Dyslipidemia/Venous Thromboembolism/Stroke Treatments and Education

Topic XII: Dyslipidemia / Venous Thromboembolism / Stroke
Introduction
DYSLIPIDEMIA
Cholesterol, whether synthesized endogenously or obtained from dietary sources, serves many important biological functions.
Dyslipidemia is a term, often used incorrectly, to denote elevated cholesterol. More correctly, dyslipidemia is a metabolic disorder that involves elevations in any lipoprotein (plasma lipid) such as VLDL, IDL, LDL, or chylomicrons. These lipoproteins consist of non-polar lipids (e.g., triglycerides, cholesteryl esters, free cholesterol) and apolipoproteins that provide for solubility, structural stability and serve as receptor ligands. Some apolipoproteins (e.g., (apo)-B100) are responsible for conveying lipids into arterial walls.
Accumulation, modification (oxidation) and transformation of lipoproteins are involved in the development of atherosclerotic plaques. Consequences then include ischemic heart disease, peripheral artery disease and acute coronary syndromes.
The medications used in the management of dyslipidemias include:
HMG-Co A Reductase Inhibitors ("statins")
Bile acid sequestrants
Fibrates
Niacin
Absorption inhibitors
Omega-3 fatty acids
PCSK9 Inhibitors
Understanding of mechanism of action, rational combination, effect on various lipoproteins, side effects, contraindications and drug interactions are essential to proper use of these agents.
Until recently, treatment was based on guidelines issued in 2001 (updated in 2004) by the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATP III). ATP III is the summation of several decades of research on the relation of atherogenic lipoproteins to atherosclerotic cardiovascular disease (ASCVD). It is based on the concept that lowering atherogenic lipoproteins will prevent ASCVD. ATP III uses a stepwise approach
Determine lipoprotein level
Identify presence of coronary heart disease or equivalent
Identify presence of risk factors for coronary heart disease, exclusive of LDL, in those without coronary heart disease or equivalent
Estimate risk and determine risk category
Using Framingham Calculator
Initiate lifestyle modification
Add drug therapy if LDL is above "goal"
Identify metabolic syndrome and treat
Treat elevated triglycerides
Consider non-LDL "goals"
In 2013, the Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Vascular Risk in Adults was issued by the American college of Cardiology / American Heart Association. This guideline is fundamentally different than ATP III. These guidelines are based on high quality evidence and the use of "statins" alone to reduce LDL from baseline (NOT to a goal) and to reduce the risk of ASCVD. Patients are a candidate for therapy if they fall into a statin benefit group:
Clinical ASCVD
Primary elevations of LDL-C ≥ 190 mg/dl
Diabetics age 40-75 with LDL-C 70-189 mg/dl
Non-diabetics without clinical ASCVD age 40-75 with LDL-C 70-189 mg/dl and estimated risk of ASCVD ≥ 7.5%
Usin the pooled cohort risk estimator
Since the publication of the 2013 ACC/AHA cholesterol guidelines, a recent manuscript entitled “2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk” was published. RCTs evaluating the safety and efficacy of non-statin therapies have provided important information regarding the potential benefits and harms of these agents in ASCVD risk reduction when used in combination with evidence-based statin therapy. This Expert Consensus Decision Pathway addresses current gaps in care for LDL-C lowering to reduce ASCVD risk and recommendations build on the evidence base established by the 2013 ACC/AHA cholesterol guideline. The recommendations attempt to provide practical guidance for clinicians and patients regarding the use of non-statin therapies to further reduce ASCVD risk in situations not covered by the guideline until such time as the scientific evidence base expands and cardiovascular outcomes trials are completed with new agents for ASCVD risk reduction.
The 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA (Multisociety) Guideline on the Management of Blood Cholesterol (aka 2018 Cholesterol Management Guideline) updates the 2013 guideline incorporating recommendations of the National Lipid Association (NLA), previous focused updates to the 2013 guideline, and newly available randomized controlled trials. Key components of these recommendations include:
Emphasis is on heart-healthy lifestyle for all, particularly younger individuals. Further supported by updated U.S. Preventive Services Task Force in late 2020
Four statin benefit groups: a. Clinical ASCVD:
History of acute coronary syndrome, MI, stable or unstable angina, coronary or arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease
Primary severe hypercholesterolemia (LDL-C 190 mg/dL or greater)
Patiets with diabetes age 40-75 and LDL-C of 70-189 mg/dL
Primary prevention (in select patients after assessment with PCE to estimate 10-year ASCVD risk)
First-line therapy for patients with clinical ASCVD continues to be high-intensity (or maximally tolerated) statin therapy.
