Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

BACKGROUND

We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention.

METHODS

In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.

RESULTS

The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=−4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group.

CONCLUSIONS

Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424.)

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Urinary Incontinence in Women

Importance  Urinary incontinence, the involuntary loss of urine, is a common health condition that may decrease quality of life. Ten to twenty percent of women and up to 77% of women residing in nursing homes have urinary incontinence, yet only 25% seek or receive treatment.

Observations  This review summarizes the evaluation and therapeutic options for women affected by urinary incontinence. The initial assessment should focus on understanding the effect of incontinence on quality of life, the patient’s goals and preferences for treatment, the results of previous treatments, and the presence of concomitant conditions, such as advanced pelvic organ prolapse, that may require referral. Infection and hematuria need to be ruled out. In the absence of urinary infection or serious underlying pathology (such as cancer or serious neurologic disease) associated with urinary incontinence, the clinician should initiate unsupervised pelvic muscle exercises and lifestyle modifications appropriate to the patient to reduce her symptoms. These recommendations can include weight loss, adequate hydration, avoidance of excessive fluids, and regular voiding intervals that reduce urgency incontinence episodes. Urgency incontinence medications, with timely reassessment of symptoms, can be started without extensive evaluation. Specialist treatments for urgency incontinence include onabotulinumtoxinA and percutaneous or implanted neuromodulators. Stress incontinence surgery, the midurethral sling, is associated with symptom improvement in 48% to 90% of women and has low rates of mesh complications (<5%).

Conclusions and Relevance  Urinary incontinence is common in women, although few seek care despite many effective treatment options. Clinicians should prioritize urinary incontinence detection, identify and treat modifiable factors, incorporate patient preference into evaluation and treatment, initiate conservative and medical therapy, and refer to specialists when underlying pathology is identified or conservative measures are ineffective.

Reference: JAMA. 2017;318(16):1592-1604. 

Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes

Question  What is the effect of oral semaglutide on glycemic control in patients with type 2 diabetes?

Finding  In this randomized clinical trial of 632 patients with type 2 diabetes followed up for 31 weeks, oral semaglutide significantly reduced hemoglobin A1c level by up to 1.9% vs placebo (0.3%).

Meaning  Oral semaglutide resulted in better glycemic control than placebo over 26 weeks. Phase 3 studies are warranted to assess longer-term and clinical outcomes, as well as safety.

Reference: JAMA. 2017;318(15):1460-1470.

Association Between Use of Non–Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation

Question  What is the risk of major bleeding among patients with nonvalvular atrial fibrillation treated with non–vitamin K oral anticoagulants (NOACs) in combination with medications that share metabolic pathways?

Findings  Among 91 330 NOAC users in Taiwan, the risk of major bleeding was significantly increased with concurrent use of amiodarone, fluconazole, rifampin, or phenytoin compared with NOAC use alone.

Meaning  Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs.

Reference: JAMA. 2017;318(13):1250-1259.

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial

Background

LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9).

Methods

In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633.

Findings

Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events.

Interpretation

There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations.

A multifaceted intervention to improve treatment with oral anticoagulants in atrial fibrillation (IMPACT-AF): an international, cluster-randomised trial

Background

Oral anticoagulation is underused in patients with atrial fibrillation. We assessed the impact of a multifaceted educational intervention, versus usual care, on oral anticoagulant use in patients with atrial fibrillation.

Methods

This study was a two-arm, prospective, international, cluster-randomised, controlled trial. Patients were included who had atrial fibrillation and an indication for oral anticoagulation. Clusters were randomised (1:1) to receive a quality improvement educational intervention (intervention group) or usual care (control group). Randomisation was carried out centrally, using the eClinicalOS electronic data capture system. The intervention involved education of providers and patients, with regular monitoring and feedback. The primary outcome was the change in the proportion of patients treated with oral anticoagulants from baseline assessment to evaluation at 1 year. The trial is registered at ClinicalTrials.gov, number NCT02082548.

