Stroke Risk in AF - IJN Collegeijncollege.edu.my/PDF/Dr -SurinderAnticoagulation WKS...Stroke Risk in AF Who and When to give OACs Dr. Surinder Kaur Khelae, MBBS, MRCP, FHRS Consultant

Stroke Risk in AFWho and When to give OACs

Dr. Surinder Kaur Khelae, MBBS, MRCP, FHRSConsultant ElectrophysiologistInstitute Jantung Negara

Dec 2012

AF is a common disorder

Responsible for a third of all hospitalizations for cardiac rhythm disturbances1

Estimated prevalence:

– Europe: 4.5 million1

– USA: 5.1 million2

Affects approximately 2.5% of the US population2

Nearly one in four people at age 55 years will go on to develop AF (24% of men and 22% of women)3

1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030; 2. Miyasaka Y et al. Circulation 2006;114:119–25; 3. Heeringa J et al. Eur Heart J 2006;27:949–53

2

Dec 2012

Prevalence of AF increases with age

Prevalence at baseline assessed in 6808 participants in a European population-based study

Data from Heeringa J et al. Eur Heart J 2006;27:949–533

Women (n=4053)

Age (yrs)

Pre

vale

nce

(%

)

0

5

10

15

20

55–59 60–64 65–69 70–74 75–79 80–84 >85

Men (n=2590)

Dec 2012

Prevalence of AF predicted to more than double by 2050

Miyasaka Y et al. Circulation 2006;114:119–254

0

8

10

12

16

2050

People

with A

F in t

he U

SA (

mill

ions)

Year

2000 2010 2020 2030 2040

6

4

2

14

Projected incidence of AF assuming no further increase in age-adjusted incidence

Projected incidence of AF assuming a continued increase in age-adjusted incidence as evident in 1980–2000

Dec 2012

Risk factors for AF (1)

Advancing age

Cardiovascular diseases:

– Hypertension

– Diabetes mellitus, insulin resistance, metabolic syndrome

– Myocardial infarction

– Congestive heart failure

– Valvular disease and heart surgery

Excessive alcohol intake

Family history of AF

Male gender

Sawin CT et al. N Engl J Med 1994;331:1249–52;

Kannel WB, Benjamin EJ. Med Clin North Am 2008;92:17–405

Dec 2012

Risk factors for AF (2)

Echocardiographic abnormalities:

– Left atrial enlargement

– Increased left ventricular wall thickness

– Reduced left ventricular fractional shortening

Thyroid disorders

– Hyperthyroidism increases risk 3-fold

Inflammation

– E.g. myocarditis, pericarditis, systemic inflammation, pneumonia

Sleep apnoea

Sawin CT et al. N Engl J Med 1994;331:1249–52; Kannel WB, Benjamin EF. Med Clin North Am 2008;92:17–40;

ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–20306

Dec 2012

Stroke is the leading complication of AF

AF increases the risk of all types of stroke 5-fold1

Without prevention, approximately 1 in 20 patients will have a stroke each year2

AF is responsible for nearly one-third of all strokes3

1. Savelieva I et al. Ann Med 2007;39:371–91; 2. Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449–57; 3. Hannon N et al. Cerebrovasc Dis 2010;29:43–9

7

Dec 2012

Most strokes associated with AF are ischaemic

Based on data collected in the Danish National Indicator Project for 39 484 patients hospitalized for stroke (80% of all stroke admissions in Denmark) including 6294 patients with AF); OAC use not recorded

Andersen KK et al. Stroke 2009;40:2068–72

8

Types of stroke in patients with AF

Ischaemic92%

(n=5810)

Haemorrhagic8%

(n=484)

Dec 2012

Ischaemic stroke in AF likely to result in persistent disability or death

Gladstone DJ et al. Stroke 2009;40:235–40

Outcomes of first ischaemic stroke in high-risk patients with AF (n=597)

Persisting disabilityModified Rankin scale ≥2

Death

60

40

0

50

30

20

10Pro

port

ion o

f patients

(%

)

9

60%

20%

Dec 2012

Ischaemic stroke in AF is more likely to recur

10

Marini C et al. Stroke 2005;36:1115–9

Patients with AF (n=869)

Patients without AF (n=2661)

Recurrent stroke after ischaemic stroke

Months after first stroke

Cum

ula

tive p

robabili

ty

of

recu

rrence

(%

)

