atherosclerotic

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Adding to Statins: Achieving Optimum Reduction of “Bad” Cholesterol

Khairunnisa Semesta, MA

Atherosclerotic cardiovascular disease (ASCVD) is the number one cause of death in the Western world.[1] Since 2016, cardiovascular diseases have caused 1 in 3 deaths in the United States, and this trend is expected to continue in the future. There is a well-established relationship between ASCVD and elevated levels of low-density lipoprotein C (LDL-C), often called “bad” cholesterol because of its potential to accumulate in the blood vessels and contribute to the formation of fat plaques.[2] People with familial hypercholesterolemia (an autosomal dominant genetic disease caused by mutations in the LDLR, LDLRAP, APOB, and PCSK9 genes)[3] are also at risk for ASCVD due to their genetic predisposition to high cholesterol levels.

Currently, the standard of care is statin, a group of drugs that inhibits the HMGR enzyme, a key player in the cholesterol synthesis pathway. Over 55% patients undergo statin management to lower their LDL-C levels and consequently reduce morbidity and mortality.[4] However, 7 out of 10 patients on statins do not achieve their LDL-C goal. In addition, patients on statins still have residual risk of experiencing cardiovascular events and premature mortality.[5] This is due to multiple factors: nonadherence to statin management, which typically is consumed daily; drug intolerance due to the development of statin-associated muscle symptoms[6]; heterogeneity in response[7]; and others. As such, patients who are unable to control their cholesterol levels on maximum statin dose typically require an additional therapy.

Exploring additional therapies for patients who are unable to control their cholesterol levels on statins alone is the goal of the Add on Efficacy: Oral, Nonstatin Therapies for Lowering LDL-C Program in Scientific Sessions 2021, presented by Harold Bays, MD (Medical Director and President of the Louisville Metabolic and Atherosclerosis Research Center) and sponsored by Esperion Therapeutics. Until 2020, there was only one FDA-approved oral nonstatin therapy for ASCVD management: a drug called ezetimibe, which inhibits intestinal cholesterol absorption.[8] In 2020, bempedoic acid (Nexletol™) and bempedoic acid plus ezetimibe (Nexlizet™) were approved as adjuncts to diet and maximally tolerated statin therapy for patients with ASCVD or familial hypercholesterolemia who require additional lowering of LDL-C. Bempedoic acid inhibits ACL, a key enzyme in the cholesterol synthesis pathway. By week 12 of treatment, bempedoic acid and the combination of bempedoic acid and ezetimibe led to 17-18% and 38% and mean reduction of LDL-C, respectively, compared to patients given placebo and maximally tolerated statin dose.

Although statins have typically been the first line therapy for the management of ASCVD, current trends point to the need of developing additional and orthogonal therapies to achieve optimal LDL-C levels. To this end, multiple therapies are used clinically, including oral medications like bempedoic acid, ezetimibe, and bile acid sequestrants as well as other forms of therapeutics like PCSK9-inhibiting antibodies.[9] Beyond this session on non-statin therapies, Scientific Sessions 2021 provides other updates on current clinical management and emerging breakthroughs in cardiovascular health – make sure you tune in to other sessions on November 14-15, 2021!

Reference

[1] Nichols M, et al. (2014) Eur Heart J 35:2950–9

[2] Mihaylova, B. et al. (2012) Lancet 380:581–90

[3] Bouhairie, V. E. and Goldberg, A. C. (2015) Cardiol Clin 33.2: 169-79

[4] Bittner, V. et al, (2015) Journal of the American College of Cardiology, 66.17: 1873-1875

[5] Go, A. S., et al. (2014) Circulation 129: e28-e292

[6] Ward, N. C., et al. (2019) Circ Res 124:328–350

[7] Akyea, R. K. et al. (2019) Heart 105:975–981

[8] Miura, S. and Saku, K. (2008) Intern Med 47.13: 1165-1170

[9] Gupta, M. et al. (2020) Expert Opin investing Drugs 29(6):611-622.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

 
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AHA Scientific Statement on Diagnosis and Management of Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA)

Sivabaskari Pasupathy, PhD

Pathophysiology of a classic acute MI is attributed to the concept of coronary atherothrombosis leading to myocardial ischaemia and ultimately infarction. The overall prognostic benefit with coronary revascularization has been established in these patients. Recently, there is a significant research and clinical interest in acute MI presentations without evidence of significant atherothromotic lesions, so that revascularization therapies are considered inappropriate. These presentations are referred as Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) and is now an established clinical entity. The AHA just released the first scientific statement on diagnosis and management of MINOCA and is an important read1. The document provides the first formal updated definition of MINOCA and clinically useful framework and algorithms for the diagnostic evaluation and management of these patients.

The key points from the statement are:

 

The diagnosis of MINOCA is made in patients with acute MI due to myocardial ischemia.

  1. Acute myocardial infarction as per the “Fourth Universal definition of MI” Criteria
  2. Nonobstructive coronary arteries on angiography: the absence of obstructive disease on angiography (ie, no coronary artery stenosis ≥50%) in any major epicardial vessel
  3. No specific alternate diagnosis for the clinical presentation: Alternate diagnoses include but are not limited to non-ischemic causes such as sepsis, pulmonary embolism, and myocarditis

 

The “Traffic Light” Sequence for the Diagnosis of MINOCA.

Involving a clever adaptation of traffic light sequence, a very detailed diagnostic algorithm was provided for the diagnosis of MINOCA.