Findings

2281 patients from five countries (Argentina, n=343; Brazil, n=360; China, n=586; India, n=493; and Romania, n=499) were enrolled from 48 clusters between June 11, 2014, and Nov 13, 2016. Follow-up was at a median of 12·0 months (IQR 11·8–12·2). Oral anticoagulant use increased in the intervention group from 68% (804 of 1184 patients) at baseline to 80% (943 of 1184 patients) at 1 year (difference 12%), whereas in the control group it increased from 64% (703 of 1092 patients) at baseline to 67% (732 of 1092 patients) at 1 year (difference 3%). Absolute difference in the change between groups was 9·1% (95% CI 3·8–14·4); odds ratio of change in the use of oral anticoagulation between groups was 3·28 (95% CI 1·67–6·44; adjusted p value=0·0002). Kaplan-Meier estimates showed a reduction in the secondary outcome of stroke in the intervention versus control groups (HR 0·48, 95% CI 0·23–0·99; log-rank p value=0·0434).

Interpretation

A multifaceted and multilevel educational intervention, aimed to improve use of oral anticoagulation in patients with atrial fibrillation and at risk for stroke, resulted in a significant increase in the proportion of patients treated with oral anticoagulants. Such an intervention has the potential to improve stroke prevention around the world for patients with atrial fibrillation.

Funding

Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer.

Reference: The Lancet, Volume 390, No. 10104, p1737–1746, 14 October 2017

Is late-life dependency increasing or not? A comparison of the Cognitive Function and Ageing Studies (CFAS)

Background

Little is known about how the proportions of dependency states have changed between generational cohorts of older people. We aimed to estimate years lived in different dependency states at age 65 years in 1991 and 2011, and new projections of future demand for care.

Methods

In this population-based study, we compared two Cognitive Function and Ageing Studies (CFAS I and CFAS II) of older people (aged ≥65 years) who were permanently registered with a general practice in three defined geographical areas (Cambridgeshire, Newcastle, and Nottingham; UK). These studies were done two decades apart (1991 and 2011). General practices provided lists of individuals to be contacted and were asked to exclude those who had died or might die over the next month. Baseline interviews were done in the community and care homes. Participants were stratified by age, and interviews occurred only after written informed consent was obtained. Information collected included basic sociodemographics, cognitive status, urinary incontinence, and self-reported ability to do activities of daily living. CFAS I was assigned as the 1991 cohort and CFAS II as the 2011 cohort, and both studies provided prevalence estimates of dependency in four states: high dependency (24-h care), medium dependency (daily care), low dependency (less than daily), and independent. Years in each dependency state were calculated by Sullivan’s method. To project future demands for social care, the proportions in each dependency state (by age group and sex) were applied to the 2014 England population projections.

Findings

Between 1991 and 2011, there were significant increases in years lived from age 65 years with low dependency (1·7 years [95% CI 1·0–2·4] for men and 2·4 years [1·8–3·1] for women) and increases with high dependency (0·9 years [0·2–1·7] for men and 1·3 years [0·5–2·1] for women). The majority of men’s extra years of life were spent independent (36·3%) or with low dependency (36·3%) whereas for women the majority were spent with low dependency (58·0%), and only 4·8% were independent. There were substantial reductions in the proportions with medium and high dependency who lived in care homes, although, if these dependency and care home proportions remain constant in the future, further population ageing will require an extra 71 215 care home places by 2025.

Interpretation

On average older men now spend 2·4 years and women 3·0 years with substantial care needs, and most will live in the community. These findings have considerable implications for families of older people who provide the majority of unpaid care, but the findings also provide valuable new information for governments and care providers planning the resources and funding required for the care of their future ageing populations.

Funding

Medical Research Council (G9901400) and (G06010220), with support from the National Institute for Health Research Comprehensive Local research networks in West Anglia and Trent, UK, and Neurodegenerative Disease Research Network in Newcastle, UK.

Reference: The Lancet, Volume 390, No. 10103, p1676–1684, 7 October 2017