Evolving Management Paradigm for Stable Ischemic Heart Disease Patients: JACC Review Topic of the Week.

Management of stable coronary artery disease (CAD) has been based on the assumption that flow-limiting atherosclerotic obstructions are the proximate cause of angina and myocardial ischemia in most patients and represent an important target for revascularization. However, the role of revascularization in reducing long-term cardiac events in these patients has been limited mainly to those with left main disease, 3-vessel disease with diabetes, or decreased ejection fraction. Mounting evidence indicates that nonepicardial coronary causes of angina and ischemia, including coronary microvascular dysfunction, vasospastic disorders, and derangements of myocardial metabolism, are more prevalent than flow-limiting stenoses, raising concerns that many important causes other than epicardial CAD are neither considered nor probed diagnostically. There is a need for a more inclusive management paradigm that uncouples the singular association between epicardial CAD and revascularization and better aligns diagnostic approaches that tailor treatment to the underlying mechanisms and precipitants of angina and ischemia in contemporary clinical practice.

Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics.

The aims of this clinical review are to: (i) highlight the importance of elevated baseline triglycerides (TG) in the setting of well-controlled low-density lipoprotein cholesterol (LDL-C) on statins as a major contributor to residual atherosclerotic cardiovascular disease (ASCVD) risk, particularly among patients with type 2 diabetes mellitus, metabolic syndrome, and obesity whose distinctive lipid phenotype cannot be optimally treated with LDL-C reduction therapy alone; (ii) describe the findings and clinical implications of the landmark REDUCE-IT trial in which ethyl eicosapentaenoic acid significantly improved ASCVD outcomes. While many genetic studies have shown that elevated TG are an independent causal factor for ASCVD, prior placebo-controlled trials using niacin, fibrates, omega-3 fatty acids, and dietary supplement fish oil preparations have failed to demonstrate significant CV event reduction when added to statin therapy. In contrast, the REDUCE-IT trial in 8179 participants showed convincingly that the administration of 4 g daily of icosapent ethyl (an ethyl ester of eicosapentaenoic acid) in patients at high risk for ASCVD with increased levels of baseline TG [median value, 2.44 mmol/L (216.0 mg/dL)] but well-controlled LDL-C [median value, 1.94 mmol/L (75.0 mg/dL)] reduced significantly incident events across both the trial primary endpoint and multiple prespecified secondary endpoints, including cardiovascular death, as well as both subsequent and total primary endpoint and key secondary endpoint events. Icosapent ethyl unequivocally contributed to ASCVD event reduction over and above statin therapy. The REDUCE-IT trial results should alter our approach to managing a growing population of hypertriglyceridaemic patients whose lipid phenotype requires more intensive treatment beyond LDL-C lowering alone.

Unmet Need for Adjunctive Dyslipidemia Therapy in Hypertriglyceridemia Management.

Despite the important role of high-intensity statins in reducing atherosclerotic cardiovascular disease events in secondary and primary prevention, substantial residual risk persists, particularly among high-risk patients with type 2 diabetes mellitus, metabolic syndrome, and obesity. Considerable attention is currently directed to the role that elevated triglycerides (TGs) and non-high-density lipoprotein cholesterol levels play as important mediators of residual atherosclerotic cardiovascular disease risk, which is further strongly supported by genetic linkage studies. Previous trials with fibrates, niacin, and most cholesterol ester transfer protein inhibitors that targeted high-density lipoprotein cholesterol raising, and/or TG lowering, have failed to show conclusive evidence of incremental event reduction after low-density lipoprotein cholesterol levels were "optimally controlled" with statins. Although omega-3 fatty acids are efficacious in lowering TG levels and may have pleiotropic effects such as reducing plaque instability and proinflammatory mediators of atherogenesis, clinical outcomes data are currently lacking. Several ongoing randomized controlled trials of TG-lowering strategies with an optimal dosage of omega-3 fatty acids are nearing completion.

