Omega-3 fatty acids and cardiovascular prevention: is the jury still out?

The cardiovascular benefits of omega-3 polyunsaturated fatty acids (O3FA) remain a point of confusion in clinical medicine. Recently two large, randomised trials were published with discordant findings regarding the overall benefits of omega-3 supplementation, resulting in unnecessary confusion and therapeutic nihilism. Epidemiological studies clearly show high intake of fish and measured O3FA (mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) in tissues are inversely associated with cardiovascular events and total mortality. These fatty acids are 'essential' and depend almost entirely on intake with very little production from within the body. The efficacy of supplementation depends on background tissue levels, in contradistinction to drug therapy. Insufficient dosing of omega-3 supplementation using less than 1 g/day and lack of titration to target by failing to measure O3FA levels in the blood may explain these conflicting trial outcomes. We review the current evidence regarding O3FA supplementation and cardiovascular outcomes, describe possible reasons for the discrepant results in the literature including recent controversial data around the mineral oil comparator used in REDUCE-IT and discuss the potential use of the omega-3 index to guide management and optimise supplementation in those at greatest risk.

Randomised clinical trial using Coronary Artery Calcium Scoring in Australian Women with Novel Cardiovascular Risk Factors (CAC-WOMEN Trial): study protocol.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death in women around the world. Aboriginal and Torres Strait Islander women (Australian Indigenous women) have a high burden of CVD, occurring on average 10-20 years earlier than non-Indigenous women. Traditional risk prediction tools (eg, Framingham) underpredict CVD risk in women and Indigenous people and do not consider female-specific 'risk-enhancers' such as hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM) and premature menopause. A CT coronary artery calcium score ('CT-calcium score') can detect calcified atherosclerotic plaque well before the onset of symptoms, being the single best predictor for future cardiac events. A CT-calcium score may therefore help physicians intensify medical therapy in women with risk-enhancing factors. METHODS AND ANALYSIS: This multisite, single-blind randomised (1:1) controlled trial of 700 women will assess the effectiveness of a CT-calcium score-guided approach on cardiovascular risk factor control and healthy lifestyle adherence, compared with standard care. Women without CVD aged 40-65 (35-65 for Aboriginal and Torres Strait Islander women) at low-intermediate risk on standard risk calculators and with at least one risk-enhancing factor (eg, HDP, GDM, premature menopause) will be recruited. Aboriginal and Torres Strait Islander women will be actively recruited, aiming for ~10% of the sample size. The 6-month coprimary outcomes will be low-density lipoprotein cholesterol and systolic blood pressure. Barriers and enablers will be assessed, and a health economic analysis performed. ETHICS AND DISSEMINATION: Western Sydney Local Health District Research Ethics Committee (HREC 2021/ETH11250) provided ethics approval. Written informed consent will be obtained before randomisation. Consent will be sought for access to individual participant Medicare Benefits Schedule, Pharmaceutical Benefits Scheme claims usage through Medicare Australia and linked Admitted Patient Data Collection. Study results will be disseminated via peer-reviewed publications and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12621001738819p.

Implementation and prospective evaluation of the Country Heart Attack Prevention model of care to improve attendance and completion of cardiac rehabilitation for patients with cardiovascular diseases living in rural Australia: a study protocol.

