Magdalena Sobieraj-Teague

Effect of Aspirin on Mortality in the Primary Prevention of Cardiovascular Disease

OBJECTIVE The lack of a mortality benefit of aspirin in prior meta-analyses of primary prevention trials of cardiovascular disease has contributed to uncertainty about the balance of benefits and risks of aspirin in primary prevention. We performed an updated meta-analysis of randomized controlled trials of aspirin to obtain best estimates of the effect of aspirin on mortality in primary prevention. METHODS Eligible articles were identified by searches of electronic databases and reference lists. Outcomes of interest were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and bleeding. Data were pooled from individual trials using the DerSimonian-Laird random-effects model, and results are presented as relative risk (RR) and 95% confidence intervals (CIs). RESULTS Nine randomized controlled trials enrolling 100,076 participants were included. Aspirin reduced all-cause mortality (RR 0.94; 95% CI, 0.88-1.00), myocardial infarction (RR 0.83; 95% CI, 0.69-1.00), ischemic stroke (RR 0.86; 95% CI, 0.75-0.98), and the composite of myocardial infarction, stroke, or cardiovascular death (RR 0.88; 95% CI, 0.83-0.94), but did not reduce cardiovascular mortality (RR 0.96; 95% CI, 0.84-1.09). Aspirin increased the risk of hemorrhagic stroke (RR 1.36; 95% CI, 1.01-1.82), major bleeding (RR 1.66; 95% CI, 1.41-1.95), and gastrointestinal bleeding (RR 1.37; 95% CI, 1.15-1.62). A lack of availability of patient-level data precluded exploration of benefits and risks of aspirin in key subgroups. CONCLUSION Aspirin prevents deaths, myocardial infarction, and ischemic stroke, and increases hemorrhagic stroke and major bleeding when used in the primary prevention of cardiovascular disease.

Accuracy and clinical usefulness of the CoaguChek S and XS Point of Care devices when starting warfarin in a hospital outreach setting

OBJECTIVE To assess clinical usefulness of CoaguChek S and XS monitors to measure International Normalised Ratio (INR) when starting warfarin in community patients. METHODS INR in consecutive patients starting warfarin plus enoxaparin was measured in the laboratory and on capillary blood at home using CoaguChek S or XS point of care (POC) devices. INR was measured daily until >2.0 for 2 consecutive readings. Linear regression and Bland Altman plots were derived to compare POC with laboratory INR. Percentages of POC measurements within 0.5 and 0.8 units of laboratory INR <2.0, 2.0-3.5 and >3.5 were calculated. Clinical utility was assessed using previously reported criteria. RESULTS 200 CoaguChek S and 337 CoaguChek XS results were obtained from 57 and 98 patients respectively and paired with laboratory values. Correlation was acceptable between CoaguChek S and laboratory INRs (r(2)=0.7732), and excellent between CoaguChek XS and laboratory INRs (r(2)=0.9514). Bland-Altman plots showed an increasing difference between laboratory INR above 3.0 for CoaguChek S INRs but no systematic bias with increasing CoaguChek XS INRs. 83.5% of CoaguChek S and 93.5% of CoaguChek XS INRs were within 0.5 units of laboratory INR. 90% of CoaguChek S and 99.4% of the CoaguChek XS INRs were within 0.8 units of laboratory INR. Clinical agreement occurred in 89% and 99.7% of cases by expanded criteria and 82% and 99.4% of cases by narrow criteria when using CoaguChek S and CoaguChek XS respectively. CONCLUSIONS The CoaguChek XS is suitable for outpatient INR monitoring when starting warfarin.

The risk of iatrogenic bleeding in acute coronary syndromes and long-term mortality.

Purpose of review This review examines the association between bleeding and adverse outcomes in patients with acute coronary syndrome and explores mechanisms behind this association and strategies for reducing bleeding complications in acute coronary syndrome. Recent findings Bleeding is a common complication of antithrombotic treatment in acute coronary syndrome, and major bleeding occurs in around 5% of patients. Important risk factors for major bleeding include increasing age, female sex, renal impairment, and invasive procedures. Recent studies suggest that major bleeding in patients with acute coronary syndrome is independently associated with an increase of early and long-term morbidity and mortality. This may be due to the direct effects of anaemia and hypovolaemia, the treatment modification or withdrawal, or the adverse effects of transfusion. Bleeding complications may be reduced by use of new antithrombotic agents and by improved attention to dosing with current agents. Summary Future studies should examine the effects on overall morbidity and mortality of strategies designed to reduce bleeding complications in patients with acute coronary syndrome. There is a need to apply uniform definitions of bleeding severity. Future trials should report all clinically relevant bleeding outcomes and transfusions. Studies are needed to investigate methods to reduce the risk of bleeding, better understand mechanisms of adverse outcome after bleeding, and establish best practice for the management of bleeding including appropriate use of transfusion in patients with acute coronary syndrome.

