Higher Baseline Low-density Lipoprotein Cholesterol Levels Research Articles

Moderate-intensity statin plus ezetimibe combination therapy versus high-intensity statin monotherapy according to baseline LDL-C levels: a prespecified subgroup analysis of RACING Trial

Abstract Aims To compare the effects of moderate-intensity statin plus ezetimibe combination therapy to high-intensity statin monotherapy based on baseline low-density lipoprotein cholesterol (LDL-C) levels. Methods and results In the RACING trial, 3780 atherosclerotic cardiovascular disease (ASCVD) patients were randomly assigned to moderate-intensity statin plus ezetimibe combination therapy or high-intensity statin monotherapy based on baseline LDL-C levels of <100 mg/dL (n=2817) or ≥100 mg/dL (n=963). In the prespecified analysis, the primary outcome (a composite of cardiovascular death, major cardiovascular event, or stroke at 3 years) and key secondary outcome (achievement of LDL-C <70 mg/dL) were reported according to baseline LDL-C levels. The occurrence of the primary outcome did not differ between the combination therapy and the monotherapy groups among those with lower and higher baseline LDL-C levels (8.6% versus 10.1%, hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.37 to 1.09; and 10.5% versus 9.3%, HR 1.13, 95% CI 0.76 to 1.70, respectively) without an interaction (P=0.232). The 1-, 2-, and 3-year achievement of LDL-C <70 mg/dL was greater in the combination therapy group, regardless of baseline LDL-C levels. For secondary safety outcomes, no significant interactions between the treatment strategies and baseline LDL-C levels were found. Conclusion Among ASCVD patients, the effect of moderate-intensity statin plus ezetimibe combination therapy was consistent across the baseline LDL-C levels for the 3-year composite of cardiovascular death, major cardiovascular event, or stroke, and even associated with greater achievement of LDL-C <70 mg/dL compared to high-intensity statin monotherapy.

Unmet Need for Further LDL-C Lowering in India despite Statin Therapy: Lipid Association of India Recommendations for the Use of Bempedoic Acid.

Lipid-lowering therapy plays a crucial role in reducing adverse cardiovascular (CV) events in patients with established atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia. Lifestyle interventions along with high-intensity statin therapy are the first-line management strategy followed by ezetimibe. Only about 20-30% of patients who are on maximally tolerated statins reach recommended low-density lipoprotein cholesterol (LDL-C) goals. Several factors contribute to the problem, including adherence issues, prescription of less than high-intensity statin therapy, and de-escalation of statin dosages, but in patients with very high baseline LDL-C levels, including those with familial hypercholesterolemia and those who are intolerant to statins, it is critical to expand our arsenal of LDL-C-lowering medications. Moreover, in the extreme risk group of patients with an LDL-C goal of ≤30 mg/dL according to the Lipid Association of India (LAI) risk stratification algorithm, there is a significant residual risk requiring the addition of non-statin drugs to achieve LAI recommended targets. This makes bempedoic acid a welcome addition to the existing non-statin therapies such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. A low frequency of muscle-related side effects, minimal drug interactions, a significant reduction in high-sensitivity C-reactive protein (hsCRP), and a lower incidence of new-onset or worsening diabetes make it a useful adjunct for LDL-C lowering. However, the CV outcomes trial results are still pending. In this LAI consensus document, we discuss the pharmacology, indications, contraindications, advantages, and evidence-based recommendations for the use of bempedoic acid in clinical practice.

Intensified lipid-lowering treatment with alirocumab in patients with coronary heart disease

BackgroundAtherosclerotic cardiovascular disease is the leading cause of death and disability in the Western world.ObjectiveTo characterise adults with confirmed coronary heart disease (CHD) and primary heterozygous familial or non-familial hypercholesterolaemia...

