2015 pharmacotherapy specialty examination review course:...

2015 Pharmacotherapy Specialty Examination Review Course:

Cardiovascular Disease: Secondary Prevention Case #1

Snehal H. Bhatt, Pharm.D., BCPS Associate Professor of Pharmacy Practice

MCPHS University Boston, Massachusetts

Learning Objectives: At the conclusion of this session, given a patient case, the participant should be able to

1. Correctly answer case-based questions about appropriate treatment and monitoring of a complex patient with multiple conditions, including acute decompensated heart failure/electrolyte disturbances, ACS and GERD.

2. Develop a plan to address continuity of care issues. 3. Formulate a medication therapy plan for smoking cessation. 4. Determine how to manage drug-drug and drug-disease interactions in a patient with ischemic

heart disease. 5. Discuss quality of life in this population 6. Identify and recommend appropriate resource organizations/groups to assist a specific patient.

Format: Today’s session will be a highly interactive discussion of the attached case studies. Premise: You are a clinical pharmacy specialist working in a large tertiary care academic medical center. Your job is to recommend and critically evaluate the response to cardiovascular medications prescribed for this patient for acute coronary syndromes and related cardiovascular diseases that require admission to the hospital. You are also responsible for assisting in optimizing medication therapies to ensure safe and effective transition of care from the hospital to home.

______________________________________________________________________________________________ ©2015 American Society of Health-System Pharmacists, Inc. All rights reserved.

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Cardiovascular Disease: Secondary Prevention Case # 1 Date: June, 2015 Initials BV

DOB/Age 57 years old

Sex M

Race/Ethnicity African American

Source Patient and medical records

Chief Complaint/History of Present Illness (CC/HPI) (including symptom analysis for CC): “Sharp, shooting chest pain” BV is a 57-year-old man who was awakened from sleep at 2 am with what he describes as 10/10 sharp, shooting substernal chest pain that radiates down his left arm and up to the left side of his neck. He has never experienced anything like this and immediately called 911. While being transported in the ambulance, he was given two 0.3-mg sublingual nitroglycerin tablets and four baby aspirin (81-mg chewable tablets) as a single dose. Upon arrival at the emergency department, he was stable, but still complained of 6/10 chest pain. An ECG was immediately obtained and cardiac enzymes were sent for urgent assay. The ECG revealed > 1 mm ST-elevations in the anterior leads. Minutes later, cardiac enzymes were noted to be positive, and a code STEMI was called. The cardiac catheterization laboratory was opened, and BV was transferred immediately.

Past Medical History (major illnesses and surgeries) From Medical Record Hypertension Dyslipidemia Pre-diabetes CKD – Stage II

Current Prescription/OTC Medications Start Date Drug Name/Strength/Regimen Indication

9/2012 Aspirin 81 mg once daily ASCVD Prevention Chlorthalidone 25 mg orally once daily Hypertension Lisinopril 20 mg orally once daily Hypertension, CKD (Stage II) Amlodipine 5 mg orally once daily Hypertension Atorvastatin 20 mg orally once daily Dyslipidemia Metformin 500 mg orally twice a day Type 2 Diabetes Mellitus Vaccinations: Influenza vaccine: Fall annually Pharmacy(ies) Used:

Neighborhood Pharmacy RX Payment: Private Insurance (prefers generic medications, unsure of what his copays are)

Meds Admin by: Self

Drug Allergies/Adverse Effects: NKDA Family Medical History: Non-contributory


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Social History

Residence: lives at home w/ wife

Occupation: City worker (snow plow driver in winter and road worker all other times of year)

Smoking: Smokes cigarettes 1 ppd x 20 years EtOH: He drinks 2-3 beers most days of the week

Illicit Drugs: Never Diet: Reports eating 3 meals per day and just eats what his wife cooks. Has not really kept track of how much salt he eats daily.

Education: High School graduate Family/Social Environment: Lives with wife; has two sons (22, 24) and one daughter (26); all children live in the area, but not with his him and his wife

Review of Systems: Per HPI:

Objective Data (observations/vital signs/physical examination/labs) BP= 147/60 mm Hg Pulse= 57 bpm, regular RR = 17/min T = 97.6 °F Height = 6’ 0” Weight = 200 lb BMI =27.1 kg/m2 Waist Circumference: 38 inches Remarkable physical exam findings: Gen: Pleasant male in acute distress from chest pain Chest: 6/10 radiating sub sternal chest pain Lungs: Mild inspiratory and expiratory crackles ¼ of the way up both lung fields bilaterally Extremities: Trace bilateral edema of both lower extremities Laboratory Tests

Chem Panel CBC Na = 140 mEq/L WBC = 8.1 x 109/L K = 4.2 mEq/L Hgb = 12.0 g/dL Cl = 103 mEq/L Hct = 37.2% CO3 = 18 mg/dL Platelets = 260 x 109/L BUN = 18 mg/dL SCr = 1.0 mg/dL Glucose = 124 mg/dL Ca = 9.4 mg/dL Mg: 1.6 mg/dL

Miscellaneous (obtained in the emergency department) Troponin T: 3.08 ng/mL CK-MB: 45 ng/mL CK: 475 ng/mL

Summary of 2013 ACC/AHA STEMI Pharmacotherapy Recommendations:


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Antiplatelet Therapy to Support Primary Percutaneous Coronary Intervention (PCI) for ST-Elevation Myocardial Infarction (STEMI) Class I

1. Aspirin 162 to 325 mg should be given before primary PCI. (Level of Evidence: B). 2. After PCI, aspirin should be continued indefinitely. (Level of Evidence: A). 3. A loading dose of a P2Y12 receptor inhibitor should be given as early as possible or at time of

primary PCI. Options include: a. Clopidogrel 600 mg (Level of Evidence: B) b. Prasugrel 60 mg (Level of Evidence: B) c. Ticagrelor 180 mg (Level of Evidence: B)

4. P2Y12 inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (bare-metal or drug-eluting), using the following maintenance doses:

a. Clopidogrel 75 mg daily (Level of Evidence: B) b. Prasugrel 10 mg daily (Level of Evidence: B) c. Ticagrelor 90 mg twice a day (Level of Evidence: B) (Note: Aspirin should be dosed at 81

mg daily with ticagrelor) Class IIa

1. It is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses (Level of Evidence: B).

2. It is reasonable to start treatment with an intravenous glycoprotein (GP) IIb/IIIa receptor antagonist in selected patients with STEMI who are receiving unfractionated heparin (UFH). Examples include:

a. Abciximab: 0.25-mg/kg IV bolus, then 0.125 mcg/kg/min (maximum 10 mcg/min) (Level of Evidence: A)

b. High bolus-dose tirofiban: 25-mcg/kg IV bolus, then 0.15 mcg/kg/min (Level of Evidence: B). In patients with CrCl <30 mL/min, reduce infusion by 50%

c. Double-bolus eptifibatide: 180-mcg/kg IV bolus, then 2 mcg/kg/min; a second 180-mcg/kg bolus is administered 10 min after the first bolus (Level of Evidence: B). In patients with CrCl <30 mL/min, reduce infusion by 50%

Class III: Harm Prasugrel should not be administered to patients with a history of prior stroke or transient ischemic attack. (Level of Evidence: B). Anticoagulant Therapy to Support Primary PCI for STEMI Class I

1. For patients with STEMI, the following supportive anticoagulant regimens are recommended:

a. UFH, with additional boluses administered as needed to maintain therapeutic activated clotting time levels, taking into account whether a GP IIb/ IIIa receptor antagonist has been administered. (Level of Evidence: C). Dosing: 50 – 70 units/kg bolus (with GP IIb/IIIa), or 70 – 100 units/kg (without GP IIb/IIIa). Repeat bolus doses as needed to achieve a therapeutic ACT (200 – 250 seconds with GP IIb/IIIa, 250 – 300 seconds without).

b. Bivalirudin with or without prior treatment with UFH. (Level of Evidence: B). Dosing: 0.75 mg/kg IV bolus, followed by 1.75 mg/kg/hr infusion.


