PCSK9 inhibitors: a non-statin cholesterol-lowering treatment option

Elevated low-density lipoprotein cholesterol (LDL-C) plays a major role in the development of atherosclerotic cardiovascular disease. Statins are the first-line treatment to lower LDL-C in patients with hypercholesterolemia; however, some high cardiovascular risk patients may have inadequate responses to statin therapy or are intolerant to statins, and may need additional and/or alternative non-statin therapies to further reduce their LDL-C levels. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of circulating LDL-C levels, have received considerable attention as promising non-statin therapeutic options for the management of hypercholesterolemia. This review provides a brief overview of the history and science of PCSK9 inhibitors, focusing on two PCSK9 monoclonal antibodies that have been approved by the US Food and Drug Administration: alirocumab and evolocumab. Recently released and forthcoming clinical trial data will be discussed, as well as the practical application of patient populations that may benefit from PCSK9 inhibitors. Finally, the recent expert recommendations regarding the use of PCSK9 inhibitors and other non-statin therapies to treat patients with inadequate LDL-C-lowering on statin therapy will be summarized.     

New Directions in Managing Dyslipidemia

Statin therapy has long been the mainstay of dyslipidemia management due to superior reduction in morbidity and mortality from cardiovascular disease. However, many patients who take statins fail to meet low-density lipoprotein-cholesterol targets, have recurrent atherosclerotic cardiovascular disease, or are statin intolerant. Recent updates give guidance on prevention of atherosclerotic cardiovascular disease in all patients, including those for whom statin therapy is contraindicated or insufficient. Other classes of medications, such as ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, can lower low-density lipoprotein cholesterol and may also improve cardiovascular outcomes. This report explores dyslipidemia management guidelines, reviews the use of ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, and provides recommendations for nurse practitioners.     

Future directions in lipid therapies

Cholesterol management to reduce the burden of cardiovascular disease is a major public health concern. Despite widespread recognition of lipid abnormalities as cardiovascular risk factors, significant cardiovascular event reductions with cholesterol-lowering therapies, and dissemination of treatment guidelines, most high-risk patients are not at target lipid levels. In addition to lifestyle changes, four major drug classes are available to modify lipid levels: fibrates, niacin, resins, and statins. High efficacy and tolerability in clinical trials make statins the most widely prescribed of these agents. Newer, more potent members of this class and novel formulations of niacin and resins may provide more effective therapy for dyslipidemia with fewer side effects. Several agents in development (cholesterolabsorption inhibitors and ACAT inhibitors) exploit mechanisms of action complementary to those of current treatments and combined with statins may produce greater improvements in lipid profiles than are now possible. These innovations should enable a greater number of patients to achieve more aggressive cholesterol goals, thereby reducing the risk of cardiovascular events.     

Patient-based evaluations of primary care for cardiovascular diseases: a comparison between conventional and complementary medicine

Background Patients with chronic diseases, including cardiovascular conditions, increasingly rely on complementary and alternative medical (CAM) therapies. Objectives The Swiss Program for Complementary Medicine Evaluation offers a unique opportunity to analyse cardiovascular patients’ satisfaction with CAM and conventional medical (COM) therapies. The treatment choices of doctors certified in conventional as well as complementary therapies also could be studied. Methods A national observational evaluation on treatment satisfaction of patients consulting COM or CAM doctors. Out of this evaluation project, data related to patients with cardiovascular diseases were specifically analysed for patient satisfaction with treatment and outcome when treated by COM or CAM doctors. Results Of 199 included doctors (78 COM, 121 CAM) treating cardiovascular patients, COM doctors treated twice as many cardiovascular patients per doctor than CAM doctors. CAM doctors treated less than 1/3 of their cardiovascular patients solely by CAM, while they treated 42% exclusively by COM therapies. Patients seeing a CAM doctor had a significantly longer consultation and were more likely to be highly satisfied with overall treatment outcome and patient‐practitioner communication. Moreover, patients seeing a CAM doctor and being treated solely by a CAM therapy more often report ‘complete fulfilment of outcome expectation’ and ‘high overall satisfaction with treatment’, although their symptoms less often disappear totally than those of COM therapy‐treated patients. Conclusion CAM therapies are not the first treatment choice for cardiovascular diseases. However, even though CAM doctors preferentially apply COM therapies, cardiovascular patients treated by CAM doctors are more likely to be satisfied with the overall treatment outcome, possibly because of the longer and better patient–practitioner interaction.     

