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New In Coagulation

WHAT'S NEW IN COAGULATION: JULY 2011

FDA Safety Review Probing Drospirenone's Potential Association With VTE Risk

The Food and Drug Administration announced it is conducting a safety review of oral contraceptive drugs that contain drospirenone to evaluate the risk for venous thromboembolism (VTE) associated with these products. Two recent reports in the British Medical Journal found a twofold to threefold greater risk of blood clots in women taking pills like Bayer's Yaz," the FDA said. The agency expects to "have results later this summer of an 800,000-person study it commissioned to examine the risks."

The FDA advised healthcare professionals to continue following the "recommendations on drug labels when prescribing oral contraceptive products that contain drospirenone." In addition, clinicians should "discuss the known benefits and potential risks of drospirenone-containing products with patients and educate them about the signs and symptoms of VTE, a term that incorporates both deep vein thrombosis and pulmonary embolism. The European Medicines Agency "concluded on May 27 that such birth control pills carry a higher risk" of VTE and that warning labels "should be updated accordingly." However, the EMA "noted the overall risk of blood clot from any birth control method remains small and stopped short of advising women to stop taking pills containing drospirenone.

Ticagrelor Approved in Canada

Health Canada has granted approval to ticagrelor for the secondary prevention of atherothrombotic events in patients with ACS,. Canada joins the EU and a range of other countries in approving the drug, to be marketed in Canada as Brilinta. Meanwhile, in the US, the FDA has twice postponed a decision on ticagrelor since an advisory committee voted recommending approval of the agent in July 2010. In February, the company announced that the FDA has accepted its resubmission of the new drug application (NDA) and has set a new date for a decision on approval of July 20, 2011.

Support for the approval comes primarily from the 18000-patient PLATO trial, conducted in 43 countries around the world, showing that ticagrelor plus aspirin reduced the primary end point--a composite of death from vascular causes, MI, or stroke--by 16% compared with clopidogrel plus aspirin over 12 months (9.8% of patients receiving ticagrelor suffered a primary-end-point event compared with 11.7% of those taking clopidogrel [p<0.001]).

But the outcome in the subset of 1814 patients in the US and Canada was worse in those taking ticagrelor than in those on clopidogrel, with a primary end point occurring in 11.9% of ticagrelor-treated patients compared with 9.6% of those on clopidogrel, although the difference was not significant. That so-called "North American anomaly" is believed to be the key reason why the FDA has taken its time making a decision on the drug. The company has previously said that the additional analyses of the PLATO trial requested by the FDA focused primarily on interactions between ticagrelor and aspirin, which is typically given in higher doses in the US than in Europe in ACS. The most common adverse events reported by patients on ticagrelor include an increase in bleeding (such as nosebleeds), shortness of breath, and headache.

Time to Revisit Dabigatran Dose in the United States?

The lower dose of dabigatran (Pradaxa; Boehringer Ingelheim), tested but not approved in the United States for stroke prevention in patients with atrial fibrillation, may be best after all for patients older than 75 years, a new analysis suggests.

Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trialists publish "previously unreported" safety results for both the 110-mg and 150-mg dose of dabigatran vs warfarin for different types of major bleeding and in key subgroups, most notably individuals older than 75 years. A key finding in the new analysis, they say, is an increased risk for extracranial bleeding with dabigatran, 150 mg twice daily, in patients 75 years and older.

The RE-LY trial enrolled more than 18,000 patients with atrial fibrillation at risk for stroke to receive dabigatran, 110 mg or 150 mg twice daily, or warfarin at a dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median of 2 years. The trial was conducted in 976 centers in 44 countries. The trial showed that dabigatran, 110 mg twice daily, compared with warfarin was associated with a similar risk for stroke and a lower risk for major bleeding and that dabigatran, 150 mg twice daily, was associated with a lower risk for stroke and a similar risk for major bleeding.