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Class III: Harm Fondaparinux should not be used as the sole anticoagulant because of the risk of catheter thrombosis. (Level of Evidence: B). Summary of routine pharmacotherapy medications after STEMI: Beta Blockers Class I

1. Oral beta blockers should be initiated in the first 24 hours in patients with STEMI who do not have any of the following: signs of heart failure (HF), evidence of a low-output state, increased risk for cardiogenic shock,‖ or other contraindications to use of oral beta blockers (PR interval more than 0.24 seconds, second- or third-degree heart block, active asthma, or reactive airways disease). (Level of Evidence: B).

2. Beta blockers should be continued during and after hospitalization for all patients with STEMI

and with no contraindications to their use. (Level of Evidence: B)

3. Patients with initial contraindications to the use of beta blockers in the first 24 hours after STEMI should be reevaluated to determine their subsequent eligibility. (Level of Evidence: C)

Class IIa

1. It is reasonable to administer intravenous beta blockers at the time of presentation to patients with STEMI and no contraindications to their use who are hypertensive or have ongoing ischemia. (Level of Evidence: B).

Renin-Angiotensin-Aldosterone System Inhibitors Class I

1. An angiotensin-converting enzyme inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction less than or equal to 0.40, unless contraindicated. (Level of Evidence: A).

2. An angiotensin receptor blocker should be given to patients with STEMI who have indications

for but are intolerant of angiotensin-converting enzyme inhibitors. (Level of Evidence: B).

3. An aldosterone antagonist should be given to patients with STEMI and no contraindications who are already receiving an angiotensin-converting enzyme inhibitor and beta blocker and who have an ejection fraction less than or equal to 0.40 and either symptomatic HF or diabetes mellitus. (Level of Evidence: B).

Class IIa

1. Angiotensin-converting enzyme inhibitors are reasonable for all patients with STEMI and no contraindications to their use. (Level of Evidence: A).

Lipid Management Class I


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1. High-intensity statin therapy should be initiated or continued in all patients with STEMI and no contraindications to its use. (Level of Evidence: B).

2. Examples of high-intensity and moderate-intensity statins, as defined in the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol:

High Intensity Statin Moderate Intensity Statin

Atorvastatin 40 – 80 mg daily Atorvastatin 10 – 20 mg daily

Rosuvastatin 20 – 40 mg daily Rosuvastatin 5 – 10 mg daily

Pravastatin 40 – 80 mg daily

Fluvastatin 40 mg twice daily Fluvastatin XL 80 mg daily

Lovastatin 40 mg daily

Pitavastatin 2 – 4 mg daily

Simvastatin 20 – 40 mg daily

Adapted from: Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Nov 12. Epub ahead of print. http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.citation

Presentation Questions

1. Which of the following represents the best initial anticoagulant pharmacotherapy for this patient?

a. Unfractionated heparin b. Enoxaparin c. Fondaparinux d. Bivalirudin

2. Based on clinical trial data, which of the following P2Y12 inhibitors was associated with a

reduction in all-cause mortality with given in combination with aspirin? a. Ticagrelor b. Prasugrel c. Clopidogrel d. Ticlopidine

3. Based on current clinical data, which of the following represents the optimal dose of aspirin for

this patient? a. Enteric-coated aspirin 81 mg daily for 1 month b. Enteric-coated aspirin 325 mg daily for 6 months followed by 81 mg daily indefinitely c. Aspirin 81 mg daily indefinitely d. Aspirin 325 mg daily indefinitely


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http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.citation

4. Which of the following represents the optimal duration of dual antiplatelet (DAPT) therapy for

this patient? a. 1 month b. 6 months c. 9 months d. At least 12 months

5. Which of the following represents the best lipid-lowering pharmacotherapy plan for this

patient? a. Rosuvastatin 10 mg po daily b. Simvastatin 20 mg po daily c. Pravastatin 40 mg po daily d. Atorvastatin 80 mg po daily

6. Which of the following therapies should be initiated to reduce all-cause mortality in this patient? a. Aliskiren b. Eplerenone c. Valsartan d. Furosemide

7. Which of the following represents the best outpatient monitoring regimen to minimize the risk

of hyperkalemia in this patient? a. Check serum potassium 4 weeks after hospital discharge b. Check serum creatinine and serum potassium within 1 week after hospital discharge and

again 4 weeks later c. Check serum potassium within 1 week after hospital discharge and again 4 weeks later d. Check serum creatinine and serum potassium 4 weeks after hospital discharge

8. Which of the following should be initiated to reduce complications from apical akinesis?

a. Warfarin for 3 months, Goal INR: 2 – 2.5 b. Warfarin for 3 months: Goal INR 2.5 – 3.5 c. Unfractionated heparin during hospitalization d. Enoxaparin during hospitalization

9. Which of the following medications is the most appropriate recommendation for smoking

cessation for this patient? a. Varenicline b. Nortriptyline c. Nicotine patch d. Bupropion SR

10. Two years later, BV presents to the hospital with acute decompensated heart failure. Which of

the following should be initiated at this time? a. Torsemide 40 mg PO x 1 dose b. Furosemide 80 mg IV x 1 dose c. Metolazone 2.5 mg PO x 1 dose d. Chlorothiazide 500 mg IV x 1 dose


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11. In addition to diuretic therapy, which of the following represents the best approach to managing hyponatremia in this patient?

a. Start oral tolvaptan b. Give 3 % sodium chloride IV c. Start IV conivaptan d. Use fluid restriction

12. Which of the following represents the best acid suppressive therapy recommendation to

minimize both bleeding risk and potential dual antiplatelet therapy (DAPT) drug interactions in this patient?

a. Pantoprazole 40 mg daily b. Esomeprazole 20 mg daily c. Omeprazole 20 mg daily d. Omeprazole 20 mg daily plus ranitidine 150 mg twice daily


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References and Recommended Reading: Acute Coronary Syndromes: O’Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013; 127:529-55. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI guidelines for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011; 124:e574-e651. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Nov 12. Epub ahead of print. http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.citation Stone GW, Witzenbichler B, Guagliumi G et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008; 358:2218-30. Mauri L, Kereiakes DJ, Yeh RW et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014; 371:2155-66. Cannon CP, Harrington RA, James S et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndrome (PLATO): a randomized double-blind study. Lancet. 2010; 375:283-93. Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004; 350:1495-504. Jneid H, Anderson JL, Wright RS et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2012; 126:875-910. U.S. Food and Drug Administration. Information for healthcare professionals: update to the labeling of clopidogrel bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). November 17, 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm.


