atrialfibrillaon: developingapathwaytobeer’ paentcare’nmshp.org/resources/documents/speaker...

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Atrial Fibrilla0on: Developing a pathway to be<er pa0ent care Laura McDermo,, CFNP, CACP Tiffany Montoya, PharmD, PhC Allison Burne,, PharmD, PhC, CACP Linda Kelly, PharmD, CACP Jamie Glasgow, PharmD

Disclosures •  The presenters have nothing to disclose (except a nerdy passion for an0coagula0on)

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Learning Objec0ves: Technicians

Name commonly used clinical predic0on tools to assess thrombo0c and bleeding risk in atrial fibrilla0on pa0ents

List oral an0coagula0on medica0ons used for stroke preven0on in atrial fibrilla0on

Describe key pa0ent characteris0cs that must be considered when selec0ng an oral an0coagulant for stroke preven0on in atrial fibrilla0on

Learning Objec0ves: Pharmacists

Explain use of thrombo0c and bleeding risk clinical predic0on tools to guide therapy decisions for atrial fibrilla0on pa0ents

Summarize ini0al and ongoing management of atrial fibrilla0on pa0ents

Design an evidence-‐based pharmacotherapy regimen for a pa0ent with atrial fibrilla0on based on their clinical characteris0cs and pa0ent preferences

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Outline Ini0al management of new onset atrial fibrilla0on (AF)

Selec0ng a rate vs. rhythm control strategy

Thrombo0c and bleed risk assessment tools in AF

Choosing an oral an0coagulant with your pa0ent

Cardioversion and abla0on

Peri-‐opera0ve management

Triple an0thrombo0c therapy

Background of project •  Alternate 0tles for this presenta0on:

•  “Whoa, really?” •  “Show me the evidence” •  “Hmmm…maybe we shouldn’t be doing that”

•  Core content addresses common, challenging ques0ons that come up in everyday prac0ce

•  Varying prac0ce approaches that are some0mes based on

•  “what we’ve always done” •  “provider intui0on”

•  Goal: review contemporary and emerging literature and incorporate into a standardized, evidence-‐based city-‐wide (or broader) clinical pathway

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Background of project •  Resources

•  ACC/AHA/HRS 2014 Guideline for Management of Pa0ents with Atrial Fibrilla0on1

•  Intermountain Health 2013 Guide to Outpa0ent Management of Atrial Fibrilla0on2

•  Pub Med Search for current, relevant ar0cles that address our ques0ons

•  Input from local, regional and na0onal frontline clinicians involved with the management of atrial fibrilla0on pa0ents

•  End-‐product: Clinical pathway for op0mizing management of inpa0ent and outpa0ent atrial fibrilla0on pa0ents

1) J Am Coll Cardiol. 2014;64(21):e1-‐e76. doi:10.1016/j.jacc.2014.03.022 2) h<ps://intermountainhealthcare.org/ext/Dcmnt?ncid=522592305

Pa0ent Case •  Anita Neuwdrugh is a 66 yo female with PMH of DM II, hyperlipidemia, hypertension, morbid obesity, obstruc0ve sleep apnea, CAD with placement of drug-‐elu0ng stent in 2009

•  Medica0ons: insulin glargine, insulin lispro, atorvasta0n, aspirin, clopidogrel, lisinopril, carvedilol, and nitroglycerin as needed for pain.

•  Chief complaint: shortness of breath and palpita0ons for the last “few days” •  BP 102/54 mm Hg, HR 156 bpm, SCr 0.72 mg/dL, HA1c 6.8% •  EKG shows atrial fibrilla0on with rapid ventricular response •  Carvedilol DC’d; metoprolol 5 mg IV push X1 then 25 mg PO QID for immediate rate control

•  Therapeu0c enoxaparin 1mg/kg BID started empirically

•  ECHO shows EF 55-‐60%, no valvular stenosis or regurgita0on, no intracardiac thrombus

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AF: Ini0al Management AF: Ini0al M

anagement

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Selec0ng rate vs. rhythm control strategy 1: Determine the type of AF (paroxysmal, persistent, or permanent)

