Module 12 Data (Dyslipidemia & Statin Benefit groups - Anticoagulation)

Question 1

For Study purposes, please focus treatment plans based on:
* 2013 ACC/AHA Blood Cholesterol Guidelines for ASCVD Prevention (IE. Statin Benefit Groups)
* 2016/2017 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for Additional LDL-lowering

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Question 2

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
* Intent of guidance was only ASCVD risk reduction
o Does not provide a comprehensive approach to detection, evaluation and treatment of lipid disorders
o Not intended for patients with complex lipid disorders
o No recommendations for add-on therapy to lower LDL after optimal statin dosing
o Lifestyle modification Remains critical component both prior to and in concert with the use of cholesterol lowering drug therapies despite being only given minimal attention in the 2013 guidance. Lifestyle modifications should still include:
 o TLC Diet
 o Weight reduction
 o Increased physical activity
 o Tobacco avoidance
 o Alcohol avoidance

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Question 3

Statin benefit groups:
*
o 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
o No RCT to support titrating cholesterol lowering drug therapy of LDL-C and Non-HDL-C to specific levels (ie. There is not a target LDL (eg. <70mg/dl), etc)

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Question 4

Statin benefit groups:

o Guidelines encompass patients 40-75 years of age
 In lower risk patients (5-7.5%, < 40 or > 75 yrs) clinicians should discuss with patients:
 ASCVD risk reduction benefits (30% RRR MIS, 45% HIS)
 Adverse effects (diabetes NNH 200)
 Drug-drug interactions
 FH of premature CAD (< 55yo M, < 65yo F)
 Patient preferences
 Ask yourself: Will benefits of the use of a statin in this population (younger than 40, older than 75 or low risk) offset the potential of treatment burden, risk of adverse events and duration required to realize these benefits

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Question 5

Defining Statin Intensity.
* I have said up to this point not to memorize doses, You should however be able to choose a statin based on the intensity required.
* Example: A patient with a primary elevation of LDL > 190 (familial hypercholesterolemia) should be on a high intensity statin; thus atorvastatin 40-80mg or rousavastatin 20-40mg is reasonable
o By definition high intensity statins reduce LDL at least 50% from baseline while moderate intensity statins reduce LDL 30-50% from baseline

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Question 6

A “yes” answer to any of these questions (below) means the patient is a potential candidate for statin therapy.

(1) Clinical ASCVD
* Does the patient have clinical atherosclerotic cardiovascular disease (ASCVD) including any of the following? Acute coronary syndromes , A history of myocardial infarction , Stable or unstable angina , Coronary or other arterial revascularization , Stroke, Transient ischemic attack or Peripheral arterial disease presumed to be of atherosclerotic origin
o High intensity statin (moderate intensity if >75 years or intolerant on high intensity)
o This is an example of our patient from last week with SIHD.

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Question 7

A “yes” answer to any of these questions (below) means the patient is a potential candidate for statin therapy.

(2) Primary elevations of LDL-C ≥ 190mg/dl
* Does the patient have an LDL level ≥190 mg/dL without treatment?
o High intensity statin (moderate intensity if not a candidate for high intensity)
o Addition of non-statins if max intensity statin is achieved to further need to lower LDL-C (low level evidence IIb).
 The use of non-statins addressed in text and cited in ATPIII

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Question 8

A “yes” answer to any of these questions (below) means the patient is a potential candidate for statin therapy.

(3) Diabetics age 40-75 with LDL-C 70-189mg/dl and without clinical ASCVD
* Is the patient 40 to 75 years of age and does the patient have diabetes (either type 1 or type 2)?
o Moderate intensity statin
o High intensity statin use based on Extrapolation of data for primary prevention in high risk (≥ 7.5% 10 yr risk) who did not have diabetes (lower level of evidence IIa, B)

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Question 9

A “yes” answer to any of these questions (below) means the patient is a potential candidate for statin therapy.

(4) Non-diabetics without clinical ASCVD age 40-75 with LDL-C 70-189mg/dl and estimated risk of ASCVD ≥ 7.5% (10 yr risk should be calculated using the pooled cohort equations)
* Web Tool for estimating risk- http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/
* Is the patient 40 to 75 years of age and is the patient’s 10-year risk of cardiovascular events ≥7.5 ?
o Moderate to high intensity statin

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Question 10

Major Risk Factors for CHD (other than benefit groups)
* Cigarette smoking
* Hypertension (BP ³140/90 mmHg or on antihypertensive medication)
* Low HDL cholesterol (<40 mg/dL)†
* Family history of premature CHD
o CHD in male first degree relative <55yrs
o CHD in female first degree relative <65yrs
* Age (men ³45 years; women ³55 years)
* HDL cholesterol ³60 mg/dL counts as a “negative” risk factor

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Question 11

• Statins
  o o Major side effects: Myopathy
   § Temporarily d/c statin and assess for rhabdomyolysis if severe & other conditions that cause muscle symptoms
   Re-challenge with lower or same dose of statin
   If statin causative then give lower dose of different statin
   Per 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

