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1.  Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials 
PLoS Medicine  2012;9(9):e1001310.
A systematic review and meta-analysis conducted by Kazem Rahimi and colleagues re-evaluates the hypothesis, generated in previous studies, that statins may reduce the risk of venous thromboembolic events. Their meta-analysis does not support the previous findings.
Background
It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins.
Methods and Findings
We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78–1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72–1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76–1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82–1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80–1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out.
Please see later in the article for the Editors' Summary.
Conclusions
The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out.
Editors' Summary
Background
Blood normally flows smoothly throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Occasionally, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood towards the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the leg) include pain, swelling, and redness in the affected limb. DVT is treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a pulmonary embolism (PE), a life-threatening condition characterized by chest pain, breathlessness, coughing, and dizziness. Little is known about how to prevent DVTs and PEs but risk factors for these venous thromboembolic events include having an inherited blood clotting disorder, oral contraceptive use, having surgery, and prolonged inactivity (on long-haul plane flights, for example).
Why Was This Study Done?
In 2009, a secondary (add-on) analysis of data from a randomized controlled trial (RCT, a study that randomly assigns individuals to receive different treatments and compares the outcomes associated with each treatment) called the JUPITER trial reported that rosuvastatin—a cholesterol-lowering drug (statin)—halved the risk of venous thromboembolic events among apparently healthy adults. The JUPITER trial was initiated to test whether statins reduce the risk of strokes, heart attacks, and other cardiovascular diseases (conditions that involve the heart and the blood vessels) among adults with raised levels of a predictor for these diseases called C-reactive protein; statins reduce the levels of this protein as well as those of cholesterol. Because fewer than 100 of the participants in the JUPITER trial developed a DVT or PE, the reduction in the risk of a venous thromboembolic event among the participants who took rosuvastatin could have happened by chance. In this systematic review and meta-analysis of 29 RCTs of statins that collected information on many more venous thromboembolic events, the researchers test the hypothesis that statins substantially reduce the risk of such events. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 RCTs (105,759 participants) that compared the effects of statins with control (dummy) tablets and seven (40,594 participants) that compared an intensive statin regimen with a standard regimen. They then obtained largely unpublished information about the venous thromboembolic events that occurred during these trials (about 1,000 DVTs and PEs) from the original investigators. In the trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events. Thus, although events occurred in 465 participants who were given statins (0.9% of the participants) and in 521 participants who were given control tablets (1% of the participants), this difference in outcomes was not statistically significant—it could have happened by chance. Exclusion of the JUPITER trial results from the meta-analysis did not alter this finding. The researchers also found no evidence that intensive statin therapy reduced the risk of venous thromboembolic events compared to standard therapy.
What Do These Findings Mean?
The findings of this meta-analysis do not support the suggestion that statins, either at the standard dose or at higher doses, reduce the risk of venous thromboembolic events substantially among healthy adults. It is possible that the effect of statins has been underestimated in this meta-analysis because of missing data or because of some other source of bias. Furthermore, because the total number of events in this meta-analysis is still relatively modest, these findings do not rule out the possibility that statins may reduce the risk of venous thromboembolic events by up to about one-fifth in some or all individuals. Additional large RCTs are now needed to investigate whether statin treatment does in fact reduce the risk of venous thromboembolic events in adults and, if it does, whether all statins have a similar effect and whether statin treatment is beneficial in everyone or only in specific subgroups of people.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001310.
This study is further discussed in a PLOS Medicine Perspective by Frits Rosendaal
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolisms), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, on pulmonary embolism, and on statins; a Behind the Headlines article describes the JUPITER trial and its implications
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and statins (in English and Spanish)
doi:10.1371/journal.pmed.1001310
PMCID: PMC3445446  PMID: 23028261
2.  Point-of-Care International Normalized Ratio (INR) Monitoring Devices for Patients on Long-term Oral Anticoagulation Therapy 
Executive Summary
Subject of the Evidence-Based Analysis
The purpose of this evidence based analysis report is to examine the safety and effectiveness of point-of-care (POC) international normalized ratio (INR) monitoring devices for patients on long-term oral anticoagulation therapy (OAT).
Clinical Need: Target Population and Condition
Long-term OAT is typically required by patients with mechanical heart valves, chronic atrial fibrillation, venous thromboembolism, myocardial infarction, stroke, and/or peripheral arterial occlusion. It is estimated that approximately 1% of the population receives anticoagulation treatment and, by applying this value to Ontario, there are an estimated 132,000 patients on OAT in the province, a figure that is expected to increase with the aging population.
Patients on OAT are regularly monitored and their medications adjusted to ensure that their INR scores remain in the therapeutic range. This can be challenging due to the narrow therapeutic window of warfarin and variation in individual responses. Optimal INR scores depend on the underlying indication for treatment and patient level characteristics, but for most patients the therapeutic range is an INR score of between 2.0 and 3.0.
The current standard of care in Ontario for patients on long-term OAT is laboratory-based INR determination with management carried out by primary care physicians or anticoagulation clinics (ACCs). Patients also regularly visit a hospital or community-based facility to provide a venous blood samples (venipuncture) that are then sent to a laboratory for INR analysis.
Experts, however, have commented that there may be under-utilization of OAT due to patient factors, physician factors, or regional practice variations and that sub-optimal patient management may also occur. There is currently no population-based Ontario data to permit the assessment of patient care, but recent systematic reviews have estimated that less that 50% of patients receive OAT on a routine basis and that patients are in the therapeutic range only 64% of the time.
Overview of POC INR Devices
POC INR devices offer an alternative to laboratory-based testing and venipuncture, enabling INR determination from a fingerstick sample of whole blood. Independent evaluations have shown POC devices to have an acceptable level of precision. They permit INR results to be determined immediately, allowing for more rapid medication adjustments.
POC devices can be used in a variety of settings including physician offices, ACCs, long-term care facilities, pharmacies, or by the patients themselves through self-testing (PST) or self-management (PSM) techniques. With PST, patients measure their INR values and then contact their physician for instructions on dose adjustment, whereas with PSM, patients adjust the medication themselves based on pre-set algorithms. These models are not suitable for all patients and require the identification and education of suitable candidates.
Potential advantages of POC devices include improved convenience to patients, better treatment compliance and satisfaction, more frequent monitoring and fewer thromboembolic and hemorrhagic complications. Potential disadvantages of the device include the tendency to underestimate high INR values and overestimate low INR values, low thromboplastin sensitivity, inability to calculate a mean normal PT, and errors in INR determination in patients with antiphospholipid antibodies with certain instruments. Although treatment satisfaction and quality of life (QoL) may improve with POC INR monitoring, some patients may experience increased anxiety or preoccupation with their disease with these strategies.
Evidence-Based Analysis Methods
Research Questions
1. Effectiveness
Does POC INR monitoring improve clinical outcomes in various settings compared to standard laboratory-based testing?
Does POC INR monitoring impact patient satisfaction, QoL, compliance, acceptability, convenience compared to standard laboratory-based INR determination?
Settings include primary care settings with use of POC INR devices by general practitioners or nurses, ACCs, pharmacies, long-term care homes, and use by the patient either for PST or PSM.
2. Cost-effectiveness
What is the cost-effectiveness of POC INR monitoring devices in various settings compared to standard laboratory-based INR determination?