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http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.citation

Heart Failure: Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; 62:e147-239 Heart Failure Society of America. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010; 16(6):e1-e194. Hyponatremia: Verbalis JG, Goldsmith SR, Greenberg A et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013; 126:S1-S42. U.S. Food and Drug Administration. Samsca (tolvaptan): drug warning—potential risk of liver injury. January 25, 2013. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm336669.htm. Smoking Cessation: Cahill K, Stevens S, Perera R et al. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013; 5:CD009329. University of California San Francisco Center for Tobacco Control Research and Education. Smoking cessation leadership center. http://tobacco.ucsf.edu/content/rx-change-clinician-assisted-tobacco-cessation Patient resource organizations: Mended Hearts: a national and community non-profit support group for patients and families with heart disease. http://mendedhearts.org American Heart Association patient tools and resources for cardiovascular diseases. http://www.heart.org/HEARTORG/Conditions/Conditions_UCM_001087_SubHomePage.jsp


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http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm336669.htm

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm336669.htm

http://tobacco.ucsf.edu/content/rx-change-clinician-assisted-tobacco-cessation

http://tobacco.ucsf.edu/content/rx-change-clinician-assisted-tobacco-cessation

http://mendedhearts.org/

http://www.heart.org/HEARTORG/Conditions/Conditions_UCM_001087_SubHomePage.jsp

Snehal H. Bhatt, Pharm.D., BCPS

Associate Professor

MCPHS University

Clinical Pharmacist

Beth Israel Deaconess Medical Center

Cardiovascular Disease: Secondary Prevention Case # 1

Disclosure

• I declare that I have served on the advisory board and speaker’s bureau for Janssen Pharmaceuticals, Inc.

Learning Objectives

• Correctly answer case‐based questions about appropriate treatment and monitoring of a complex patient with multiple conditions, including, acute decompensated heart failure/electrolyte disturbances, ACS, and GERD.

• Develop a plan to address continuity of care issues.

• Formulate a medication therapy plan for smoking cessation.

• Determine how to manage drug – drug and drug‐disease interactions in a patient with ischemic heart disease.

• Discuss quality of life in this population.

• Identify and recommend appropriate resource organizations/groups to assist a specific patient.

Premise

• You are a clinical pharmacy specialist working in a tertiary care academic medical center.

• Your job is to recommend and critically evaluate the response to cardiovascular medications prescribed for this patient for acute ischemic heart disease management, along with optimizing his medication regimen after hospital discharge.

• The medical team will rely on your expertise to optimize drug therapy for multiple chronic cardiovascular conditions

• 57 year‐old African‐American man– Presents with crushing sub‐sternal chest pain

– Awakened from sleep with 10/10 pain

– Called 911 who quickly arrived to his home:

• Treatments given while in ambulance:– Nitroglycerin 0.3 mg SL x 2 dose

– Aspirin 324 mg (4 x 81mg tablets) chewed po x 1 dose

• ECG: ST‐elevations

Case Case• Past Medical History:

– Hypertension– Dyslipidemia– Pre‐diabetes– CKD – Stage II

• Current Medications:– Aspirin 81 mg once daily – Chlorthalidone 25 mg po once daily– Lisinopril 20 mg once daily – Amlodipine 5 mg once daily – Atorvastatin 20 mg once daily– Metformin 500 mg twice a day


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Case: Code STEMI

• Physical Exam:– Mild inspiratory and expiratory crackles ¼ of the way up both lung fields bilaterally

– Trace bilateral edema of both lower extremities

• ECG: > 1 mm ST‐Elevations V3‐V4• Laboratory Data:

– Troponin T: 3.08 ng/mL– CK‐MB: 45 ng/mL– CK: 475 ng/mL– Calcium: 9.4 mg/dL– Magnesium: 1.6 mEq/dL

140

4.2 18

103124

1.0

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Question # 1Which of the following represents the best initial anticoagulant pharmacotherapy?

A. Unfractionated heparin

B. Enoxaparin

C. Fondaparinux

D. Bivalirudin

Anticoagulant Therapy to Support Primary PCI

O’Gara PT et al. Circulation. 2013; 127:529–55.

For patients with STEMI undergoing primary PCI, the following supportive anticoagulant regimens are recommended:

• UFH, with additional boluses administered as needed to maintain therapeutic activated clotting time levels, taking into account whether a GP IIb/IIIa receptor antagonist has been administered; or

• Bivalirudin with or without prior treatment with UFH.

I IIa IIb III

I IIa IIb III

Anticoagulant Therapy to Support Primary PCI


In patients with STEMI undergoing PCI who are at high risk of bleeding, it is reasonable to use bivalirudin monotherapy in preference to the combination of UFH and a GP IIb/IIIa receptor antagonist.

Fondaparinux should not be used as the sole anticoagulant to support primary PCI because of the risk of catheter thrombosis.

I IIa IIb III

I IIa IIb III

Harm

3602 pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…

Primary PCICABG – Medical Rx–

UFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)

Bivalirudin monotherapy(± provisional GP IIb/IIIa)

Aspirin, thienopyridineR

1:1

3000 pts eligible for stent randomization R 1:3

Bare metal stent TAXUS paclitaxel-eluting stent

Clinical follow-up: 30 days, 6 months, 1 year, then yearly through 5 years

Horizons‐AMI Trial

Stone GW et al. N Engl J Med. 2008; 358:2218-30.

12.1

8.3

5.5

9.2

4.9 5.4

0

5

10

15

20

Net adverse clinical events Major bleeding* MACE**

30 day event rates (%

)

Heparin + GPIIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800)

Psup = 1.00

Primary Outcomes

Stone GW et al. N Engl J Med. 2008; 358:2218-30.

PNI ≤ 0.0001Psup ≤ 0.0001

PNI ≤ 0.0001Psup = 0.006

1 endpoint 1 endpoint

Net adverse clinical effects = MACE + Major BleedingMACE = All cause death, reinfarction, ischemic TVR or stroke


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30 Day MACE ComponentsUFH + GP IIb/IIIa

(N=1802)Bivalirudin(N=1800)

P Value

Death 3.1% 2.1% 0.058

‐ Cardiac 2.9% 1.8% 0.035

‐ Non cardiac 0.2% 0.3% 0.75

Reinfarction 1.8% 1.8% 0.90

‐ Q‐wave 1.2% 1.4% 0.66

‐ Non Q‐wave 0.7% 0.4% 0.50

Ischemic TVR* 1.9% 2.6% 0.18

‐ Ischemic TLR** 1.8% 2.5% 0.14

‐ Ischemic remote TVR 0.3% 0.3% 1.0

Stroke 0.6% 0.7% 0.69

Stone GW et al. N Engl J Med. 2008; 358:2218-30.* = Target Vessel Revascularization** = Target Lesion Revascularization

30 Day Bleeding EndpointsUFH + GP IIb/IIIa

(N=1802)Bivalirudin(N=1800)

P Value

Protocol Major, non CABG* 8.3% 4.9% <0.0001

Protocol Major, All 10.8% 6.8% <0.0001

Protocol Minor 15.4% 8.6% <0.0001

Blood transfusion 3.5% 2.1% 0.01

TIMI Major 5.0% 3.1% 0.003

TIMI Minor 4.6% 2.8% 0.008

TIMI Major or Minor 9.6% 5.9% <0.0001

GUSTO Life threatening (LT) /Severe 0.6% 0.4% 0.65

GUSTO Moderate 5.0% 3.1% 0.003

GUSTO LT or Severe or Moderate 5.6% 3.5% 0.003

Stone GW et al. N Engl J Med. 2008; 358:2218-3a0.*Primary endpoint

Bivalirudin: Conflicting data!

