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Importance Deep vein thrombosis (DVT) isolated to the calf veins (distal to the popliteal vein) is frequently detected with duplex ultrasonography and may result in proximal thrombosis or pulmonary embolism (PE). Objective To evaluate whether therapeutic anticoagulation is associated with a decreased risk for proximal DVT or PE after diagnosis of an isolated calf DVT. Design, Setting, and Participants All adult patients with ultrasonographic detection of an isolated calf DVT from January 1, 2010, to December 31, 2013, at the Vascular Laboratory of the University of California, Davis, Medical Center were included. Patients already receiving therapeutic anticoagulation and those with a chronic calf DVT, a contraindication to anticoagulation, prior venous thromboembolism within 180 days, or diagnosis of a PE suspected at the time of calf DVT diagnosis were excluded. Data were analyzed from August 18, 2015, to February 14, 2016. Exposures Intention to administer therapeutic anticoagulation. Main Outcomes and Measures Proximal DVT or PE within 180 days of the diagnosis of the isolated calf DVT. Results From 14 056 lower-extremity venous duplex studies, we identified 697 patients with an isolated calf DVT and excluded 313 of these. The remaining 384 patients were available for analysis (222 men [57.8%]; 162 women [42.2%]; mean [SD] age, 60 [16] years). The calf DVT involved an axial vein (anterior tibial, posterior tibial, or peroneal) in 243 patients (63.2%) and a muscular branch (soleus or gastrocnemius) in 215 (56.0%). Physicians attempted to administer therapeutic anticoagulation in 243 patients (63.3%), leaving 141 control participants. Proximal DVT occurred in 7 controls (5.0%) and 4 anticoagulation recipients (1.6%); PE, in 6 controls (4.3%) and 4 anticoagulation recipients (1.6%). Therapeutic anticoagulation was associated with a decreased risk for proximal DVT or PE at 180 days (odds ratio [OR], 0.34; 95% CI, 0.14-0.83) but an increased risk for bleeding (OR, 4.35; 95% CI, 1.27-14.9), findings that persisted after adjustment for confounding factors (ORs, 0.33 [95% CI, 0.12-0.87] and 4.87 [95% CI, 1.37-17.3], respectively) and sensitivity analyses. Conclusions and Relevance Rates of proximal DVT or PE are low after isolated calf DVT. Therapeutic anticoagulation is associated with a reduction of these outcomes but an increase in bleeding.

In developing policies for use of expensive agents, such as those used for the treatment of rheumatoid arthritis, managed care organizations have invoked “stepped care,” in which physicians and patients must first try more established and less costly agents. N-of-1 clinical trials are multiple crossover trials in a single patient. In this cost-minimization analysis, we show that offering patients with rheumatoid arthritis the opportunity to participate in an n-of-1 trial comparing methotrexate with etanercept could save costs relative to open access while preserving clinical freedom relative to mandatory stepped care. In the primary model, the n-of-1 trial option was 15% more expensive than stepped care but 47% cheaper than open access to etanercept. More research is needed on the acceptability, safety, and generalizability of this promising approach.

It is unclear how frequently unprovoked venous thromboembolism (VTE) reflects the presence of an occult cancer.The California Cancer Registry was used to identify diagnosed cases of 19 common malignancies during a 6-year period. Cases were linked to a hospital discharge database to identify incident VTE events in the year before the cancer diagnosis date. The standardized incidence ratio (SIR) of unprovoked VTE was determined by using the age-, race-, and sex-specific incidence rates in California.Among 528,693 cancer cases, 596 (0.11%) were associated with a diagnosis of unprovoked VTE within 1 year of the cancer diagnosis, compared with 443.0 expected cases (SIR, 1.3; 95% confidence interval, 1.2-1.5; P.001). Among cases with metastatic-stage cancer, the SIR was 2.3 (95% confidence interval, 2.0-2.6; P.001), whereas for all other stages, the SIR was 1.07 (95% confidence interval, 0.97-1.18; P = .09). The incidence of preceding VTE was increased over that expected only during the 4-month period immediately preceding the cancer diagnosis date (P.001). Only 7 cancer types were associated with a significantly elevated SIR: acute myelogenous leukemia; non-Hodgkin lymphoma; and renal cell, ovarian, pancreatic, stomach, and lung cancer (SIR range, 1.8-4.2).In the year preceding the diagnosis of cancer, the number of cases with unprovoked VTE was modestly higher than expected, and almost all of the unexpected VTE cases were associated with a diagnosis of metastatic-stage cancer within 4 months. Given the timing and advanced stage of the unexpected cases, it is unlikely that earlier diagnosis of these cancers would have significantly improved long-term survival.

