Anticoagulant

Derivation and validation of QStroke score for predicting risk of ischaemic stroke in primary care and comparison with other risk scores: a prospective open cohort study.

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Abstract

Objective To develop and validate a risk algorithm (QStroke) to estimate risk of stroke or transient ischaemic attack in patients without prior stroke or transient ischaemic attack at baseline; to compare (a) QStroke with CHADS2 and CHA2DS2VASc scores in patients with atrial fibrillation and (b) the performance of QStroke with the Framingham stroke score in the full population free of stroke or transient ischaemic attack.

Design Prospective open cohort study using routinely collected data from general practice during the study period 1 January 1998 to 1 August 2012.

Setting 451 general practices in England and Wales contributing to the national QResearch database to develop the algorithm and 225 different QResearch practices to validate the algorithm.

Participants 3.5 million patients aged 25-84 years with 24.8 million person years in the derivation cohort who experienced 77 578 stroke events. For the validation cohort, we identified 1.9 million patients aged 25-84 years with 12.7 million person years who experienced 38 404 stroke events. We excluded patients with a prior diagnosis of stroke or transient ischaemic attack and those prescribed oral anticoagulants at study entry.

Main outcome measures Incident diagnosis of stroke or transient ischaemic attack recorded in general practice records or linked death certificates during follow-up.

Risk factors Self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol to high density lipoprotein cholesterol concentrations, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 1 diabetes, type 2 diabetes, renal disease, rheumatoid arthritis, coronary heart disease, congestive cardiac failure, valvular heart disease, and atrial fibrillation

Results The QStroke algorithm explained 57% of the variation in women and 55% in men without a prior stroke. The D statistic for QStroke was 2.4 in women and 2.3 in men. QStroke had improved performance on all measures of discrimination and calibration compared with the Framingham score in patients without a prior stroke. Among patients with atrial fibrillation, levels of discrimination were lower, but QStroke had some improved performance on all measures of discrimination compared with CHADS2 and CHA2DS2VASc.

Conclusion QStroke provides a valid measure of absolute stroke risk in the general population of patients free of stroke or transient ischaemic attack as shown by its performance in a separate validation cohort. QStroke also shows some improvement on current risk scoring methods, CHADS2 and CHA2DS2VASc, for the subset of patients with atrial fibrillation for whom anticoagulation may be required. Further research is needed to evaluate the cost effectiveness of using these algorithms in primary care.

 

What is already known on this topic

  • Methods to identify patients at high or low risk of stroke are needed to identify patients for whom interventions may be required, especially those with atrial fibrillation for whom anticoagulation might be needed
  • Current methods for risk scoring, such as CHADS2 and CHA2DS2VASc, are not based on a statistical model, do not include many established risk factors, nor provide absolute risk estimates of stroke
  • We have developed a new algorithm to quantify absolute risk of primary stroke which includes established risk factors and which is designed to work with the QRISK2 cardiovascular disease algorithm
  • QStroke provides a valid measure of absolute stroke risk in the general population of patients free of stroke or transient ischaemic attack as shown by its performance in a separate validation cohort
  • QStroke shows some improvement on current risk scoring methods, CHADS2and CHA2DS2VASc, for the subset of patients with atrial fibrillation for whom anticoagulation may be required
  • Further research is needed to evaluate the clinical outcomes and cost effectiveness of using these algorithms in primary care

What this study adds

 

Source: BMJ

Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism.

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Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism. Methods In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. Results In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. Conclusions Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo.

Source:NEJM

Studies of Extended Anticoagulant Therapies for VTE Highlight Tradeoffs.

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For the extended treatment of venous thromboembolism, the newer anticoagulants dabigatran and apixaban show advantages and disadvantages compared with older therapies, according to three studies in the New England Journal of Medicine. (Physician’s First Watch covered the apixaban study when it was published online last December.)

The dabigatran studies, conducted by the manufacturer, included patients who had completed 3 months of initial therapy and whose risks for recurrence were judged to be either at equipoise or increased.

In one study, patients were randomized to dabigatran or warfarin treatment for up to 36 months. Regarding VTE recurrence, dabigatran (1.8%) was noninferior to warfarin (1.3%), and rates of major bleeding did not differ statistically. However, acute coronary syndromes were more frequent with dabigatran (0.9% vs. 0.2%).

The other study compared dabigatran with placebo for up to 12 months. Dabigatran proved superior to placebo in preventing VTE recurrence (0.4% vs. 5.6%). Dabigatran was associated with an almost threefold increased risk for major bleeds.

An editorialist examines the tradeoffs presented by the newer therapies and urges trials that compare them directly with one another, with warfarin, and with aspirin.

Source: NEJM

 

 

Extended Treatment After Unprovoked Venous Thromboembolism.

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Apixaban, which is not yet FDA-approved for VTE, lowered recurrence by about 7 percentage points during 1 year.

In patients who have completed courses of initial anticoagulation for unprovoked venous thromboembolism (VTE), extended treatment with warfarin, the oral factor Xa inhibitor rivaroxaban (Xarelto), or (to a lesser extent) aspirin can lower the rate of recurrence. How does apixaban (Eliquis), another oral factor Xa inhibitor, fare in this regard? In an industry-sponsored randomized trial, 2500 patients who had just completed 6 to 12 months of standard anticoagulation for deep venous thrombosis or pulmonary embolism received twice-daily doses of 5-mg apixaban, 2.5-mg apixaban, or placebo. The qualifying VTE events were unprovoked in 92% of cases.

