Antonio Marchiori

Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome.

Summary.  Background: About 30% of patients with an episode of adequately treated deep venous thrombosis (DVT) develop the postthrombotic syndrome (PTS) within 2 years. During treatment with vitamin K antagonists (VKA) patients spend only 60% of time between an International Normalized Ratio (INR) of 2.0 and 3.0. We hypothesized that patients who spend a large amount of their time beneath this range will have an increased risk of the PTS. Objective: To investigate the relation between the quality of anticoagulant therapy with VKA and the risk of the development of the PTS. Methods: The time spent beneath the therapeutic range was calculated for patients with a first episode of DVT, who were treated with VKA for at least 3 months. At follow‐up assessments for a maximum of 5 years, presence and severity of signs and symptoms of PTS were recorded. Results: A total of 244 patients, with a median duration of follow‐up of 4.9 years were included for analysis. Of these, 81 patients (33%) developed the PTS. The multivariate model showed that patients who spend more than 50% of their time beneath an INR level of 2.0 are at higher risk for PTS [odds ratio (OR): 2.71, 95% CI: 1.44–5.10]. Conclusions: Low quality treatment with VKA, which is a common condition, is related to the occurrence of the PTS in patients with DVT. Strategies aimed at improving the quality of long‐term anticoagulation might have the potential to reduce the incidence of this complication.

Incidence of arterial cardiovascular events in patients with idiopathic venous thromboembolism. A retrospective cohort study.

Recent data have shown a higher incidence of arterial events in patients with venous thromboembolism (VTE) of unknown origin than in those with the secondary form of disease. Whether patients with idiopathic VTE have a higher risk of subsequent arterial events than the general population is unknown. The aim was to evaluate the rates of subsequent arterial events in patients with idiopathic VTE and control subjects. In a retrospective cohort study we compared the rates of subsequent arterial events (i.e. acute myocardial infarction, ischemic stroke and peripheral arterial disease) in 151 consecutive patients with objectively confirmed spontaneous VTE and 151 control subjects randomly selected from the database of two family physicians. We collected information about cardiovascular risk-factors (hypertension, hypercholesterolemia, diabetes, obesity and smoke) at the time of VTE episode, or corresponding date for the controls, and considered the follow-up from this time. Patients and controls who had suffered from arterial events before the index date were excluded. During a mean follow-up of 43.1 (+/- 21.7) months there were 16 arterial events in the VTE patients and six in the control group (HR, 2.84;95% CI,1.11 to 7.27; p = 0.03). The difference remained significant after adjusting for age and other cardiovascular risk factors (HR 2.86;95% CI,1.07 to 7.62). Overall mortality was also higher in the VTE patients (12 vs.4 deaths). In conclusion, arterial events are more common in patients with previous idiopathic VTE than in the general population. These findings may have practical implications.

Risk stratification and outcomes in hemodynamically stable patients with acute pulmonary embolism: a prospective, multicentre, cohort study with three months of follow-up

Summary.  Background: The role of risk stratification in normotensive patients with acute pulmonary embolism (PE) is still unclear. Objectives: We evaluated, in these patients, the usefulness of six prognostic markers for predicting in‐hospital adverse events related to PE and 3‐month mortality. Patients/Methods: Two hundred and one consecutive patients with confirmed acute PE and normal blood pressure, who were administered conventional anticoagulation, were recruited in a multicentre prospective cohort study with 3 months of follow‐up. At baseline, they received a comprehensive risk‐evaluation including echocardiographic assessment of right ventricular dysfunction, determination of troponin I, brain natriuretic peptide and D‐dimer, arterial blood gas analysis and a clinical score. Primary outcome of the study was PE‐related in‐hospital death or clinical deterioration. Secondary outcomes were in‐hospital and 3‐month all‐cause mortality. Results: The primary outcome occurred in one patient (0.5%), who died from PE during hospitalization. The in‐hospital and 3‐month all‐cause mortality were 2% and 9%, respectively. None of the prognostic markers was predictive of the primary outcome. Clinical score, troponin I and hypoxemia predicted in‐hospital all‐cause mortality (P = 0.02, 0.01 and < 0.01, respectively). Clinical score (HR, 4.7; 95% CI, 1.9–12.0), D‐dimer (4.8; 1.4–16.3), hypoxemia (5.7; 2.1–15.1) and troponin I (7.5; 2.5–22.7) were predictors of 3‐month all‐cause mortality on univariate analysis. On multivariate analysis clinical score and troponin I remained independently predictive. Conclusions: We did not find prognostic markers useful as predictors of in‐hospital PE‐related adverse events. Clinical score, troponin I and hypoxemia predicted in‐hospital all‐cause mortality. Clinical score and troponin I independently predicted 3‐month all‐cause mortality.