Inclusion Criteria
English-language RCTs, systematic reviews, and meta-analyses
Publication dates: 1996 to November 25, 2008
Population: patients on OAT
Intervention: anticoagulation monitoring by POC INR device in any setting including anticoagulation clinic, primary care (general practitioner or nurse), pharmacy, long-term care facility, PST, PSM or any other POC INR strategy
Minimum sample size: 50 patients Minimum follow-up period: 3 months
Comparator: usual care defined as venipuncture blood draw for an INR laboratory test and management provided by an ACC or individual practitioner
Outcomes: Hemorrhagic events, thromboembolic events, all-cause mortality, anticoagulation control as assessed by proportion of time or values in the therapeutic range, patient reported outcomes including satisfaction, QoL, compliance, acceptability, convenience
Exclusion criteria
Non-RCTs, before-after studies, quasi-experimental studies, observational studies, case reports, case series, editorials, letters, non-systematic reviews, conference proceedings, abstracts, non-English articles, duplicate publications
Studies where POC INR devices were compared to laboratory testing to assess test accuracy
Studies where the POC INR results were not used to guide patient management
Method of Review
A search of electronic databases (OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library, and the International Agency for Health Technology Assessment [INAHTA] database) was undertaken to identify evidence published from January 1, 1998 to November 25, 2008. Studies meeting the inclusion criteria were selected from the search results. Reference lists of selected articles were also checked for relevant studies.
Summary of Findings
Five existing reviews and 22 articles describing 17 unique RCTs met the inclusion criteria. Three RCTs examined POC INR monitoring devices with PST strategies, 11 RCTs examined PSM strategies, one RCT included both PST and PSM strategies and two RCTs examined the use of POC INR monitoring devices by health care professionals.
Anticoagulation Control
Anticoagulation control is measured by the percentage of time INR is within the therapeutic range or by the percentage of INR values in the therapeutic range. Due to the differing methodologies and reporting structures used, it was deemed inappropriate to combine the data and estimate whether the difference between groups would be significant. Instead, the results of individual studies were weighted by the number of person-years of observation and then pooled to calculate a summary measure.
Across most studies, patients in the intervention groups tended to have a higher percentage of time and values in the therapeutic target range in comparison to control patients. When the percentage of time in the therapeutic range was pooled across studies and weighted by the number of person-years of observation, the difference between the intervention and control groups was 4.2% for PSM, 7.2% for PST and 6.1% for POC use by health care practitioners. Overall, intervention patients were in the target range 69% of the time and control patients were in the therapeutic target range 64% of the time leading to an overall difference between groups of roughly 5%.
Major Complications and Deaths
There was no statistically significant difference in the number of major hemorrhagic events between patients managed with POC INR monitoring devices and patients managed with standard laboratory testing (OR =0.74; 95% CI: 0.52- 1.04). This difference was non-significant for all POC strategies (PSM, PST, health care practitioner).
Patients managed with POC INR monitoring devices had significantly fewer thromboembolic events than usual care patients (OR =0.52; 95% CI: 0.37 - 0.74). When divided by POC strategy, PSM resulted in significantly fewer thromboembolic events than usual care (OR =0.46.; 95% CI: 0.29 - 0.72). The observed difference in thromboembolic events for PSM remained significant when the analysis was limited to major thromboembolic events (OR =0.40; 95% CI: 0.17 - 0.93), but was non-significant when the analysis was limited to minor thromboembolic events (OR =0.73; 95% CI: 0.08 - 7.01). PST and GP/Nurse strategies did not result in significant differences in thromboembolic events, however there were only a limited number of studies examining these interventions.
No statistically significant difference was observed in the number of deaths between POC intervention and usual care control groups (OR =0.67; 95% CI: 0.41 - 1.10). This difference was non-significant for all POC strategies. Only one study reported on survival with 10-year survival rate of 76.1% in the usual care control group compared to 84.5% in the PSM group (P=0.05).
Summary Results of Meta-Analyses of Major Complications and Deaths in POC INR Monitoring Studies
Patient Satisfaction and Quality of Life
Quality of life measures were reported in eight studies comparing POC INR monitoring to standard laboratory testing using a variety of measurement tools. It was thus not possible to calculate a quantitative summary measure. The majority of studies reported favourable impacts of POC INR monitoring on QoL and found better treatment satisfaction with POC monitoring. Results from a pre-analysis patient and caregiver focus group conducted in Ontario also indicated improved patient QoL with POC monitoring.
Quality of the Evidence
Studies varied with regard to patient eligibility, baseline patient characteristics, follow-up duration, and withdrawal rates. Differential drop-out rates were observed such that the POC intervention groups tended to have a larger number of patients who withdrew. There was a lack of consistency in the definitions and reporting for OAT control and definitions of adverse events. In most studies, the intervention group received more education on the use of warfarin and performed more frequent INR testing, which may have overestimated the effect of the POC intervention. Patient selection and eligibility criteria were not always fully described and it is likely that the majority of the PST/PSM trials included a highly motivated patient population. Lastly, a large number of trials were also sponsored by industry.
Despite the observed heterogeneity among studies, there was a general consensus in findings that POC INR monitoring devices have beneficial impacts on the risk of thromboembolic events, anticoagulation control and patient satisfaction and QoL (ES Table 2).
GRADE Quality of the Evidence on POC INR Monitoring Studies
CI refers to confidence interval; Interv, intervention; OR, odds ratio; RCT, randomized controlled trial.
Economic Analysis
Using a 5-year Markov model, the health and economic outcomes associated with four different anticoagulation management approaches were evaluated:
Standard care: consisting of a laboratory test with a venipuncture blood draw for an INR;
Healthcare staff testing: consisting of a test with a POC INR device in a medical clinic comprised of healthcare staff such as pharmacists, nurses, and physicians following protocol to manage OAT;
PST: patient self-testing using a POC INR device and phoning in results to an ACC or family physician; and
PSM: patient self-managing using a POC INR device and self-adjustment of OAT according to a standardized protocol. Patients may also phone in to a medical office for guidance.
The primary analytic perspective was that of the MOHLTC. Only direct medical costs were considered and the time horizon of the model was five years - the serviceable life of a POC device.
From the results of the economic analysis, it was found that POC strategies are cost-effective compared to traditional INR laboratory testing. In particular, the healthcare staff testing strategy can derive potential cost savings from the use of one device for multiple patients. The PSM strategy, however, seems to be the most cost-effective method i.e. patients are more inclined to adjust their INRs more readily (as opposed to allowing INRs to fall out of range).
Considerations for Ontario Health System
Although the use of POC devices continues to diffuse throughout Ontario, not all OAT patients are suitable or have the ability to practice PST/PSM. The use of POC is currently concentrated at the institutional setting, including hospitals, ACCs, long-term care facilities, physician offices and pharmacies, and is much less commonly used at the patient level. It is, however, estimated that 24% of OAT patients (representing approximately 32,000 patients in Ontario), would be suitable candidates for PST/PSM strategies and willing to use a POC device.
There are several barriers to the use and implementation of POC INR monitoring devices, including factors such as lack of physician familiarity with the devices, resistance to changing established laboratory-based methods, lack of an approach for identifying suitable patients and inadequate resources for effective patient education and training. Issues of cost and insufficient reimbursement strategies may also hinder implementation and effective quality assurance programs would need to be developed to ensure that INR measurements are accurate and precise.
Conclusions
For a select group of patients who are highly motivated and trained, PSM resulted in significantly fewer thromboembolic events compared to conventional laboratory-based INR testing. No significant differences were observed for major hemorrhages or all-cause mortality. PST and GP/Nurse use of POC strategies are just as effective as conventional laboratory-based INR testing for thromboembolic events, major hemorrhages, and all-cause mortality. POC strategies may also result in better OAT control as measured by the proportion of time INR is in the therapeutic range and there appears to be beneficial impacts on patient satisfaction and QoL. The use of POC devices should factor in patient suitability, patient education and training, health system constraints, and affordability.
Keywords
anticoagulants, International Normalized Ratio, point-of-care, self-monitoring, warfarin.
PMCID: PMC3377545  PMID: 23074516
3.  Trousseau's Syndrome in Association with Cholangiocarcinoma: Positive Tests for Coagulation Factors and Anticardiolipin Antibody 
Journal of Korean Medical Science  2006;21(1):155-159.
