Standardized low-molecular-weight heparin bridging regimen in outpatients on oral anticoagulants undergoing invasive procedure or surgery: an inception cohort management study.

BACKGROUND: Bridging therapy with low-molecular-weight heparin is usually recommended in patients who must stop oral anticoagulants before surgical or invasive procedures. To date, there is no universally accepted bridging regimen tailored to the patient's thromboembolic risk. This prospective inception cohort management study was designed to assess the efficacy and safety of an individualized bridging protocol applied to outpatients. METHODS AND RESULTS: Oral anticoagulants were stopped 5 days before the procedure. Low-molecular-weight heparin was started 3 to 4 days before surgery and continued for 6 days after surgery at 70 anti-factor Xa U/kg twice daily in high-thromboembolic-risk patients and prophylactic once-daily doses in moderate- to low-risk patients. Oral anticoagulation was resumed the day after the procedure with a boost dose of 50% for 2 days and maintenance doses afterward. The patients were followed up for 30 days. Of the 1262 patients included in the study (only 15% had mechanical valves), 295 (23.4%) were high-thromboembolic-risk patients and 967 (76.6%) were moderate- to low-risk patients. In the intention-to-treat analysis, there were 5 thromboembolic events (0.4%; 95% confidence interval, 0.1 to 0.9), all in high-thromboembolic-risk patients. There were 15 major (1.2%; 95% confidence interval, 0.7 to 2.0) and 53 minor (4.2%; 95% confidence interval, 3.2 to 5.5) bleeding episodes. Major bleeding was associated with twice-daily low-molecular-weight heparin administration (high-risk patients) but not with the bleeding risk of the procedure. CONCLUSIONS: This management bridging protocol, tailored to patients' thromboembolic risk, appears to be feasible, effective, and safe for many patients, but safety in patients with mechanical prosthetic valves has not been conclusively established.

Poor anticoagulation quality in the first 3 months after unprovoked venous thromboembolism is a risk factor for long-term recurrence.

BACKGROUND AND AIM: Several factors are associated with an increased risk of recurrent venous thromboembolism (VTE). The aim of the study was to investigate whether the quality of oral anticoagulation therapy (OAT) is a long-term risk factor for recurrence of VTE after OAT interruption. METHODS AND RESULTS: A total of 297 patients (170 males) with a recent acute unprovoked VTE episode were prospectively monitored during OAT in our anticoagulation clinic and followed up for 21 months after OAT interruption. Recurrent events were recorded in 42 subjects for 493 years of follow-up [14.1% of patients; 8.5% patient-years (pt-y)] after OAT withdrawal. The rate of recurrence was not correlated to OAT duration. Subjects experiencing recurrence after OAT interruption had spent significantly more time at markedly subtherapeutic international normalized ratio (INR) levels (<1.5) and less time within the therapeutic range (2.0-3.0 INR) during OAT. Relative risk (RR) of recurrence was significantly higher [2.77 (95% confidence interval (CI) 1.49-5.18; P = 0.001) and 2.70 (95% CI 1.39-5.25; P = 0.003) at univariate and multivariate analysis, respectively] in those who spent more time (upper quintile) at INR values <1.5, being especially evident in the first 90 days of OAT. RR was significantly higher at univariate [2.05 (95% CI 1.07-3.96; P = 0.031)] but not at multivariate [1.98 (95% CI 0.98-4.0; P = 0.056)] analysis when the entire OAT period was considered. Subjects in the upper quintile of time spent at INR values <1.5 had significantly higher D-dimer values when OAT was stopped and after 3 months. CONCLUSIONS: The amount of time that subjects with an acute unprovoked VTE event spend at near-normal INR values (<1.5) during the first 3 months of treatment is associated with higher D-dimer values measured during OAT and after its interruption and is a significant risk factor for late VTE recurrence.

Oral anticoagulation treatment in the elderly: a nested, prospective, case-control study.

