Evaluation and Management of Dyslipidemia in Patients Treated with Lorlatinib.

The use of lorlatinib, an anaplastic lymphoma kinase (ALK) inhibitor for the treatment of ALK-positive metastatic non-small cell lung cancer, is associated with dyslipidemia in over 80% of patients. Clinical trial protocols for the management of lorlatinib-associated dyslipidemia differ from clinical practice guidelines for the management of dyslipidemia to prevent cardiovascular disease, in that they are based on total cholesterol and triglyceride levels rather than on the low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol levels that form the basis of current cardiovascular guideline recommendations. In order to simplify and harmonize the management of cardiovascular risk in patients with lorlatinib, an advisory committee consisting of a medical oncologist, a cardiologist, and two pharmacists with expertise in cardiology and oncology aimed to develop a simplified algorithm, adapted from the Canadian Cardiovascular Society dyslipidemia recommendations. Recommendations for the evaluation and management of hypercholesterolemia and isolated hypertriglyceridemia in patients treated with lorlatinib are outlined. These recommendations are based on data collected in a large number of lipid-lowering therapy trials applicable to individuals with and without cancer. Considering the relatively long life expectancy and improving prognosis of patients with ALK translocations, this specific patient population should be treated as are patients without cancer and are likely to derive the same benefits from lipid-lowering therapy.

Optimizing screening and management of cardiovascular health in prostate cancer: A review.

In clinical practice, cancer management does not consistently encompass screening and identification of cardiovascular (CV) risk. The use of androgen deprivation therapy (ADT) in prostate cancer has been associated with increased CV risk and development of metabolic syndrome, necessitating identification of patients at risk in this population (e.g., those with pre-existing CV disease). A multidisciplinary team of Canadian physicians was assembled to develop a series of recommendations intended to identify patients who may benefit from optimal management of their CV disease and/or modification of cardiac risk factors. A key goal was the development of a simple screening tool for identification of patients with pre-existing CV disease. This simple and inclusive set of recommendations are intended for use within urology clinics to facilitate holistic approaches and simplify the management of patients.

Simplified Canadian Definition for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal codominant lipoprotein disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease. Definitions for FH rely on complex algorithms that are on the basis of levels of total or LDL-C, clinical features, family history, and DNA analysis that are often difficult to obtain. We propose a novel simplified definition for FH. Definite FH includes: (1) elevated LDL-C (≥ 8.50 mmol/L); or (2) LDL-C ≥ 5.0 mmol/L (for age 40 years or older; ≥ 4.0 mmol/L if age younger than 18 years; and ≥ 4.5 mmol/L if age is between 18 and 39 years) when associated with at least 1 of: (1) tendon xanthomas; or (2) causal DNA mutation in the LDLR, APOB, or PCSK9 genes in the proband or first-degree relative. Probable FH is defined as subjects with an elevated LDL-C (≥ 5.0 mmol/L) and the presence of premature atherosclerotic cardiovascular disease in the patient or a first-degree relative or an elevated LDL-C in a first-degree relative. LDL-C cut points were determined from a large database comprising > 3.3 million subjects. To compare the proposed definition with currently used algorithms (ie, the Simon Broome Register and Dutch Lipid Clinic Network), we performed concordance analyses in 5987 individuals from Canada. The new FH definition showed very good agreement compared with the Simon Broome Register and Dutch Lipid Clinic Network criteria (κ = 0.969 and 0.966, respectively). In conclusion, the proposed FH definition has diagnostic performance comparable to existing criteria, but adapted to the Canadian population, and will facilitate the diagnosis of FH patients.

Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation: Concordance With Clinical Outcomes.

BACKGROUND: Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with changes in reverse cholesterol transport and inflammation. METHODS AND RESULTS: Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% (P=0.0009) and 18.7% (P=0.00001) in participants with the GG and AG genotypes, respectively, but the change was -1.0% (P=0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups (P=0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype (P=0.005). There was a significant genetic effect for change in efflux for dalcetrapib (P=0.02), but not with placebo. CONCLUSIONS: Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov; Unique Identifiers: NCT00658515 and NCT01059682.

Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: results from the PREPAIR randomized study.

OBJECTIVES: The objective of this study was to compare the level of platelet inhibition achieved by 3 different clopidogrel loading regimens in patients undergoing elective angiography and percutaneous coronary intervention when appropriate. BACKGROUND: Optimal platelet inhibition is a key therapeutic goal for patients undergoing percutaneous coronary intervention. Although 600 mg has been described as the maximum absorbed dose when given as a single bolus, the effects of 2 boluses given 24 h apart have not been described. METHODS: Patients (n = 148) were randomly assigned to one of 3 regimens: Group A, clopidogrel 300 mg the day before (>or=15 h) + 75 mg the morning of the procedure; Group B, clopidogrel 600 mg the morning of the procedure (>or=2 h); and Group C, clopidogrel 600 mg the day before (>or=15 h) and 600 mg the morning of the procedure (>or=2 h). Blood samples were obtained at baseline and immediately before angiography. Peak and late platelet aggregation were measured in platelet rich plasma, with researchers blinded to treatment allocation. RESULTS: There was a consistent difference favoring Group C in all aggregation parameters. Percent inhibition in Groups A, B, and C was 31.4%, 29.0%, and 49.5%, respectively, for peak aggregation (5 micromol/l adenosine diphosphate; p < 0.0001) and 54.1%, 57.7%, and 81.1%, respectively, for late aggregation (p < 0.0001). Similar striking reductions were observed when 20 micromol/l adenosine diphosphate was used. All comparisons between Group C and the other 2 groups were statistically significant, and those between Groups A and B were not. CONCLUSIONS: Clopidogrel 600-mg double bolus achieves greater platelet inhibition than conventional single loading doses.