Thromboembolic events are reported to occur with a high frequency in the setting of malignancy. However, reports on an association between cholangiocarcinoma and pulmonary thromboembolism, thus far, are almost lacking. We present here an unusual case of a 56-yr-old patient presenting cholangiocarcinoma and unexplained pulmonary thromboembolism. The patient had been quite healthy before the diagnosis. Coagulation tests showed elevated levels of fibrinogen, fibrinogen degradation product (FDP), D-dimer, and IgM anticardiolipin antibody (aCL Ab). The thromboemboli were resolved 3 weeks after anticoagulant therapy using low-molecular-weight-heparin. Then, follow-up coagulation tests showed a marked decrease to normal in aCL Ab titer as well as the normalization of FDP and D-dimer levels. In this case, we describe pulmonary thromboembolism caused by hypercoagulable state associated with cholangiocarcinoma and speculate that such a thrombotic phenomenon could be regressed by anticoagulant therapy.
doi:10.3346/jkms.2006.21.1.155
PMCID: PMC2733966  PMID: 16479083
Cholangiocarcinoma; Pulmonary Embolism; Heparin; Heparin, Low-Molecular-Weight
4.  Relationship between the Occurrence of Thromboembolism and INR Measurement Interval in Low Intensity Anticoagulation after Aortic Mechanical Valve Replacement 
Background
We investigated changes in the International Normalized Ratio (INR) and its measurement interval in patients with thromboembolic events who were treated by low intensity anticoagulation therapy after isolated mechanical aortic valve replacement.
Materials and Methods
Seventy-seven patients who underwent surgery from June 1990 to September 2006 were enrolled in the study and observed until August 2008. The patients were followed up at 4~8 week intervals and their warfarin (Coumadin)® dosage was adjusted aiming for a target range of INR 1.5~2.5. The rate of thromboembolic events was obtained. Changes in the mean INR and INR measurement interval were comparatively analyzed between the normal group (event free group, N=52) who had no anticoagulation-related complications and the thromboembolic group (N=10). Hospital records were reviewed retrospectively.
Results
The observation period was 666.75 patient-years. Thromboembolic events occurred in 10 patients. The linearized occurrence rate of thromboembolism was 1.50%/patient-years. Actuarial thromboembolism-free rates were 97.10±2.02% at 5 years, 84.30±5.22% at 10 years, and 67.44±12.14% at 15 years. The percentages of INR within the target range and mean INR were not statistically significantly different for the normal and thromboembolic groups. However, the mean INR during the segmented period just before the events showed a significantly lower level in the thromboembolic group (during a 4 month period: normal group, 1.86±0.14 vs. thromboembolic group, 1.50±0.28, p<0.001). The mean intervals of INR measurement during the whole observation period showed no significant differences between groups, but in the segmented period just before the events, the interval was significantly longer in thromboembolic group (during a 6 month period: normal group, 49.04±9.47 days vs. thromboembolic group, 65.89±44.88 days, p<0.01).
Conclusion
To prevent the occurrence of thromboembolic events in patients who receive isolated aortic valve replacement and low intensity anticoagulation therapy, we suggest that it would be safe to maintain an INR level above 1.8 and to measure the INR at least every 7~8 weeks.
doi:10.5090/kjtcs.2011.44.3.220
PMCID: PMC3249306  PMID: 22263155
Mechanical heart valve; Thromboembolism; Anticoagulation; INR measurement interval
5.  Primary Angioplasty for the Treatment of Acute ST-Segment Elevated Myocardial Infarction 
Executive Summary
One of the longest running debates in cardiology is about the best reperfusion therapy for patients with evolving acute myocardial infarction (MI). Percutaneous transluminal coronary angioplasty (ANGIOPLASTY) is a surgical treatment to reopen a blocked coronary artery to restore blood flow. It is a type of percutaneous (through-the-skin) coronary intervention (PCI) also known as balloon angioplasty. When performed on patients with acute myocardial infarction, it is called primary angioplasty. Primary angioplasty is an alternative to thrombolysis, clot-dissolving drug therapy, for patients with acute MI associated with ST-segment elevation (STEMI), a change recorded with an electrocardiogram (ECG) during chest pain.
This review of the clinical benefits and policy implications of primary angioplasty was requested by the Ontario Health Technology Advisory Committee and prompted by the recent publication of a randomized controlled trial (RCT) in the New England Journal of Medicine (1) that compared referred primary angioplasty with on-site thrombolysis. The Medical Advisory Secretariat reviewed the literature comparing primary angioplasty with thrombolysis and other therapies (pre-hospital thrombolysis and facilitated angioplasty, the latter approach consisting of thrombolysis followed by primary angioplasty irrespective of response to thrombolysis) for acute STEMI.
There have been many RCTs and meta-analyses of these RCTs comparing primary angioplasty with thrombolysis and these were the subject of this analysis. Results showed a statistically significant reduction in mortality, reinfarction, and stroke for patients receiving primary angioplasty. Although the individual trials did not show significant improvements in mortality alone, they did show it for the outcomes of nonfatal reinfarction and stroke, and for an end point combining mortality, reinfarction, and stroke. However, researchers have raised concerns about these studies.
A main concern with the large RCTs is that they lack consistency in methods. Furthermore, there is some question as to their generalizability to practice in Ontario. Across the RCTs, there were differences in the type of thrombolytic drug, the use of stenting versus balloon-only angioplasty, and the use of the newer antiplatelet glycoprotein IIb/IIIa. The largest trial did not offer routine follow-up angioplasty for patients receiving thrombolysis, which is the practice in Ontario, and the meta-analysis included trials with streptokinase, an agent seldom used in hospitals in Ontario. Thus, the true magnitude of mortality benefit can only be surmised from head-to-head comparisons of current standard therapies for primary angioplasty and for thrombolysis.
By taking a more restrictive sample of the available studies, the Medical Advisory Secretariat conducted a review that was more consistent with patterns of practice in Ontario and selected trials that used accelerated alteplase as the thrombolytic agent.
Results from this meta-analysis suggest that the rates for primary angioplasty are significantly better for mortality, reinfarction, and stroke, in the short term (30 days), and for mortality, reinfarction, and the combined end point at 6 months. When primary angioplasty was compared with in-hospital thrombolysis, results showed a significant reduction in adverse event rates associated with primary angioplasty. However, 1 large RCT of pre-hospital thrombolysis (i.e., thrombolysis given by paramedics before arriving at the hospital) compared with primary angioplasty documented that pre-hospital thrombolysis is an equivalent intervention to primary thrombolysis in terms of survival. Furthermore, a meta-analysis of studies that compared pre-hospital thrombolysis with in-hospital thrombolysis showed a reduction in all hospital mortality rates in favour of pre-hospital thrombolysis, supporting the findings of the pre-hospital thrombolysis study. (2)
Clinical trials to date have reported that hospital stay is often reduced for patients who receive primary angioplasty compared with thrombolysis. Using a cost-analysis performed alongside the only study from Ontario, the Medical Advisory Secretariat concluded that there might be savings associated with primary angioplasty. These savings may partly offset the investment the provincial government would have to make to increase access to this technology. These savings should also be shown outside of a clinical trial protocol if the overall efficiencies of primary angioplasty are to be verified.
Based on this health technology policy analysis, the Medical Advisory Secretariat concludes that primary angioplasty has advantages with respect to mortality and combined end points compared with in-hospital thrombolysis (Level 1 evidence). However, pre-hospital thrombolysis improves survival compared with in-hospital thrombolysis (Level 1 evidence) and is equivalent to primary angioplasty (Level 1 evidence).
Results from the literature review raise concerns about the loss of therapeutic advantage due to treatment delays, time lapse from symptom onset to revascularization, time-of-day variations, the hospital volume of procedures, and the ability of hospitals to achieve in practice what RCTs have shown.
Furthermore, questions relevant to applying primary angioplasty widely, involve the diagnosis by paramedics, ambulance diversion protocols, paramedic training, and inter-hospital transfer protocols. These logistical considerations need to be addressed to realise the potential to improve patient outcomes. In its analysis, the Medical Advisory Secretariat concludes that it is unrealistic to reorganise the emergency medical services across Ontario to fully implement a primary angioplasty program.