INTRODUCTION: Despite extensive evidence of its benefits and recommendation by guidelines, cardiac rehabilitation (CR) remains highly underused with only 20%-50% of eligible patients participating. We aim to implement and evaluate the Country Heart Attack Prevention (CHAP) model of care to improve CR attendance and completion for rural and remote participants. METHODS AND ANALYSIS: CHAP will apply the model for large-scale knowledge translation to develop and implement a model of care to CR in rural Australia. Partnering with patients, clinicians and health service managers, we will codevelop new approaches and refine/expand existing ones to address known barriers to CR attendance. CHAP will codesign a web-based CR programme with patients expanding their choices to CR attendance. To increase referral rates, CHAP will promote endorsement of CR among clinicians and develop an electronic system that automatises referrals of in-hospital eligible patients to CR. A business model that includes reimbursement of CR delivered in primary care by Medicare will enable sustainable access to CR. To promote CR quality improvement, professional development interventions and an accreditation programme of CR services and programmes will be developed. To evaluate 12-month CR attendance/completion (primary outcome), clinical and cost-effectiveness (secondary outcomes) between patients exposed (n=1223) and not exposed (n=3669) to CHAP, we will apply a multidesign approach that encompasses a prospective cohort study, a pre-post study and a comprehensive economic evaluation. ETHICS AND DISSEMINATION: This study was approved by the Southern Adelaide Clinical Human Research Ethics Committee (HREC/20/SAC/78) and by the Department for Health and Wellbeing Human Research Ethics Committee (2021/HRE00270), which approved a waiver of informed consent. Findings and dissemination to patients and clinicians will be through a public website, online educational sessions and scientific publications. Deidentified data will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: ACTRN12621000222842.

Omega-3 fatty acids ameliorate vascular inflammation: A rationale for their atheroprotective effects.

BACKGROUND AND AIMS: Clinical trials have demonstrated reductions in major adverse cardiovascular events with purified high-dose eicosapentaenoic acid (EPA), independent of effects on lipids. We aimed to investigate whether omega-3 fatty acids reduce vascular inflammation, a critical mediator of atherosclerosis, and hypothesised that EPA is superior to docosahexaenoic acid (DHA). METHODS: In a double-blind randomised controlled trial and cell-culture study, 40 healthy volunteers were supplemented with 4 g daily of either EPA, DHA, fish oil (2:1 EPA:DHA), or placebo for 30 days. Serum was incubated with TNF-stimulated human umbilical vein endothelial cells (HUVECs), and markers of acute vascular inflammation (AVI) were measured. The effects of EPA, DHA (600 mg/kg/day), olive oil, or no treatment were also measured in preclinical models of [1] AVI using a periarterial collar (C57Bl/6J; n = 40 mice) and [2] atherosclerosis where ApoE-/- mice (n = 40) were fed a 16-week atherogenic diet. RESULTS: EPA supplementation reduced expression of C-C motif chemokine ligand 2 (CCL2) by 25% compared to placebo (p = 0.03). In the AVI model, EPA reduced vascular expression of VCAM1 by 43% (p = 0.02) and CCL2 by 41% (p = 0.03). Significant inverse correlations were observed between EPA levels and vascular expression of VCAM1 (r = -0.56, p = 0.001) and CCL2 (r = -0.56, p = 0.001). In ApoE-/- mice, EPA reduced aortic expression of Il1b by 44% (p = 0.04) and Tnf by 49% (p = 0.04), with similar inverse correlations between EPA levels and both Il1b (r = -0.63, p = 0.009) and Tnf (r = -0.50, p = 0.04). CONCLUSIONS: Supplementation with EPA, more so than DHA, ameliorates acute and chronic vascular inflammation, providing a rationale for the cardiovascular benefit observed with high dose omega-3 fatty acid administration.

Oral Calcium Supplements Associate With Serial Coronary Calcification: Insights From Intravascular Ultrasound.