How Low to Go With Lipid-Lowering Therapies in a Cost-effective and Prudent Manner

The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol was a landmark document guiding health care professionals around the globe on how to administer lipid-lowering therapies. Those guidelines were primarily focused on statin therapy benefit groups. The writing committee found insufficient evidence for specific low-density lipoprotein cholesterol (LDL-C) treatment targets. There have been many important updates in the lipid literature since the publication of that document. Most importantly, clinical trials have provided definitive evidence for the pivotal role of LDL-C in atherogenesis and the improvement in clinical outcomes by means of aggressive LDL-C reduction. Ezetimibe, evolocumab, and alirocumab treatment resulted in substantial reductions in major adverse cardiovascular outcomes. These data encourage a discussion on whether LDL-C targets are warranted in primary and/or secondary prevention, and if so, how low should those targets be. In order to answer such questions, the costs and safety of such therapies, as well as the safety of very low levels of LDL-C need to be addressed. This review discusses the relationship between LDL-C lowering and cardiovascular risk reduction, the efficacy, safety, and cost-effectiveness of high-intensity lipid-lowering therapies, and the recommendations from the most recent lipid guidelines.     

Incorporation of PCSK9 inhibitors into prevention of atherosclerotic cardiovascular disease

Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) has become recently more complex than ever, leaving the clinicians perplexed with outdated guidelines and emerging evidence about new LDL-C lowering therapies. 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines have focused on high intensity statin therapy for specific groups of patients, while abandoning long established LDL-C goals, a strategy which no longer seems valid. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors have emerged as the add-on therapy on top of statins and/or ezetimibe for the treatment of hypercholesterolemia and ASCVD prevention. In several clinical trials, PCSK9 inhibitors have demonstrated their safety and robust LDL-C-lowering power. One completed cardiovascular (CV) outcomes trial (FOURIER; Further Cardiovascular Outcomes Research with PCSK9 Inhibitions in Subjects with Elevated Risk) has demonstrated that PCSK9 inhibition reduces rates of CV death as well as non-fatal stroke and MI, while another major CV outcome trial is under way (ODYSSEY-OUTCOMES). Several trials studying CV benefits of novel LDL-C-lowering therapies are also being conducted. Prompt revision of ACC/AHA guidelines is necessary. In the meantime, physicians need to use clinical judgment integrating the most recent evidence into their practice.     

Practical Considerations for the Use of Subcutaneous Treatment in the Management of Dyslipidaemia

Suboptimal drug adherence represents a major challenge to effective primary and secondary prevention of cardiovascular disease. While adherence is influenced by multiple considerations, polypharmacy and dosing frequency appear to be rate-limiting factors in patient satisfaction and subsequent adherence. The cardiovascular and metabolic therapeutic areas have recently benefited from a number of advances in drug therapy, in particular protease proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and incretin-based therapies, respectively. These drugs are administered subcutaneously and offer efficacious treatment options with reduced dosing frequency. Whilst patients with diabetes and diabetologists are well initiated to injectable therapies, the cardiovascular therapeutic arena has traditionally been dominated by oral agents. It is therefore important to examine the practical aspects of treating patients with these new lipid-lowering agents, to ensure they are optimally deployed in everyday clinical practice.     

Erectile dysfunction and statin treatment in high cardiovascular risk patients

Erectile dysfunction (ED) has been associated with risk factors for atherosclerosis. Medications used for atherosclerosis have also been implicated in ED. The aim of this study is to investigate the relationship of erectile function to cardiovascular risk factors and specific drug therapies before and after 6 months of statin therapy. In this prospective observational study, International Index of Erectile Function (IIEF) scores were measured in 93 men attending cardiovascular risk clinics. Cardiovascular risk factors and drug therapies were assessed prior to initiation and after 6 months of statin therapy. Prior to statin therapy, the median IIEF score was 21 (range 0-25), and 57% had impairment of erectile function. After statin therapy, IIEF scores were reduced to 6.5 (range 0-25) (p < 0.001), and 22% experienced new onset ED. Before statin therapy no correlation was observed between IIEF score and any individual cardiovascular risk factor. After 6 months of statin therapy, correlations were observed between lower IIEF scores (r = 0.62; p < 0.001) and age and diabetes and weakly with smoking. Differences in dose, relative efficacy or relative lipophilicity of statin prescribed showed no correlation with change in IIEF score. This study suggests ED following statin therapy is more likely in patients with severe endothelial dysfunction due to established cardiovascular risk factors including age, smoking and diabetes.     