2: Iden0fy and correct (if possible) underlying causes of AF

1. January CT, et al. J Am Coll Cardiol 2014;64:e1-‐76

2. Gillis AM, et al. Can J Cardiol 2011;27(1):47-‐59

*Management of these risk factors prevents AF recurrence

• No difference in mortality between rate and rhythm control in most pa0ents

• Fewer embolic events, hospitaliza0ons, adverse events in HF pa0ents with rate control strategy

3: Determine pa0ent-‐specific factors that influence the choice between rate-‐control and rhythm control strategies

Selec0ng rate vs. rhythm control strategy

Factors favoring rate control: Factors that may favor rhythm control:

Persistent AF Persistent symptoms remain the most compelling indica0on

Less symptoma0c Difficulty in achieving adequate rate control

Age ≥65 Younger pa0ent (<65yoa)

HTN Tachycardia-‐mediated cardiomyopathy

No history of HF HF clearly exacerbated by AF

Previous failure of an0arrhythmic drug 1st episode of AF or paroxysmal AF

Pa0ent preference Precipitated by an acute illness

Pa0ent preference


2. Grace Frankel et al. Canadian Family Physician: Vol 59: February 2013

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Rate vs. rhythm control

4: Choose an appropriate pharmacologic agent, considering pa0ent-‐specific factors and comorbidi0es.


Rhythm Control

Rate Control

What is Non-‐Valvular AF?

•  Non-‐valvular AF •  AF in the absence of rheuma0c mitral stenosis, any mechanical or bioprosthe0c heart valve replacement, or mitral valve repair

•  Valvular heart disease •  Mitral/aor0c/pulmonic/tricuspid stenosis, regurgita0on or prolapse

•  Valvular AF-‐ These pa-ents are NOT candidates for DOACs •  AF with accompanying mitral stenosis and pa0ents with mechanical prosthe0c valves

•  Bioprothe0c valves where not excluded from all the DOAC trials •  PaHents with valve involvement that may be candidates for DOACs

•  “Valvular heart diseases, such as mitral regurgita0on, aor0c stenosis, or aor0c insufficiency, that do not result in condi0ons of low flow in the lev atrium, and do not apparently ↑ the risk of thromboembolism compared with that entailed by AF, and probably do not make thrombo-‐embolic risk less responsive to DOACs compared with most forms of ‘non-‐valvular’ AF.”

1. January CT, et alJ Am Coll Cardiol 2014;64:e1-‐76

2. De Caterina, R, et al. European Heart Journal 2014;35:3328-‐3335

Transla0on: Cardiology consult

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Pa0ent case (cont’d) •  Given Anita’s clinical characteris0cs and non-‐severe symptoms, it is decided to ini0ate rate control for long-‐term management

•  Because she is s0ll in atrial fibrilla0on, she is at risk for a stroke or systemic embolism

•  What clinical scoring tool would you use to determine her annual risk of stroke and whether she needs an0coagula0on?

A.  CHADS2 B.  HAS-‐BLED C.  Framingham D.  CHA2DS2-‐VASc

Risk Factor Score Conges0ve heart failure/LV dysfunc0on 1 Hypertension 1 Age ≥ 75 years 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease (Prior MI, PAD or aor0c plaque)

1

Age 65-‐74 years 1 Sex category (i.e. female gender) 1

CHA2DS2-‐VASc Score

LV = leO ventricle; TIA= transient ischemic a,ack; TE = thromboembolism; MI= myocardial infarcHon; PAD= peripheral artery disease

Lip GY, et al.. Chest. 2010 Feb;137(2):263-‐72. Pub Med PM

ID: 19762550.