Largely on the basis of these findings, the US Food and Drug Administration (FDA) in October 2010 approved dabigatran for the prevention of stroke and systemic embolism in patients with AF. The agency approved 2 doses: 150 mg twice daily and, for a small subset of patients with severe renal impairment, 75 mg twice daily, which was not studied in RE-LY. In Canada, both the 110-mg and 150-mg doses are approved.

In the new analysis of bleeding reported now in Circulation, dabigatran, 110 mg twice daily, compared with warfarin was associated with a lower risk for major bleeding (2.87% vs 3.57%; P = .002), whereas dabigatran, 150 mg twice daily, was associated with a similar risk for major bleeding (3.31% vs 3.57%; P = .32).

They found a "significant treatment-by-age interaction. In the under 75s, both doses of dabigatran compared with warfarin are associated with reduced bleeding, but in the over 75s the lower dose of dabigatran (110 mg [twice daily]) is associated with a similar risk of bleeding compared with warfarin and the higher dose (150 mg [twice daily]) is associated with a higher risk of bleeding compared with warfarin."

More Stroke Patients Getting Thrombolytic Therapy

The rate of thrombolytic therapy use in the United States approximately doubled from 2005 to 2009.By conservative estimates, 3.4% to 5.2% of ischemic stroke patients in the United States received recombinant tissue-type plasminogen activator (rtPA) in 2009, up from 1.8% to 2.1% in 2004.

A 2008 report in Stroke by some of the same researchers showed that the rate of thrombolytic use for ischemic stroke increased only slightly between 2001 and 2004, at a rate of 0.04% to 0.09% per year.The new report, which represents an update on rtPA use for ischemic stroke from 2005 to 2009, is "strikingly different" in that it suggests a near doubling of rates of use.This more recent increase in treatment was consistent using either pharmacy billing records or ICD-9 [International Classification of Diseases, Ninth Revision] codes to estimate thrombolytic use.DRG 559 increased payment to hospitals for acute stroke patients to $11,500 compared with $6400 for DRG 14 (intracranial hemorrhage or stroke with infarct) and $4900 for DRG 15 (nonspecific cerebrovascular accident or precerebral occlusion without infarct).

In May 2009, the American Heart Association/American Stroke Association also endorsed expansion of the tPA treatment window from 3 to 4.5 hours on the strength of the third European Cooperative Acute Stroke Study (ECASS 3).

Using the ICD-9 code 99.10 (injection or infusion of thrombolytic agent), thrombolytic use increased by 28% in the MEDPAR database and 24% per year in the Premier database, they report. When considering pharmacy billing codes, the rate of thrombolytic use for all patients within Premier increased from 2.4% in 2005 to 4.5% in 2009. Inclusion of patients with transient ischemic attack or hemorrhagic stroke who received any.

New System Classifies Causes of Abnormal Uterine Bleeding

The International Federation of Gynecology and Obstetrics (FIGO) has approved a new classification system (PALM-COEIN) for causes of abnormal uterine bleeding (AUB) in nongravid women of reproductive age. Of the 9 categories in the new FIGO classification system (PALM-COEIN), the first 4 are defined as visually objective structural criteria (PALM: polyp, adenomyosis, leiomyoma, and malignancy and hyperplasia). The second 4 are unrelated to structural abnormalities (COEI: coagulopathy, ovulatory dysfunction, endometrial, and iatrogenic), and the final category is for entities that are not yet classified (N).

After a thorough 5-year review process beginning with workshops in 2005, a group of clinician-investigators from 17 countries on 6 continents who had substantial experience in AUB research developed and revised a draft system that was distributed for comments.

The PALM categories (polyp, adenomyosis, leiomyoma, and malignancy and hyperplasia) refer to discrete (structural) entities that can be measured visually with imaging techniques, such as sonography and/or histopathology testing. The "polyp" category lends itself to the development of a subclassification for clinical or investigative use based on a combination of variables, including polyp dimension, location, number, and morphologic and histologic features. The "leiomyoma" category is subdivided into patients with at least 1 submucosal myoma and those with myomas that do not affect the endometrial cavity.Within the "malignancy and hyperplasia" group, it was proposed that malignant or premalignant lesions, such as atypical endometrial hyperplasia, endometrial carcinoma, and leiomyosarcoma, be categorized as such within the major category, but further described with use of existing World Health Organization and FIGO classification and staging systems.

