1. health and fitness
2. therapy

Giovanni Lares, PharmD
Anticoagulation Clinic, Internal Medicine, ACC
October 30, 2013
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Discuss differences in pharmacokinetics and pharmacodynamics in the elderly
Describe key considerations associated with anticoagulation in elderly patients
Apply cultural sensitivity concepts to engage in discussions related to anticoagulation in elderly patients
Determine an optimal anticoagulation regimen in an elderly patient
Identify risks and benefits associated with new anticoagulation agents
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Increase in clotting factors I, V, VIII, IX, XIIIa
Increased platelet activity
 Increased IL‐6 increased fibrinogen, PAI‐1, CRP, platelet aggregation
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Decreased serum albumin
 Increased serum concentration of protein bound drugs
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Increased total body fat
 Increased Vd of lipophilic drugs
 Decreased Vd for hydrophilic drugs
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Comorbidities (e.g. heart failure, diabetes, etc) Decreased hepatic first‐pass metabolism
 Decreased liver mass, perfusion
 Increased bioavailability of some drugs
 Impaired phase 1 metabolism
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Decreased renal excretion
 Increased bioavailability of some drugs
Drug Metab Rev 2009;41:67
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Treatment/prevention of thrombosis
 DVT, PE
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Prevention of stroke in patients with artificial heart valves
 Lifelong anticoagulation indicated in patients with mechanical valves
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Prevention of stroke in patients with atrial fibrillation (AF) and concomitant risk factors
 CHADS2 score ≥1
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Atrial fibrillation is highly prevalent in older adults  1.5% of adults aged 60 to 70 years  10% of adults aged >80 years
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AF increases the risk of stroke 4‐ to 5‐fold, across all age groups
Risk of stroke attributable to AF increases with age
 1.5% risk in ages 50 to 59 years
 23.5% in ages 80 to 89 years 
Strokes in AF are more severe and disabling, and associated with high mortality ~50% at 1 year Circulation 2011;123:104-23
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Off warfarin
On warfarin
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CHADS2
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Congestive Heart Failure = 1 point
Hypertension = 1 point
Age >75 years = 1 point
Diabetes = 1 point
Stroke or TIA = 2 points
CHA2DS2VASC
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Congestive Heart Failure = 1 point
Hypertension = 1 point
Age >75 years = 2 points
Diabetes = 1 point
Stroke/TIA/systemic
thromboembolism = 2 points
Vascular disease = 1 point
Age 65 – 74 years = 1 point
Sex Category (female) = 1 point
Moderate-high risk: ≥2 points
Low risk: 0 – 1 point
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Despite its benefit in elderly patients, warfarin is underutilized
 Used in only one‐third of eligible patients >85 years despite lack of contraindications
 Providers & Patients  Physicians underestimate stroke prevention by as much as 22% and overestimate bleeding risk by as much as 670%  AF patients aged 70‐85 years, when educated on risk/benefits, 61% chose warfarin, 47% of those not on warfarin would have chosen it  Interview study of physicians and patients with high risk of stroke
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 Minimum number of strokes prevented (100 pts/2y) to justify warfarin was lower for patients than for physicians (1.8 vs. 2.5, p=0.009)  Maximum number of bleeds acceptable to patients (100 pts/2y) was higher than for physicians (17.4 vs. 10.3, p<0.001) Ann Intern Med 1999;131:927–34
BMJ 2000;320:1380-4
BMJ 2001;323:1-7
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HAS‐BLED Score (AF)
 Hypertension = 1 point
 Abnormal renal/hepatic function = 1 point
 1 point for each  Stroke = 1 point
 Bleeding history or anemia = 1 point
 Labile INR = 1 point  Elderly (age > 75 years) = 1 point
 Drugs (NSAIDs, antiplatelet, EtOH) = 1 point  1 point for each
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High risk (> 4%/year) ≥4 points
Moderate risk (2‐4%/year) 2 – 3 points
Low risk (< 2%/year) 0 – 1 point
Chest 2010;138(5):1093-100.