•  Preferred over CHADS2 in ACC/AHA/HRS 2014 guideline •  Similar c-‐sta0s0cs for performance •  More readily iden0fies pa0ents with low CHADS2 score (0-‐1) who might be at risk for stroke

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Stroke Risk Assessment Lopes et al, AHRQ

No.13-‐EHC-‐113-‐EF, 2013

CHADS2 Stroke risk/yr (%)

CHA2DS2-‐VASc Stroke risk/yr (%)

0 0.9-‐1.9 0 0.3-‐0.7

1 2.8-‐4.3 1 0.9-‐1.5

2 4.0-‐6.1 2 2.9

3 5.9-‐9.9 3 4.3-‐4.6

4 8.5-‐14.9 4 6.5-‐6.7

5 12.5-‐16.7 5 10

6 17.2-‐18.5 6 12.5-‐13.6

7 14-‐15.7

8 14.1-‐15.2

9 15.9-‐17.4

RX an0

coagula0

on

Pa0ent Preferences “par0cipants tend to view stroke as a worse outcome than bleed… ...a reasonable trade-‐off to assume between stroke and bleeds would be a burden ra0o of GI bleeds to nonfatal stroke (thrombo0c or hemorrhagic) in the range of 2:1 to 3:1”

MacLean S et al. CHEST 2012

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Pa0ent Preferences

What is max # of bleeds a pa0ent is willing to experience to prevent a stroke? •  172 pa0ents surveyed •  12% “medica0on averse” •  ~60% “risk averse or tolerant” •  Treatment threshold

•  Willing to ini0ate AC for ARR of 0.8% (NNT=125) or 15% RRR in stroke

•  Warfarin NNT=25

•  Bleeding ra0o •  Willing to accept 4.4 major bleeds

to prevent 1 stroke •  Substan0al amount of interpa0ent

variability and differences in opinion regarding an0coagula0on

•  Highlights the importance of shared decision making

Lahaye, et al. Thromb Haem

ost 2014; h<p://dx.doi.org/10.1160/TH13-‐05-‐0424

Bleeding Risk Assessment

1. 1)Hemoglobin <13 g/dl men; <12 g/dl women 2. 2)Es0mated glomerular filtra0on rate <30 ml/min or dialysis-‐dependent

3. 3)Diagnosed hypertension 4. 4)Systolic blood pressure >160 mmHg 5. 5)Presence of chronic dialysis or renal transplanta0on or serum crea0nine ≥200 mmol/L

6. 6)Chronic hepa0c disease (eg cirrhosis) or biochemical evidence of significant hepa0c derangement (eg bilirubin 2 x upper limit of normal, in associa0on with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.)

7. 7)Unstable/high INRs or poor 0me in therapeu0c range (eg <60%) 8. 8)Concomitant use of drugs, such as an0platelet agents, non-‐steroidal an0-‐inflammatory drugs, or alcohol abuse etc. 9. 9) Cirrhosis, two-‐fold or greater eleva0on of AST or APT, or albumin <3.6 g/dl 10)Platelets <75,000, use of an0platelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia 6. 11)Prior hospitaliza0on for bleeding 7. 12)Most recent hematocrit <30 or hemoglobin <10 g/dl 8. 13)CYP2C9*2 and/or CYP2C9*3 9. 14)Alzheimer's demen0a, Parkinson's disease, schizophrenia, or any condi0on predisposing to repeated falls

ATRIA

Anemia1 3

Severe renal disease2 3

Age ≥ 75 years 2

Any prior hemorrhage 1

Hypertension3 1

HAS-‐BLED

Hypertension4 1

Abnormal renal5 or liver func0on6

1

Stroke 1

Bleeding 1

Labile INR7 1

Elderly (>65 years) 1

Drugs8 or alcohol 1

HEMORR2HAGES

Hepa0c9 or renal disease2

1

Ethanol abuse 1

Malignancy 1

Older age 1

Reduced platelet number or func0on10

1

Rebleeding11 2

Hypertension4 1

Anemia12 1

Gene0c factors13 1

Excessive fall risk14 1

Stroke 1

Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol. 2012 Jul 24. PMID: 22858389

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Comparing Bleeding Risk Scores

HAS-‐BLED was the only score that demonstrated a significant predicHve performance for intracranial hemorrhage

(c-‐index: 0.75; 95% CI: 0.56 to 0.95; p = 0.03).

Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol. 2012 Jul 24. PMID: 22858389

Pa0ent Case (Cont’d) •  66 yo female with PMH of DM II, hyperlipidemia, hypertension, morbid obesity, obstruc0ve sleep apnea, CAD with placement of drug-‐elu0ng stent in 2009

•  BP 102/54 mm Hg, HR 156 bpm, SCr 0.72 mg/dL •  ECHO shows EF 55-‐60%, no valvular stenosis or regurgita0on, no intracardiac thrombus

•  Medica0ons: insulin glargine, insulin lispro, atorvasta0n, aspirin, clopidogrel, lisinopril, metoprolol, nitroglycerin as needed for chest pain

•  Anita’s CHA2DS2-‐VASc score is: •  Her HAS-‐BLED score is:

5 (HTN, DM, vasc. dz, age, female)

2 (age >65, anHplatelet use)

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•  HAS-‐BLED •  0-‐1: low risk (1.1% per year) •  2: intermediate risk (1.9% per year) •  ≥3: high risk (4.9% per year)

•  Bleed risk scores should never be used as the sole reason to NOT an0coagulate a pa0ent

•  Modify bleeding risk factors

•  Stop ASA and/or clopidogrel whenever possible •  Control blood pressure •  Reduce fall risk (medica0on review, physical therapy, etc) •  Maximize 0me that INR is ‘in range’ if warfarin employed •  Consider DOAC due to improved safety profile

Op0mizing Risk vs. Benefit of An0coagula0on

•  Anita’s risk factors warrant long-‐term an0coagula0on therapy •  Which agent(s) should be ini0ated?

Atrial FibrillaHon

Valvular

warfarin (I, Level B)

Non-‐valvular

CHA2DS2-‐VASc Score (0)

No therapy reasonable (IIa, Level B)

CHA2DS2-‐VASc Score (1)

No therapy -‐or-‐

ASA or OAC (IIb, Level C)

CHA2DS2-‐VASc Score (≥2)

OAC warfarin (Ia) DOAC (Ib)

1. January CT, et alJ Am Coll Cardiol 2014;64:e1-‐76

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Warfarin vs. Aspirin for Stroke PrevenHon

Warfarin vs.

placebo RRR 68%

ASA vs. placebo RRR 21%

Warfarin vs. ASA

RRR 52%

Arch Intern Med 1994;154:1449-‐57; Arch Intern Med 1997;157:1237-‐40; Van Walraven C. JAMA 2002;288:2441-‐8.

Canadian and ESC Guidelines:

DOACs recommended over warfarin

DOACs-‐ Mechanism of Ac0on

Adapted from: Weitz JI, Bates SM. J Thromb Haemost 2005; 3: 1843-‐53.

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DOACs vs. Warfarin in NVAF Ruff CT, et al. Lancet 2014; 383:955-‐62

Meta-‐analysis of 42,411 pa0ents

•  ↓stroke by 19% (mostly hemorrhagic stroke)↓ICH; ↓ all cause mortality •  Consistent across all subgroups-‐ age, sex, DM, prior stroke/TIA, CrCl, CHADS2, TTR

Major Bleeding: Case Fatality Rates in NVAF

Warfarin DOAC n % n %

ROCKET AF 55/386 14% 27/395 7%

Dabigatran systema0c review

53/407* 13% 57/627*

9%

ARISTOTLE 55/462 12% 34/327 10%

ENGAGE AF-‐TIMI 48 59/524 11% 32/418 21/254

8% 8%

Patel et al. NEJM 2011; Majeed et al. Circ 2013; Granger et al. NEJM 2011; Giugliano et al. NEJM 2013.

Major bleeding with warfarin has a high risk of death that has not diminished over the last several decades

*es0mated from paper

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IniHaHon of AnHcoagulaHon Is pa0ent good candidate for DOAC

therapy instead of warfarin? No contraindica0ons (mech. valve, valvular AF, pregnancy, etc.)

