Short-term prognosis of breakthrough venous thromboembolism in anticoagulated patients.

BACKGROUND: Evidence for guideline recommendations for the treatment of venous thromboembolism (VTE) during anticoagulant therapy is scarce. We aimed to observe and to describe the management of VTE occurring during anticoagulant therapy. METHODS: This prospective multi-center, observational study included patients with objectively confirmed VTE during anticoagulant therapy (breakthrough event), with a follow-up of 3 months, after the breakthrough event. RESULTS: We registered 121 patients with a breakthrough event, with a mean age of 56 years (range, 19 to 90); 61 were male (50%). Fifty-eight patients (48%) had an active malignancy. At the time of the breakthrough event, 57 patients (47%) were treated with a vitamin K antagonist (VKA), 53 patients (44%) with low-molecular-weight heparin (LMWH) and 11 patients (9%) with direct oral anticoagulants, unfractionated heparin, or VKA plus LMWH. A total of 21 patients (17%) were receiving a subtherapeutic dose of an anticoagulant. The main regimens to treat recurrence in patients on VKA were: switch to LMWH (33%), temporary double treatment with LMWH and VKA (23%), and VKA with a higher target INR (19%). In patients with a breakthrough on LMWH, the most frequently chosen regimen was a permanent dose increase (74%). During 3-month follow-up, 7% of patients had a second breakthrough event and 8% experienced major or clinically relevant non-major bleeding. CONCLUSION: There is wide variation in the management of VTE during anticoagulant treatment, reflecting a heterogeneous and complex clinical situation. Despite intensifying anticoagulation, the risk of a second breakthrough event in this population is 7%.

No added value of the age-adjusted D-dimer cut-off to the YEARS algorithm in patients with suspected pulmonary embolism.

Essentials Imaging is warranted in the majority of patients to confirm or rule out pulmonary embolism (PE). The age-adjusted D-dimer (ADJUST) reduced the number of required imaging tests in patients ≥ 50 years. The YEARS algorithm was designed to improve the efficiency in patients with suspected PE. There was no added value of implementing ADJUST in the YEARS algorithm in our cohort. SUMMARY: Background The YEARS algorithm was designed to simplify the diagnostic work-up of pulmonary embolism (PE) and to reduce the number of necessary computed tomography pulmonary angiography (CTPA) scans. An alternative strategy to reduce the number of CTPAs is the age-adjusted D-dimer cut-off (ADJUST) in patients aged 50 years or older. We aimed to investigate whether a combination of both diagnostic strategies might save additional CTPAs. Methods The YEARS algorithm consists of three items (clinical signs of deep venous thrombosis, hemoptysis, 'PE most likely diagnosis') with simultaneous D-dimer testing using a pre-test dependent threshold. We performed a post hoc analysis in 3465 patients managed according to YEARS to compare the number of patients managed without CTPA scans and associated diagnostic failures in hypothetical scenarios with different YEARS-ADJUST combinations. Results Following the YEARS algorithm, 1651 patients (48%) were managed without CTPA; PE was diagnosed in 456 (13%) patients at baseline and 18 patients with initial normal testing suffered venous thromboembolism (VTE) during 3-month follow-up (failure rate 0.61%; 95% confidence interval [CI], 0.36-0.96). If ADJUST had been fully integrated in YEARS, 1627 patients (47%) would have been managed without CTPA (absolute decrease of 0.69%; 95% CI -1.7 to 3.0), at cost of four additional missed PE diagnoses at baseline, for a projected 3-month VTE failure rate of 0.75% (95% CI, 0.49-1.13). None of the other studied scenarios showed relevant improvements in efficiency as well, but all led to more missed diagnoses. Conclusion In our cohort, there was no added value of implementing ADJUST in the YEARS algorithm.

Permissive Attitude Towards Drug Use, Life Satisfaction, and Continuous Drug Use Among Psychoactive Drug Users in Hong Kong.