The care gap: underuse of statin therapy in the elderly

Atherosclerotic diseases are responsible for the majority of deaths in the elderly, and they can also increase the risk of disability. Statins are first-line therapies for lowering lipid levels and have been shown to reduce the risk of cardiovascular events in large-scale clinical trials. There is a growing body of evidence that statins are as efficacious at lowering lipid levels and reducing the risk of coronary heart disease (CHD) in elderly patients as in younger individuals. Furthermore, as this population is at a greater absolute risk of CHD, they may receive greater absolute benefits from treatment. However, despite these benefits, many elderly individuals at risk of CHD and stroke are not receiving adequate lipid-lowering therapy, which could help them to maintain their health and independence. Further, prospective randomised trials are required to guide physicians in the treatment of elderly patients at risk of atherosclerotic disease, thereby resolving the current undertreatment.     

Novel pharmacotherapies of familial hyperlipidemia

Familial hyperlipidemia is an inherited metabolic disorder characterized by elevated lipid and/or lipoprotein levels in the blood. Despite improvements in lipid-lowering therapy during the last decades, it still remains a substantial contributor to the incidence of cardiovascular disease since patients on current conventional therapies do not achieve their target LDL-cholesterol levels. With a view to lower LDL-cholesterol levels, a number of new therapeutic strategies have been developed over recent years. In this review, we provide an overview of these treatment options that are currently in clinical development and may offer alternative or adjunctive therapies for this high-risk population.     

Treatment of patients with diabetes with GLP-1 analogues or DPP-4- inhibitors: a hot topic for cardiologists?

Novel drugs for the treatment of patients with diabetes are of interest for cardiologists if they reduce the risk of cardiovascular events. However, as documented by the current discussion about the potential benefits of glitazones, high hopes can fail. Initial beneficial cardiovascular effects shown in proof-of-concept studies were muted by the apparent higher mortality in the metaanalysis of studies with rosiglitazone. Having this in mind, how should one judge about new, emerging antidiabetic therapies, in particular those influencing the incretin axis? The rapidly increasing use of GLP-1 analogues and DPP-4 inhibitors for the treatment of type 2 diabetes mellitus may be of major interest for the cardiologist. Potential beneficial actions on the cardiovascular system so far shown in animal experiments and small proof of concept studies may provide the rationale for using these drugs specifically in diabetic patients with secondary complications such as macrovascular disease or diabetic cardiomyopathy. Theoretically, these new therapies could also proof beneficial in patients with heart failure, independently of concomittend diabetes mellitus. However, many unanswered questions need to be addressed in the near future to extend the experimental findings to potential benefits of real life patients. In summary a new class of antidiabetic drugs, which could possibly directly influence cardiovascular effects of diabetes mellitus and thus possibly treat or even prevent life threatening complications has become available. Further studies both assessing surrogate parameters as well as hard endpoint studies are needed to support the hypothesis generated from the summarized experimental studies.     

Cardiovascular biomarkers and surrogate end points: key initiatives and clinical trial challenges

Biomarkers have proven to be critical tools in both cardiovascular clinical practice and clinical research. In clinical practice, biomarkers are used to identify patients at risk for disease, stratify disease severity, guide intervention decisions and monitor patient response to therapy. Biomarkers are also used extensively to improve the design of cardiovascular clinical trials, identify ‘at-risk’ populations, allow for preliminary screening for response, identify appropriate dose ranges, study subgroup differences and identify early safety concerns. The purpose of this paper is to describe current key cardiovascular biomarker initiatives and to outline some of the important considerations in applying these biomarkers in a clinical trial setting, utilizing the examples of HDL cholesterol, HDL-targeted therapies and imaging tools used to assess HDL-targeted therapies as a case study.     

Cardiovascular disease

The primary care physician is in a position to advise patients on the efficacy of alternative and complementary therapies as they relate to cardiovascular diseases. Anti-oxidant vitamin supplementation has not been shown to be efficacious in decreasing cardiovascular events. N-3 fatty acids appear to be beneficial in secondary prevention of cardiovascular events but their use in primary prevention is not clear. Adoption of vegetable-based diets, including whole grains, can be recommended to decrease cardiovascular events, lower cholesterol and help lower blood pressure. For patients with hypercholesterolemia, cholestin, a red-yeast rice supplement, has been shown to be effective. Garlic supplements may have some mild cholesterol-lowering effect, but this effect is not significant enough to recommend clinically. Herbal therapies with hawthorn and ubiquinone (Q10) are of possible benefit in congestive heart failure. An integrated program of rigorous diet, exercise and stress reduction in motivated patients with cardiovascular disease may have value as an alternative to cardiovascular medications and surgical interventions.     