Background Montelukast sodium, a potent, oral, specific leukotriene-receptor antagonist, has demonstrated clinical efficacy in the treatment of chronic asthma. Loratadine, a selective histamine type 1 (H 1 )-receptor antagonist, has demonstrated antiallergic properties. Leukotriene-receptor antagonists given concomitantly with H 1 -receptor antagonists have been shown to have additive effects in the prevention of bronchospasm in antigen-challenge models. Objective To determine whether montelukast plus loratadine provides improved efficacy to montelukast alone in the treatment of chronic asthma. Methods The efficacy of montelukast alone vs montelukast-loratadine was studied in a 10-week, multicenter, randomized, double-blind, 2 × 2 crossover study. After a 2-week placebo run-in period, patients received montelukast sodium (10 mg) plus loratadine (20 mg), or montelukast sodium (10 mg) plus placebo once daily for 2 weeks. After a 2-week placebo washout period, patients were crossed over to receive 2 weeks of the other active treatment regimen, followed by another 2-week placebo washout period. Results Montelukast given concomitantly with loratadine caused significant improvement in percentage of change from baseline in forced expiratory volume in 1 second (FEV 1 ) compared with montelukast alone (13.86% vs 9.72%; P = .001). The average additional effect of loratadine (least square mean difference in percentage of change from baseline in FEV 1 ) was 4.15% (95% confidence interval, 1.65%-6.65%). Key secondary end points (mean daily β-agonist use, daytime and nighttime symptom scores, morning and evening peak expiratory flow rate, and the Patient Global Evaluation) all showed significant improvement with montelukast-loratadine ( P Conclusion Montelukast-loratadine significantly improved end points of asthma control during a 2-week treatment period.

Little is known about the incidence and time course of clinical thromboembolic events after total hip or knee arthroplasty, particularly after hospital discharge.We used a linked hospital discharge database provided by the State of California to identify cases diagnosed as having deep vein thrombosis or pulmonary embolism within 3 months of unilateral total hip or knee arthroplasty. Also, we surveyed orthopedic surgeons to estimate the frequency of postoperative thromboprophylaxis during July 1991 through June 1993. Medical charts were audited to determine the accuracy of the coded records.Among 19,586 primary hip and 24,059 primary knee arthroplasties, the cumulative incidence of deep vein thrombosis or pulmonary embolism within 3 months of surgery was 556 (2.8%) after hip arthroplasty and 508 (2.1%) after knee arthroplasty. The diagnosis of thromboembolism was made after hospital discharge in 76% and 47% of the total hip and total knee arthroplasty cases, respectively (P.001), with a median time of diagnosis of 17 days and 7 days after surgery, respectively (P.001). Questionnaire results indicated that 95% of all cases received thromboprophylaxis and that the frequency, type, and duration of thromboprophylaxis was virtually identical after hip and knee arthroplasty.There is a difference in the temporal patterns of clinically symptomatic thromboembolic complications after total hip and total knee arthroplasty, suggesting differences in pathogenesis or natural history. The findings suggest that to further reduce thromboembolic outcomes, earlier, more intense prophylaxis may be needed for total knee arthroplasty, and more prolonged prophylaxis may be required after total hip arthroplasty.

Background: The incidence of explicity defined life-threatening bleeding during warfarin sodium therapy is largely unknown, as are the prognosis for and treatment of patients who have such bleeding. In addition, the location of the source of the life-threatening bleeding and the risk factors associated with life-threatening bleeding are not well-defined. Objectives: To determine the incidence of explicitly defined life-threatening bleeding during warfarin therapy, to identify the site of bleeding, to determine the risk factors for life-threatening bleeding, and to determine the risk of subsequent bleeding among patients receiving warfarin therapy. Methods: A cross-sectional prevalence study was conducted and data were combined with those obtained during prospective observation of a dynamic cohort of patients followed up in 2 university-affiliated and 3 Veterans Administration anticoagulation clinics. Results: For this study, 1999 patients were followed up for 3865 patient-years; 32 patients (11 women, 21 men, mean age of 60 years) met criteria for life-threatening bleeding, an incidence of 0.83 events/100 patient-years (95% confidence interval, 0.54-1.12). The most common indication for warfarin was to prevent thromboembolism because the patient had a mechanical heart valve (17/32 patients, 53%). The gastrointestinal tract was the definite or likely site of bleeding in 21 (66%) of the 32 patients. The prothrombin time ratio was longer than 2.0 or the international normalized ratio was longer than 4.5 in 16 (55%) of the 29 patients in whom a coagulation time was measured. Fourteen (44%) of the 32 patients had a history of peptic ulcer disease or gastrointestinal bleeding. Warfarin was restarted in 26 (81%) of the 32 patients. Twenty-five of 26 patients were followed up for a median of 30 months (range, 5-143 months); 14 (56%) of the 25 patients had a subsequent bleeding event, with 8 (57%) of the 14 having 1 or more additional life-threatening bleeding events (1 fatal) after a median of 11.5 months (range, 0.5-22 months). Conclusions: We conclude that in this cohort: (1) the incidence of life-threatening bleeding was rare, (2) the gastrointestinal tract was the site of bleeding in two thirds of the patients who experienced life-threatening bleeding, (3) most patients who experienced life-threatening bleeding had multiple risk factors for bleeding, including excessive anticoagulation, and (4) the risk of subsequent bleeding was extremely high among the patients who continued to receive warfarin therapy. (Arch Intern Med. 1996;156:1197-1201)

