Association of Antithrombotic Drug Use With Incident Intracerebral Hemorrhage Location.

BACKGROUND AND OBJECTIVES: Few population-based studies have assessed associations between the use of antithrombotic (platelet antiaggregant or anticoagulant) drugs and location-specific risks of spontaneous intracerebral hemorrhage (s-ICH). In this study, we estimated associations between antithrombotic drug use and the risk of lobar vs nonlobar incident s-ICH. METHODS: Using Danish nationwide registries, we identified cases in the Southern Denmark Region of first-ever s-ICH in patients aged 50 years or older between 2009 and 2018. Each verified case was classified as lobar or nonlobar s-ICH and matched to controls in the general population by age, sex, and calendar year. Prior antithrombotic use was ascertained from a nationwide prescription registry. We calculated odds ratios (aORs) for associations between the use of clopidogrel, aspirin, direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA), and lobar and nonlobar ICH in conditional logistic regression analyses that were adjusted for potential confounders. RESULTS: A total of 1,040 cases of lobar (47.9% men, mean age [SD] 75.2 [10.7] years) and 1,263 cases of nonlobar s-ICH (54.2% men, mean age 73.6 [11.4] years) were matched to 41,651 and 50,574 controls, respectively. A stronger association with lobar s-ICH was found for clopidogrel (cases: 7.6%, controls: 3.5%; aOR 3.46 [95% CI 2.45-4.89]) vs aspirin (cases: 22.9%, controls: 20.4%; aOR 2.14 [1.74-2.63; p = 0.019). Corresponding estimates for nonlobar s-ICH were not different between clopidogrel (cases: 5.4%, controls: 3.4%; aOR 2.44 [1.71-3.49]) and aspirin (cases: 20.7%, controls: 19.2%; aOR 1.77 [1.47-2.15]; p = 0.12). VKA use was associated with higher odds of both lobar (cases: 14.3%, controls: 6.1%; aOR 3.66 [2.78-4.80]) and nonlobar (cases: 15.4%, controls: 5.5%; aOR 4.62 [3.67-5.82]) s-ICH. The association of DOAC use with lobar s-ICH (cases: 3.5%, controls: 2.7%; aOR 1.66 [1.02-2.70]) was weaker than that of VKA use (p = 0.006). Corresponding estimates for nonlobar s-ICH were not different between DOACs (cases: 5.1%, controls: 2.4%; aOR 3.44 [2.33-5.08]) and VKAs (p = 0.20). DISCUSSION: Antithrombotics were associated with higher risks of s-ICH, but the strength of the associations varied by s-ICH location and drug, which may reflect differences in the cerebral microangiopathies associated with lobar vs nonlobar hemorrhages and the mechanisms of drug action.

Cardiovascular and renal outcomes among patients with type 2 diabetes using SGLT2 inhibitors added to metformin: a population-based cohort study from the UK.

INTRODUCTION: Large numbers of patients with type 2 diabetes receive treatment with a sodium-glucose co-transporter-2 inhibitor (SGLT2i). We investigated whether the cardiorenal preventative effects found in clinical trials are also seen in clinical practice where patient characteristics and adherence to treatment differ. RESEARCH DESIGN AND METHODS: Using UK primary care electronic health records, we followed two cohorts of patients with type 2 diabetes prescribed metformin: SGLT2is (N=12 978) and a matched comparator of patients not using an SGLT2i at the start of follow-up (N=44 286). Independent follow-ups were performed to identify the study outcomes: cardiovascular (CV) composite (comprising non-fatal myocardial infarction (MI)/ischemic stroke (IS) requiring hospitalization and CV death), severe renal disease, and all-cause mortality. Cox regression was used to estimate adjusted HRs. RESULTS: Mean follow-up was 2.3 years (SGLT2i cohort) and 2.1 years (comparison cohort). Mean age was 59.6 years (SD ±10.2, SGLT2i cohort) and 60.4 years (SD ±10.0, comparison cohort). SGLT2i new users were associated with a reduced risk of the CV composite (HR 0.75, 95% CI: 0.61 to 0.93), severe renal disease (HR 0.55, 95% CI: 0.46 to 0.67), and all-cause mortality (HR 0.56, 95% CI: 0.49 to 0.63), with risk reductions similar irrespective of baseline chronic kidney disease. Reduced risks were seen for IS (HR 0.51, 95% CI: 0.36 to 0.74) but not MI (HR 0.98, 95% CI: 0.74 to 1.28). Results were consistent in sensitivity analyses. CONCLUSIONS: In this population-based study, SGLT2is were associated with significant CV, renal and survival benefits among individuals with type 2 diabetes on metformin; the CV benefit was driven by a reduced risk of ischemic stroke.