BACKGROUND: Whether elderly patients are at increased risk of complications during oral anticoagulant treatment (OAT) is still a matter of debate. METHOD: Bleeding and thrombotic events occurring during OAT in 461 patients, aged 75 years or older when they started OAT, and in 461 patients younger than 70 years, matched for sex, OAT indication, and treating center, were examined in a prospective, multicenter, inception-cohort study. RESULTS: Bleeding rate was 9.9% and 6.6% patient-years in elderly and young patients, respectively (P = .07), and 2.1% and 1.1% for major bleeding (P = .19); 6 and 1 events, respectively, were fatal (all intracranial, relative risk, 6.4; P = .05). In the elderly, bleeding rate was lower (4.5%) for international normalized ratios (INRs) between 2.0 and 2.9; it was higher during the first 90 treatment days (P = .05) and when arterial vascular disease was the indication for OAT (P = .03). Thrombosis rate was 4.2% and 2.5% patient-years in elderly and young patients, respectively (P = .10); however, 13 and 5 events were fatal (relative risk, 2.8; P = .04). Thrombosis rate was lower (1.5%) for INRs between 2.0 and 2.9; it was higher during the first 90 treatment days (P<.001) and 6 of 7 venous events occurred at lower than 2.0 INRs. CONCLUSIONS: A nonsignificant trend was noted toward a higher rate of both bleeding and thrombotic complications in elderly vs matched younger patients. Intracranial bleeding and fatal thrombotic events were significantly more frequent in the elderly. Our results also indicate that lower than 2.0 INRs do not preclude bleeding in the elderly nor offer adequate protection from thrombotic events. Moderate anticoagulation (2.0-3.0 INRs) in elderly patients seems the safest and most effective.

Incidence of cancer after a first episode of idiopathic venous thromboembolism treated with 3 months or 1 year of oral anticoagulation.

BACKGROUND: A prolonged treatment with oral anticoagulants has been claimed to reduce the incidence of newly diagnosed cancer in the long-term follow-up of patients with venous thromboembolism. OBJECTIVES: In a multicenter prospective study we assessed the incidence of newly diagnosed clinically overt cancer in patients with a first episode of idiopathic venous thromboembolism (VTE) treated with oral anticoagulants for 3 months or 1 year. PATIENTS AND METHODS: Consecutive patients with an idiopathic venous thromboembolism who had completed 3 months of oral anticoagulant therapy without having a recurrence, bleeding or newly diagnosed cancer were randomized to discontinue oral anticoagulant therapy or to continue it for nine additional months. Idiopathic venous thromboembolism was defined as thrombosis occurring in the absence of known cancer, known thrombophilia, or temporary risk factors for venous thromboembolism. All patients were followed up for at least 1 year after randomization. RESULTS: A total of 429 patients, 265 patients with DVT and 164 with PE, were followed up for an average of 43.7 months after randomization. A newly diagnosed cancer occurred in 32 patients (7.5%), 13 (6.2%) of the 210 patients treated for 3 months and 19 (8.7%) of the 219 patients treated for 1 year (RR = 0.71, 95% confidence interval 0.36-1.41). CONCLUSIONS: The incidence of newly diagnosed clinically overt cancer is not reduced in patients with idiopathic venous thromboembolism treated with 1-year anticoagulant treatment compared with patients treated for 3 months.

Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study.

The occurrence of a "rebound hypercoagulable state" in patients after dicontinuation of oral anticoagulants is still a matter of debate and no definite recommendation can be made on the best procedure for anticoagulant withdrawal. The present study investigated the changes in the levels of markers of activated blood coagulation in 32 patients (pts) in whom warfarin treatment (for venous thromboembolic disease) was randomly withdrawn abruptly (n = 17, group A) or gradually (n = 15, group B: 2/3 of initial dose the 1st week, 1/3 the 2nd weeks and nothing from the 3rd week on). Blood was sampled at baseline, once a week for the first three weeks and after 2 months. At the 1st week group A had significantly higher F1+2 and TAT values (p < 0.001); at the 2nd week F1+2 levels remained higher (p < 0.05) though INR values were not different from those of group B. After baseline, higher than normal F1+2 levels were recorded in 32/66 (48%) controls in group A vs 15/60 (25%) in group B (p < 0.01); at the 2nd week, 10/17 (59%) patients in group A vs 1/15 (7%) in group B still had higher than normal F1+2 levels (p < 0.01). The values of areas under curve (AUC) and maximum concentrations of all variables were not statistically different in the two groups; however, very high levels were observed in a few cases of group A. Thrombotic events (one DVT recurrence and one thrombophlebitis in a varicose vein) occurred in 2 pts of group A, both with high F1+2 and TAT AUC values.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of activated partial thromboplastin time and factor IX in subjects attending an anticoagulation clinic.