Finally, it is important to evaluate the potential of this technology in the context of Ontario’s health system. This includes urban and rural considerations, the ability to expand access to primary angioplasty and to minimize symptom-to-assessment time through a diverse strategy including public awareness. Therefore, a measured, evaluative approach to adopting this technology is warranted.
Furthermore, the alternative approach to pre-hospital or early thrombolysis, especially within 120 minutes from onset of symptoms, should be considered when developing the approach to improving outcomes for acute MI. This could include efforts to decrease the symptom-to-thrombolysis time through strategies such as a concerted public education program to expedite presentation to emergency rooms after onset of symptoms, a pre-hospital ECG and thrombolysis checklist in ambulances to reduce door-to-needle time on arrival at emergency rooms, and, especially in remote areas, access to pre-hospital thrombolysis.
The Medical Advisory Secretariat therefore recommends that this analysis of primary angioplasty be viewed in the overall context of all interventions for the management of acute MI and, in particular, of improving access to primary angioplasty and maximising the use of early thrombolysis.
Outcomes for patients with acute MI can be improved if efforts are made to optimise the interval from symptom onset to thrombolysis or angioplasty. This will require concerted efforts, including public awareness through education to reduce the symptom-to-emergency room time, and maximising efficiencies in door-to-intervention times for primary angioplasty and for early thrombolysis.
Primary angioplasty and early thrombolysis cannot be considered in isolation from one another. For example, patients who have persistent STEMI 90 minutes after receiving thrombolysis should be considered for angioplasty (“rescue angioplasty”). Furthermore, for patients with acute MI who are in cardiac shock, primary angioplasty is considered the preferred intervention. The concomitant use of primary angioplasty and thrombolysis (“facilitated angioplasty”) is considered experimental and has no place in routine management of acute MI at this time. In remote parts of the province, consideration should be given to introducing pre-hospital thrombolysis as the preferred intervention through upgrading a select number of paramedics to advanced care status.
PMCID: PMC3387753  PMID: 23074449
6.  Idiopathic venous thromboembolism and thrombophilia  
Journal of Medicine and Life  2011;4(1):57-62.
During the past decade idiopathic venous thromboembolism has become a separate entity, a chronic illness which has required prolonged anticoagulation and other prevention strategies to avoid recurrences. This article reviews recent developments regarding unprovoked venous thromboembolism and its relation with thrombophilia. In the beginning, the latest definition of idiopathic venous thromboembolism is presented. The article continues with statistics about thrombophilia, related venous thromboembolism, and a classification of major thrombophilic factors according to their intrinsic risk of thrombosis and of thrombotic recurrences. Great interest is given to the predictors of recurrence and the importance of prolonged anticoagulation is underlined. The antiphospholipid antibody syndrome, the most common acquired thrombophilia, is presented separately. The revised diagnosis criteria are discussed. Some characteristics of the antiphospholipid syndrome are worth presenting: the risk of both venous and arterial thrombosis, the high risk of thrombotic recurrence and the diversity of antiphospholipid antibodies.
Patients experiencing idiopathic venous thromboembolic event have a great risk of recurrence, and highly benefit from long time anticoagulation. Natural coagulation inhibitors deficiencies, homozygous factor V Leiden and prothrombin G20210A and the antiphospholipid syndrome, increase the risk of first venous thrombosis and their recurrences and require adequate prevention.
Abbreviations: VTE–venous thromboembolism, HRT–hormone replacement therapy, AVK–antivitamin K, FVL–factor V Leiden, PT G20210A–prothrombin G20210A, TAFI–thrombin activatable fibrinolysis inhibitor, PAI–1–plasminogen activator inhibitor 1, T–PA–tissue plasminogen activator, APS–antiphospholipid syndrome, LA–lupus anticoagulant, Abeta2GP1–anti beta2 glycoprotein 1.
PMCID: PMC3056423  PMID: 21505575
thromboembolism; hypercoagulability; antiphospholipid syndrome; recurrence
7.  Older renal cell cancer patients experience increased rates of venous thromboembolic events: a retrospective cohort study of SEER-Medicare data 
BMC Cancer  2013;13:209.
Background
Venous thromboembolic co-morbidities can have a significant impact on treatment response, treatment options, quality of life, and ultimately, survival from cancer. The extent of venous thromboembolic co-morbidity among older renal cell cancer patients is poorly described in the literature. It is important to understand the scope of venous thromboembolic events, before and after diagnosis, in order to offer renal cell cancer patients optimal care and improved quality of life.
Methods
The main goal of this study was to estimate and describe the incidence of venous thromboembolic events before and after renal cell cancer diagnosis. SEER-Medicare linked data (1991–2003) was utilized for this retrospective cohort analysis (n = 11,950) of older renal cell cancer patients (≥ 65 years). Incidence rates and proportions in addition to multivariable Cox proportional hazard and logistic regression models were utilized to describe the incidence and relative risk of venous thromboembolic events.
Results
We observed that in the 12 months after diagnosis, 8.3% of renal cell cancer patients experienced a deep venous thrombosis, 2.4% experienced a pulmonary embolism, and 3.9% experienced other thromboembolic events. Nearly 70% of venous thromboembolic events occurred in the first 90 days after renal cell cancer diagnosis. Renal cell cancer patients were 2–4 times more likely to have a venous thromboembolic event in the 12 months after cancer diagnosis than non-cancer patients followed during the same time frame. Recent history of a venous event substantially increased the risk of that same event in the 12 months after diagnosis (HR = 5.2-18.8).
Conclusion
Venous thromboembolic events are common and serious co-morbidities that should be closely monitored in older renal cell cancer patients, particularly during the first 3 months following diagnosis and among those with a recent history of a venous thromboembolic event.
doi:10.1186/1471-2407-13-209
PMCID: PMC3648500  PMID: 23621951
Venous thromboembolism; Renal cell carcinoma; Incidence; Co-morbidity; Pulmonary embolism; Deep vein thrombosis
8.  Bivalirudin-based versus conventional heparin anticoagulation for postcardiotomy extracorporeal membrane oxygenation 
Critical Care  2011;15(6):R275.
Introduction
Extracorporeal membrane oxygenation (ECMO) after cardiac operations (postcardiotomy) is commonly used for the treatment of acute heart failure refractory to drug treatment. Bleeding and thromboembolic events are the most common complications of postcardiotomy ECMO. The present study is a retrospective comparison of the conventional heparin-based anticoagulation protocol with a bivalirudin-based, heparin-free protocol. Endpoints of this study are blood loss, allogeneic blood product use, and costs during the ECMO procedure.
Methods
A retrospective study was undertaken in the setting of cardiac surgery, anesthesia, and intensive care departments of a university research hospital. Twenty-one patients (12 adults and nine children) who underwent postcardiotomy ECMO from 2008 through 2011 were retrospectively analyzed. The first consecutive eight patients were treated with heparin-based anticoagulation (H-group) and the next 13 consecutive patients with bivalirudin-based anticoagulation (B-group). The following parameters were analyzed: standard coagulation profile, thromboelastographic parameters, blood loss, allogeneic blood products use, thromboembolic complications, and costs during the ECMO treatment.
Results
Patients in the B-group had significantly longer activated clotting times, activated partial thromboplastin times, and reaction times at thromboelastography. The platelet count and antithrombin activity were not significantly different, but in the H-group a significantly higher amount of platelet concentrates, fresh frozen plasma, and purified antithrombin were administered. Blood loss was significantly lower in the B-group, and the daily cost of ECMO was significantly lower in pediatric patients treated with bivalirudin. Thromboembolic complications did not differ between groups.
Conclusions
Bivalirudin as the sole anticoagulant can be safely used for postcardiotomy ECMO, with a better coagulation profile, less bleeding, and allogeneic transfusions. No safety issues were raised by this study, and costs are reduced in bivalirudin-treated patients.
doi:10.1186/cc10556
PMCID: PMC3388709  PMID: 22099212
9.  Recurrence of thromboembolic disease after discontinuing anticoagulant therapy A study of factors affecting incidence 
British Heart Journal  1970;32(3):359-364.
