Gerd Lärfars

Prolonged thromboprophylaxis with dalteparin after surgical treatment of achilles tendon rupture: a randomized, placebo-controlled study.

Objectives: Prophylaxis against thromboembolic complications has become routine after major orthopedic surgery. In contrast, it remains an issue for debate whether prophylaxis after minor surgery and immobilization is necessary, even though these treatments are well-known risk factors for deep-vein thrombosis (DVT). The objective of this study was to evaluate the efficacy of dalteparin during lower-limb immobilization after surgical treatment of Achilles tendon rupture. Design Setting, and Patients: Randomized, placebo-controlled, double-blind study of 105 consecutive patients surgically treated for Achilles tendon rupture in a trauma hospital. DVT screening with color duplex sonography was conducted 3 weeks and 6 weeks after surgery. All DVTs were confirmed with phlebography. Intervention was placebo or dalteparin (5000 U) given subcutaneously once daily for 6 weeks postoperatively. Main Outcome Measure: DVT incidence. Results: Primary endpoint analysis was available for 91 patients. DVT was diagnosed in 16 of 47 patients (34%) in the dalteparin group and in 16 of 44 patients (36%) in the placebo group. These figures are not significantly different (P = 0.8). Proximal DVT was diagnosed in 1 patient (2%) in the dalteparin group and in 3 patients (6%) in the placebo group (P = 0.6). No pulmonary emboli or major bleeding occurred in either of the groups. Conclusions: DVT is common after surgical treatment of Achilles tendon rupture, and therefore effective thromboprophylaxis is desirable. In our study, thromboprophylaxis with dalteparin, however, does not affect the incidence of DVT during immobilization after Achilles tendon rupture surgery. Long-term effects of immobilization, such as the risk for postthrombotic syndrome, need to be investigated further.

Prolonged thromboprophylaxis with Dalteparin during immobilization after ankle fracture surgery A randomized placebo-controlled, double-blind study

Background Skeletal trauma and immobilization are well-known risk factors for deep vein thrombosis (DVT) and pulmonary embolism (PE). While prophylaxis against thromboembolic complications has become routine after major orthopedic surgery, whether or not prophylaxis after minor surgery and lower limb immobilization is necessary is still under debate. Methods In a double-blind, placebo-controlled study, 272 consecutive patients were randomized to receive either thromboprophylaxis with Dalteparin (n = 136) or placebo (n = 136) for 5 weeks after ankle fracture surgery. All patients received 1 week of initial treatment with Dalteparin before randomization. A unilateral phlebography was performed when the cast was removed. Results The overall incidence of DVT was 21% (95% CI: 13–29%) in the Dalteparin group and 28% (CI: 19– 37%) in the placebo group (risk ratio = 0.8, CI: 0.6–1.1; p = 0.3). The incidence of proximal DVTs was 4% and 3%, respectively. No major bleeding occurred. Interpretation We found no significant difference in the incidence of DVT between the 2 treatment groups and our results do not support prolonged thromboprophylaxis. The overall incidence of DVT was high, reflecting the potential risk of PE and post-thrombotic syndrome after ankle fracture surgery. Most of the DVTs were asymptomatic, however, and were located in distal veins.

Risk factors for venous thromboembolism in pre-and postmenopausal women

INTRODUCTION Hemostasis in women is affected by changes of estrogen levels. The role of endogenous estrogens on risk of venous thromboembolism (VTE) remains unclear. The aim of this study was to investigate the importance of acquired and genetic risk factors for VTE in pre-and postmenopausal women. METHOD In a nationwide case-control study we included as cases 1470 women, 18 to 64years of age with a first time VTE. The 1590 controls were randomly selected and matched by age to the cases. Information on risk factors was obtained by interviews and DNA-analyses. We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS The ORs were generally of similar magnitude in pre- and postmenopausal women. The highest risk was for the combination of surgery and cast (adjusted OR 54.12, 95% CI 16.62-176.19) in postmenopausal women. The adjusted OR for use of menopausal hormone therapy was 3.73 (95% CI 1.86-7.50) in premenopausal and 2.22 (95% CI 1.54-3.19) in postmenopausal women. Overweight was linked to an increased risk and exercise to a decreased risk, regardless of menopausal status. CONCLUSION Menopausal status had only minor influence on the risk levels. Acquired transient risk factors conveyed the highest risks for VTE.