Study UFH Dose Ischemic Endpoints

Major Bleeding Stent Thrombosis

HEAT – PPCI 70 units/kg UFH: 5.7%Bival: 8.7%

UFH: 3.1%Bival: 3.5%(no significant difference)

UFH: 0.9%Bival: 3.4%

BRIGHT 100 units/kg UFH: 13.2%Bival: 8.8%

UFH: 7.5%Bival: 4.1%

UFH: 0.9%Bival: 0.6% (no significant difference)

Shazad A et al. Lancet 2014;384:1849-58.

Han Y et al. JAMA 2015;313:1336-46.

Major Bleeding

Study Bivalirudin Heparin

HORIZONS‐AMI 89/1800 (5%) 149/1802 (8%)

EUROMAX 28/1089 (3%) 67/1109 (6%)

BRIGHT 4/729 (1%) 14/724 (2%)

HEAT PPCI 32/905 (4%) 28/907 (3%)

OVERALL 308/10 600 (3%) 593/10 900 (5%)

Cavendar MA. Lancet 2014;384:599-606.

Acute Stent Thrombosis

Study Bivalirudin Heparin

HORIZONS‐AMI 21/1571 (1.3%) 4/1553 (0.2%)

EUROMAX 12/1089 (1.1%) 2/1109 (0.2%)

HEAT PPCI 20/697 (2.8%) 6/682 (0.8%)

OVERALL 53/3357 (1.5%) 12/3344 (0.3%)

Cavendar MA. Lancet 2014;384:599-606.

Dosing: Anticoagulants: STEMI with Primary PCI



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Question # 2Based on clinical trial data, which of the following P2Y12inhibitors was associated with a reduction in all‐cause mortality when given in combination with aspirin for the treatment of ACS?

A. Ticagrelor

B. Prasugrel

C. Clopidogrel

D. Ticlopidine

Antiplatelet Therapy to Support Primary PCI for STEMI


A loading dose of a P2Y12 receptor inhibitor should be given as early as possible or at time of primary PCI to patients with STEMI. Options include:

• Clopidogrel 600 mg; or

I IIa IIb III

• Prasugrel 60 mg; or

• Ticagrelor 180 mg

Antiplatelet Therapy to Support Primary PCI for STEMI


P2Y12 inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (BMS or DES) during primary PCI using the following maintenance doses:

• Clopidogrel 75 mg daily; or

I IIa IIb III

• Prasugrel 10 mg daily; or

• Ticagrelor 90 mg twice a day*

*The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.

PLATO Study Design

Wellentin L et al. N Engl J Med. 2009; 361:1045-57.

Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding

6–12-month exposure

ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,

then 75 mg daily maintenance;(additional 300 mg allowed pre PCI)

Ticagrelor180 mg loading dose, then

90 mg bid maintenance;(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) or STEMI (if primary PCI)Clopidogrel-treated or -naive;

randomised within 24 hours of index event (N=18,624)

All patientsTicagrelor(n=9,333)

Clopidogrel(n=9,291)

HR for (95% CI) p value

Primary objective, n (%)

CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001

Secondary objectives, n (%)

Total death + MI + stroke

CV death + MI + stroke +ischemia + TIA + arterial thrombotic events

Myocardial infarction

CV death

Stroke

901 (10.2)

1,290 (14.6)

504 (5.8)

353 (4.0)

125 (1.5)

1,065 (12.3)

1,456 (16.7)

593 (6.9)

442 (5.1)

106 (1.3)

0.84 (0.77–0.92)

0.88 (0.81–0.95)

0.84 (0.75–0.95)

0.79 (0.69–0.91)

1.17 (0.91–1.52)

<0.001

<0.001

0.005

0.001

0.22

All‐cause mortality 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001


Results: Primary and Secondary Endpoints


No Significant Differences

0

% p

er y

ear

PLATO major bleeding

1

2

3

4

5

6

7

8

9

10

12

11

13

TIMI major bleeding

Red cell transfusion*

PLATO life-threatening/

fatal bleeding

Fatal bleeding

11.611.2

7.9 7.7

8.9 8.9

5.8 5.8

0.3 0.3

TicagrelorClopidogrelTotal Major Bleeding


14

Wellentin L et al. N Engl J Med. 2009; 361:1045-57.p=0.026 p=0.025 p=NS p=NS

9

% p

er

yea

r

Non-CABGPLATO major

bleeding

8

7

6

5

4

3

2

1

0Non-CABGTIMI major bleeding

CABGPLATO major

bleeding

CABG TIMI major bleeding

4.5

3.8

2.8

2.2

7.4

7.9

5.3

5.8

TicagrelorClopidogrel

Non‐CABG and CABG‐related Major Bleeding Case Continues

• Two drug‐eluting stents (DES) are placed in the left anterior descending artery (LAD).

Question # 3Based on current clinical data, which of the following represents the optimal dose of aspirin?

A. Enteric‐coated aspirin 81 mg daily for 1 month

B. Enteric‐coated aspirin 325 mg daily for 6 months followed by 81 mg daily indefinitely

C. Aspirin 81 mg daily indefinitely

D. Aspirin 325 mg daily indefinitely

Aspirin Recommendations:Primary PCI for STEMI


Aspirin 162 to 325 mg should be given before primary PCI.

After PCI, aspirin should be continued indefinitely.

I IIa IIb III

I IIa IIb III

Aspirin Dosing: Primary PCI for STEMI


It is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses after primary PCI.

I IIa IIb III

Aspirin Recommendations: PCI Guidelines

• Patients not on aspirin therapy should be given nonenteric aspirin 325 mg before PCI (Level of Evidence: B)

• After PCI, use of aspirin should be continued indefinitely (Level of Evidence: A)

• After PCI, it is reasonable to use aspirin 81 mg per day in preference to higher maintenance doses (Class IIa, Level of Evidence: B)

Levine GN et al. Circulation. 2011; 124:e574-e651.


15

Enteric Coated Aspirin

• 400 healthy volunteers screened for response to 325 mg

– Either Enteric coated or plain aspirin

• All patients in plain aspirin group responded pharmacologically

• 17‐49% were non‐responders in the enteric coated aspirin group

– Required multiple doses to correct

Grosser T. Circulation. 2013; 127:377-85.

Question # 4Which of the following represents the optimal duration of dual antiplatelet (DAPT) therapy?

A. 1 month

B. 6 months

C. 9 months

D. At least 12 months

Duration of DAPT:Primary PCI for STEMI


P2Y12 inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (BMS or DES) during primary PCI using the following maintenance doses:

• Clopidogrel 75 mg daily; or

I IIa IIb III

• Prasugrel 10 mg daily; or

• Ticagrelor 90 mg twice a day

I IIa IIb IIIContinuation of a P2Y12 inhibitor beyond 1 year may be considered in patients undergoing DES placement.

