patients revealed a significant decrease in pulmonary embolism assessed at day 12 of therapy (ARR=3.7%; NNT=27) but a significant increase in the rate of recurrent symptomatic DVT over the next 2 years (absolute risk increase [ARI]=9.2%; number needed to harm [NNH]=11; LOE=1b).¹⁶ The available evidence does not support the use of vena caval filters in the management of the patient with an initial and uncomplicated DVT.

Activity

Patients with acute DVT have traditionally been confined to bed rest for a period of 3 to 7 days, yet there is no evidence that this practice improves clinical outcomes. A study of 638 patients with DVT who were allowed to ambulate with compression stockings demonstrated a low incidence of pulmonary emboli documented by ventilation-perfusion scan when compared with that in the literature (LOE=4).¹⁷ A more recent randomized trial of 126 patients with acute proximal vein thrombosis compared 8 days of strict bed rest with early mobilization; there was no statistically significant difference in the incidence of scintigraphically detectable pulmonary embolism (LOE=1b).¹⁸ These studies do not currently support the previous recommendation of bed rest for the acute treatment of DVT.

Extended Therapy

After the initial evaluation, stabilization, and treatment of a patient with DVT, a plan is needed to minimize the risk of recurrent thromboembolism and chronic postphlebitic complications. Although unsupported by specific evidence, most recommendations include the discontinuation and avoidance of any exogenous estrogen therapy. Oral anticoagulation with warfarin decreases the incidence of recurrent thromboembolic events, while the extended use of compression stockings decreases the development of the postphlebitic syndrome.

Oral Anticoagulation with Warfarin

For a patient presenting with a first DVT, oral anticoagulation with warfarin should be initiated on the first day of treatment, after heparin loading is complete. Adequacy of therapy is monitored by measurement of the INR, a standardization of the plasma thromboplastin ratio now used to correct for the variance between laboratories resulting from the use of different thromboplastin reagents. The antithrombotic effect of warfarin is best established after 3 to 5 days; it is for this reason that heparin is overlapped with warfarin during the first several days of therapy. The algorithm in Table 3 has been shown to improve the success of achieving a stable and therapeutic INR by day 5 of therapy with less initial risk of hemorrhagic complication (LOE=1b).¹⁹ The heparin may be discontinued when the INR is within the therapeutic range of 2.0 to 3.0 for patients with DVT (LOE=5).¹⁴

The optimal duration of oral anticoagulant therapy for a first episode of DVT varies and depends on whether risk factors are transient or persistent. A comparison of 6 weeks versus 6 months of oral anticoagulant therapy found an increased risk of recurrent venous thromboembolism in the 6-week group. The risk decreased from 18.1% with 6 weeks of treatment to 9.5% with 6 months; 12 patients would have to be treated for 6 months instead of 6 weeks to prevent 1 episode of recurrent venous thromboembolism (NNT=12; LOE=1b).²⁰ A subsequent comparison of 3 months of anticoagulation with extended oral anticoagulation for approximately 10 months found a reduction in the risk of recurrent venous thromboembolism (ARR=26%; NNT=4) but an increased risk of major bleeding (ARI=3.8%; NNH=26) in the extended therapy group over a period of 2 years (LOE=1b).²¹ In general, a longer duration of oral anticoagulant therapy is not surprisingly associated with a decreased risk of venous thromboembolic recurrence and an increased risk of bleeding complications. Using the data from the previously mentioned study, for every 100 patients given extended therapy instead of the traditional 3 months there will be 4 additional major bleeds and 25 fewer episodes of recurrent venous thromboembolism. A recent Cochrane review of 1500 patients in 4 studies similarly found a decreased risk of recurrent venous thromboembolism with prolonged warfarin therapy (0.9% vs 12%, ARR=11.1; NNT=9) but an increased incidence of major bleeding (2.1% vs 0%, ARI=2.1%; NNH=48; LOE=1a).²² In the case of recurrent DVT, lifetime anticoagulant therapy should be considered in the absence of risk factors for bleeding. The specific recommendations for duration of oral anticoagulation have been adapted from the American College of Chest Physicians (LOE=5)¹⁵ and are included in Figure 1.

Compression Stockings

The addition of compression stockings to standard oral anticoagulant therapy is supported by a study of 194 patients comparing the use of knee-high 30 to 40 mm Hg custom-fitted graded compression stockings over a 2-year period and a median follow-up of 76 months. The development of mild-moderate postphlebitic syndrome was decreased by 58% (ARR=27.1%; NNT=3.7), and the incidence of severe postphlebitic syndrome was decreased by 51% (ARR=12%; NNT=8.3). Although there was not a significant difference in the rate of recurrent venous thromboembolism, extended use of compression stockings improved the long-term clinical course and should be considered a valuable addition in the long-term management of DVT (LOE=1b).²³

Investigation for possible malignancy or coagulation defect

Although there is an increased incidence of cancer at the time of presentation in patients with idiopathic DVT (ie, no clear predisposing cause such as bed rest), a complete medical evaluation including history, physical examination, and basic laboratory studies has been shown to adequately detect malignancy in this setting. A retrospective study of 986 consecutive patients found no difference in cancer incidence over the next 34 months among the 142 DVT patients and 844 patients with DVT ruled out by the clinical evaluation outlined in Table 4 (LOE=4).²⁴ A prospective cohort study of 260 patients with DVT provided 2 years of regular follow-up visits and found that all subsequent cancers were diagnosed because the patient became symptomatic and sought care from a general practitioner (LOE=2b).²⁵ Beyond initial and age-appropriate cancer screening, there is no evidence that an aggressive search for an underlying malignancy is warranted.