HEMHORR(2)HAGES Score
 Hepatic or renal disease = 1 point
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 1 point for each
Ethanol abuse = 1 point
Malignancy = 1 point
Older age (>75 years) = 1 point
Reduced platelet count/function = 1 point
 Platelets<75,000, use of antiplatelets, NSAID
Rebleeding = 2 points
Hypertension = 1 point
Anemia = 1 point
Genetic factors = 1 point
 CYP2C9*2, CYP2C9*3
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Excessive fall risk = 1 point
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Stroke = 1 point
 Alzheimer’s, Parkinson’s, etc.
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Patients >80 years
II
Chest 2010;138(5):1093-100.
Circulation 2007;115:2689-96.
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Limited data in elderly patients
 Risk ranges 2.5‐13.1 per 100 person‐years
▪ Increased risk with INR>4, first 90 days of warfarin use
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Risk of intracranial hemorrhage (ICH) is about 0.5% per year with INR 2‐3
 Increased risk: SBP≥160mmHg, DBP≥90mmHg (4‐fold), concurrent high dose ASA
Circulation 2007;115:2689-96.
Ann Intern Med1994;120:897–902.
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Fall risk is frequently listed as a barrier to anticoagulation in the elderly
 33% of people >65 fall each year
 Average number of falls is 1.8 per year
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A Markov decision model using 49 published studies:
 Average stroke risk 6%, average fall risk 33%, life expectancy average 13 years
 Conclusion: ▪ A patient with AF would have to fall 295 times in one year for the risk of anticoagulation to outweigh its benefits Arch Intern Med 1999;159:677-85.
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57 elderly patients enrolled in an anticoagulation clinic were screened with the mini‐mental state exam (MMSE): 
Conclusion: The presence of cognitive impairment should not necessarily preclude the use of warfarin in elderly patients enrolled in an anticoagulation clinic.
Drugs Aging 2012; 29(4):307-317.
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Tablet Strength Color
1mg
Pink
2mg
Purple
2.5mg
Green
3mg
Tan
4mg
Blue
5mg
Peach
6mg
Teal
7.5mg
Yellow
10mg
White
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Mechanism of
Action
Interferes with the production of vitamin-K dependent clotting
factors (II, VII, IX, and X) by inhibiting vitamin K oxide
reductase
Route
PO
PK
Onset of anticoagulant effect: 24 – 72 h
Full therapeutic effect: 5 – 7 days
Duration: 2 – 5 days
Metabolism: CYP2C9, CYP1A2, CYP3A4
Adverse Effects Skin necrosis and limb gangrene
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Chest 2012; 141(2):e44s-e88s
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Warfarin interferes with the production of clotting factors from their inactive form—it has no effect on existing, active clotting factors
 Anticoagulant activity relies on the natural catabolism of existing clotting factors and their corresponding half‐lives.
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Protein
Half-Life
(hr)
VII
4–6
IX
21 – 30
X
27 – 48
II
60 – 72
Protein C
9
Protein S
60
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Consider warfarin 2.5mg daily in the following:
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Age >75 years old
BMI<18.5, Body weight <50kg
CHF
Liver disease
Clinical hyperthyroidism
GI, genitourinary, or CNS bleed within last 2 months
Concomitant meds known to increase warfarin sensitivity
▪ E.g. amiodarone
 High bleeding risk
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Drug‐Drug interactions
 Major:
▪ Antibiotics, NSAIDs, steroids, OCs, Amiodarone
▪ EtOH, smoking
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Warfarin‐Disease interactions
Warfarin‐Diet interactions
 Consistency in vitamin K intake, NOT avoidance
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Complete blood count
 Monitor for possible bleeding complications
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PT and INR
 Monitor for therapeutic effectiveness
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Advantages (relative to warfarin) 
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Less interactions with drugs and foods No routine monitoring; fixed dosing
Reduced risk of intracranial hemorrhage Faster onset
Disadvantages (relative to warfarin) 
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No readily available test to monitor dosing No antidote