Very low factor IX (FIX) levels in patients during oral anticoagulant (OA) treatment, due to mutations in the FIX gene, with prolonged activated partial thromboplastin time (aPTT) and associated with bleeding complications have recently been described. We measured aPTT in 595 OA patients while being within therapeutic ranges. Patients were divided into increasing international normalized ratio (INR) classes, and FIX determined in those belonging to the first and fifth quintiles of the aPTT distribution in each INR class. Results obtained in patients of all the first aPTT quintiles were compared with those of all the fifth quintiles. While INR was not different (2.79 versus 2.77 INR), aPTT was longer (1.65 versus 1.21 ratio; P < 0.0001) and FIX lower (0.29 versus 0.44 IU/ml; P < 0.0001) in patients of the fifth quintiles. Only one patient had a markedly reduced FIX (0.03 IU/ml). Bleeding rate was 4.8 and 6.2% patient-years (not significant) in patients of the first and fifth quintiles, respectively. We therefore found that FIX levels vary greatly in spite of similar achieved anticoagulation intensity; very low FIX is, however, a rare condition. In conclusion, screening for the recently identified mutations in FIX gene does not seem justified, and identifying patients with disproportionately prolonged aPTT, to detect those with particularly low FIX levels, is difficult because of the effect of the achieved anticoagulation intensity. Therefore, aPTT measurement is indicated only in patients with increased bleeding during OA.

Assessment of mental ability in elderly anticoagulated patients: its reduction is associated with a less satisfactory quality of treatment.

Mental capacity was assessed in 311 apparently self-sufficient patients (> or = 60 years of age, 170 men) under stabilised oral anticoagulant treatment (OAT) by administering the Hodkinson's Abbreviated Mental Test (AMT). The international normalized ratios (INR) recorded during the 3 months before and the 3 after the data of test administration were examined by the INR-Day software program. The percentage of time spent within, below or above the intended therapeutic range was calculated in patients who scored abnormally at AMT, and compared with matched controls with normal AMT results. Forty patients [12.9%; 28 women (19.8%) and 12 men (7.1%), P < 0.0011] had abnormal AMT results; the rate seemed to increase with age. Most of these patients (35, 75%) had only elementary education. Patients with abnormal AMT results spent more time outside the intended therapeutic ranges than 40 matched controls (20.9% of the observed time vs 13.7%, P < 0.0001; odds ratio 1.68, CI 1.53-1.84). Unsuspected reduction of mental ability or attention levels was found in a number of elderly patients receiving OAT; these patients presented longer periods of either under- or over-anticoagulation and were, therefore, exposed to a higher risk of thrombotic or bleeding complications. Anticoagulation clinics would be advised to assess mental abilities in elderly patients before starting OAT.

Contribution of a new, rapid, quantitative and automated method for D-dimer measurement to exclude deep vein thrombosis in symptomatic outpatients.

Ninety-nine consecutive outpatients with symptoms suggestive of deep vein thrombosis (DVT) were tested for the presence of D-dimer using a new, rapid method (BC D-Dimer) based on the agglutination principle and performed on a BCT analyzer. Dimertest Gold EIA and VIDAS D-Dimer devices were used as comparative methods. Venography was performed in all patients, with DVT diagnosed in 39 of them (34 proximal). The BC D-Dimer test proved to be rapid, automated and well suited for individual tests with a good reproducibility (coefficient of variation % 1.5-5.3). Its performance was comparable with that of the other methods, as indicated by the areas under the receiver operating characteristic curves (Gold EIA 0.95; VIDAS 0.95; BC D-Dimer 0.91) and the coefficients of correlation (Pearson's coefficients from 0.832 to 0.876). On the basis of the Kappa coefficients, there was quite a good concordance between the three tests. At the cut-off levels that provided the highest sensitivity (97.4%, for all the tests), the negative predictive values were similar for all methods, at over 95%. The corresponding specificity ranged from 62.7 to 81.7%. In conclusion, this study shows that the new method can be included in prospective clinical trials to test the utility of D-dimer measurement in combination with other non-invasive diagnostic procedures in the management of the diagnosis of DVT.

