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1

Laura C. Halder, Pharm.D.

Postgraduate Year Two Pharmacy Resident – Cardiology

Abbott Northwestern Hospital – Allina Health

October 30, 2014

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1. List two major changes to the 2013

cholesterol treatment guidelines.

2. Classify a statin as low, moderate, or high

intensity.

3. Describe the recommended management of

statin induced myopathy.

• Statins:

– Pravastatin (Pravachol)

– Atorvastatin (Lipitor)

– Rosuvastatin (Crestor)

– Simvastatin (Zocor)

• Niacin

• Fibrates

• Fish oil

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“Treat to target”

Issues with treat to target:

1. Unclear target in current clinical trial data

2. Unclear magnitude of risk reduction with each

different target

3. Does not consider potential adverse effects from

multidrug therapy

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Clinical ASCVD

• Acute coronary syndrome

• History of MI

• Stable or unstable angina

• Coronary revascularization

• Stroke

• TIA

• Peripheral arterial disease

No clinical ASCVD:

• LDL ≥ 190 mg/dL

• Diabetes age 40 – 75 &

LDL 70 – 189 mg/dL

• LDL 70 – 189 mg/dL &

estimated 10 year ASCVD

risk ≥ 7.5%

ASCVD: atherosclerotic cardiovascular disease

1

2

3

4

Exclusions: heart failure and dialysis

Moderate Intensity

LDL ↓ 30% - <50%

Atorvastatin 10 – 20 mg

Pitavastatin 2 – 4 mg

Fluvastatin 40 mg BID

Fluvastatin XL 80 mg

Lovastatin 40 mg

Pravastatin 40 – 80 mg

Simvastatin 20 – 40 mg

Rosuvastatin 5- 10 mg

High Intensity

LDL ↓ ≥50%

Atorvastatin 40 – 80 mg

Rosuvastatin 20 – 40 mg

Low Intensity

LDL ↓<30%

Pitavastatin 1 mg

Fluvastatin 20 – 40 mg

Lovastatin 20 mg

Pravastatin 10 – 20 mg

Simvastatin 10 mg

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Clinical ASCVD

Age ≤ 75

High intensity

Age > 75

Moderate or high intensity*

1

*Consider statin benefits,

risks, and patient preferences

Statin for secondary prevention

LDL ≥ 190 mg/dL

Diabetes

Age 40 - 75

Moderate intensity

ASCVD risk ≥ 7.5% high intensity

ASCVD ≥ 7.5%

Moderate to high intensity

Statin benefit unclear

High intensity

Yes No

No Yes

Yes Yes No

ASCVD risk calculated using http://my.americanheart.org/cvriskcalculator

2

3

4

• Statin as primary prevention

• If age ≥ 21 and LDL ≥ 190: high intensity statin

– If unable to tolerate use highest intensity tolerated

– Evaluate for secondary causes

– Intensify statin for 50% decrease in LDL

– May add non-statin drug once statin maximized

LDL ≥ 190 mg/dL

High intensity statin

2

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• If diabetes and LDL 70 – 189:

– Moderate intensity statin

– 10 year ASCVD risk ≥ 7.5%: high intensity statin

– If age <40 or >75, consider risks, benefits, and

patient preferences when starting statin

Diabetes

Age 40 - 75

Moderate intensity ASCVD risk ≥ 7.5% high intensity

3

• If age 40 – 75, no diabetes, and LDL 70 – 189:

– Calculate 10 year ASCVD risk

– Risk ≥ 7.5%: moderate or high intensity

– Risk 5 – 7.5%: consider moderate intensity

– Risk < 5%: discussion about statin benefits, risks,

and patient preferences

ASCVD ≥ 7.5%

Moderate to high intensity

Statin benefit unclear

4

• New onset diabetes:

– 0.1 – 0.3 cases per 100 patients

– Statins caused 54 new cases of DM but prevented

134 vascular events

• Hemorrhagic stroke: 0.01 cases per 100 patients

• Cognitive decline: no published evidence

– Similar rates to placebo in randomized trials

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• Multiple comorbidities

• Muscle disorders

• Renal or hepatic function dysfunction

• Previous statin intolerance

• Previous hemorrhagic stroke

• ALT > 3x ULN

• Drug interactions

• Age > 75 years

• Asian ancestry

ULN: upper limit of normal

Myalgia:

Normal CK

Myositis: Elevated CK

Rhabdomyolysis:

CK > 3x ULN

• Rate of muscle symptoms in trials: 1.5 – 5%

• Rate of muscle symptoms in practice: 5 – 10%

Muscle symptoms

CK: creatinine kinase

• Establish baseline muscle symptoms:

– Arthritis symptoms

– Muscle aches during activity

• Risk factors:

– Older age

– Female gender

– Smaller body size

– Hypothyroidism

– History of muscular problems

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Mild – moderate muscle symptoms:

1. Stop statin and evaluate possible causes

2. If symptoms resolve, give original or lower dose to

establish causal relationship

a) If causal relationship, switch to original or lower dose

b) Once low dose tolerated, increase dose as tolerated

3. If symptoms do not resolve, consider other causes

a) If other causes found, resume at original dose

• Severe muscle symptoms

– Immediately stop statin

– Check CK, creatinine, urinalysis

• No target LDL

• Baseline fasting lipid panel

• Repeat 4 – 12 weeks after initiating statin to

assess adherence and response to therapy

• Two consecutive LDL < 40, reasonable to reduce

statin dose

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• Baseline ALT and CK

• Check ALT & CK if signs of statin intolerance

• No longer check LFTs regularly

• Evaluation of diabetes onset per screening

guidelines

• Few trials, most are observational

• No evidence of improved ASCVD outcomes when

used in place of or in addition to statin

• May consider role in statin intolerance or less than

anticipated response to statins

– Currently no evidence

• Choose best statin intensity for select patients

• Limited use of LDL levels

• Statin myopathy is not always a contraindication

• Role of non-statin agents still uncertain

• Therapeutic lifestyle modifications still have a role

• Unanswered questions:

– Role of non-statin agents in severe statin intolerance

– Statins in chronic kidney disease and HF

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1. Identify three benefits of the novel oral

anticoagulants compared to warfarin.

2. Compare the key differences between the

novel oral anticoagulants.

3. Recognize two limitations of the novel oral

anticoagulants.

Dabigatran

Rivaroxaban Apixaban

Warfarin

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• Dabigatran (Pradaxa®) – 2010

• Rivaroxaban (Xarelto®) – 2011

• Apixaban (Eliquis ®) – 2012

Compared to warfarin:

+ Rapid onset of action

+ No routine lab monitoring

+ Few drug or dietary interactions

+ More predictable anticoagulant effect

+ Fixed dosing

• Lack of reversal agents

• Limited indications

– No indication for:

• Thromboembolism in oncology patients

• Mechanical valves

• Thrombophilia

• Pregnancy

• Cash price:

– NOAC: ~$3000/year

– Warfarin: ~48/year

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Non Valvular

A Fib

VTE

Treatment

VTE

Prophylaxis

Post Op VTE

Prophylaxis

Dabigatran Yes Yes No No

Rivaroxaban Yes Yes Yes Yes

Apixaban Yes Yes Yes Yes

Take with a full glass of water, with or without food

Indication Dose CrCl (ml/min) Adjustment

DVT & PE 150 mg BID > 30: none

< 30 ml/min: not studied

Atrial

fibrillation

150 mg BID > 50 ml/min: none

15 – 30 ml/min: 75 mg BID

<30 ml/min: not studied

• Low protein binding dialyzable

• Half life:

– Normal: 12 – 17 hours

– Elderly 14 – 17 hours

– Mild to moderate renal impairment: 15 – 18 hours

– Severe renal impairment: 28 hours

• Time to peak: 1 hour quick effect no bridging

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Indication Dose

CrCl (ml/min)

Dose Adjustment

VTE treatment 15 mg BID x 21 days,

then 20 mg daily

≥ 30: none

< 30: avoid use

VTE prevention 20 mg daily ≥ 30: none

< 30: avoid use

Atrial fibrillation 20 mg daily > 50: none

15- 50: 15 mg daily

<15: avoid use

HD: avoid use

Post Op DVT prevention 10 mg daily > 50: none

30-50: none, use caution

<30: avoid use

HD: avoid use

• Bioavailability is dose dependent:

– 10 mg: 80-100%

– 20 mg: 66%

• 15 or 20 mg doses: administer with evening meal

or largest meal of the day

• 10 mg dose: with or without food

• High absorption rate in stomach avoid use in

feeding tubes distal to stomach

• Absorption:

– Rapid no bridging

– Max: 2 – 4 hours after administration

• Protein binding: high not dialyzable

• Half-life:

– Normal: 5 – 9 hours

– Elderly: 11 – 13 hours

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• First NOAC to consider weight and age for dosing!