Dosage adjustment for CKD III‐IV; CKD V contraindicated Limited data in older patients with comorbidities
Cost Increased risk of stroke with abrupt discontinuation
▪ Black Box warning
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Dabigatran*
(Pradaxa®)
Rivaroxaban
(Xarelto®)
Apixaban
(Eliquis®)
Mechanism of
Action
Direct Thrombin
Inhibitor
Factor Xa inhibitor
Factor Xa inhibitor
Approved
Indications
Non-valvular AF
Non-valvular AF
DVT/PE treatment
DVT prophylaxis
Non-valvular AF
Dosing
110mg BID
150mg BID
10mg daily
15mg daily
20mg daily
2.5mg BID
5mg BID
Metabolism
Renal
Renal/Hepatic
Renal
Drug-Drug
Interactions
P-gp inhibitor
CYP3A4 substrate
P-gp inhibitor
CYP3A4 substrate
P-gp inhibitor
CHADS2 studied
2.1
3.5
2.1
*Listed on 2012 Beers Criteria as “Use with caution” due to increased risk of bleeding in adults
≥75 years, lack of evidence of safety in CrCl<30ml/min
NEJM 2009; 361:1139-51, NEJM 2011;365:883-90, NEJM 2011;365:981-92
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Inclusion Criteria
Exclusion Criteria
RE‐LY
(Dabigatran)
AF + ≥1 of: TIA/CVA, LVEF <40%, or HF Age ≥75 or 65‐74 + DM, HTN, or CAD
Valvular disease
CVA within 14 days
CrCl<30ml/min
Active liver disease
Pregnancy
ROCKET‐AF
(Rivaroxaban)
AF and prior TIA /CVA/systemic embolus Valvular disease/prosthetic valve CVA within 14 days or severe CVA within 3 or months AF and CHADS2 ≥2
CrCl <30 ml per minute or
Known significant liver disease AF and Age ≥75 or 65‐74 plus DM, HTN, or CAD
Pregnancy
Condition with bleeding predisposition Aspirin >100 mg qd ARISTOTLE: (Apixaban)
AF and CHADS2 ≥1
Valvular disease/prosthetic valve CVA within 7 days
CrCl <25 ml per minute Condition with bleeding predisposition 25
Aspirin >165 mg qd, or aspirin plus clopidogrel
Outcome
(RR ± 95% CI)
RE-LY
ROCKET AF
(Dabigatran 150mg BID) (Rivaroxaban 20mg/day)
ARISTOTLE
(Apixaban 5mg BID)
Warfarin TTR
64%
55%
62.2%
Stroke/Systemic
Embolic Event
0.66 (0.53–0.82)
0.88 (0.75–1.03)
0.79 (0.66–0.95)
Ischemic stroke
0.76 (0.60–0.98)
0.94 (0.75–1.17)
0.92 (0.74–1.13)
Hemorrhagic
stroke
0.26 (0.14–0.49)
0.59 (0.37–0.93)
0.51 (0.35–0.75)
Major bleeding
0.93 (0.81–1.07)
1.04 (0.90–1.20)
0.69 (0.60–0.80)
Intracranial
hemorrhage
0.40 (0.27–0.60)
0.67 (0.47–0.93)
0.42 (0.30–0.58)
NEJM 2009; 361:1139-51
NEJM 2011;365:883-90
NEJM 2011;365:981-92
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Close monitoring & lifestyle modification when using warfarin
Management of excessive anticoagulation Control of hypertension
Interventions to reduce the risk of falls Avoid NSAIDs Treatment of GI pathology (Ulcers, H. Pylori) Close attention to patients with cognitive impairment Interventional procedures 
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Catheter ablation Left atrial appendage closure devices (still being investigated) Surgical MAZE and LAA resection Treatment decisions are not final—they should evolve and adapt as patient’s risk factors and therapy goals change.
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Circulation 2011;123:e269-e367
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ACC/AHA/ESC 2011 Focused Update Recommendation:
 CHADS2 = 0
▪ May also use with CHADS2 = 1, though warfarin is preferred
 Use in addition to clopidogrel in patients with AF in whom warfarin therapy is considered unsuitable due to patient preference or assessment of patient’s ability to safely sustain anticoagulation
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Aspirin and low‐intensity warfarin (INR<2) not recommended
Circulation 2011;123:e269-e367
Lancet 1996;348:633
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Circulation 2011;123:e269-e367
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AA is a healthy 72 year old male with a history of non‐valvular atrial fibrillation and hypertension. He has been on warfarin for 10 years (TTR 70%) and is interested in starting Pradaxa. He is currently taking the following medications:
 Hydrochlorothiazide 25mg daily
 Amiodarone 200mg daily
 Warfarin 2.5mg QHS
 Pertinent labs (10/30/13):
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140 101 25
‐‐‐‐‐‐‐|‐‐‐‐‐‐‐‐‐|‐‐‐‐‐‐‐‐<98
3.4 23 1.5
BP: 132/79
HR: 65
Ht: 6’0”
Hct/Hgb/PLT: 40.6/14.0/287
INR 2.0
Wt: 82kg
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Stroke Risk: CHA2DS2VASC = 2 (HTN, age)
 2.2% risk of stroke
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Bleed Risk: HAS‐BLED = 1 (low risk)
Is this patient eligible for Pradaxa?