Comparison of new rapid methods for D-dimer measurement to exclude deep vein thrombosis in symptomatic outpatients.

Eighty-seven outpatients consecutively admitted to the emergency unit of our hospital with clinically suspected first deep vein thrombosis (DVT) of a leg had D-dimer levels measured by the following recently introduced fast methods: VIDAS (bioMerieux), LPIA (Mitsubishi), Nephelotex (Biopool), Nycocard (Nycomed) and Instant.I.A. (Diagnostica Stago). A latex agglutination test (Minutex, Biopool) was also performed and a classical ELISA (Gold EIA, Agen) used as reference. Venography was performed in all patients, with DVT diagnosed in 42 (37 proximal). All the new methods can be adopted in emergency situations, since they are suited for individual tests, are rapid and the reagents ready to use. All the methods proved to have a good interassay reproducibility. The new D-dimer and latex agglutination tests showed negative (88-96%) and positive (63-81%) predictive values similar to those of ELISA (92% and 71%, respectively), though the still wide confidence intervals suggest larger patient population series be investigated. As regards clinical application, the use of these tests to rule out DVT should be tested in prospective clinical follow-up trials where anticoagulation is withheld in subjects with negative non-invasive reliable vascular tests and normal D-dimer levels.

Pharmacodynamic effects on blood coagulation of a new low molecular weight heparin (alfa-LMWH) in healthy volunteers and gynecological surgery patients.

The pharmacodynamic properties of a new LMWH (alfa-LMWH) were investigated in 8 healthy volunteers after single subcutaneous administrations of 7,500, 15,000 and 30,000 anti-XaU doses at weekly intervals. Anti-Xa and anti-IIa heparin activities were monitored together with aPTT, thrombin time, bleeding time and euglobulin lysis time. No relevant changes in bleeding time or major side-effects were ever recorded. A group of 26 patients submitted to gynaecological surgery were then investigated to determine the dosage schedule for prophylaxis of post-operative deep vein thrombosis. Two subgroups received daily subcutaneous doses of 7,500 and 15,000 anti-XaU alfa-LMWH respectively, beginning 2 h before surgery; the third subgroup received 5,000 IU calcium heparin three times daily over the seven postoperative days. The following tests were peri-operatively monitored: anti-Xa heparin activity, aPTT, PT, fibrinogen, Antithrombin III. No differences in intra-operative bleeding or side-effects were recorded. On the basis of the levels of anti-Xa heparin activity and the negligible effects on aPTT, the dose of 7500 anti-XaU was selected at single daily administration for thromboprophylaxis in gynecological surgery.

[Deep venous thrombosis. Evaluation of a non-invasive diagnostic procedure based on compression ultrasonography and measurement of D-dimer plasma levels]. / Trombosi venosa profonda. Validazione di una procedura diagnostica non invasiva basata su ultrasonografia con compressione associata a dosaggio dei D-dimeri plasmatici.