OBJECTIVES: This study sought to evaluate and assess the extent of serial coronary artery calcification in response to oral calcium supplementation. BACKGROUND: Oral calcium supplements are frequently used despite their cardiovascular safety remaining controversial. Their effects on serial coronary calcification are not well established. METHODS: In a post hoc patient-level analysis of 9 prospective randomized trials using serial coronary intravascular ultrasound, changes in serial percentage of atheroma volume (PAV) and calcium indices (CaI) were compared in matched segments of patients coronary artery disease who were receiving concomitant calcium supplements (n = 447) and in those who did not receive supplements (n = 4,700) during an 18- to 24-month trial period. RESULTS: Patients (mean age 58 ± 9 years; 73% were men; 43% received concomitant high-intensity statins) demonstrated overall annualized changes in PAV and CaI with a mean of -0.02 ± 1.9% (p = 0.44) and a median of 0.02 (interquartile range: 0.00 to 0.06) (p < 0.001) from baseline, respectively. Following propensity-weighted mixed modeling adjusting for treatment and a range of demographic, clinical, ultrasonic, and laboratory parameters (including but not limited to sex, race, baseline, and annualized change in PAV, baseline CaI, concomitant high-intensity statins, diabetes mellitus, renal function), there were no significant between-group differences in annualized changes in PAV (least-squares mean: 0.09; 95% confidence interval [CI]: -0.20 to 0.37 vs. 0.01; 95% CI: -0.27 to 0.29; p = 0.092) according to calcium supplement intake. Per a multivariable logistic regression model accounting for the range of covariates described, calcium supplementation independently associated with an increase in annualized CaI (odds ratio: 1.15; 95% CI: 1.05 to 1.26; p = 0.004). CONCLUSIONS: Oral calcium supplementation may increase calcium deposition in the coronary vasculature independent of changes in atheroma volume. The impact of these changes on plaque stability and cardiovascular outcomes requires further investigation.

Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial.

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. Design, Setting, and Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. Main Outcomes and Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%). Conclusions and Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

The fish-oil paradox.

PURPOSE OF REVIEW: Increasing interest has focused on the potential cardioprotective effects of the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the basis of findings from epidemiology and cohort studies. This review will summarize the findings of contemporary clinical trials of omega-3 fatty acids. RECENT FINDINGS: Although a large clinical trial performed prior to the widespread use of statins demonstrated cardiovascular benefit with fish oils, subsequent studies have failed to reproduce this result. More recent studies have demonstrated a reduction in cardiovascular risk with administration of high-dose EPA, but not a carboxylic acid formulation containing both EPA and DHA or with lower doses of omega-3 fatty acids. SUMMARY: Administration of omega-3 fatty acids differing in either composition or dose produce variable effects on cardiovascular outcomes. This has implications for both the public health and pharmacological approach to cardiovascular prevention.

Coronary artery calcium scoring in cardiovascular risk assessment of people with family histories of early onset coronary artery disease.

OBJECTIVES: To assess the predictive value of the Australian absolute cardiovascular disease risk (ACVDR) calculator and other assessment tools for identifying Australians with family histories of early onset coronary artery disease (CAD) who have coronary artery calcification. DESIGN, SETTING, PARTICIPANTS: People without known CAD were recruited at seven Australian hospitals, October 2016 - January 2019. Participants were aged 40-70 years, had a family history of early onset CAD, and a 5-year ACVDR of 2-15%. MAIN OUTCOME MEASURES: CT coronary artery calcium score greater than zero (any coronary calcification) or greater than 100 (calcification warranting lipid therapy). RESULTS: 1059 participants were recruited; 477 (45%) had non-zero coronary artery calcium scores (median 5-year ACVDR, 4.8% [IQR, 2.9-7.6%]; median coronary artery calcium score, 41.7 [IQR, 8-124]); 582 (55%) did not (median 5-year ACVDR, 3.2% [IQR, 2.0-4.6%]). Of 151 participants with calcium scores of 100 or more, 116 (77%) were deemed to be at low cardiovascular risk by Australian guidelines, while 14 of 75 participants at intermediate risk (19%) had zero calcium scores. The sensitivity of the ACVDR calculator for identifying people with non-zero calcium scores (area under receiver operator curve [AUC], 0.674) was lower than that of the pooled cohort equation (AUC, 0.711; P < 0.001). ACVDR (10-year)- and Multi-Ethnic Study of Atherosclerosis (MESA)-predicted risk categories concurred for 511 participants (48%); classifications were concordant for 925 participants (87%) when the ACVDR was supplemented by calcium scores. CONCLUSIONS: Coronary artery calcium scoring should be considered as part of the heart health check for patients at intermediate ACVDR risk and with family histories of early onset CAD. Alternative risk calculators may better select such patients for further diagnostic testing and primary prevention therapy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN 12614001294640; 11 December 2014 (prospective).

Translating evidence from clinical trials of omega-3 fatty acids to clinical practice.