Measurement of methemoglobin formation from oxyhemoglobin a real-time, continuous assay of nitric oxide release by human polymorphonuclear leukocytes

We have evaluated the spectrophotometric measurement (at 401 vs. 411 nm) of nitric oxide (NO)-dependent methemoglobin formation from oxyhemoglobin in order to assess NO release from human polymorphonuclear neutrophil leukocytes (PMN). S-nitroso-D,L-acetyl-penicillamine (SNAP, 25-200 microM), a donor of NO, induced a dose-dependent methemoglobin formation. Furthermore, when PMN were activated with N-formyl-methionylleucyl-phenylalanine or phorbol myristate acetate in the presence of superoxide dismutase (SOD) and catalase, methemoglobin formation ensued. The amount of methemoglobin formed was dependent on the amounts of oxyhemoglobin and stimulus used, and the number of PMN in the assay. The NO synthase (NOS) inhibitors NG-monomethyl-L-arginine or nitro-L-arginine methyl ester did not affect methemoglobin generation from oxyhemoglobin induced by SNAP but inhibited that mediated by activated PMN with IC50 values of 250 microM and 340 microM, respectively. The substrate for NO formation from NOS, L-arginine in concentrations up to 1 mM did not significantly influence the methemoglobin formation either induced by SNAP or activated PMN. Exclusion of SOD did not affect SNAP-dependent oxidation of oxyhemoglobin. Exclusion of SOD from the cell-containing system attenuated methemoglobin formation, and if catalase was also excluded the response was further reduced. Finally, PMN from a patient with X-linked chronic granulomatous disease, unable to produce superoxide anions, showed a similar production of methemoglobin from HbO2 as did healthy PMN, activated with the respective agonists. We conclude that spectrophotometric measurement of methemoglobin formation from oxyhemoglobin in the presence of SOD and catalase is a suitable method for the measurement of NO release from PMN, with the benefits of a real-time, continuous assay.

Evaluation of Wells score and repeated D-dimer in diagnosing venous thromboembolism.

BACKGROUND Patients presenting with symptoms suggestive of venous thromboembolism (VTE), i.e., deep vein thrombosis (DVT) and pulmonary embolism (PE), are common at the emergency departments. However, of those, only 15-25% actually have the disease. The aims of this study were to determine (1) if low pre-test probability (PTP) using the Wells score, together with a normal D-dimer, safely excludes VTE in outpatients and (2) if a follow-up D-dimer adds extra information. METHODS Patients (n=151, 68% women) with suspected VTE, a PTP below 1.5, and a D-dimer test (TinaQuant) below 0.5 mg/L were included in the study and underwent no further diagnostic investigations. Patients (n=177, 54% women) with D-dimer levels of 0.5 mg/L or higher or a PTP of 1.5 or higher were excluded. A follow-up D-dimer test was conducted 3-7 days after the initial hospital visit and further diagnostic investigations were made if test results were abnormal. Patients were studied for 3 months. RESULTS A follow-up D-dimer test was conducted in 101/151 cases (67%), 13/101 of which revealed elevated D-dimer levels. None of these 13 patients had persistent symptoms or was diagnosed with VTE. All 151 patients were contacted after 3 months; none of them had clinical signs of VTE. Of the 177 patients excluded, 45 (25%) were diagnosed with VTE. Of the 176/328 (151+177) patients with normal D-dimer levels, only 1 had VTE (<0.01%). CONCLUSION A normal PTP using the Wells score and a normal D-dimer safely excludes VTE at the emergency department. A follow-up D-dimer test adds no further information.