P0260CLINICAL PROFILE OF PATIENTS INITIATING EVOLOCUMAB IN SPANISH NEPHROLOGY UNITS: A RESTROSPECTIVE, OBSERVATIONAL STUDY IN CLINICAL PRACTICE (RETOSS-NEPHRO)

Abstract Background and Aims Cardiovascular disease is the primary cause of morbidity and mortality in patients with chronic kidney disease (CKD). Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers serum low density lipoprotein cholesterol (LDL-C) levels. Evolocumab is indicated for adult patients with hypercholesterolaemia or mixed dyslipidaemia who are unable to reach LDL-C goals with the maximum tolerated dose of statin or are statin intolerant. This study was conducted to describe clinical characteristics, reasons for therapy initiation and treatment effects in patients treated with evolocumab in Spanish Nephrology units. Method Retrospective, observational, chart review of consecutive patients initiating evolocumab (Feb-2016 to Aug-2018) in 15 Spanish Nephrology Units. Patient characteristics, lipid modifying therapies and lipid profiles over time were retrospectively collected at 24 weeks pre- and 12±4 weeks post-evolocumab initiation. Results 60 patients were enrolled: 53.3% women; mean (SD) age, 56.9 (12.8) years; mean (SD) body mass index, 28.0 (4.7) kg/m2; 45.0% had familial hypercholesterolemia (FH) (5.0% homozygous, 23.3% heterozygous, 16.7% undetermined FH); from the total population, 35% were in primary prevention and 65.0% started evolocumab after previous Atherosclerotic Cardiovascular Disease [ASCVD]. Regarding renal function, mean (SD) eGFR was 62.6 (30.0) ml/min/1.73m2; 51.7% of patients had eGFR <60 ml/min/1.73m2 (CKD stage>2), 50.0% had proteinuria (>300 mg/g) and 10.0% had nephrotic syndrome. Other CV risk factors were hypertension (75.0%), diabetes (25.0%), and smoking (21.7%); 40.0% of patients were statin intolerant. At evolocumab initiation, 41.7% of patients were on a high intensity statin, 18.3% on moderate intensity statin and 50.0% were receiving ezetimibe. Mean (SD) LDL-C at evolocumab initiation was 179.7 (62.9) mg/dL (53.4% of patients with LDL-C≥160; 29.3% ≥190). Mean (SD) baseline HDL-C and total cholesterol were 48.5 (15.0) mg/dL and 273.1 (82.7) mg/dL, respectively. After 12 weeks, evolocumab resulted in LDL-C reductions of 60.1%, to a mean (SD) of 72.7 (80.3) mg/dL, with similar results observed in patients in primary/secondary prevention, with CKD stage >2/≤2 or with/without proteinuria. Conversely, patients with/without FH showed significant differences between their reductions (46.6% vs 76.6%, respectively, p=0.0276). At week 12, 90.0% of patients reached LDL-C levels <100 mg/dL, 70.0% <70 mg/dL, and 55.0% <55mg/dL, while eGFR levels and statin use remained stable. Conclusion In Spanish Nephrology Units, evolocumab was predominantly prescribed in patients with FH, ASCVD and/or CKD stage >2. Initial evolocumab use was aligned with ESC/EAS dyslipidaemia guidelines, but with higher baseline LDL-C levels than the recommended thresholds. After 12 weeks of evolocumab treatment, LDL–C levels were more than halved and the majority of patients achieved both the 2016 and 2019 EAS/ESC targets of LDL-C control.

Una puntuación de riesgo genético predice recurrencias en pacientes jóvenes con infarto agudo de miocardio

