Emulating a target trial in case-control designs: an application to statins and colorectal cancer

BACKGROUND: Previous case-control studies have reported a strong association between statin use and lower cancer risk. It is unclear whether this association reflects a benefit of statins or is the result of design decisions that cannot be mapped to a (hypothetical) target trial (that would answer the question of interest). METHODS: We outlined the protocol of a target trial to estimate the effect of statins on colorectal cancer incidence among adults with low-density lipoprotein (LDL) cholesterol below 5 mmol/L. We then emulated the target trial using linked electronic health records of 752 469 eligible UK adults (CALIBER 1999-2016) under both a cohort design and a case-control sampling of the cohort. We used pooled logistic regression to estimate intention-to-treat and per-protocol effects of statins on colorectal cancer, with adjustment for baseline and time-varying risk factors via inverse-probability weighting. Finally, we compared our case-control effect estimates with those obtained using previous case-control procedures. RESULTS: Over the 6-year follow-up, 3596 individuals developed colorectal cancer. Estimated intention-to-treat and per-protocol hazard ratios were 1.00 (95% confidence interval [CI]: 0.87, 1.16) and 0.90 (95% CI: 0.71, 1.12), respectively. As expected, adequate case-control sampling yielded the same estimates. By contrast, previous case-control analytical approaches yielded estimates that appeared strongly protective (odds ratio 0.57, 95% CI: 0.36, 0.91, for ≥5 vs. <5 years of statin use). CONCLUSIONS: Our study demonstrates how to explicitly emulate a target trial using case-control data to reduce discrepancies between observational and randomized trial evidence. This approach may inform future case-control analyses for comparative effectiveness research

Association of smoking with amyotrophic lateral sclerosis risk and survival in men and women: a prospective study

<p>Abstract</p> <p>Background</p> <p>Previous epidemiologic studies have examined the association of smoking with amyotrophic lateral sclerosis (ALS) incidence, but their results have been inconsistent. Moreover, limited information exists on the association between smoking and survival in ALS patients. We evaluated the association of smoking with ALS incidence and survival in a population-based cohort.</p> <p>Methods</p> <p>We conducted a case-control study nested in the General Practice Research Database, a computerized clinical database in the United Kingdom. Cases were 1143 individuals with a diagnosis of ALS; 11,371 matched controls were selected among GPRD participants free of ALS. Predictors of survival were determined in the ALS cases. Smoking information was obtained from the computer database.</p> <p>Results</p> <p>Smoking was not associated with the risk of ALS in this population. The rate ratio (RR) of ALS comparing ever versus never smokers was 1.04, 95% confidence interval (CI) 0.80-1.34. In analysis stratified by gender, however, ever smoking was associated with ALS in women (RR 1.53, 95% CI 1.04-2.23) but not in men (RR 0.75, 95% CI 0.53-1.06). Mortality was 71% after 2.1 average years of follow-up. Old age and female sex were associated with lower survival. Smoking was a predictor of mortality only in women. Comparing ever versus never smokers, RR (95% CI) of death was 1.31 (1.04-1.65) in women, and 0.90 (0.72-1.11) in men.</p> <p>Conclusion</p> <p>In this large population-based study, smoking was associated with ALS risk and worse survival in women but not in men.</p

Análisis del consumo simultáneo de medicamentos y plantas medicinales en población española mayor de 65 años

