Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians.

Recommendations Recommendation 1: Low-molecular-weight heparin (LMWH) rather than unfractionated heparin should be used whenever possible for the initial inpatient treatment of deep venous thrombosis (DVT). Either unfractionated heparin or LMWH is appropriate for the initial treatment of pulmonary embolism. Consistent evidence demonstrates that LMWH is superior to unfractionated heparin for the initial treatment of DVT, particularly for reducing mortality and reducing the risk for major bleeding during initial therapy. Additional trials are needed to more rigorously examine the efficacy of LMWH for the initial treatment of pulmonary embolism, but systematic reviews of existing trials indicate that LMWH is at least as effective as unfractionated heparin for these patients as well. In addition, trials of unfractionated heparin in pulmonary embolism show that many patients are subtherapeutic or supratherapeutic while receiving unfractionated heparin, whereas LMWH is quickly and consistently therapeutic, an important consideration in the treatment of VTE. Recommendation 2: Outpatient treatment of DVT, and possibly pulmonary embolism, with LMWH is safe and cost-effective for carefully selected patients and should be considered if the required support services are in place. In trials that compared inpatient and outpatient treatment, the rates of recurrent DVT, major bleeding, and death during follow-up differed only slightly. These studies were conducted among highly selected groups of patients and in clinical systems with the required support services in place. Several studies allowed a brief inpatient admission for stabilization of the patients before randomization to the outpatient group. While some studies enrolled patients with concomitant pulmonary embolism, most excluded such patients. Inclusion criteria were strict: Most studies excluded patients with previous VTE, thrombophilic conditions, or significant comorbid illnesses; pregnant patients; and those unlikely to adhere to outpatient therapy. Therefore, this recommendation cannot be generalized (1). Recommendation 3: Compression stockings should be used routinely to prevent postthrombotic syndrome, beginning within 1 month of diagnosis of proximal DVT and continuing for a minimum of 1 year after diagnosis. The evidence demonstrated a marked reduction in the incidence and severity of postthrombotic syndrome among patients wearing compression stockings, either over-the-counter stockings or custom-fit stockings, if use was initiated within 1 month diagnosis of proximal DVT. Most diagnoses of postthrombotic syndrome occurred early, within the first 2 years after DVT. Recommendation 4: There is insufficient evidence to make specific recommendations for types of anticoagulation management of VTE in pregnant women. During pregnancy, women have a 5-fold increased risk for VTE compared with nonpregnant women. Clinicians should avoid vitamin K antagonists in pregnant women because these drugs cross the placenta and are associated with embryopathy between 6 and 12 weeks' gestation, as well as fetal bleeding (including intracranial hemorrhage) at delivery. Neither LMWH nor unfractionated heparin crosses the placenta, and neither is associated with embryopathy or fetal bleeding. Recommendation 5: Anticoagulation should be maintained for 3 to 6 months for VTE secondary to transient risk factors and for more than 12 months for recurrent VTE. While the appropriate duration of anticoagulation for idiopathic or recurrent VTE is not definitively known, there is evidence of substantial benefit for extended-duration therapy. For VTE secondary to transient risk factors, 3 or 6 months of treatment was associated with similar risks for recurrent VTE. In the single study that exclusively enrolled patients presenting with a second episode of VTE, extended-duration (>12 months or indefinite) anticoagulant therapy was associated with fewer recurrences than was termination after 6 months of therapy. For patients with idiopathic VTE (including those with recurrent VTE), extended-duration therapy decreased the relative risk for recurrence by 64% to 95%. Length of therapy in the trials varied widely, from greater than 3 months to 12 months to up to 4 years. The results for extended-duration therapy reflect follow-up only to 4 years; the riskbenefit ratio is not known for longer durations. Clinicians should weigh the benefits, harms, and patient preferences in deciding on the duration of anticoagulation. Recommendation 6: LMWH is safe and efficacious for the long-term treatment of VTE in selected patients (and may be preferable for patients with cancer). Evidence from high-quality randomized trials supports the use of LMWH as comparable to oral anticoagulation for VTE in selected patients. Low-molecular-weight heparin may be a useful treatment for patients in whom control of the international normalized ratio (INR) is difficult and may be more efficacious