In contrast to the PALM group, the COEIN group (coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) includes nonstructural entities that are not defined on imaging or histopathology testing. The "iatrogenic" category refers to AUB associated with the use of exogenous gonadal steroids, intrauterine systems or devices, or other systemic or local agents.

The diagnosis of chronic AUB requires unpredictability, excessive duration, abnormal volume, and/or abnormal frequency of menses for at least the previous 3 months. Structured history should determine ovulatory function, potential related medical disorders, medications, and lifestyle factors that might contribute to AUB. Subsequent appropriate investigation may be based in part on the future fertility desires of the patient. Ancillary testing should include hemoglobin and/or hematocrit, testing for conditions that could contribute to an ovulatory disorder (thyroid function, prolactin levels, and serum androgen levels), and either referral to a hematologist or appropriate tests for von Willebrand's disease if a structured history suggests coagulopathy.

The developers of the new system intended it for practical and feasible use by clinicians in most countries worldwide to readily and consistently classify patients with AUB. Because of a lack of availability in many countries, the use of magnetic resonance imaging (MRI) for characterization of structural lesions of the uterus was not feasible; therefore, use of MRI was not included as a mandatory tool to classify patients with chronic AUB.

Dabigatran Cost-Effectiveness Depends on Risk, INR Control

Whether use of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) in atrial fibrillation (AF) meets the standard criteria for cost-effectiveness compared with warfarin depends largely on the patient's risk of stroke or hemorrhage and how tightly anticoagulation could be managed on the latter drug. Cost-effectiveness is defined as a cost of less than $50000 per quality-adjusted life-year (QALY) gained and was based primarily on data from the >18000-patient RE-LY trial.

Dabigatran 150 mg twice-daily met the cost-effectiveness threshold in patients considered high risk for either stroke or hemorrhage unless they maintained "excellent" INR control. Warfarin was cost-effective in patients with only moderate risk for those complications, unless for whatever reason INR control was poor, the group concluded.

Patients unwilling to get their INR monitored by any method--including self-monitoring or point-of-care testing--should receive dabigatran instead. Patients whose adherence to taking medicines is poor should receive warfarin rather than dabigatran, because dabigatran needs to be taken twice daily.

Dabigatran at 150 mg twice daily was associated with a quality-adjusted survival of 8.65 QALYs; it was 8.54 QALYs for dabigatran 110 mg twice daily and 8.40 QALYs for warfarin. Overall, the higher dabigatran dose cost $86000 per QALY compared with warfarin; it was $150000 per QALY for the lower dose.But dabigatran 150 mg twice daily met the cost-effectiveness threshold among patients with a moderate stroke risk, reflected by a CHADS₂ score of 2, as long as the risk of hemorrhage was put at about 6% per year. It was cost-effective at any risk of hemorrhage among patients with a greater stroke risk--that is, a CHADS₂ score of >3. It was never cost-effective when the CHADS₂ score was only 0 or 1.

If the cost of dabigatran 150 mg twice daily was put at less than $1800 per year, it met the cost-effectiveness threshold compared with warfarin regardless of stroke and hemorrhage risks, according to the group. In an analysis by degree of INR control, the higher dabigatran dose was cost-effective for patients with a CHADS₂ of at least 2 among patients who on warfarin would spend <57.1% of their time with INR in the therapeutic range (the lowest quartile for medical centers participating in RE-LY). On the other hand, it wasn't ever cost-effective vs warfarin in the setting of INR control >72.6% of the time (the highest quartile for RE-LY centers).

Pharmacogenomics of Warfarin: Clinical Implications

There is currently a wealth of data surrounding genetic polymorphisms in 2 genes, CYP2C9 and VKORC1, and how these specific polymorphisms affect variation in warfarin dose requirements, international normalized ratio (INR) control during warfarin initiation, and, for certain variants, bleeding outcomes in patients treated with warfarin.^[1] The strength of this evidence prompted the US Food and Drug Administration (FDA) to update the drug label for warfarin in 2007 and then again in January 2010 with recommendations for initiation dose modifications in carriers of the specific CYP2C9 and VKORC1 variants.