Adequate renal and liver func0on

Lack of major P-‐gp or CYP3A4 drug interac0ons

Ability to obtain DOAC for dura0on of therapy

Good adherence record with medica0ons and therapies

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Pa0ent Case (Cont’d) •  Consulta0on with Anita reveals she is a good candidate for a DOAC •  However, she:

•  Expresses a preference for an an0coagulant that requires regular monitoring so she can “know how she’s doing”

•  Has some concerns about the current lack of an an0dote for the DOACs

•  She is to be discharged on warfarin 5 mg PO QPM, along with metoprolol 50 mg PO BID for her AF

•  Also, you were successful in ge�ng her clopidogrel discon0nued •  What else should be done in regards to an0coagula0on therapy? A. Con0nue heparin infusion, overlap with warfarin and keep her in-‐house un0l INR >2 B.  Stop the heparin infusion and discharge on warfarin only C.  Stop the heparin infusion and discharge her on full enoxaparin induc0on/bridge to overlap with warfarin un0l INR >2

InducHon/bridging anHcoagulaHon in AF

•  If acute thrombus is ruled out on ECHO, recommend NO LMWH •  Kim, et al “heparin bridging during warfarin therapy

ini0a0on increased bleeding without the benefit of preven0ng stroke in NVAF”, p. 189.

•  Rou0ne warfarin induc0on •  Begin 5mg daily and first INR check 3 – 5 days •  Referral to an0coagula0on management service

Kim, et al. 2014. J Thromb & Haemo, 13:182-‐190

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What About AF and SubtherapeuHc INR? •  Pa0ents with AF on warfarin will oven present to inpa0ent or outpa0ent se�ng with a low INR

•  Should we employ parenteral an0coagulants un0l INR >2? “If there is no urgent need for an immediate an-coagulant effect (eg, in chronic stable AF), warfarin administra-on can be commenced without the concurrent use of a rapid-‐ac-ng an-coagulant.” – CHEST 2012; 141(2)(Suppl):e44S–e88S •  For these pa0ents that get admi<ed to the hospital with an acute illness, may consider VTE prophylaxis (vs. full dose bridging an0coagula0on) un0l INR >2 or un0l discharge •  Do not need to be discharged on prophylaxis even if INR <2 •  Boost warfarin dose and ensure prompt follow up

Pa0ent Case (Cont’d) •  Anita shows up for her an0coagula0on appointment •  Her INR is therapeu0c at 2.3 •  She reports to you that, despite her metoprolol being 0trated up to 100 mg PO BID, she is s0ll experiencing severe episodes of shortness of breath, fa0gue and a “racing heart”

•  What addi0onal therapeu0c op0ons are there to address Anita’s ongoing symptoms?

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Electrical Cardioversion (CV)

Restoring sinus rhythm does not significantly impact stroke risk!

Radiofrequency Abla0on

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Abla0on/CV An0coagula0on •  The pa0ent calls asking when should she stop her warfarin prior to her procedure.

What is the correct answer? 1.  Hold warfarin 5 days prior to procedure 2.  Con0nue therapeu0c an0coagula0on 3.  Hold warfarin, bridge with LMWH

Abla0on/Cardioversion • TherapeuHc AC (INR ≥2) for 4 weeks prior • Increased risk of cardioembolic event around 0me of procedure • Elec0ve procedure • CV: re-‐ini0a0on of forceful blood flow could dislodge clot if present • Abla0on: catheter manipula0on within atria • Diligently maintain therapeuHc AC for 3 weeks post

•  High rate of recurrence • Loss of atrial kick • Abla0on -‐ inflammatory response/scar 0ssue forma0on

J Am Coll Cardiol. 2014;64(21):e1-‐e76. doi:10.1016/j.jacc.2014.03.022

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DOACs & AF Abla0on/CV •  X-‐VeRT

•  First prospec0ve randomized trial of DOAC vs warfarin for CV

•  Reasonable alterna0ve •  Allows for more rapid, predictable an0coagula0on

•  Lakkireddy et al., 2014, JACC •  Mul0center, observa0onal registry of AF pa0ents undergoing AF Abla0on •  Uninterrupted rivaroxaban is as safe and efficacious in preven0ng periprocedural bleeding and thromboembolic events...as uninterrupted warfarin therapy

Cappato et al., (2014) Eur Heart J doi:10.1093/eurheartj/eju367 Lakkireddy et al., 2014, JACC, 62; 10, 982-‐988

Pa0ent Case (Cont’d) •  Anita’s abla0on goes well and she is in normal sinus rhythm •  Should her an0coagula0on be stopped?