than oral anticoagulants in patients with cancer. Background Deep venous thrombosis in the lower extremities is the most frequent manifestation of VTE, and the most life-threatening manifestation is pulmonary embolism. An important complication of DVT is postthrombotic syndrome, which may result in lifelong limb pain and edema (2). Venous thromboembolism recurs in about 20% of patients after 5 years of observation, but this rate varies greatly depending on the presence of risk factors for recurrence (2, 3). The intent of this guideline is to provide evidence-based recommendations for management of VTE. The target audience is all clinicians caring for patients who have received a diagnosis of DVT or pulmonary embolism. The target patient population is patients who have been given a diagnosis of pulmonary embolism or lower-extremity DVT. Methods The American Academy of Family Physicians (AAFP) nominated this topic to the Agency for Healthcare Research and Quality Evidence-Based Practice Centers (EPC) program, and the American College of Physicians (ACP) supported the nomination. Recommendations are based on evidence from only high-quality randomized trials unless otherwise stated. This is the second of 2 joint guidelines by the ACP and the AAFP covering the diagnosis and management of VTE. The intent of this guideline is to provide evidence-based recommendations for management of VTE. Diagnosis of VTE is the other guideline and is covered in a paper by Qaseem and colleagues (4). The guideline is based on a systematic review of the evidence, as detailed in a comprehensive evidence report published in 2003 (5); that review has been updated in the accompanying background paper in this issue (30) by members of the Johns Hopkins University Evidence-based Practice Center who prepared the original report. Those papers contain substantial additional detail about the evidence for each recommendation in this guideline. The AAFP and the ACP formulated the following questions relevant to the management of VTE. The EPC authors reviewed the evidence that was available to answer each question. This evidence is summarized below. Evidence Summary Is Heparin or LMWH Safer and More Efficacious for Initial Treatment of VTE? Is It Cost-Effective or Cost-Saving to Use LMWH rather than Unfractionated Heparin for the Initial Treatment of VTE? The EPC authors found 16 systematic reviews of randomized trials that reviewed rates of recurrent venous thromboembolism, major bleeding, or death (513). Of the 11 reviews that pooled the trial results, none demonstrated that unfractionated heparin was superior to LMWH in preventing recurrent DVT. Patients treated with LMWH had significantly fewer episodes of bleeding than those treated with unfractionated heparin. Nine of 10 reviews showed that LMWH significantly reduced mortality during the 3 to 6 months of follow-up compared with unfractionated heparin (14). Only 4 systematic reviews reported summary results separately for patients with pulmonary embolism, concluding that LMWH was as effective as unfractionated heparin in these patients (9, 11, 14, 15). In addition, heparin-induced thrombocytopenia is a possibility with both therapies, although LMWH is less likely to cause antibody formation for this condition. In summary, the evidence suggests that LMWH is superior to unfractionated heparin for treating DVT of the lower extremities, particularly for reducing mortality and the risk for major bleeding during initial therapy. It is at least as safe and effective as unfractionated heparin for patients with pulmonary embolism. For the initial treatment of VTE, LMWH is either cost-saving or cost-effective compared with unfractionated heparin. Is Outpatient Treatment of VTE Safe and Effective Compared with Inpatient Treatment? Twelve studies compared the outcomes of patients with VTE treated with LMWH administered at home to the outcomes of those treated with unfractionated heparin in the hospital (9, 10, 1624). Three of these were randomized trials (1618); the other 9 were cohort studies. An additional 5 studies, including 2 randomized trials (25, 26) compared outcomes and costs for patients receiving LMWH at home to those for patients receiving LWMH in the hospital (2529). Seven of the studies allowed a brief inpatient admission for stabilization of the patients before randomization to the outpatient group. Four of these studies enrolled patients with concomitant pulmonary embolism (21, 24, 27, 29). Inclusion criteria were strict: Most studies excluded patients with previous VTE, thrombophilic conditions, or significant comorbid illnesses; pregnant patients; and patients unlikely to adhere to outpatient therapy. Very few studies reported on the adequacy of anticoagulation in the unfractionated heparin groups or after transition from heparin to warfarin. All the studies were carried out in settings with well-developed patient education and home care support infrastructures. The rates of recurrent DVT in the different treatmen