However, despite the strong and consistent association data surrounding these variants and a variety of warfarin-related outcomes, there is a paucity of data demonstrating their benefit in clinical practice. The few studies performed to date were either underpowered or lacked adequate control populations and demonstrated inconsistent results.^[2,3] Although larger, appropriately powered, randomized controlled trials are expected to deliver results within the coming years, these trials might not answer all relevant questions, such as how to incorporate novel anticoagulants, how to measure the cost-effectiveness of testing, and how to evaluate the effect of genetic variants on hard clinical endpoints such as bleeding and thrombosis.

As of now, there are no clear guidelines to direct clinical practice on the use of genetic testing to inform warfarin therapy administration. Those that do exist recommend against routine testing, as no prospective clinical trial has yet demonstrated any clinical benefit.^[4] Until such data are available, these recommendations are unlikely to change.

Dabigatran, an oral direct thrombin inhibitor that has proven superior to warfarin in lowering the risk for stroke, systemic embolism, and/or hemorrhage,^[5] does not seem to have the same pharmacogenetic considerations as warfarin, and thus its use bypasses the need for pharmacogenetic testing. However, dabigatran comes with a significant cost disadvantage and is renally cleared, so warfarin might still be preferred in certain patients. Therefore, there remains a need for guidance on how to use genetic testing to inform warfarin therapy in selected individuals.

Embolism Prophylaxis, Education of High-Risk Patients Needed

Hospitals need to pick up the pace in prescribing anticoagulation therapy for prophylaxis against deep vein thrombosis (DVT) and pulmonary embolism (PE), and do a better job of educating their patients who are at high risk, according to researchers here at Hospital Medicine 2011: Society of Hospital Medicine (SHM) Annual Meeting. The first survey involved 500 adult patients (mean age, 52 years; 64% women) who had been hospitalized for at least 3 days within 12 months of sampling. The group rates of DVT therapy varied by subgroup: ambulation (63%), compression stocking (39%), mechanical compression (37%), aspirin (37%), anticoagulant injection (29%), and anticoagulant pill (28%).

Less than one third of the respondents reported DVT prophylaxis anticoagulation therapy, either an anticoagulant pill or injection, but more than 40% surveyed reported a family history of blood clotting disorder.

Among respondents surveyed, 72% had not heard of DVT, and 85% had not heard of PE,. But these patients did have a family history of a blood clotting disorder."Adherence varied, with most patient complaints centered on warfarin use. Respondents said the "therapy was very or moderately difficult to use," and comments focused on the injections being a problem.The 148 patients using low–molecular weight heparin also cited injections as a down side of this therapy Most patients (99%) scored higher points in awareness when asked whether they recognized the important dangers from a blood clot, as well as the added risk during hospitalization; however, almost half (46%) said their doctor did not provide information about blood clot risk related to hospitalization.

HeartMate II Patients Need Less Anticoagulation Therapy

Data from 64 HeartMate II (Thoratec) left ventricular assist device (LVAD) patients treated at the Henry Ford Hospital in Detroit suggest that many of the patients implanted with the continuous-flow LVAD are being given too much anticoagulation therapy [ Most centers report a 25% GI bleeding rate with the HeartMate II device in patients on warfarin and aspirin, which is significantly greater than what was seen in patients implanted with the previous-generation HeartMate XVE LVAD and treated with just aspirin, he said. "Continuous-flow pumps can produce arteriovenous malformations [AVMs] in the gut, and that can cause GI bleeding, which is one of the downsides of continuous-flow pumps compared with pulsatile pumps, so this has become a significant problem,because it's a continuous-flow pump and the capillary bed is not seeing pulsatile flow, that leads to the development of AVMs.