Introduction and objectivesTo evaluate whether a genetic risk score (GRS) improves prediction of recurrent events in young nondiabetic patients presenting with an acute myocardial infarction (AMI) and identifies a more aggressive form of atherosclerosis. MethodsWe conducted a prospective study with consecutive nondiabetic patients aged <55 years presenting with AMI. We performed a genetic test, cardiac computed tomography, and analyzed several biomarkers. We studied the association of a GRS composed of 11 genetic variants and a primary composite endpoint (cardiovascular mortality, a recurrent event, and cardiac hospitalization). ResultsA total of 81 patients were studied and followed up for a median of 4.1 years. There were 24 recurrent cardiovascular events. Compared with the general population, study participants had a higher prevalence of 9 out of 11 risk alleles. The GRS was significantly associated with recurrent cardiovascular events, especially when baseline low-density lipoprotein cholesterol (LDL-C) levels were elevated. Compared with the low-risk GRS tertile, the multivariate-adjusted HR for recurrences was 10.2 (95%CI, 1.1-100.3; P=.04) for the intermediate-risk group and was 20.7 (2.4-181.0; P=.006) for the high-risk group when LDL-C was≥2.8 mmol/L (≥ 110mg/dL). Inclusion of the GRS improved the C-statistic (ΔC-statistic=0.086), cNRI (continuous net reclassification improvement) (30%), and the IDI (integrated discrimination improvement) index (0.05). Cardiac computed tomography frequently detected coronary calcified atherosclerosis but had limited value for prediction of recurrences. No association was observed between metalloproteinases, GRS and recurrences. ConclusionsA multilocus GRS may identify individuals at increased risk of long-term recurrences among young nondiabetic patients with AMI and improve clinical risk stratification models, particularly among patients with high baseline LDL-C levels.

A genetic risk score predicts recurrent events after myocardial infarction in young adults.

To evaluate whether a genetic risk score (GRS) improves prediction of recurrent events in young nondiabetic patients presenting with an acute myocardial infarction (AMI) and identifies a more aggressive form of atherosclerosis. We conducted a prospective study with consecutive nondiabetic patients aged <55 years presenting with AMI. We performed a genetic test, cardiac computed tomography, and analyzed several biomarkers. We studied the association of a GRS composed of 11 genetic variants and a primary composite endpoint (cardiovascular mortality, a recurrent event, and cardiac hospitalization). A total of 81 patients were studied and followed up for a median of 4.1 years. There were 24 recurrent cardiovascular events. Compared with the general population, study participants had a higher prevalence of 9 out of 11 risk alleles. The GRS was significantly associated with recurrent cardiovascular events, especially when baseline low-density lipoprotein cholesterol (LDL-C) levels were elevated. Compared with the low-risk GRS tertile, the multivariate-adjusted HR for recurrences was 10.2 (95%CI, 1.1-100.3; P=.04) for the intermediate-risk group and was 20.7 (2.4-181.0; P=.006) for the high-risk group when LDL-C was≥2.8mmol/L (≥ 110mg/dL). Inclusion of the GRS improved the C-statistic (ΔC-statistic=0.086), cNRI (continuous net reclassification improvement) (30%), and the IDI (integrated discrimination improvement) index (0.05). Cardiac computed tomography frequently detected coronary calcified atherosclerosis but had limited value for prediction of recurrences. No association was observed between metalloproteinases, GRS and recurrences. A multilocus GRS may identify individuals at increased risk of long-term recurrences among young nondiabetic patients with AMI and improve clinical risk stratification models, particularly among patients with high baseline LDL-C levels.

Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses

Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). Changes in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150mg every 2weeks (Q2W). Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75mg Q2W, with possible dose increase to 150mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150mg Q2W. Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production.

Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering

Effects on specific fatal and nonfatal end points appear to vary for low-density lipoprotein cholesterol (LDL-C)-lowering drug trials. To evaluate whether baseline LDL-C level is associated with total and cardiovascular mortality risk reductions. Electronic databases (Cochrane, MEDLINE, EMBASE, TCTMD, ClinicalTrials.gov, major congress proceedings) were searched through February 2, 2018, to identify randomized clinical trials of statins, ezetimibe, and PCSK9-inhibiting monoclonal antibodies. Two investigators abstracted data and appraised risks of bias. Intervention groups were categorized as "more intensive" (more potent pharmacologic intervention) or "less intensive" (less potent, placebo, or control group). The coprimary end points were total mortality and cardiovascular mortality. Random-effects meta-regression and meta-analyses evaluated associations between baseline LDL-C level and reductions in mortality end points and secondary end points including major adverse cardiac events (MACE). In 34 trials, 136 299 patients received more intensive and 133 989 received less intensive LDL-C lowering. All-cause mortality was lower for more vs less intensive therapy (7.08% vs 7.70%; rate ratio [RR], 0.92 [95% CI, 0.88 to 0.96]), but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with greater reductions in all-cause mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.91 [95% CI, 0.86 to 0.96]; P = .001; absolute risk difference [ARD], -1.05 incident cases per 1000 person-years [95% CI, -1.59 to -0.51]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Cardiovascular mortality was lower for more vs less intensive therapy (3.48% vs 4.07%; RR, 0.84 [95% CI, 0.79 to 0.89]) but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with a greater reduction in cardiovascular mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.86 [95% CI, 0.80 to 0.94]; P < .001; ARD, -1.0 incident cases per 1000 person-years [95% CI, -1.51 to -0.45]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Trials with baseline LDL-C levels of 160 mg/dL or greater had the greatest reduction in all-cause mortality (RR, 0.72 [95% CI, 0.62 to 0.84]; P < .001; 4.3 fewer deaths per 1000 person-years) in a meta-analysis. More intensive LDL-C lowering was also associated with progressively greater risk reductions with higher baseline LDL-C level for myocardial infarction, revascularization, and MACE. In these meta-analyses and meta-regressions, more intensive compared with less intensive LDL-C lowering was associated with a greater reduction in risk of total and cardiovascular mortality in trials of patients with higher baseline LDL-C levels. This association was not present when baseline LDL-C level was less than 100 mg/dL, suggesting that the greatest benefit from LDL-C-lowering therapy may occur for patients with higher baseline LDL-C levels.

The Role of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors in the Management of Dyslipidemia.

Treatment with statins substantially reduces cardiovascular morbidity and mortality both in patients with and without established cardiovascular disease. Accordingly, statins represent the cornerstone of lipid-lowering treatment. However, there are still unmet clinical needs in the management of dyslipidemia. Indeed, it is difficult to achieve low-density lipoprotein cholesterol (LDL-C) targets in many patients, particularly in those at very high cardiovascular risk or in those with very high baseline LDL-C levels [e.g. with heterozygous familial hypercholesterolemia (FH)]. Moreover, a sizable proportion of patients are not able to tolerate high doses of statins, mostly due to muscle-related adverse effects. In these patient populations, inhibition of proprotein convertase subtilisin-kexin type 9 (PCSK9) with monoclonal antibodies appears to represent a useful tool for achieving LDL-C targets. In the present review, we summarize the current knowledge on the effects of the PCSK9 inhibitors alirocumab and evolocumab on lipid levels in various populations and discuss the role of these agents in the management of dyslipidemia. In addition to a substantial reduction in LDL-C levels (by 50-60%), PCSK9 inhibitors also lower triglyceride, non-high-density lipoprotein cholesterol (non-HDL-C) and lipoprotein (a) levels and increase HDL-C levels. Preliminary data suggest that PCSK9 inhibitors are safe. However, ongoing randomized, placebo-controlled trials will provide definitive evidence on the safety of these novel agents and on their effects on cardiovascular morbidity and mortality. Given the high cost of PCSK9 inhibitors, their use should be restricted to carefully selected, veryhigh risk patients until the results of these trials are available.

Determinants of Bezafibrate-induced Improvements in LDL Cholesterol in Dyslipidemic Patients with Diabetes.