Use of an Algorithm for Administering Subcutaneous Heparin in the Treatment of Deep Venous Thrombosis

Patients with deep venous thrombosis of the lower extremities are usually treated with an initial course of unfractionated or low-molecular-weight heparin, followed by long-term oral anticoagulation [1, 2]. The use of nomograms for the intravenous administration of unfractionated heparin assures that almost all patients will promptly achieve sustained anticoagulation [3-5]. Subcutaneous heparin has been shown to be as effective and safe as intravenous heparin [6]; in addition, low-molecular-weight heparins may facilitate the early discharge of suitable patients from the hospital, with the accompanying advantage of a relatively low cost. However, no accepted guidelines exist with which to achieve adequate anticoagulation with subcutaneous administration of heparin. We implemented a weight-based algorithm for the subcutaneous administration of unfractionated heparin and evaluated the efficacy and safety of this therapy in 70 outpatients with proximal venous thrombosis. Methods Patients Eligible patients were consenting symptomatic outpatients who had a first episode of proximal venous thrombosis, as assessed by compression ultrasonography. Exclusion criteria were contraindications to anticoagulation, ongoing full-dose anticoagulant therapy, pregnancy, and poor life expectancy. The institutional ethical board approved the investigation. Intervention Patients were given an intravenous bolus of sodium heparin (Liquemin, Roche, Basel, Switzerland) and a subcutaneous injection of calcium heparin (Calciparina, Italfarmaco, Milan, Italy) in doses adjusted according to body weight (Table 1). Table 1. Algorithm for the Adjustment of Subcutaneous Heparin Doses* The first activated partial thromboplastin time (aPT) was done after 6 hours, and subsequent dose adjustments during the first 48 hours were scheduled twice daily according to the algorithm shown in Table 1. The aPT was performed in the mid-interval. Adjustments were arranged in steps to be run up or down according to aPT, regardless of body weight. The target aPT range (50 to 90 seconds) was calibrated to correspond to a heparin plasma level (as expressed by antifactor Xa [aXa] activity) of 0.35 to 0.70 U/mL. To avoid unnecessary overanticoagulation [7, 8], an aXa assay was scheduled if the aPT was subtherapeutic 6 hours after the administration of 25 000 U of heparin. If the aXa level exceeded 0.35 U/mL, the heparin dose was not modified. After the first 48 hours, heparin administration was managed on the basis of daily aPT determinations. Sodium warfarin therapy was begun on the first or second day and was continued for 12 weeks, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0. Heparin therapy was discontinued if the international normalized ratio in patients who had received the study drug for at least 5 days was greater than 2.0 for 2 consecutive days. Clinical Evaluation Patients were examined daily for signs and symptoms of recurrent thromboembolism, bleeding, or the occurrence of heparin-induced thrombocytopenia (decrease in platelet count to <109 cells/L or to >50% below the baseline count). Follow-up visits were scheduled after 1 and 3 months. Patients were asked to return to the study center if clinical manifestations of recurrent thromboembolism occurred. Recurrent venous thromboembolism was diagnosed according to standard methods [9, 10]. Bleeding was defined as major if it was intracranial or retroperitoneal or was associated with a decrease in the hemoglobin level of at least 2.0 g/dL. Autopsy was intended for all decedents in whom pulmonary embolism could not be excluded. Study Outcomes and Analysis We determined the proportion of patients who achieved the therapeutic threshold (aPT 50 seconds) within 24 and 48 hours and the time elapsed from initiation of heparin therapy until achievement of the threshold aPT. We calculated the percentage of patients with supratherapeutic aPT that persisted for more than 12 hours. We also evaluated the rate of recurrent thromboembolism during heparin treatment and follow-up and the rate of major bleeding occurring during heparin treatment and during the following 48 hours. Descriptive statistics were calculated according to standard methods; 95% CIs were estimated by using the exact method. The time from initiation of heparin therapy until achievement of the aPT threshold was calculated according to the Kaplan-Meier method. Results Patients Twenty-seven of 97 eligible patients were excluded because of ongoing full-dose anticoagulant therapy (15 patients), contraindications to heparin (4 patients), refusal to participate (4 patients), poor life expectancy (3 patients), and pregnancy (1 patient). Thus, 70 patients were enrolled (25 men; median age, 65 years). Three patients weighed less than 50 kg, 21 weighed 50 to 70 kg, and 46 weighed more than 70 kg. Risk factors for thrombosis were identifiable in 51 patients: cancer (20 patients), prolonged immobilization (14 patients), recent trauma (9 patients), thrombophilia (5 patients), and estrogen therapy (3 patients). Biological Outcomes Eighty-seven percent of patients (61 of 70) achieved the aPT threshold within 24 hours, and 99% (69 of 70) achieved the threshold in 48 hours. Figure 1 shows the Kaplan-Meier curve for the heparin therapeutic threshold. Seven patients (10.0% [95% CI, 4.1% to 19.5%]) had supratherapeutic aPT that persisted for more than 12 hours. In 2 of the 4 patients who had a subtherapeutic aPT despite the administration of 25 000 U of heparin, the aXa assay showed a plasma heparin level greater than 0.35 U/mL. Figure 1. Cumulative proportion of patients reaching the therapeutic threshold (activated