OBJECTIVES: To examine the effects of a permissive attitude towards regular and occasional drug use, life satisfaction, self-esteem, depression, and other psychosocial variables in the drug use of psychoactive drug users. Psychosocial factors that might affect a permissive attitude towards regular / occasional drug use and life satisfaction were further explored. METHODS: We analysed data of a sample of psychoactive drug users from a longitudinal survey of psychoactive drug abusers in Hong Kong who were interviewed at 6 time points at 6-month intervals between January 2009 and December 2011. Data of the second to the sixth time points were stacked into an individual time point structure. Random-effects probit regression analysis was performed to estimate the relative contribution of the independent variables to the binary dependent variable of drug use in the last 30 days. RESULTS: A permissive attitude towards drug use, life satisfaction, and depression at the concurrent time point, and self-esteem at the previous time point had direct effects on drug use in the last 30 days. Interestingly, permissiveness to occasional drug use was a stronger predictor of drug use than permissiveness to regular drug use. These 2 permissive attitude variables were affected by the belief that doing extreme things shows the vitality of young people (at concurrent time point), life satisfaction (at concurrent time point), and self-esteem (at concurrent and previous time points). Life satisfaction was affected by sense of uncertainty about the future (at concurrent time point), self-esteem (at concurrent time point), depression (at both concurrent and previous time points), and being stricken by stressful events (at previous time point). CONCLUSIONS: A number of psychosocial factors could affect the continuation or discontinuation of drug use, as well as the permissive attitude towards regular and occasional drug use, and life satisfaction. Implications of the findings for prevention and intervention work targeted at psychoactive drug users are discussed.

Clot structure and fibrinolytic potential in patients with post thrombotic syndrome.

INTRODUCTION: Post-thrombotic syndrome (PTS) is a chronic sequel of deep vein thrombosis (DVT). The clot structure and fibrinolytic potential in PTS is currently unknown. OBJECTIVE: To assess the fibrinolytic potential and clot structure in patients with PTS. MATERIALS AND METHODS: Patients with a history of DVT were included in a case-control study: patients with PTS (cases n=30) and without PTS (controls n=30), and 30 apparently healthy individuals (HI) without venous thromboembolism (VTE) or venous insufficiency were enrolled. Fibrinolysis and clot structure were assessed by turbidimetric assays, permeation, and confocal microscopy. Fibrinogen was measured by Clauss and fibrinogen γ' by ELISA. RESULTS: We observed a significant trend of decreasing maximum turbidity from HI (median 0.52 [IQR 0.46-0.62]), to controls (0.49 [IQR 0.41-0.55]), to cases (0.46 [IQR 0.39-0.49]) p=0.020. Fibrinogen was lower in patients (cases and controls) (3.69g/L [IQR 3.31-4.26]) compared to HI (4.17 [IQR 3.69-4.65]) p=0.041. Patients with recurrent VTE had lower maximum turbidity and lower permeation than patients with one episode of VTE; (0.31 [IQR 0.25-0.39] versus 0.38 [IQR 0.34-0.44] p=0.008) and (6.0×10(-9)/cm(2) [IQR 5.1-7.9] versus 7.7×10(-9)/cm(2) [IQR 6.0-10.0] p=0.047) respectively, at equal fibrinogen levels. There were no differences in lysis time, confocal microscopy, or fibrinogen γ'. CONCLUSIONS: Lower maximum turbidity, indicating a tendency towards thinner fibres and denser clots, was found in patients with PTS as well as in patients with recurrent VTE. Fibrinogen levels did not explain these differences in clot structure. The abnormal clot structure may contribute to the increased thrombotic risk profile in patients with PTS.

In vivo increase in thrombin generation by four-factor prothrombin complex concentrate in apixaban-treated healthy volunteers.

BACKGROUND: Four-factor prothrombin complex concentrate (PCC) (Cofact; Sanquin Blood Supply) 50 IU kg(-1) increased thrombin generation beyond baseline values in healthy, rivaroxaban-treated subjects. OBJECTIVE: To assess whether infusion with doses of 37.5 IU kg(-1) and 25 IU kg(-1) PCC reverses the anticoagulant effect of high-dose apixaban, another oral direct factor Xa inhibitor. METHODS: In a randomized, double-blind, placebo-controlled, crossover study, six healthy subjects received twice-daily apixaban 10 mg for 3.5 days followed by a single bolus of 37.5 IU kg(-1) PCC, 25 IU kg(-1) PCC, or placebo. The primary outcome was the effect of PCC 15 min after infusion on thrombin generation (endogenous thrombin potential [ETP]); secondary outcomes were the immediate effect of PCC on prothrombin time (PT) and the effect of PCC as compared with placebo over a period of 24 h on ETP and PT. RESULTS: Fifteen minutes after infusion of 37.5 IU kg(-1) and 25 IU kg(-1) PCC, ETP increased from 41% ± 11% to 56% ± 23% (P = 0.06) and from 44% ± 12% to 51% ± 15% (P = 0.03), respectively. ETP significantly differed over time between 37.5 IU kg(-1) PCC and placebo during 24 h after infusion (P < 0.01). Both PCC doses restored apixaban-induced PT prolongation after 15 min (P < 0.01), and this was sustained over a period of 24 h. CONCLUSION: Both 37.5 IU kg(-1) PCC and 25 IU/kg PCC improved coagulation parameters in healthy subjects, suggesting partial reversal of the anticoagulant effect of apixaban. This implies that PCC might be considered in patients with apixaban-associated bleeding. However, ETP was not immediately restored to pre-apixaban levels, suggesting that these doses are too low to instantly and fully restore hemostasis at peak apixaban levels.

Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis.

BACKGROUND: Recommendations for management of cancer-related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low-quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies. METHODS: Patients with cancer and VTE despite anticoagulant therapy were reported to the registry. Data on treatments, VTE events, major bleeding, residual thrombosis symptoms and death were collected for the following 3 months. Breakthrough VTE and subsequent recurrences were objectively verified. Outcomes with different treatment strategies were compared with Cox proportional hazards regression. RESULTS: We registered 212 patients with breakthrough VTE. Of those, 59% had adenocarcinoma and 73% had known metastases. At the time of the breakthrough event, 70% were on low-molecular-weight heparin (LMWH) and 27% on a vitamin K antagonist (VKA); 70% had a therapeutic or supratherapeutic dose. After breakthrough the regimen was: unchanged therapeutic dose in 33%, dose increased in 31%, switched to another drug in 24%; and other management in 11%. During the following 3 months 11% had another VTE, 8% had major bleeding and 27% died. Of the survivors, 74% had residual thrombosis symptoms. Additional VTE recurrence was less common with LMWH than with a VKA (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.11-0.70) but similar with unchanged or increased anticoagulant intensity (HR, 1.09; 95% CI, 0.45-2.63). The bleeding rate did not increase significantly with dose escalation. CONCLUSION: Morbidity and mortality are high after recurrence of cancer-related VTE despite anticoagulation. Further treatment appears to be more effective with LMWH than with a VKA.

Accuracy of aPTT monitoring in critically ill patients treated with unfractionated heparin.

INTRODUCTION: The anticoagulant effect of unfractionated heparin (UFH) is usually monitored by means of the activated partial thromboplastin time (aPTT). In critically ill patients, however, increased levels of acute phase proteins may decrease the accuracy of the aPTT, leading to inadequate UFH dosing. In these circumstances, the anti-Xa assay is recommended for monitoring. OBJECTIVE: We aimed to analyse the accuracy of the aPTT for the monitoring of UFH dosing in critically ill patients. METHODS: In critically ill patients treated with therapeutic doses of UFH, we compared aPTT levels with simultaneously measured anti-Xa levels as the gold standard. Sensitivity and specificity of the aPTT were determined for different cut-off points, receiver operating characteristic (ROC) curves were constructed and their areas under the curve (AUCs) were calculated. RESULTS: A total of 171 paired blood samples from 58 patients were analysed. Concordant aPTT and anti-Xa values were observed in 108 (63.2%) data pairs. In 33 data pairs (19.3%) the aPTT was discordantly high and in 30 data pairs (17.5%) discordantly low. The sensitivity of the aPTT in detecting UFH underdosing and overdosing was 0.63 and 0.37, respectively. When considering alternative thresholds, ROC curves for underdosing and overdosing had AUCs of 0.71 and 0.81, respectively. CONCLUSION: In this small cohort of critically ill patients, the aPTT was accurate in 63.2% of the blood samples. Its sensitivity to detect UFH underdosing and overdosing was low (0.63 and 0.37, respectively). We conclude that in critically ill patients, the aPTT is not accurate enough to detect UFH underdosing and overdosing.

Biomarkers for post thrombotic syndrome: a case-control study.