Our previous "J-BENEFIT (Japan BEzafibrate cliNical EFfectIveness and Tolerability)" study demonstrated that bezafibrate improves blood lipid profiles and glucose control in dyslipidemic patients with diabetes. However, bezafibrate did not significantly improve low-density lipoprotein cholesterol (LDL-C), although some patients showed decreases while others showed increases in the LDL-C levels. Therefore, a subgroup analysis of the J-BENEFIT study was conducted to identify factors influencing the bezafibrate-induced changes in the LDL-C levels. Of the 3,316 patients in the J-BENEFIT study, 2,116 not treated with other lipid-lowering drugs were enrolled in the current study, and the effects of 24-week treatment with bezafibrate on the LDL-C levels were analyzed. A reduction in the LDL-C level of ≥ 25% occurred in 253 patients, and a logistic-regression analysis was used to identify factors associated with this improvement. Among the 2,116 overall patients, bezafibrate treatment significantly increased the LDL-C levels from 123.9±36.7 to 125.7±31.3 mg/dL. The subanalysis showed that the treatment responses varied according to the baseline LDL-C level, with significant decreases in the ≥ 160 and ≥ 140-＜160 mg/dL groups, no significant decrease in the ≥ 120-＜140 mg/dL group and a significant increase in the ＜120 mg/dL group. A multivariate logistic-regression analysis of the data for the patients with an LDL-C of ≥ 25% identified a female sex, the use of anti-hypertensive and hypoglycemic agents and a high baseline LDL-C level to be significant determinants of the LDL-C response to bezafibrate. Our results showed that treatment with bezafibrate improves the LDL-C levels and lipid profiles in dyslipidemic diabetic patients, especially women, subjects co-treated with anti-hypertensive or hypoglycemic agents and those with high baseline LDL-C levels.

LDL cholesterol as a novel risk factor for contrast-induced acute kidney injury in patients undergoing percutaneous coronary intervention

Background: Low density lipoprotein cholesterol (LDL-C) is associated with endothelial dysfunction, inflammation and increased vasoconstriction, which are involved in the development of contrast-induced acute kidney injury (CI-AKI). However, whether LDL-C is an independent risk factor of CI-AKI in patients undergoing percutaneous coronary intervention (PCI) is unknown. Methods: We prospectively enrolled 3236 consecutive patients undergoing PCI between January 2010 and September 2012. Multivariate logistic regression analysis was used to determine whether LDL-C is an independent risk factor of CI-AKI. CI-AKI was defined as an absolute increase in serum creatinine of ≥0.5 mg/dL or ≥25% over the baseline value within 48–72 h after contrast exposure. Results: CI-AKI was observed in 338 patients (10.4%). Patients with CI-AKI had a significantly higher rate of in hospital mortality (4.4% vs. 0.5%, p < 0.001), and significantly higher rates of other in hospital complications compared with those without CI-AKI. The LDL-C quartiles were as follows: Q1 (<2.04 mmol/L), Q2 (2.04–2.61 mmol/L), Q3 (2.61–3.21 mmol/L) and Q4 (>3.21 mmol/L). Patients with high baseline LDL-C levels were more likely to develop CI-AKI and composite end points including all-cause mortality, renal replacement therapy, non-fatal myocardial infarction, acute heart failure, target vessel revascularization or cerebrovascular accident during the observation period of hospitalization (8.9%, 9.9%, 10.5%, 12.6%, p = 0.001, and 5.0%, 5.2%, 6.1%, 8.1%, respectively; p = 0.007). Univariate logistic analysis showed that LDL-C levels (increment 1 mmol/L) were significantly associated with CI-AKI (odds ratio = 1.25, 95% confidence interval (CI), 1.11–1.39, p < 0.001). Furthermore, LDL-C remained a significant risk factor of CI-AKI (odds ratio = 1.23, 95% CI, 1.04–1.45, p = 0.014), even after adjusting for potential confounding risk factors. Conclusions: Measurement of plasma LDL-C concentrations in patients undergoing PCI may be helpful to identify those who are at risk of CI-AKI and poor in hospital outcomes.

LDL Lowering After Acute Coronary Syndrome: Is Lower Better?