Acute Kidney Injury in Patients with Non-Valvular Atrial Fibrillation Treated with Rivaroxaban or Warfarin: A Population-Based Study from the United Kingdom.

Purpose: To compare the risk of acute kidney injury (AKI) among users of rivaroxaban vs warfarin. Patients and Methods: We identified two cohorts of patients with non-valvular atrial fibrillation (NVAF) who initiated rivaroxaban (15/20 mg/day, N = 6436) or warfarin (N = 7129) excluding those without estimated glomerular filtration rate values recorded in the year before oral anticoagulant (OAC) initiation and those with a history of end-stage renal disease or AKI. We used two methods to define AKI during follow-up (mean 2.5 years): coded entries (method A) and the Aberdeen AKI phenotyping algorithm (method B) using recorded renal function laboratory values during the study period to identify a sudden renal deterioration event. Cox regression was used to calculate hazard ratios (HRs) for AKI with rivaroxaban vs warfarin use, adjusted for confounders. Results: The number of identified incident AKI cases was 249 (method A) and 723 (method B). Of the latter, 104 (14.4%) were also identified by method A. After adjusting for age, sex, baseline renal function and comorbidity, HRs (95% CIs) for AKI were 1.19 (0.92-1.54; p=0.18) using method A and 0.80 (0.68-0.93; p<0.01) using method B. Estimates stratified by baseline level of chronic kidney disease were largely consistent with the main estimates. Conclusion: Our results support a beneficial effect of rivaroxaban over warfarin in terms of AKI occurrence in patients with NVAF. More research into how best to define AKI using primary care records would be valuable for future studies.

Impact of non-adherence to direct oral anticoagulants amongst Swedish patients with non-valvular atrial fibrillation: results from a real-world cost-utility analysis.

AIMS: A third of non-valvular atrial fibrillation (NVAF) patients are non-adherent to direct oral anticoagulants (DOACs). Estimates of the economic value of full adherence and the cost of two types of adherence improving interventions are important to healthcare planners and decision-makers. METHODS: A cost-utility analysis estimated the impact of non-adherence over a 20-year horizon, for a patient cohort with a mean age of 77 years, based on data from the Stockholm Healthcare database of NVAF patients with incident stroke between 2011 and 2018. Adherence was defined using a medication possession ratio (MPR) cut-off of 90%; primary outcomes were the number of ischemic strokes and associated incremental cost-utility ratio. RESULTS: Hypothetical comparisons between cohorts of 1,000 patients with varying non-adherence levels and full adherence (MPR >90%) predicted an additional number of strokes ranging from 117 (MPR = 81-90%) to 866 (MPR <60%), and years of life lost ranging from 177 (MPR = 81- 90%) to 1,318 (MPR < 60%; discounted at 3%). Chronic disease co-management intervention occurring during each DOAC prescription renewal and patient education intervention at DOAC initiation will be cost-saving to the health system if its cost is below SEK 143 and SEK 4,655, and cost-effective if below SEK 858 and SEK 28,665, respectively. CONCLUSION: Adherence improving interventions for NVAF patients on DOACs such as chronic disease co-management and patient education can be cost-saving and cost-effective, within a range of costs that appear reasonable to the Swedish healthcare system.

Atrial fibrillation (AF) is the most common type of chronic cardiac arrhythmia and a major risk factor for ischemic stroke (IS). The objective of this study was to compare the costs and health outcomes associated with adherence to direct oral anticoagulant (DOAC) therapy in Sweden. The study also aimed to demonstrate the potential benefits of developing interventions to improve DOAC adherence. DOAC therapy (DOACs; apixaban, dabigatran, edoxaban, and rivaroxaban) has been approved in Europe for the prevention of stroke in adult patients with AF. It has been demonstrated to provide warfarin-similar reductions in stroke risk in NVAF patients, with reductions in mortality and intracranial hemorrhage. However, non-adherence to DOAC medication prevents patients and healthcare systems from fully benefiting from DOAC therapy, resulting in a lower benefit than those seen in randomized controlled trials. DOAC non-adherence is where AF patients deviate from the DOAC treatment regimen as prescribed by health providers. This study suggested that non-adherence to DOAC therapy has a substantial impact on ischemic stroke risk and significant additional healthcare system costs. Patient education and chronic disease co-management (two types of DOAC adherence improving intervention) can be cost-saving and cost-effective within a range of costs that appear reasonable to the Swedish healthcare system. Healthcare policy-makers should prioritize initiatives aimed at improving DOAC adherence in order to improve outcomes in AF.