Inherited thrombophilias are associated with an increased risk for venous thromboembolic disease, yet the diagnosis of one of these defects does not substantially change the clinical management of initial or recurrent DVT. Likewise, counseling regarding the increased risk associated with prolonged immobilization, surgery, pregnancy, and exogenous estrogen therapy would be unchanged. A sensible approach may be to screen for hereditary thrombophilias (factor V Leiden, protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, and hyperhomocysteinuria) in the case of recurrent DVT, a younger patient, or a family history of thromboembolic disease. In the event that an inherited thrombophilia is diagnosed, further screening and possible identification of other family members could lead to avoidance of known secondary risk factors and subsequent thromboembolic events. The typical patient with an initial episode of DVT will not benefit from the investigation for an inherited coagulation defect.

Conclusions

The clinical and economic outcomes associated with DVT can be improved with a simple evidence-based approach to therapy Figure 1. Management of a first episode of DVT should begin with immediate anticoagulation with LMWH, preferably at home if there are no contraindications to outpatient management. Oral anticoagulation should be instituted at initial presentation and continued for a period of 3 to 6 months depending on individual risk factors for bleeding. The addition of compression stockings provides symptomatic relief and decreases the incidence of symptomatic postphlebitic syndrome. Extensive evaluation for malignancy or an inherited thrombophilia is not warranted in most cases of DVT.

Deep vein thrombosis (DVT), defined as a partial or complete occlusion of a deep vein by thrombus, is a relatively uncommon yet important diagnosis in primary care practice. Population-based studies have estimated the age-adjusted incidence of DVT at 48 per 100,000 persons per year, with age-specific rates increasing steadily as the patient grows older.^1,2 A typical family physician could expect to diagnose 1 or 2 patients with DVT each year. In addition to age, other personal risk factors for the development of DVT include previous thromboembolism, pregnancy and the postpartum period, malignancy, inherited thrombophilias, and exogenous estrogen therapy. Environmental risk factors include immobility, trauma, surgery, and intensive care. The classic Virchow triad (stasis, vascular damage, and hypercoagulability) describes the basic pathophysiologic factors that alone or more commonly in combination promote the development of thrombosis.

The previous article in this series described the evaluation of the patient with suspected DVT. In this article I will outline an evidence-based approach to treating a patient with a confirmed diagnosis of DVT Figure 1. Special attention will be given to the selection of cost-effective interventions that minimize the likelihood of acute or long-term complications.

Initial Therapy

Prompt anticoagulation with heparin is the first priority in treating the patient with DVT by preventing the local extension, embolization, and recurrence of venous thromboembolic disease. Heparin acts immediately to catalyze the inhibition of several activated coagulation factors and leads to the stabilization of the intravascular thrombus. Heparinization is typically continued for 3 to 5 days until a stable and therapeutic international normalized ratio (INR) is established with oral warfarin therapy. There are 2 approved approaches available for the acute anticoagulant treatment of DVT: intravenous unfractionated heparin (UH) and subcutaneous low-molecular-weight heparin (LMWH). In the case of a significant contraindication to anticoagulation or a recurrent thromboembolic event despite adequate anticoagulation, an inferior vena caval filter is the treatment of choice.

Unfractionated Heparin

Traditionally the initial treatment of DVT has been anticoagulation with intravenous UH; the goal of this therapy is the prompt establishment of an activated partial thromboplastin time (APTT) of 1.5 to 2.5 times the control.³ The failure to achieve a therapeutic APTT within 24 hours has been associated with an increased likelihood of recurrent thromboembolism (23% vs 5%, absolute risk reduction [ARR]=18%; number needed to treat [NNT]=5.5; level of evidence [LOE]=1b).^4,5 Several protocols for managing UH therapy have been shown to achieve therapeutic anticoagulation more rapidly than traditional approaches. Figure 2 summarizes a weight-based heparin dosing nomogram that has been proved effective, safe, and superior to standard therapy in a randomized controlled trial; this particular protocol achieved therapeutic anticoagulation in 97% of patients within 24 hours (LOE=1b).⁶ Patients treated with UH should remain hospitalized until therapeutically anticoagulated with oral warfarin.

Low-Molecular-Weight Heparin

After the approval of enoxaparin for the treatment of DVT in 1998, acute outpatient management of DVT with LMWH became possible. The advantages of LMWH include fixed dosing, a subcutaneous route of administration, and a more predictable anticoagulant response. Laboratory monitoring is unnecessary except in patients with renal insufficiency, as a result of better bioavailability, longer half-life, and dose-independent clearance. If monitoring of LMWH is necessary, an anti-Xa level of 0.4 to 0.7 U per mL is the goal of therapy.⁷ The only LMWHs currently approved and labeled by the United States Food and Drug Administration for the treatment of acute DVT are enoxaparin at a dosage of 1 mg per kg administered subcutaneously twice daily or 1.5 mg per kg once daily (inpatient therapy only) and tinzaparin at a dosage of 175 anti-Xa IU per kg administered subcutaneously once daily.

The safety and effectiveness of LMWH therapy for acute DVT were demonstrated in a recent meta-analysis of 11 randomized controlled trials with a total of 3674 patients. In comparison with unfractionated heparin, LMWH significantly reduced the risk of death over 3 to 6 months. A trend toward a reduction in recurrent thromboembolic events was also observed. It was concluded that more than 5 negative trials would have to be published in the future and included in a metaanalysis to negate this mortality advantage of LMWH. A summary of this metaanalysis is provided in Table 1 (LOE=1a).⁸ A subsequent meta-analysis of 13 randomized controlled trials with a total of 4447 patients with venous thromboembolism (DVT or pulmonary embolism) found a similar statistically significant reduction in mortality (ARR=1.6%; NNT=60) yet only a trend toward reduction in the risk of recurrent thromboembolism and major bleeding (LOE=1a).⁹ From this information it is apparent that LMWH is at least as safe and effective as UH in the treatment of DVT and that 1 death is prevented for every 60 patients treated with LMWH instead of UH.