BACKGROUND: Clinical diagnosis of deep venous thrombosis (DVT) of the leg is unreliable. An accurate diagnosis is important for therapeutic decision since anticoagulant treatment, though potentially dangerous, is useless in case of a false positive diagnosis, whereas a false negative diagnosis may lead to withdrawal of an extremely necessary anticoagulation. Contrast venography is still recognized as the gold standard method for the diagnosis of DVT, but in recent years a variety of accurate non-invasive methods has been developed. The ultrasound compression sonography (CUS) is considered a simple non invasive test highly sensitive and specific for proximal DVT in symptomatic outpatients, though non adequately sensitive and specific for isolated calf DVT. Plasma D-dimer levels (DD, fibrin degradation products) have a high negative predictive value for DVT. The aim of this study, performed in outpatients with suspected leg DVT, was to validate, versus venography, a non-invasive, easy to perform and fast diagnostic procedure based on a combination of CUS and D-dimer test. End points of the procedure were: confirmation or exclusion of proximal DVT; suspicion of isolated calf DVT in which case the test would be repeated in a few days to detect any possible proximalization of thrombosis. MATERIALS AND METHODS: Sixty-eight consecutive outpatients, 37 male, with clinically suspected first episode of leg DVT were eligible and examined with CUS, DD test and venography. RESULTS: The results showed that the diagnostic procedure under examination has a high sensibility and specificity for DVT. CONCLUSIONS: It can thus be recommended as routine diagnostic procedure in symptomatic outpatients with suspected DVT reserving venography special cases only.

D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. The Multicentre Italian D-dimer Ultrasound Study Investigators Group.

OBJECTIVE: To investigate the efficacy of using a rapid plasma D-dimer test as an adjunct to compression ultrasound for diagnosing clinically suspected deep vein thrombosis. DESIGN: D-dimer concentrations were determined in all patients with a normal ultrasonogram at presentation. Repeat ultrasonography was performed 1 week later only in patients with abnormal D-dimer test results. MAIN OUTCOME AND MEASURES: Patients with normal ultrasonograms were not treated with anticoagulants and were followed for 3 months for thromboembolic complications. SETTING: University research and affiliated centres. SUBJECTS: 946 patients with clinically suspected deep vein thrombosis. RESULTS: Ultrasonograms were abnormal at presentation in 260 (27.5%) patients. Of the remaining 686 patients tested for D-dimer, 88 (12.8%) had abnormal concentrations. During follow up venous thromboembolic complications occurred in one of the 598 patients who were not treated with anticoagulants and who had an initial normal ultrasonogram and D-dimer concentration, whereas thromboembolic complications occurred in two of the 83 untreated patients who had abnormal D-dimer concentrations but a normal repeat ultrasonogram. The cumulative incidence of venous thromboembolic complications during follow up was 0.4% (95% confidence interval 0% to 0.9%). The rapid plasma D-dimer test used as an adjunct to compression ultrasonography resulted in a reduction in the mean number of repeat ultrasound examinations and additional hospital visits from 0.7 to 0.1 per patient. CONCLUSIONS: Testing for D-dimer as an adjunct to a normal baseline ultrasound examination decreased the number of subsequent ultrasound examinations considerably without any increased risk of venous thromboembolic complications in patients not receiving anticoagulants. The use of ultrasound and testing for D-dimer enabled treatment decisions to be made at the time of presentation in most patients.

The Wells rule and D-dimer for the diagnosis of isolated distal deep vein thrombosis.

BACKGROUND: Pretest clinical probability with the Wells rule and D-dimer have been widely investigated for the diagnosis of symptomatic proximal deep vein thrombosis (DVT) of the lower limbs, but they have not been formally tested for symptomatic isolated distal DVT diagnosis. OBJECTIVE: To evaluate the diagnostic accuracy of the Wells rule and D-dimer for isolated distal DVT. DESIGN, SETTING, AND PATIENTS: This was a single-center, cross-sectional study including 873 consecutive outpatients with suspected DVT, in whom pretest clinical probability determination, D-dimer determination (STA Liatest; cut-off of < 500 ng mL(-1) ) and complete compression ultrasonography of both lower limbs were performed. RESULTS: The isolated distal DVT prevalence was 12.4% (90/725). The sensitivity of the Wells rule for isolated distal DVT was 47% (95% confidence interval [CI] 36-57%), the specificity was 74% (95% CI 70-77%), and the negative and positive predictive values were 91% (95% CI 88-93%) and 20% (95% CI 15-26%), respectively. Patients with isolated distal DVT had higher D-dimer levels than patients without DVT (1759 ± 1576 vs. 862 ± 1079 ng mL(-1) , P = 0.0001). D-dimer was negative in 13 patients with isolated distal DVT. D-dimer sensitivity and specificity for isolated distal DVT were 84% (95% CI 75-91%) and 50% (95% CI 46-54%), respectively, with a negative predictive value of 96% (95% CI 93-98%). In patients with low pretest clinical probability, the D-dimer negative predictive value was 99% (95% CI 95-100%). CONCLUSION: In clinically suspected DVT with negative proximal compression ultrasonography, pretest clinical probability with the Wells rule has a low diagnostic accuracy for isolated distal DVT. D-dimer has a better negative predictive value, but alone it does not exclude isolated distal DVT. In patients with low pretest clinical probability, D-dimer had a negative predictive value of > 95% for isolated distal DVT.