Pre- and post-stroke oral antithrombotics and mortality in patients with ischaemic stroke.

BACKGROUND: Reducing stroke occurrence requires the effective management of cardiovascular and other stroke risk factors. PURPOSE: To describe pre- and post-stroke medication use, focusing on antithrombotic therapy and mortality risk, in individuals hospitalised for ischaemic stroke (IS) in the United Kingdom. METHOD: Using primary care electronic health records from the United Kingdom, we identified patients hospitalised for IS (July 2016-September 2019) and classed them into three groups: atrial fibrillation (AF) diagnosed pre-stroke, AF diagnosed post-stroke, and non-AF stroke (no AF diagnosed pre-/post-stroke). We determined use of cardiovascular medications in the 90 days pre- and post-stroke and calculated mortality rates. RESULTS: There were 3201 hospitalised IS cases: 76.2% non-AF stroke, 15.7% AF pre-stroke, and 8.1% AF post-stroke. Oral anticoagulant (OAC) use increased between the pre- and post-stroke periods as follows: 54.3%-78.7% (AF pre-stroke group), 2.3%-84.8% (AF post-stroke group), and 3.4%-7.3% (non-AF stroke group). Corresponding increases in antiplatelet use were 30.8%-35.4% (AF pre-stroke group) 38.5%-47.5% (AF post-stroke group), and 37.5%-87.3% (non-AF stroke group). Among all IS cases, antihypertensive use increased from 66.8% pre-stroke to 78.8% post-stroke; statin use increased from 49.6%-85.2%. Mortality rates per 100 person-years (95% CI) were 17.30 (14.70-20.35) in the AF pre-stroke group and 9.65 (8.81-10.56) among all other stroke cases. CONCLUSION: Our findings identify areas for improvement in clinical practice, including optimising the level of OAC prescribing to patients with known AF, which could potentially help reduce the future burden of stroke.

Statins and Colorectal Cancer Risk: A Population-Based Case-Control Study and Synthesis of the Epidemiological Evidence.

(1) Background: The pleiotropic effects of statins may explain a chemoprotective action against colorectal cancer (CRC). Many studies have tested this hypothesis, but results have been inconsistent so far. Moreover, few have examined statins individually which is important for determining whether there is a class effect and if lipophilicity and intensity may play a role. (2) Methods: From 2001-2014, we carried out a study comprised of 15,491 incident CRC cases and 60,000 matched controls extracted from the primary healthcare database BIFAP. We fit a logistic regression model to compute the adjusted-odds ratios (AOR) with their 95% confidence intervals (CIs). Additionally, we carried out a systematic review and meta-analysis. (3) Results: Current use of statins showed a reduced risk of CRC (AOR = 0.87; 95% CI: 0.83-0.91) not sustained after discontinuation. The association was time-dependent, starting early (AOR6months-1year = 0.85; 95% CI: 0.76-0.96) but weakened beyond 3-years. A class effect was suggested, although only significant for simvastatin and rosuvastatin. The risk reduction was more marked among individuals aged 70 or younger, and among moderate-high intensity users. Forty-eight studies were included in the meta-analysis (pooled-effect-size = 0.90; 95% CI: 0.86-0.93). (4) Conclusions: Results from the case-control study and the pooled evidence support a moderate chemoprotective effect of statins on CRC risk, modified by duration, intensity, and age.

Renal decline in patients with non-valvular atrial fibrillation treated with rivaroxaban or warfarin: A population-based study from the United Kingdom.