The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) study recently demonstrated that administration of high doses of omega-3 fatty acids confers cardiovascular benefit in high-risk patients with the modest hypertriglyceridemia. This provided optimism for a therapeutic area that has challenged the field of cardiovascular prevention for 2 decades. However, it raises a number of questions including understanding the mechanism underscoring this benefit, how best to use these therapies and whether similar results will be observed with alternative omega-3 fatty acid preparations. Contemporary clinical trials of omega-3 fatty acids and their attempt to prevent cardiovascular events will be reviewed.

High-Dose Omega-3 Fatty Acids in Cardiovascular Prevention: Finally Living Up to Their Potential?

Despite the widespread use of statins in the setting of high cardiovascular risk, many patients continue to experience clinical events. This highlights the need to identify additional therapeutic strategies for high-risk patients. Interest in the use of omega-3 polyunsaturated fatty acids to prevent cardiovascular disease has been high for several decades. Despite promising results from before the statin era, many clinical trials have produced disappointing findings regarding products containing conventional doses of omega-3 fatty acids. More recent clinical trials using high doses of omega-3 fatty acids in targeted populations have suggested potential benefit when targeting the risk driven by atherogenic dyslipidemia. We review the clinical implications of completed and ongoing trials.

Medical and lifestyle management of peripheral arterial disease.

OBJECTIVE: Peripheral arterial disease (PAD) is a global health issue associated with impaired functional capacity and elevated risk of major adverse cardiovascular events (MACEs). With changing risk factor profiles and an aging population, the burden of disease is expected to increase. This review considers evidence for the noninvasive management of PAD and makes clinical recommendations accordingly. METHODS: A comprehensive literature review was performed to examine the evidence for smoking cessation, exercise therapy, antiplatelet therapy, anticoagulant therapy, antihypertensive therapy, lipid-lowering therapy, and glycemic control in diabetes for patients with PAD. RESULTS: Nicotine replacement, bupropion, and varenicline are safe and more effective than placebo in achieving smoking abstinence. Wherever it is practical and available, supervised exercise therapy is ideal treatment for intermittent claudication. Alternatively, step-monitored exercise can increase walking performance and the participant's compliance with less staff supervision. Clopidogrel is preferable to aspirin alone for all patients. However, small studies support the use of dual antiplatelet therapy after revascularization to improve limb outcomes. More recently, the addition of low-dose rivaroxaban to aspirin alone was proven to be more effective in reducing MACEs without a significant increase in major bleeding. However, the exact role of direct oral anticoagulant therapy in the management of PAD is still being understood. Evidence is emerging for more intensive blood pressure and lipid-lowering therapy than traditional targets. Whereas research in PAD is limited, there is clinical scope for an individualized approach to these risk factors. The management of diabetes remains challenging as glycemic control has not been demonstrated to improve macrovascular outcomes. Any potential impact of glycemic control on microvascular disease needs to be weighed against the risks of hypoglycemia. Sodium-glucose cotransporter 2 inhibitors appear to reduce MACEs, although caution is advised, given the increased incidence of lower limb amputation in clinical trials of canagliflozin. CONCLUSIONS: Medical and lifestyle management of PAD should aim to improve functional outcomes and to reduce MACEs. Smoking cessation counseling or pharmacotherapy is recommended, although new strategies are needed. Whereas supervised exercise therapy is ideal, there can be barriers to clinical implementation. Other initiatives are being used as an alternative to walking-based supervised exercise therapy. More studies are required to investigate the role of intensive glycemic, blood pressure, and dyslipidemia control in patients with PAD. Overall, a multifactorial approach is recommended to alter the natural history of this condition.

Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial.

It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.

Lowering triglycerides to modify cardiovascular risk: will icosapent deliver?

Despite the clinical benefits of lowering levels of low-density lipoprotein cholesterol, many patients continue to experience cardiovascular events. This residual risk suggests that additional risk factors require aggressive modification to result in more effective prevention of cardiovascular disease. Hypertriglyceridemia has presented a considerable challenge with regard to understanding its role in the promotion of cardiovascular risk. Increasing evidence has established a clear causal role for elevated triglyceride levels in vascular risk. As a result, there is increasing interest in the development of specific therapeutic strategies that directly target hypertriglyceridemia. This has seen a resurgence in the use of omega-3 fatty acids for the therapeutic lowering of triglyceride levels. The role of these agents and other emerging strategies to reduce triglyceride levels in order to decrease vascular risk are reviewed.

