Hyperlipidemias: McPherson R

McPherson R, Frohlich J, Fodor G, Genest J, Canadian Cardiovascular Society. · University of Ottawa Heart Institute, Ottawa, Canada. · Can J Cardiol. · Pubmed #16971976 links to  free full text

Abstract: Since the last publication of the recommendations for the management and treatment of dyslipidemia, new clinical trial data have emerged that support a more vigorous approach to lipid lowering in specific patient groups. The decision was made to update the lipid guidelines in collaboration with the Canadian Cardiovascular Society. A systematic electronic search of medical literature for original research consisting of blinded, randomized controlled trials was performed. Meta-analyses of studies of the efficacy and safety of lipid-lowering therapies, and of the predictive value of established and emerging risk factors were also reviewed. All recommendations are evidence-based, and have been reviewed in detail by primary and secondary review panels. Major changes include a lower low-density lipoprotein cholesterol (LDL-C) treatment target (lower than 2.0 mmol/L) for high-risk patients, a slightly higher intervention point for the initiation of drug therapy in most low-risk individuals (LDL-C of 5.0 mmol/L or a total cholesterol to high-density lipoprotein cholesterol ratio of 6.0) and recommendations regarding additional investigations of potential use in the further evaluation of coronary artery disease risk in subjects in the moderate-risk category.

Moride Y, Hegele RA, Langer A, McPherson R, Miller DB, Rinfret S. · Faculty of Pharmacy, Université de Montreal, Montréal, Quebec. · Can J Cardiol. · Pubmed #18401470 links to  free full text

Abstract: Peer-reviewed, evidence-based recommendations for statin use in primary prevention of cardiovascular events are limited. A narrative review of published randomized controlled trials and meta-analyses was conducted to critically appraise the benefits and risks of statins in primary prevention. Statins effectively reduce plasma concentrations of low-density lipoprotein cholesterol, and reduce the risk of cardiovascular events and death. The greatest benefits are observed in high-risk subjects, such as patients with diabetes or hypertension. Serious cardiovascular events should not be included among serious adverse events because they are efficacy outcomes and are dependent on the baseline risk of patients. Rates of specific serious adverse events, such as cancer and rhabdomyolysis, seem to be similar between the statin and control arms of the clinical trials examined. Thus, the benefits of statins in primary prevention outweigh the risks, particularly among high-risk patients. However, the benefit-risk ratio would likely be optimized through interventions designed to increase persistence and adherence in a real-life setting.

McPherson R. · Ottawa Heart Institute, Ottawa, Canada. · Can J Cardiol. · Pubmed #10653926 No free full text.

Abstract: Coronary artery disease (CAD) is the major cause of death in women. Postmenopausal status is associated with a twofold increase of risk for cardiovascular events, in part because of detrimental changes in plasma lipoproteins and endothelial function. Hormone replacement therapy (HRT) has beneficial effects on plasma lipids, flow-mediated vasodilation and fibrinolysis that could be expected to have positive effects on the incidence of cardiovascular events in many postmenopausal women. However, oral HRT also has procoagulant effects and clearly increases the risk of venous thromboembolism. The prothrombotic effects of oral estrogen are not a major concern for the majority of healthy women and major studies including the Framingham Heart Study and the Nurses' Health Study showed that HRT use is associated with protection from cardiovascular disease. In contrast, the Heart and Estrogen/progestin Replacement Study (HERS) failed to show a beneficial effect of oral HRT on cardiovascular events in older women with advanced CAD. In such women, the acute prothrombotic effects of oral estrogen may outweigh the long-term antiatherosclerotic effects of HRT. Until the results of other randomized controlled studies are complete, advice regarding HRT should be based on anticipated benefits on CAD risk factors versus the overall risk of both venous and arterial thrombosis.

McPherson R. · Ottawa Heart Institute, Ottawa, Canada. · Can J Cardiol. · Pubmed #10653924 No free full text.

Abstract: Coronary artery disease (CAD) is the leading cause of death for women. In large part because of increased age at presentation and a greater frequency of concomitant morbidities, women who develop CAD have a poorer prognosis than do men. Although the long term outcome of revascularization procedures is good, the associated procedural morbidity and mortality in women is high. More emphasis should be placed on the primary and secondary prevention of CAD in women. Although women respond well to risk factor modification, including lipid-lowering therapies, recent data indicate that their awareness of risk factors and prevention strategies is poor. Physician risk factor assessment and adherence to current guideline recommendations are essential in preventing the development or progression of CAD in women.