BACKGROUND: Reports suggest that renal decline is greater among patients with non-valvular atrial fibrillation (NVAF) treated chronically with warfarin vs. some non-vitamin K antagonist oral anticoagulants. METHODS AND RESULTS: Using primary care electronic health records from the United Kingdom we followed adults with NVAF and who started rivaroxaban (20 mg/day, N = 5338) or warfarin (N = 6314), excluding those with estimated glomerular filtration rate (eGFR) <50 ml/min/1.73m2, end-stage renal disease (ESRD) or no eGFR or serum creatinine (SCr) values recorded in the previous year. Outcomes were: doubling SCr levels, ≥30% decline in eGFR and progression to ESRD. We calculated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome. Average eGFR slope was estimated using mixed model regression. After a mean follow-up 2.5 years, the number of incident cases of adverse renal events within the two cohorts was: doubling SCr (n = 322), ≥30% decline in eGFR (n = 1179), and progression to ESRD (n = 22). Adjusted HRs (95% CIs) for the renal outcomes among rivaroxaban vs. warfarin users were: doubling SCr, 0.63 (0.49-0.81); ≥30% decline in eGFR, 0.76 (0.67-0.86); ESRD, 0.77 (0.29-2.04). Similar results were observed among patients with diabetes or heart failure. Estimated mean decline in renal function over the study period was 2.03 ml/min/1.73 m2/year among warfarin users and 1.65 ml/min/1.73 m2/year among rivaroxaban users (p = 0.03). CONCLUSIONS: We found clear evidence that patients with NVAF, preserved renal function at baseline and treated with rivaroxaban had a markedly reduced risk and rate of renal decline compared with those treated with warfarin.

Trends in the use of oral anticoagulants, antiplatelets and statins in four European countries: a population-based study.

PURPOSE: To evaluate time trends in the prevalence of antithrombotic and statin use in four European countries. METHODS: Using population-based data from the United Kingdom, Denmark, Spain and Italy between 2010 and 2018, we calculated standardized annual prevalence proportions of antithrombotics and statin use, and changes in prevalence proportions (2018 vs. 2010). RESULTS: Prevalence proportion of statins increased from 24.8% to 24.6% (UK), 21.0% to 22.3% (Region of Southern Denmark [RSD]), 12.9% to 14.3% (Udine, Italy), and 20.3% to 23.2% (Spain). Prevalence proportions of antithrombotics declined in all four countries: 18.7% to 15.9% (UK; - 2.8% points), 18.9% to 18.1% (RSD; - 0.8% points), 17.7% to 16.6% (Udine; - 1.1% points) and 15.0% to 13.6% (Spain; - 1.4% points). These declines were driven by reductions in low-dose aspirin use: 15.3% to 8.9% (UK; - 6.4% points), 16.3% to 9.5% (RSD; - 6.8% points), 13.5% to 11.6% (Udine; - 1.9% points), and 10.2% to 8.8% (Spain; - 1.4% points). In the UK, low-dose aspirin use declined from 9.1% to 4.3% (- 4.8% points) for primary CVD prevention, and from 49.6% to 36.9% (- 12.7% points) for secondary prevention. Oral anticoagulant use gradually increased but did not fully account for the decrease in low-dose aspirin use. CONCLUSIONS: Antithrombotic use in the UK, RSD, Udine and Spain declined between 2010 and 2018, driven by a reduction in use of low-dose aspirin that is not completely explained by a gradual increase in OAC use. Use of statins remained constant in the UK, and increased gradually in the RSD, Udine and Spain.

Validation of venous thromboembolism diagnoses in patients receiving rivaroxaban or warfarin in The Health Improvement Network.

PURPOSE: To describe the effect that validation of venous thromboembolism (VTE) coded entries in the health improvement network (THIN) has on incidence rates of VTE among a cohort of rivaroxaban/warfarin users. METHODS: Among 36 701 individuals with a first prescription for rivaroxaban/warfarin between 2012 and 2015, we performed a two-step VTE case identification process followed by a two-step case validation process involving manual review of patient records. A valid case required a coded entry for VTE at some point after their first rivaroxaban/warfarin prescription with evidence of referral/hospitalization either as a coded entry or entered as free text. Positive predictive values (PPVs) with 95% confidence intervals (CIs) were calculated using validated cases as the gold standard. Incidence rates were calculated per 1000 person-years with 95% CIs. RESULTS: We identified 2166 patients with a coded entry of VTE after their initial rivaroxaban/warfarin prescription; incidence rate of 45.31 per 1000 person-years (95% CI: 43.49-47.22). After manual review of patient records including the free text, there were 712 incident VTE cases; incidence rate of 14.90 per 1000 person-years (95% CI: 13.85-16.02). The PPV for coded entries of VTE alone was 32.9%, and the PPV for coded entries of VTE with a coded entry of referral/hospitalization was 39.8%; this increased to 69.6% after manual review of coded clinical entries in patient records. CONCLUSIONS: Among rivaroxaban/warfarin users in THIN, valid VTE case identification requires manual review of patient records including the free text to prevent outcome misclassification and substantial overestimation of VTE incidence rates.

