Anticoagulant treatment and COVID-19 mortality among older adults living in nursing homes in Sweden.

Background: Anticoagulants (AC) were introduced in March 2020 as standard of care in nursing home (NH) residents affected with COVID-19 in the Stockholm region, Sweden. ACs are proven to reduce the risk of complications and mortality from COVID-19 among patients of other ages and settings, but there is limited scientific evidence underpinning this practice in the NH setting. Methods: This matched cohort study included 182 NH residents in the Stockholm Region diagnosed with COVID-19 in March-May 2020. The main exposure was any AC treatment. Exposed (n = 91), 49% prevalent (pre-COVID-19 diagnosis) AC and 51% incident AC were compared with unexposed controls (n = 91). The outcome was 28-days all-cause mortality after COVID-19 infection. The mortality odds ratios (OR) were assessed using logistic regression, adjusted for age, sex, multimorbidity, and mobility, also stratified by incident or prevalent AC-type, age group, and sex. Results: Of the 182 individuals diagnosed with COVID-19 (median age 88 years, 68% women), 39% died within 28 days after diagnosis. Use of either incident or prevalent AC was associated with a reduced, adjusted 28-day mortality (OR[95% CI]: 0.31[0.16-0.62]). In stratified analyses, the association was significant in both age groups: 70-89 (OR: 0.37 [0.15-0.89]) and 90-99 years of age (OR: 0.22 [0.07-0.65]. In sex-stratified analysis, the AC-lowering effect was significant in women only (OR: 0.28[0.11-0.67]). In the analyses stratified by AC type, the mortality-lowering effect was observed for both prevalent AC (OR: 0.35[0.12-0.99]) and incident AC (OR: 0.29[0.11-0.76]). Conclusions: Both prevalent and incident use of ACs in prophylactic dosing was associated with reduced 28-day mortality among older individuals with COVID-19 in a NH setting. The effect was seen across age-strata and in women. The findings present new insight in best practice for individuals diagnosed with COVID-19 in the NH setting.

Should relational effects be considered in health care priority setting?

It is uncontroversial to claim that the extent to which health care interventions benefit patients is a relevant consideration for health care priority setting. However, when effects accrue to the individual patient, effects of a more indirect kind may accrue to other individuals as well, such as the patient's children, friends, or partner. If, and if so how, such relational effects should be considered relevant in priority setting is contentious. In this paper, we illustrate this question by using disease-modifying drugs for Alzheimer's disease as a case in point. The ethical analysis begins by sketching the so-called prima facie case for ascribing moral weight to relational effects and then moves on to consider a number of objections to it. We argue that, whereas one set of objections may be dismissed, there is another set of arguments that poses more serious challenges for including relational effects in priority setting.

Novel drug candidates targeting Alzheimer's disease: ethical challenges with identifying the relevant patient population.

Intensive research is carried out to develop a disease-modifying drug for Alzheimer's disease (AD). The development of drug candidates that reduce Aß or tau in the brain seems particularly promising. However, these drugs target people at risk for AD, who must be identified before they have any, or only moderate, symptoms associated with the disease. There are different strategies that may be used to identify these individuals (eg, population screening, cascade screening, etc). Each of these strategies raises different ethical challenges. In this paper, we analyse these challenges in relation to the risk stratification for AD necessary for using these drugs. We conclude that the new drugs must generate large health benefits for people at risk of developing AD to justify the ethical costs associated with current risk stratification methods, benefits much larger than current drug candidates have. This conclusion raises a new set of ethical questions that should be further discussed.

Survival of esophageal and gastric cancer patients with adjuvant and palliative chemotherapy-a retrospective analysis of a register-based patient cohort.