Current status of statin therapy for stroke prevention

Stroke is a leading cause of mortality and long-term disability in the Western world. Lipid abnormalities are a key risk factor for stroke, elevated LDL-cholesterol being the most common abnormality. No clear association has been demonstrated between elevated LDL-cholesterol and stroke incidence, possibly due to the lack of appropriate etiopathophysiological classification of stroke in most studies. Nonetheless, statin therapy is associated with significant reduction in first and recurrent stroke, and there remains a net benefit despite a significant but small increase in hemorrhagic stroke. Following a stroke, indirect evidence supports continuation of prestroke statin therapy while the impact of de novo statin therapy in acute stroke remains uncertain. International guidelines advise an objective assessment of cardiovascular risk to determine the appropriateness of statins for primary prevention and near universal use of statins for secondary prevention after the acute phase of ischemic stroke. There is lack of consensus with regard to the choice of agent, timing of initiation, dose and duration of therapy. Some guidelines advocate high-dose atorvastatin while others suggest the use of simvastatin owing to generic availability and low cost. While the benefits of preventive interventions for stroke are well established and clearly outlined in international guidelines, there is poor application of such measures in clinical practice. This article summarizes the current understanding of the role of statins in stroke prevention and early studies of potential interventions to overcome the barriers to effective statin therapy for secondary prevention. There is a clear need for further research into identifying deficiencies in long-term management, barriers to optimal secondary prevention and novel interventions to overcome these barriers.     

Impact of Xuezhikang on coronary events in hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS)

Abstract

Background. The lowering of cholesterol concentrations in individuals at high risk for cardiovascular disease improves clinical outcome. Xuezhikang has a marked impact on lipids.

Methods. In this randomized, double-blinded, placebo-controlled, parallel-group clinical trial, a total of 2704 hypertensive patients with previous myocardial infarction (MI) were assigned either to placebo (n = 1341) or to Xuezhikang (0.6 g twice daily, n = 1363) for an average of 4.5 years. The primary end-point was recurrent coronary events; the secondary end-point was all-cause mortality and other clinical events, including adverse effects.

Results. There were no differences between the Xuezhikang and placebo group in base-line characteristics. However, Xuezhikang treatment reduced the incidence of coronary events by 43.0% (P = 0.02), deaths from coronary heart disease (CHD) by 30.0% (P < 0.01), and all-cause mortality by 35.8% (P = 0.001).

Conclusions. This study, for the first time, demonstrated that long-term Xuezhikang therapy resulted in significant reduction in cardiovascular events and death in Chinese hypertensive patients with previous MI in a safe manner.     

Dyslipidemia: Current Therapies and Strategies to Overcome Barriers for Use

Dyslipidemia continues to be a major predictor of adverse cardiovascular outcomes in patients with risk factors as well as diagnosed atherosclerotic cardiovascular disease. Recent clinical trials and national guidelines from the US Preventive Services Task Force, American College of Cardiology, and American Heart Association have reinforced a paradigm shift from quantitative reduction of low-density lipoprotein cholesterol targets to prevention and risk factor reduction. Optimized medical therapies have become more inclusive of patients in both the primary and secondary care settings. Although statins continue to be a cornerstone of all recommended therapeutic options, many barriers to patient adherence with medical therapy exist. As medical options change to include the newer lipid-lowering treatments, patient adherence and provider practice challenges can diminish the benefits these medications offer. Although the phenomenon of adherence is complex, multidisciplinary teams, technology, improved communication, prior authorization, step-wise approaches, and the streamlining of the appeal process have shown benefit to mitigate cardiovascular disease-related sequelae. A current overview of practitioner barriers such as organizational restrictions, as well as patient challenges such as poor health literacy and poverty, are examined. Collaborative, multidisciplinary planning and interventions are reviewed with suggestions to increase patient adherence and optimize treatment regimens. This article reinforces existing knowledge while providing new insights to these issues.     