INTRODUCTION: There is limited knowledge on the etiology of post thrombotic syndrome (PTS), although several mechanisms have been proposed. The objectives are to explore the role of different pathogenic mechanisms for PTS, through measurement of an elaborate panel of biomarkers in patients with and without PTS. MATERIALS AND METHODS: Patients with a history of deep vein thrombosis (DVT) with PTS (cases) and without PTS after minimal 2years follow-up (controls), were selected from the outpatient clinic of two Dutch hospitals. As a reference to the normal population healthy individuals (HI) without a history of venous thromboembolism were invited to participate. The population consisted of: 26 cases, 27 controls, and 26 HI. A panel of predefined biomarkers was measured in venous blood. RESULTS: D-dimer showed a decreasing trend from cases to controls to HI; p=0.010. Thrombin/antithrombin complex levels were significantly higher in cases than in controls; p=0.032, and HI; p=0.017. APC-ratio was significantly lower in cases compared to controls; p=0.032, and HI; p=0.011. A significant trend of increasing proTAFI from cases, to controls, and HI; p=0.002 was found. There were no differences in inflammatory markers (CRP, Interleukin-6, Interleukin-8). Thrombomodulin, tissue-plasminogen activator, and von Willebrand factor were higher in patients compared to HI. There was a significant trend of decreasing sVCAM, from cases, to controls, and HI; p=0.029. CONCLUSIONS: Patients with PTS displayed increased coagulation activity, an altered pattern of fibrinolytic marker expression, and increased endothelial activation. We found no evidence of systemic inflammation in patients with PTS at 63months since the last DVT.

Ethnicity and risk factors in needle sharing among intravenous drug users in Sichuan Province, China.

Combining survey and ethnographic data, this research examined differences in the risk factors associated with needle sharing amongst intravenous drug users (IDUs) in the Sichuan Province of China. A comparison was made between the province's majority Han population and its Yi minority. We developed a theoretical framework consisting of risk factors at the individual level (including risk factors such as lack of AIDS knowledge, low self-efficacy, and economic pressure), interpersonal level (having an IDU primary partner and lack of family support), and community level (social discrimination). The findings suggested that the Yi minority group was more socially disadvantaged and had a higher risk of contracting HIV than the Han group. Furthermore, the factors that put them at risk were different to those which affected the Han group. OLS regression results showed that, for Han IDUs, needle sharing was positively associated with having an IDU primary partner and with economic pressure. On the other hand, for the minority group, needle sharing was significantly associated with being male, AIDS knowledge, the lack of family support, and social discrimination. These findings highlight the need for HIV prevention work to target marginalized populations in China, such as ethnic minorities, and to tailor appropriate prevention strategies to meet the specific needs of different groups.

Substance abuse and developments in harm reduction.

A drug is a substance that produces a psychoactive, chemical or medicinal effect on the user. The psychoactive effect of mood-altering drugs is modulated by the user's perception of the risks of drug use, his or her ability to control drug use and the demographic, socioeconomic and cultural context. The ability to control drug use may vary along a continuum from compulsive use at one end to controlled use at the other. The "drug problem" has been socially constructed, and the presence of a moral panic has led to public support for the prohibitionist approach. The legalization approach has severely attacked the dominant prohibitionist approach but has failed to gain much support in society because of its extreme libertarian views. The harm reduction approach, which is based on public health principles, avoids the extremes of value-loaded judgements on drug use and focuses on the reduction of drug-related harm through pragmatic and low-threshold programs. This approach is likely to be important in tackling the drug problem in the 21st century.

Previous participation in outpatient methadone program and residential treatment outcome: a research note from Hong Kong.

Methadone maintenance programs are good examples of harm-reduction efforts because heroin addicts stabilized on methadone have been found to be able to reduce illicit drug use and criminality and improve their life condition, even though they have not achieved abstinence. While excluding the criterion of abstinence allows the harm-reduction approach to distinguish itself from traditional treatment, little research attention has been paid to the relationship between methadone programs and abstinence-oriented treatment programs. This research note reports some of the findings of a study of 77 former male clients of SARDA, a voluntary residential treatment agency in Hong Kong, pertaining to such a relationship. Findings suggest that a client's previous participation in the Outpatient Methadone Program of the Department of Health could facilitate successful outcome in his subsequent participation in SARDA's treatment program and help him to continue his drug-free status in the post-SARDA treatment period. Conceptual and policy implications of the findings are discussed. [Translations are provided in the International Abstracts Section of this issue.]

Drug use and drug policy in Hong Kong: changing patterns and new challenges.

This paper is a sociohistorical examination of drug misuse and drug policy in Hong Kong. It briefly traces the history of drug policy since Hong Kong became a colony of Britain in the nineteenth century, and then highlights the major drug issues that have emerged in the past several decades. Drug policy in Hong Kong has gone through three stages, from "Government Opium Monopoly" (1841-1945) to "The Prohibition Era" (1946-1960) to "Enlightened Prohibition" (1961-1995). The evolution in drug policy is analyzed in the light of both domestic and international social, economic, and political forces affecting Hong Kong. The major drug issue in the past two decades has been the trends of rising levels of drug use among young people and the increasing popularity of psychoactive drugs among young drug users. It is argued that these trends may be understood in terms of rapid social change resulting from industrialization and socioeconomic growth since the 1960s, and the presence of conditions favorable to the demand and supply of psychoactive drugs. Lastly, major challenges to future drug policy in Hong Kong are discussed.