Schneck DW, Knopp RH, Ballantyne CM, McPherson R, Chitra RR, Simonson SG. · AstraZeneca LP, Wilmington, Delaware 19850-5437, USA. · Am J Cardiol. · Pubmed #12505568 No free full text.

Abstract: The lipid-lowering effects of rosuvastatin and atorvastatin were determined across their dose ranges in a 6-week, randomized, double-blind trial. Three hundred seventy-four hypercholesterolemic patients with fasting low-density lipoprotein (LDL) cholesterol > or =160 but <250 mg/dl (> or =4.14 but <6.47 mmol/L) and fasting triglycerides <400 mg/dl (<4.52 mmol/L) and without active arterial disease within 3 months of entry received once-daily rosuvastatin (5, 10, 20, 40, or 80 mg [n = 209]) or atorvastatin (10, 20, 40, or 80 mg [n = 165]). The percentage decrease in plasma LDL cholesterol versus dose was log-linear for each drug, ranging from -46.6% to -61.9% for rosuvastatin 10 and 80 mg, compared with -38.2% to -53.5% for atorvastatin 10 and 80 mg. The dose curve for rosuvastatin yielded an 8.4% greater decrease in LDL cholesterol compared with atorvastatin at any given dose (p <0.001). Similarly greater decreases were observed for rosuvastatin across the dose range in total cholesterol (-4.9%), non-high-density lipoprotein (non-HDL) cholesterol (-7.0%), apolipoprotein B (-6.3%), and related ratios versus atorvastatin (all p <0.001). Because dose responses for HDL cholesterol, triglycerides, and apolipoprotein A-I were non-log-linear and nonparallel between the 2 drugs, percentage changes from baseline were compared at each dose. Significantly greater increases for rosuvastatin compared with atorvastatin were observed for HDL cholesterol at 40 and 80 mg, and for apolipoprotein A-I at 80 mg. Significantly greater triglyceride decreases were seen at 80 mg with atorvastatin over rosuvastatin. Both rosuvastatin and atorvastatin were well tolerated over 6 weeks.

McPherson R, Hanna K, Agro A, Braeken A, Anonymous00123. · University of Ottawa Heart Institute, Ontario, Canada. · Clin Ther. · Pubmed #11589262 No free full text.

Abstract: BACKGROUND: Potential cost differences between statins are driven primarily by drug costs, differential lowering effects on low-density lipoprotein cholesterol (LDL-C) levels, and adverse drug interactions and reactions. OBJECTIVE: The purpose of this study was to compare the efficacy, safety, and direct treatment costs of cerivastatin and branded pravastatin in adult patients with primary hypercholesterolemia over a 1-year period. METHODS: This was a multicenter (48 sites), randomized, open-label, parallel-group, optional dose-titration study conducted in Canada. Patients aged 18 to 75 years with documented primary hypercholesterolemia (mean LDL-C > or = 160 mg/dL [> or = 4.5 mmol/L] and at least 1 fasting triglyceride measurement < or = 400 mg/dL [< or = 4.5 mmol/L]) that did not respond adequately to dietary intervention were enrolled. Patients who were on a diet at study entry were instructed to continue that diet for the duration of the study. Patients not following a diet were also entered into the study provided they had received previous dietary counseling and were unwilling or unable to comply with this dietary advice. Before randomization, treating physicians were required to record a target lipid level for each patient and then instructed to randomize patients to treatment with any dose and any titration schedule of cerivastatin or branded pravastatin according to their normal practice. Physicians were not required to titrate the study drug dose if the patient did not achieve the predefined target goal. Lipid analyses were conducted at baseline/randomization and at months 3, 6, 9, and 12. All samples drawn for lipid analyses were collected after a fast of > or = 10 hours. A cost-minimization approach was used to compare the direct treatment costs between cerivastatin and branded pravastatin. Since the analysis was from the perspective of the third-party payer (Ministries of Health), only costs attributed to the third-party payer were included. RESULTS: A total of 417 patients were randomized to once-daily treatment with cerivastatin 0.1 mg to 0.4 mg (n = 209) or branded pravastatin 10 mg to 40 mg (n = 208); 39 (9.4%) of patients discontinued prematurely, 19 (4.6%) because of an adverse event. The incidence of adverse events was similar for cerivastatin (73.6%) and branded pravastatin (74.9%). The majority of adverse events were mild or moderate and included headache, nausea, pain, and dizziness. Both cerivastatin and pravastatin were effective in lowering LDL-C to target levels (mean reduction 29.8% and 27.5%, respectively, P = 0.35). An LDL-C decrease of > or = 20% from baseline to end point was achieved in 74.2% of cerivastatin patients and 74.0% of pravastatin patients. The annualized direct hyperlipidemia treatment cost was 19% higher in the branded pravastatin group compared with the cerivastatin group. A sensitivity analysis designed to examine the impact of generic pricing on the cost-minimization analysis indicated that the cost difference between cerivastatin and generic pravastatin was not significant. CONCLUSIONS: Both cerivastatin and branded pravastatin were well tolerated and effective in lowering LDL-C by > or = 20% versus baseline. A cost savings in favor of cerivastatin was a reflection of the lower drug acquisition cost of cerivastatin compared with branded pravastatin.