• Take with or without food

Indication Dose Renal Dose Adjustment

Atrial fibrillation 5 mg BID 2.5 mg BID if two of the following:

-- Age ≥ 80

-- Body weight ≤ 60 kg

-- SCr ≥ 1.5

VTE treatment 10 mg BID x 7 days,

then 5 mg BID

No dose adjustment

SCr > 2.5 or CrCl <25: not studied

VTE Prophylaxis 2.5 mg BID after 6

months treatment

No dose adjustment

SCr > 2.5 or CrCl <25: not studied

Post Op

DVT prevention

2.5 mg daily No dose adjustment

CrCl <30: not studied

• High protein binding not dialyzable

• Rapid onset no bridging

• Half-life: ~ 12 hours

• Dyspepsia (dabigatran)

• GI bleeding

• Hemorrhage

• Hematuria

• Anemia

• Epistaxis

• Bruising

Bleeding risk factors:

• Concomitant

anticoagulants

• Renal impairment

• Elderly

• Low body weight

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• Anticoagulants

• Antiplatelets

• CYP 3A4 inducers or inhibitors

– Amiodarone

– Dronedarone

– Azoles

– Carbamazepine

Dabigatran Rivaroxaban Apixaban

Thrombin Time (TT) Yes No No

Activated Partial

Thrombin Time (aPTT)

Yes Yes Yes

Prothrombin time (PT) No Yes Yes

International

Normalized Ratio (INR)

No Yes Yes

Specific

Assay*

Peak 184 ng/mL 290 ng/mL 1.3 units/mL

Trough 90 ng/mL 32 ng/mL 0.84 units/mL

* Not readily available at most institutions

* Does not assess efficacy of anticoagulation

• Always consider risk of thrombosis versus

procedural risk of bleeding

• Planning is key with no reversal agents

• Rapid onset/offset = short period to hold drug

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NOAC

CrCl

(ml/min)

Last Dose Before

Surgery (hrs)

Resumption After

Surgery (hrs)

Major Minor Major Minor

Dabigatran ≥ 50 24 48 – 72 48 – 72

24

30 – 49 48 – 72 96

Rivaroxaban ≥ 50 24 48 – 72 48 – 72 24

30 – 49 48 72

Apixaban ≥ 50 24 48 – 72 48 – 72 24

30 – 49 48 72

General principles:

1. Discontinue NOAC

2. Baseline lab assessment – Hgb, aPTT, PT, TT

– Drug level

– Renal function

3. Supportive care – Surgical procedures as appropriate

– Hydration

– Transfusion

4. Activated charcoal – Must be given within 2 hours of last NOAC dose

• No specific agent or guidelines available

• Dialysis only an option for dabigatran

• Potential options – PCC or Factor VII

– Not FDA approved

– Prothrombotic risk

– Limited evidence

– Conflicting data on impact of coagulation parameters

– Unknown efficacy on bleeding

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Edoxaban (Lixiana®)

• Approved in Japan

• Factor Xa inhibitor

• Once daily

• Indications: A. fib and VTE treatment and prevention

• Renal dose adjusted

• Mechanism of action:

– Direct thrombin inhibitor: dabigatran

– Factor X inhibitor: rivaroxaban, apixaban

• Indications vary for each NOAC

• Dose varies based on indication and renal function

– Apixaban dose based on age, weight, and creatinine

– Rivaroxaban must be taken with food

• Poor candidates for NOAC: – Active bleeding

– Hematologic disorder

– Prosthetic heart valve

– Poor renal function

– Pregnancy or breast feeding

– Liver disease

– Stable on warfarin (INR in range > 65%)

• Compliance and education is important!

• Careful perioperative management to limit bleeding risk

• Few options for reversal

• Individual drug levels are limited and facility specific

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• Levy JH. Pharmacology and Safety of New Oral Anticoagulants. Clin Lab Med. 2014; 34: 443-52.

• Tran H, Joseph J, Young L, et al. New oral anticoagulants: a practical guide on prescription, laboratory testing, and peri-procedural/bleeding management. International Medicine Journal. 2014; 44: 525-36.

• Lip GY and Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J. 2014; 35(18): 1844-55.

• 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. Circulation. 2013; 00:000 – 000.

• Katz DH, Intwala SS, Stone NJ. Addressing Statin Adverse Effects in the Clinic: The 5 Ms. J Cardiovasc Pharmacol Ther. 2014; 1 – 10.

• Lopez-Jimenez F, Simha V, Thomas RJ, et al. A Summary and Critical Assessment of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Filling the Gaps. Mayo Clin Proc. 2014; 89(9): 1257 – 78.

• Rivaroxaban [package insert]. Gurabo,, PR: Janssen Ortho, LLC; 2014.

• Apixaban [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2014.

• Dabigatran [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2014.