Ongoing challenges for pharmacotherapy for dyslipidemia.

INTRODUCTION: While increasing evidence has led to lipid-modifying therapy achieving an important role in the treatment guidelines for the prevention of cardiovascular disease, these agents are suboptimally used and there remains a considerable risk of clinical events. Accordingly, there is a need to develop more effective lipid-modifying approaches in many patients. AREAS COVERED: A literature search was performed of topical manuscripts focusing on factors influencing use of established therapies and new agents in development that target a range of lipid factors. EXPERT OPINION: More intensive efforts are required to ensure that statin use is maximized in higher risk patients. A range of novel therapies, including proprotein convertase subtilisin kexin-type 9 and cholesteryl ester transfer protein inhibitors, may provide additional protection, although this remains to be established by clinical trials.

A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial).

BACKGROUND: A novel omega-3 formulation in free fatty acid form (OM3-FFA) has as much as 4-fold greater bioavailability than ethyl ester forms and reduces triglyceride (TG) levels in patients with severe hypertriglyceridemia. OBJECTIVE: This study was designed to evaluate the efficacy of adding OM3-FFA (2 or 4 g/d) to statin therapy for lowering non-HDL-C and TG levels in subjects with persistent hypertriglyceridemia and at high risk for cardiovascular disease. METHODS: In this double-blind, parallel-group study, 647 diet-stable patients with fasting TG levels ≥ 200 mg/dL and <500 mg/dL (treated with a maximally tolerated dose of statin or statin with ezetimibe) and at high risk for cardiovascular disease were randomized to 6 weeks of treatment with capsules of control (olive oil [OO]) 4 g/d, OM3-FFA 2 g/d (plus 2 g/d OO), or OM3-FFA 4 g/d. Assessments included fasting serum levels of lipids and apolipoproteins (apo); plasma concentrations of eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid; and laboratory safety values and adverse events. RESULTS: In the 627 subjects in the intention to treat sample, non-HDL-C levels were reduced with OM3-FFA 2 g/d and OM3-FFA 4 g/d (-3.9% and -6.9%, respectively) compared with OO (-0.9%) (both, P < 0.05), as were TG levels (-14.6% and -20.6%, respectively, vs -5.9%; both, P < 0.001). LDL-C levels increased with OM3-FFA 2 g/d (4.6%) compared with OO (1.1%) (P = 0.025) but not with OM3-FFA 4 g/d (1.3%). Total cholesterol and VLDL-C concentrations were reduced compared with OO with both OM3-FFA dosages, and the total cholesterol/HDL-C ratio and apo AI and apo B levels were significantly lowered with OM3-FFA 4 g/d only (all at least P < 0.05). Percent changes from baseline in HDL-C did not differ between OO and either OM3-FFA group. Plasma concentrations of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were significantly increased and arachidonic acid was significantly reduced in both OM3-FFA treatment groups compared with the OO responses (all, P < 0.001). Withdrawals related to treatment-emergent adverse events ranged from 0.9% with OO to 3.2% with OM3-FFA 4 g/d. CONCLUSIONS: OM3-FFA was well tolerated and lowered non-HDL-C and TG levels at both 2- and 4-g/d dosages in patients with persistent hypertriglyceridemia taking a statin, with the 4-g/d dosage providing incremental improvements compared with 2 g/d.

Epanova(®) and hypertriglyceridemia: pharmacological mechanisms and clinical efficacy.