McPherson R, Angus C, Murray P, Genest J, Anonymous00107. · University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Am Heart J. · Pubmed #11376309 No free full text.

Abstract: BACKGROUND: Recent studies have demonstrated that women at high risk for cardiovascular disease (CVD) benefit from cholesterol lowering to an extent similar to that of men. The ability to achieve established treatment goals for low-density lipoprotein cholesterol (LDL-C) in women with clearly defined risk factors has not been examined in detail. METHODS AND RESULTS: We have determined the efficacy and frequency of achieving target levels for LDL-C with atorvastatin on the basis of National Cholesterol Education Program Adult Treatment Panel II recommendations in 318 women according to the presence of CVD (198 women) or risk factors for CVD (120 women) and the presence of mixed dyslipidemia with obesity with or without CVD (72 women). Mean baseline LDL-C concentrations for women with established CVD were in the upper 10% of the distribution for age-matched North American women and, for those without CVD, were also extremely elevated and were in the top 5% of the LDL-C distribution for age-matched women in this population. The majority of participants without CVD (63%) reached LDL-C targets (LDL-C <or=160 mg/dL [4.1 mmol/L] if <2 CHD risk factors and LDL-C <or=130 mg/dL [3.4 mmol/L] if >or=2 CVD risk factors) with 10 mg atorvastatin and 79% reached targets with up to 20 mg of atorvastatin. For women with established CVD, 34% achieved an LDL-C <or=100 mg/dL (2.6 mmol/L) with 10 mg and 60% reached this target with up to 20 mg of atorvastatin. With maximal titration to the LDL-C target, up to and including 80 mg atorvastatin, 87% of women without CVD and 80% of women with established CVD achieved LDL-C targets. The presence of mixed dyslipidemia with obesity did not affect the frequency of achieving LDL-C targets. CONCLUSION: Atorvastatin is very effective in achieving National Cholesterol Education Program Adult Treatment Panel II target concentrations for LDL-C in the majority of women with established CVD or CVD risk factors.

Grover SA, Dorais M, Paradis G, Fodor JG, Frohlich JJ, McPherson R, Coupal L, Zowall H. · Centre for the Analysis of Cost-Effective Care, Montreal General Hospital, Que. · CMAJ. · Pubmed #11107461 links to  free full text

Abstract: BACKGROUND: There is strong evidence to support the treatment of abnormal blood lipid levels among people with cardiovascular disease. Primary prevention is problematic because many individuals with lipid abnormalities may never actually develop cardiovascular disease. We evaluated the 1998 Canadian lipid guidelines to determine whether they accurately identify high-risk adults for primary prevention. METHODS: Using data from the Lipid Research Clinics and receiver operating characteristic (ROC) curves, we compared the diagnostic performance of the 1998 lipid guidelines when risk factors for coronary artery disease (CAD) were counted versus calculating risk using Framingham risk equations. We also compared the diagnostic accuracy of the 1998 guidelines with guidelines previously published by the National Cholesterol Education Program in the United States and the 1988 Canadian Consensus Conference on Cholesterol and then used Canadian Heart Health Survey data to forecast lipid screening and treatment rates for the Canadian population. RESULTS: The Framingham risk equations were more accurate than counting risk factors for predicting CAD risk (areas under the ROC curves, 0.83 [standard deviation (SD) 0.02] v. 0.77 [SD 0.03], p < 0.05). Risk counting was a particularly poor method for predicting risk for women. The 1998 Canadian guidelines identified high-risk individuals more accurately than the earlier guidelines, but the increased accuracy was largely due to a lower false-positive rate or a higher true-negative rate (i.e., increased test specificity). Using the 1998 lipid guidelines we estimate that 5.9 million Canadians currently free of cardiovascular disease would be eligible for lipid screening and 322,705 (5.5%) would require therapy. INTERPRETATION: Calculating risk using risk equations is a more accurate method to identify people at high risk for CAD than counting the number of risk factors present, especially for women, and the 1998 Canadian lipid screening guidelines are significantly better at identifying high-risk patients than the 1988 guidelines. Many of our findings were incorporated into the new 2000 guidelines.