Low density lipoprotein cholesterol (LDL-C) levels are a major risk factor for the development of acute coronary syndrome (ACS) and for recurrent events after ACS. Lowering LDL-C after ACS leads to a significant reduction in recurrent events and overall mortality. A lower limit at which LDL-C reduction fails to decrease risk has not been determined, and lowering LDL-C below current guideline-defined targets may provide incremental benefit. While the absolute risk is small, more intensive statin therapy is associated with a higher incidence of myopathy, rhabdomyolysis, liver enzyme abnormalities and incident diabetes, but not with an increase in malignancies or all-cause mortality. It is important that clinicians recognize ACS patients as being at very high risk, and provide these patients with intensive lifestyle and pharmacologic therapy for all modifiable risk factors. Within this framework, either a strategy of "intensive statin treatment after ACS" or a strategy of "aggressive LDL-C targets after ACS" would be appropriate based on currently available data. Combination lipid-lowering therapy does not have a firm evidence base at this point, but may be appropriate in patients with limited statin tolerance or very high baseline LDL-C levels. Newer therapies, such as LDL apheresis, antisense oligonucleotide sequences to apolipoprotein B (apoB) and preprotein convertase subtilin kexin 9 (PCSK9) inhibitors, are currently in clinical trials and may represent important advances in LDL-C lowering therapy in the future.

Efficacy and Safety of Rosuvastatin Therapy for Children With Familial Hypercholesterolemia

This study was undertaken to evaluate the efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. Familial hypercholesterolemia is a common inherited disorder causing markedly elevated low-density lipoprotein cholesterol (LDL-C) levels from birth and resulting in premature atherosclerosis. In children, statins have been shown to be effective in reducing LDL-C, restoring flow-mediated dilation, and slowing carotid intima-media thickening. However, few children in these trials achieved current LDL-C goals. This study comprised a 12-week double-blind, randomized, placebo-controlled trial, followed by a 40-week open-label, titration-to-goal extension phase in 177 pubertal children, ages 10 to 17 years, with familial hypercholesterolemia. Participants were randomly assigned to placebo or rosuvastatin 5, 10, or 20 mg once daily. Compared with placebo, rosuvastatin 5, 10, and 20 mg reduced LDL-C by 38%, 45%, and 50%, respectively (p < 0.001 for each group vs. placebo). With a maximum allowed dose of 20 mg, 40% achieved the treatment goal of <110 mg/dl during the open-label, titration-to-goal phase. Rosuvastatin was well tolerated, with no apparent adverse impact on growth or development. In children with familial hypercholesterolemia, rosuvastatin 20 mg daily reduced LDL-C by 50%. Nonetheless, only 40% attained the consensus LDL-C target of <110 mg/dl, reflecting these patients' high baseline LDL-C levels (mean, 232 mg/dl). (Pediatric Lipid-Reduction Trial of Rosuvastatin [PLUTO]; NCT00355615).

211: Low-Density Lipoprotein Cholesterol Lowering by High-Efficacy Statins: Are Older Women at an Advantage?

Synopsis: In the PROSPER trial, high-risk, older women had higher low-density lipoprotein cholesterol (LDL-C) levels than men at baseline (154 vs. 139 mg/dL), resulting in higher on-treatment LDL-C despite marginally greater response to statin treatment. Purpose: We assessed the more effective statins by sex and age subgroups in a trial of high-risk patients. Methods: In the SOLAR trial (4522US/0003), 1632 patients with LDL-C 130 –250 mg/dL were randomized to rosuvastatin (RSV) 10 mg, atorvastatin (ATV) 10 mg, or simvastatin (SMV) 20 mg for 6 weeks. LDL-C reductions from baseline were compared between treatment groups by ANCOVA and LDL-C goal attainment by logistic regression. Results: Mean age was 62y; the cohort was 58% male and 91% had CHD or CHD risk-equivalents. Mean baseline LDL-C for women and men 65y was 168 and 166 mg/dL, respectively. For women and men 65y, mean baseline LDL-C was 176 and 164 mg/dL. In all 4 subgroups, % LDL-C reduction and % of patients achieving LDL 100 mg/dL were greater for RSV than for ATV or SMV (Table). Older women achieved greater LDL-C reduction than younger women, but goal attainment was not more frequent, apparently due to higher baseline LDL-C levels. Of older women and men, 67% and 73% respectively achieved LDLC 100 mg/dL with RSV 10 mg. Conclusions: Baseline LDL-C was elevated in older women, but increased statin response produced final LDL-C values similar to those of younger women. Goal attainment in older patients suggested a gender difference that should be confirmed in further studies.

