Thiazide Diuretics and Risk of Colorectal Cancer: A Population-Based Cohort Study.

Evidence from clinical trials and observational studies on the association between thiazide diuretics and colorectal cancer risk is conflicting. We aimed to determine whether thiazide diuretics are associated with an increased colorectal cancer risk compared with dihydropyridine calcium channel blockers (dCCBs). A population-based, new-user cohort was assembled using the UK Clinical Practice Research Datalink. Between 1990-2018, we compared thiazide diuretic initiators with dCCB initiators and estimated hazard ratios (HR) with 95% confidence intervals (CIs) of colorectal cancer using Cox proportional hazard models. Models were weighted using standardized morbidity ratio weights generated from calendar time-specific propensity scores. The cohort included 377,760 thiazide diuretic initiators and 364,300 dCCB initiators, generating 3,619,883 person-years of follow-up. Compared with dCCBs, thiazide diuretics were not associated with colorectal cancer (weighted HR = 0.97, 95% CI: 0.90, 1.04). Secondary analyses yielded similar results, although an increased risk was observed among patients with inflammatory bowel disease (weighted HR = 2.45, 95% CI: 1.13, 5.35) and potentially polyps (weighted HR = 1.46, 95% CI: 0.93, 2.30). Compared with dCCBs, thiazide diuretics were not associated with an overall increased colorectal cancer risk. While these findings provide some reassurance, research is needed to corroborate the elevated risks observed among patients with inflammatory bowel disease and history of polyps.

Usefulness of MRI-Based Local Surveillance After Surgical Treatment of Musculoskeletal Soft-Tissue Sarcomas: A Systematic Review and Meta-Analysis.

BACKGROUND. The value of routine MRI follow-up after surgical treatment of musculoskeletal soft-tissue sarcoma (STS) is controversial. OBJECTIVE. The purpose of this study was to evaluate the usefulness of MRI-based surveillance for musculoskeletal STS represented by the proportion of local recurrences (LRs) discovered by MRI versus clinically, stratified by imaging surveillance intensity; the characteristics of LRs detected on imaging versus clinically; and the impact of imaging surveillance on survival. EVIDENCE ACQUISITION. Multiple electronic databases were searched systematically for articles published through November 28, 2022, about controlled trials and cohort studies on the usefulness of MRI-based surveillance for musculoskeletal STS. The risk of bias was assessed using an adapted Newcastle-Ottawa scale. Random-effects meta-analyses of the proportion of LRs discovered by MRI as opposed to clinically were conducted. The association of low- versus high-intensity surveillance with the proportion of LR detected on MRI was assessed with a chi-square test of subgroup differences; for this latter assessment, high intensity was defined as at least one local surveillance imaging examination for low-risk tumors and at least three imaging examinations for high-risk tumors during the first 2 posttreatment years. EVIDENCE SYNTHESIS. A total of 4821 titles and abstracts were identified, and 19 studies were included. All studies were retrospective cohorts. There was substantial variability in follow-up approaches. The risk of bias was moderate in 32% and high in 68% of studies. The pooled proportion of LRs detected on MRI was 53% (95% CI, 36-71%) with high-intensity surveillance and 6% (95% CI, 3-9%) with low-intensity surveillance (p < .01). Comparison of LR characteristics (LR size, depth, grade, location, resection margins) detected on imaging versus clinically identified inconsistent results between studies. Trends toward better survival for imaging-detected LRs or more frequent imaging use were noted in four studies. CONCLUSION. When used at a high intensity, MRI-based surveillance can detect many clinically occult LRs, although the studies are small, occasionally yielded conflicting results, and are often of poor quality. A survival benefit could be associated with imaging use, but further research is needed to evaluate the causality of any observed survival differences. CLINICAL IMPACT. MRI-based surveillance after surgical treatment of musculoskeletal STS is useful to detect clinically occult LRs and could improve patient outcomes.

Hydrochlorothiazide use and risk of keratinocyte carcinoma and melanoma: A multisite population-based cohort study.