Several studies have demonstrated the efficacy and safety of administering LMWH at home. One study of 400 patients with DVT compared home therapy with LMWH with inpatient UH and failed to demonstrate any significant difference in risk of recurrent thromboembolism or major bleeding (LOE=1b).¹⁰ Additionally, no difference in these clinical outcomes was found in another prospective study comparing patient self-injection with injection by home care nurse (LOE=2b).¹¹ Patients are both capable and willing to participate in this treatment regimen; 91% were pleased with home therapy, and 70% felt comfortable with self-injection of LMWH (LOE=2c).¹²

A cost-effectiveness analysis published in 1999 studied the economic viability of universal treatment of acute DVT with LMWH. The cost of initial care was higher in hospitalized patients receiving LMWH, but this was partly offset by the reduced costs for early complications. Treatment with LMWH increased the quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient LMWH treatment was $7820 per additional quality-adjusted life-year. Sensitivity analysis demonstrated that LMWH was cost saving when at least 8% of the patients were treated at home or if late complications were assumed to occur 25% less frequently in patients receiving LMWH. It was concluded that LMWH is highly cost-effective and is the preferred treatment for DVT (LOE=1b).¹³

Because using LMWH to treat outpatients with DVT has the potential to reduce health care costs, several organizations have published recommendations or guidelines suggesting an outpatient alternative for uncomplicated DVT.^3,14,15 It is generally agreed that patients with an uncomplicated DVT, good cardiopulmonary reserve, no excessive bleeding risk, and normal renal function can safely be treated with LMWH at home. Those with the comorbidities or the possible contraindications to anticoagulation noted in Table 2 should typically be hospitalized for initial management. Also, the home therapy patient will require education on the correct dosage and administration of LMWH, recognition of adverse events, and available resources to address problems or questions during the treatment course. Although there is limited evidence to support these specific recommendations, current expert opinion favors a conservative approach in the selection of patients for home treatment of DVT (LOE=5).

Whether patients are treated in the hospital or at home, LMWH should be considered the primary standard treatment for DVT. The relative safety, tolerability, efficacy, and cost-effectiveness of LMWH make it the obvious and preferred therapeutic alternative.

Vena Caval Filter Placement

Placement of an inferior vena caval filter is reserved for patients with a contraindication to anticoagulation, a serious complication of anticoagulation, or recurrent thromboembolism despite adequate anticoagulation. To date there have been no randomized or cohort studies directly comparing inferior vena caval interruption with standard anticoagulation therapy. However, a recent clinical trial of vena caval filter placement in 400 anticoagulated patients revealed a significant decrease in pulmonary embolism assessed at day 12 of therapy (ARR=3.7%; NNT=27) but a significant increase in the rate of recurrent symptomatic DVT over the next 2 years (absolute risk increase [ARI]=9.2%; number needed to harm [NNH]=11; LOE=1b).¹⁶ The available evidence does not support the use of vena caval filters in the management of the patient with an initial and uncomplicated DVT.

Activity

Patients with acute DVT have traditionally been confined to bed rest for a period of 3 to 7 days, yet there is no evidence that this practice improves clinical outcomes. A study of 638 patients with DVT who were allowed to ambulate with compression stockings demonstrated a low incidence of pulmonary emboli documented by ventilation-perfusion scan when compared with that in the literature (LOE=4).¹⁷ A more recent randomized trial of 126 patients with acute proximal vein thrombosis compared 8 days of strict bed rest with early mobilization; there was no statistically significant difference in the incidence of scintigraphically detectable pulmonary embolism (LOE=1b).¹⁸ These studies do not currently support the previous recommendation of bed rest for the acute treatment of DVT.

Extended Therapy

After the initial evaluation, stabilization, and treatment of a patient with DVT, a plan is needed to minimize the risk of recurrent thromboembolism and chronic postphlebitic complications. Although unsupported by specific evidence, most recommendations include the discontinuation and avoidance of any exogenous estrogen therapy. Oral anticoagulation with warfarin decreases the incidence of recurrent thromboembolic events, while the extended use of compression stockings decreases the development of the postphlebitic syndrome.

Oral Anticoagulation with Warfarin

For a patient presenting with a first DVT, oral anticoagulation with warfarin should be initiated on the first day of treatment, after heparin loading is complete. Adequacy of therapy is monitored by measurement of the INR, a standardization of the plasma thromboplastin ratio now used to correct for the variance between laboratories resulting from the use of different thromboplastin reagents. The antithrombotic effect of warfarin is best established after 3 to 5 days; it is for this reason that heparin is overlapped with warfarin during the first several days of therapy. The algorithm in Table 3 has been shown to improve the success of achieving a stable and therapeutic INR by day 5 of therapy with less initial risk of hemorrhagic complication (LOE=1b).¹⁹ The heparin may be discontinued when the INR is within the therapeutic range of 2.0 to 3.0 for patients with DVT (LOE=5).¹⁴