•  At follow up appointment 1 month later, EKG shows NSR •  Should her an0coagula0on be stopped?

•  CV/abla0on only to alleviate persistent symptoms •  These procedures have not been shown to reduce stroke risk

•  Recommended consider con0nuing an0coagula0on in pa0ents with persistent stroke risk factors

2014 AHA/ACC/HRS Guideline for the Management of Pa0ents With Atrial Fibrilla0on

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A word about peri-‐opera0ve bridging… •  The BRIDGE Trial •  Randomized, double-‐blind, placebo controlled trial of therapeu0c bridge therapy in pa0ents interrup0ng warfarin with AF (n=1884) •  Dalteparin 100 IU/kg twice daily •  Placebo injec0ons twice daily

•  30 day outcomes: stroke, systemic embolism, transient ischemic a<ack, and major bleeding

N Engl J Med 2015 Jun 22 [EPUB] PMID: 26095867

The BRIDGE Trial

N Engl J Med 2015 Jun 22 [EPUB] PMID: 26095867

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The BRIDGE Trial

•  Foregoing bridging did not lead to more clots •  Bridging did cause ~3X more major bleeds

A word about triple anHthromboHc therapy (TAT)

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Therapy Regimen HR (95% CI) Warfarin monotherapy 1 (Reference) Aspirin monotherapy 0.93 (0.88–0.98) Clopidogrel monotherapy 1.06 (0.87–1.29) Aspirin + clopidogrel 1.66 (1.32–2.04) Warfarin + aspirin 1.83 (1.72–1.96) Warfarin + clopidogrel 3.08 (2.32–3.91) Triple therapy 3.70 (2.89–4.76)

Risk of Bleeding with Single, Dual, or Triple Therapy

Adapted from: Hansen ML. Arch Intern Med 2010;170:1433-‐41.

Pa0ents on chronic an0coagula0on for AF

undergoing PCI followed 1 year

Triple therapy ASA (81 mg),

clopidogrel, warfarin

Clopidogrel + warfarin

Dewilde W

. Lancet 2013;381:1107-‐15.

Triple Therapy vs. Warfarin + Clopidogrel in ACS and AF (WOEST Trial)

Treatment Primary End Point Any Bleeding (%)

HR (95% CI) Stent Thrombosis

Triple therapy 44.4 0.36 (0.26–0.50) p<0.0001

No difference

Clopidogrel + VKA 19.4

R

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Oral AnHcoagulaHon and AnHplatelets in Atrial FibrillaHon PaHents AOer Myocardial InfarcHon or Coronary IntervenHon (Danish Registry) •  An0thrombo0c Treatment Regimens:

• Warfarin, clopidogrel or aspirin alone •  Dual an0platelet therapy • Warfarin plus aspirin • Warfarin plus clopidogrel • Warfarin plus clopidogrel and aspirin

•  Results: • Warfarin plus clopidogrel = TAT in safety and efficacy •  All-‐cause mortality was significantly higher in all other study arms compared to warfarin + clopidogrel

Lambert et al. J Am Coll Cardiol. 2013 Sep 10;62(11):981-‐9.

N = 12,165

An0thrombo0c Cocktails •  Following coronary revasculariza0on (percutaneous or surgical) in pa0ents with AF and a CHA2DS2VASc score of ≥ 2, it may be reasonable to use clopidogrel (75 mg once daily) concurrently with oral an0coagulants but without aspirin (Level of Evidence: B)1

• Consider avoid un0l more data available: •  Combina0on of DOACs and newer P2Y12 inhibitors •  DOACs and any dual an0platelet therapy

1) J Am Coll Cardiol. 2014;64(21):e1-‐e76. doi:10.1016/j.jacc.2014.03.022

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Thank you

atrialfibrillaon: developingapathwaytobeer’ paentcare’nmshp.org/resources/documents/speaker...

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