In the study, 14 patients (21.9%) had a GI bleed, appearing after an average of 460 days of ventricular support with the device. All the patients were taking 81 mg of aspirin daily plus warfarin, with a target INR of 2.0 to 2.5; at the time of the index event, the patients' average INR was 2.18.Patients with a GI bleed were transfused with an average of 5.4 units of packed red blood cells. By comparison, a recent study comparing transfusions in HeartMate II patients with HeartMate XVE patients found HeartMate II patients required an average of 6.3 units of packed red blood cells vs 3.8 units for HeartMate XVE patients. The average INR at the index event in that study was 1.67.

However, GI bleeds did not significantly affect survival in the Henry Ford Hospital study. There was no significant difference in age, gender, race, etiology of heart failure, diabetes, chronic renal insufficiency, body surface area, or body-mass index between the patients with or without a GI bleed. The only independent predictor of GI bleeding was a previous history of it; 35.7% of patients who had a GI bleed during the study period had had one before, while 16.0% of the patients who did not have a GI bleed while on the LVAD had had one previously (p=0.016). Anticoagulation was held in all patients after their GI bleed followed by a switch to lower-dose regimens. Despite the reduction of anticoagulation, there were no thromboembolic complications.

The incidence of major neurological events in this group was 7.8% (five patients), with one thromboembolic stroke and four intracranial hemorrhages, occurring after a median of 234 days of LVAD support. By comparison, in the pivotal trial of the HeartMate II, the rates of disabling stroke were 11% for the HeartMate II patients vs 12% for the control group treated with the HeartMate XVE. The patients who suffered one of these events were, on average, about a decade older (57.5 vs 47.6; p=0.004), had a higher incidence of chronic renal insufficiency (80.0% vs 55.9%; p=0.024), and had a higher INRs (3.46 vs 2.18; p=0.002) at the time of the index event, but there were no other significant differences. Statistical analysis of these data shows an INR over 3 is associated with a 3.34-times greater risk of an adverse neurological event. Patients suffering adverse neurological events had a 60% chance of dying within 90 days.

Platelet Reactivity Changes Over Time, Affects Assays

Platelet reactivity in patients treated with clopidogrel varies over time, according to the results of a new study, with investigators showing that platelet reactivity measured during the hospital stay for PCI declined when measured again at one month [1]. Platelet reactivity varied in more than 25% of patients treated with clopidogrel after one month, suggesting that platelet-function assays taken before or shortly after PCI might not be helpful in guiding treatment decisions.

Among patients treated with clopidogrel, there is a wide variability in the platelet response, with some individuals with high on-treatment platelet reactivity having an increased risk of recurrent ischemic events, including stent thrombosis. Several clinical, genetic, and cellular factors are responsible for the variability in platelet reactivity, with different gene polymorphisms accounting for 15% to 20% of the variation in pharmacodynamic response.In total, 300 patients undergoing PCI for ischemic heart disease were included in the analysis, and on-clopidogrel platelet reactivity was assessed with VerifyNow P2Y12 (Accumetrics Inc, San Diego, CA) at one and six months. According to prespecified definitions, 107 patients were considered poor clopidogrel responders at baseline, 40 were considered poor responders at one month, and 38 patients were considered poor responders at six months. From baseline to one month, 83 of the 300 patients changed their responsiveness status, while 50% of patients labeled as clopidogrel nonresponders became responders at 30 days and remained responders over time, said Valgimigli. Gene polymorphisms explained 18% of this trend.

Importantly, the investigators also report that on-clopidogrel response at 30 days was better able to stratify the risk of ischemic events than responsiveness to treatment measured at the time of PCI. On-clopidogrel platelet reactivity was a stronger predictor when evaluated at one month (hazard ratio [HR] 28.5; p<0.01) when compared with baseline assessments (HR 3.1; p=0.02).The researchers designed an algorithm that would help clinicians identify patients likely to be poor responders to clopidogrel at one month. The risk score combined baseline patient characteristics, including on-clopidogrel platelet reactivity measured at baseline, genetic status, and creatinine clearance. The researchers plan to test the prognostic value of the risk score on clinical outcomes in an upcoming clinical study.