The optimal duration of oral anticoagulant therapy for a first episode of DVT varies and depends on whether risk factors are transient or persistent. A comparison of 6 weeks versus 6 months of oral anticoagulant therapy found an increased risk of recurrent venous thromboembolism in the 6-week group. The risk decreased from 18.1% with 6 weeks of treatment to 9.5% with 6 months; 12 patients would have to be treated for 6 months instead of 6 weeks to prevent 1 episode of recurrent venous thromboembolism (NNT=12; LOE=1b).²⁰ A subsequent comparison of 3 months of anticoagulation with extended oral anticoagulation for approximately 10 months found a reduction in the risk of recurrent venous thromboembolism (ARR=26%; NNT=4) but an increased risk of major bleeding (ARI=3.8%; NNH=26) in the extended therapy group over a period of 2 years (LOE=1b).²¹ In general, a longer duration of oral anticoagulant therapy is not surprisingly associated with a decreased risk of venous thromboembolic recurrence and an increased risk of bleeding complications. Using the data from the previously mentioned study, for every 100 patients given extended therapy instead of the traditional 3 months there will be 4 additional major bleeds and 25 fewer episodes of recurrent venous thromboembolism. A recent Cochrane review of 1500 patients in 4 studies similarly found a decreased risk of recurrent venous thromboembolism with prolonged warfarin therapy (0.9% vs 12%, ARR=11.1; NNT=9) but an increased incidence of major bleeding (2.1% vs 0%, ARI=2.1%; NNH=48; LOE=1a).²² In the case of recurrent DVT, lifetime anticoagulant therapy should be considered in the absence of risk factors for bleeding. The specific recommendations for duration of oral anticoagulation have been adapted from the American College of Chest Physicians (LOE=5)¹⁵ and are included in Figure 1.

Compression Stockings

The addition of compression stockings to standard oral anticoagulant therapy is supported by a study of 194 patients comparing the use of knee-high 30 to 40 mm Hg custom-fitted graded compression stockings over a 2-year period and a median follow-up of 76 months. The development of mild-moderate postphlebitic syndrome was decreased by 58% (ARR=27.1%; NNT=3.7), and the incidence of severe postphlebitic syndrome was decreased by 51% (ARR=12%; NNT=8.3). Although there was not a significant difference in the rate of recurrent venous thromboembolism, extended use of compression stockings improved the long-term clinical course and should be considered a valuable addition in the long-term management of DVT (LOE=1b).²³

Investigation for possible malignancy or coagulation defect

Although there is an increased incidence of cancer at the time of presentation in patients with idiopathic DVT (ie, no clear predisposing cause such as bed rest), a complete medical evaluation including history, physical examination, and basic laboratory studies has been shown to adequately detect malignancy in this setting. A retrospective study of 986 consecutive patients found no difference in cancer incidence over the next 34 months among the 142 DVT patients and 844 patients with DVT ruled out by the clinical evaluation outlined in Table 4 (LOE=4).²⁴ A prospective cohort study of 260 patients with DVT provided 2 years of regular follow-up visits and found that all subsequent cancers were diagnosed because the patient became symptomatic and sought care from a general practitioner (LOE=2b).²⁵ Beyond initial and age-appropriate cancer screening, there is no evidence that an aggressive search for an underlying malignancy is warranted.

Inherited thrombophilias are associated with an increased risk for venous thromboembolic disease, yet the diagnosis of one of these defects does not substantially change the clinical management of initial or recurrent DVT. Likewise, counseling regarding the increased risk associated with prolonged immobilization, surgery, pregnancy, and exogenous estrogen therapy would be unchanged. A sensible approach may be to screen for hereditary thrombophilias (factor V Leiden, protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, and hyperhomocysteinuria) in the case of recurrent DVT, a younger patient, or a family history of thromboembolic disease. In the event that an inherited thrombophilia is diagnosed, further screening and possible identification of other family members could lead to avoidance of known secondary risk factors and subsequent thromboembolic events. The typical patient with an initial episode of DVT will not benefit from the investigation for an inherited coagulation defect.

Conclusions

The clinical and economic outcomes associated with DVT can be improved with a simple evidence-based approach to therapy Figure 1. Management of a first episode of DVT should begin with immediate anticoagulation with LMWH, preferably at home if there are no contraindications to outpatient management. Oral anticoagulation should be instituted at initial presentation and continued for a period of 3 to 6 months depending on individual risk factors for bleeding. The addition of compression stockings provides symptomatic relief and decreases the incidence of symptomatic postphlebitic syndrome. Extensive evaluation for malignancy or an inherited thrombophilia is not warranted in most cases of DVT.

Deep vein thrombosis (DVT), defined as a partial or complete occlusion of a deep vein by thrombus, is a relatively uncommon yet important diagnosis in primary care practice. Population-based studies have estimated the age-adjusted incidence of DVT at 48 per 100,000 persons per year, with age-specific rates increasing steadily as the patient grows older.^1,2 A typical family physician could expect to diagnose 1 or 2 patients with DVT each year. In addition to age, other personal risk factors for the development of DVT include previous thromboembolism, pregnancy and the postpartum period, malignancy, inherited thrombophilias, and exogenous estrogen therapy. Environmental risk factors include immobility, trauma, surgery, and intensive care. The classic Virchow triad (stasis, vascular damage, and hypercoagulability) describes the basic pathophysiologic factors that alone or more commonly in combination promote the development of thrombosis.

The previous article in this series described the evaluation of the patient with suspected DVT. In this article I will outline an evidence-based approach to treating a patient with a confirmed diagnosis of DVT Figure 1. Special attention will be given to the selection of cost-effective interventions that minimize the likelihood of acute or long-term complications.