PURPOSE: The survival of esophageal and gastric cancer patients treated with chemotherapy is rarely assessed outside of clinical trials. Therefore, we compared the effectiveness of various curative or palliative chemotherapy regimens on the survival of esophageal and gastric cancer patients in a "real world" clinical setting. METHODS: We identified a cohort of 966 incident esophageal and gastric cancer patients in Stockholm/Gotland County (a low-risk Western population) during 2008-2013. Patients who received chemotherapy with curative intention (n = 279) and palliative intention (n = 182) were analyzed separately. Using Cox proportional hazards regression models, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and adjusted for the potential confounding factors: age, sex, TNM stage, radiotherapy, comorbidity, marital status, education, income, and country of birth. RESULTS: In esophageal cancer patients with curative treatment intention, we observed a higher hazard for death among patients who received carboplatin-fluorouracil compared to patients who received cisplatin-fluorouracil, corresponding to a HR of 2.18 (95% CI 1.09-4.37). Conversely, in patients with cancer in the gastroesophageal junction who had a curative treatment intention at diagnosis, we observed a reduced hazard for death among those who received fluorouracil-oxaliplatin, compared to patients who received cisplatin-fluorouracil (HR 0.28; 95% CI 0.08-0.96). CONCLUSION: Among patients with esophageal cancer who received treatment with curative intention, cisplatin-fluorouracil was associated with better survival compared to carboplatin-fluorouracil, while patients with gastroesophageal junction cancer who were treated with cisplatin-fluorouracil had worse survival compared to fluorouracil-oxaliplatin.

Snus users had high levels of nicotine, cotinine and 3-hydroxycotinine in their breastmilk, and the clearance was slower than in smoking mothers.

AIM: Using snus, an oral moist tobacco, has increased among pregnant women in Sweden, the only European Union country where sales are legal. This study evaluated whether snus generated similar concentrations of nicotine and its metabolites in breastmilk to cigarette smoking. METHODS: We analysed 49 breastmilk samples from 33 nursing mother - 13 snus users, six cigarette smokers and 14 controls - for concentrations of nicotine, cotinine and 3-hydroxycotinine. The mothers were recruited at antenatal clinics in Sweden from 2007 to 2012. RESULTS: The median nicotine concentration in breastmilk of the snus users was 38.7 ng/mL (0-137) versus 24.0 ng/mL (0-56) in smokers, with median cotinine levels of 327.6 ng/mL (37-958) versus 164.4 ng/mL and median 3-hydroxycotinine levels of 202.7 ng/mL (28-452) versus 112.4 (0-231), respectively. Nicotine was still detected in the breastmilk of eight of the 13 snus users after abstaining from tobacco for a median duration of 11 hours (0.6-12.5), while the breastmilk of the smokers was nicotine-free after four hours' abstinence. CONCLUSION: Snus users had high levels of nicotine and metabolites in their breastmilk and nicotine was found even after 12.5 hours of abstinence.

Tumor Necrosis Factor Inhibitors and Cancer Recurrence in Swedish Patients With Rheumatoid Arthritis: A Nationwide Population-Based Cohort Study.

Background: Use of tumor necrosis factor inhibitors (TNFi) in patients with a history of cancer remains a clinical dilemma. Objective: To investigate whether TNFi treatment in rheumatoid arthritis (RA) is associated with increased risk for cancer recurrence. Design: Population-based cohort study based on linkage of nationwide registers. Setting: Sweden. Participants: Patients with RA who started TNFi treatment between 2001 and 2015, after being diagnosed with cancer, and matched patients with RA and a history of the same cancer who had never received biologics. Measurements: The primary outcome was the first recurrence of cancer. Adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs), taking into account time, cancer type, and whether the cancer was invasive or in situ (or tumor, node, metastasis [TNM] classification system stage in a subset of patients). Results: Among 467 patients who started TNFi treatment (mean time after cancer diagnosis, 7.9 years), 42 had cancer recurrences (9.0%; mean follow-up, 5.3 years); among 2164 matched patients with the same cancer history, 155 had recurrences (7.2%; mean follow-up, 4.3 years) (HR, 1.06 [95% CI, 0.73 to 1.54). Hazard ratios were close to 1 in analyses of patient subsets matched on cancer stage or with similar time from index cancer diagnosis to the start of TNFi treatment, as well as in unmatched analyses. Several CIs had upper limits close to 2. Limitation: The outcome algorithm was partly nonvalidated, and channeling bias was possible if patients with a better index cancer prognosis were more likely to receive TNFi. Conclusion: The findings suggest that TNFi treatment is not associated with increased risk for cancer recurrence in patients with RA, although meaningful risk increases could not be ruled out completely. Primary Funding Source: ALF (an agreement in Stockholm County Council concerning medical education and research in health and medical care), the Swedish Cancer Society, the Swedish Foundation for Strategic Research, and the Swedish Research Council.

Maternal snuff use and cotinine in late pregnancy-A validation study.