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Question 12

Statins

o § Elevated LFTs
 low risk. See below
o It appears likely that statin therapy confers a small increased risk of developing diabetes, and that the risk is slightly greater with intensive statin therapy than moderate statin therapy.
 As would be expected, given the evidence from clinical trials that statins reduce CV events in patient with diabetes, both randomized trials and observational studies suggest that the beneficial effects of statins on CV events and mortality outweigh any increased risk conferred by promoting the development of diabetes

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Question 13

Statin CIs:

o § Absolute: liver disease, alcoholism, pregnancy or lactation
 What would a safe option be in these situations?
o § Relative: use with certain drugs

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Question 14

Statin Monitoring

o § Myalgia- baseline, 6-12 weeks after initiation, and at each follow-up visit
o § CK- Enzyme used as a marker for damage in CK rich tissues such as the heart or muscle.
 Should NOT be routinely measured.
 Baseline (in high risk individuals) and PRN muscle symptoms
o § LFTs- baseline and then periodically (6 weeks and yearly) and/or prn symptoms**
 “all currently marketed statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of serum alanine aminotransferase (ALT) does not appear to detect or prevent serious liver injury in association with statins.”
 Measure baseline ALT and ONLY remeasure if symptoms suggest hepatotoxicity
o § Lipid panel
 Consider rechecking lipid panel 4-12 wks after initiation to assess for adherence but not to adjust therapy
 Recall that therapy with statins is NOT to achieve a specific Total cholesterol or LDL value
 lower risk patients (5-7.5%, < 40 or > 75 yrs) clinicians should discuss with patients:

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Question 15

Note- The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of simvastatin should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. Simvastatin is not even listed in the chart above!

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Question 16

• Bile acid sequestrants

o Although historically used as add on therapy for additional LDL lowering (Prior to 2013 guidance, Specific goals (eg LDL < 70) were considered pharmacological endpoints.) This now serves as a reasonable alternative for those who are pregnant or wish to become pregnant and such therapy outweighs risk. Recall, bile acid sequestrants are NOT absorbed systemically
o o Side effects
 § GI distress/constipation
 § ADEK deficiency
o o Contraindications
 § Elevated TG (especially >500 mg/dL)
 § Bowel obstruction
o o Drug interactions
 § Cholestyramine and colestipol decrease absorption of other drug

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Question 17

• Ezetimibe
• ENHANCE study results- combo of ezetimibe and simvastatin not more effective in decreasing carotid artery thickness compared to simvastatin alone (even though LDL was lower with combo)
• Increased risk of rhabdomyolysis when combined with statin .. ?
• ASCVD risk reduction benefits
  o efficacy for clinical outcomes not clearly established
  o No information supporting the routine use of nonstatin drugs combined with statin therapy to reduce further ASCVD events when 2014 ACC/AHA guidance was published
  o Published in 2015, the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) randomized 18,144 patients with ACS to simvastatin 40 mg/d plus ezetimibe 10 mg/d or simvastatin alone. With median follow-up of 6 years, simvastatin+ezetimibe was found to reduce the primary outcome of CV mortality, major CV event, or nonfatal stroke (34.7% vs. 32.7%; P=0.016; NNT 50). There was no reduction in all-cause or CV mortality with simvastatin+ezetimibe, though there was a reduction in MI and stroke.
   Bottom line - Among individuals with recent ACS, the addition of ezetimibe to moderate-intensity statin therapy is associated with a reduction in CV mortality, major CV event, or nonfatal stroke when compared to statin therapy alone.
   Considerations that may favor the initial choice of ezetimibe include: patients who require <25% additional lowering of LDL, patients with recent ACS <3 months, cost considerations with recent availability of generic ezetimibe and future cost savings, ease of use as oral agent with low pill burden, patient preferences, heart failure, hypertension, age >75 years, diabetes, stroke, CABG, PVD, eGFR <60, and smoking.

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Question 18

• Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors:
  o Approved as adjunctive therapy to diet and maximally tolerated statin therapy in adult patients with familial hypercholesterolemia or established atherosclerotic cardiovascular disease.
  o Significant decreases in Total cholesterol and LDL and increases in HDL
   They are capable of lowering LDL-C by as much as 60 percent in patients on statin therapy. In addition, they produce clinical benefits, such as reductions in the rates of stroke or myocardial infarction
   Their use is associated with lower rates of myocardial infarction and stroke. A mortality benefit has not been established
  o Use has NOT been evaluated by 2014 current guidelines. Trials that are available may be compromised by short duration
  o The 2017 Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial randomized patients with established atherosclerotic disease on background moderate- or high-intensity statin therapy (70% high intensity) to the PCSK9 inhibitor evolocumab versus placebo and assessed for a primary outcome of major CV events (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization). At median follow-up 26 months, evolocumab was associated with an absolute 1.5% reduction in major cardiovascular events (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization), driven primarily by reductions in nonfatal MI, stroke, and revascularization. Treatment of 74 patients with evolocumab over 2 years would be expected to prevent one CV death, MI, or stroke. LDL was reduced by 59% from a median of 92 to 30 in the evolocumab group. There was no overall or CV-specific mortality benefit with evolocumab, although CV death rates were notably low (< 2%) in both groups. Effects of evolocumab were consistent regardless of baseline LDL level or intensity of background statin use.
  o Place in therapy - no guidelines have been published that reflect the results of this trial.