Initial Therapy

Prompt anticoagulation with heparin is the first priority in treating the patient with DVT by preventing the local extension, embolization, and recurrence of venous thromboembolic disease. Heparin acts immediately to catalyze the inhibition of several activated coagulation factors and leads to the stabilization of the intravascular thrombus. Heparinization is typically continued for 3 to 5 days until a stable and therapeutic international normalized ratio (INR) is established with oral warfarin therapy. There are 2 approved approaches available for the acute anticoagulant treatment of DVT: intravenous unfractionated heparin (UH) and subcutaneous low-molecular-weight heparin (LMWH). In the case of a significant contraindication to anticoagulation or a recurrent thromboembolic event despite adequate anticoagulation, an inferior vena caval filter is the treatment of choice.

Unfractionated Heparin

Traditionally the initial treatment of DVT has been anticoagulation with intravenous UH; the goal of this therapy is the prompt establishment of an activated partial thromboplastin time (APTT) of 1.5 to 2.5 times the control.³ The failure to achieve a therapeutic APTT within 24 hours has been associated with an increased likelihood of recurrent thromboembolism (23% vs 5%, absolute risk reduction [ARR]=18%; number needed to treat [NNT]=5.5; level of evidence [LOE]=1b).^4,5 Several protocols for managing UH therapy have been shown to achieve therapeutic anticoagulation more rapidly than traditional approaches. Figure 2 summarizes a weight-based heparin dosing nomogram that has been proved effective, safe, and superior to standard therapy in a randomized controlled trial; this particular protocol achieved therapeutic anticoagulation in 97% of patients within 24 hours (LOE=1b).⁶ Patients treated with UH should remain hospitalized until therapeutically anticoagulated with oral warfarin.

Low-Molecular-Weight Heparin

After the approval of enoxaparin for the treatment of DVT in 1998, acute outpatient management of DVT with LMWH became possible. The advantages of LMWH include fixed dosing, a subcutaneous route of administration, and a more predictable anticoagulant response. Laboratory monitoring is unnecessary except in patients with renal insufficiency, as a result of better bioavailability, longer half-life, and dose-independent clearance. If monitoring of LMWH is necessary, an anti-Xa level of 0.4 to 0.7 U per mL is the goal of therapy.⁷ The only LMWHs currently approved and labeled by the United States Food and Drug Administration for the treatment of acute DVT are enoxaparin at a dosage of 1 mg per kg administered subcutaneously twice daily or 1.5 mg per kg once daily (inpatient therapy only) and tinzaparin at a dosage of 175 anti-Xa IU per kg administered subcutaneously once daily.

The safety and effectiveness of LMWH therapy for acute DVT were demonstrated in a recent meta-analysis of 11 randomized controlled trials with a total of 3674 patients. In comparison with unfractionated heparin, LMWH significantly reduced the risk of death over 3 to 6 months. A trend toward a reduction in recurrent thromboembolic events was also observed. It was concluded that more than 5 negative trials would have to be published in the future and included in a metaanalysis to negate this mortality advantage of LMWH. A summary of this metaanalysis is provided in Table 1 (LOE=1a).⁸ A subsequent meta-analysis of 13 randomized controlled trials with a total of 4447 patients with venous thromboembolism (DVT or pulmonary embolism) found a similar statistically significant reduction in mortality (ARR=1.6%; NNT=60) yet only a trend toward reduction in the risk of recurrent thromboembolism and major bleeding (LOE=1a).⁹ From this information it is apparent that LMWH is at least as safe and effective as UH in the treatment of DVT and that 1 death is prevented for every 60 patients treated with LMWH instead of UH.

Several studies have demonstrated the efficacy and safety of administering LMWH at home. One study of 400 patients with DVT compared home therapy with LMWH with inpatient UH and failed to demonstrate any significant difference in risk of recurrent thromboembolism or major bleeding (LOE=1b).¹⁰ Additionally, no difference in these clinical outcomes was found in another prospective study comparing patient self-injection with injection by home care nurse (LOE=2b).¹¹ Patients are both capable and willing to participate in this treatment regimen; 91% were pleased with home therapy, and 70% felt comfortable with self-injection of LMWH (LOE=2c).¹²

A cost-effectiveness analysis published in 1999 studied the economic viability of universal treatment of acute DVT with LMWH. The cost of initial care was higher in hospitalized patients receiving LMWH, but this was partly offset by the reduced costs for early complications. Treatment with LMWH increased the quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient LMWH treatment was $7820 per additional quality-adjusted life-year. Sensitivity analysis demonstrated that LMWH was cost saving when at least 8% of the patients were treated at home or if late complications were assumed to occur 25% less frequently in patients receiving LMWH. It was concluded that LMWH is highly cost-effective and is the preferred treatment for DVT (LOE=1b).¹³

Because using LMWH to treat outpatients with DVT has the potential to reduce health care costs, several organizations have published recommendations or guidelines suggesting an outpatient alternative for uncomplicated DVT.^3,14,15 It is generally agreed that patients with an uncomplicated DVT, good cardiopulmonary reserve, no excessive bleeding risk, and normal renal function can safely be treated with LMWH at home. Those with the comorbidities or the possible contraindications to anticoagulation noted in Table 2 should typically be hospitalized for initial management. Also, the home therapy patient will require education on the correct dosage and administration of LMWH, recognition of adverse events, and available resources to address problems or questions during the treatment course. Although there is limited evidence to support these specific recommendations, current expert opinion favors a conservative approach in the selection of patients for home treatment of DVT (LOE=5).

Whether patients are treated in the hospital or at home, LMWH should be considered the primary standard treatment for DVT. The relative safety, tolerability, efficacy, and cost-effectiveness of LMWH make it the obvious and preferred therapeutic alternative.