INTRODUCTION: Oral moist snuff is widely used in Sweden including during pregnancy. Maternal snuff use has been associated with increased risks of adverse pregnancy outcomes in epidemiological studies. Self-reported maternal snuff use has not been validated previously. The main objective of this study was to validate self-reported snuff use in pregnancy in a prospective cohort study and in the Medical Birth Register. MATERIAL AND METHODS: A prospective Swedish cohort study, 2005-2011, in which 572 women were asked to participate. Of 474 recruited women, 381 non-smokers (263 snuff users and 118 non-tobacco users) were included in the main analyses. Participants prospectively reported snuff use through questionnaires. Medical Birth Register data on the participants was obtained. Maternal urine cotinine was collected in late pregnancy and was used as a biomarker. RESULTS: Cotinine levels in maternal urine confirmed a high validity of self-reported snuff use through questionnaires in late pregnancy; sensitivity and specificity values were 98% and 96%, respectively. In the Medical Birth Register, 45% of the snuff users were misclassified as nonusers in late pregnancy. There were significant differences in median cotinine levels between users of mini pouches and users of standard pouches, but there was a great difference of cotinine levels among users with similar number of pouches used daily. CONCLUSIONS: Self-reported snuff use through questionnaires has high validity. In the Medical Birth Register, in late pregnancy, many snuff users were misclassified as nonusers. As a consequence, there is a risk of underestimating the harmful effects of snuff use when using late pregnancy Medical Birth Register data.

Prenatal Exposure to Snus Alters Heart Rate Variability in the Infant.

INTRODUCTION: Maternal use of smoked tobacco during pregnancy causes significant morbidity and mortality in the human infant including alterations in autonomic control with increased risk of sudden infant death syndrome. We hypothesized that maternal snus (smokeless tobacco) use during pregnancy affects autonomic cardiac regulation in the infant, as measured by heart rate variability (HRV) and the low frequency and high frequency ratio (LF/HF ratio). METHODS: A prospective observational study of 56 infants of women who used snus (n = 23) or cigarettes (n = 13) during pregnancy versus tobacco- and nicotine-free controls (n = 19). The nicotine dose was estimated by questionnaires at 4 timepoints pre- and post-natally. The infants' urine cotinine concentration and HRV during 2 hours of sleep were studied 1-2 months after birth. RESULTS: LF/HF ratio was higher in snus (mean 3.31; 95% CI 2.78-3.83) and smoke (3.51;2.54-4.47) compared to controls (2.15; 1.76-2.54, p = .002). Early prenatal nicotine exposure "without" any further exposure increased the LF/HF ratio (3.19; 2.55-3.84, p = .02). Continuous prenatal nicotine exposure "without" postnatal exposure was also associated with a residual increase in LF/HF ratio (4.40; 3.38-5.42, p < .001). There was no difference between infants exposed to smokeless versus smoked tobacco, suggesting a common constituent (nicotine) altering autonomic cardiac regulation. CONCLUSION: Infants to mothers who used snus during pregnancy showed lower vagal activity with an increased LF/HF ratio compared to controls, and similar to infants of smokers. Even early prenatal exposure to snus has a lasting impact on autonomic cardiac regulation suggesting a fetal "re-programing" of the developing autonomic nervous system. IMPLICATIONS: The results indicate that smokeless tobacco (Swedish snus) affects the developing autonomic nervous system during gestation. Even if exposure is interrupted during the first or second trimester, effects in autonomic cardiac regulation are seen in the 1-2 month-old infant. This underlines the importance of abstaining from all types of tobacco use during the whole pregnancy. Our findings may also have more general relevance to other routes by which nicotine can be delivered to a fetus and newborn.

Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers.

OBJECTIVES: Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. METHODS: Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were calculated across countries by taking the size of the register into account. RESULTS: Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab-exposed patients were 1.1 (95% CI 0.9 to 1.4), 1.2 (0.99 to 1.6) and 1.3 (0.6 to 2.6), respectively. Incidence rates in tocilizumab and abatacept-exposed patients were also not significantly increased. IRR versus biologic-naïve patients were: TNFi 1.1 (95% CI 0.8 to 1.6); rituximab 1.2 (0.5 to 2.9). CONCLUSIONS: This large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi.

Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden.