Feasibility study to identify women of childbearing age at risk of pregnancy not using any contraception in The Health Improvement Network (THIN) database.

BACKGROUND: Worldwide the rate of unplanned pregnancies is more than 40%. Identifying women at risk of pregnancy can help prevent negative outcomes and also reduce healthcare costs of potential complications. It can also allow the investigation of the natural history of pregnancy outcomes, such as ectopic pregnancies or miscarriages. The use of medical records databases has been a crucial development in the field of pharmacoepidemiology - e.g. The Health Improvement Network (THIN) database is a validated database representative of the UK population. This project aimed to test the feasibility of identifying a population of women of childbearing age who are at risk of pregnancy not using any contraception in THIN database. METHODS: First a cohort of women of childbearing age (15-45yo) was identified. By applying a computer-based algorithm, containing codes for contraception methods or other suggestion of contraception, the risk of pregnancy was then ascertained. Next, two validation steps were implemented: 1) Revision of medical records/free text and 2) Questionnaires were sent to primary care practitioners (PCP) of women whose medical records had been reviewed. Positive predicted values (PPV) were calculated. RESULTS: A total of 266,433 women were identified in THIN. For the first validation step, 123 records were reviewed, with a PPV of 99.2% (95%CI: 95.5-99.9). For the questionnaires step, the PPV was of 82.3% (95%CI: 70-91.1). Information on sexual behaviour and attitudes towards conception was not captured by THIN. CONCLUSION: This study shows that by applying a comprehensive computer-based algorithm, THIN can be used to identify women at risk of pregnancy.

Bleeding associated with low-dose aspirin: Comparison of data from the COMPASS randomized controlled trial and routine clinical practice.

Randomized controlled trials (RCTs) have strong internal validity but often have limited external validity. Observational studies have good generalizability and an increasing role in key healthcare decision making. We compared incidence rates of intracranial and major gastrointestinal bleeds in the low-dose aspirin arm (N = 9126) of the COMPASS double-blind RCT (conducted at 602 centres in 33 countries) with those from an observational cohort of preventative low-dose aspirin users (N = 54,140) in a primary care database representative of the UK general population - The IQVIA Medical Research Data UK (IMRD-UK). In our observational study analysis, we restricted follow-up to 2 years to be comparable with the duration of the COMPASS trial. Among low-dose aspirin users, incidence rates per 1000 person-years (95% confidence intervals [CIs]) in the IMRD-UK cohort and COMPASS trial participants, respectively, were 0.6 (0.5-0.8) vs. 1.4 (0.9-2.1) for intracranial bleeds, and 3.5 (3.1-3.8) vs. 3.7 (2.9-4.8) for major gastrointestinal bleeds. These broadly comparable bleeding rates among COMPASS trial participants and an observational cohort of low-dose aspirin users in IMRD-UK support the use of the latter for generating robust therapeutic evidence, and indicate that the rates from the COMPASS trial are broadly consistent with realistic population-based rates.

Reduction in use of cyproterone/ethinylestradiol (Diane-35 and generics) after risk minimization measures in the Netherlands, UK and Italy.

OBJECTIVES: To study the effect of risk minimization measures taken in 2013 for cyproterone acetate/ethinylestradiol (CPA/EE) on initiation, concomitant use of other hormonal contraceptives (HC) and potential indications. STUDY DESIGN: This retrospective study included data on CPA/EE use in 2011-2017 from the Netherlands, UK, and Italy. RESULTS: The initiation rate of CPA/EE decreased by 44%-91% between 2011 and 2017. Proportions with concomitant use of other HC (<3%) and approved indications did not change over time. CONCLUSION: Apart from a strong reduction in CPA/EE use following risk minimization measures, no major changes were observed regarding concomitant use of other HC or potential reasons for use.