Reconsidering the Gatekeeper Paradigm for Percutaneous Coronary Intervention in Stable Coronary Disease Management.

Major randomized clinical trials over the last decade support the role of optimal medical therapy for the initial management approach for patients with stable coronary artery disease (CAD), whereas percutaneous coronary intervention (PCI) ought to be reserved for patients with persistent symptoms despite optimal medical therapy. Likewise, several studies have continued to demonstrate the superiority of coronary artery bypass grafting surgery over PCI in many patients with extensive multivessel CAD, especially those with diabetes. Nevertheless, the decision-making paradigm for patients with stable CAD often continues to propagate the upfront use of "ad hoc PCI" and disadvantages alternative therapeutic approaches. In our editorial, we discuss how multiple systemic and interpersonal factors continue to favor early revascularization with PCI in stable patients. We discuss whether the interventional cardiologist can be an unbiased "gatekeeper" for the use of PCI or whether other physicians should also be involved with the patient in decision-making. Finally, we offer suggestions that can redefine the gatekeeper role to facilitate an evidence-based approach that embraces shared decision-making.

The therapeutic role of niacin in dyslipidemia management.

There is abundant epidemiologic evidence to support the independent, inverse relationship between low levels of high-density lipoprotein cholesterol (HDL-C) and incident cardiovascular (CV) risk, the clinical importance of which is underscored by the high prevalence of low HDL-C in populations with coronary heart disease (CHD), with or without elevated levels of low-density lipoprotein cholesterol (LDL-C). The National Cholesterol Education Program recommended that optimal treatment for high-risk patients includes both lowering LDL-C and non-HDL-C to risk stratified levels and raising HDL-C when it is <40 mg/dL, although no target level for the latter lipoprotein was suggested. Niacin is the most powerful agent currently available for raising low levels of HDL-C. It also induces significant reductions in triglycerides, lipoprotein(a), and LDL-C levels while also favorably altering LDL particle size and number. In the Coronary Drug Project, niacin treatment was associated with significant reductions in CV events and long-term mortality, similar to the reductions seen in the statin monotherapy trials. In combination trials, niacin plus a statin or bile acid sequestrant produces additive reductions in CHD morbidity and mortality and promotes regression of coronary atherosclerosis. Recently, 2 clinical outcome trials (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes [AIM-HIGH] and Second Heart Protection Study [HPS-2 THRIVE]) failed to show a reduction in CV events in patients treated to optimally low levels of LDL-C. Despite favorable effects on HDL-C and triglycerides, these studies did not demonstrate incremental clinical benefit with niacin when added to simvastatin, although notable limitations were identified in each of these trials. Thus, there is insufficient evidence from clinical trials to recommend HDL-targeted therapy for additional event reduction at the present time. However, niacin should continue to be used as an adjuvant therapy for reducing atherogenic lipoprotein burden in patients who have not reached their risk stratified LDL-C and non-HDL-C targets.

A TACTful reappraisal of chelation therapy in cardiovascular disease.

Atherosclerotic cardiovascular disease (CVD) is highly prevalent and, despite therapeutic advances, remains a leading cause of morbidity and mortality. Many patients with CVD seek additional alternative therapies when symptoms are not controlled with evidence-based therapies. Although its therapeutic efficacy is unproven, chelation therapy with ethylenediamine tetra acetic acid (EDTA) is increasingly being used in patients with CVD. Early studies of chelation in atherosclerotic CVD provided the basis for the randomized Trial to Assess Chelation Therapy (TACT), in which chelation with disodium EDTA was compared with placebo in patients who had experienced a myocardial infarction. Here, we discuss the results, limitations, and implications of TACT in the context of other studies in the field. We believe that the findings from TACT are not robust and do not marshal evidence in support of the potential clinical use of chelation therapy for CVD, with the potential exception of certain high-risk cohorts such as patients with diabetes mellitus. Therefore, chelation is unlikely to become a widely-accepted approach until additional data are available.