Awan Z, Alrasadi K, Francis GA, Hegele RA, McPherson R, Frohlich J, Valenti D, de Varennes B, Marcil M, Gagne C, Genest J, Couture P. · McGill University Health Center/Royal Victoria Hospital, 687 Pine avenue West, Montréal, QC H3A 1A1, Canada. · Arterioscler Thromb Vasc Biol. · Pubmed #18239150 links to  free full text

Abstract: BACKGROUND: Patients with homozygous familial hypercholesterolemia (hmzFH) attributable to LDL receptor gene mutations have shown a remarkable increase in survival over the last 20 years. Early onset coronary heart disease (CHD) and calcific aortic valve stenosis are the major complications of this disorder. We now report extensive premature calcification of the aorta in patients with hmzFH. METHODS AND RESULTS: We examined 25 hmzFH patients from Canada; mean age was 32 years (range 5 to 54), and mean baseline cholesterol before treatment was 19+/-5 mmol/L (737+/-206 mg/dL). Aortic calcification was quantified using computed tomography (CT). An elevated mean calcium score was found in patients by age 20 and correlated with age (r(2)=0.53, P=0.001). One quarter (24%) of patients underwent aortic valve surgery. CONCLUSIONS: We document premature severe aortic calcifications in all adult hmzFH patients studied. These presented considerable surgical management challenges. Strategies to identify and monitor aortic calcification in hmzFH by noninvasive techniques are required, as are clinical trials to determine whether additional or more intensive therapies will prevent the progression of such calcifications. Whether vascular calcifications in hmzFH subjects are related to sustained increases in LDL-C levels or to other mechanisms, such as abnormal osteoblast activity, remains to be determined.

Stirnadel H, Lin X, Ling H, Song K, Barter P, Kesäniemi YA, Mahley R, McPherson R, Waeber G, Bersot T, Cohen J, Grundy S, Mitchell B, Mooser V, Waterworth D. · World Wide Epidemiology, GlaxoSmithKline, Harlow, UK. · Atherosclerosis. · Pubmed #17888929 No free full text.

Abstract: Atherogenic dyslipidemia, manifest by low HDL-cholesterol and high TG levels, is an important component of ATP-III defined metabolic syndrome. Here, we dissected the phenotypic and genetic architecture of these traits by assessing their relationships with other metabolically relevant measures, including plasma adipo-cytokines, highly sensitive C-reactive protein (hsCRP) and LDL particle size, in a large family data set (n=2800) and in an independent set of dyslipidemic cases (n=716) and normolipidemic controls (n=1073). We explored the relationships among these phenotypes using variable clustering and then estimated their genetic heritabilities and cross-trait correlations. In families, four clusters explained 61% of the total variance, with one adiposity-related cluster (including hsCRP), one BP-related cluster, and two lipid-related clusters (HDL-C, TG, adiponectin and LDL particle size; apoB and non-HDL-C). A similar structure was observed in dyslipidemic cases and normolipidemic controls. The genetic correlations in the families largely paralleled the phenotype clustering results, suggesting that common genes having pleiotropic effects contributed to the correlations observed. In summary, our analyses support a model of metabolic syndrome with two major components, body fat and lipids, each with two subcomponents, and quantifies their degree of overlap with each other and with metabolic-syndrome related measures (adipokines, LDL particle size and hsCRP).