Low-dose aspirin and risk of gastric and oesophageal cancer: A population-based study in the United Kingdom using The Health Improvement Network.

There is increasing interest regarding potential protective effects of low-dose aspirin against various gastrointestinal cancers. We aimed to quantify the association between use of low-dose aspirin and risk of gastric/oesophageal cancer using a population-based primary care database in the UK. Between January 2005 and December 2015, we identified a cohort of 223 640 new users of low-dose aspirin (75-300 mg/day) and a matched cohort of nonusers at the start of follow-up from The Health Improvement Network. Cohorts were followed to identify incident cases of gastric/oesophageal cancer. Nested case-control analyses were conducted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for current vs nonuse of low-dose aspirin using logistic regression. Current use was defined as when low-dose aspirin lasted 0 to 90 days before the index date (event date for cases, random date for controls) and previous duration was ≥1 year. We identified 727 incident cases of gastric cancer and 1394 incident cases of oesophageal cancer. ORs (95% CIs) were 0.46 (0.38-0.57) for gastric cancer and 0.59 (0.51-0.69) for oesophageal cancer. The effect remained consistent with no clear change seen between previous duration of low-dose aspirin use of 1-3, 3-5 or >5 years. The reduced risks was seen with 75 mg/day, and effects were consistent in lag-time analyses. In conclusion, our results indicate that use of low-dose aspirin is associated with a 54% reduced risk of gastric cancer and a 41% reduced risk of oesophageal cancer as supported by mechanistic data.

Effect of Proton Pump Inhibitors on Risks of Upper and Lower Gastrointestinal Bleeding among Users of Low-Dose Aspirin: A Population-Based Observational Study.

Estimates of the effect of proton pump inhibitors (PPIs) on risks of upper and lower gastrointestinal bleeding (UGIB and LGIB) among low-dose aspirin users in routine clinical practice are variable (UGIB) or lacking (LGIB). We aimed to establish these risks in the same observational study population. Using UK primary care data, we followed 199,049 new users of low-dose aspirin (75-300 mg/day) and matched non-users at start of follow-up to identify incident UGIB/LGIB cases. In nested case-control analyses, adjusted odds ratios (ORs) were calculated for concomitant PPI use vs. past (discontinued) PPI use among current low-dose aspirin users. For UGIB (n = 987), ORs (95% CIs) were 0.69 (0.54-0.88) for >1 month PPI use and 2.65 (1.62-4.3) for ≤1 month PPI use. Among the latter group, ORs (95% CIs) were 3.05 (1.75-5.33) for PPI initiation after start of aspirin therapy, and 1.66 (0.63-4.36) for PPI initiation on/before start of aspirin therapy. For LGIB (n = 1428), ORs (95% CIs) were 0.98 (0.81-1.17) for >1 month PPI use and 1.12 (0.73-1.71) for ≤1 month PPI use. Among low-dose aspirin users, maintaining PPI use (>1 month) was associated with a significantly reduced UGIB risk. Neither short nor long-term PPI use affected LGIB risk.

No association between use of phosphodiesterase 5 inhibitors and colorectal cancer in men with erectile dysfunction.

PURPOSE: There is an increase interest on the potential chemoprotective effect of selective phosphodiesterase 5 (PDE5) inhibitors. Several authors have shown in vivo the immune-mediated anti-tumor effect of these inhibitors on tumors arising from the digestive tract. OBJECTIVES: To test the potential effect of selective PDE5 inhibitors against colorectal cancer (CRC) onset previously observed. METHODS: We used data from The Health Improvement Network database and identified an established cohort of 200 000 new users of low-dose aspirin and a matched comparison cohort aged 40-84 years between 1 January 2000 and 31 December 2011. A follow-up to identify CRC cases was performed within an extensive validation exercise. Nested case-control analyses compared PDE5 inhibitors vs non-use on CRC risk were performed. RESULTS: Restricting to males (59.3% controls and 59.5% cases), no association was observed among current users of PDE5 inhibitors (1.05 [95% CI: 0.69-1.60]) and neither among recent (1.36 [95% CI: 0.81-2.28]) or past users (1.06 [95% CI: 0.72-1.58]). No duration response effect was found. CONCLUSIONS: Our results do not support an increased risk of CRC associated with the use of PDE5 inhibitors among men with erectile dysfunction.