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Question 19

2016/2017 ACC Expert Consensus Decision Pathway (ECDP) on the Role of Non-statin Therapies for cholesterol lowering
* The algorithms endorse the 4 evidence-based statin benefit groups identified in the 2013 ACC/AHA cholesterol guidelines and assume that the patient is currently taking or has attempted to take a statin, given that this is the most effective initial therapy

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Question 20

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Question 22

• Choosing Ezetimibe vs. Pcsk9
  o Ezetimibe - IMPROVE-IT identified 9 clinical variables (congestive heart failure, hypertension, age >75 years, diabetes, stroke, CABG, PAD, eGFR <60 ml/min and smoking have greatest likelihood of benefit from the addition of ezetimibe to statin therapy following ACS
   Patients requiring <25% additional LDL-C lowering
   Cost $
   Patients requesting oral therapies
  o PCSK9
   Patients requiring >25% additional LDL-C lowering
   Cost $$$
   SQ administration
   CV outcomes trials not completed

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Question 23

ATPIII/NLA
* Utilizes a stepwise approach to the treatment of dyslipidemia

o Step 1: Determine lipoprotein levels (Screening and detection)
 Check FLP every 5 years (or with changes in risk factors (including weight gain), co-morbidities, new secondary causes for premature ASCVD in a first degree relative) in patients > 20yo
Requires a 9-12 hour fast
 ¢Total Cholesterol <200mg/dL
¢LDL Cholesterol <100 mg/dL (Depends on risk)
¢HDL Cholesterol <40♀ / 50♂ mg /dL (Low) ³60mg/dL (High)
¢Triglycerides <150mg/dL

o Step 2: Determine presence of major risk factors (other than LDL) and rule out secondary causes
 table 12-8 (Major risk factors)
 ¢Cigarette smoking
¢Hypertension (BP ³130/80 mmHg or on antihypertensive medication)
¢Low HDL cholesterol (<40 mg/dL♀, <50mg/dl♂)†
¢Family history of premature CHD
¢Age (men ³45 years; women ³55 years)
 Secondary causes
 —Diet: excessive intake of saturated fat and/or calories, alcohol consumption, anorexia
—Drugs: diuretics, beta-blockers, cyclosporine, estrogen, progestins, glucocorticoids, anabolic steroids, retinoids, protease inhibitors, atypical antipsychotics
—Disease: chronic liver disease, primary biliary cirrhosis, chronic renal failure, nephrotic syndrome, Cushing’s syndrome, systemic lupus erythematosus
—Dysmetabolism: hypothyroidism, diabetes, obesity, insulin resistance

o Step 3: Identify presence of CHD or CHD risk equivalents
 CHD Equivalents
 ¢Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease)
¢Diabetes OR Evidence of end organ damage
¢Multiple risk factors that confer a 10-year risk for CHD >20% (Framingham)

o Step 4: Identification / Estimation of risk
 ATP III
 ¢For patients with 0–1 risk factor, 10 year risk assessment not required
 ¢For patients with multiple (2+) risk factors Use Framingham risk tables to perform 10-year risk assessment
 10-year CVD Risk Calculator (Risk Assessment Tool for Estimating Your 10-year Risk of Having a Heart Attack Version)

o Step 5: Determine therapeutic goals
 NOTE THIS IS DRASTICALLY DIFFERENT THAN 2013 ACC/AHA GUIDANCE WHERE LDL GOALS ARE NOT UTILIZED

o Step 6: TLC
 A comprehensive approach to treating dyslipidemia, including addressing modifiable risk factors, is required to reduce the risk of first and subsequent ASCVD events

o Step 7: Consider adding drug therapy if LDL is above goal

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Question 27

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Question 28

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Question 29

Pharmacotherapy for elevated TGs * Triglycerides become a primary concern with significant elevations (>500mg/dl) o Primary goal is to prevent pancreatitis * Separate guideline on triglycerides (Circulation 2012)(Not addressed in this course)

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Question 30

* o Niacin o Often "touted" for its ability to not only lower TG, but raise HDL o Side effects -flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity, myositis/rhabdomyolysis  Flushing / pruritis can be minimized by pretreatment with ASA (as this is a prostaglandin mediated event), using a slow release formulation, gradual dose titration, avoiding hot beverages / spicy foods at time of administration.  Note: The text book indicates that NSAIDs can be used for this purpose. They will eliminate the "flushing" as they also inhibit prostaglandins, however daily administration of NSAIDs would be associated with higher rates of bleeding, ulcer, GI issues, etc than simple used of low doses ASA  So called "flush free" niacin is a complex molecule that can not be broken down and although it is not associated with flushing, it is of no therapeutic value * o LFTs (baseline and q 6-12 wks x 1 yr, then periodically and/or prn symptoms) uric acid, glucose, GI adverse effects, flushing, CPK prn symptoms

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Question 31

* o Fenofibrate only if TG > 500 mg/dl and benefits judged to outweigh risks o No Gemfibrozil - New guidelines also advise against use of gemfibrozil with statins.