BACKGROUND: The association between hydrochlorothiazide (HCTZ) and skin cancer remains controversial. OBJECTIVE: To determine whether HCTZ is associated with an increased risk of skin cancer compared with angiotensin-converting enzyme inhibitors and calcium channel blockers. METHODS: Two new-user, active comparator cohorts were assembled using 6 Canadian databases. Site-specific hazard ratios (HRs) with 95% CIs were estimated using standardized morbidity ratio weighted Cox proportional hazard models and pooled using random-effects meta-analysis. RESULTS: HCTZ was not associated with an overall increased risk of keratinocyte carcinoma compared with angiotensin-converting enzyme inhibitors or calcium channel blockers, although increased risks were observed with longer durations (≥10 years; HR: 1.12; 95% CI: 1.03-1.21) and higher cumulative doses (≥100,000 mg; HR: 1.49; 95% CI: 1.27-1.76). For melanoma, there was no association with angiotensin-converting enzyme inhibitors, but a 32% increased risk with calcium channel blockers (crude incidence rates: 64.2 vs 58.4 per 100,000 person-years; HR: 1.32; 95% CI: 1.19-1.46; estimated number needed to harm at 5 years of follow-up: 1627 patients), with increased risks with longer durations and cumulative doses. LIMITATIONS: Residual confounding due to the observational design. CONCLUSIONS: Increased risks of keratinocyte carcinoma and melanoma were observed with longer durations of use and higher cumulative doses of HCTZ.

After DES implantation, DAPT for 1 y vs. ≤6 mo increased major bleeding in patients with high baseline bleeding risk.

SOURCE CITATION: Palmerini T, Bruno AG, Redfors B, et al. Risk-benefit of 1-year DAPT after DES implantation in patients stratified by bleeding and ischemic risk. J Am Coll Cardiol. 2021;78:1968-86. 34763774.

mRNA COVID-19 vaccines were linked to myocarditis at 28 d (0.15 to 10 excess events/100 000 vaccinated persons).

SOURCE CITATION: Karlstad Ø, Hovi P, Husby A, et al. SARS-CoV-2 vaccination and myocarditis in a Nordic cohort study of 23 million residents. JAMA Cardiol. 2022;7:600-12. 35442390.

In HF, SGLT2 inhibitors reduce HF hospitalizations at up to 2 y.

SOURCE CITATION: Zou X, Shi Q, Vandvik PO, et al. Sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a systematic review and meta-analysis. Ann Intern Med. 2022;175:851-61. 35404670.

A randomized controlled trial of renin-angiotensin-aldosterone system inhibitor management in patients admitted in hospital with COVID-19.

BACKGROUND: Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection coronavirus disease 2019 (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes. METHODS: The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-to-treat principle. RESULTS: Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients' mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); P = .60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06-2.62]; P = .027); RAASi discontinuation increased brain natriuretic peptide levels (% change from baseline: +16.7% vs -27.5%; P = .024) and the incidence of acute heart failure (33% vs 4.2%, P = .016). CONCLUSION: RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased brain natriuretic peptide levels and may increase risk of acute heart failure; where possible, RAASi should be continued.

To Adjust or Not to Adjust: The Role of Different Covariates in Cardiovascular Observational Studies.

Covariate adjustment is integral to the validity of observational studies assessing causal effects. It is common practice to adjust for as many variables as possible in observational studies in the hopes of reducing confounding by other variables. However, indiscriminate adjustment for variables using standard regression models may actually lead to biased estimates. In this paper, we differentiate between confounders, mediators, colliders, and effect modifiers. We will discuss that while confounders should be adjusted for in the analysis, one should be wary of adjusting for colliders. Mediators should not be adjusted for when examining the total effect of an exposure on an outcome. Automated statistical programs should not be used to decide which variables to include in causal models. Using a case scenario in cardiology, we will demonstrate how to identify confounders, colliders, mediators and effect modifiers and the implications of adjustment or non-adjustment for each of them.

Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression-Brief Report.