On 169 occasions anticoagulant therapy for thromboembolic disease was stopped electively and patients were followed for 16 subsequent weeks. The records of those who remained well and those who suffered a relapse were compared in an attempt to identify factors that might affect liability to thromboembolic relapse.
During the follow-up period there were 37 thromboembolic recurrences, an incidence of 22 per cent. None occurred among the patients in whom the original diagnosis of thromboembolic disease was discarded or when a predisposing cause had ceased to be present. There was an inverse relation between liability to relapse and degree of prothrombin time prolongation.
No significant relation could be shown between liability to relapse and any of the following: sex and age; type and severity of the initiating thromboembolic episode; history of earlier thromboembolic disease or relapse after stopping earlier anticoagulant courses; presence of hypertension, hypercholesterolaemia, or diabetes mellitus; type of anticoagulant drug used, duration of therapy, and method of stopping treatment.
Patients with overt occlusive arterial disease at more than one site had a significantly increased liability to relapse when compared with patients with symptomatic disease at a single site. In the group of 134 subjects receiving anticoagulant therapy for coronary arterial disease, occurrence of a thromboembolic episode during the course of treatment and the presence of angina of effort in the months before it was discontinued were both associated with a significant increase in liability to relapse. It is suggested that, ideally, anticoagulant therapy should be continued indefinitely in any patient whose pattern of disease thus increases the likelihood of a thromboembolic recurrence.
PMCID: PMC487334  PMID: 5420082
10.  Whole Blood Gene Expression Analyses in Patients With Single Versus Recurrent Venous Thromboembolism 
Thrombosis research  2011;128(6):536-540.
Introduction
Venous thromboembolism may recur in up to 30% of patients with a spontaneous venous thromboembolism after a standard course of anticoagulation. Identification of patients at risk for recurrent venous thromboembolism would facilitate decisions concerning the duration of anticoagulant therapy.
Objectives
In this exploratory study, we investigated whether whole blood gene expression data could distinguish subjects with single venous thromboembolism from subjects with recurrent venous thromboembolism.
Methods
40 adults with venous thromboembolism (23 with single event and 17 with recurrent events) on warfarin were recruited. Individuals with antiphospholipid syndrome or cancer were excluded. Plasma and serum samples were collected for biomarker testing, and PAXgene tubes were used to collect whole blood RNA samples.
Results
D-dimer levels were significantly higher in patients with recurrent venous thromboembolism, but P-selectin and thrombin-antithrombin complex levels were similar in the two groups. Comparison of gene expression data from the two groups provided us with a 50 gene probe model that distinguished these two groups with good receiver operating curve characteristics (AUC 0.75). This model includes genes involved in mRNA splicing and platelet aggregation. Pathway analysis between subjects with single and recurrent venous thromboembolism revealed that the Akt pathway was up-regulated in the recurrent venous thromboembolism group compared to the single venous thromboembolism group.
Conclusions
In this exploratory study, gene expression profiles of whole blood appear to be a useful strategy to distinguish subjects with single venous thromboembolism from those with recurrent venous thromboembolism. Prospective studies with additional patients are needed to validate these results.
doi:10.1016/j.thromres.2011.06.003
PMCID: PMC3726737  PMID: 21737128
genomics; risk factors; deep vein thrombosis
11.  Hyperthyroidism: A rare cause of pulmonary embolism: Report of two cases 
Several disorders of coagulation and fibrinolysis have been widely reported in patients with hyperthyroidism. Most reports have focused on only the venous thromboembolism risk, and few of them have studied specifically the association between hyperthyroidism and pulmonary embolism (PE). We report two cases of Graves’ disease complicated by PE. The first patient is a 32 year-old man, and the second patient is a 23-year-old female. PE was suspected on the basis of pulmonary hypertension in patient one, and clinical presentation in the other patient. The first patient had also right heart failure. PE was confirmed in both patients by a lung perfusion-ventilation scan test. Thrombophilia screen revealed normal findings in the first patient and an elevation in coagulation factor VIII in the second one. Both patients received heparin, followed by oral anticoagulant therapy. In addition, they were treated with radioactive iodine resulting in partial recovery from hyperthyroidismforpatient oneand clinical euthyroidism for patient two. The former died of acute heart failure secondary to a chest infection, while the later was lost to follow-up. In conclusion, hyperthyroidism is associated with increased risk of venous thromboembolism, including PE. Potential mechanisms involved in this association include endothelial dysfunction, decreased fibrinolytic activity, and increased coagulation factors levels. Thyroid evaluation is recommended in patients with unprovoked venous thromboembolic events. Conversely, the diagnosis of venous thromboembolism should be considered in patients with hyperthyroidism, particularly if additional prothrombotic risk factors are present.
doi:10.4103/2230-8210.122640
PMCID: PMC3872694  PMID: 24381893
Hyperthyroidism; pulmonary embolism; venous thromboembolism; factor VIII levels
12.  Current and Former Smoking and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(9):e1001515.
In a meta-analysis of 32 observational studies involving 3,966,184 participants and 35,151 events, Suhua Wu and colleagues found that current, ever, and former smoking was associated with risk of venous thromboembolism.
Please see later in the article for the Editors' Summary
Background
Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose–response relationship exists.
Methods and Findings
We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09–1.25) for ever smokers, 1.23 (95% CI 1.14–1.33) for current smokers, and 1.10 (95% CI 1.03–1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%–11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%–8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24–1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%–12.3%) for ever smoking, 5.8% (95% CI 3.6%–8.2%) for current smoking, and 2.7% (95% CI 0.8%–4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4–26.7) cases per 100,000 person-years.
Conclusions
Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Blood normally flows throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. Occasionally, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep within the body, usually in a leg, is called deep vein thrombosis (DVT) and can cause pain, swelling, and redness in the affected limb. DVT can be treated with drugs that stop the blood clot from getting larger (anticoagulants) but, if left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are collectively known as venous thromboembolism (VTE). Risk factors for VTE include having an inherited blood clotting disorder, oral contraceptive use, prolonged inactivity (for example, during a long-haul plane flight), and having surgery. VTEs are present in about a third of all people who die in hospital and, in non-bedridden populations, about 10% of people die within 28 days of a first VTE event.
Why Was This Study Done?
Some but not all studies have reported that smoking is also a risk factor for VTE. A clear demonstration of a significant association (a relationship unlikely to have occurred by chance) between smoking and VTE might help to reduce the burden of VTE because smoking can potentially be reduced by encouraging individuals to quit smoking and through taxation policies and other measures designed to reduce tobacco consumption. In this systematic review and meta-analysis, the researchers examine the link between smoking and the risk of VTE in the general population and investigate whether heavy smokers have a higher risk of VTE than light smokers. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 32 observational studies (investigations that record a population's baseline characteristics and subsequent disease development) that provided data on smoking and VTE. Together, the studies involved nearly 4 million participants and recorded 35,151 VTE events. Compared with never smokers, ever smokers (current and former smokers combined) had a relative risk (RR) of developing VTE of 1.17. That is, ever smokers were 17% more likely to develop VTE than never smokers. For current smokers and former smokers, RRs were 1.23 and 1.10, respectively. Analysis of only studies that adjusted for body mass index (a measure of body fat and a known risk factor for conditions that affect the heart and circulation) yielded a slightly higher RR (1.30) for current smokers compared with never smokers. For ever smokers, the population attributable fraction (the proportional reduction in VTE that would accrue in the population if no one smoked) was 8.7%. Notably, the risk of VTE increased by 10.2% for every additional ten cigarettes smoked per day and by 6.1% for every additional ten pack-years. Thus, an individual who smoked one pack of cigarettes per day for 40 years had a 26.7% higher risk of developing VTE than someone who had never smoked. Finally, smoking was associated with an absolute risk increase of 24.3 cases of VTE per 100,000 person-years.