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Question 32

Omega-3 ethyl esters o Decreases TG by 20-50%— o May be associated with increases in LDL depending on the DHA to EPA ratios o Large doses can interfere with platelet function and cause bleeding

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Question 33

* o Icosapent Ethyl o Decrease TG 33% o NOT associated with changes in LDL

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Question 34

* IPE effects on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

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Question 36

Metabolic Syndrome (not addressed by ACC/AHA 2013 * Weight reduction * Increase physical activity * Control other disease states- HTN, DM * ASA 81mg daily for CHD and DM pts * Control lipids (typically high TG, low HDL)

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Question 37

The Case of A 44-year-old woman has a 10-year history of type 2 diabetes... (Based on 2013 ACC / AHA Guidance) This patient has diabetes, is between the ages of 40 and 75 years, and has an LDL–C between 70 and 189 mg/dL, placing her in a statin benefit group. The primary prevention CARDS trial showed that men and women with diabetes, but without clinical ASCVD, experienced a reduction in ASCVD events from a moderate intensity statin, atorvastatin 10 mg/day. In addition, the Cholesterol Treatment Trialists (CTT) 2008 and 2010 meta-analyses have found that statins reduce ASCVD events in proportion to the magnitude of LDL–C lowering in individuals with and without diabetes, and in individuals with diabetes with and without clinical ASCVD. Therefore, a high-intensity statin is also an option for individuals with diabetes and 10-year ASCVD risk ≥7.5%, as it is in those without diabetes. In addition, the 2010 CTT meta-analysis also found the reduction in the relative risk of ASCVD was similar across the range of LDL–C levels ≥70 mg/dL. While some might order an apolipoprotein B or LDL particle number, neither is needed to make a decision to start a statin because she is already in a statin benefit group due to having diabetes. The ACCORD trial did not show benefit of fenofibrate added to a statin in women with elevated triglycerides and low HDL–C levels. Moreover, the 2008 and 2010 CTT meta-analyses found that statins reduce ASCVD events regardless of HDLC or triglyceride levels, and are therefore the drugs of choice for ASCVD risk reduction in individuals with abnormal triglyceride or HDL–C levels. Although bile acid sequestrants can lower hemoglobin A1c, they can also markedly elevate triglyceride levels. Bile acid sequestrants are best started with the triglycerides are <250-300 mg/dL. Tighter diabetes control and lifestyle modification with more physical activity and a heart healthy diet with vegetables, fruits, and less sugar sweetened foods and drinks (often a Mediterranean style diet) would help control the diabetes as well as lower the triglycerides. To date, there are no HDL–C raising drugs that have been shown to reduce ASCVD events in statin-treated individuals

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Question 38

Heparin - binds to antithrombin III (AT-III), a serine protease, and by acting as a catalytic template enhances the inactivation of active clotting factors (primarily IIa, Xa; also IXa, XIa, XIIa, XIIIa) * Half-life of 0.4 to 2.5 hours, and increases with increasing doses (average 1.5 hours) o o Onset / Offset ≈ 6 hours o Dosing comparable with IV and SC, except may take longer to get to therapeutic effect with SC dosing due to poor bioavailability o Continuous IV infusion preferred to intermittent IV injection due to less bleeding o Dosing  o Traditional dosing methods have employed heparin at a 5000U bolus and 1000U/h infusion. This approach did not take into account pharmacokinetic and pharmacodynamic variables.  o Weight-based heparin dosing: 80U/kg bolus then 18U/kg/h  § Both supported by CHEST o o Low Dose SC Heparin : For surgical/medical prophylaxis: Usually 5000 units SC Q8-12h

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Question 39

* Monitoring - The anticoagulant effect of heparin is monitored by the activated partial thromboplastin time (aPTT), which is sensitive to the effects of heparin on thrombin, factors IXa and Xa o o Therapeutic range defined as 1.5 to 2.5 times control o o In general, monitor aPTT 6 hours after initiation of heparin therapy (The time needed to reach steady state (4-5x T1/2). No changes to therapy should be made prior to achieving steady state  Continue this monitoring until patient's aPTT is stable, then monitor aPTT once daily. o o √ Hgb/Hct and platelets at baseline in addition to aPTT... Why .. see below?? o o Thrombocytopenia  o Type I –Early- (HAT) – Mild, transient, develops 2-3 days into therapy; due to temporary sequestration of platelets due to heparin's mild platelet aggregating effect. Resolves  o Type II – Delayed - (HIT) – Late onset due to antibody-mediated response; develops 5-14 days into therapy; thrombosis can result due to irreversible aggregation of platelets by heparin  § Contraindication for future use  § Treatment  Stop heparin  Recommend the use of non-heparin anticoagulants (DTIs)  Other ADRs, CIs??  Reversal with protamine