Guidelines on the management of secondary prophylaxis of vascular events in stable patients in primary care

Atherothrombosis, thrombus formation superimposed on an existing atherosclerotic plaque, is an acute process leading to ischaemic events such as myocardial infarction, stroke and critical limb ischaemia. Patients presenting with clinical conditions associated with atherothrombosis are at increased risk of subsequent vascular events. The beneficial effect of antiplatelet therapies for short-term and long-term secondary prevention of atherothrombotic events has been established. These guidelines aim to provide evidence-based recommendations that will assist in the antiplatelet-mediated secondary prophylaxis of vascular events in patients with stable cardiovascular disease treated in the primary healthcare setting. Medline and the Cochrane library were accessed using free-text strategies in the domains of antiplatelet agents and antithrombotics. Development of the guidelines was driven by a series of Steering Committee meetings, in which the quality of relevant studies was assessed and identified using narrative summary. These guidelines present evidence and recommendations for the treatment of numerous atherothrombotic indications depending on individual patient circumstances.     

Platelet activation in myocardial ischemic syndromes

Platelets play a central role in the pathogenesis of atherosclerois and thrombosis. Platelet adhesion and aggregate formation are critical events that occur in unstable coronary syndromes. Platelet activation precedes the formation of homotypic and heterotypic aggregates. In the last 10 years, researchers have described the presence of activated platelets in the systemic circulation in various cardiovascular disease states, particularly acute coronary syndromes. This review describes the evidence for platelet activation in acute myocardial ischemic syndromes, describes the pathophysiology responsible for its occurrence, and discusses how platelet activation and reactivity may affect the use of concomitant drug therapies and patient prognosis.     

Electrospinning of biomimetic scaffolds for tissue-engineered vascular grafts: threading the path

Tissue-engineered vascular grafts (TEVGs) offer an alternative to synthetic grafts for the surgical treatment of atherosclerosis and congenital heart defects, and may improve graft patency and patient outcomes after implantation. Electrospinning is a versatile manufacturing process for the production of fibrous scaffolds. This review aims to investigate novel approaches undertaken to improve the design of electrospun scaffolds for TEVG development. The review describes how electrospinning can be adapted to produce aligned nanofibrous scaffolds used in vascular tissue engineering, while novel processes for improved performance of such scaffolds are examined and compared to evaluate their effectiveness and potential. By highlighting new drug delivery techniques and porogenic technologies, in addition to analyzing in vitro and in vivo testing of electrospun TEVGs, it is hoped that this review will provide guidance on how the next generation of electrospun vascular graft scaffolds will be designed and tested for the potential improvement of cardiovascular therapies.     

Cardiovascular risk reduction: What do recent trials with rosuvastatin tell us?

Abundant evidence from large-scale clinical trials supports the importance of lowering low-density lipoprotein cholesterol (LDL-C) to decrease the risk of cardiovascular disease (CVD) events. The LDL-C targets in various guidelines remain important treatment goals but, even in trials where statin therapy achieves substantial reduction of LDL-C, a significant number of CVD events still occur and the residual risk remains high. These findings suggest that lipid parameters other than LDL-C, such as high-density lipoprotein cholesterol (HDL-C), triglycerides, and LDL particle size, can influence the risk of CVD. On this basis, other strategies that can alter the lipid profile, in particular raising HDL.C, may provide additional benefits. Other factors such as HDL-C functionality and susceptibility to oxidation and inflammatory factors can also influence cardiovascular risk. In addition to the modifications of the lipid profile, statins have cholesterolindependent beneficial pleiotropic effects. The contribution of these effects to event reduction is not yet fully understood. Recently, the body of evidence has expanded to support the use of intensive statin therapy in broader patient populations. The JUPITER trial has shown the benefit of intensive statin treatment in low-risk subjects with high levels of high-sensitivity C-reactive protein and average levels of LDL-C. Unlike the setting of primary and secondary prevention, the results of statin trials in patients with heart failure have shown no clear benefit in terms of survival. The recently published AURORA trial was carried out to investigate the effect of rosuvastatin in patients with end-stage renal disease undergoing chronic hemodialysis. In this trial no benefit on cardiovascular events was shown with statin therapy. In conclusion, large outcomes trials have clearly shown that statin treatments have a favorable benefit/risk profile in a large range of patients at different levels of risk, with the exception of patients with heart failure and those with renal disease undergoing dialysis. Further evidence is needed on the role of therapeutic strategies on the so-called residual risk.