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Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial

Author/s: 
Butler, CC, van der Velden, AW, Bongard, E, Saville, BR, Holmes, J, Coenen, S, Cook, J, Francis, NA, Lewis, RJ, Godycki-Cwirko, M, Llor, C, Chlabicz, S, Lionis, C, Seifert, B, Sundvall, PD, Colliers, A, Aabenhus, R, Bjerrum, L, Jonassen Harbin, N, Lindbæk M, Glinz, D, Bucher, HC, Kovacs, B, Radzeviciene Jurgute, R, Touboul Lundgren, P, Little, P, Murphy, AW, De Sutter, A, Openshaw, P, de Jong, MD, Connor, JT, Matheeussen, V, Ieven, M, Goossens, H, Verheij, TJ

BACKGROUND:

Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups.

METHODS:

We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921.

FINDINGS:

Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group.

INTERPRETATION:

Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner.

FUNDING:

European Commission's Seventh Framework Programme.

Keywords 
influenza flu Tamiful oseltamivir

Final Update Summary: Abdominal Aortic Aneurysm: Screening

Author/s: 
U. S. Preventive Services Task Force

IMPORTANCE:

An abdominal aortic aneurysm (AAA) is typically defined as aortic enlargement with a diameter of 3.0 cm or larger. The prevalence of AAA has declined over the past 2 decades among screened men 65 years or older in various European countries. The current prevalence of AAA in the United States is unclear because of the low uptake of screening. Most AAAs are asymptomatic until they rupture. Although the risk for rupture varies greatly by aneurysm size, the associated risk for death with rupture is as high as 81%.

OBJECTIVE:

To update its 2014 recommendation, the USPSTF commissioned a review of the evidence on the effectiveness of 1-time and repeated screening for AAA, the associated harms of screening, and the benefits and harms of available treatments for small AAAs (3.0-5.4 cm in diameter) identified through screening.

POPULATION:

This recommendation applies to asymptomatic adults 50 years or older. However, the randomized trial evidence focuses almost entirely on men aged 65 to 75 years.

EVIDENCE ASSESSMENT:

Based on a review of the evidence, the USPSTF concludes with moderate certainty that screening for AAA in men aged 65 to 75 years who have ever smoked is of moderate net benefit. The USPSTF concludes with moderate certainty that screening for AAA in men aged 65 to 75 years who have never smoked is of small net benefit. The USPSTF concludes that the evidence is insufficient to determine the net benefit of screening for AAA in women aged 65 to 75 years who have ever smoked or have a family history of AAA. The USPSTF concludes with moderate certainty that the harms of screening for AAA in women aged 65 to 75 years who have never smoked and have no family history of AAA outweigh the benefits.

RECOMMENDATIONS:

The USPSTF recommends 1-time screening for AAA with ultrasonography in men aged 65 to 75 years who have ever smoked. (B recommendation) The USPSTF recommends that clinicians selectively offer screening for AAA with ultrasonography in men aged 65 to 75 years who have never smoked rather than routinely screening all men in this group. (C recommendation) The USPSTF recommends against routine screening for AAA with ultrasonography in women who have never smoked and have no family history of AAA. (D recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for AAA with ultrasonography in women aged 65 to 75 years who have ever smoked or have a family history of AAA. (I statement).

Keywords 
abdominal aortic aneurysm recommendation AAA ultrasonography risk smoke

Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study

Author/s: 
Santema, B.T., Ouwerkerk, W., Tromp, J., Sama, I.E., Ravera, A., Regitz-Zagrosek, V.

Summary

Background

Guideline-recommended doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), and β blockers are similar for men and women with heart failure with reduced ejection fraction (HFrEF), even though there are known sex differences in pharmacokinetics of these drugs. We hypothesised that there might be sex differences in the optimal dose of ACE inhibitors or ARBs and β blockers in patients with HFrEF.

Methods

We did a post-hoc analysis of BIOSTAT-CHF, a prospective study in 11 European countries of patients with heart failure in whom initiation and up-titration of ACE inhibitors or ARBs and β blockers was encouraged by protocol. We included only patients with left ventricular ejection fraction less than 40%, and excluded those who died within the first 3 months. Primary outcome was a composite of time to all-cause mortality or hospitalisation for heart failure. Findings were validated in ASIAN-HF, an independent cohort of 3539 men and 961 women with HFrEF.

Findings

Among 1308 men and 402 women with HFrEF from BIOSTAT-CHF, women were older (74 [12] years vs 70 [12] years, p<0·0001) and had lower bodyweights (72 [16] kg vs 85 [18] kg, p<0·0001) and heights (162 [7] cm vs 174 [8] cm, p<0·0001) than did men, although body-mass index did not differ significantly. A similar number of men and women reached guideline-recommended target doses of ACE inhibitors or ARBs (99 [25%] vs 304 [23%], p=0·61) and β blockers (57 [14%] vs 168 [13%], p=0·54). In men, the lowest hazards of death or hospitalisation for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and β blockers, but women showed approximately 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels. These sex differences were still present after adjusting for clinical covariates, including age and body surface area. In the ASIAN-HF registry, similar patterns were observed for both ACE inhibitors or ARBs and β blockers, with women having approximately 30% lower risk at 50% of the recommended doses, with no further benefit at higher dose levels.

Interpretation

This study suggests that women with HFrEF might need lower doses of ACE inhibitors or ARBs and β blockers than men, and brings into question what the true optimal medical therapy is for women versus men.

Funding

European Commission.

Keywords 
Cardiology Vascular medicine
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