Duration of DAPT: UA/NSTEMI and PCI Guidelines

• In patients receiving a stent (Bare Metal Stent or Drug‐eluting Stent) during PCI for ACS, P2Y12 inhibitor therapy should be given for at least 12 months.

• Level of Evidence: B (both guidelines)

Levine GN. Circulation. 2011; 124:e574-e651.

Jneid H. Circulation. 2012; 126:875-910.

Dual antiplatelet therapy (DAPT) Study

• Objectives:– In patients with DES: whether DAPT beyond 12 months is associated with: —reduction in stent thrombosis and/or

—major adverse cardiovascular and cerebrovascular events (MACCE)

– Defined as a composite of: Death, MI, stroke

– To determine the impact of prolonged DAPT on moderate or severe bleeding

Mauri L et al. N Engl J Med 2014;371:2155-66.

DAPT Study Design


12 Month observational period: Open label ASA +

Thienopyridine(n: 25,682)

3‐Month observational period: On ASA,

off Thienopyridine

THIENOPYRIDINE + ASPIRIN(n: 5020)

PLACEBO + ASPIRIN(n: 4941)

0 12 30 33Time in months after index stent procedure

Thienopyridine: Clopidogrel (65%), Prasugrel (35%) of patients enrolled


16

Results: MACCE Endpoint


# At Risk

Thienopyridine 5020 4917 4840 4778 4702 4611 4554 3029

Placebo 4941 4799 4715 4635 4542 4476 4412 2997

12‐30 Months: HR 0.71 (0.59‐0.85) 4.3% vs. 5.9% P<0.001

Thienopyridine Placebo

10%

8%

6%

4%

2%

0%

Cum

ulat

ive

Inci

denc

e of

D

eath

, Myo

card

ial I

nfar

ctio

n or

Str

oke

12 15 18 21 24 27 30 33

Months After Enrollment

Primary Analysis Period

Study Drug Treatment Ends

Results: Stent Thrombosis


# At Risk

Thienopyridine 5020 4934 4870 4828 4765 4686 4642 3110

Placebo 4941 4845 4775 4721 4651 4603 4556 3105

12‐30 Months: HR 0.29 (0.17‐0.48) 0.4% vs. 1.4% P<0.001


10%

8%

6%

4%

2%

0%

Cum

ulat

ive

Inci

den

ce o

f S

tent

Thr

ombo

sis

12 15 18 21 24 27 30 33

Months After Enrollment

Primary Analysis Period

Study Drug Treatment Ends

DAPT: Safety results

0

0.5

1

1.5

2

2.5

Moderate or severebleeding

Moderate Severe

2.5

1.7

0.8

1.6

1

0.6

Cumulative In

cidence (%)



p=0.001p=0.004 p=0.15

P2Y12 Inhibitors: Clinical Pearls

• Prasugrel:– should not be administered to patients with a history of prior stroke or transient ischemic attack.

– Generally not recommended in patients with age ≥ 75 years old

• Ticagrelor:– the recommended maintenance dose of aspirin to be used with is 81 mg daily.

Brilinta (ticagrelor) prescribing information. Wilmington, DE: AstraZeneca, LP; 2013 Dec.

Effient (prasugrel) prescribing information. Indianapolis, IN: Eli Lilly and Company; 2013 Nov.

Question # 5Which of the following represents the best lipid‐lowering pharmacotherapy plan?

A. Rosuvastatin 10 mg po daily

B. Simvastatin 20 mg po daily

C. Pravastatin 40 mg po daily

D. Atorvastatin 80 mg po daily

2013 STEMI Guidelines:Lipid Management


High-intensity statin therapy should be initiated or continued in all patients with STEMI and no contraindications to its use.

It is reasonable to obtain a fasting lipid profile in patients with STEMI, preferably within 24 hours of presentation.

I IIa IIb III

I IIa IIb III


17

2013 ACC/AHA Cholesterol Guidelines

• Statin therapy recommended in 4 groups:1. Adults with clinical ASCVD (atherosclerotic cardiovascular

disease)

2. Adults with LDL‐C ≥190 mg/dL

3. Adults 40 to 75 years of age with diabetes

4. Adults ≥7.5% estimated 10‐year risk of ASCVD

• ASCVD:– Inclusion criteria for secondary prevention statin RCTs:

— Acute Coronary Syndromes, hx MI, unstable angina

— Stroke/TIA

— Peripheral artery disease

Stone NJ et al. Circulation. 2013 Nov 12. Epub ahead of print.


• Appropriate intensity of statin therapy is recommended to reduce the risk of ASCVD by lowering LDL‐C and non‐HDL‐C

• Patients with clinical ASCVD– Age < 75 years‐old = High intensity statin

• “Treat to target” and “lower is best” strategies are no longer advocated



• High Intensity statins: (reduce LDL ≥ 50%)

– Atorvastatin 80 mg daily

– Atorvastatin 40 mg daily

— Down‐titration in the IDEAL trial

– Rosuvastatin 20 mg (40mg) daily


4,162 patients with an Acute Coronary Syndrome < 10 days

ASA + Standard Medical Therapy

“Standard Therapy”Pravastatin 40 mg daily

“Intensive Therapy”Atorvastatin 80 mg daily

Duration: Mean 2 year follow-up (>925 events)

PROVE IT ‐ TIMI 22: Study Design

Cannon CP et al. N Engl J Med. 2004; 350:1495-504.

2x2 Factorial: Gatifloxacin vs. placebo

Double-blind

Primary Endpoint: Death, MI, Documented unstable angina requiring hospitalization, Stroke

Results Summarized

• Primary endpoint: 16% reduction in the hazard ratio favoring atorvastatin (p= 0.005)

• Secondary Endpoints:

– Death/MI/urgent revascularization: 25% reduction

• No difference in discontinuation rates

– No difference in myalgias, no rhabdomyolysis

– Increase ALT > 3 times: 3.3% vs. 1.1%


Atorvastatin Pravastatin p value

Death due to CHD, MI, or revasculazation*

0.029

Death, MI or urgent revasculaization*

<0.001

Death from any cause (%) 2.2 3.2 NSp=0.07

Death from CHD (%) 1.1 1.4 NS

MI (%) 6.6 7.4 NS

Stroke (%) 1.0 1.0 NS

Revascularization (%) 16.3 18.8 < 0.05

Unstable angina requiringhospitalization (%)

3.8 5.1 < 0.05


Components of the Primary Endpoint


18

Case Continues:

• Patient experiences worsening shortness of breath post PCI

• ECHO:

– Ejection Fraction (EF): 30 – 35%

– Apical Akinesis

– Suggestions of LV Mural Thrombus

Current Medications• Aspirin 81 mg po daily• Clopidogrel 75 mg po daily • Lisinopril 20 mg po daily• Atorvastatin 80 mg po daily• Carvedilol 3.125 mg po BID• Chlorthalidone 25 mg po daily• Docusate 100 mg po BID PRN• Nitroglycerin 0.3mg SL PRN chest pain

• Medication changes:– D/C Amlodipine – to allow for addition of carvedilol– D/C Ticagrelor – cost concerns, changed to clopidogrel– Temporarily withholding metformin, contrast dye exposure during PCI

Question # 6Which of the following therapies should be initiated to reduce all‐cause mortality?

