Plasma concentration of atorvastatin metabolites correlates with low-density lipoprotein cholesterol reduction in patients with coronary heart disease.

In this exploratory study from a randomized double-blinded crossover trial including 70 patients with coronary heart disease and self-perceived muscular side effects of statins, we aimed to determine the relationship between low-density lipoprotein cholesterol (LDL-C) reduction and atorvastatin metabolite plasma concentrations. All patients underwent a 7 weeks treatment period with atorvastatin 40 mg/day and a 7 weeks placebo period in random order. Nonlinear regression with a three-parameter equation explored the relationship between percentage LDL-C reduction (statin vs. placebo) and the pharmacokinetic variables. Mean LDL-C reduction was 49% (range 12% to 71%). The sum of 4-OH-atorvastatin acid and lactone correlated moderately with the LDL-C response (Spearman ρ 0.27, 95% confidence interval [CI]: 0.03 to 0.48). Accordingly, nonlinear regression showed R2 of 0.14 (95% CI: 0.03 to 0.37, R2 adjusted equaled 0.11). Even a perfect underlying correlation of 1.0 showed R2 = 0.32 by simulation, using historical intra-individual LDL-C variation (8.5%). The 90% inhibitory concentration was 2.1 nmol/L, and the 4-OH-metabolite sum exceeded this threshold in 34% of the patients. In conclusion, trough plasma concentrations of 4-OH-atorvastatin metabolites correlated moderately to the LDL-C reduction. A plateau LDL-C response was observed above a pharmacokinetic threshold, below which the response was highly variable. The usefulness of monitoring concentrations of atorvastatin metabolites to optimize the individual dosage have limitations, but its supportive potential may be pursued in relevant patient subsets to achieve adequate efficacy at the lowest possible dose. The results add knowledge to the overall understanding of the variable LDL-C response mediated by atorvastatin.

Preventable clinical and psychosocial factors predicted two out of three recurrent cardiovascular events in a coronary population.

BACKGROUND: The relative importance of lifestyle, medical and psychosocial factors on the risk of recurrent major cardiovascular (CV) events (MACE) in coronary patients' needs to be identified. The main objective of this study is to estimate the association between potentially preventable factors on MACE in an outpatient coronary population from routine clinical practice. METHODS: This prospective follow-up study of recurrent MACE, determine the predictive impact of risk factors and a wide range of relevant co-factors recorded at baseline. The baseline study included 1127 consecutive patients 2-36 months after myocardial infarction (MI) and/or revascularization procedure. The primary composite endpoint of recurrent MACE defined as CV death, hospitalization due to MI, revascularization, stroke/transitory ischemic attacks or heart failure was obtained from hospital records. Data were analysed using cox proportional hazard regression, stratified by prior coronary events before the index event. RESULTS: During a mean follow-up of 4.2 years from study inclusion (mean time from index event to end of study 5.7 years), 364 MACE occurred in 240 patients (21, 95% confidence interval: 19 to 24%), of which 39 were CV deaths. In multi-adjusted analyses, the strongest predictor of MACE was not taking statins (Relative risk [RR] 2.13), succeeded by physical inactivity (RR 1.73), peripheral artery disease (RR 1.73), chronic kidney failure (RR 1.52), former smoking (RR 1.46) and higher Hospital Anxiety and Depression Scale-Depression subscale score (RR 1.04 per unit increase). Preventable and potentially modifiable factors addressed accounted for 66% (95% confidence interval: 49 to 77%) of the risk for recurrent events. The major contributions were smoking, low physical activity, not taking statins, not participating in cardiac rehabilitation and diabetes. CONCLUSIONS: Coronary patients were at high risk of recurrent MACE. Potentially preventable clinical and psychosocial factors predicted two out of three MACE, which is why these factors should be targeted in coronary populations. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT02309255. Registered at December 5th, 2014, registered retrospectively.

Prognostic factors in malignant ovarian germ cell tumours (The Surveillance, Epidemiology and End Results experience 1978-2010).