Thromboprophylaxis With Dalteparin vs Unfractionated Heparin

Patients in the intensive care unit (ICU) are among the highest risk patients in the hospital for venous thromboembolism because of complex acute and chronic illness, multiple interventions, and immobility.^[1,2] The authors sought to determine whether subcutaneous low-molecular-weight heparin is superior to unfractionated heparin for preventing the primary outcome of proximal leg deep vein thrombosis (DVT) in critically ill patients. They randomly assigned 3764 patients to receive either dalteparin plus placebo or unfractionated heparin. DVT was assessed by compression ultrasonography within 2 days of ICU admission, twice weekly, and as clinically indicated. Overall, no difference was found in DVT rates between the 2 groups (5.1% of patients receiving dalteparin and 5.8% receiving unfractionated heparin, P = .57). However, the proportion of patients with pulmonary emboli (PE) was significantly lower with dalteparin (1.3% vs 2.3%, P = .01). No difference was found in major bleeding or hospital mortality. The investigators concluded that dalteparin is not superior to unfractionated heparin in preventing proximal lower extremity DVT.

High CK Phenotypes May Signal Greater Bleeding Risk

Patients who have naturally high levels of the enzyme creatinine kinase (CK)--who are already known to have a higher risk of hypertension than those with lower levels of CK--appear to have attenuated platelet aggregation, which could indicate they are at higher risk of bleeding when taking anticoagulants such as clopidogrel.

Around 50% of black people and 25% of whites have high CK, hypertension-prone phenotypes,.Black people have quite a high risk for any bleeding. For example, in patients with ST-elevation MI who underwent fibrinolysis, the relative risk was 1.4. We also found that black women have a four times greater mortality risk during childbirth because of bleeding, but most astounding was the finding that when clopidogrel was used in blacks they have a higher relative risk of bleeding, of 3.3; this is quite surprising because it was actually thought this group of people would have a lower risk because they are slow metabolizers of the prodrug of clopidogrel.

High serum CK might attenuate platelet aggregation and maybe high CK confers a low risk of thrombotic events and a higher bleeding risk. When active CK is in serum it apparently 'eats away,' so to speak, the ADP such that ADP-dependent platelet aggregation is reduced.

It was found in a general population that people with high CK, regardless of ethnicity, typically would be the people who have high BP, so they get treated more often, but the treatment fails more often, so we are trying now to use baseline CK as a measure of difficult-to-treat hypertensive patients.

Apixaban Noninferior to Warfarin in AF Patients: ARISTOTLE

Topline results from the ARISTOTLE trial, comparing apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) with warfarin in subjects with atrial fibrillation (AF) and risk factors for stroke, suggest that the oral direct factor Xa inhibitor is noninferior to the older standard for the prevention of stroke and systemic embolism.ARISTOTLE enrolled over 18000 AF patients in more than 1000 centers in roughly 40 countries, the press release notes. The trial randomized patients to either a twice-daily dose of apixaban 5 mg or dose-adjusted warfarin.

Earlier this year, apixaban proved itself superior to aspirin in the 5599-patient AVERROES study, conducted in patients with AF at risk for stroke who were not suitable candidates for warfarin therapy, as reported by heartwire. Preliminary AVERROES results were also released early, after a predefined interim analysis by the independent data monitoring committee saw a clear and "clinically important reduction in stroke and systemic embolism.

The first approval for apixaban was last month, in Europe, where regulators granted it approval for use in the 27 countries of the EU for the prevention of venous-thromboembolic (VTE) events in adult patients who have undergone elective hip- or knee-replacement surgery.