Rationale and Design of the Informing Fresh versus Old Red Cell Management (INFORM) Trial: An International Pragmatic Randomized Trial.

Although red blood cell transfusion is a potentially lifesaving intervention in severely anemic and acutely bleeding patients, some observational studies have suggested that prolonged red cell storage before transfusion is associated with harm. INFORM is a large, pragmatic, randomized controlled trial comparing the effect of the shorter storage with longer storage red blood cell transfusions on inhospital mortality in hospitalized patients who require a blood transfusion. The trial is being conducted in centers in Australia, Canada, Israel, and the United States and is expected to enroll 31497 patients. If the results of INFORM indicate that shorter storage red blood cell transfusion is associated with superior outcomes compared with standard issue red blood cell transfusion, consideration may be given to shortening blood storage times. If, in contrast, the INFORM trial provides no evidence of harm from longer storage red blood cells, clinicians and patients may be reassured that current blood inventory management strategies are appropriate.

Red blood cell storage and in-hospital mortality: a secondary analysis of the INFORM randomised controlled trial

BACKGROUND No randomised trials have addressed whether exposure to red blood cells (RBCs) stored longer than 35 days is associated with harm in patients. We aimed to assess the risk of in-hospital mortality associated with transfusing blood stored longer than 35 days. METHODS We did a secondary analysis of the INforming Fresh versus Old Red cell Management (INFORM) trial, a pragmatic, multicentre, randomised controlled trial of patients (≥18 years) admitted to one of six hospitals in Australia, Canada, Israel, and the USA and expected to need RBC transfusions. Patients were randomly assigned (2:1) to receive blood in inventory stored for the longest time (standard care) or the shortest time, using a random allocation schedule and stratified by centre and patient ABO blood group. The primary objective of the INFORM trial was to assess all-cause in-hospital mortality in patients with blood group A and O who were transfused. For our exploratory secondary analysis, we classified individuals into one of three mutually exclusive exposure categories on the basis of the maximum storage duration of any blood unit patients had received on each day in hospital: exclusively exposed to RBCs stored no longer than 7 days, exposed to at least one unit of RBCs stored 8-35 days, and exposed to least one unit of RBCs stored longer than 35 days. Our primary objective was to determine the effect on risk of in-hospital death of time-dependent exposure to RBCs stored longer than 35 days compared with exclusive exposure to RBCs stored no longer than 7 days, both in patients of blood groups A and O and all patients. The INFORM trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN08118744. FINDINGS Between April 2, 2012, and Oct 21, 2015, 31 497 patients were recruited, and 24 736 patients were eligible for inclusion in this analysis. We excluded nine patients for whom information about the storage duration of transfused blood was missing and one patient whose sex was unknown. 4480 (18%) patients were exposed to RBCs with longest storage, 1392 (6%) patients were exposed exclusively to RBCs with shortest storage, and 18 854 (76%) patients were exposed to RBCs stored 8-35 days. Median follow-up was 11 days (IQR 6-20). Exposure to RBCs stored longer than 35 days was not associated with increased risk of in-hospital death compared with exclusive exposure to the freshest RBC units after adjusting for demographic variables, diagnosis category, and blood product use history (in patients with blood group A or O: hazard ratio 0·94, 95% CI 0·73-1·20, p=0·60; in all patients: 0·91, 0·72-1·14, p=0·40). The risk of in-hospital death also did not differ between patients exposed to blood stored 8-35 days and patients exposed to blood stored 7 days or less (in patients with blood group A or O: 0·92, 0·74-1·15, p=0·48; in all patients: 0·90, 0·73-1·10, p=0·29). INTERPRETATION These data provide evidence that transfusion of blood stored for longer than 35 days has no effect on in-hospital mortality, which suggests that current approaches to blood storage and inventory management are reasonable. FUNDING Canadian Institutes for Health Research, Canadian Blood Services, and Health Canada.

Novel protein C gene mutation in a compound heterozygote resulting in catastrophic thrombosis in early adulthood: diagnosis and long-term treatment with subcutaneous protein C concentrate.