D-dimer and residual vein obstruction as risk factors for recurrence during and after anticoagulation withdrawal in patients with a first episode of provoked deep-vein thrombosis.

D-dimer and residual venous obstruction (RVO) have been separately shown to be risk factors for recurrent venous thromboembolism (VTE) after a first episode of unprovoked proximal deep-vein thrombosis (DVT). It was the objective of this study to assess the predictive value of D-dimer and residual vein obstruction (RVO), alone and in combination, for recurrence after provoked DVT of the lower limbs. A total of 296 consecutive patients with a first episode of symptomatic provoked proximal DVT were evaluated at a university hospital in Bologna, Italy. On the day of anticoagulation withdrawal (T0), RVO was determined by compression ultrasonography. D-dimer levels (cut-off: 500 ng/ml) were measured at T0 and after 30 ±10 days (T1). The main outcome was recurrent VTE during a two-year follow-up. D-dimer was abnormal in 11.6% (32/276) and 31% (85/276) of subjects at T0 and at T1, respectively. RVO was present in 44.8% (132/294) of patients. Recurrence rate was 5.1% (15/296; 95% confidence interval [CI]: 3-8%; 3% patient-years; 95% CI: 2-5 %). An abnormal D-dimer either at T0 or at T1 was associated with an adjusted hazard ratio (HR) for recurrence of 4.2 (95% CI:1.2-14.2; p=0.02) and 3.8 (95%CI: 1.2-12.1; p=0.02), respectively, when compared with normal D-dimer. The HR for recurrence associated with RVO was not significant, and RVO did not increase the recurrence risk associated with an abnormal D-dimer either at T0 or T1. In conclusion, an abnormal D-dimer during vitamin K antagonist (VKA) treatment or at one month after VKA withdrawal is a risk factor for recurrence in patients with provoked DVT, while RVO at the time of anticoagulation withdrawal is not.

Venous thromboembolism in young women; role of thrombophilic mutations and oral contraceptive use.

AIMS: The interaction between the R506Q mutation of factor V and the G20210A mutation of prothrombin with oral contraceptives on venous thromboembolism was evaluated. METHODS AND RESULTS: Three hundred and one women of reproductive age who had venous thromboembolism (140 while using oral contraceptives) and 650 healthy women (173 on oral contraceptives at presentation) were examined. Of the patients, 19.3% were carriers of R506Q (two homozygotes) and 9.6% were heterozygous carriers of G20210A; eight patients (2.7%) were heterozygous for both mutations. Among controls, 2.9% were carriers of R506Q, 3.1% of G20210A, while one case was a heterozygous carrier of both mutations. The relative risk (odds ratio) associated with carriership of R506Q or G20210A mutations was 10.3 and 4.7, respectively; it was 45.6 in carriers of both mutations. The odds ratio of using oral contraceptives in the absence of both mutations was 2.4. The odds ratios according to oral contraceptives use and the presence of R506Q or G20210A or both mutations were 41.0, 58.6 and 86.5, respectively. While the odds ratio for R506Q remains elevated (8.9) in non-oral contraceptive users, the odds ratio for G20210A was 2.0 and did not reach statistical significance. CONCLUSIONS: Our data showed a strong interaction between oral contraceptive use and the presence of either R506Q or G20210A mutations. In non-oral contraceptive users the risk of venous thromboembolism was significantly increased in carriers of R506Q but not in those with the G20210A mutation.