What Do These Findings Mean?
These findings indicate that cigarette smoking is associated with a statistically significant, slightly increased risk for VTE among the general population and reveal a dose-relationship between smoking and VTE risk. They cannot prove that smoking causes VTE—people who smoke may share other unknown characteristics (confounding factors) that are actually responsible for their increased risk of VTE. Indeed, these findings identify body mass index as a potential confounding factor that might affect the accuracy of estimates of the association between smoking and VTE risk. Although the risk of VTE associated with smoking is smaller than the risk associated with some well-established VTE risk factors, smoking is more common (globally, there are 1.1 billion smokers) and may act synergistically with some of these risk factors. Thus, smoking behavior should be considered when screening individuals for VTE and in the prevention of first and subsequent VTE events.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001515.
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolism), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, and on pulmonary embolism; SmokeFree is a website provided by the UK National Health Service that offers advice on quitting smoking
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
The World Health Organization provides information about the dangers of tobacco (in several languages)
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and the dangers of smoking (in English and Spanish)
doi:10.1371/journal.pmed.1001515
PMCID: PMC3775725  PMID: 24068896
13.  Anticoagulant therapy for deep vein thrombosis (DVT) in pregnancy 
Background
Thromboembolic complications are much higher in pregnancy due to procoagulant changes. Heparin does not cross the placenta and the use of unfractionated heparin (UFH) is the current established practice in prophylaxis and treatment for thromboembolism in pregnancy.
Objectives
To compare the effectiveness of anticoagulant therapies for the treatment of deep vein thrombosis in pregnancy. The anticoagulant drugs included are UFH, low molecular weight heparin (LMWH) and warfarin.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (March 2010) and reference lists of retrieved studies.
Selection criteria
Randomised controlled trials comparing any combination of warfarin, UFH, LMWH and placebo in pregnant women.
Data collection and analysis
We used methods described in the Cochrane Handbooks for Systemic Reviews of Interventions for assessing the eligibility of studies identified by the search strategy. A minimum of two review authors independently assessed each study.
Main results
We did not identify any eligible studies for inclusion in the review.
We identified three potential studies; after assessing eligibility, we excluded all three as they did not meet the prespecified inclusion criteria. One study compared LMWH and UFH in pregnant women with previous thromboembolic events and, for most of these women, anticoagulants were used as thromboprophylaxis. There were only three women who had a thromboembolic event during the current pregnancy and it was unclear whether the anticoagulant was used as therapy or prophylaxis. We excluded one study because it included only women undergoing caesarean birth. The third study was not a randomised trial.
Authors’ conclusions
There is no evidence from randomised controlled trials on the effectiveness of anticoagulation for deep vein thrombosis in pregnancy. Further studies are required.
doi:10.1002/14651858.CD007801.pub2
PMCID: PMC4238056  PMID: 20556784
Anticoagulants [*therapeutic use]; Heparin [therapeutic use]; Heparin, Low-Molecular-Weight [therapeutic use]; Pregnancy Complications, Hematologic [*drug therapy]; Venous Thrombosis [*drug therapy]; Warfarin [therapeutic use]; Female; Humans; Pregnancy
14.  Diagnosis and treatment of deep-vein thrombosis and approach to venous thromboembolism in obstetrics and gynecology 
Deep vein thrombosis (DVT) is a common condition in which the approach to its diagnosis has evolved over the years. Currently, an algorithm strategy combining pre-test probability, D-Dimer testing and compression ultrasound imaging allows for safe and convenient investigation of suspected lower-extremity thrombosis. Patients with low pre-test probability and a negative D-Dimer test result can have proximal DVT excluded without the need for diagnostic imaging. The mainstay of treatment of DVT is anticoagulation therapy, whereas interventions such as thrombolysis and placement of inferior vena cava filters are reserved for special situations. The use of low-molecular-weight heparin (LMW) allows for outpatient management of most patients with DVT. The duration of anticoagulation therapy depends on whether the primary event was idiopathic or secondary to a transient risk factor. More research is required to optimally define the factors that predict an increased risk of recurrent DVT to determine which patients can benefit from extended anticoagulant therapy. DVT is also a serious problem in the antenatal and postpartum period of pregnancy. Thromboembolic complications are the leading cause of both maternal and fetal morbidity and mortality. The incidence of venous thromboembolism during normal pregnancy is six-fold higher than in the general female population of childbearing age. The treatment of DVT during pregnancy deserves special mention, since oral anticoagulation therapy is generally avoided during pregnancy because of the teratogenic effects in the first trimester and the risk of fetal intracranial bleeding in the third trimester. LMW heparin is the treatment of choice for DVT during pregnancy. If acute DVT occurs near term, interrupting anticoagulation therapy may be hazardous because of the risk of pulmonary embolism. In this situation, placement of a retrievable inferior vena cava filter must be considered. However, there is no consensus as to what the appropriate dose should be and whether anti-Xa levels need to be monitored.
doi:10.5152/jtgga.2011.39
PMCID: PMC3939275  PMID: 24591986
Venous thrombosis; heparin; low- molecular- weight: heparin; anticoagulants; partial thromboplastin time; thromboembolism in pregnancy
15.  Intraarterial Tirofiban Thrombolysis for Thromboembolisms During Coil Embolization for Ruptured Intracranial Aneurysms 
Objective
Thromboembolus can occur during endovascular coil embolization. The aim of our study was to show our experience of intraarterial (IA) tirofiban infusion for thromboembolism during coil embolization for ruptured intracranial aneurysms.
Methods
This retrospective analysis was conducted in 64 patients with ruptured aneurysms who had emergent endovascular coil embolization from May 2007 to April 2011 at a single institute. Thromboembolic events were found in ten patients (15.6%). Anticoagulation treatment with intravenous heparin was started after the first coil deployment in ruptured aneurysmal sac. When a thrombus or embolus was found during the procedure, we tried to resolve them without delay with an initial dosage of 0.3 mg of tirofiban up to 1.2 mg.
Results
Three patients of four with total occlusion had recanalizations of thrombolysis in myocardial infarction (TIMI) grade III and five of six with partial occlusion had TIMI grade III recanalizations. Eight patients showed good recovery, with modified Rankin Scale (mRS) score of 0 and one showed poor outcome (mRS 3 and 6). There was no hemorrhagic or hematologic complication.
Conclusion
IA tirofiban can be feasible when thromboembolic clots are found during coil embolization in order to get prompt recanalization, even in patients with subarachnoid hemorrhage.
doi:10.7461/jcen.2012.14.1.5
PMCID: PMC3471250  PMID: 23210024
Aneurysm coiling; Thromboembolism; Tirofiban; Intracranial aneurysm
16.  Impact of Venous Thromboembolism and Anticoagulation on Cancer and Cancer Survival 
Journal of Clinical Oncology  2009;27(29):4902-4911.