Kiss RS, Kavaslar N, Okuhira K, Freeman MW, Walter S, Milne RW, McPherson R, Marcel YL. · University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario, K1Y 4W7, Canada. · Arterioscler Thromb Vasc Biol. · Pubmed #17303779 links to  free full text

Abstract: OBJECTIVE: We have used a multitiered approach to identify genetic and cellular contributors to high-density lipoprotein (HDL) deficiency in 124 human subjects. METHODS AND RESULTS: We resequenced 4 candidate genes for HDL regulation and identified several functional nonsynonymous mutations including 2 in apolipoprotein A-I (APOA1), 4 in lecithin:cholesterol acyltransferase (LCAT), 1 in phospholipid transfer protein (PLTP), and 7 in the ATP-binding cassette transporter ABCA1, leaving 88% (110/124) of HDL deficient subjects without a genetic diagnosis. Cholesterol efflux assays performed using cholesterol-loaded monocyte-derived macrophages from the 124 low HDL subjects and 48 control subjects revealed that 33% (41/124) of low HDL subjects had low efflux, despite the fact that the majority of these subjects (34/41) were not carriers of dysfunctional ABCA1 alleles. In contrast, only 2% of control subjects presented with low efflux (1/48). In 3 families without ABCA1 mutations, efflux defects were found to cosegregate with low HDL. CONCLUSIONS: Efflux defects are frequent in low HDL syndromes, but the majority of HDL deficient subjects with cellular cholesterol efflux defects do not harbor ABCA1 mutations, suggesting that novel pathways contribute to this phenotype.

Bourgault C, Davignon J, Fodor G, Gagné C, Gaudet D, Genest J, Lavoie MA, Leiter L, McPherson R, Sénécal M, Marentette M, Sebaldt RJ. · McGill University, Montreal, Canada. · Can J Cardiol. · Pubmed #16308595 links to  free full text

Abstract: BACKGROUND: Although statins are widely used to reduce low density lipoprotein cholesterol (LDL-C), there is little information about patient profiles, treatment patterns and goal achievement among statin-treated patients in Canada. OBJECTIVES: To assess the profile of statin-treated patients and to determine whether they are achieving recommended targets for LDL-C. METHODS: The Canadian Lipid Study -- Observational (CALIPSO) was a cross-sectional study involving Canadian physicians who were among the top statin prescribers. Each physician enrolled up to 15 patients who were at least 18 years of age with a diagnosis of hyper-cholesterolemia and who had been using a statin for at least eight weeks. Sociodemographics, coronary artery disease (CAD) risk factors, pretreatment and current lipid levels, and history of lipid-lowering therapy were reported for 3721 patients. RESULTS: Sixty-eight per cent of statin-treated patients were at high CAD risk according to the 2003 Canadian guidelines, 46.4% had established cardiovascular disease, 33.9% had diabetes and 59.5% had hypertension. Average LDL-C reductions of 32% (37% for high-risk patients) were initially required to reach goal. At the study visit, patients had been treated for an average of 4.3 years and 24.2% were using a high statin dose. Despite statin therapy, 27.2% of all patients and 36.4% of those at high CAD risk had not achieved LDL-C targets. For 67.4% of these patients, the current therapy was not modified at the study visit. CONCLUSIONS: Despite effective therapies, many treated patients are not achieving recommended LDL-C targets. Strategies should be implemented to promote achievement of lipid treatment goals for high-risk patients, thereby reducing the risk of cardiovascular events and their associated clinical and economic burdens.

Genest J, McPherson R, Frohlich J, Fodor G. · Division of Cardiology, Royal Victoria Hospital, McGill University, Montréal, Que. · CMAJ. · Pubmed #15824410 links to  free full text

This publication has no abstract.

Genest J, Frohlich J, Fodor G, McPherson R, Anonymous00240. · Royal Victoria Hospital, McGill University, Montréal, Que. · CMAJ. · Pubmed #14581310 links to  free full text

This publication has no abstract.

McPherson R. · University of Ottawa Heart Institute, Ottawa, Canada. · Can J Cardiol. · Pubmed #10350678 No free full text.

Abstract: Data from a number of population-based primary prevention trials clearly indicate that reducing total serum cholesterol levels leads to a reduced risk of coronary artery disease and death. Similarly, for patients with coronary artery disease, reducing total serum cholesterol levels proved to be an effective secondary prevention strategy, leading to a reduced risk of coronary events and death. Targeting high risk patients is a particularly important component of primary prevention. The overall benefit of treatment is significantly reduced when cholesterol-lowering strategies are initiated later in life. To assist in both primary and secondary prevention strategies, an outline of guidelines developed by a Health Canada working group for the management of hyperlipidemia have recently been published.