A. Aliskiren

B. Eplerenone

C. Valsartan

D. Furosemide

Renin‐Angiotensin‐Aldosterone System Inhibitors


An ACE inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or EF less than or equal to 0.40, unless contraindicated.

An ARB should be given to patients with STEMI who have indications for but are intolerant of ACE inhibitors.

I IIa IIb III

I IIa IIb III

ACE inhibitors are reasonable for all patients with STEMI and no contraindications to their use.

I IIa IIb III

Aldosterone Antagonists


An aldosterone antagonist should be given to patients with STEMI and no contraindications who are already receiving an ACE inhibitor and beta blocker and who have an EF less than or equal to 0.40 and either symptomatic HF or diabetes mellitus.

I IIa IIb III

Eplerenone (n = 3,313)Eplerenone (n = 3,313)

Placebo(n = 3,319)Placebo

(n = 3,319)

Endpoints (at mean of 16 month follow‐up):

Primary – 1) death from any cause and 2) death or hospitalization from CV causes

Endpoints (at mean of 16 month follow‐up):

Primary – 1) death from any cause and 2) death or hospitalization from CV causes

EPHESUS Trial

Pitt B. N Engl J Med. 2003; 348:1309-21.

Optimal medical therapy(ACE inhibitors, angiotensin‐receptor blockers, diuretics, and beta‐blockers,

coronary reperfusion therapy)

Optimal medical therapy(ACE inhibitors, angiotensin‐receptor blockers, diuretics, and beta‐blockers,

coronary reperfusion therapy)

6,632 patients with acute MI complicated by

heart failure and systolic left ventricular

dysfunction Acute MI in prior 3‐14 days

Left ventricular dysfunction (EF <40%)

Heart failure (in non‐diabetics but not required for diabetics)

6,632 patients with acute MI complicated by

heart failure and systolic left ventricular

dysfunction Acute MI in prior 3‐14 days

Left ventricular dysfunction (EF <40%)

Heart failure (in non‐diabetics but not required for diabetics)


19

EPHESUS Trial: Primary Endpoints

14.4%

16.7%

0%

5%

10%

15%

20%

Pitt B. N Engl J Med. 2003; 348:1309-21.

All‐cause MortalityRR 0.85p=0.008

All‐cause MortalityRR 0.85p=0.008

26.7%

30.0%

0%

10%

20%

30%

40%

CV Death or HospitalizationRR 0.83p=0.005

CV Death or HospitalizationRR 0.83p=0.005

EplerenoneEplerenone PlaceboPlaceboEplerenoneEplerenone PlaceboPlacebo

EPHESUS Trial: Serious Adverse Events

5.5%

3.9%

0%

2%

4%

6%

8%

Pitt B. N Engl J Med. 2003; 348:1309-21.

Serious hyperkalemia

p=0.002

Serious hyperkalemia

p=0.002

0.5%0.6%

0.0%

0.5%

1.0%

1.5%

Gynecomastiap=0.70

Gynecomastiap=0.70

EplerenoneEplerenone PlaceboPlaceboEplerenoneEplerenone PlaceboPlacebo

Question # 7Which of the following represents the best outpatient monitoring regimen to minimize the risk of hyperkalemia?

A. Check serum potassium 4 weeks after hospital discharge

B. Check serum creatinine and serum potassium within 1 week after hospital discharge and again 4 weeks later

C. Check serum potassium within 1 week after hospital discharge and again 4 weeks later

D. Check serum creatinine and serum potassium 4 weeks after hospital discharge

Outpatient Potassium Monitoring

• Heart Failure Society of America Guidelines:

– It is recommended that serum potassium concentration be monitored frequently following initiation or change in an aldosterone antagonist.

– Monitoring should reflect protocols followed in clinical trials (Strength of Evidence: A)

Heart Failure Society of America. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010; 16(6):e1-e194.

Potassium Monitoring: Clinical Trials

• Clinical trials of aldosterone antagonists

– EPHESUS: The serum potassium concentration was measured 48 hours after the initiation of treatment, at one, four, and five weeks, at all scheduled study visits, and within one week after any change of dose

– EMPHASIS‐HF

— Similar recommendations

Pitt B. N Engl J Med. 2003; 348:1309-21.Zannad F. N Engl J Med. 2011;364:11-21.

Question # 8Which of the following should be initiated to reduce complications from apical akinesis?

A. Warfarin for 3 months, Goal INR: 2 – 2.5

B. Warfarin for 3 months: Goal INR 2.5 – 3.5

C. Unfractionated heparin during hospitalization

D. Enoxaparin during hospitalization


20

Anticoagulation


Anticoagulant therapy with a vitamin K antagonist is reasonable for patients with STEMI and asymptomatic LV mural thrombi.

Targeting vitamin K antagonist therapy to a lower international normalized ratio (e.g., 2.0 to 2.5) might be considered in patients with STEMI who are receiving DAPT.

Anticoagulant therapy may be considered for patients with STEMI and anterior-apical akinesis or dyskinesis.

I IIa IIb III

I IIa IIb III

I IIa IIb III

Anticoagulation

• In LV thrombus, without anticoagulation:– Risk of embolization is 10‐15%– Most events occur within the first 3 – 4 months

• No randomized trials, only observational data• Meta‐analysis of 7 observational studies

– 270 patients with anterior MI and LV thrombus (ECHO documented)

– Anticoagulation = 86 % reduction in the rate of embolization

– Odds ratio 0.14, 95% CI 0.04‐0.52

Vaitkus PT. J Am Coll Cardiol. 1993; 22(4):1004-9.

Question # 9Which of the following medications is the most appropriate recommendation for smoking cessation?

A. Varenicline

B. Nortriptyline

C. Nicotine Patch

D. Bupropion SR

Post Hospitalization Plan of Care


Encouragement and advice to stop smoking and to avoid secondhand smoke should be provided to patients with STEMI.

I IIa IIb III

Smoking Cessation Counseling

• The 5 A’s

– Ask patient if they smoke

– Advise tobacco users to quit

– Assess the patient’s: readiness to quit

– Assist the patient with quitting

– Arrange follow‐up care

Fiore MC, Jaén CR, Baker TB et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health

Service. May 2008.

Smith SC et al. Circulation. 2011; 124:2458-73.

Smoking Cessation Pharmacotherapy

• First line therapy: Many options!—Nicotine replacement therapies (NRT)

– Patch– Gum– Lozenge– SL Tablets– Sprays– Inhaler

– Bupropion SR– Varenicline

• Second line options: many more!– TCAs– Clonidine– Anxiolytics: Buspirone, Benzodiazepines, Beta‐Blockers


21

Cochrane Network Meta‐analysis

• Identified 267 studies = 101,804 patients

• Nicotine replacement therapy (NRT), bupropion and varenicline all improve the chances of quitting.

• Combination use of NRT is as effective as varenicline – More effective than single types of NRT

Cahill K et al. Cochrane Database Syst Rev. 2013; 5:CD009329.Cahill K et al. Cochrane Database Syst Rev. 2013; 5:CD009329.

