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Introduction Patients with a history of myocardial infarction (MI) are at very high risk of subsequent cardiovascular events. This study evaluated the association of treatment intensity and adherence to lipid-lowering therapies (LLT) with major adverse cardiovascular events (MACE) among post-MI patients in Germany. Methods We carried out a retrospective cohort study using German health claims data (2010–2015). We included patients ≥ 18 years, with a history of MI and who started an LLT (statin and/or ezetimibe), between 2011 and 2013. The follow-up period started 1 year after the second LLT prescription and continued until MACE, all-cause death or December 31, 2015, whichever occurred first. Treatment intensity was classified based on expected low-density lipoprotein cholesterol reduction; adherence was measured by the proportion of days covered using prescription data. A combined adherence-adjusted intensity variable was created by multiplying intensity and adherence. We used Cox proportional hazards models to control for age, sex, Charlson Comorbidity Index and other cardiovascular risk factors at baseline. Results A total of 14,944 patients were included. Mean age was 66.7 (SD = 13.0) years; 68.7% of patients were men. Each 10% increase in treatment intensity, adherence, or adherence-adjusted intensity was associated with a decrease in the risk of MACE of 17% (HR = 0.83, 95% CI 0.79–0.87), 5% (HR = 0.95, 95% CI 0.94–0.97), and 14% (HR = 0.86, 95% CI 0.83–0.90), respectively. Conclusions Higher treatment intensity and/or adherence of LLT was associated with significantly lower risk of MACE in post-MI patients. Strategies to tailor intensity to patient profiles and improve adherence could reduce the risk of cardiovascular events. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01697-8.

Background Over time, guidelines for dyslipidemia management in patients at high risk of atherosclerotic cardiovascular disease (CVD) changed with the goal of improving patient outcomes. Guidelines have been released by the European Joint Task Force in 2007, 2012 and 2016, European Society of Cardiology in 2011, 2016 and 2019, Joint British Societies in 2014, and National Institute for Health and Care Excellence in 2014. Purpose Evaluate cardiovascular risk factors, treatment patterns, and cardiovascular outcomes over time related to dyslipidemia management. Methods Ten prevalent cohorts of patients with documented CVD receiving lipid-lowering therapy (LLT) were created using Clinical Research Practice Datalink (CPRD) records as of January 1, each year from 2008 through 2017. For each cohort, we identified CVD risk factors and LLT, and estimated the 1-year composite rate of fatal and nonfatal myocardial infarction (MI), ischemic stroke (IS), or revascularization. Patient follow-up was censored at the earliest of one year, end of data, or the outcome of interest. Patients in each cohort were required to be ≥18 years old, have ≥1 years of available medical history, and have received ≥2 LLT prescriptions in the prior year. Documented CVD was defined as MI, IS, angina, revascularization, transient ischemic attack, carotid stenosis, abdominal aortic aneurysm, or peripheral arterial disease. Patients could be in multiple cohorts. Results Annual patient counts ranged from 170,501 to 179,137 through 2013 and declined to 94,418 by 2017 (due to fewer patients in the overall CPRD data). Comparing 2008, 2011 (when ESC guidelines were revised) and 2017 showed the following for CVD risk factors: mean age was 71.6, 72.3, and 72.5 years; males were 59.9%, 61.1%, and 63.1%; current smoking was 15.1%, 15.2%, and 13.9%; type 2 diabetes was 18.4%, 20.2%, and 22.4%; stage 3–5 chronic kidney disease was 22.4%, 25.1%, and 22.8%; history of MI was 22.5%, 23.9%, and 27.4%; history of IS was 5.5%, 6.6%, and 7.9%; LDL Conclusions After 2011 in the UK, there was an increased use of high intensity statins, a greater proportion of patients with LDL levels Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen

Introduction Both intensity and adherence to lipid lowering therapies (LLT) play an important role in effectiveness of the therapies in patients at risk for cardiovascular events. Purpose To evaluate the association of adherence and treatment intensity with cardiovascular outcomes and all-cause mortality in very high-risk patients (as defined by the current ESC guidelines) treated with statin and/or ezetimibe. Methods Retrospective cohort study was based on German health claims data (2010–2015) obtained from German Institute for Health Research (InGef) database and included patients ≥18 years with an initial LLT treatment (statin and/or ezetimibe) in 2011–2013, and diagnoses of cardiovascular disease (CVD), stage 4 or 5 chronic kidney disease (CKD) or type 2 diabetes mellitus (DM). Patients must have had at least 2 LLT prescriptions in the first year to ensure intention of treatment. Follow-up period started 1 year after the second LLT prescription and continued until one of the events of the composite study endpoint (hospitalisation for myocardial infarction, unstable angina, ischemic stroke, heart failure, revascularization, or all-cause death) or 31.12.2015, whichever occurred earlier. Adherence was measured annually by the proportion of days covered (PDC) using prescription data. Treatment intensity was quantified based on expected LDL-C reduction as described in the American College of Cardiology and American Heart Association (ACC/AHA) 2018 guidelines. Adherence and treatment intensity were multiplied to create a combined measure of intensity after accounting for adherence. Results 73,257 patients of the CVD cohort were 68 (SD=12) years old, 59% men; the DM cohort (no CVD) had 13,584 patients, age 64 (10), 47% men; 472 patients in the CKD cohort (no CVD) were 65 (15) years old, 46% men. In a Cox proportional hazards model, each 10% increase in treatment intensity (LDL-C lowering) was associated with 18% lower risk of CV event in the CVD (HR 0.82, 95% CI 0.82–0.83), 21% - in the DM (HR 0.79, 95% CI 0.76–0.83), and 15% - in the CKD (HR 0.85, 95% CI 0.75–0.97) cohorts. Similarly, each 10% increase in adherence (PDC) was associated with 6% lower risk of CV event in the CVD (HR 0.94, 95% CI 0.93–0.94), 7% - in the DM (HR 0.93, 95% CI 0.91–0.94), and 7% - in the CKD (HR 0.93, 95% CI 0.89–0.97) cohorts. Each 10% increase in adherence-adjusted intensity was associated with 16% lower risk of CV event in the CVD (HR 0.84, 95% CI 0.83 - 0.85), 19% - in the DM (HR 0.81, 95% CI 0.78–0.85), and 17% - in the CKD (HR 0.83, 95% CI 0.72–0.96) cohorts. The models controlled for age, sex, Charlson comorbidity index and other cardiovascular risk factors at baseline. Conclusions A higher adherence and/or treatment intensity of LLT was associated with significantly lower risk of CV outcomes or all-cause death in German very high-risk patients. Strategies to tailor intensity to patient profile and improve adherence could further lower risk of CV events. Acknowledgement/Funding Amgen Europe GmbH

Objective: To assess the prevalence of patients at very high risk of cardiovascular (CV) events in the United Kingdom (UK) and evaluate low-density lipoprotein cholesterol (LDL-C) values and treatment patterns in these patients. Methods: This cross-sectional study used primary care data from UK electronic medical records in the Clinical Practice Research Datalink (CPRD) in 2013. Very high-risk patients were defined per European Society of Cardiology guidelines as those with hyperlipidemia (assessed by co-medication) and documented cardiovascular disease (CVD) or hyperlipidemia and type 2 diabetes (DM2) without CVD (DM2w/oCVD). All analyses were descriptive. Results: Data from 4,940,226 patients were captured in the CPRD in 2013. Of these, 5% of patients had received ≥2 lipid-modifying therapy prescriptions and were at very high risk of CVD (3% [n = 138,536] had documented CVD, 2% [n = 98,743] had DM2w/oCVD). In documented CVD patients, coronary artery disease (73%) was the most frequent type of event (25% had myocardial infarction [MI]), followed by cerebrovascular disease (18%), and peripheral arterial disease (9%); 21% had experienced multiple CV events, 25% had DM2, and 3% had MI within 1 year. In documented CVD and DM2w/oCVD patients, >95% received statin treatment; 24% received high-intensity statin, and 1.5% statin plus ezetimibe. Across both populations, 64–66% had LDL-C levels ≥1.8 mmol/L, 27–28% ≥2.5 mmol/L, 6–7% ≥3.5 mmol/L, and 3% had levels ≥4.0 mmol/L, respectively. Conclusion: A well-defined proportion of patients remain at very high-risk of CVD. Statin therapy needs optimization, but, for some patients with high LDL-C levels, multiple CV events, MI within 1 year, or CVD and DM2, additional more intensive therapy may be needed.