Risk of bleeding events among patients with systemic sclerosis and the general population in the UK: a large population-based cohort study.

INTRODUCTION/OBJECTIVES: To compare the risk of different bleeding outcomes between patients with systemic sclerosis (SSc) and the general population free of SSc. METHODS: Using UK electronic primary care data (2000-2012), 1314 patients with SSc and a matched SSc-free comparison cohort (n = 19,992) were followed until December 2013 to identify bleeding, confirmed following manual review of patient records including free text comments. Incidence rates were calculated and Cox regression used to estimate adjusted hazard ratios (HRs; SSc cohort vs. matched general population cohort) adjusted for confounders. RESULTS: One hundred and twenty-seven bleeding events occurred in the SSc cohort and 1762 in the general population cohort; incidence rates per 1000 person-years for the SSc cohort and general population cohort were 0.5 versus 0.3 for hemorrhagic stroke, 4.1 versus 3.3 for gastrointestinal bleeding, 2.5 versus 1.7 for pulmonary hemorrhage, 8.4 versus 7.5 for urogenital bleeding, and 15.5 versus 12.9 for any of the aforementioned bleedings. Adjusted HRs (95% confidence intervals) were 1.21 (1.00-1.46) for any bleeding, 1.51 (0.54-4.21) for hemorrhagic stroke, 1.50 (0.96-2.35) for pulmonary hemorrhage, 1.08 (0.75-1.54) for gastrointestinal bleeds, and 1.28 (1.00-1.64) for urogenital bleeds. HRs were more often higher in SSc patients with organ involvement than without organ involvement and in those with diffuse cutaneous SSc. CONCLUSION: Our results are consistent with a moderately increased risk of bleeding in SSc patients. Further evidence from large SSc patient cohorts is needed to confirm this finding.Key Points• The risk of experiencing a major bleed may be higher among patients with SSc than the general population.• Further large and well-designed studies are needed to corroborate our findings.

Impact of chronic kidney disease definition on assessment of its incidence and risk factors in patients with newly diagnosed type 1 and type 2 diabetes in the UK: A cohort study using primary care data from the United Kingdom.

AIM: To estimate the incidence and risk factors of chronic kidney disease (CKD) in patients with newly-diagnosed diabetes using different CKD definitions. METHODS: Using UK primary care data, patients with diabetes (type 1, 4691; type 2, 109,365) and no CKD were followed to identify newly-diagnosed CKD, classified by a broad and narrow CKD definition (to capture diabetes-induced CKD, termed diabetic kidney disease, DKD). Adjusted incidence rates of CKD/DKD were calculated, and risk factors identified using Cox regression. RESULTS: There were 404 CKD cases and 147 DKD cases among patients with type 1 diabetes (T1D), and 29,104 CKD cases, 9284 DKD cases among patients with type 2 diabetes (T2D). Adjusted incidence rates of CKD per 100 years were 5.4 (T1D) and 5.5 (T2D); for DKD they were 1.9 and 1.5, respectively. Risk factors for CKD/DKD were older age, high social deprivation, obesity, cardiovascular disease, hypertension and smoking. Poor glycaemic control in the year after diabetes diagnosis was a strong predictor of CKD/DKD occurrence beyond this first year, and a risk factor for CKD/DKD in T2D. CONCLUSIONS: CKD and DKD remain common in diabetics in the decade after diagnosis. Early prevention of T2D and aggressive treatment of risk factors is urgent.

Risk of Acute Myocardial Infarction Among New Users of Allopurinol According to Serum Urate Level: A Nested Case-Control Study.

OBJECTIVES: To test the hypothesis that allopurinol reduces the risk of acute myocardial infarction (AMI) in hyperuricemic patients and to assess whether the effect is dependent on dose, duration and serum uric acid (SUA) level attained after treatment. METHODS: Nested case-control study over the period 2002-2015. From a cohort of patients aged 40-99 years old, we identified incident AMI cases and randomly selected five controls per case, matched for exact age, sex and index date. Adjusted odds ratios (AOR) and 95% CI were computed through unconditional logistic regression. Only new users of allopurinol were considered. RESULTS: A total of 4697 AMI cases and 18,919 controls were included. Allopurinol use was associated with a reduced risk of AMI mainly driven by duration of treatment (AOR ≥180 days = 0.71; 95% CI: 0.60-0.84). Among long-term users (≥180 days), the reduced risk was only observed when the SUA level attained was below 7 mg/dL (AOR<6 mg/dL = 0.64; 95% CI: 0.49-0.82; AOR6-7mg/dL = 0.64; 95%CI:0.48-0.84); AOR>7mg/dL = 1.04; 95% CI: 0.75-1.46; p for trend = 0.001). A dose-effect was observed but faded out once adjusted for the SUA level attained. The reduced risk of AMI occurred in both patients with gout and patients with asymptomatic hyperuricemia. CONCLUSIONS: The results confirm a cardioprotective effect of allopurinol which is strongly dependent on duration and SUA level attained after treatment.