Vena Caval Filter Placement

Placement of an inferior vena caval filter is reserved for patients with a contraindication to anticoagulation, a serious complication of anticoagulation, or recurrent thromboembolism despite adequate anticoagulation. To date there have been no randomized or cohort studies directly comparing inferior vena caval interruption with standard anticoagulation therapy. However, a recent clinical trial of vena caval filter placement in 400 anticoagulated patients revealed a significant decrease in pulmonary embolism assessed at day 12 of therapy (ARR=3.7%; NNT=27) but a significant increase in the rate of recurrent symptomatic DVT over the next 2 years (absolute risk increase [ARI]=9.2%; number needed to harm [NNH]=11; LOE=1b).¹⁶ The available evidence does not support the use of vena caval filters in the management of the patient with an initial and uncomplicated DVT.

Activity

Patients with acute DVT have traditionally been confined to bed rest for a period of 3 to 7 days, yet there is no evidence that this practice improves clinical outcomes. A study of 638 patients with DVT who were allowed to ambulate with compression stockings demonstrated a low incidence of pulmonary emboli documented by ventilation-perfusion scan when compared with that in the literature (LOE=4).¹⁷ A more recent randomized trial of 126 patients with acute proximal vein thrombosis compared 8 days of strict bed rest with early mobilization; there was no statistically significant difference in the incidence of scintigraphically detectable pulmonary embolism (LOE=1b).¹⁸ These studies do not currently support the previous recommendation of bed rest for the acute treatment of DVT.

Extended Therapy

After the initial evaluation, stabilization, and treatment of a patient with DVT, a plan is needed to minimize the risk of recurrent thromboembolism and chronic postphlebitic complications. Although unsupported by specific evidence, most recommendations include the discontinuation and avoidance of any exogenous estrogen therapy. Oral anticoagulation with warfarin decreases the incidence of recurrent thromboembolic events, while the extended use of compression stockings decreases the development of the postphlebitic syndrome.

Oral Anticoagulation with Warfarin

For a patient presenting with a first DVT, oral anticoagulation with warfarin should be initiated on the first day of treatment, after heparin loading is complete. Adequacy of therapy is monitored by measurement of the INR, a standardization of the plasma thromboplastin ratio now used to correct for the variance between laboratories resulting from the use of different thromboplastin reagents. The antithrombotic effect of warfarin is best established after 3 to 5 days; it is for this reason that heparin is overlapped with warfarin during the first several days of therapy. The algorithm in Table 3 has been shown to improve the success of achieving a stable and therapeutic INR by day 5 of therapy with less initial risk of hemorrhagic complication (LOE=1b).¹⁹ The heparin may be discontinued when the INR is within the therapeutic range of 2.0 to 3.0 for patients with DVT (LOE=5).¹⁴

The optimal duration of oral anticoagulant therapy for a first episode of DVT varies and depends on whether risk factors are transient or persistent. A comparison of 6 weeks versus 6 months of oral anticoagulant therapy found an increased risk of recurrent venous thromboembolism in the 6-week group. The risk decreased from 18.1% with 6 weeks of treatment to 9.5% with 6 months; 12 patients would have to be treated for 6 months instead of 6 weeks to prevent 1 episode of recurrent venous thromboembolism (NNT=12; LOE=1b).²⁰ A subsequent comparison of 3 months of anticoagulation with extended oral anticoagulation for approximately 10 months found a reduction in the risk of recurrent venous thromboembolism (ARR=26%; NNT=4) but an increased risk of major bleeding (ARI=3.8%; NNH=26) in the extended therapy group over a period of 2 years (LOE=1b).²¹ In general, a longer duration of oral anticoagulant therapy is not surprisingly associated with a decreased risk of venous thromboembolic recurrence and an increased risk of bleeding complications. Using the data from the previously mentioned study, for every 100 patients given extended therapy instead of the traditional 3 months there will be 4 additional major bleeds and 25 fewer episodes of recurrent venous thromboembolism. A recent Cochrane review of 1500 patients in 4 studies similarly found a decreased risk of recurrent venous thromboembolism with prolonged warfarin therapy (0.9% vs 12%, ARR=11.1; NNT=9) but an increased incidence of major bleeding (2.1% vs 0%, ARI=2.1%; NNH=48; LOE=1a).²² In the case of recurrent DVT, lifetime anticoagulant therapy should be considered in the absence of risk factors for bleeding. The specific recommendations for duration of oral anticoagulation have been adapted from the American College of Chest Physicians (LOE=5)¹⁵ and are included in Figure 1.

Compression Stockings

The addition of compression stockings to standard oral anticoagulant therapy is supported by a study of 194 patients comparing the use of knee-high 30 to 40 mm Hg custom-fitted graded compression stockings over a 2-year period and a median follow-up of 76 months. The development of mild-moderate postphlebitic syndrome was decreased by 58% (ARR=27.1%; NNT=3.7), and the incidence of severe postphlebitic syndrome was decreased by 51% (ARR=12%; NNT=8.3). Although there was not a significant difference in the rate of recurrent venous thromboembolism, extended use of compression stockings improved the long-term clinical course and should be considered a valuable addition in the long-term management of DVT (LOE=1b).²³

Investigation for possible malignancy or coagulation defect

Although there is an increased incidence of cancer at the time of presentation in patients with idiopathic DVT (ie, no clear predisposing cause such as bed rest), a complete medical evaluation including history, physical examination, and basic laboratory studies has been shown to adequately detect malignancy in this setting. A retrospective study of 986 consecutive patients found no difference in cancer incidence over the next 34 months among the 142 DVT patients and 844 patients with DVT ruled out by the clinical evaluation outlined in Table 4 (LOE=4).²⁴ A prospective cohort study of 260 patients with DVT provided 2 years of regular follow-up visits and found that all subsequent cancers were diagnosed because the patient became symptomatic and sought care from a general practitioner (LOE=2b).²⁵ Beyond initial and age-appropriate cancer screening, there is no evidence that an aggressive search for an underlying malignancy is warranted.