Background: Portable instruments that measure the prothrombin time and automatically calculate the international normalized ratio (INR) with the use of a drop of whole blood have simplified the treatment of patients who are receiving warfarin therapy. The accuracy of these portable monitors has never been determined by comparing INR results with a criterion (gold) standard INR determination. Methods: Duplicate whole-blood INR determinations were made with two commercially available portable INR monitors. Duplicate frozen-plasma samples were measured with four different thromboplastin reagents, each with a different international sensitivity index. The criterion standard INR was determined by using an international reference thromboplastin and the manual tilt-tube technique. Agreement was evaluated by determining how accurately laboratory and monitor INR determinations matched criterion standard values in designating a sample to be within or outside of currently recommended INR target ranges. Results: Two of the laboratory methods, which used relatively sensitive thromboplastins, showed close agreement with the criterion standard, whereas two laboratory methods that used less sensitive thromboplastin reagents showed poor agreement. Both of the portable monitors fell between these extremes. The two best laboratory methods were significantly better (P Conclusions: There is large interlaboratory variation in the accuracy of INR determinations. Laboratory methods that used insensitive (high international sensitivity index) thromboplastins performed poorly. Accuracy of monitor measurements appears satisfactory. (Arch Intern Med. 1995;155:1861-1867)

Expert consultation by means of established practice guidelines has been shown to lead to improved accuracy of inpatient anticoagulation therapy, with a reduction in the frequency of hemorrhagic complications. We evaluated a different strategy to improve the accuracy of in-hospital anticoagulation: pharmacy-based, computer-assisted dosing of intravenous heparin therapy.Patients treated with computer-assisted dosing of heparin (N = 131) were compared with a randomly selected historical cohort (N = 57) in whom heparin therapy was managed by the primary physician. All patients treated by the pharmacy team received a bolus of heparin, 70 U/kg of ideal body weight, except for patients with pulmonary embolism, who received 100 U/kg of ideal body weight. A computer-generated infusion dose was selected (generally 13 to 16 U/kg per hour). The target was an activated partial thromboplastin time (APTT) ratio of 1.8 times the patient's baseline APTT, with a therapeutic range of 1.5 to 2.5 times baseline. Computer-assisted dosage recommendations were generated after each APTT measurement.In the historical control group, 62% of the patients achieved a therapeutic APTT during the first 24 hours; 17% failed to reach a therapeutic level by 48 hours. The median time to reach a therapeutic APTT was 15 hours. Of all 696 APTTs in this group, 42% were below, 43% in, and 15% above the therapeutic range. In the computer-assisted group, 90% achieved a therapeutic APTT within 24 hours (P.001); 97% had a therapeutic APTT by 48 hours (P.01). The median time to achieve a therapeutic APTT was 7 hours (P.001). Of all 880 APTTs in this group, 17% were below, 75% in, and 8% above the therapeutic range (P.001).Pharmacy-based, computer-assisted dosing of heparin is feasible and results in faster and more accurate anticoagulant dosing.

Background. — Office-based anticoagulation monitors offer significant advantages in convenience, yet their performance has been inadequately characterized. Methods.— We characterized the performance of a portable anticoagulation monitoring system with respect to precision and agreement with a reference laboratory. Eighty-five patients from a university outpatient anticoagulation clinic provided 143 whole blood sample pairs for evaluating agreement between the monitor and the laboratory. Fifty-four patients each provided a second pair of samples for assessing the monitor's precision, and 23 pairs of measurements from the reference laboratory were used for assessing the laboratory's precision. Anticoagulation was measured using International Normalized Ratio (INR) values. Agreement between monitor and laboratory was evaluated as the difference between paired measurements. Precision was calculated as the within-patient standard deviation based on paired values. Results.— Within the range of 2.0 to 3.0 INR units, the monitor yielded values that were up to 0.3 units higher on average than the laboratory values. Within the range of greater than 3.0 to 4.5 INR units, the monitor yielded values that were up to 0.5 units lower on average than the laboratory values. Seventy-five percent of paired monitor and laboratory values were within 0.7 INR units; 90% were within 0.9 units. Within-patient standard deviation was 0.23 units for the monitor and 0.19 units for the laboratory. Conclusions.— The monitor differed systematically from the laboratory and was moderately less precise. The magnitude of these effects was not great, however, and accuracy was best at around INR = 3.0, the border between low and high therapeutic ranges. The clinic-based monitor is useful for patients requiring frequent surveillance of anticoagulation status. ( Arch Intern Med . 1992;152:589-592)

Although the gastrointestinal and systemic features of Behcet's syndrome and inflammatory bowel disease overlap to a considerable extent, they are generally viewed as two distinct diseases. We evaluated three members of a family who have inflammatory bowel lesions, two of whom met criteria for Behcet's syndrome. The propositus had classic features of both Crohn's ileocolitis and Behcet's syndrome. A daughter, who never met criteria for Behcet's syndrome, had undergone colectomy for ulcerative colitis. A second daughter had classic features of Behcet's syndrome, including recurrent episodes of colitis with distinct aphthous ulcers in the colon. The findings in this family suggest that inflammatory bowel disease and Behcet's syndrome may be closely related and part of a spectrum of disease rather than distinct disease entities.