Asymptomatic deep venous thrombosis is associated with a low risk of post-thrombotic syndrome.

UNLABELLED Post-thrombotic syndrome (PTS) is a well-recognized condition that develops after symptomatic deep venous thrombosis, but the clinical significance and late complications of asymptomatic deep venous thrombosis (ADVT) are unclear. OBJECTIVE To determine whether ADVT following minor surgery affects venous function and contributes to the later development of PTS. PATIENTS/METHODS The study included 83 patients operated on for Achilles tendon rupture; 38 patients with postoperative ADVT and 45 patients without (control group). The follow-up examinations five years after the operation comprised computerised strain-gauge plethysmography, colour duplex ultrasonography, clinical scoring of venous disease, and quality of life (QOL). RESULTS Villalta scores, CEAP classification and QOL did not differ between groups. PTS (=Villalta score > or =5) was found in three ADVT patients (8%) and in two controls (4%). Ultrasonography revealed post-thrombotic changes in 55% of ADVT patients and in none of the controls. Deep venous reflux occurred in 22 ADVT patients and in three controls (P<0.001). There was no difference between groups in plethysmographic variables, demonstrating that the ultrasonographic abnormalities were of negligible haemodynamic significance. CONCLUSIONS PTS is not a common sequel to ADVT after minor surgery. Although more than 50% of patients with ADVT developed post-thrombotic changes according to ultrasound, these changes did not result in haemodynamically significant venous dysfunction.

Stimulus-dependent transduction mechanisms for nitric oxide release in human polymorphonuclear neutrophil leukocytes

The production of nitric oxide (NO) may play an important role in functional responses of the human polymorphonuclear neutrophil granulocytes (PMNs). Others have described the presence of both an inducible, Ca2+-independent and a constitutionally expressed, Ca2+-dependent nitric oxide synthase (NOS) in human PMNs. However, the conditions for production and release of NO in human PMNs are still largely unknown. We assessed mechanisms for activation of NO release from human PMNs and particularly the dependence on extracellular and intracellular Ca2+. We addressed this question by applying a variety of agonists with known and differing mechanisms of activation in PMNs and measuring the released NO by two highly sensitive and specific real-time methods for detection of NO, the oxidation of oxyhemoglobin to methemoglobin and an electrochemical method. We found that human PMNs activated with the surface receptor-dependent agonist, N-formyl-methionyl-leucyl-phenylalanine (fMLP); the calcium ionophore, A23187; or the direct stimulator of protein kinase C, phorbol myristate acetate (PMA), produced NO which was inhibited by a specific NOS inhibitor, NG-monomethyl-L-arginine. The NO production induced by fMLP or A23187 was dependent on the presence of extracellular Ca2+, but this was not the case for PMA. The stimulatory effect of fMLP was almost completely inhibited by Bordetella pertussis toxin. These results indicate an NOS activity in purified human PMNs in vitro, and the transduction mechanisms for the agonists used show strong similarity with previously known pathways for other neutrophil functions.

Oral cladribine for B‐cell chronic lymphocytic leukaemia: report of a phase II trial with a 3‐d, 3‐weekly schedule in untreated and pretreated patients, and a long‐term follow‐up of 126 previously untreated patients

Summary.  A phase II study was undertaken to evaluate the efficacy and toxicity of a new schedule of cladribine administration (10 mg/m2 orally daily for 3 d every 3 weeks) in 107 patients with B‐cell chronic lymphocytic leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria were defined. The results of the 63 previously untreated patients were retrospectively compared with 63 from an earlier study using a 5‐d monthly schedule. The compiled data were analysed for prognostic factors for survival. No significant difference regarding response were seen in the two cohorts of the 126 previously untreated patients. The complete response (CR), nodular partial response (nPR) and partial response (PR) rates were 15%, 21% and 41%. Quality of response had no impact on survival. The 3‐ and 5‐year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow‐up of 54 months. Pretreatment haemoglobin < 11·0 g/dl and elevated beta‐2‐microglobulin had a negative influence on survival. Major infections occurred in 21% of patients in the 3‐d study compared with 35% in the 5‐d study. The overall response (OR) and CR rates in the 40 previously treated patients were 34% and 5% respectively. Median overall survival was 24 months and median progression‐free survival for responding patients was 14 months. Cladribine used as a single agent is an effective treatment with an acceptable safety profile for pretreated and untreated B‐CLL. The achievement of complete remission was not a prerequisite for long‐term survival.