OBJECTIVE: To reanalyze data from recent randomized trials of statins to assess whether the benefits and risks of statins are mediated primarily via their LDL-C (low-density lipoprotein cholesterol) lowering effects or via other mechanisms. APPROACH AND RESULTS: We adapted Egger regression, a technique frequently used in Mendelian randomization studies to detect genetic pleiotropy, to reanalyze the available randomized control trial data of statin therapy. For cardiovascular end points, each 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 0.77 (95% confidence interval, 0.71-0.84) with an intercept that was indistinguishable from zero (intercept, -0.0032; [95% confidence interval, -0.090 to 0.084]; P=0.94), indicating no pleiotropy. For incident diabetes mellitus, a 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 1.07 (95% confidence interval, 0.99-1.16) and an intercept nondistinguishable from zero (intercept, -0.015; [95% confidence interval, -0.30 to 0.27]; P=0.91), again indicating no pleiotropy. CONCLUSIONS: Our reanalysis of the randomized control trial data using Egger regression adds to the existing evidence that the cardiovascular benefits of statins and their association with incident diabetes mellitus are mediated primarily, if not entirely, via their LDL-C lowering properties rather than by any pleiotropic effects.

A Framework for Aiding the Translation of Scientific Evidence into Policy: The Experience of a Hospital-Based Technology Assessment Unit.

OBJECTIVES: Very few practical frameworks exist to guide the formulation of recommendations at hospital-based health technology assessment (HTA) units. The objectives of our study were: (i) to identify decision criteria specific to the context of hospital-based health technologies and interventions, (ii) to estimate the extent to which the expert community agrees on the importance of the identified criteria, (iii) to incorporate the identified criteria into a decision-aid tool, and (iv) to illustrate the application of a prototype decision-aid tool. METHODS: Relevant decision criteria were identified using existing frameworks for HTA recommendations, our past experience, a literature search, and feedback from a survey of diverse stakeholders. RESULTS: Based on the survey results, twenty-three decision criteria were incorporated into the final framework. We defined an approach that eschewed a scoring system, but instead relied on a visual means for arriving at a final recommendation, by juxtaposing the importance rating for each criterion against the results of the health technology assessment. For a technology to be approved, a majority of criteria considered important should also have received favorable findings. CONCLUSIONS: We created a simple and practical decision-aid tool that incorporates all decision criteria relevant to a hospital-based HTA unit. With its ease of use and accessibility, our tool renders the subjective decision-making process more structured and transparent.

A Non-inferiority Framework for Cost-Effectiveness Analysis.

BACKGROUND: Traditional decision rules have limitations when a new technology is less effective and less costly than a comparator. We propose a new probabilistic decision framework to examine non-inferiority in effectiveness and net monetary benefit (NMB) simultaneously. We illustrate this framework using the example of repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) for treatment-resistant depression. METHODS: We modeled the quality-adjusted life-years (QALYs) associated with the new intervention (rTMS), an active control (ECT), and a placebo control, and we estimated the fraction of effectiveness preserved by the new intervention through probabilistic sensitivity analysis (PSA). We then assessed the probability of cost-effectiveness using a traditional cost-effectiveness acceptability curve (CEAC) and our new decision-making framework. In our new framework, we considered the new intervention cost-effective in each simulation of the PSA if it preserved at least 75 percent of the effectiveness of the active control (thus demonstrating non-inferiority) and had a positive NMB at a given willingness-to-pay threshold (WTP). RESULTS: rTMS was less effective (i.e., associated with fewer QALYs) and less costly than ECT. The traditional CEAC approach showed that the probabilities of rTMS being cost-effective were 100 percent, 39 percent, and 14 percent at WTPs of $0, $50,000, and $100,000 per QALY gained, respectively. In the new decision framework, the probabilities of rTMS being cost-effective were reduced to 23 percent, 21 percent, and 13 percent at WTPs of $0, $50,000, and $100,000 per QALY, respectively. CONCLUSIONS: This new framework provides a different perspective for decision making with considerations of both non-inferiority and WTP thresholds.

Imputation of Baseline LDL Cholesterol Concentration in Patients with Familial Hypercholesterolemia on Statins or Ezetimibe.