In patients at very high risk (i.e., recurrent ASCVD events) and in whom LDL-C remains greater than 70 mg/dL, adding non-statins for further LDL-C reduction is reasonable. This recommendation incorporates findings from IMPROVE-IT (with ezetimibe) and ODYSSEY OUTCOMES and FOURIER (with the PCSK9 monoclonal antibody therapies alirocumab and evolocumab, respectively) trials.
Provide further guidance on clinician-patient risk discussion in patients for primary prevention and to guide statin intensity in those with diabetes with risk enhancers.
Increase emphasis on repeated lipid measurements
It is important to note the National Lipid Association (NLA) has endorsed the most recent 2018 cholesterol management guidelines
Together, these guidelines should be used to guide clinical judgment.
"Clinical practice guidelines are statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options"
-- Institute of Medicine 2011
VENOUS THROMBOEMBOLISM
Venous Thromboembolism (VTE) is formation of a clot in the venous vasculature due to stasis in blood flow (e.g., immobility, obesity, surgery), vascular damage (e.g., trauma, surgery) or coagulopathy (e.g., cancer, antiphospholipid syndrome, pregnancy). Other risk factors include age, prior VTE and some medications. VTE's are referred to as provoked as in the case of immobility or unprovoked as in the case of clotting disorders and manifest as either deep vein thrombosis (DVT) or pulmonary embolism (PE).
Identification of at risk individuals and prevention should be the primary focus. Measures utilized are non-pharmacologic (mechanical) and pharmacologic (anticoagulants). Pharmacologic possibilities include unfractionated heparin, low molecular weight heparins (dalteparin, enoxaparin), factor Xa inhibitors (fondaparinux, rivaroxaban, apixaban), direct thrombin inhibitors (dabigatran, bivalirudin) and warfarin. All of these agents have a narrow therapeutic index dictating the practitioner be an expert in their use.
Treatment of a VTE, following a definitive diagnosis, also utilizes the same medications just described. If warfarin is to be used, it should be overlapped with unfractionated heparin or LMWHs until a therapeutic INR is obtained because during the initiation of warfarin, a transient state of hypercoagulability is induced. The immediate goal of therapy is to prevent further clot formation, embolization and death while long term goals are to prevent sequelae and recurrent DVT's.
Statement regarding the use of various anticoagulants is NOT meant to imply all agents are appropriate in all patient populations, are interchangeable or carry FDA approval for all indications.
Choosing a specific strategy for prevention or treatment requires that the clinician consider not only the indication and patient's specific risk, but other factors as well: guidelines, emerging therapies, appropriate dosing, route of administration, comorbidities (e.g., renal impairment), contraindications (e.g., pregnancy), potentially serious side effects, drug interactions, the availability of antidotes, the need for monitoring, length of therapy and patient education.
STROKE

The focus of this course will be on primary and secondary prevention of acute ischemic stroke, a condition that results from cerebral vascular occlusion either by thrombus formation at the site of blockage or emboli that dislodged from non-cerebral source (e.g., cardioembolic).
As with most disease states, there are both modifiable and nonmodifiable risk factors. (Primary) Prevention begins with non-pharmacological interventions that address modifiable risk factors such as smoking cessation, physical inactivity and excess alcohol consumption. Pharmacologic management identifies comorbid conditions such as hypertension, dyslipidemias, diabetes and atrial fibrillation and whose goal it is to use medications that will 1) treat those conditions, 2) provide benefits beyond the immediate indication (pleiotropic effects) and 3) reduce the risk of stroke. Low dose aspirin may be indicated in those with an elevated risk for cardiovascular event.
Secondary prevention includes non pharmacological interventions (not addressed here) and with pharmacologic therapy that includes the use of antiplatelets and anticoagulants in addition to management of comorbid conditions.
Secondary Prevention of Ischemic Stroke
Recommended/Preferred
Alternative
Non-Cardioembolic
Clopidogrel (75 mg once daily
Aspirin/Extended-release dipyridamole (25 mg/200 mg bid)
Aspirin (81 mg once daily)
Cilostazol (100 mg bid)
Cardioembolic
(non-valvular)
Dabigatran, 150 mg bid
Warfarin
(target range, INR 2.0-3.0)