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Question 40

LMWHs - binds to antithrombin III (AT-III), a serine protease, BUT maintain preferential inhibition of factor Xa over IIa (2:1-4:1 vs heparin 1:1) * Usual route SC administration * Advantages over heparin o o Longer t1/2 allows for QD-BID dosing o o More predictable anticoagulation effects o o Monitoring – not necessary other than periodic CBC; does require dose adjustment for renal insufficiency o o ADRs similar to heparin; however the incidence of thrombocytopenia is decreased vs. UFH, but cross reactivity is significant * o LMWHs are not interchangeable o Pregnancy category B

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Question 41

Fondaparinux - binds to antithrombin III (AT-III), a serine protease, BUT inhibits Xa ONLY * Contraindications CrCl <30ml/min, Wt <50Kg, * Cautiously Plts <100,000/mm3 * Monitoring – not necessary other than periodic CBC; does require dose adjustment for renal insufficiency

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Question 42

Oral Xa inhibitors - reversible and select inhibitor of free and clot bound factor Xa, resulting in decrease thrombin generation and thrombus formation * No routine monitoring

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Question 43

Oral DTIs - Direct IIa (thrombin) inhibitor * √ CBC, renal function (no routine monitoring like INR) * No dietary restrictions

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Question 44

Warfarin - VKA- Vitamin K is a cofactor required to make (by carboxylation of the glutamyl residues) the active forms of the vitamin K dependent clotting factors (II, VII, IX, X) and protein C and protein S * Genetic variations in VKOR and P450 making titration difficult * Monitoring - INR o o Goal INR is 2-3 (target 2.5) for treatment and prophylaxis for most indications (DVT, PE, Afib) o Significant drug interactions o Dosing  o Initial  § Most Patients: 5mg* to 10mg for first 1 or 2 days, with subsequent dosing based on the INR response  § Elderly, CHF, debilitated, malnourished, or with elevated bleeding risk: Start at or below ~ 5mg  o Adjustments  § generally made by calculating the weekly dose and reducing or increasing the weekly dose by 5 to 20%  § the effect of a small dose change may not be evident for 5 to 7 days  o Overlap with Heparin/LMWH  § Necessary since protein C (half-life 8h, an anticoagulant) and factor VII (half-life 6h) decline rapidly due to short half-lives, but other coagulation factors (factor II, half-life 60h) are decreased more slowly. Combination of active coagulation factors with decreased protein C levels creates a transient hypercoagulable state  Patient education?  pregnancy category X

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Question 45

 Managing elevated INR with phytonadione (aka Vitamin K)

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Question 50

Therapeutics aFib * The CHADS2 score is has been extensively validated and is easy for clinicians to remember and use: * For patients with AF, including those with paroxysmal AF, who are at low risk of stroke (eg, CHADS2 score = 0), no therapy rather than antithrombotic therapy * For patients with AF, including those with paroxysmal AF, who are at intermediate or high risk of stroke (eg, CHADS2 score = 1 or 2), we recommend oral anticoagulation o o For patients with AF, including those with paroxysmal AF, for recommendations in favor of oral anticoagulation (excluding recommendations for patients with mitral stenosis, stable coronary artery disease, intracoronary stents, and acute coronary syndrome), we suggest dabigatran 150 mg twice daily rather than adjusted-dose vitamin K antagonist (VKA) therapy (target INR range, 2.0-3.0) o o For patients with AF and mitral stenosis, we recommend adjusted-dose VKA therapy (target INR range, 2.0-3.0) * o Novel oral anticoagulants (NOACs) reduce cardioembolic events (all-cause stroke or systemic embolism) and intracranial bleeding and may reduce mortality compared to warfarin (level II evidence) in patients with atrial fibrillation o Reasonable in certain patients

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Question 51

Essential Components of Therapeutic Lifestyle Changes - Dietary cholesterol: <200 mg/day. - Saturated fats: Total fat range should be 25%-35% for most cases. <7% of total calories and reduce intake of trans fatty acids. - Therapeutic options for LDL-lowering plant stanols/sterols: 2 g/day - Increased viscous (soluble) fiber: 10-25 g/day - Total calories: Adjust caloric intake to maintain desirable body weight and prevent weight gain. - Physical activity: ≥ 150 min/week of moderate or higher intensity activity.

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Question 52

Therapeutic lifestyle changes are the foundation of care in treating dyslipidemia.

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Question 53

Therapeutic lifestyle changes should be the first approach tried in all patients, but pharmacotherapy should be instituted concurrently in higher risk patients. TLC includes dietary restrictions as well as regular exercise and weight reduction if overweight or obese. Additionally, consumption of plant stanol/sterols and dietary fiber should be encouraged as they may reduce LDL cholesterol by 20% - 25%.

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Question 54

Don't pursue weight reduction in patients if they're underweight.