During 1 year of treatment, the incidence of symptomatic or fatal recurrent VTE was 9% in the placebo group and 2% in both apixaban groups — a significant difference. For several composite endpoints that also included all-cause mortality or arterial thrombotic events, apixaban consistently conferred a 7- to 8-percentage-point advantage over placebo. Rates of major bleeding were lower than 1% in all three groups.

Comment: Apixaban recently was FDA-approved for patients with atrial fibrillation. If it is approved eventually for extended treatment following VTE, it will become another option for patients with this condition. However, several caveats apply: This study lasted for only 12 months, most participants were relatively young (mean age, 57), most had normal renal function, and the drug will be expensive. Studies in which apixaban and alternative therapies are compared directly, and additional data on safety and efficacy in older and sicker patients, would

be valuable.

Source: Journal Watch General Medicine

Newer Oral Anticoagulants Associated with ‘Dramatic Increase’ in Bleeding After ACS .

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When used to prevent thrombotic events after an acute coronary syndrome, the newer oral anticoagulants (for example, apixaban, dabigatran, and rivaroxaban) are associated with increased rates of major bleeding that offset their antithrombotic benefit, according to an Archives of Internal Medicine meta-analysis.

Researchers examined seven randomized controlled trials comprising over 30,000 patients who were hospitalized with ACS and received antiplatelet therapy. Compared with placebo recipients, those on new-generation oral anticoagulants had “a dramatic increase in major bleeding events.” Significant (but moderate) reductions in the risks for stent thrombosis and other ischemic events were seen, but there was no significant effect on overall mortality.

An editorialist concludes that routine use of these drugs in patients with ACS “is unwarranted.”

Source: Archives of Internal Medicine

 

Resuming Warfarin After a GI Bleed: Benefits Appear to Outweigh the Risks .

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Many patients who’ve had a warfarin-associated gastrointestinal bleed can safely resume warfarin therapy soon after the bleeding event, according to an industry-funded, retrospective study in the Archives of Internal Medicine.

Researchers identified some 440 adults who experienced a GI bleed while taking warfarin; nearly 60% either stayed on warfarin continuously or resumed treatment within about a week (median time to retreatment, 4 days). Compared with patients who did not restart warfarin, those who continued or resumed treatment had a significantly lower 90-day incidence of thrombosis (0.4% vs. 5.5%) and death (6% vs. 20%). The most common causes of death were cancer, infection, and cardiac disease.

Patients who continued or restarted warfarin did have more recurrent GI bleeds (10% vs. 6%), but this difference did not achieve statistical significance. None of the recurrent bleeds were fatal.

Archives commentators conclude: “We believe that most patients with warfarin-associated GI bleeding and indications for continued long-term antithrombotic therapy should resume anticoagulation within the first week following the hemorrhage.”

Source: Archives of Internal Medicine

Aspirin Linked to Reduced Mortality in Prostate Cancer.

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In men who’ve undergone treatment for localized prostate cancer with radical prostatectomy or radiotherapy, aspirin use is associated with reduced prostate cancer mortality, researchers report in the Journal of Clinical Oncology.

Nearly 6000 men treated for localized prostate cancer were identified from a U.S. cancer registry. About one third took anticoagulants (aspirin, clopidogrel, enoxaparin, or warfarin) at some point during roughly 6 years’ follow-up, with aspirin being most commonly used.

Overall, prostate cancer mortality was significantly lower among anticoagulant users than nonusers (actuarial 10-year risk estimate, 3% vs. 8%). Patients with high-risk disease derived the greatest benefit. In subanalyses according to anticoagulant type, a significant risk reduction was seen only with aspirin (adjusted hazard ratio, 0.43).

The researchers note that coagulation plays a role in metastasis. They hypothesize, then, that aspirin’s effects on platelet aggregation may offer protection against metastasis.

Source: Journal of Clinical Oncology

 

HAS-BLED for Assessing Bleeding Risk with Anticoagulation: Best of the Mediocre.

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Notwithstanding a lackluster performance, HAS-BLED beat two other scoring systems in a comparative analysis of trial data.

Bleeding continues to be the Achilles heel of systemic anticoagulation, whether the agent used is warfarin or any of the new anticoagulants entering the market. Predictive models for bleeding include the following:

ATRIA (anticoagulation and risk factors in atrial fibrillation)

Investigators for the AMADEUS trial comparing warfarin with idraparinux (JW Gen Med Feb 26 2008) retrospectively applied all three scoring systems to the 2293 patients randomized to the warfarin arm. Although none of the three demonstrated more than modest efficacy in predicting any clinically relevant bleeding (c-index range, 0.50–0.60), HAS-BLED — the simplest to use — outperformed the others, especially with regard to intracranial hemorrhage (c-index, 0.75).

Comment: Although their predictive value is limited, these scoring systems quantify bleeding risk and thus are better than qualitative clinical judgment alone. The simple HAS-BLED model performed better than the others and is a reasonable tool to assess bleeding risk in clinical practice, at least for now.

Source: Journal Watch Cardiology