1.00.5 1.5 2.0 2.5 3.0 3.5

NRT vs. Placebo

Comparisons

Bupropion vs. Placebo

Varenicline vs. Placebo

Varenicline vs. NRT

Bupropion vs. NRT

Varenicline vs. Bupropion

Odds Ratio(95% CI)

Number of Studies

1.84 (1.71‐1.99) 119

1.82 (1.6 – 2.06) 36

2.88 (2.4‐3.47) 15

0.99 (0.86‐1.13) 9

1.57 (1.29‐1.91) 0

1.59 (1.29‐1.96) 3

Comparison of Therapies Smoking Abstinence for ≥ 6 Months

Varenicline Warnings

• A meta‐analysis of 15 clinical trials, including a trial in patients with stable cardiovascular disease

– Demonstrated cardiovascular events were infrequent overall

– Reported more frequently in patients treated with varenicline

– These events occurred primarily in patients with known cardiovascular disease

Chantix (vareniciline) prescribing information. New York, NY: Pfizer Labs; 2013 Feb.

Precautions: Nicotine Replacement

• Recent (< 2 weeks) myocardial infarction

• Serious underlying arrthymias

• Serious or worsening angina pectoris

University of California San Francisco Center for Tobacco Control Research and Education. Smoking cessation leadership center. URL in ref list.

Smoking Cessation ResourcesInternet based Resources:

• Smoking cessation leadership center– http://smokingcessationleadership.uscf.edu

• Treatobacco.netNon‐pharmaceutical Cessation Support

• ASPIRE: MD Anderson Cancer Center • Become an Ex

– http://www.becomeanex.com

• Quit Key – handheld device for gradual reduction• Quit Net – online comprehensive support program

– http://www.quitnet.com

Pharmaceutical Company Aids:• Nicorette: http://www.nicorette.com• NicoDerm CQ: http://www.nicodermcq.com• Chantix: http://www.chantix.com• Nicotrol: http://www.nicotrol.com

University of California San Francisco Center for Tobacco Control Research and Education. Smoking cessation leadership center. URL in ref list.

Quality of Life Related Issues

• Likely to be reduced acutely:

– Post STEMI

– Quitting smoking

– Starting carvedilol

• Encourage family friend support

– Consider cardiac rehabilitation

– Consider additional community/online resources


22

Additional Patient Resources

• Mended Hearts: National and community non‐profit support group for patients and families with heart disease. http://mendedhearts.org

• American Heart Association patient tools and resources for cardiovascular diseases. http://www.heart.org/HEARTORG/Conditions/Conditions_UCM_001087_SubHomePage.jsp

ACS: Discharge Summary• 57 year‐old African‐American man with extensive cardiac history:

HTN, Dyslipidemia, presented with anterior STEMI. • Current Medications:

– Aspirin 81 mg po daily– Clopidogrel 75 mg po daily– Lisinopril 20 mg po daily– Atorvastatin 80 mg po daily– Eplerenone 25 mg po daily– Carvedilol 3.125 mg po BID– Metformin 500 mg po BID– Bupropion SR 150 mg po BID– Warfarin – Docusate 100 mg po BID PRN– Nitroglycerin 0.3 mg SL PRN chest pain

Case Continues

• 2 years later, patient is now admitted for acute decompensated heart failure

• Past Medical History:– Hypertension– Dyslipidemia– Anterior STEMI– Stage 2 CKD – GERD (diagnosed 6 months ago, after he did not respond to over‐the‐counter options)

• Current Medications:– Aspirin 81 mg po daily– Clopidogrel 75 mg po daily – Lisinopril 20 mg po daily– Eplerenone 25 mg po daily– Atorvastatin 80 mg po daily– Carvedilol 6.25 mg po BID– Metformin 1000 mg po BID– Omeprazole 20 mg po daily– Nitroglycerin 0.3 mg SL PRN chest pain

Case Continues

• Pertinent Laboratory data:

– Na: 130 mEq/L

– K: 4.8 mEq/L

– Serum creatinine: 1.4 mg/dL

Case Continues

• ECG: no ischemic changes

• ECHO: EF 30 – 35%

• Physical exam:– 3 + pitting edema up to the calves

– Crackles: ½ way up lung fields bilaterally

– Weight: increased 15 lb over past week

• Chest X‐Ray: Pulmonary edema

• NT‐pro‐BNP: 5800 ng/mL

Question # 10Which of the following should be initiated at this time?

A. Torsemide 40 mg PO x 1 dose

B. Furosemide 80 mg IV x 1 dose

C. Metolazone 2.5 mg PO x 1 dose

D. Chlorothiazide 500 mg IV x 1 dose


23

Diuretics in Hospitalized Patients with Heart Failure

Patients with HF admitted with evidence of significant fluid overload should be promptly treated with intravenous loop diuretics to reduce morbidity.

If patients are already receiving loop diuretic therapy, the initial intravenous dose should equal or exceed their chronic oral daily dose and should be given as either intermittent boluses or continuous infusion. Urine output and signs and symptoms of congestion should be serially assessed, and the diuretic dose should be adjusted accordingly to relieve symptoms, reduce volume excess, and avoid hypotension.

Yancy CW et al. J Am Coll Cardiol. 2013; 62:e147-239.

I IIa IIb III

I IIa IIb III

Question # 11In addition to diuretic therapy, which of the following represents the best approach to managing hyponatremia?

A. Start oral tolvaptan

B. Give 3 % sodium chloride IV

C. Start IV conivaptan

D. Use fluid restriction

Hyponatremia Expert Panel Recommendations: Heart Failure

Verbalis JG et al. Am J Med. 2013; 126:S1-S42.

• For patients with mild to moderate symptoms, begin with fluid restriction (1 L/day total): – If signs of volume overload are present, administer loop diuretics.

• For severely symptomatic patients with very low or rapidly falling sodium: – treatment should consist of hypertonic saline (3%) combined with loop diuretics to prevent fluid overload;

• If the serum sodium does not correct to the desired level: – lift the fluid restriction and start either conivaptan or tolvaptan

HFSA Guidelines: Hyponatremia

• Fluid restriction (2 L/day) is recommended in patients with moderate hyponatremia (serum sodium < 130 mEq/L) and should be considered to assist in treatment of fluid overload in other patients.

– Strength of Evidence: C

Heart Failure Society of America. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010; 16(6):e1-e194.

Arginine Vasopressin Antagonists

In patients hospitalized with volume overload, including HF, who have persistent severe hyponatremia and are at risk for or having active cognitive symptoms despite water restriction and maximization of guideline‐directed medical therapy (GDMT), vasopressin antagonists may be considered in the short term to improve serum sodium concentration in hypervolemic, hyponatremic states with either a V2 receptor selective or a nonselective vasopressin antagonist.


I IIa IIb III

Recent Tolvaptan Warning

• Risk of liver injury has been described in those with pre‐existing liver disease when exposed to AVP antagonists

U.S. Food and Drug Administration. Samsca (tolvaptan): drug warning—potential risk of liver injury. January 25, 2013. URL in ref list.