Red:  to exclude myocardial injury causes without ischemic context (Eg: Sepsis, Pulmonary Embolism)

Yellow: to exclude clinically subtle non-ischemic mechanisms of myocardial injury (Eg: Clinically overlooked CAD, Takotsubo, Myocardits)

Green: the final diagnosis of MINOCA is made upon a clear evidence of an ischemic context.

 

 

Specific causes of MINOCA Presentations: Atherosclerotic vs Nonatherosclerotic Causes of Myocardial Necrosis

Plaque disruption:

  • Reported in approximately 1/3 of MINOCA undergoing IVUS.
  • Authors recommend invasive imaging studies (IVUS or OCT) if available

Coronary Spasm:

  • Reported in approximately 50% of MINOCA undergoing provocative spasm testing.
  • Predilection for spasm in Asians compared with Caucasians.
  • Spasm testing appears to be safe in MINOCA cohort.

Microvascular Dysfunction:

  • Need to be studied in MINOCA population

Coronary embolism/Thrombosis:

  • Consider the inherited hypercoagulable states in patients with MINOCA, especially in younger women

Spontaneous Coronary Artery Dissection

  • Rare
  • Should be suspected mainly in young women

 

 

Management strategies for MINOCA

Given that there is currently no randomized clinical trials or guidelines on treating MINOCA, the statement suggests careful considerations in managing patients. Overall, a ‘working diagnosis’ approach should be adopted, with cardioprotective therapies and treatments targeting the underlying cause considered.

 

The full AHA statement on MINOCA can be found here.

 

Reference:

  1. Tamis-Holland Jacqueline E, Jneid H, Reynolds Harmony R, Agewall S, Brilakis Emmanouil S, Brown Todd M, Lerman A, Cushman M, Kumbhani Dharam J, Arslanian-Engoren C, Bolger Ann F, Beltrame John F and null n. Contemporary Diagnosis and Management of Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease: A Scientific Statement From the American Heart Association. Circulation. 0:CIR.0000000000000670.
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What Do The New Lipid Guidelines Mean For Patients?

Elizabeth Knight, PhD, DNP

One of the highly anticipated stories for Scientific Sessions 2018 was the new lipid guidelines. Following the reactions on Twitter during the session, I read a lot of opinions on CAC scoring and the pros and cons of its use to further stratify those at intermediate risk. Also trending – when to target LDL-C, now that thresholds are back on the table. These are the kinds of topics that typically get a lot of attention: which drugs, which targets, which tests? Conveniently, tests and prescriptions are also reasonably easy for clinicians to implement in practice.

In addition to my work as a nurse scientist, I’m a primary care provider who works with undeserved, often uninsured patients. CAC scores are, frankly, not highly relevant to my practice (at least until you can get them for $4 at Walmart). There were, however, two aspects of the new guidelines that caught my attention as a clinician serving this population. First, that it’s officially OK to measure non-fasting lipid levels. Second, that a clinician-patient discussion is recommended before initiating statin therapy for primary prevention. While these topics may seem entirely separate,  both are highly relevant to patient experiences of care. Primary prevention of ASCVD (or any condition) hinges on clinician-patient interaction because by definition, these patients are not yet sick. They have to buy in, and they do so (or not) based on their experiences with us as their care providers. Which dose of which medication to prescribe is irrelevant if a patient does not wish to take it.

The implications of non-fasting labs for patients are not hard to grasp, but this change will particularly impact patients who face barriers to care including transportation issues and the inability to take time off work. It’s a more impactful change that seems to remove a barrier to high-quality care, and I’m glad to see it.

The risk discussion, though not new, is more complex. Per the guidelines, it should include “a review of major risk factors (cigarette smoking, elevated blood pressure, LDL-C, hemoglobin A1C, and calculated 10-year risk of ASCVD); the presence of risk-enhancing factors; the potential benefits of lifestyle and statin therapies; the potential for adverse effects and drug–drug interactions; consideration of costs of statin therapy; and patient preferences and values”. Did you get all that? Now, imagine that you don’t have any medical or scientific background. You’ve been sitting in the waiting room for an hour, you skipped breakfast because you were getting fasting labs, and you are feeling a little nervous. Your doctor is talking fast because she’s running behind. Does this sound familiar? Is the review of major risk factors going well? Is it conducive to shared decision-making and buy-in?

My point isn’t that we can’t or shouldn’t have the conversation about risk, but that we need to find effective ways to have this conversation even though we face constraints on our time. A conversation, according to Merriam-Webster online, is an “oral exchange of sentiments, observations, opinions, or ideas”. Key word: exchange. The literature shows us different ways to communicate risk to patients, although we don’t have consistent data on what works and what doesn’t, and for whom. Yet even if we identify methods for us to best communicate the information, we still need to receive information from the patient and incorporate that into our ultimate shared decision. This is not easy. It will require a broader kind of work to improve. To effectively implement these guidelines will require work to understand how patients understand and how clinicians spend limited time. These guidelines use science to guide us in what to do– now we need science to help us learn how to do it.

Image: text from “Top 10 Take-Home Messages to Reduce Risk of Atherosclerotic Cardiovascular Disease Through Cholesterol Management” displayed by frequency via WordItOut (worditout.com)

 

Source: Grundy SM, et al. 2018 Cholesterol Clinical Practice Guidelines: Executive Summary
https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000624