Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults

Objectives To determine the subgroup specific associations between usual blood pressure and risk of peripheral arterial disease, and to examine the relation between peripheral arterial disease and a range of other types of vascular disease in a large contemporary cohort.

Design Cohort study.

Setting Linked electronic health records from 1990 to 2013 in the United Kingdom. Participants 4,222,459 people aged 30-90 years, registered at a primary care practice for at least one year and with a blood pressure measurement.

Main outcome measures Time to first diagnosis of new onset peripheral arterial disease and time to first diagnosis of 12 different vascular events.

Results A 20 mm Hg higher than usual systolic blood pressure was associated with a 63% higher risk of peripheral arterial disease (hazard ratio 1.63, 95% confidence interval 1.59 to 1.66). The strength of the association declined with increasing age and body mass index (P<0.001 for interaction) but was not modified by sex or smoking status. Peripheral arterial disease was associated with an increased risk of 11 different vascular events, including ischaemic heart disease (1.68, 1.58 to 1.79), heart failure (1.63, 1.52 to 1.75), aortic aneurysm (2.10, 1.79 to 2.45), and chronic kidney disease (1.31, 1.25 to 1.38), but not haemorrhagic stroke. The most common initial vascular event among those with peripheral arterial disease was chronic kidney disease (24.4% of initial events), followed by ischaemic heart disease (18.5% of initial events), heart failure (14.7%), and atrial fibrillation (13.2%). Overall estimates from this cohort were consistent with those derived from traditional studies when we pooled the findings in two meta-analyses.

Conclusions Raised blood pressure is a strong risk factor for peripheral arterial disease in a range of patient subgroups. Furthermore, clinicians should be aware that those with established peripheral arterial disease are at an increased risk of a range of other vascular events, including chronic kidney disease, ischaemic heart disease, heart failure, atrial fibrillation, and stroke.

Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults by Connor A Emdin, et al. BMJ 2015; 351 :h4865 (Published 29 September 2015)

Use of the English urgent referral pathway for suspected cancer and mortality in patients with cancer: cohort study

Objective To assess the overall effect of the English urgent referral pathway on cancer survival.

Setting 8049 general practices in England.

Design Cohort study. Linked information from the national Cancer Waiting Times database, NHS Exeter database, and National Cancer Register was used to estimate mortality in patients in relation to the propensity of their general practice to use the urgent referral pathway.

Participants 215,284 patients with cancer, diagnosed or first treated in England in 2009 and followed up to 2013.

Outcome measure Hazard ratios for death from any cause, as estimated from a Cox proportional hazards regression.

Results During four years of follow-up, 91,620 deaths occurred, of which 51,606 (56%) occurred within the first year after diagnosis. Two measures of the propensity to use urgent referral, the standardised referral ratio and the detection rate, were associated with reduced mortality. The hazard ratio for the combination of high referral ratio and high detection rate was 0.96 (95% confidence interval 0.94 to 0.99), applying to 16% (n=34,758) of the study population. Patients with cancer who were registered with general practices with the lowest use of urgent referral had an excess mortality (hazard ratio 1.07 (95% confidence interval 1.05 to 1.08); 37% (n=79,416) of the study population). The comparator group for these two hazard ratios was the remaining 47% (n=101,110) of the study population. This result in mortality was consistent for different types of cancer (apart from breast cancer) and with other stratifications of the dataset, and was not sensitive to adjustment for potential confounders and other details of the statistical model.

Conclusions Use of the urgent referral pathway could be efficacious. General practices that consistently have a low propensity to use urgent referrals could consider increasing the use of this pathway to improve the survival of their patients with cancer.

Use of the English urgent referral pathway for suspected cancer and mortality in patients with cancer: cohort study by Henrik Møller, et al. BMJ 2015; 351 :h5102 (Published 13 October 2015)

Association Between Hospitalization With Community-Acquired Laboratory Confirmed Influenza Pneumonia and Prior Receipt of Influenza Vaccination

Importance Few studies have evaluated the relationship between influenza vaccination and pneumonia, a serious complication of influenza infection.

Objective To assess the association between influenza vaccination status and hospitalization for community-acquired laboratory-confirmed influenza pneumonia.