BACKGROUND: Familial hypercholesterolemia (FH) is the most frequent genetic disorder seen clinically and is characterized by increased LDL cholesterol (LDL-C) (>95th percentile), family history of increased LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) in the patient or in first-degree relatives, presence of tendinous xanthomas or premature corneal arcus, or presence of a pathogenic mutation in the LDLR, PCSK9, or APOB genes. A diagnosis of FH has important clinical implications with respect to lifelong risk of ASCVD and requirement for intensive pharmacological therapy. The concentration of baseline LDL-C (untreated) is essential for the diagnosis of FH but is often not available because the individual is already on statin therapy. METHODS: To validate a new algorithm to impute baseline LDL-C, we examined 1297 patients. The baseline LDL-C was compared with the imputed baseline obtained within 18 months of the initiation of therapy. We compared the percent reduction in LDL-C on treatment from baseline with the published percent reductions. RESULTS: After eliminating individuals with missing data, nonstandard doses of statins, or medications other than statins or ezetimibe, we provide data on 951 patients. The mean ± SE baseline LDL-C was 243.0 (2.2) mg/dL [6.28 (0.06) mmol/L], and the mean ± SE imputed baseline LDL-C was 244.2 (2.6) mg/dL [6.31 (0.07) mmol/L] (P = 0.48). There was no difference in response according to the patient's sex or in percent reduction between observed and expected for individual doses or types of statin or ezetimibe. CONCLUSIONS: We provide a validated estimation of baseline LDL-C for patients with FH that may help clinicians in making a diagnosis.

Statin medications and the risk of gynecomastia.

OBJECTIVE: Case reports have suggested an increased risk of gynecomastia with HMG-CoA reductase inhibitors (ie, statins). A recent meta-analysis also found that statins decrease circulating testosterone levels in men. We investigated whether statin use was associated with an increased risk of gynecomastia. DESIGN: Case-control study. PATIENTS: A cohort of patients from a random sample of 9 053 240 US subjects from the PharMetrics Plus™ health claims database from 2006 to 2016 was created. MEASUREMENTS: New cases of gynecomastia requiring at least two ICD-9 codes were identified from the cohort and matched to 10 controls by follow-up time and age using density-based sampling. Rate ratios (RRs) for users of statins were computed using conditional logistic regression adjusting for alcoholic cirrhosis, hyperthyroidism, testicular cancer, Klinefelter syndrome, obesity, hypogonadism, hyperprolactinemia and use of spironolactone, ketoconazole, H2 receptor antagonists (H2 blockers), risperidone, testosterone and androgen deprivation therapy. RESULTS: Our cohort included 6147 cases of gynecomastia and 61 470 corresponding matched controls. The adjusted RR for current, recent and past statin use with respect to gynecomastia was 1.19 (1.04-1.36), 1.38 (1.15-1.65) and 1.20 (1.03-1.40), respectively. CONCLUSIONS: Statin use is associated with an increased risk of developing gynecomastia. Clinicians should be cognizant of this effect and educate patients accordingly.

Risk of acute myocardial infarction with real-world NSAIDs depends on dose and timing of exposure.

PURPOSE: Real-life use of nonsteroidal anti-inflammatory drugs (NSAIDs) is dynamic. This study aimed to characterize the temporal association between time-varying NSAID exposure and acute myocardial infarction (MI). METHODS: Nested case-control analyses were conducted on a Quebec administrative health cohort. NSAID dose, confounders, and outcome status were determined for each day of follow-up. To better account for dose and timing of past exposures, flexible weighted cumulative exposure models were also fitted. RESULTS: The cohort consisted of 233 816 older adults including 21 256 acute MI cases. Dose-related increased risks of MI were found with current use of all NSAIDs. In models not accounting for duration of use, ORs (95%CI) for the most common current daily dose vs. no current exposure were: celecoxib 200 mg: 1.16 (1.10, 1.22), diclofenac 150 mg: 1.59 (1.38, 1.84), ibuprofen 1200 mg: 1.42 (1.17, 1.74), naproxen 750 mg: 1.38 (1.21, 1.58), and rofecoxib 25 mg: 1.54 (1.43, 1.66). Weighted cumulative exposure models confirmed that all NSAIDs-including naproxen-are associated with an increased risk of MI and suggested that doses taken up to 3 weeks ago for rofecoxib, ibuprofen, and naproxen and up to 75 days ago for diclofenac and celecoxib may contribute to the current MI risk. However, the celecoxib risk seems to require continuous use for more than 30 days, whereas for other NSAIDs, a heightened MI risk occurs within 7 days. CONCLUSIONS: Weighted cumulative exposure analysis uncovered NSAID-specific differences in the immediate MI risk and how this risk seems to accumulate. KEY POINTS Accurate assessment of drug safety requires an etiologically correct model encompassing all relevant aspects of exposure. Weighted cumulative exposure models suggest that the relative importance of past doses on the risk of MI differs among NSAIDs. All common NSAIDs are associated with an increased MI risk. Celecoxib MI risk seems to depend on continuously using the drug for more than 30 days, whereas for ibuprofen, rofecoxib, diclofenac, and naproxen, a heightened MI risk occurs within 7 days of use.