24

Question # 12Which of the following represents the best acid suppressive therapy recommendation for BV to minimize both bleeding and potential dual antiplatelet therapy (DAPT) drug interactions

A. Pantoprazole 40 mg dailyB. Esomeprazole 20 mg

dailyC. Omeprazole 20 mg dailyD. Omeprazole 20 mg daily

plus ranitidine 150 mg twice daily

GI bleedingDual antiplatelet therapyConcomitant anticoagulant

Algorithm to Assess GI Risk With Antiplatelet Therapy

Bhatt DL et al. JACC. 2008; 52:1502–17.

Assess GI risk factors

History of ulcer complication History of ulcer disease (nonbleeding)

Test for H pylori; treat if infected

More than one risk factor:Aged 60 years or moreCorticosteroid useDyspepsia or GERD symptoms

Need for antiplatelet therapy

Yes

Yes

No

PPI

Yes

Yes

Clopidogrel – PPI Drug Interaction

• VERY controversial!!!

• Studies associated with interaction:– Case‐control, cohort studies (retrospective)

– Platelet reactivity studies

• Studies that suggest no interaction exists– Case‐control, cohort studies (retrospective)

– COGENT trial

Clopidogrel and PPIs – The OCLA studyClopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite

PPIs are strong inhibitors of CYP2C19 activity

‐32.6

‐43.3-50-45-40-35-30-25-20-15-10-50

PR

I V

aria

tio

n (

%)

Omeprazole (n=64)

Placebo (n=60)

PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)

p<0.0001

Gilard et al. J Am Coll Cardiol. 2008; 51:256-60.

Ho PM et al. JAMA. 2009; 301:937-44.

0.70

0.60

0.50

0.40

0.30

0.20

0.10

00 90 180 270 360 450 540 630 720 810 900 990 1080

Days Since Discharge

Pro

po

rtio

n o

f D

ea

ths

or

Re

curr

en

t AC

S

Neither clopidogrel nor PPIPPI without clopidogrelClopidogrel + PPIClopidogrel without PPI

n = 8205

Retrospective Cohort: Risk of All‐Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI

Standard‐Dose Clopidogrel + Omeprazole Versus Standard‐Dose Clopidogrel + Pantoprazole: Cross Over Comparison

Angiolillo DA et al. Clin Pharmacol Ther. 2011; 89:65-74.

Mean ± SEM of Vasodilator‐Stimulated Phosphoprotein Phosphorylation‐Platelet Reactivity Index (%)

LD, loading dose; MD, maintenance dose; SEM, standard error of the mean; VASP-PRI, vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index.

• After coadministering omeprazole (left panel) or pantoprazole (right panel) with clopidogrel (300-mg LD/75-mg/day MD), the estimated treatment differences (90% CIs) at Day 5 were:

– 20.7% (90% CI, 14.1% to 27.2%; P<0.0001) for omeprazole and

– 3.9% (–2.7% to 10.4%; P=0.3319) for pantoprazole.

0

10

20

30

40

50

60

70

80

90

100

Day 1Predose

Day 2Predose

Day 5 Post‐dose

VA

SP

-PR

I (%

)

Clopidogrel alone

Clopidogrel +omeprazole

0

10

20

30

40

50

60

70

80

90

100

Day 1Predose

Day 2Predose

Day 5 Post‐dose

VA

SP

-PR

I (%

)

Clopidogrel alone

Clopidogrel +pantoprazole

Clopidogrel ± Omeprazole Clopidogrel ± Pantoprazole


25

COGENT Trial: Methods

• Multicenter, international, randomized, double‐blind, double‐dummy, placebo‐controlled, parallel group, phase 3 efficacy and safety study of CGT‐2168, a fixed‐dose combination of clopidogrel (75 mg) and omeprazole (20 mg), compared with clopidogrel.

• Patients were stratified based on two baseline factors: H. pylori serology (positive or negative) and concomitant use of any NSAID.

• All patients were to receive enteric coated aspirin at a dose of 75 to 325 mg.

Bhatt DL et al. N Engl J Med. 2010; 363:1909-17.

COGENT Trial: Endpoints• The GI endpoint:

– Upper GI bleeding, – Bleeding of presumed occult GI origin with decrease in hemoglobin of ≥ 2 g/dL

or decrease in hematocrit ≥ 10%, – Asymptomatic gastroduodenal ulcer confirmed by endoscopy or radiography,– Pain of presumed GI origin with underlying multiple erosive disease confirmed

by endoscopy, obstruction, or perforation.

• The cardiovascular endpoint: – composite of cardiovascular death, non‐fatal MI, CABG or PCI, or ischemic

stroke.

• The initial planned sample size was 3200 patients, an accrual period of 1 year, and maximum follow up of 2 years. As a low rate of gastrointestinal events was observed as the trial was ongoing, the sample size target was increased to 4200 and then ~5000 (143 GI events). The study ended when the sponsor declared bankruptcy.


COGENT Trial: Enrollment and Results

• Enrollment:– 3873 patients (Below the modified target of 4200, and then 5000)

– Median follow‐up 106 days (essentially 3.5 months)– 109 adjudicated cardiovascular events – 55 adjudicated GI events (below the 143 that had been planned)

• Cardiovascular endpoint results:– 55 events: (clopidogrel + PPI group) vs. 54 events (p=0.98)– 180 day event rate: 4.9% (clopidogrel + PPI) vs. 5.7%

—HR: 0.99 (95% CI: 0.68 – 1.44, p=0.96)


FDA Label Change: Clopidogrel

• Avoid clopidogrel + omeprazole– Separating the doses in time will not avoid the interaction

• Additional medications that should be avoided:– Esomeprazole– Cimetidine– Fluconazole, Ketoconazole, Voriconazole– Etravirine– Felbamate– Fluoxetine, Fluvoxamine– TiclopidineU.S. Food and Drug Administration. Information for healthcare professionals: update to the labeling of clopidogrel

bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). November 17, 2009. URL in ref list.

Inpatient and Transitions of Care

Throughout the hospitalization as appropriate, before hospital discharge, at the first post discharge visit, and in subsequent follow‐up visits, the following should be addressed:

a. initiation of GDMT if not previously established and not contraindicated

b. precipitant causes of HF, barriers to optimal care transitions, and limitations in post‐discharge support

c. assessment of volume status and supine/upright hypotension with adjustment of HF therapy, as appropriate

d. titration and optimization of chronic oral HF therapy

e. assessment of renal function and electrolytes, where appropriate

f. assessment and management of comorbid conditions

g. reinforcement of HF education, self‐care, emergency plans, and need for adherence

h. consideration for palliative care or hospice care in selected patients.


I IIa IIb III

Interval Summary• 59 year‐old African‐American man with extensive cardiac history: HTN,

Dyslipidemia, Anterior STEMI (2 years ago), now with symptomatic acute heart failure secondary to reduced ejection fraction (HFrEF)

• Current Medications: Current labs:– Aspirin 81 mg po daily– Clopidogrel 75 mg po daily– Furosemide 40 mg po daily – Carvedilol 6.25 mg po BID– Lisinopril 20 mg po daily– Eplerenone 25 mg po daily– Atorvastatin 80 mg po daily– Metformin 1000 mg po BID– Pantoprazole 40 mg po daily– Nitroglycerin 0.3 mg SL PRN chest pain

138

4.3

104

18

24

1.3120


26

2015 pharmacotherapy specialty examination review course:...

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