The A-SACT (Achievement in Singapore of Cholesterol Targets) Study in Patients with Coronary Heart Disease

Cardiovascular disease remains a leading cause of death worldwide, with hypercholesterolemia being a major risk factor. Evidence-based consensus guidelines have recommended consideration of increasingly stringent cholesterol-lowering goals, yet most patients do not meet these targets. Coronary heart disease (CHD) event and mortality rates and mean serum cholesterol levels have declined in Singapore in recent years; however, certain groups remain at elevated risk. To determine (i) proportions of patients with CHD in Singapore who achieved goals for serum low-density lipoprotein-cholesterol (LDL-C); and (ii) factors influencing goal attainment. A historical cohort study was conducted using records from the Singapore Cardiac Databank, a national registry of CHD patients. Serum LDL-C goal attainment was assessed in 5174 survivors of acute myocardial infarction or coronary revascularization (i.e. coronary artery bypass graft surgery or percutaneous coronary interventions), of whom 3811 (73.7%) were at very high risk. At baseline, the mean patient age was 60.3 years, mean serum value of total cholesterol was 228 mg/dL, and mean LDL-C was 163 mg/dL. Of all CHD patients, approximately 70% did not achieve a serum LDL-C target of <100 mg/dL. Most patients receiving HMG-CoA reductase inhibitor (statin) regimens were treated initially with low- to medium-equipotency regimens and were never titrated to stronger regimens. The vast majority (approximately 94%) of patients at very high risk did not achieve the stringent serum LDL-C target of <70 mg/dL. Patients receiving higher potency statins were significantly more likely to achieve LDL-C goals, whereas those with higher baseline LDL-C levels or Malaysian ethnicity were less likely to achieve LDL-C goals. Most CHD patients in the large group of Singapore residents with CHD in the present study did not achieve recommended LDL-C targets. A more effective disease-management approach, including patient education concerning lifestyle modification (e.g. diet, physical activity), efforts to enhance medication adherence, and more effective, well tolerated therapies such as high-equipotency or high-dose statins and statin combination regimens, may be needed to improve achievement of consensus cholesterol targets. This is the first study of cholesterol goal attainment in a large group of Southeast Asians and serves as a baseline for future evaluations in Asian populations.

Menopausal hormone therapy informed consent

A little over a year ago now, the large hormone therapy clinical trial of the Women’s Health Initiative came to an abrupt halt. The publication of the results rocked the medical community and our patients because a class of drugs once thought to be associated overwhelmingly with benefit was found to cause more harm than good. Now doctors have the dilemma of how to inform patients of the results of the Women’s Health Initiative in a way that will help them make the best decision for themselves of whether they should use of these agents for hot flashes, night sweats, vaginal dryness, or prevention of osteoporosis. In the thousands of daily conversations on this topic, the scenario used to look like this: The patient came to the office asking questions about menopause. When the practitioner determined the patient was going through the menopausal transition, the doctor wrote a prescription for hormone pills or patches, saying they would address her concerns by replacing the hormones her body used to make. They would abolish her hot flashes, slow her bone loss, and reduce her risk of a heart attack. The patient asked if the pills caused breast cancer. Probably in some women, the doctor would acknowledge, but argued that the benefits to the heart and bones were worth taking the chance. Now the patient comes to the office and asks about the confusing information she has been reading on the increased risk of heart attack, strokes, blood clots, and dementia with hormone use. The doctor acknowledges the information has changed and is very important, but the decision to use or not to use hormones is up to her. She has menopausal symptoms and wants a solution. However, she is looking for something safe that does not cause more problems than it solves.