Design, Setting, and Participants The Etiology of Pneumonia in the Community (EPIC) study was a prospective observational multicenter study of hospitalizations for community acquired pneumonia conducted from January 2010 through June 2012 at 4 US sites. In this case-control study, we used EPIC data from patients 6 months or older with laboratory-confirmed influenza infection and verified vaccination status during the influenza seasons and excluded patients with recent hospitalization, from chronic care residential facilities, and with severe immunosuppression. Logistic regression was used to calculate odds ratios, comparing the odds of vaccination between influenza-positive (case) and influenza-negative (control) patients with pneumonia, controlling for demographics, comorbidities, season, study site, and timing of disease onset. Vaccine effectiveness was estimated as (1−adjusted odds ratio)×100%. Exposure Influenza vaccination, verified through record review.

Main Outcomes and Measures Influenza pneumonia, confirmed by real-time reversetranscription polymerase chain reaction performed on nasal/oropharyngeal swabs. Results Overall, 2767 patients hospitalized for pneumonia were eligible for the study; 162 (5.9%) had laboratory-confirmed influenza. Twenty-eight of 162 cases (17%) with influenza-associated pneumonia and 766 of 2605 controls (29%) with influenza-negative pneumonia had been vaccinated. The adjusted odds ratio of prior influenza vaccination between cases and controls was 0.43 (95% CI, 0.28-0.68; estimated vaccine effectiveness, 56.7%; 95% CI, 31.9%-72.5%).

Conclusions and Relevance Among children and adults hospitalized with community acquired pneumonia, those with laboratory-confirmed influenza-associated pneumonia, compared with those with pneumonia not associated with influenza, had lower odds of having received influenza vaccination.

Association Between Hospitalization With Community-Acquired Laboratory Confirmed Influenza Pneumonia and Prior Receipt of Influenza Vaccination by Carlos G. Grijalva, et al. JAMA. 2015;314(14):1488-1497

Early Physical Therapy vs Usual Care in Patients With Recent-Onset Low Back Pain: A Randomized Clinical Trial

Importance Low back pain (LBP) is common in primary care. Guidelines recommend delaying referrals for physical therapy.

Objective To evaluate whether early physical therapy (manipulation and exercise) is more effective than usual care in improving disability for patients with LBP fitting a decision rule.

Design, Setting, and Participants Randomized clinical trial with 220 participants recruited between March 2011 and November 2013. Participants with no LBP treatment in the past 6 months, aged 18 through 60 years (mean age, 37.4 years [SD,10.3]), an Oswestry Disability Index (ODI) score of 20 or higher, symptom duration less than 16 days, and no symptoms distal to the knee in the past 72 hours were enrolled following a primary care visit. Interventions All participants received education. Early physical therapy (n108) consisted of 4 physical therapy sessions. Usual care (n112) involved no additional interventions during the first 4 weeks.

Main Outcomes and Measures Primary outcome was change in the ODI score (range: 0- 100; higher scores indicate greater disability; minimum clinically important difference, 6 points) at 3 months. Secondary outcomes included changes in the ODI score at 4-week and 1-year follow-up, and change in pain intensity, Pain Catastrophizing Scale (PCS) score, fear-avoidance beliefs, quality of life, patient-reported success, and health care utilization at 4-week, 3-month, and 1-year follow-up.

Results One-year follow-up was completed by 207 participants (94.1%). Using analysis of covariance, early physical therapy showed improvement relative to usual care in disability after 3 months (mean ODI score: early physical therapy group, 41.3 [95% CI, 38.7 to 44.0] at baseline to 6.6 [95% CI, 4.7 to 8.5] at 3 months; usual care group, 40.9 [95% CI, 38.6 to 43.1] at baseline to 9.8 [95% CI, 7.9 to 11.7] at 3 months; between-group difference, −3.2 [95% CI, −5.9 to −0.47], P=.02). A significant difference was found between groups for the ODI score after 4 weeks (between-group difference, −3.5 [95% CI, −6.8 to −0.08], P=.045]), but not at 1-year follow-up (between-group difference, −2.0 [95% CI, −5.0 to 1.0], P=.19). There was no improvement in pain intensity at 4-week, 3-month, or 1-year follow-up (between-group difference, −0.42 [95% CI, −0.90 to 0.02] at 4-week follow-up; −0.38 [95% CI, −0.84 to 0.09] at 3-month follow-up; and −0.17 [95% CI, −0.62 to 0.27] at 1-year follow-up). The PCS scores improved at 4 weeks and 3 months but not at 1-year follow-up (between-group difference, −2.7 [95% CI, −4.6 to −0.85] at 4-week follow-up; – 6 – −2.2 [95% CI, −3.9 to −0.49] at 3-month follow-up; and −0.92 [95% CI, −2.7 to 0.61] at 1- year follow-up). There were no differences in health care utilization at any point.