Changes in the hemostatic system and chronic hemostatic activation are frequently observed in patients with cancer, even in the absence of venous thromboembolism (VTE). VTE is a leading cause of death among patients with cancer and contributes to long-term mortality in patients with early as well as advanced-stage cancer. Mounting evidence suggests that components of the clotting cascade and associated vascular factors play an integral part in tumor progression, invasion, angiogenesis, and metastasis formation. Furthermore, there are intriguing in vitro and animal findings that anticoagulants, in particular the low molecular weight heparins (LMWHs), exert an antineoplastic effect through multiple mechanisms, including interference with tumor cell adhesion, invasion, metastasis formation, angiogenesis, and the immune system. Several relatively small randomized controlled clinical trials of anticoagulation as cancer therapy in patients without a VTE diagnosis have been completed. These comprise studies with LMWH, unfractionated heparin, and vitamin K antagonists, with overall encouraging but nonconclusive results and some limitations. Meta-analyses performed for the American Society of Clinical Oncology VTE Guidelines Committee and the Cochrane Collaboration suggest overall favorable effects of anticoagulation on survival of patients with cancer, mainly with LMWH. However, definitive clinical trials have been elusive and questions remain regarding the importance of tumor type and stage on treatment efficacy, the impact of fatal thromboembolic events, optimal anticoagulation therapy, and safety with differing chemotherapy regimens. Although the LMWHs and related agents hold promise for improving outcomes in patients with cancer, additional studies of their efficacy and safety in this setting are needed.
doi:10.1200/JCO.2009.22.4584
PMCID: PMC2799059  PMID: 19738120
17.  Intracranial hemorrhage during GliaSite RTS manipulation in an anticoagulated patient 
The GliaSite radiation therapy system (RTS) is an implantable balloon brachytherapy applicator used to deliver iodine-125 in the treatment of recurrent high-grade gliomas. Patients generally tolerate the procedure well, with only rare reports of adverse events such as wound infection, meningitis, and symptomatic radiation necrosis. Hemorrhagic complications have not been reported. We present a case report describing intracranial hemorrhage during GliaSite manipulation in a patient receiving long-term anticoagulation for a previously diagnosed pulmonary embolism. The GliaSite RTS and the management of venous thromboembolism in patients with brain tumors are reviewed. These events suggest that normalizing coagulation status during GliaSite balloon inflation and deflation should be considered.
doi:10.1017/S1460396907005031
PMCID: PMC2630704  PMID: 19173012
Glioblastoma multiforme; Venous thromboembolism; Anticoagulation; Intracranial hemorrhage; GilaSite RTS; Brachytherapy
18.  The Relationship of the Factor V Leiden Mutation and Pregnancy Outcomes for Mother and Fetus 
American journal of perinatology  2011;29(3):225-230.
Objective
We sought to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden (FVL) mutation without a personal history of thromboembolism, and to evaluate the impact of maternal and fetal FVL mutation carriage or other thrombophilias on the risk of adverse outcomes.
Methods
Women with a singleton pregnancy and no history of thromboembolism were recruited at 13 clinical centers before 14 weeks of gestation from April 2000 to August 2001. Each was tested for the FVL mutation, as was the resultant conceptus after delivery or after miscarriage, when available. The incidence of thromboembolism (primary outcome), and of other adverse outcomes, was compared between FVL mutation carriers and noncarriers. We also compared adverse outcomes in a secondary nested carrier-control analysis of FVL mutation and other coagulation abnormalities. In this secondary analysis, we defined carriers as women having one or more of the following traits: carrier for FVL mutation, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, or lupus anticoagulant-positive, heterozygous for prothrombin G20210A or homozygous for the 5,10 methylenetetrahydrofolate reductase mutations. Carriers of the FVL mutation alone (with or without activated protein C resistance) were compared with those having one or more other coagulation abnormalities and with controls with no coagulation abnormality.
Results
One hundred thirty-four FVL mutation carriers were identified among 4,885 gravidas (2.7%), with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation carriers (0%, 95% confidence interval 0–2.7%). Three pulmonary emboli and one deep venous thrombosis occurred (0.08%, 95% confidence interval 0.02–0.21%), all occurring in FVL mutation noncarriers. In the nested carrier-control analysis (n = 339), no differences in adverse pregnancy outcomes were observed between FVL mutation carriers, carriers of other coagulation disorders, and controls. Maternal FVL mutation carriage was not associated with increased pregnancy loss, preeclampsia, placental abruption, or small for gestational age births. However, fetal FVL mutation carriage was associated with more frequent preeclampsia among African-American (15.0%) and Hispanic (12.5%) women than white women (2.6%, P = .04), adjusted odds ratio 2.4 (95% confidence interval 1.0–5.2, P = .05).
Conclusion
Among women with no history of thromboembolism, maternal heterozygous carriage of the FVL mutation is associated with a low risk of venous thromboembolism in pregnancy. Neither universal screening for the FVL mutation, nor treatment of low-risk carriers during pregnancy is indicated.
doi:10.1055/s-0031-1285097
PMCID: PMC3770153  PMID: 21818732
19.  Continuation of vitamin K antagonists as acceptable anticoagulation regimen in patients undergoing pulmonary vein isolation 
Netherlands Heart Journal  2011;20(1):12-15.
Background
Recent studies have demonstrated that radiofrequency isolation of the pulmonary veins (PVI) is an effective treatment for symptomatic atrial fibrillation. Based on these positive results, non- pharmacological therapy has been incorporated in the guidelines for drug refractory atrial fibrillation, resulting in an increased popularity. The prevention of thromboembolic complications remains an important issue.
Methods
In January 2010, we adopted an anticoagulation strategy based on continuation of vitamin K antagonists (VKAs) and selective use of transoesophageal echocardiogram (TEE). We retrospectively analysed the results of this strategy in all patients referred for PVI treatment. VKAs were started for all patients 2 months prior to treatment. Discontinuation of oral anticoagulation was considered 3 months after treatment based on thromboembolic and bleeding risk profile. Bleeding and thromboembolic complications were registered during outpatient clinic follow-up up until 3 months.
Results
We performed 151 PVI procedures from January 2010 to March 2011. All patients were seen 6 weeks after discharge. No transient ischaemic accidents or ischaemic cerebrovascular incidents occurred pre-, peri- or postprocedure. Four (2.7%) procedures were complicated by tamponade requiring pericardiocentesis.
Conclusions
Our data support the increasing evidence for continuation of periprocedural administration of VKAs complemented by a selective TEE approach as a safe therapy for thromboembolic complications.
doi:10.1007/s12471-011-0223-0
PMCID: PMC3247635  PMID: 22161077
Anticoagulation; Atrial fibrillation; Catheter ablation; Stroke; Transesophageal echocardiography
20.  Adherence to local guidelines for venous thromboprophylaxis: a cross-sectional study of medical inpatients in Argentina 
Thrombosis Journal  2011;9:18.
Background
Venous thromboembolism prophylaxis has been shown to safely and cost-effectively reduce the incidence of thromboembolic events in medical inpatients. However, there is a gap between evidence and medical practice. The aim of this study was evaluate the appropriateness of prescribing venous thromboembolism prophylaxis in accordance with local recommendations for medical inpatients.
Methods
This cross-sectional study included 310 prescriptions of medical general-ward admitted patients of two university hospitals of Buenos Aires, Argentina.
Data was collected using filled-out prescriptions, medical records and interviews with the head attending physician. Information was gathered at different times during 16 days randomly selected over September 2007 and January 2008.
Results
One hundred eighty eight patients' prescriptions (60.6%) were appropriate according to the institutional guidelines. Inappropriateness was due to excessive (14.2%), insufficient (15.8%) and absent (9.4%) prescribing. According to the recommendations of the American College of Chest Physicians, 256 (82.6%) patients received appropriate prophylaxis. Twenty-nine patients (9.4%) were considered at low risk for thromboembolism and did not need pharmacologic or mechanical prophylaxis. One hundred three patients (33.2%) had at least one major risk factor for venous thromboembolism. Compliance with the institutional guidelines was more frequently in the case of high risk patients. Complex preventive measures and low risk patients were related to lower adherence to recommendations. In the multivariate analysis, predictors of inappropriateness were the requirement of a surgical procedure and absence of prophylaxis prescribing at admission. In contrast, patients with a diagnosis of gastrointestinal disorders had lower odds of inappropriateness than those with an infectious disease.
Conclusions
Most medical inpatients received some thromboprophylaxis measure, but the compliance with recommendations was less frequent. Efforts should be made to improve the appropriate prescription.
doi:10.1186/1477-9560-9-18
PMCID: PMC3286366  PMID: 22172213
21.  Breast Cancer as an Acquired Thrombophilic State 
Journal of Breast Cancer  2012;15(2):148-156.