Comparison of treatment with fluvastatin extended-release 80-mg tablets and immediate-release 40-mg capsules in patients with primary hypercholesterolemia

Background: According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines, hypercholesterolemic patients with greater risk for cardiovascular heart disease require more aggressive lowering of low-density lipoprotein cholesterol (LDL-C) levels. Numerous studies have demonstrated that despite these guidelines, patients often do not reach their target levels, and that physicians frequently do not titrate the drug beyond the starting dose. For these patients, it may be more suitable to initiate treatment with a higher starting dose of statin. With the immediate-release (IR) formulation of fluvastatin, the maximal dose of 80 mg is recommended to be administered in divided doses (40 mg BID). An extended-release (ER) formulation of fluvastatin at a higher dose (fluvastatin ER 80 mg) was designed to provide greater LDL-C lowering with QD dosing. Use of this formulation should bring more patients into compliance with target LDL-C levels. Objective: This analysis compared the efficacy and tolerability of fluvastatin ER 80 mg QD and fluvastatin IR 40 mg QD in lowering total cholesterol, LDL-C, triglyceride, and apolipoprotein (apo) B levels and raising high-density lipoprotein cholesterol (HDL-C) and apo A-I levels in patients with hypercholesterolemia over a 12-week treatment period. Methods: This was a prospective, multicenter, double-blind, double-dummy, randomized, parallel-group, active-controlled study. Patients with primary hypercholesterolemia who qualified for lipid-lowering drug therapy based on NCEP ATP II guidelines were randomized to fluvastatin ER 80 mg QD or fluvastatin IR 40 mg QD, and treated for 12 weeks. Results: A total of 173 patients were randomized to treatment: 86 to the fluvastatin ER 80-mg group and 87 to the fluvastatin IR 40-mg group. Compared with fluvastatin IR 40 mg, fluvastatin ER 80 mg produced greater mean reductions in LDL-C (32% vs 22%, respectively; P < 0.001). For each of the 3 coronary heart disease (CHD) risk groups (defined by the NCEP), as well as for the total population studied, more patients from the fluvastatin ER 80-mg group than the IR 40 group achieved NCEP ATP II target LDL-C levels (79% vs 47%, respectively [ P = NS], for patients with <2 risk factors; 58% vs 15%, respectively [ P < 0.001], for patients with ≥2 risk factors; and 40% vs 14%, respectively [ P = 0.012], for patients with CHD). The 80-mg ER dose of fluvastatin provided 9.1% greater LDL-C lowering than the 40-mg IR dose. The incidence of elevations in transaminase levels was low and similar for both doses, with 1 patient in each of the treatment groups being discontinued due to repeated elevation of transaminases >3× the upper limit of normal (ULN). Clinically relevant elevations in creatine kinase (ie, ≥10× ULN) were not observed with either dose. Nine patients (5 in the fluvastatin ER group and 4 in the fluvastatin IR group) discontinued because of adverse events. Conclusions: Treatment with fluvastatin ER 80 mg resulted in greater reductions in LDL-C, total cholesterol, and apo B levels compared with fluvastatin IR 40 mg, with clinically equivalent reduction in triglyceride levels and elevation of HDL-C levels. Furthermore, there were few tolerability concerns of clinical relevance with either formulation and no clinically meaningful difference in the tolerability parameters between the 2 formulations. For patients with higher baseline LDL-C levels, and for patients who require greater LDL-C lowering, it may be appropriate to initiate therapy with fluvastatin ER 80 mg. Use of the higher starting dose likely would bring a greater proportion of high-risk patients into compliance with NCEP ATP II target LDL-C levels and would provide LDL-C lowering that is in the same range that has been proved in clinical trials to be associated with reductions in CHD event rates.