‘‘Good enough for rats …Good enough for rats …… but what about … but what about

humans?’humans?’

Anna CumiskyAnna Cumisky

Mary KwokMary Kwok

Michelle LunaMichelle Luna

Andrea MatherAndrea Mather

Emily OakfordEmily Oakford

Razi ZaidiRazi Zaidi

SummarySummary Mr JA Mr JA

– HxHx– ExaminationExamination– InvestigationsInvestigations

Atrial fibrillationAtrial fibrillation Warfarin as part of AF managementWarfarin as part of AF management

HistoryHistory Mr JA Mr JA 82 yr old retired civil servant82 yr old retired civil servant PCPC L sided hemiplegiaL sided hemiplegia HPCHPC 18:00 (19/05) found in chair, head turned 18:00 (19/05) found in chair, head turned

to R unable to stand. Previously moved well to R unable to stand. Previously moved well about flat. L side weak, mouth dropped on about flat. L side weak, mouth dropped on L side. GP called.L side. GP called.

Pt denied headache, trauma, fall, fever, Pt denied headache, trauma, fall, fever, cough, sputum, SOB, n&v, diarrhoea.cough, sputum, SOB, n&v, diarrhoea.

Pt coughed when fluids or water were Pt coughed when fluids or water were given orallygiven orally

PMHPMH– 08/02 TIA lasting 30 min.08/02 TIA lasting 30 min.AMH referral- MRI normal.AMH referral- MRI normal.Diagnosed AF aspirin then warfarin startedDiagnosed AF aspirin then warfarin started10/02 pt fell. Colonic haematoma and necrotic 10/02 pt fell. Colonic haematoma and necrotic

gall bladder suffered. Bowel obstruction gall bladder suffered. Bowel obstruction resulted. Emergency laparotomy at Parksideresulted. Emergency laparotomy at Parkside

Warfarin stoppedWarfarin stopped– Generalised OAGeneralised OA 1994 Total hip replacement 1994 Total hip replacement

L&RL&R– 1992 Varicose veins1992 Varicose veins– 1992 Benign Prostatic hypertrophy1992 Benign Prostatic hypertrophy– Hypertension 1988Hypertension 1988

DHDH– Enalapril 5mg odEnalapril 5mg od– Digoxin 125 mg odDigoxin 125 mg od– Finasteride 5 mg odFinasteride 5 mg od– Quinine Bisulphate 300 mg od noctQuinine Bisulphate 300 mg od noct– Paracetamol 1g qdsParacetamol 1g qds– Haematoma following Warfarin in past. No Haematoma following Warfarin in past. No

other allergiesother allergies

FHFH– Mother died in 80s strokeMother died in 80s stroke– Father died ?MI in 70’sFather died ?MI in 70’s– Other FH unknownOther FH unknown

SHSH– Lives with wife in flatLives with wife in flat– Non-smoker Non-smoker – 7 units alcohol/ week7 units alcohol/ week– Domestic help only, no carersDomestic help only, no carers– Mobile in flat. Self uses commode at night. Mobile in flat. Self uses commode at night.

Occasionally goes outside using stick to walk.Occasionally goes outside using stick to walk.

On ExaminationOn Examination

GeneralGeneral– Pt appeared exhaustedPt appeared exhausted– Head tilted to RHead tilted to R– Responsiveness, communication slowResponsiveness, communication slow– Well-perfusedWell-perfused– T 38.9, BP 224/103, HR 69 bpm,RR T 38.9, BP 224/103, HR 69 bpm,RR

20/min, Sats 100 % on 4L oxygen20/min, Sats 100 % on 4L oxygen– No JACCOLNo JACCOL

CVSCVS– HR 69 irregularly irregularHR 69 irregularly irregular– HS 1+2+ ESM 3/6HS 1+2+ ESM 3/6– JVP JVP

RS, Abdo, PVSRS, Abdo, PVS– NADNAD

GCS 13/15GCS 13/15 MMS 7/10MMS 7/10

Neuro ExamNeuro Exam CN difficult to assess CN difficult to assess

– L VII palsyL VII palsy Upper limbUpper limb (R)(R) (L)(L)

– Power Power 4/54/5 0/50/5– ToneTone normalnormal normalnormal– ReflexesReflexes normalnormal briskbrisk

Lower limbLower limb (R)(R) (L)(L)– PowerPower 4/54/5 0/50/5– ToneTone normalnormal normalnormal– ReflexesReflexes normalnormal absentabsent– PlantarsPlantars extensorextensor extensorextensor

Differential DiagnosisDifferential Diagnosis

Stroke/ TIA depending on duration of Stroke/ TIA depending on duration of sxsx

Cerebral neoplasmCerebral neoplasm Subdural bleedSubdural bleed Todd’s PalsyTodd’s Palsy Cerebral metastases ?Ca elsewhereCerebral metastases ?Ca elsewhere