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Question 55

Current patient groupings for hyperlipidemia prevention with statins: - ASCVD. - - Reduce LDL by ≥ 50% - - - Use high intensity statin - LDL cholesterol ≥ 150mg/dl - - Reduce LDL by ≥ 50% - - - Use high intensity statin - Age 40-75, DM, LDL chol 70-189 - - Reduce LDL by 30-49% - - - Use moderate intensity statin - No ASCVD/DM, 10-yr risk >7.5%, LDL 70-189 - - Reduce LDL by 30-50% - - - Use mod-to-high intensity statin

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Question 56

No matter what, get a baseline lipid panel every annual visit. Otherwise you won't have a baseline to base your target LDL reduction on. "50% of what?"

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Question 58

Group 1 (not 2, 3, or 4) is secondary prevention because they already have the disease. They already have ASCVD. In the other three groupings you're trying to prevent it.

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Question 59

Ignore the low-intensity statins.

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Question 60

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Question 61

HIGH INTENSITY STATINS: - Atorvastain 40-80+ mg - Rosuvastatin 20-40+ mg

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Question 62

"AR ya high?" - Atorvastatin 40-80+ mg - Rosuvastatin 20-40+ mg

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Question 63

Clinicians hate simvastatin due to so many drug interactions. Also has the highest association with SAMS, or statin-associated muscle symptoms (which can lead to rhabdomyolysis).

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Question 64

Fluvastatin has short and long acting doses. - Fluvastatin XL 80 mg daily - Fluvastatin 40 mg BID

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Question 65

There is no longer a target LDL. Lipid goals should be assessed by determining if the patient has achieved their target LDL cholesterol reduction based on their statin benefit group (eg, clinical ASCVD patient on a high intensity statin should achieve at least 50% reduction in LDL cholesterol; if baseline LDL cholesterol values not available to calculate percent reduction then achieving an LDL cholesterol of less than 70 mg/dl or a non-HDLc of less than 100 mg/dl are additional targets).

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Question 66

If rhabdo is suspected, DC statin immediately if serum transaminase levels (liver function tests; ASTs/ALTs) rise to three times the upper limit of normal, or if patient develops signs or symptoms of myopathy. Assess patient for rhabdo. After symptoms resolve, re-challenge with a lower dose of same statin and monitor. If it happens again, try lower dose of alternate statin.

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Question 67

Myopathy is defined as muscle weakness not necessarily associated with creatine kinase elevations.

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Question 68

Rhabdo is defined as muscle symptoms with marked elevation in CK at 50 times the upper limit of normal and creatine elevation usually associated with myoglobinuria and brown urine. Rhabdo itself is very rare.

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Question 69

Things that can lead to rhabdo: - small body frame and frailty - multisystem disease - perioperative periods - multiple medications - specific concomittant medications or consumption: - - fibrates (especially gemfibrozil) - - nicotinic acid - - cyclosporine - - azole antifungals - - macrolide ABTs - - protease inhibitors - - nefazodone - - verapamil - - amiodarone - - >1 quart grapefruit juice - - alcohol abuse

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Question 70

Patient CAN take fenofibrate with a statin. You just have to monitor.

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Question 71

Gemfibrozil is completely contraindicated with simvastatin.

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Question 72

Gemfibrozil is cautioned against statins besides simvastatin.

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Question 73

What if a patient falls into a statin benefit group, but is outside the age range for which the guidelines were meant (eg, >75 years of age)? - There are no randomized controlled trials in persons older than 80 years at baseline. Randomized controlled trial findings in younger patients and 75+ subgroups and in observational studies support treatment in secondary prevention of ASCVD, but trial evidence in primary prevention is less clear. Available data do not imply specific harms in older patients and, therefore, judicious primary prevention is possible. However, persons older than 75 years are biologically a very heterogenous group with frequent frailty, comorbid conditions, and multiple concomittant drugs. All these, as well as personal preferences, must be taken into account in treatment decisions.

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Question 74

What if a patient falls into a statin benefit group, but is outside the age range for which the guidelines were meant (eg, >75 years of age)? - Statin treatment is only one way to prevent ASCVD in older people. Treatment of hypercholesterolemia should be started far before 75-80 years, and there is no need to discontinue statin treatment due to chronological age alone. After 75 years, treatment should be started in patients with ASCVD and judiciously in primary prevention. Like all prevention, statin treatment should be discontinued when palliative treatment is started. Ongoing and planned trials in 70+ individuals will give more information about primary prevention in older persons.

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Question 75

What other medications are available for LDL and triglyceride lowering? - Cholesterol Absorption Inhibitor: Ezetimibe ( -18% / -7% to -9%) - Bile Acid Sequestrants: Cholestyramine, Colesevelam, Colestipol (-15% to -30% / increase triglycerides) - Nicotinic acid: Niacin ER and IR (-5% to -25% / -11 to -60%) - Fibric Acid Derivatives: Fenofibrate and Gemfibrozil (-30% to +45% / -20% to -60%) - Omega 3 fatty acids: Lovaza, Vascepa, Epanova, and OMTRYG. Only Vascepa: (-5% / -27%) All others: (increase LDL/decrease triglycerides) - Micosomal Transfer Protein Inhibitor: Lomitapide (-40% / -45%) - Antisense Oligonucleotide: Mipomersem (-25% / -18%) - Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): Alirocumab and evolocumab (LDL and total cholesterol only)

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Question 76

The flushing is unbearable in Niacin IR. Give ER instead.