Stroke in Adults With Congenital Heart Disease: Incidence, Cumulative Risk, and Predictors.

BACKGROUND: Stroke is an important cause of morbidity and mortality, although there is a lack of comprehensive data on its incidence, cumulative risk, and predictors in patients with adult congenital heart disease. METHODS AND RESULTS: This retrospective study of 29 638 Quebec patients with adult congenital heart disease aged 18 to 64 years between 1998 and 2010 was based on province-wide administrative data. The cumulative risk of ischemic stroke estimated up to age 64 years was 6.1% (95% confidence interval [CI], 5.0-7.0%) in women and 7.7% (95% CI, 6.4-8.8%) in men; the risk of hemorrhagic stroke was 0.8% (95% CI, 0.4-1.2%) and 1.3% (95% CI, 0.8-1.8%), respectively. Compared with rates reported for the general Quebec population, age-sex standardized incidence rates of ischemic stroke were 9 to 12 times higher below age 55 years and 2 to 4 times higher in the age group 55 to 64 years; hemorrhagic stroke rates were 5 to 6 times (age <55 years) and 2 to 3 times higher. Using a combination of stepwise model selection and Bayesian model averaging, the strongest predictors of ischemic stroke were heart failure (odds ratio for age group 18-49 years, 5.94 [95% CI, 3.49-10.14], odds ratio for age group 50-64 years, 1.68 [95% CI, 1.06-2.66]), diabetes mellitus (odds ratio, 2.33 [95% CI, 1.66-3.28]), and recent myocardial infarction (odds ratio, 8.38 [95% CI, 1.77-39.58]). CONCLUSIONS: Among patients with adult congenital heart disease, 1 in 11 men and 1 in 15 women experienced a stroke between ages 18 and 64 years. Stroke incidence was considerably higher than in the general population, especially at a younger age. The most important predictors of ischemic stroke were heart failure, diabetes mellitus, and recent myocardial infarction. Additional research is required to see whether advances in the management of adult congenital heart disease may reduce this substantial stroke rate.

Coronary revascularization in diabetic patients: a systematic review and Bayesian network meta-analysis.

BACKGROUND: The optimal revascularization technique in diabetic patients is an important unresolved question. PURPOSE: To compare long-term outcomes between the revascularization techniques of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). DATA SOURCES: English-language publications in PubMed, the Cochrane Central Register of Controlled Trials, Ovid, and EMBASE between 1 January 1990 and 1 June 2014. STUDY SELECTION: Two investigators independently reviewed randomized, controlled trials comparing PCI (with drug-eluting or bare-metal stents) with CABG in adults with diabetes with multivessel or left main coronary artery disease. DATA EXTRACTION: Study design, quality, patient characteristics, length of follow-up, and outcomes were extracted. For duplicate publications, outcomes were obtained from the publication with the longest follow-up. DATA SYNTHESIS: 40 studies were combined using a Bayesian network meta-analysis that accounted for the variation in stent choice. The primary outcome, a composite of all-cause mortality, nonfatal myocardial infarction, and stroke, increased with PCI (odds ratio [OR], 1.33 [95% credible interval {CrI}, 1.01 to 1.65]). Percutaneous coronary intervention resulted in increased mortality (OR, 1.44 [CrI, 1.05 to 1.91]), no change in the number of myocardial infarctions (OR, 1.33 [CrI, 0.86 to 1.95]), and fewer strokes (OR, 0.56 [CrI, 0.36 to 0.88]). LIMITATIONS: Study design and length of follow-up were heterogeneous, and results were driven primarily by a single study. Costs and nonvascular complications of the interventions were not examined. CONCLUSION: Coronary artery bypass grafting seems to be the preferred revascularization technique in diabetics, especially if long-term survival is anticipated. However, because of residual uncertainties and increased risk for stroke with CABG, clinical judgment is required when choosing a revascularization technique in patients with diabetes. PRIMARY FUNDING SOURCE: Fonds de recherche du Québec-Santé.