Objetivos: Analizar el uso apropiado o inapropiado de la utilización conjunta de medicamentos y preparados de plantas medicinales que realiza la población mayor de 65 años en la provincia de Guadalajara (España). Materiales y métodos: Estudio observacional, descriptivo, de corte transversal, realizado en Guadalajara (España) capital y provincia. La recogida de datos de los pacientes se efectuó durante los años 2012 y 2013. Siendo, por tanto, las variables dependientes usadas el porcentaje de consumo de Preparados de plantas medicinales y el porcentaje de consumo de medicamentos. La población diana fueron pacientes polimedicados mayores de 65 años, varones o mujeres, que residieran en sus casas o en Residencias de Ancianos y que voluntariamente decidieron participar en este trabajo. Resultados: Se incluyeron 384 pacientes, 129 fueron varones (33,60%). Consumieron plantas medicinales el 88,30%. Consumieron PCPM 183 (47,6%) y PIPM 339 que representó el 88,3%. Con consumo total de 852 infusiones al día, un promedio de 2,21 infusiones diarias. Se encontraron 22 asociaciones potencialmente peligrosas y 10 potencialmente beneficiosas. Conclusiones: Se ha puesto de manifiesto que ciertas asociaciones de planta-medicamento, pueden contribuir a mejorar la situación del paciente, pero también ha evidenciado la necesidad de una atención farmacéutica en el consumo de preparados de plantas medicinales en relación con la farmacoterapia que tiene prescrita, a fin de evitar combinaciones que pudieran reducir la eficacia de los tratamientos o incrementar el riesgo de otras alteraciones

Análisis del consumo simultáneo de medicamentos y plantas medicinales en población española mayor de 65 años

Objetivos: Analizar el uso apropiado o inapropiado de la utilización conjunta de medicamentos y preparados de plantas medicinales que realiza la población mayor de 65 años en la provincia de Guadalajara (España). Materiales y métodos: Estudio observacional, descriptivo, de corte transversal, realizado en Guadalajara (España) capital y provincia. La recogida de datos de los pacientes se efectuó durante los años 2012 y 2013. Siendo, por tanto, las variables dependientes usadas el porcentaje de consumo de Preparados de plantas medicinales y el porcentaje de consumo de medicamentos. La población diana fueron pacientes polimedicados mayores de 65 años, varones o mujeres, que residieran en sus casas o en Residencias de Ancianos y que voluntariamente decidieron participar en este trabajo. Resultados: Se incluyeron 384 pacientes, 129 fueron varones (33,60%). Consumieron plantas medicinales el 88,30%. Consumieron PCPM 183 (47,6%) y PIPM 339 que representó el 88,3%. Con consumo total de 852 infusiones al día, un promedio de 2,21 infusiones diarias. Se encontraron 22 asociaciones potencialmente peligrosas y 10 potencialmente beneficiosas. Conclusiones: Se ha puesto de manifiesto que ciertas asociaciones de planta-medicamento, pueden contribuir a mejorar la situación del paciente, pero también ha evidenciado la necesidad de una atención farmacéutica en el consumo de preparados de plantas medicinales en relación con la farmacoterapia que tiene prescrita, a fin de evitar combinaciones que pudieran reducir la eficacia de los tratamientos o incrementar el riesgo de otras alteraciones

Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer:a nested case-control study

Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer

The per-protocol effect of immediate versus deferred antiretroviral therapy initiation

OBJECTIVE: The START trial found a lower risk of a composite clinical outcome in HIV-positive individuals assigned to immediate initiation of antiretroviral therapy (ART) compared with those assigned to deferred initiation. However, 30% of those assigned to deferred initiation started ART earlier than the protocol specified. To supplement the published intention-to-treat effect estimates, here we estimate the per-protocol effect of immediate versus deferred ART initiation in START. DESIGN: The START trial randomized 4685 HIV-positive participants with CD4 counts > 500 /mm to start ART immediately after randomization (immediate initiation group) or to wait until the CD4 count dropped below 350 cells/mm or an AIDS diagnosis (deferred initiation group). METHODS: We used the parametric g-formula to estimate and compare the cumulative 5-year risk of the composite clinical outcome in the immediate and deferred initiation groups had all the trial participants adhered to the protocol. RESULTS: We estimated that the 5-year risk of the composite outcome would have been 3.2% under immediate ART initiation and 7.0% under deferred initiation. The difference of 3.8% (95% confidence interval 1.5,6.5) was larger than the intention-to-treat effect estimate of 3.1%, corresponding to a difference in effect estimates of 0.72% (-0.35,2.35). CONCLUSIONS: The intention-to-treat effect estimate may underestimate the benefit of immediate ART initiation by 23%. This estimate can be used by patients and policy makers who need to understand the full extent of the benefit of changes in ART initiation policies

Lifestyle variables and the risk of myocardial infarction in the General Practice Research Database