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Question 77

Regarding omega 3 fatty acids you need to get patient up to 4 grams a day if they want any clinical benefit. Otherwise it's a waste of their money and your time.

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Question 78

Which of these LDL-lowering meds are safe during pregnancy? - O3FAs - nicotinic acid: Niacin - bile acid sequestrants: 3 coles

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Question 79

Common adverse effects and how can these ADRs be minimized or prevented? - Statins: Most frequent side effects are constipation, abdominal pain, diarrhea, and nausea. Statins should be discontinued promptly if serum transaminase levels (liver function tests) rise to three times upper limit or if patient develops s/sx of myopathy.

Answer 79

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Question 80

Common adverse effects and how can these ADRs be minimized or prevented? - Ezetimibe: Overall incidence of adverse events reported with ezetimibe alone was similar to that reported with placebo and generally similar between ezetimibe with a statin and statin alone. The frequency of increased transaminases was slightly higher in patients receiving ezetimibe plus a statin compared with those receiving statin monotherapy.

Answer 80

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Question 81

Common adverse effects and how can these ADRs be minimized or prevented? Bile Acid Sequestrants (BAS): Main side effects are nausea, constipation, bloating, and flatulence, although these may be less with colesevelam. Increasing fluid and dietary fiber intake may relieve constipation and bloating. BASs impair absorption of fat-soluble vitamins.

Answer 81

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Question 82

Common adverse effects and how can these ADRs be minimized or prevented? - Nicotinic acids: SEs include flushing, itching, gastric distress, HA, hepatotoxicity, hyperglycemia, and hyperuricemia. Taking an aspirin 30 minutes prior to dose helps with flushing.

Answer 82

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Question 83

Common adverse effects and how can these ADRs be minimized or prevented? - Fibric Acid Derivatives: Most common SEs are nausea, diarrhea, abdominal pain, and rash. Increased risk of rhabdomyolyis when given with a statin. Fibric acids are associated with gallstones, myositis, and hepatitis.

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Question 84

Common adverse effects and how can these ADRs be minimized or prevented? - All products are obtained from oil of fish. Should be used with caution in patients with known hypersensitivity to fish and/or shellfish. SEs include: - - Lovaza/Omtryg: eructation, dyspepsia, taste perversion - - Vascepa: arthralgia - - Epanova: diarrhea, nausea, abdominal pain/discomfort. DC'd in US

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Question 85

Common adverse effects and how can these ADRs be minimized or prevented? - Lomitapide: GI SEs and elevation in liver enzymes and hepatic fat are common.

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Question 86

Common adverse effects and how can these ADRs be minimized or prevented? - Mipomersem: Injection site reactions, hepatic fat, and liver enzyme elevations are common.

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Question 87

Common adverse effects and how can these ADRs be minimized or prevented? - PCSK9: - - Alirocumab: ISRs, nasopharyngitis, influenza, URTIs, UTIs, elevation in liver enzymes. - - Evolocumab: ISRs, nasopharyngitis, influenza, URTIs, UTIs, back pain

Answer 87

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Question 88

What is metabolic syndrome? - Although alternative definitions exist, metabolic syndrome is generally considered a constellation of common cardiovascular risk factors including HTN, abdominal obesity, dyslipidemia, and insulin resistance. - According to a joint statement from a shit-ton of organizations, pts must meet at least three of the following criteria for the diagnosis of metabolic syndrome: - - Increased waist circumference 40 inches (or 102 cm) in men and 35 inches (or 89 cm) in women. - - Triglycerides of 150 mg/dL or greater, or active treatment to lower triglycerides. - - Low HDL cholesterol (<40 mg/dl) in men, (<50 mg/dl) in women, or active treatment to raise HDLc. - - SBP of 130 mmhg or greater, DBP 85 mmhg or greater, or active treatment with antihypertensive therapy - - Fasting blood glucose of 100 mg/dl or greater, or active treatment for diabetes.

Answer 88

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Question 89

For the purpose of this course, the information regarding stroke will not include surgical interventions or fibrinolytic therapy.

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Question 90

What is the MOA of heparin (that is to say what clotting factors does heparin inhibit) and how is therapy monitored and adjusted? - Heparin MOA: IIa and Xa - Heparin exerts its anticoagulant effect by augmenting the natural anticoagulant, AT (antithrombin). UFH and other anticoagulants will not dissolve a formed clot but prevent its propagation and growth.

Question 91

Heparin Monitoring and Adjustment: - The response to UFH can be monitored using a variety of lab tests including the aPTT, the whole blood clotting time, activated clotting time (ACT), antifactor Xa activity, and the plasma heparin concentration. Although it has several limitations, the aPTT is the most widely used test in clinical practice to monitor UFH. - Achieving a therapeutic aPTT in the first 24 hours after initiating UFH is critical because it has been shown to lower the risk of recurrent VTE. The infusion rate is then adjusted based on lab monitoring of the patient's response.