Cancer is an acquired thrombophilic condition manifested by increased incidence of venous and arterial thromboembolic complications. Despite progress that has been achieved in treatments over the recent years, thromboembolism remains a major complication in patients with breast cancer; it is accompanied by significant morbidity and mortality. Approximately, 1% of breast cancer patients develop venous thromboembolism within 2 years with the highest incidence occurring in the 6 months post diagnosis. Metastatic disease and their comorbidities are the strongest predictors of the development of thrombotic event. The diagnosis of venous thromboembolism is associated with a higher risk of death within 2 years of diagnosis. Thromboembolic events in cancer patients range from abnormal laboratory coagulation tests without specific symptoms to massive thomboembolism and disseminated intravascular coagulation. The underlying pathophysiology is complex and includes the prothrombotic properties of cancer cells, which can be enhanced by anticancer treatment modalities, such as surgery, hormonal agents, and chemotherapy. Primary thromboprophylaxis in cancer patients should be individualized according to risk. For secondary prevention, several clinical studies have shown that low molecular weight heparin has improved patients' compliance, cancer outcomes and overall survival. This review summarizes the available data on the pathogenesis and clinical approach of hemostatic changes in breast cancer.
doi:10.4048/jbc.2012.15.2.148
PMCID: PMC3395737  PMID: 22807931
Blood coagulation; Breast neoplasms; Hemostasis; Thrombosis
22.  Thromboembolism 
Clinical Evidence  2010;2010:0208.
Introduction
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low-molecular-weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.
Key Points
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. About 5% to 15% of people with untreated DVT may die from pulmonary embolism.The risk of recurrence of thromboembolism falls over time, but the risk of bleeding from anticoagulation remains constant.
Oral anticoagulants are considered effective in people with proximal DVT compared with no treatment, although we found few trials. In people with proximal DVT or pulmonary embolism, long-term anticoagulation reduces the risk of recurrence, but high-intensity treatment has shown no benefit. Both approaches increase the risk of major bleeding. Low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin, and may be as effective as oral anticoagulants, although all are associated with some adverse effects.We don't know how effective tapering off of oral anticoagulant agents is compared with stopping abruptly.We don't know whether once-daily LMWH is as effective as twice-daily administration at preventing recurrence. Home treatment may be more effective than hospital-based treatment at preventing recurrence, and equally effective in reducing mortality. Vena cava filters reduce the short-term rate of pulmonary embolism, but they may increase the long-term risk of recurrent DVT.Elastic compression stockings reduce the incidence of post-thrombotic syndrome after a DVT.
In people with isolated calf DVT, anticoagulation with warfarin may reduce the risk of proximal extension, although prolonged treatment seems no more beneficial than short-term treatment.
Anticoagulation may reduce mortality compared with no anticoagulation in people with a pulmonary embolus, but it increases the risk of bleeding. We found few studies that evaluated treatments for pulmonary embolism. LMWH may be as effective and safe as unfractionated heparin.Thrombolysis seems as effective as heparin in treating people with major pulmonary embolism, but it is also associated with adverse effects.The use of computerised decision support may increase the time spent adequately anticoagulated, and reduce thromboembolic events or major haemorrhage, compared with manual dosage calculation.
PMCID: PMC2907619
23.  Thromboembolism 
Clinical Evidence  2011;2011:0208.
Introduction
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low molecular weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.
Key Points
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. About 5% to 15% of people with untreated DVT may die from pulmonary embolism.The risk of recurrence of thromboembolism falls over time, but the risk of bleeding from anticoagulation remains constant.
Oral anticoagulants are considered effective in people with proximal DVT compared with no treatment, although we found few trials. In people with proximal DVT or pulmonary embolism, long-term anticoagulation reduces the risk of recurrence, but high-intensity treatment has shown no benefit. Both approaches increase the risk of major bleeding. Low molecular weight heparin (LMWH) is more effective than unfractionated heparin, and may be as effective as oral anticoagulants, although all are associated with some adverse effects.We don't know how effective tapering off of oral anticoagulant agents is compared with stopping abruptly.We don't know whether once-daily LMWH is as effective as twice-daily administration at preventing recurrence. Home treatment may be more effective than hospital-based treatment at preventing recurrence, and equally effective in reducing mortality. Vena cava filters reduce the short-term rate of pulmonary embolism, but they may increase the long-term risk of recurrent DVT.Elastic compression stockings reduce the incidence of post-thrombotic syndrome after a DVT compared with placebo or no treatment.
In people with isolated calf DVT, anticoagulation with warfarin may reduce the risk of proximal extension, although prolonged treatment seems no more beneficial than short-term treatment.
Anticoagulation may reduce mortality compared with no anticoagulation in people with a pulmonary embolus, but it increases the risk of bleeding. We found few studies that evaluated treatments for pulmonary embolism. LMWH may be as effective and safe as unfractionated heparin. Thrombolysis seems as effective as heparin in treating people with major pulmonary embolism, but it is also associated with adverse effects.The use of computerised decision support may increase the time spent adequately anticoagulated, and reduce thromboembolic events or major haemorrhage, compared with manual dosage calculation.
PMCID: PMC3217723  PMID: 21385473
24.  Increased platelet reactivity and significant changes in coagulation markers after cavopulmonary connection 
Heart  2001;85(1):61-65.
OBJECTIVE—To evaluate platelet reactivity and coagulation markers after surgical palliation of univentricular hearts.
DESIGN AND PATIENTS—Cross sectional survey of 24 patients, median age 11 (range 4-22) years, at 2 (range 0.5-6) years after a total cavopulmonary connection (TCPC; n = 14) or a bidirectional Glenn anastomosis (Glenn; n = 10).
MAIN OUTCOME MEASURES—Platelet reactivity and/or coagulation markers were measured in 20 patients (four excluded because of anticoagulant treatment) and compared with 33 healthy controls, median age 12 (range 6-16) years.
RESULTS—None of the patients had clinically apparent thromboembolic events. However, increased platelet reactivity was observed ex vivo both after collagen induced platelet aggregation (median 73% (interquartile range 61-84%) in patients, and 61% (47-69%) in controls; p < 0.01), and after ADP induced platelet aggregation (69% (53-77%) in patients, and 56% (40-66%) in controls; p < 0.05). Concentrations of protein S antigen, antithrombin III, and protein C activity were reduced after both TCPC and Glenn. A concomitant decrease was seen in coagulation factor II, VII, X, and factor VII clot activity.
CONCLUSIONS—Several abnormalities in the coagulation system were observed after bidirectional Glenn anastomosis, similar to alterations previously described in Fontan operated and TCPC patients. Antithrombotic treatment in these patients is still an unresolved issue, but aspirin is often recommended. This study shows that such a strategy is rational and the results suggest that antiplatelet treatment may be advantageous, either alone or in combination with oral anticoagulant treatment.


Keywords: Fontan procedure; thrombosis; platelets; coagulation
doi:10.1136/heart.85.1.61
PMCID: PMC1729588  PMID: 11119465
25.  Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy 
Background
Whether to continue oral anticoagulant therapy beyond 6 months after an “unprovoked” venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants.
Methods
In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5–7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p < 0.10) with high interobserver reliability to derive a clinical decision rule.
Results
We identified 91 confirmed episodes of recurrent venous thromboembolism during follow-up after discontinuing oral anticoagulation therapy (annual risk 9.3%, 95% CI 7.7%–11.3%). Men had a 13.7% (95% CI 10.8%–17.0%) annual risk. There was no combination of clinical predictors that satisfied our criteria for identifying a low-risk subgroup of men. Fifty-two percent of women had 0 or 1 of the following characteristics: hyperpigmentation, edema or redness of either leg; D-dimer ≥ 250 μg/L while taking warfarin; body mass index ≥ 30 kg/m2; or age ≥ 65 years. These women had an annual risk of 1.6% (95% CI 0.3%–4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%–17.3%).
Interpretation
Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men. (http://Clinicaltrials.gov trial register number NCT00261014)
doi:10.1503/cmaj.080493
PMCID: PMC2518177  PMID: 18725614

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