Inherited thrombophilias are associated with an increased risk for venous thromboembolic disease, yet the diagnosis of one of these defects does not substantially change the clinical management of initial or recurrent DVT. Likewise, counseling regarding the increased risk associated with prolonged immobilization, surgery, pregnancy, and exogenous estrogen therapy would be unchanged. A sensible approach may be to screen for hereditary thrombophilias (factor V Leiden, protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, and hyperhomocysteinuria) in the case of recurrent DVT, a younger patient, or a family history of thromboembolic disease. In the event that an inherited thrombophilia is diagnosed, further screening and possible identification of other family members could lead to avoidance of known secondary risk factors and subsequent thromboembolic events. The typical patient with an initial episode of DVT will not benefit from the investigation for an inherited coagulation defect.

Conclusions

The clinical and economic outcomes associated with DVT can be improved with a simple evidence-based approach to therapy Figure 1. Management of a first episode of DVT should begin with immediate anticoagulation with LMWH, preferably at home if there are no contraindications to outpatient management. Oral anticoagulation should be instituted at initial presentation and continued for a period of 3 to 6 months depending on individual risk factors for bleeding. The addition of compression stockings provides symptomatic relief and decreases the incidence of symptomatic postphlebitic syndrome. Extensive evaluation for malignancy or an inherited thrombophilia is not warranted in most cases of DVT.

BACKGROUND: Pentoxifylline and cilostazol are the only 2 prescription drugs labeled for treatment of intermittent claudication. No studies have compared the relative benefit of these agents. The only other therapy demonstrated to be effective is active exercise intervention, usually in the form of a walking program.

POPULATION STUDIED: The investigators enrolled 698 patients with stable moderate to severe symptoms of intermittent claudication and confirmed peripheral vascular disease. These patients had symptoms present for at least 6 months but without substantial change in the last 3 months. All patients had peripheral vascular disease confirmed by either a resting ankle/brachial index of 0.90 or lower and a 10-mm Hg or higher decrease in ankle pressure measured 1 minute after walking to maximal walking distance, or a 20-mm Hg or higher decrease in postexercise ankle pressure in the symptomatic extremity. To qualify for study inclusion, the patients needed a baseline pain-free walking distance between 53.5 meters (1 minute on treadmill protocol) and 537.7 meters (10 minutes). The study subjects were 76% men and had an average age of 66 years. Patients were ineligible who had critical lower extremity ischemia, arterial reconstruction, or sympathectomy within the previous 3 months, as were patients with an exercise capacity limited by conditions other than intermittent claudication. The 3 groups were similar in age, sex, race, smoking status, diabetes, hypercholesterolemia, hypertension, and baseline disease severity.

STUDY DESIGN AND VALIDITY: The study was a double-blind multicenter trial with patients randomized using concealed allocation to receive either cilostazol (100 mg orally twice daily), pentoxifylline (400 mg orally 3 times daily), or placebo for a 24-week period. No specific counseling about diet, smoking cessation, or exercise was offered to the patients during the study period. At baseline and every 4 weeks afterward, study participants underwent evaluation including medical history, physical examination, treadmill testing, Doppler limb pressure measurements, and assessment of adverse events.

OUTCOMES MEASURED: The primary study end point was a comparison of the relative effects of cilostazol and pentoxifylline on walking ability, as measured by maximal walking distance on a standardized treadmill test. Secondary end points included pain-free walking distance and resting Doppler limb pressures. Perception of functional ability and quality of life was measured with the Medical Outcomes Scale Short Form-36 (SF-36) and the Walking Impairment Questionnaire. In addition, physicians and patients were asked for their subjective assessment of benefit at the end of treatment.

RESULTS: Using a treadmill protocol and assessed by intention-to treat analysis, cilostazol increased the maximal walking distance by 54% over baseline (average=107 m), compared with a 30% increase with pentoxifylline (P <.001) and a 34% increase in the placebo group (P <.001). The improvement with pentoxifylline was similar to that in the placebo group (average=65 m). Walking distances progressively increased in all 3 groups and did not plateau within the 24-week study. Side effects including headache, diarrhea, and abnormal stools occurred more commonly in the cilostazol group, yet the withdrawal rate was similar between the 2 active drug treatment groups (16%-19%). Scores on the SF-36 and the Walking Impairment Questionnaire revealed no significant differences in general health perception or patient-reported walking distance. In subjective assessment by patients, 51% of the cilostazol group judged their outcome to be successful compared with 39% in the pentoxifylline group (P=.004) and 34% in the placebo group (P <.001).

BACKGROUND: Pentoxifylline and cilostazol are the only 2 prescription drugs labeled for treatment of intermittent claudication. No studies have compared the relative benefit of these agents. The only other therapy demonstrated to be effective is active exercise intervention, usually in the form of a walking program.