High adherence to the ‘Wise List’ treatment recommendations in Stockholm: a 15-year retrospective review of a multifaceted approach promoting rational use of medicines

Objectives To present the ‘Wise List’ (a formulary of essential medicines for primary and specialised care in Stockholm Healthcare Region) and assess adherence to the recommendations over a 15-year period. Design Retrospective analysis of all prescription data in the Stockholm Healthcare Region between 2000 and 2015 in relation to the Wise List recommendations during the same time period. Setting All outpatient care in the Stockholm Healthcare Region. Participants All prescribers in the Stockholm Healthcare Region. Main outcome measures The number of core and complementary substances included in the Wise List, the adherence to recommendations by Anatomic Therapeutic Chemical (ATC) 1st level using defined daily doses (DDDs) adjusted to the DDD for 2015, adherence to recommendations over time measured by dispensed prescriptions yearly between 2002 and 2015. Results The number of recommended core substances was stable (175–212). Overall adherence to the recommendations for core medicines for all prescribers increased from 75% to 84% (2000 to 2015). The adherence to recommendations in primary care for core medicines increased from 80% to 90% (2005 to 2015) with decreasing range in practice variation (32% to 13%). Hospital prescriber adherence to core medicine recommendations was stable but increased for the combination core and complementary medicines from 77% to 88% (2007 to 2015). Adherence varied between the 4 therapeutic areas studied. Conclusions High and increasing adherence to the Wise List recommendations was seen for all prescriber categories. The transparent process for developing recommendations involving respected experts and clinicians using strict criteria for handling potential conflicts of interests, feedback to prescribers, continuous medical education and financial incentives are possible contributing factors. High-quality evidence-based recommendations to prescribers, such as the Wise List, disseminated through a multifaceted approach, will become increasingly important and should be developed further to include recommendations and introduction protocols for new expensive medicines.

Electrochemical detection of nitric oxide production in human polymorphonuclear neutrophil leukocytes

The detection of nitric oxide (NO) release by human polymorphonuclear neutrophil leukocytes (PMNs) presents several difficulties, mainly due to concomitant production of O2- and H2O2, which could interfere with the measurements. A Nafion and nickel porphyrin-coated microelectrode was used to measure NO production in PMNs in vitro. It allowed detection of 6.3 +/- 1.9 nM NO in a PMN-containing system and was unaffected by added chemicals. Addition of the chemotactic oligopeptide f-met-leu-phe (fMLP; 100 nM) induced a NO release which reached a value of 71 +/- 30 pmol NO/10(6) PMN x ml(-1) 5 min after stimulation in the presence of SOD (150 U/ml). If SOD was omitted, the corresponding value was 36 +/- 20 pmol NO/10(6) PMN x ml(-1). Presence or absence of catalase did not alter the amount of NO measured. Addition of the NO-synthase inhibitor N(G)-monomethyl-L-arginine (LNMMA; 1 mM) reduced the current by 82 +/- 20%. These results agree with the rate of NO production in human PMNs when measured spectrophotometrically using the NO-dependent oxidation of oxyhaemoglobin to methaemoglobin. The NO production in human PMN was dependent on fMLP concentrations, but independent of cell-concentrations of 0.5-3.5 x 10(6)/ml. This paper shows that a electrochemical method, e.g. Nafion and porphyrin-coated microelectrode, is suitable for studies of NO release from stimulated human PMNs.