The effect of low-dose aspirin on colorectal cancer prevention and gastrointestinal bleeding according to bodyweight and body mass index: Analysis of UK primary care data.

BACKGROUND: Meta-analysis of trial data suggests that in primary cardiovascular disease (CVD) prevention bodyweight modifies low-dose aspirin's effects on colorectal cancer (CRC) and major bleeding risk. We sought to investigate whether these effects are seen in patients with or without CVD in routine clinical practice by undertaking sub-analyses of data from two cohort studies with nested-case-control analyses. METHODS: We followed ~200,000 new users of low-dose aspirin (75-300 mg/day) and a matched cohort of non-users to identify incident cases of CRC/upper gastrointestinal bleeding (UGIB). Adjusted relative risks (RRs) with 95% confidence intervals (CIs) were calculated for current vs. non-use of low-dose aspirin using logistic regression stratified by bodyweight/body mass index (BMI) strata. RESULTS: RRs (95% CIs) for CRC by bodyweight were: 0.60 (0.50-0.72) for ≤70 kg, 0.68 (0.60-0.76) for >70 kg; and by BMI were 0.60 (0.52-0.68) for ≤28 kg/m2, 0.76 (0.64-0.89) for >28 kg/m2. For UGIB, estimates were: 1.49 (1.28-1.74) for ≤90 kg, 1.78 (1.29-2.45) for >90 kg/m2, 1.44 (1.21-1.72) for ≤28 kg/m2, 1.72 (1.38-2.16) for >28 kg/m2. Results were similar in the primary CVD prevention population. CONCLUSION: Our findings suggest that the effects of low-dose aspirin in reducing CRC risk and increasing UGIB risk are not modified by bodyweight/BMI.

Population-based case-control study: chemoprotection of colorectal cancer with non-aspirin nonsteroidal anti-inflammatory drugs and other drugs for pain control.

BACKGROUND: Inflammation and overexpression of cyclooxygenase-2 (COX-2) have been described to play a key role in the progression from nonpathologic intestinal mucosa to colorectal cancer (CRC). AIMS: To assess the chemoprotective effect of non-aspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) under different patterns of use in a Mediterranean population and to explore the potential effect of symptomatic slow-acting drugs for osteoarthritis (SYSADOAs; chondroitin sulfate and glucosamine) and metamizole (or dipyrone), also reported to influence COX-2 activity. METHODS: We performed a case-control study nested in a cohort extracted from the primary care database, BIFAP. From 2001 to 2014, we included 15 491 incident cases and 60 000 random controls. To estimate the association between the drugs of interest and CRC, we built logistic regression models to compute the adjusted-odds ratios (AOR) and 95% confidence intervals (CI). RESULTS: NA-NSAIDs use was associated with a reduced risk of CRC (AOR = 0.67; 95% CI: 0.63-0.71) and increased linearly with duration of treatment (p for trend <0.001). The effect diminished upon discontinuation but persisted statistically significant up to 1 year. All individual NA-NSAIDs examined showed a decreased risk. The concomitant use of proton-pump inhibitors (PPI) had no impact on the protective effect of NA-NSAIDs; AORPPI + NSAID  = 0.64; 0.58-0.71. SYSADOA use was associated with a reduced risk (0.79; 0.69-0.90) but disappeared after the exclusion of NSAID users during the previous 1 or 3 years (0.85; 0.70-1.04 and 1.00; 0.76-1.31 respectively). Metamizole did not show a chemoprotective effect. CONCLUSIONS: NA-NSAID use is associated with a duration-dependent risk reduction of CRC not shared by SYSADOAs or metamizole.