Investigations 1Investigations 1

HaematologyHaematology

Hb 15.1 (13 - 17 g/dl)Hb 15.1 (13 - 17 g/dl) WBC WBC 12.112.1 (4-11)(4-11) Platelets 151 (150 - 450 Platelets 151 (150 - 450

g/L)g/L) Neutrophils Neutrophils 1010 (1.7 - 8)(1.7 - 8) Lymphocytes Lymphocytes 0.90.9 (1 - 4)(1 - 4) MCV MCV 9999 (80 - 97 fl)(80 - 97 fl)

Clotting ScreenClotting Screen

INR 1INR 1 APRT 1.16 APRT 1.16 TT 10 (10-14s)TT 10 (10-14s)

Investigations 2Investigations 2 BiochemistryBiochemistry

NaNa++ 134134 (135 - 145 (135 - 145 mmol/L)mmol/L)

KK+ + 4 (3.5 - 4.7 mmol/L)4 (3.5 - 4.7 mmol/L) Cl 100 (98 - 109 mmol/L)Cl 100 (98 - 109 mmol/L) Bicarbonate 24 (22 - 32 Bicarbonate 24 (22 - 32

mmol/L)mmol/L) Urea 3.7 (2.5 - 8 mmol/L)Urea 3.7 (2.5 - 8 mmol/L) Creatinine 85 (60 - 110Creatinine 85 (60 - 110

umol/L)umol/L)

Glucose 7.3 non-fastingGlucose 7.3 non-fasting Bilirubin Bilirubin 3434 (0 - 17 (0 - 17

umol/L)umol/L) ALT 16 (0-52 IU/L)ALT 16 (0-52 IU/L) ALP ALP 4545 (53 - 128 IU/L)(53 - 128 IU/L) Albumin 37 (35 - 48 g/L)Albumin 37 (35 - 48 g/L) GT GT 8080 (0 - 50 IU/L)(0 - 50 IU/L) CRP CRP 44.944.9 (<10 mg/L)(<10 mg/L)

ECGECG

AFAF– No P wavesNo P waves– Irregular but normally shaped QRSIrregular but normally shaped QRS

CXRCXR

AP filmAP film– cannot comment on heart sizecannot comment on heart size– would have otherwise been expecting would have otherwise been expecting

enlarged LA consistent with AFenlarged LA consistent with AF Volume left lungVolume left lung L hemi-diaphragm obscuredL hemi-diaphragm obscured

– ? L lower lobe collapse? L lower lobe collapse– ? Consolidation? Consolidation

Head CTHead CT

Unenhanced head CTUnenhanced head CT Marked hypo-density in middle Marked hypo-density in middle

cerebral artery (MCA) territory cerebral artery (MCA) territory consistent with infarctionconsistent with infarction

Area hyper-density within MCA Area hyper-density within MCA consistent with an acute thrombusconsistent with an acute thrombus

DiagnosisDiagnosis

Stroke resulting from Stroke resulting from thrombosis in MCA causing thrombosis in MCA causing infarction of the MCA dependent infarction of the MCA dependent brain tissue.brain tissue.

Probable cause- heart emboli Probable cause- heart emboli resulting from turbulent blood resulting from turbulent blood flow caused by AFflow caused by AF

Risk Factors for StrokeRisk Factors for Stroke AgeAge MaleMale HypertensionHypertension Diabetes mellitusDiabetes mellitus SmokingSmoking Heart disease Heart disease

(valvular, ischaemic,(valvular, ischaemic, AFAF))

Past TIAPast TIA / strokes / strokes

Family History of Family History of strokesstrokes

Peripheral vascular Peripheral vascular diseasedisease

HyperlipidaemiaHyperlipidaemia ObesityObesity Excessive Excessive

consumption of consumption of alcoholalcohol

PolycythaemiaPolycythaemia

Atrial FibrillationAtrial Fibrillation Commonest arrhythmia (1% pop)Commonest arrhythmia (1% pop) incidence with incidence with age (5-10% >65yr-olds) age (5-10% >65yr-olds) MechanismMechanism

– Multiple ‘wavelets’ of electrical activity across atria– Atrium activated at 350-600 bpm– Proportion of beats encounter refractory tissue at AVN– Ventricular rate depends on conductivity of AVN which

is influenced by ANS, drugs – Usually 120-180bpm

Common Causes of AF:Common Causes of AF:

– IHDIHD– HypertensionHypertension– Mitral valve diseaseMitral valve disease– ThyrotoxicosisThyrotoxicosis– Alcohol (binge or chronic)Alcohol (binge or chronic)– Cardiac surgery/ cannulationCardiac surgery/ cannulation– Pulmonary Hypertension (PE, COPD)Pulmonary Hypertension (PE, COPD)– Pyrexial illness (chest infection)Pyrexial illness (chest infection)

Why is AF dangerous?Why is AF dangerous?