While LDL-cholesterol lowering has become the cornerstone of cardiovascular risk reduction strategies, considerable interest in additional targeting of hypertriglyceridemia continues. While ω-3 fatty acids are commonly used in clinical practice for triglyceride lowering, no large-scale clinical trial evaluating their impact on clinical events has been performed. As a result, there remains a lack of consensus with regards to their optimal clinical use. Epanova(®) (Omthera Pharmaceuticals Inc., NJ, USA) is a novel ω-3 free fatty acid formulation, developed to maximize eicosapentenoic acid and docosahexenoic acid bioavailability with low-fat diets, suggesting a potential therapeutic advantage compared with ω-3-acid ethyl esters in the treatment of patients with hypertriglyceridemia. Additional human studies are needed to define more clearly the cellular and molecular basis for the triglyceride-lowering effects of Epanova and this drug's favorable cardiovascular effects, particularly in patients with hypertriglyceridemia.

Impact of statins on progression of atherosclerosis: rationale and design of SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: effect of Rosuvastatin versus AtorvastatiN).

BACKGROUND: Previous imaging studies have demonstrated that the beneficial impact of high-dose statins on the progression of coronary atherosclerosis associates with their ability to lower levels of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) and to raise high-density lipoprotein cholesterol (HDL-C). The Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus AtorvastatiN (SATURN, NCT00620542) aims to compare the effects of high-dose atorvastatin and rosuvastatin on disease progression. METHODS: A total of 1385 subjects with established coronary artery disease (CAD) on angiography were randomized to receive rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The primary efficacy parameter will be the nominal change in percent atheroma volume (PAV), determined by analysis of intravascular ultrasound (IVUS) images of matched coronary artery segments acquired at baseline and at 24-month follow-up. The effect of statin therapy on plasma lipids and inflammatory markers, and the incidence of clinical cardiovascular events will also be assessed. The study does not have the statistical power to directly compare the treatment groups with regard to clinical events. CONCLUSION: Serial IVUS has emerged as a sensitive imaging modality to assess the impact of treatments on arterial structure. In this study, IVUS will be used to determine whether high-dose statins have different effects on plaque progression.

Meta-analysis of comparative efficacy of increasing dose of Atorvastatin versus Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids (from VOYAGER).

Statins are the most commonly prescribed agents for lowering levels of low-density lipoprotein (LDL) cholesterol. Although dose-dependent reductions in levels of atherogenic lipids are observed with all statins, the impact of increasing dose has not been fully elucidated. An individual patient data pooled analysis was performed of 32,258 patients in studies comparing the efficacy of rosuvastatin with that of atorvastatin or simvastatin. The impact of increasing dose on lowering LDL cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B was investigated. Doubling the dose of each statin was accompanied by a 4% to 7% greater degree of lowering of all atherogenic lipids. A stronger correlation was observed between changes in LDL cholesterol and non-HDL cholesterol (r = 0.92, p <0.001) or apolipoprotein B (r = 0.76, p <0.001) than triglycerides (r = 0.14, p <0.001). On multivariate analysis, baseline lipid level (p <0.0001) and increasing statin dose (p <0.0001) were strong predictors of achieving treatment goals in high-risk patients. Increasing age was a strong independent predictor of achieving goal for all atherogenic lipids (p <0.0001). Achieving LDL cholesterol goals was also more likely in women (p <0.0001), patients with diabetes (p <0.0001), and patients without atherosclerotic disease (p = 0.0002). In contrast, normal triglyceride levels were more often observed in men (p <0.0001) and patients without diabetes mellitus (p = 0.03). In conclusion, doubling statin dose was associated with greater lowering of LDL cholesterol by 4% to 6% and non-HDL cholesterol by 3% to 6%. Greater lipid goal achievement with increasing dose supports the use of high-dose statin therapy for more effective cardiovascular prevention.

Rosuvastatin and progression of atherosclerosis.

Technological advances in arterial wall imaging have provided the opportunity to evaluate the impact of medical therapies on the progression of atherosclerosis in vivo. Arterial imaging has been extensively utilized to determine the impact of high-dose statin therapy. Using multiple imaging modalities in the carotid and coronary territories, rosuvastatin has been demonstrated to have a beneficial impact across the spectrum of cardiovascular risk. The impact of modifying levels of atherogenic lipids, HDL and markers of inflammation will be reviewed.