In cancer cell lines and rodent models, calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes, CYP27B1 and CYP24A1; however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d elemental calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months (n = 92; 23 per group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal appearing rectal mucosa were detected by standardized, automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group, CaR expression increased 27% (P = 0.03) and CYP24A1 expression decreased 21% (P = 0.79). In the vitamin D3-supplemented group, CaR expression increased 39% (P = 0.01) and CYP27B1 expression increased 159% (P = 0.06). In patients supplemented with both calcium and vitamin D3, VDR expression increased 19% (P = 0.13) and CaR expression increased 24% (P = 0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, preneoplastic risk biomarkers for colorectal neoplasms. Cancer Res; 71(2); 413–23. ©2010 AACR.

To characterize the expression of the mismatch repair gene MutL-homolog 1 (MLH1) in normal colorectal crypts in humans, and assess parameters of its expression as a potential biomarker of risk for colorectal neoplasms, we conducted a pilot, colonoscopy-based case-control study (51 cases, 154 controls) of incident, sporadic colorectal adenoma. Biopsies of normal-appearing rectal, sigmoid, and ascending colon mucosa were procured, immunohistochemically processed for MLH1 protein, and analyzed using custom quantitative image analysis procedures. MLH1 expression in the ascending colon was, on average, 49% proportionally lower in cases than controls (P = 0.03), but there was little evidence for case-control differences in the rectum and sigmoid colon. In cases and controls, average MLH1 expression in the ascending colon tended to be lower with increased age [by 56% (P = 0.02) and 25% (P = 0.16), respectively, for those ≥55 years], and with a history of colorectal cancer in a first-degree relative (by 22% [P = 0.56] and 34% [P = 0.16], respectively). Among cases, but not controls, average MLH1 expression tended to be higher with current alcohol consumption, regular aspirin use, and higher total intakes of calcium, vitamin D, and folate. There was little indication of similar differences in the rectum. These preliminary data suggest that lower MLH1 expression in the normal colonic mucosa, at least in the ascending colon, may be associated with increased risk of incident, sporadic colorectal adenoma, as well as with modifiable risk factors for colorectal neoplasms, thus supporting further investigation of MLH1 expression as a potential “treatable” biomarker of risk for colorectal neoplasms. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1599–609)

To further clarify and develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans and develop modifiable biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial to test the effects of calcium and vitamin D3, alone and in combination, on key DNA mismatch repair proteins in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D3, alone or in combination, versus placebo over 6 months. Colorectal crypt overall expression and distribution of MSH2 and MLH1 proteins in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, MSH2 expression along the full lengths of crypts increased by 61% (P = 0.11) and 30% (P = 0.36) in the vitamin D and calcium groups, respectively, relative to the placebo group. The estimated calcium and vitamin D treatment effects were more pronounced in the upper 40% of crypts (differentiation zone) in which MSH2 expression increased by 169% (P = 0.04) and 107% (P = 0.13) in the vitamin D and calcium groups, respectively. These findings suggest that higher calcium and vitamin D intakes may result in increased DNA MMR system activity in the normal colorectal mucosa of sporadic adenoma patients and that the strongest effects may be vitamin D related and in the differentiation zone of the colorectal crypt. Cancer Epidemiol Biomarkers Prev; 19(4); 1022–32. ©2010 AACR.