1) rapid ventricular rate may 1) rapid ventricular rate may CO CO hypotension, pulm hypotension, pulm congestion (HF)congestion (HF)

2) absence of organised contraction in 2) absence of organised contraction in atriumatrium stasis, stasis, risk risk thromboembolismthromboembolism

Management of AFManagement of AF Ventricular rate controlVentricular rate control

– AVN blockade eg digoxinAVN blockade eg digoxin CardioversionCardioversion

– Drug cardioversion eg amiodarone, flecainideDrug cardioversion eg amiodarone, flecainide– DC cardioversionDC cardioversion

Ablation of AVN with pacemaker insertion Anticoagulation

– “All pt with AF lasting more than a day should be anti-coagulated, unless contraindicated” sghms grey-book guidelines

Anticoagulation with Anticoagulation with WarfarinWarfarin

Mechanism of actionMechanism of action Vitamin K antagonistVitamin K antagonist Decrease biological activity of Decrease biological activity of

vitamin-K-dependent factors II, VII, IX vitamin-K-dependent factors II, VII, IX and Xand X

Block Block -carboxylation of glutamic -carboxylation of glutamic acid residues acid residues

PIVKA released into circulation (Fig)PIVKA released into circulation (Fig)

The action of vitamin K in -carboxylation of factors II (prothrombin), VII, IX and X. Oral anticoagulants (e.g. warfarin) are vitamin K antagonists and lead to accumulation in plasma of inactive molecules (PIVKA).

Factor VII decrease within 24 hrFactor VII decrease within 24 hr Prothrombin Prothrombin

– longer t 1/2longer t 1/2– falls to 50% of normal in 3 daysfalls to 50% of normal in 3 days– full anticoagulation only after thisfull anticoagulation only after this

Monitoring pt on WarfarinMonitoring pt on Warfarin Anticoagulation clinicAnticoagulation clinic Prothrombin time (PT) measuredProthrombin time (PT) measured PT expressed as INR (ratio pt PT to control PT)PT expressed as INR (ratio pt PT to control PT) Aim in AF INR 2.0-3.0 (Aim in AF INR 2.0-3.0 (recommended therapeutic recommended therapeutic

ranges by the British Society for Haematology)ranges by the British Society for Haematology) Laboratory control using INR example (Fig)Laboratory control using INR example (Fig) Need long term therapy for AF (>12 months)Need long term therapy for AF (>12 months)

The laboratory control of warfarin therapy using the international normalized ratio (INR).

Absolute contraindications Relative contraindicationsActive GI bleeding Traumatic cardiopulmonary

resuscitationAortic dissection Major surgery in the past 10 daysHead injury or CVA in the past 2months

PHx GI bleeding

Neurosurgery in the past 2 months Recent obstetric deliveryIntracranial aneurysm or neoplasm Prior arterial punctureProliferative diabetic retinopathy Prior organ biopsy

Serious traumaSevere arterial hypertension(SP>200mmHg; DP>110mmHg)Bleeding diathesis

ContraindicationsContraindications

Could Mr JA’s stroke have been Could Mr JA’s stroke have been prevented?prevented?

Alternatives to WarfarinAlternatives to Warfarin Ximelagatran -an oral direct thrombin inhibitorXimelagatran -an oral direct thrombin inhibitor No known food or pharmacokinetic drug No known food or pharmacokinetic drug

interactionsinteractions Recent studyRecent study11 showed similar outcome in terms of showed similar outcome in terms of

preventing thromboembolic eventspreventing thromboembolic events No major bleedsNo major bleeds were observed in the were observed in the

ximelagatran group. One major bleed occurred in a ximelagatran group. One major bleed occurred in a warfarin-treated patientwarfarin-treated patient

Possible alternative for warfarin contraindicated Possible alternative for warfarin contraindicated pt?pt?

1Petersen P, Grind M, Adler J; SPORTIF II Investigators.“Ximelagatran versus warfarin for stroke prevention in patients with non-valvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study.” J Am Coll Cardiol 2003 May 7;41(9):1445-51

Other References from the Other References from the New England JournalNew England Journal

““Atrial Fibrillation — Rate versus Rhythm Atrial Fibrillation — Rate versus Rhythm Control”Control” Kühlkamp V., Seipel L., Healy E. C., Bhaskarabhatla Kühlkamp V., Seipel L., Healy E. C., Bhaskarabhatla K., Manning W. J., Wyse D. G., Van Gelder I. C., K., Manning W. J., Wyse D. G., Van Gelder I. C., Crijns H. J.G.M.Crijns H. J.G.M.

““A Comparison of Rate Control and Rhythm A Comparison of Rate Control and Rhythm Control in Patients with Recurrent Persistent Control in Patients with Recurrent Persistent Atrial Fibrillation”Atrial Fibrillation”Van Gelder I. C., Hagens V. E., Bosker H. A., Kingma Van Gelder I. C., Hagens V. E., Bosker H. A., Kingma J. H., Kamp O., Kingma T., Said S. A., Darmanata J. I., J. H., Kamp O., Kingma T., Said S. A., Darmanata J. I., Timmermans A. J.M., Tijssen J. G.P., Crijns H. J.G.M., Timmermans A. J.M., Tijssen J. G.P., Crijns H. J.G.M., the Rate Control versus Electrical Cardioversion for the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group Persistent Atrial Fibrillation Study Group