PURPOSE: To evaluate the prognostic significance of age at diagnosis, extent of the disease (EOD) and socioeconomic (SES) and sociodemographic status (civil status, residency) on cause specific survival (CSS) in patients with malignant ovarian germ cell tumours (MOGCTs). To explore the cumulative incidence of a second cancer in 10-year MOGCT survivors. PATIENTS AND METHODS: 2541 patients with MOGCT, reported to the Surveillance, Epidemiology and End Results programme (1978-2010), were identified. The above mentioned prognostic factors were assessed separately for dysgerminoma and non-dysgerminoma, using Kaplan-Meier estimates and Cox Hazards Models, providing 95% confidence intervals (95% CI). RESULTS: Five-year CSS was 97% (95% CI, 96-98%), and 92% (95% CI, 91-93%), respectively for dysgerminoma, and non-dysgerminoma. Age >40 years at diagnosis and presence of metastases were significantly associated with cause specific mortality. Among non-dysgerminoma patients, decreasing SES (hazard ratio (HR), 1.59; 95% CI, 1.11-2.28) and treatment before 1990 (HR, 2.65; 95% CI, 1.83-3.85) increased mortality. In the adjusted analysis, patients from Michigan were almost 2.5 times more likely to die from MOGCT than patients from other states (HR, 2.48; 95% CI, 1.17-5.25). Second cancer was diagnosed in 10% of 10-year survivals who underwent radiotherapy and in 2% of survivals in non-radiotherapy group (p=.002). CONCLUSIONS: Increased attention should be directed towards the management of elderly MOGCT patients and those with non-dysgerminoma histology with low SES. Radiotherapy should be avoided as much as possible. Survival differences related to residency may occur when new cancer treatments are introduced.

Nationwide quality assurance of rectal cancer treatment.

OBJECTIVE: The purpose of this prospective study was to examine the influence of the efforts for nationwide quality assurance of rectal cancer treatment. The study focuses on local recurrence and overall survival. METHODS: This study includes all 3388 Norwegian patients with a rectal cancer within 15 cm from the anal verge treated with curative intent in the period November 1993-December 1999. A comprehensive educational programme was established, and training courses were arranged in different Health Regions demonstrating the TME technique. A specific Rectal Cancer Registry enabled the monitoring of outcome of rectal cancer treatment for single hospitals. Radiotherapy was given to 10% of the patients. RESULTS: The risk of local recurrence has been significantly reduced, so that in 1999 the level was 50% below that observed in 1994 (Hazard ratio (HR)1999=0.5; 95% CI 0.4-0.8, P=0.002). Similarly, during 1998, the mean national overall survival was significantly improved, compared to the rate in 1994 (HR1998=0.8; 95% CI 0.6-1.0, P=0.014). CONCLUSION: The prognosis for rectal cancer can be improved by increased organizational focus on rectal cancer treatment and by establishing a rectal cancer registry monitoring treatment standards throughout the country.

The influence of mammographic screening on national trends in breast cancer incidence.

Introducing an organized mammographic screening programme affects the breast cancer incidence rate in a population. The diagnosis is advanced in time, and initially, an increase will occur in the number of cases, followed by a drop in the rate when women leave the programme. The aim of this study was to quantify the potential effects that mammographic screening programmes have on breast cancer incidence. In addition, we wanted to investigate how the incidence of breast cancer varies between different birth cohorts, age groups and time periods in the five Nordic countries Finland, Denmark, Iceland, Norway and Sweden, adjusting for the effects of the screening programmes. Time trends were analysed over the period 1978-1997, using age-period-cohort models. In Sweden, the rates more than doubled (relative risk (RR)=2.20, 95% confidence interval (CI) 1.8-2.6) in women offered screening for the first time compared with women not offered screening. The risk remained elevated (RR=1.34, 95% CI 1.2-1.6) for women who were continued to be offered screening, compared with women who were not offered screening. Finally, the rates dropped (RR=0.68, 95% CI 0.6-0.8) when the women left the programme. This indicates that screening advances the time of diagnosis, which is a prerequisite to subsequent reduction in mortality. Analysis of secular trends, corrected for the influence of screening, showed that the rates in Finland increased by 13% per 5-year period, with a more modest increase in the other countries. There were strong cohort effects in all Nordic countries, and the risk seemed to be flattening for the youngest cohorts in most of the countries.