The exact antineoplastic effects of calcium and vitamin D3 in the human colon are unclear. Animal and in vitro studies show that these two agents reduce oxidative stress; however, these findings have never been investigated in humans. To address this, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial to test the effects of calcium and vitamin D3 on a marker of oxidative DNA damage, 8-hydroxy-2′-deoxyguanosine (8-OH-dG), in the normal colorectal mucosa. Patients (N = 92) with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months. Overall labeling and colorectal crypt distribution of 8-OH-dG in biopsies of normal-appearing rectal mucosa were detected by standardized automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, 8-OH-dG labeling along the full lengths of colorectal crypts decreased by 22% (P = 0.15) and 25% (P = 0.10) in the calcium and vitamin D3 groups, respectively, but not in the calcium plus vitamin D3 group. The estimated treatment effects were strongest among participants with higher baseline colon crypt vitamin D receptor expression (P = 0.05). Overall, these preliminary results indicate that calcium and vitamin D3 may decrease oxidative DNA damage in the normal human colorectal mucosa, support the hypothesis that 8-OH-dG labeling in colorectal crypts is a treatable oxidative DNA damage biomarker of risk for colorectal neoplasms, and provide support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 19(1); 280–91

To investigate the potential efficacy of calcium and vitamin D in reducing risk for colorectal neoplasms and to develop “treatable” phenotypic biomarkers of risk for colorectal neoplasms, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial to test the effects of these agents on cell cycle markers in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2 g/day calcium and/or 800 IU/day vitamin D3 versus placebo over 6 months. Overall expression and distributions of p21waf1/cip1 (marker of differentiation), MIB-1 (marker of short-term proliferation), and hTERT (marker of long-term proliferation) in colorectal crypts in the normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. In the calcium, vitamin D, and calcium plus vitamin D groups relative to the placebo, p21 expression increased by 201% (P = 0.03), 242% (P = 0.005), and 25% (P = 0.47), respectively, along the full lengths of colorectal crypts after 6 months of treatment. There were no statistically significant changes in the expression of either MIB-1 or hTERT in the crypts overall; however, the proportion of hTERT, but not MIB-1, expression that extended into the upper 40% of the crypts was reduced by 15% (P = 0.02) in the vitamin D plus calcium group relative to the placebo. These results indicate that calcium and vitamin D promote colorectal epithelial cell differentiation and may “normalize” the colorectal crypt proliferative zone in sporadic adenoma patients, and support further investigation of calcium and vitamin D as chemopreventive agents against colorectal neoplasms. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2933–41)

Background: Transforming growth factor-α (TGF-α), a stimulatory growth factor and member of the epidermal growth factor family, is a mediator of oncogenesis and malignant progression in colorectal carcinogenesis. Limited evidence suggests its utility as a growth-related biomarker of risk for colorectal cancer. Methods: We measured expression of TGF-α in biopsies of normal-appearing colorectal mucosa using automated immunohistochemistry and quantitative image analysis in a subsample of 29 cases and 31 controls from a colonoscopy-based case-control study (n = 203) of biomarkers of risk for incident sporadic colorectal adenoma. Diet, lifestyle, and medical history were assessed with validated questionnaires. Results: TGF-α expression in the rectum was 51% higher in cases compared with controls (P = 0.05) and statistically significantly associated with accepted risk factors for colorectal neoplasms (36% lower among nonsteroidal anti-inflammatory drug users, 49% lower among women using hormone replacement therapy, 79% higher among persons with a family history of colorectal cancer). Conclusions: TGF-α expression in the normal-appearing rectal mucosa shows promise as an early, potentially modifiable biomarker of risk for colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):65–73)