<p>Abstract</p> <p>Background</p> <p>The primary objective of this study is to estimate the association between body mass index (BMI) and the risk of first acute myocardial infarction (AMI). As a secondary objective, we considered the association between other lifestyle variables, smoking and heavy alcohol use, and AMI risk.</p> <p>Methods</p> <p>This study was conducted in the general practice research database (GPRD) which is a database based on general practitioner records and is a representative sample of the United Kingdom population. We matched cases of first AMI as identified by diagnostic codes with up to 10 controls between January 1^st, 2001 and December 31^st, 2005 using incidence density sampling. We used multiple imputation to account for missing data.</p> <p>Results</p> <p>We identified 19,353 cases of first AMI which were matched on index date, GPRD practice and age to 192,821 controls. There was a modest amount of missing data in the database, and the patients with missing data had different risks than those with recorded values. We adjusted our analysis for each lifestyle variable jointly and also for age, sex, and number of hospitalizations in the past year. Although a record of underweight (BMI <18.0 kg/m²) did not alter the risk for AMI (adjusted odds ratio (OR): 1.00; 95% confidence interval (CI): 0.87–1.11) when compared with normal BMI (18.0–24.9 kg/m²), obesity (BMI ≥30 kg/m²) predicted an increased risk (adjusted OR: 1.41; 95% CI: 1.35–1.47). A history of smoking also predicted an increased risk of AMI (adjusted OR: 1.81; 95% CI: 1.75–1.87) as did heavy alcohol use (adjusted OR: 1.15; 95% CI: 1.06–1.26).</p> <p>Conclusion</p> <p>This study illustrates that obesity, smoking and heavy alcohol use, as recorded during routine care by a general practitioner, are important predictors of an increased risk of a first AMI. In contrast, low BMI does not increase the risk of a first AMI.</p

The impact of early outcome events on the effect of tranexamic acid in post-partum haemorrhage: an exploratory subgroup analysis of the WOMAN trial.

BACKGROUND: In severe post-partum haemorrhage, death can occur within hours of bleeding onset so interventions to control the bleeding must be given immediately. In clinical trials of treatments for life-threatening bleeding, established treatments are given priority and the trial treatment is usually given last. However, enrolling patients in whom severe maternal morbidity or death is imminent or inevitable at the time of randomisation may dilute the effects of a trial treatment. METHODS: We conducted an exploratory analysis of data from the WOMAN trial, an international, randomised placebo-controlled trial of the effects of tranexamic acid on death and surgical intervention in 20,060 women with post-partum haemorrhage. We assessed the impact of early maternal death or hysterectomy due to exsanguination on the effect of tranexamic acid on each of these respective outcomes. We conducted repeated analyses excluding patients with these outcomes at increasing intervals from the time of randomisation. We quantified treatment effects using risk ratios (RR) and 99% confidence intervals (CI) and prepared cumulative failure plots. RESULTS: Among 14,923 women randomised within 3 h of delivery (7518 tranexamic acid and 7405 placebo), there were 216 bleeding deaths (1.5%) and 383 hysterectomies due to bleeding (2.8%). After excluding deaths from exsanguination at increasing time intervals following randomization, there was a significant reduction in the risk of death due to bleeding with tranexamic acid (RR = 0.41; 99% CI 0.19-0.89). However, after excluding hysterectomies at increasing time intervals post-randomization, there was no reduction in the risk of hysterectomy due to bleeding with tranexamic acid (RR = 0.79; 99% CI 0.33-1.86). CONCLUSIONS: Findings from this analysis provide further evidence that tranexamic acid reduces the risk of death from exsanguination in women who experience postpartum haemorrhage. It is uncertain whether tranexamic acid reduces the risk of hysterectomy for bleeding after excluding early hysterectomies. TRIAL REGISTRATION: ISRCTN trial registration number ISRCTN76912190, 8 Dec 2008; ClinicalTrials.gov number NCT00872469, 30 March 2009; PACTR number PACTR201007000192283, 9 Feb 2010; EudraCT number 2008-008441-38, 8 Dec 2010 (retrospectively registered)