partial thromboplastin time 50 seconds) within 48 hours of the initiation of heparin therapy. The mean (SD) heparin doses administered were 39 700 5300 U during the first day and 30 500 10 800 U during the second day. No patient required less than 10 000 U or more than 30 000 U twice daily to prolong the aPT (or aXa) level. The median duration of heparin treatment was 6.5 days (range, 5 to 12 days). Clinical Outcomes During the initial period of heparin treatment and follow-up, thromboembolism recurred in three patients (4.3% [CI, 0.9% to 12%]). One of the three (age, 93 years) died of autopsy-proven pulmonary embolism within 5 days after heparin treatment began. Both the aPT and the international normalized ratio were in the therapeutic range. The two other patients had contralateral thrombosis (one after 8 weeks and one after 10 weeks), as assessed by compression ultrasonography. In all three patients, the aPT threshold had been achieved within 24 hours of initiation of heparin therapy. No major bleeding episodes or heparin-induced thrombocytopenia occurred during heparin treatment (0% [CI, 0.0% to 5.0%]), and no patient was lost to follow-up. Five patients died during the follow-up period: Four died of cancer (one after 65 days, one after 72 days, one after 80 days, and one after 85 days), and one died of pleural hemorrhage that occurred 1 month after heparin therapy began. Discussion Our results suggest that the use of a weight-based algorithm for the subcutaneous injection of unfractionated heparin allows the rapid achievement of correct anticoagulation in almost all patients with deep venous thrombosis while avoiding prolonged periods of excessive anticoagulation. The therapeutic threshold was achieved within 24 hours in 87% of patients and within 48 hours in 99%. In only 10% of patients did supratherapeutic aPT persist for more than 12 hours. No patient had major bleeding or heparin-induced thrombocytopenia, and thromboembolism recurred in only three patients (4.3%). These results are consistent with those reported in recent studies done with either intravenous unfractionated heparin according to standardized guidelines or fixed-dose low-molecular-weight heparins [3-5, 11-13]. An intravenous loading dose was chosen because of the poor bioavailability of subcutaneous heparin [8], and weight-adjusted heparin doses were chosen because body weight is the single best predictor of individual heparin requirements [5, 14, 15]. The combination of an initial intravenous bolus and weight-adjusted heparin doses probably explains the high biological success rates achieved with our protocol, rates that are similar to those recently reported with the use of a weight-based intravenous heparin nomogram [5, 16]. Of interest, the mean daily amount of heparin required to prolong the aPT during the first 24 hours (almost 40 000 U) was greater than the dose (30 000 to 35 000 U) usually required to attain proper anticoagulation with intravenous administration [1, 3-5, 8]. The implication of this finding is that the common practice of injecting as much subcutaneous heparin as is commonly administered intravenously for the initial treatment of patients with thrombotic disorders is likely to produce insufficient anticoagulation, thereby increasing the likelihood of recurrent thromboembolism [17-19]. A few considerations deserve careful analysis. Because of a relatively small sample size and the lack of a control group, our results should be validated in other cohorts of patients to ensure external validity. In addition, because we confined our investigation to symptomatic outpatients with a first episode of venous thrombosis, widespread generalization of this therapeutic regimen requires proper evaluation in patients who develop thrombosis during hospitalization and in those presenting with pulmonary embolism or recurrent thromboembolism. In conclusion, the use of a weight-based algorithm for the subcutaneous administration of unfractionated heparin may greatly simplify the initial treatment of venous thromboembolic disorders. It enables the early mobilization of patients with venous thrombosis and allows the early discharge of suitable patients. The relatively low cost of unfractionated heparin makes this approach attractive in comparison w

Factor V Leiden (Activated Protein C Resistance) Versus Factor V Deficiency in Padua, Italy

Ten homozygous patients with factor V deficiency and 19 homozygous patients with activated protein C (APC) resistance were seen in Padua during the last 30 or 3 years, respectively. The actual numbers of heterozygous patients seen during the same periods of time were 41 and 306, respectively. All patients came from the northeastern part of Italy with a population of 10,000,000 people. The probable prevalence of homozygous patients was obtained by multiplying the actual number by four. The theoretical prevalence of heterozygous patients was obtained using the formula 2 qp, where q is the frequency of the abnormal gene as calculated by the square root of frequency of the homozygotes and p is the frequency of the normal allele as calculated by the formula p = (1 - q). Using such calculations, the number of heterozygotes probably exist ing in northeastern Italy is 39,840 and 56,497, respectively for the factor V deficiency and for APC resistance. After correction for the different observation periods (3 years vs. 30 years), there are 56,497 per 10 million people (5.6% of the population) for factor V Leiden. The prevalence of factor V deficiency is 0.39% of the population. Therefore the factor V Leiden muta tion responsible for APC resistance appears to be more preva lent than factor V deficiency on the basis of actual figures and accepted theoretical calculations.