 Non‐valvular afib
 CrCl=48.9mL/min
▪ CrCl>30mL/min: dabigatran 150mg BID
▪ CrCl 15‐30mL/min: dabigatran 75mg BID
▪ CrCl<15mL/min: not recommended
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The decision has been made to start AA on Pradaxa. How do you instruct him to start?
 Pradaxa should be started when INR<2
▪ INR = 2.0 on 10/30/13
▪ Have patient skip tonight’s warfarin dose, start Pradaxa tomorrow evening
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AA returns to the clinic several weeks later. He states that he developed a “fungal infection” a couple days ago and was prescribed ketoconazole 200mg daily by the local urgent care facility.
 Dose adjustments for concomitant administration with strong P‐gp inhibitors (dronedarone, ketoconazole)
▪ CrCl 30‐50mL/min: Decrease dose to dabigatran 75mg BID
 No dose adjustments necessary for other P‐gp inhibitors (verapamil, amiodarone, quinidine, clarithromycin)
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A few months later, AA returns to the clinic. He states that his insurance will lapse at the end of the month and he will no longer be able to afford Pradaxa. How do you proceed?
 CrCl>50mL/min: start warfarin 3 days before discontinuing Pradaxa
 CrCl 30‐50mL/min: start warfarin 2 days before discontinuing Pradaxa
 CrCl 15‐30mL/min: start warfarin 1 day before discontinuing Pradaxa
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BB is an 84 year old woman recently discharged from the hospital for new‐onset atrial fibrillation. She is discharged with warfarin 3mg daily and referred to your office for INR monitoring. PMH: HTN, OA, DM
Home Meds: Aspirin 81mg daily, amlodipine 10mg daily, metoprolol 50mg daily, Ibuprofen 400mg Q8hr prn
Social Hx: Ambulates with walker, occasional mechanical falls, grand‐daughter helps with medications
Pertinent Labs (10/30/13):
140 101 25
‐‐‐‐‐‐‐|‐‐‐‐‐‐‐‐‐|‐‐‐‐‐‐‐‐<108
3.5 23 1.0
INR 2.2
Hct/Hgb/PLT: 40.6/14.0/287
BP: 153/85
Wt: 50kg
HR: 65
Ht: 5’2”
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Stroke Risk: CHA2DS2VASC = 5
 HTN, age, DM, female
 6.7% risk of stroke
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Bleed Risk: HAS‐BLED = 4 (high risk)
 HTN, elderly (age>75 years), Drugs (Aspirin, Ibuprofen)
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Is the patient a candidate for novel anticoagulants?
 Dabigatran: not recommended in patients >75 years
 Rivaroxaban, apixaban
▪ No absolute contraindications, though caution with:
▪ Advanced age, low body weight, concomitant antiplatelet/NSAID use, renal insufficiency (CrCl 33mL/min)
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What can be done to minimize risk in this patient?
 OA: switch ibuprofen to acetaminophen (gold standard) 500mg q 6 hr prn
 BP 153/85: optimize BP medication
▪ Increased blood pressure increases risk of ICH
▪ Increase metoprolol 100mg daily
 Minimize fall risk
 Close INR follow‐up (1‐2 weeks)
▪ Recently started on warfarin at hospital discharge
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BB returns to clinic 2 weeks later for anticoagulation follow up. Her INR is 2.3 and her BP is now 135/80. She reports that the acetaminophen given at last visit has not helped with her OA. She states that she is now bed ridden all day and is requesting to switch back to her ibuprofen.
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Arch Intern Med 2002;162:541-50
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Three weeks following her last visit, BB returns to the clinic for anticoagulation follow up. Her INR is 6.1.