Answer 91

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Question 92

How does UFH compare to LMWH and fondaparinux? - Compared with UFH, LMWHs have improved pharmacodynamic and pharmacokinetic properties. They exhibit lass binding to plasma and cellular proteins, resulting in a more predictable anticoagulant response. Consequently, routine monitoring of anticoagulation activity and dose adjustments are not required in most patients. LMWHs have longer plasma half-lives, allowing once or twice-daily administration, improved SubQ bioavailability, and dose-independent renal clearance. In addition, LMWHs have a more favorable side-effect profile than UFH. Like UFH, LMWHs prevent the propagation and growth of formed thrombi. The anticoagulant effect is mediated through a specific pentasaccharide sequence that binds to AT. The primary difference in the pharmacologic activity of UFH and LMWH is their relative inhibition of thrombin (factor IIa) and factor Xa. Smaller heparion fragments (as in LMWHs) cannot bind AT and thrombin simultaneously. - Unlike thrombolytics, UFH and other anticoagulants will not dissolve a formed clot but do prevent its propagation and growth.

Answer 92

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Question 93

Unlike thrombolytics, UFH and other anticoagulants will not dissolve a formed clot but do prevent its propagation and growth.

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Question 94

When is a dosage change with heparin evident in a lab value? - An aPTT should be obtained at baseline, 6 hours after initiating the heparin infusion, and 6 hours after each dose change because this is the time required to reach steady state. UFH dose is then adjusted based on the aPTT measurement and institutional-specific therapeutic range. In patients with heparin resistance, antifactor Xa concentrations may be a more accurate method of monitoring the patient's response.

Answer 94

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Question 95

6 hours before we make any heparin dose changes.

Answer 95

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Question 96

What is the MOA of Warfarin (that is to say what clotting factors does it inhibit) and how is therapy initiated, monitored, and adjusted? - MOA: Warfarin exerts its anticoagulant effect by inhibiting production of the vitamin K-dependent coagulation factors II (prothrombin), VII, IX, and X, as well as the anticoagulant proteins C and S. Warfarin has no effect on circulation factors that have been previously formed and its therapeutic antithrombotic activity is delayed for 5 to 7 (potentially longer in slower metabolizers). This delay is related to half-lives of the clotting factors: 60 to 100 hours for factor II (prothrombin), 6 to 8 hours for factor VII, 20 to 30 hours for factor IX, and 24 to 40 hours for factor X. Proteins C and S, the natural anticoagulants, are inhibited more rapidly due to their shorter half-lives, 8 to 10 hours and 40 to 60 hours, respectively. Reductions in the concentration of natural anticoagulants before the clotting factors are depleted can lead to a paradoxical hypercoagulable state during the first few days of warfarin therapy.

Answer 96

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Question 97

In the first 1-7 days of starting warfarin the patients still run the risk of having a blood clot.

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Question 98

What is the MOA of Warfarin (that is to say what clotting factors does it inhibit) and how is therapy initiated, monitored, and adjusted? - Therapy: Warfarin displays nonlinear kinetics. Small-dose adjustments can lead to large changes in anticoagulant response. The dose of warfarin is determined by each patient's individual response to therapy and the desired intensity of anticoagulation. In addition to hepatic metabolism and genotype, warfarin dose requirements are influenced by diet, drug-drug interactions, and health status. Therefore, warfarin dose must be determined by frequent clinical and laboratory monitoring. Although there are conflicting data regarding the optimal warfarin induction regimen, when the patient's genotype is unknown, most patients can start with 5 mg daily and subsequent doses are determined based on INR response.

Answer 98

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Question 99

What is the MOA of Warfarin (that is to say what clotting factors does it inhibit) and how is therapy initiated, monitored, and adjusted? - Monitor INR and/or PT and s/sx of bleeding.

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Question 100

On warfarin, do not change diet, especially how much dark leafy greens you eat. This would alter the INR.

Answer 100

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Question 101

When is a warfarin dose change evident in a lab value? - It takes 3-4 days to see any changes.

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Question 102

When warfarin is initiated (for example for VTE) why is therapy overlapped with either heparin or LMWHs? - Warfarin has no effect on circulating coagulation factors that have been previously formed and its therapeutic antithrombotic activity is delayed for 5 to 7 days (potentially longer in slower metabolizers).

Answer 102

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Question 103

How should patients with an elevated INR be managed?

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Question 104

What are some significant interactions providers should be concerned with (both rx and OTC)?

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Question 105

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Question 106

There are several conditions (like IHD) where antiplatelets like ASA are indicated. What is a reasonable alternative to ASA? Plavix/clopidogrel

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Question 107

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Question 108

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Question 109

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Question 110

Direct Thrombin Inhibitors (DTIs): dagibatran/Pradaxa - Indication: VTE tx and prophylaxis - MOA: directly inhibits thrombin (IIa) - Monitoring: dTT (diluted thrombin time), ECT (ecarin clotting time). ECT > dTT

Answer 110

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Question 111

Direct Xa Inhibitors: ABANs (rivarox, apixaban, edox) - Indications: VTE tx and proph - MOA: direct inhibitors of factor Xa - Monitoring: anti-FXa

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Question 112

Answer 112

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