POPULATION STUDIED: The investigators enrolled 698 patients with stable moderate to severe symptoms of intermittent claudication and confirmed peripheral vascular disease. These patients had symptoms present for at least 6 months but without substantial change in the last 3 months. All patients had peripheral vascular disease confirmed by either a resting ankle/brachial index of 0.90 or lower and a 10-mm Hg or higher decrease in ankle pressure measured 1 minute after walking to maximal walking distance, or a 20-mm Hg or higher decrease in postexercise ankle pressure in the symptomatic extremity. To qualify for study inclusion, the patients needed a baseline pain-free walking distance between 53.5 meters (1 minute on treadmill protocol) and 537.7 meters (10 minutes). The study subjects were 76% men and had an average age of 66 years. Patients were ineligible who had critical lower extremity ischemia, arterial reconstruction, or sympathectomy within the previous 3 months, as were patients with an exercise capacity limited by conditions other than intermittent claudication. The 3 groups were similar in age, sex, race, smoking status, diabetes, hypercholesterolemia, hypertension, and baseline disease severity.

STUDY DESIGN AND VALIDITY: The study was a double-blind multicenter trial with patients randomized using concealed allocation to receive either cilostazol (100 mg orally twice daily), pentoxifylline (400 mg orally 3 times daily), or placebo for a 24-week period. No specific counseling about diet, smoking cessation, or exercise was offered to the patients during the study period. At baseline and every 4 weeks afterward, study participants underwent evaluation including medical history, physical examination, treadmill testing, Doppler limb pressure measurements, and assessment of adverse events.

OUTCOMES MEASURED: The primary study end point was a comparison of the relative effects of cilostazol and pentoxifylline on walking ability, as measured by maximal walking distance on a standardized treadmill test. Secondary end points included pain-free walking distance and resting Doppler limb pressures. Perception of functional ability and quality of life was measured with the Medical Outcomes Scale Short Form-36 (SF-36) and the Walking Impairment Questionnaire. In addition, physicians and patients were asked for their subjective assessment of benefit at the end of treatment.

RESULTS: Using a treadmill protocol and assessed by intention-to treat analysis, cilostazol increased the maximal walking distance by 54% over baseline (average=107 m), compared with a 30% increase with pentoxifylline (P <.001) and a 34% increase in the placebo group (P <.001). The improvement with pentoxifylline was similar to that in the placebo group (average=65 m). Walking distances progressively increased in all 3 groups and did not plateau within the 24-week study. Side effects including headache, diarrhea, and abnormal stools occurred more commonly in the cilostazol group, yet the withdrawal rate was similar between the 2 active drug treatment groups (16%-19%). Scores on the SF-36 and the Walking Impairment Questionnaire revealed no significant differences in general health perception or patient-reported walking distance. In subjective assessment by patients, 51% of the cilostazol group judged their outcome to be successful compared with 39% in the pentoxifylline group (P=.004) and 34% in the placebo group (P <.001).

BACKGROUND: Pentoxifylline and cilostazol are the only 2 prescription drugs labeled for treatment of intermittent claudication. No studies have compared the relative benefit of these agents. The only other therapy demonstrated to be effective is active exercise intervention, usually in the form of a walking program.

POPULATION STUDIED: The investigators enrolled 698 patients with stable moderate to severe symptoms of intermittent claudication and confirmed peripheral vascular disease. These patients had symptoms present for at least 6 months but without substantial change in the last 3 months. All patients had peripheral vascular disease confirmed by either a resting ankle/brachial index of 0.90 or lower and a 10-mm Hg or higher decrease in ankle pressure measured 1 minute after walking to maximal walking distance, or a 20-mm Hg or higher decrease in postexercise ankle pressure in the symptomatic extremity. To qualify for study inclusion, the patients needed a baseline pain-free walking distance between 53.5 meters (1 minute on treadmill protocol) and 537.7 meters (10 minutes). The study subjects were 76% men and had an average age of 66 years. Patients were ineligible who had critical lower extremity ischemia, arterial reconstruction, or sympathectomy within the previous 3 months, as were patients with an exercise capacity limited by conditions other than intermittent claudication. The 3 groups were similar in age, sex, race, smoking status, diabetes, hypercholesterolemia, hypertension, and baseline disease severity.

STUDY DESIGN AND VALIDITY: The study was a double-blind multicenter trial with patients randomized using concealed allocation to receive either cilostazol (100 mg orally twice daily), pentoxifylline (400 mg orally 3 times daily), or placebo for a 24-week period. No specific counseling about diet, smoking cessation, or exercise was offered to the patients during the study period. At baseline and every 4 weeks afterward, study participants underwent evaluation including medical history, physical examination, treadmill testing, Doppler limb pressure measurements, and assessment of adverse events.

OUTCOMES MEASURED: The primary study end point was a comparison of the relative effects of cilostazol and pentoxifylline on walking ability, as measured by maximal walking distance on a standardized treadmill test. Secondary end points included pain-free walking distance and resting Doppler limb pressures. Perception of functional ability and quality of life was measured with the Medical Outcomes Scale Short Form-36 (SF-36) and the Walking Impairment Questionnaire. In addition, physicians and patients were asked for their subjective assessment of benefit at the end of treatment.

RESULTS: Using a treadmill protocol and assessed by intention-to treat analysis, cilostazol increased the maximal walking distance by 54% over baseline (average=107 m), compared with a 30% increase with pentoxifylline (P <.001) and a 34% increase in the placebo group (P <.001). The improvement with pentoxifylline was similar to that in the placebo group (average=65 m). Walking distances progressively increased in all 3 groups and did not plateau within the 24-week study. Side effects including headache, diarrhea, and abnormal stools occurred more commonly in the cilostazol group, yet the withdrawal rate was similar between the 2 active drug treatment groups (16%-19%). Scores on the SF-36 and the Walking Impairment Questionnaire revealed no significant differences in general health perception or patient-reported walking distance. In subjective assessment by patients, 51% of the cilostazol group judged their outcome to be successful compared with 39% in the pentoxifylline group (P=.004) and 34% in the placebo group (P <.001).