Conclusions and Relevance Among adults with recent-onset LBP, early physical therapy resulted in statistically significant improvement in disability, but the improvement was modest and did not achieve the minimum clinically important difference compared with usual care.

Early Physical Therapy vs Usual Care in Patients With Recent-Onset Low Back Pain: A Randomized Clinical Trial by Julie M. Fritz, et al. JAMA. 2015;314(14):1459-1467.

Smoking cessation and reduction in people with chronic mental illness

The high prevalence of cigarette smoking and tobacco related morbidity and mortality in people with chronic mental illness is well documented. This review summarizes results from studies of smoking cessation treatments in people with schizophrenia, depression, anxiety disorders, and post-traumatic stress disorder. It also summarizes experimental studies aimed at identifying biopsychosocial mechanisms that underlie the high smoking rates seen in people with these disorders. Research indicates that smokers with chronic mental illness can quit with standard cessation approaches with minimal effects on psychiatric symptoms. Although some studies have noted high relapse rates, longer maintenance on pharmacotherapy reduces rates of relapse without untoward effects on psychiatric symptoms. Similar biopsychosocial mechanisms are thought to be involved in the initiation and persistence of smoking in patients with different disorders. An appreciation of these common factors may aid the development of novel tobacco treatments for people with chronic mental illness. Novel nicotine and tobacco products such as electronic cigarettes and very low nicotine content cigarettes may also be used to improve smoking cessation rates in people with chronic mental illness.

Smoking cessation and reduction in people with chronic mental illness by Jennifer W Tidey, Mollie E Miller. BMJ 2015; 351 :h4065 (Published 21 September 2015)

Association between guideline recommended drugs and death in older adults with multiple chronic conditions: population based cohort study

Objective To estimate the association between guideline recommended drugs and death in older adults with multiple chronic conditions.

Design Population based cohort study. Setting Medicare Current Beneficiary Survey cohort, a nationally representative sample of Americans aged 65 years or more. Participants 8578 older adults with two or more study chronic conditions (atrial fibrillation, coronary artery disease, chronic kidney disease, depression, diabetes, heart failure, hyperlipidemia, hypertension, and thromboembolic disease), followed through 2011.

Exposures Drugs included β blockers, calcium channel blockers, clopidogrel, metformin, renin-angiotensin system (RAS) blockers; selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs); statins; thiazides; and warfarin.

Main outcome measure Adjusted hazard ratios for death among participants with a condition and taking a guideline recommended drug relative to participants with the condition not taking the drug and among participants with the most common combinations of four conditions.

Results Over 50% of participants with each condition received the recommended drugs regardless of coexisting conditions; 1287/8578 (15%) participants died during the three years of follow-up. Among cardiovascular drugs, β blockers, calcium channel blockers, RAS blockers, and statins were associated with reduced mortality for indicated conditions. For example, the adjusted hazard ratio for β blockers was 0.59 (95% confidence interval 0.48 to 0.72) for people with atrial fibrillation and 0.68 (0.57 to 0.81) for those with heart failure. The adjusted hazard ratios for cardiovascular drugs were similar to those with common combinations of four coexisting conditions, with trends toward variable effects for β blockers. None of clopidogrel, metformin, or SSRIs/SNRIs was associated with reduced mortality. Warfarin was associated with a reduced risk of death among those with atrial fibrillation (adjusted hazard ratio 0.69, 95% confidence interval 0.56 to 0.85) and thromboembolic disease (0.44, 0.30 to 0.62). Attenuation in the association with reduced risk of death was found with warfarin in participants with some combinations of coexisting conditions.

Conclusions Average effects on survival, particularly for cardiovascular study drugs, were comparable to those reported in randomized controlled trials but varied for some drugs according to coexisting conditions. Determining treatment effects in combinations of conditions may guide prescribing in people with multiple chronic conditions.

Association between guideline recommended drugs and death in older adults with multiple chronic conditions: population based cohort study by Mary E Tinetti, et al. BMJ 2015; 351 :h4984 (Published 02 October 2015)

Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis

Background Early clinical studies suggested that the anti–interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis.

Methods In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician’s global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100).

Results At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab.

Conclusions Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis.

Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis by Mark Lebwohl, et al. N Engl J Med 2015; 373:1318-1328 October 1, 2015