What questions should be asked?
 Are you experiencing any bleeding?
 What dose of warfarin are you taking? Did you take an extra warfarin dose by mistake?
 Have any of your medications changed? What about over‐the‐
counter medications?
 Have you had any alcohol recently?
 Have you experienced any illness recently?
▪ E.g. vomiting, diarrhea, flu symptoms
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BB denies any signs and symptoms of bleeding, denies doubling up on her warfarin dose, recent alcohol or medication changes, or recent illness. Both she and her granddaughter insist that she has been taking warfarin 3mg daily since her initial hospital discharge 5 weeks ago.
 How do you proceed?
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INR <1.5 1.5‐1.9 2‐3 3.1‐3.5 3.6‐4.0 4.1‐6.0 6.0‐10.0 >10.0 GOAL INR 2‐3
WEEKLY WARFARIN DOSE
↑ 10‐20%
↑ 5‐10%*
NO CHANGE
↓ 5‐10%*
HOLD X 1 DOSE, THEN ↓ 5‐15%
HOLD X 1‐2 DOSES, THEN ↓ 10‐20% HOLD X 3‐4 DOSES, RECHECK INR, THEN ↓ 25‐50%
RECOMMEND VITAMIN K PO 2.5‐5MG
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BB returns to clinic 3 days later as instructed for anticoagulation follow up. Her INR is 3.1 and she still denies any signs or symptoms of bleeding.
 What is her new warfarin dose?
▪ Previous dose: warfarin 3mg daily (21mg/wk)
▪ New dose should be ~30% less than original weekly dose
▪ 0.7 x 21mg/wk = 14.7mg/wk
▪ Warfarin 1.5mg daily except 3mg on Mon/Wed/Fri (15mg/wk)
 1.5mg x 4 days = 6mg 3mg x 3 days = 9mg
▪ INR follow‐up: 1 week
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Assess need for oral anticoagulation (CHA2DS2VASC) Assess bleeding risk (HAS‐BLED) Is there a compelling indication for a newer anticoagulant? 
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Patient refuses warfarin Patient has unstable INRs on warfarin Are there contraindications to newer agents? Severe renal and/or liver disease, valve disease Do NOT use if history of noncompliance
Remember, the benefit of anticoagulation will most often outweigh the risk
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References
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Abbate R, Prisco D, Rostagno, et al. Age‐related changes in the hemostatic system. Intl J Clin Lab Res 1993;23(1):1‐3. Go AS, Hylek EM, Borowsky LH, et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med1999;131:927–34.
Sinnaeve PR, Brueckmann M, Clemens A, et al. Stroke prevention in elderly patients with atrial fibrillation: challenges for anticoagulation. J Int Med 2011;271:15‐24.
Jones M, McEwan P, Morgan CL, et al. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non‐valvular atrial fibrillation: a record linkage study in a large British population. Heart 2005;472‐7.
Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation. Circulation 2011;123:104‐23.
Pisters R, Lane DA, Nieuwlaat R, et al. A Novel user‐friendly score (HAS‐BLED) to assess 1‐year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093‐100.
Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:e269‐367.
Hylek EM, Evans‐Molina C, Shea C, et al. Major Hemorrhage and Tolerability of Warfarin in the First Year of Therapy Among Elderly Patients With Atrial Fibrillation. Circulation 2007;115:2689‐96.
Hylek EM, Singer DE, et al. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med1994;120:897–902. Man‐Son‐Hing M, at al. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 1999; 159:677‐85.
Khreizat HS, Whittaker P, Curtis KD, et al. The Effect of Cognitive Impairment in the Elderly on the Initial and Long‐Term Stability of Warfarin Therapy. Drugs Aging 2012; 29(4):307‐317.
Protheroe J, Fahey, Montgomery AA, et al. The impact of patients' preferences on the treatment of atrial fibrillation: observational study of patient based decision analysis. BMJ 2000;320:1380‐4.
Devereaux PJ, Anderson DR, Gardner MJ, et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ 2001;323:1‐7.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139‐51.
Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981‐92.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883‐91.
Man‐Son‐Hing M, Laupacis A. Balancing the risks of stroke and upper gastrointestinal tract bleeding in older patients with atrial fibrillation. Arch Intern Med 2002;162:541‐50.
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