Keywords: protein C deficiency; compound heterozygote; subcutaneous infusion; rivaroxaban; frameshift mutation

Resistance to proteasome inhibitors and other targeted therapies in myeloma

The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and established therapies. Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are the most well known and studied classes of novel agents targeting myeloma, with histone deacetylase inhibitors, nuclear export inhibitors and several other approaches also being actively investigated. However, in parallel with the development and clinical use of these novel myeloma therapies is the emergence of novel mechanisms of resistance, many of which remain elusive, particularly for more recently developed agents. Whilst resistance mechanisms have been best studied for proteasome inhibitors, particularly bortezomib, class effects do not universally apply to all class members, and within‐class differences in efficacy, toxicity and resistance mechanisms have been observed. Although immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression, the unique cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within‐class differences in clinical efficacy and resistance patterns. This review describes the major classes of novel therapies for myeloma, highlights the major clinical trials within each class and discusses known resistance mechanisms.

Percutaneous closure of the left atrial appendage was noninferior to warfarin in atrial fibrillation

Question In patients with nonvalvular atrial fibrillation, is percutaneous closure of the left atrial appendage (LAA) noninferior to warfarin for preventing stroke? Methods Design Randomized controlled trial. ClinicalTrials.gov NCT00129545. Allocation Concealed.* Blinding Unblinded.* Follow-up period Mean 18 months. Setting 59 sites in the USA and Europe. Patients 707 patients 18 years of age (mean age 72 y, 70% men) who had nonvalvular atrial fibrillation and CHADS2 risk score 1. Exclusion criteria included LAA thrombus, patent foramen ovale, mobile aortic atheroma, and symptomatic carotid artery disease. Intervention The LAA was closed percutaneously using the WATCHMAN device, followed by 45 days of warfarin, which was discontinued if transesophageal echocardiography showed complete closure of the LAA or residual peridevice flow <5 mm in width; after warfarin was stopped, clopidogrel, 75 mg/d, and aspirin, 81 to 325 mg/d, were given to 6 months and aspirin was given alone thereafter (n =463). The control group received warfarin for the duration of the study with a target international normalized ratio (INR) between 2.0 and 3.0. Outcomes Composite efficacy outcome (ischemic or hemorrhagic stroke, cardiovascular or unexplained death, or systemic embolism) and composite safety outcome (major bleeding or procedure-related complication). Patient follow-up 100% (intention-to-treat analysis). Main results Percutaneous closure of the LAA was noninferior to warfarin therapy for efficacy but was associated with increased risk for the composite safety outcome, including serious pericardial effusion in 4.8% of patients (Table). Conclusion In patients with atrial fibrillation, percutaneous closure of the left atrial appendage was noninferior to warfarin for preventing stroke but increased adverse events. Percutaneous closure of the left atrial appendage (LAA) vs warfarin for preventing stroke in atrial fibrillation Outcomes Events/100 person-y At a mean 18 mo LAA closure Warfarin Rate ratio (95% CI) Composite efficacy outcome 3.0 4.9 0.62 (0.35 to 1.25) RRI (CI) NNH (CI) Composite safety outcome 7.4 4.4 69% (1 to 219) 33 (11 to 2273) Abbreviations defined in Glossary. Composite efficacy outcome = ischemic or hemorrhagic stroke, cardiovascular or unexplained death, or systemic embolism; composite safety outcome = major bleeding or procedure-related complication. RRI, NNH, and CI calculated from data in article. Criterion for noninferiority was met because the upper limit of the CI was <2.0. Commentary Warfarin prevents stroke in patients with atrial fibrillation but is inconvenient and causes bleeding. Many patients may not benefit from treatment because of suboptimal INR control. LAA occlusion is theoretically an attractive alternative to warfarin for stroke prevention in atrial fibrillation but remains unproven. The results reported by Holmes and colleagues suggest that the WATCHMAN LAA occlusion device is noninferior to warfarin for stroke prevention in atrial fibrillation, but important caveats should be noted. First, the noninferiority margin allowed for a 2-fold increase in risk for the composite efficacy outcome and the 95% CI did not exclude a 25% relative risk increase. Second, the stroke rate in the warfarin group was unexpectedly high (3.2 per 100 patient-y), particularly considering that most patients had a CHADS2 score of 1 or 2. Third, in the LAA occlusion group, 12% of patients did not receive the device, and by 6 months, approximately 1 in 5 patients remained on warfarin. Patients who discontinued warfarin required ongoing aspirin and clopidogrel, an antithrombotic strategy that is less effective than warfarin but associated with a similar rate of bleeding (1). Fourth, 1 in 20 patients in the device group had a serious adverse event requiring intervention (pericardial effusion drainage or device retrieval). Holmes and colleagues showed that percutaneous placement of an LAA occlusion device is feasible. However, major safety concerns need to be overcome and efficacy needs to be better established before the device can be considered as an alternative to warfarin anticoagulation in patients with atrial fibrillation. In the meantime, the emergence of new anticoagulants that are more effective, safe, and convenient than warfarin (2) will make future attempts to replace anticoagulant therapy with LAA occlusion devices even more challenging.