OBJECTIVE: To investigate the risk of squamous cell and basal cell skin cancer in patients with rheumatoid arthritis naive to biologic drugs, in patients starting tumour necrosis factor (TNF) inhibitor treatment, and in the general population. DESIGN: Population based cohort study. SETTING: Nationwide data from Sweden. PARTICIPANTS: Cohort of patients with rheumatoid arthritis naive to biologics (n=46 409), cohort of patients with rheumatoid arthritis starting TNF inhibitor treatment as first biologic in 1998-2012 (n=12 558), and matched general population comparator cohort, identified through national quality of care and health registers. MAIN OUTCOME MEASURE: Hazard ratio of first in situ or invasive squamous cell skin cancer (1998-2012) and first basal cell cancer (2004-12). RESULTS: For basal cell cancer, the hazard ratio was 1.22 (95% confidence interval 1.07 to 1.41) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.14 (0.98 to 1.33; 236 v 1587 events) comparing TNF inhibitor treated patients with biologics-naive patients. For squamous cell cancer, the hazard ratio was 1.88 (1.74 to 2.03) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.30 (1.10 to 1.55; 191 v 847 events) comparing TNF inhibitors with biologics-naive patients; the latter translated to an annual number needed to harm in the order of 1600. Among people with a history of squamous cell or basal cell cancer, TNF inhibitors did not further increase risks. CONCLUSION: A small to moderately increased risk of basal cell cancer was seen in biologics-naive rheumatoid arthritis patients, with no further effect of TNF inhibitors. For squamous cell cancer, the risk was nearly doubled in biologics-naive patients, with a further 30% increase in risk among patients treated with TNF inhibitors; this translates to one additional case for every 1600 years of treatment experience, assuming that this association reflected causality. Vigilance regarding skin malignancies may be advisable in rheumatoid arthritis, irrespective of TNF inhibitor treatment. Most of the increase in risk for non-melanoma skin cancer in patients with rheumatoid arthritis treated with TNF inhibitors originates from factors other than that treatment.

TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study.

OBJECTIVE: To investigate the risk of breast cancer recurrence in rheumatoid arthritis (RA)-patients with tumour necrosis factor inhibitor (TNFi) treatment and a history of breast cancer, taking several breast cancer, comorbidity and RA-related prognostic factors into account. METHODS: 143 female TNFi-treated patients (1999-2010) with RA and a history of breast cancer before start of TNFi were identified through register linkages, and matched 1:1 from a cohort of 1598 comparable biologics-naive individuals. 120 TNFi-treated and 120 matched biologics-naive individuals with a history of equally recent/distant breast cancer met the eligibility criteria and comprised the final study population. The primary outcome was first recurrence of breast cancer. Through register-linkages and chart review, individuals were followed until 2011. HRs for recurrence were calculated using Cox regression. RESULTS: The median time from breast cancer diagnosis until TNFi-treatment/start of follow-up was 9.4 years. Modest differences in breast cancer characteristics and/or treatment among TNFi-treated and biologics-naive individuals were noted at time of breast cancer diagnosis. Median follow-up from TNFi start was 4.9 years (4.6 years among biologics-naive). Among the TNFi-treated, 9 developed a breast cancer recurrence (crude incidence rate 15/1000 person-years) during follow-up, compared with 9 among the matched biologics-naive (16/1000 person-years). The adjusted corresponding HR was 1.1 (95% CI 0.4 to 2.8). CONCLUSIONS: Among patients with RA and a history of breast cancer, those who started TNFi-treatment did not experience more breast cancer recurrences than patients with RA treated otherwise. The generalisability of our findings to women with a very recent or a poor prognosis of breast cancer remains unknown.

Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden.