Beyond liver and culture: a review of theories and research in drinking among Chinese in North America.

Low levels of alcohol consumption and drinking problems have been consistently found among the Chinese in North America and in other Chinese societies. Two theories of Chinese drinking have been popular in the literature. First, the physiological explanation attributes the light alcohol use among the Chinese to their high propensity to flush, which protects them from heavy drinking. Second, the cultural explanation suggests that Chinese cultural values emphasizing moderation and self-restraint discourage drinking to the point of drunkenness. A review of existing research shows that both explanations are not supported by adequate empirical research findings and are plagued with conceptual and methodological shortcomings. It is also noted that both theories cannot explain why some Chinese do become heavy or problem drinkers. It is suggested that we should look beyond physiological and cultural factors for a better understanding of contemporary Chinese drinking patterns.

Approaches to ethnicity: clearing roadblocks in the study of ethnicity and substance use.

This paper reviews a number of indicators of ethnicity commonly used in alcohol/drug use studies. These include the racial, natal, symbolic and cultural approaches to ethnicity. The utility and limitations of each of these approaches is scrutinized. Because ethnicity is a multidimensional concept, using only one dimension, as is the case in many alcohol/drug use studies, is inadequate. One of the major weaknesses of studies of ethnicity and substance use is the failure to recognize the presence of subcultural differences within an ethnic group. Implications of the present review for future research in ethnicity and substance use/misuse and for future development of culturally sensitive programs and services are discussed.

Ethnic identification and alcohol use among Canadian-born and foreign-born high school students in Toronto.

Unlike other demographic and sociopsychological correlates of student alcohol and other drug use, the variable of ethnic identification and its possible effects on student substance use have not received adequate attention from researchers. This paper seeks to examine the relationship between ethnic identification and alcohol use on the basis of data collected from a survey of 667 high school students in Toronto. Results show that when other variables (sociodemographic, school, family, availability, and informal social control) are controlled for, the relationship between ethnic identification and alcohol use remains significant in Canadian-born students but not in foreign-born students. Also, foreign-born students are found to exhibit lower levels of alcohol use than their Canadian-born counterparts, regardless of cultural origin. Implications of the findings for future studies of ethnicity and alcohol/drug use and for prevention efforts are discussed.

Ethnicity and alcohol/drug use revisited: a framework for future research.

Despite the large pool of research findings pertaining to ethnic and racial variations in the use of drugs (including alcohol), the relationship between ethnicity and drug use has not been thoroughly examined. This paper describes some of the major findings regarding ethnic and racial variations in drug use, and examines the methodological limitations of such studies. Moreover, this paper addresses the problem of shortage of theoretical explanations for ethnic variations in drug use. It is argued that the variable of ethnicity has not been properly conceptualized and measured in most studies. Cultural and structural aspects of ethnicity at both the individual and collective levels are examined, and their possible contributions to more rigorous research on the relationship between ethnicity and drug use are discussed.

Stability of cisplatin, iproplatin, carboplatin, and tetraplatin in commonly used intravenous solutions.

The stability of cisplatin, iproplatin, carboplatin, and tetraplatin in common intravenous solutions was studied. Admixtures of each drug in each of the following vehicles were prepared in glass containers: 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose and 0.45% sodium chloride injection (admixtures were prepared in plastic bags also), and 5% dextrose and 0.225% sodium chloride injection. Drug concentrations were monitored for 24 hours using stability-indicating high-performance liquid chromatographic methods. The stability of cisplatin and tetraplatin was related to the chloride ion content of the infusion fluid; when the infusion fluid contained 0.9% sodium chloride, each of these drugs was present at greater than 90% of the original concentration after six hours. The stability of iproplatin was not related to chloride concentration. A slight increase in the decomposition rate of carboplatin was observed in the presence of chloride ion. Carboplatin and iproplatin are stable for 24 hours in all the infusion fluids studied, but carboplatin should not be diluted with solutions containing chloride ions because of possible conversion to cisplatin. Cisplatin is stable for 24 hours in admixtures containing sodium chloride concentrations of 0.3% or greater. Tetraplatin is stable for six hours in admixtures containing sodium chloride concentrations of at least 0.018%.