Experimental Anti-Clotting Drug Beats Clopidogrel When Used In Tandem With Low-Dose Aspirin

Heart patients taking AstraZeneca Plc (AZN)'s Brilinta (ticagrelor) blood-thinner and more than 300 milligrams of aspirin fared worse than those taking Sanofi and Bristol-Myers Squibb Co. (BMY)'s Plavix (clopidogrel), according to a new analysis of a study. When taken with lower doses of aspirin, Brilinta beat Plavix in preventing heart attacks, strokes and early death, according to the research presented" Monday at the American Heart Association's Emerging Science Series seminar. "The analysis found no systematic errors in the analyzed trial, called Plato." In December, the Food and Drug Administration asked for additional analysis of the trial, which compared ticagrelor with clopidogrel.

The new analysis of the >18 000-patient PLATO trial by geography, "differentiated the 1413 patients randomized in the US vs 17 211 randomized in other countries. The geographic variation in aspirin effect on the primary end point seen in PLATO could have arisen by chance. However, he said the geographic findings were confirmed in separate analyses conducted independently by both AstraZeneca and the Duke Clinical Research Institute."

Open vs Laparoscopic Colorectal Surgery May Double VTE Risk

The incidence of perioperative venous thromboembolism (VTE) was nearly twice as high after open colorectal (OC) surgery vs laparoscopic colorectal (LC) surgery. Using the Nationwide Inpatient Sample database, the investigators identified 149,304 patients who underwent elective LC and OC surgery during a 60-month period from 2002 through 2006. The primary study endpoint was the incidence of VTE, stratified according to surgical site, pathology type, and at-risk patient population during hospitalization for LC or OC surgery.

Compared with LC cases, OC cases had a significantly higher incidence of VTE (2036/141,456 [1.44%] vs 65/7848 [0.83%]; P < .001). Patients with inflammatory bowel disease and those undergoing rectal resections had the highest overall rate of VTE compared with other classifications based on pathologic condition and surgical site. Compared with patients who underwent LC surgery, those who underwent OC surgery were almost twice as likely to develop VTE. Other statistically significant risk factors for VTE in OC and LC surgery were cancer, obesity, and congestive heart failure.

Limitations of this study include those inherent in the use of a large administrative database, lack of information concerning the use and duration of thromboprophylaxis in the 2 groups, and lack of data concerning a specific indication for surgery in about 30% of the population.

Use Low-Dose Aspirin With Ticagrelor: PLATO

The antiplatelet ticagrelor (Brilinta, AstraZeneca) seems to work better at preventing clinical events in patients with ACS when it's accompanied by low-dose as opposed to high-dose aspirin, suggests a new analysis of the PLATO trial that is being interpreted cautiously by both its investigators and expert observers . Low-dose aspirin was defined as <300 mg/day, high-dose aspirin as doses above that threshold.

Such an interaction between aspirin dosage and ticagrelor effects could possibly explain the trial's so-called "North American anomaly," in which outcomes were superior with the new drug vs clopidogrel Those divergent outcomes are thought to be the reason why US regulators have postponed decisions on whether to approve ticagrelor, while the drug has already been approved for the PLATO indication in Canada, Europe, and other parts of the world. An FDA decision on ticagrelor is expected by July 20, also as reported by heartwire .

PLATO enrolled >18 000 patients in 43 countries on nearly every continent. In it, as heartwire has covered extensively, ticagrelor was associated with a 16% reduction in the composite primary end point vs clopidogrel, with both drugs accompanied by aspirin, over a mean of 12 months. In the overall trial, the absolute rates were 9.8% for those taking ticagrelor and 11.7% for the clopidogrel group (p<0.001).

But in a prospectively defined subgroup analysis, as previously reported, the rates were 11.9% and 9.6%, respectively. In the trial overall, the ticagrelor-to-clopidogrel hazard ratio (HR) for the primary end point was 0.79 (95% CI, 0.71–0.88) for those getting low-dose aspirin and 1.45 (95% CI, 1.01–2.09) for those getting high-dose aspirin.

In analyses that accounted for 37 patient factors and characteristics at baseline and afterward (including other demographics, body-mass index and waist circumference, smoking status, troponin levels, other medications currently and before randomization, comorbidities, time to first aspirin dose at randomization, and history of revascularization), only differences in aspirin use explained a significant portion of the effect of geography on outcomes.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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