OBJECTIVES: To investigate the potential association between tumour necrosis factor (TNF) inhibitor treatment and malignant melanomas in rheumatoid arthritis, melanoma risks in rheumatoid arthritis patients not treated with biological drugs, and risk of all site cancer with TNF inhibitors as used in rheumatoid arthritis. DESIGN: Population based cohort study. SETTING: Prospectively recorded data from national clinical, health, and demographic registers in Sweden 2001-10. Patients with rheumatoid arthritis treated (n = 10,878) or not (n = 42,198) with TNF inhibitors and matched general population comparators (n = 162,743). MAIN OUTCOME MEASURES: The primary outcome was first invasive melanoma in people without any history of invasive cancer of any type. Hazard ratios were estimated using Cox regression, comparing non-biological drug treated rheumatoid arthritis patients with the general population comparator and TNF inhibitor treated rheumatoid arthritis patients with those not treated with biological drugs. Secondary outcomes included in situ melanomas, second primary melanomas, and all site cancer. RESULTS: 113 first invasive melanomas occurred in rheumatoid arthritis patients not treated with biological drugs, and 393 occurred in the general population comparator cohort. Rheumatoid arthritis patients not treated with biological drugs were not at significantly increased risk of melanoma compared with the general population (hazard ratio 1.2, 95% confidence interval 0.9 to 1.5). 38 first invasive melanomas occurred in rheumatoid arthritis patients treated with TNF inhibitors; these patients had an increased risk of melanoma compared with rheumatoid arthritis patients not treated with biological drugs (hazard ratio 1.5, 1.0 to 2.2; 20 additional cases per 100,000 person years). The risk of a second primary melanoma was non-significantly increased (hazard ratio 3.2, 0.8 to 13.1; n=3 v 10) in rheumatoid arthritis patients treated with TNF inhibitors compared with those not treated with biological drugs. CONCLUSION: Overall, patients with rheumatoid arthritis who have not been treated with biological drugs are not at increased risk of invasive melanoma compared with the general population. Rheumatoid arthritis patients selected for TNF inhibitor treatment are not at increased overall risk for cancer but have a 50% increased relative risk of invasive melanoma. Given the small increase in absolute risk, these finding may not markedly shift the overall risk-benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons.

Usage, risk, and benefit of weight-loss drugs in primary care.

Purpose. To investigate the use of the weight-loss drugs rimonabant, sibutramine, and orlistat in primary care and to characterize the patients receiving the drugs. Methods. In this retrospective, descriptive study, 300 randomly selected patients having started weight-loss drug treatment at 15 primary care centres were investigated using the patient's medical records and their complete drug purchase data. Results. Even though 48% of the patients specifically demanded drug treatment, 77% continued treatment less than one year. 28% of rimonabant patients and 32% of sibutramine patients had a history of depression or antidepressant treatment. 41% of sibutramine patients had a history of hypertension and/or cardiovascular disease. 36% had no documented weight after treatment initiation. Conclusions. These results suggest that weight-loss drug treatment was often initiated upon patient request but was of limited clinical benefit as it was managed in a large portion of Swedish primary carecenters.

Does cancer that occurs during or after anti-tumor necrosis factor therapy have a worse prognosis? A national assessment of overall and site-specific cancer survival in rheumatoid arthritis patients treated with biologic agents.

OBJECTIVE: Tumor necrosis factor (TNF) may affect tumor development and spreading. While data on the incidence of cancer following anti-TNF therapy have been published, the purpose of this study was to examine the clinical presentation and outcome of cancers that develop during or after anti-TNF therapy. METHODS: By linking data from Swedish clinical registries of rheumatoid arthritis (RA) patients, including Anti-Rheumatic Therapy in Sweden (ARTIS), the Swedish Biologics Register, with nationwide data on hospitalizations and outpatient visits for RA, we assembled a cohort of 78,483 RA patients who were alive in 1999 or who entered the cohort thereafter. Of these, 8,562 patients started therapy with a biologic agent (98% started an anti-TNF) during the period from January 1, 1999 to December 31, 2007. Linkage to the Swedish Cancer Register and other registers identified first primary cancers occurring during 1999-2007 as well as post-cancer survival through March 31, 2009. Through this linkage, we identified 314 cancers in patients who were undergoing, or had a history of, treatment with biologic agents and 4,650 cancers in patients who were biologics-naive at the time of cancer diagnosis. The distributions of tumor stage among the biologics-exposed and the biologics-naive patients were compared. The relative risk of death among the biologics-exposed versus the 586 matched biologics-naive cancer cases were assessed by Cox regression analyses. Through chart review in a defined subset, we gathered additional clinical information and validated the diagnoses. RESULTS: For all cancers combined, the distribution of cancer stages at the time of cancer diagnosis was largely similar between those in the biologics-exposed and the matched biologics-naive groups. Based on the total of 113 deaths among those with cancer in the biologics-exposed group versus the 256 deaths among those with cancer in the biologics-naive group, the relative risk of death following cancer associated with exposure to anti-TNF was 1.1 (95% confidence interval 0.8-1.6). CONCLUSION: During routine care, cancers that occur following anti-TNF therapy are not characterized by any markedly altered stage at presentation or by altered post-cancer survival rates.

Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment?

OBJECTIVE: To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions. METHODS: By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received. RESULTS: During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed. CONCLUSION: During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.