10

12

8

6

4

2

00 2 4 6 8 10

P=0.0398

Dec 2012

Management of AF has two broad objectives

ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429;

ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al. J Am Coll Cardiol 2011;57:e101–98 11

Prevention of complications, including

thromboembolism (particularly ischaemic

stroke) and heart failure

Relief of symptoms

Choice of antithrombotic therapy should be tailored to the patient based on:

Risk of thromboembolism

Risk of bleeding

Dec 2012

Assessing stroke risk: CHADS2

CHADS2 criteria Score

CHF 1

Hypertension 1

Age ≥75 yrs 1

Diabetes mellitus 1

Stroke/TIA 2

CHF = congestive heart failure; TIA = transient ischaemic attack

Gage BF et al. JAMA 2001;285:2864–7012

Annual stroke rate (%)*

CH

AD

S2

score

30

0

2

3

4

5

6

0 5 10 15 20 25

1

Dec 2012

Assessing stroke risk: CHA2DS2-VASc

CHA2DS2-VASc criteria Score

CHF/LV dysfunction 1

Hypertension 1

Age 75 yrs 2

Diabetes mellitus 1

Stroke/TIA/TE 2

Vascular disease 1

Age 65–74 yrs 1

Sex category (i.e. female gender) 1

*Theoretical rates without therapy; assuming that warfarin provides a 64% reduction in stroke risk, based on Hart RG et al. 2007; TE = thromboembolism; TIA = transient ischaemic attack; LV = left ventricular

Lip G et al. Chest 2010;137:263-72; Lip G et al. Stroke 2010;41:2731–8; Camm J et al. Eur Heart J 2010; 31:2369–429; Hart RG et al. Ann Intern Med 2007;146:857–67

13

Total score

Patients (n=7329)

Adjusted stroke rate (%/year)*

0 1 0.0

1 422 1.3

2 1230 2.2

3 1730 3.2

4 1718 4.0

5 1159 6.7

6 679 9.8

7 294 9.6

8 82 6.7

9 14 15.2

Dec 2012

Assessing bleeding risk: HAS-BLED

HAS-BLED risk criteria Score

Hypertension 1

Abnormal renal or liver

function (1 point each)1 or 2

Stroke 1

Bleeding 1

Labile INRs 1

Elderly (e.g. age >65 yrs) 1

Drugs or alcohol

(1 point each)1 or 2

*P value for trend = 0.007; INR = international normalized ratio

Pisters R et al. Chest 2010;138:1093–100; ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–42914

HAS-BLED total score

NNumberof bleeds

Bleeds per 100 patient-yrs*

0 798 9 1.13

1 1286 13 1.02

2 744 14 1.88

3 187 7 3.74

4 46 4 8.70

5 8 1 12.5

6 2 0 0.0

7 0 – –

8 0 – –

9 0 – –

Dec 2012

ESC 2012 focused update: choice of anticoagulant

*Includes rheumatic valvular disease and prosthetic valves; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist; Camm AJ et al. Eur Heart J 2012;33:2719–47

15

Yes

Atrial fibrillation

Valvular AF*

<65 years and lone AF (including females)

Assess risk of strokeCHA2DS2-VASc score

No antithrombotictherapy

Oral anticoagulant therapy

NOAC VKA

0 1

No (i.e. non-valvular)

Yes

No

≥2

Assess bleeding risk (HAS-BLED score)

Consider patient values and preferences

= CHA2DS2-VASc 0

= best option

= CHA2DS2-VASc 1

= CHA2DS2-VASc ≥2

= alternative option

Dec 2012

Global AF registry

Funded by a grant from Boehringer Ingelheim

Aim: to compare regional differences in predisposing conditions for AF and its treatment – Focus on BP management and anticoagulation

Prospective registry across all continents– Patients enrolled between January 2008 and April 2011

– 47 countries, 163 sites, 15 174 patients

Includes patients presenting to an emergency department– AF or atrial flutter (primary or secondary diagnosis)

– Enrolled between January 2008 and April 2011

Prevalence of risk factors adjusted for ageBP = blood pressureHealey J et al. ESC 2011; e-slides available at http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=1355(accessed September 2011)

16

http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=1355

Dec 2012

Global AF registry: participating countries

Region Sites Patients

North America 18 1802

South America 23 1127

Western Europe 19 1975

Eastern Europe 22 2536

Healey J et al. ESC 2011; e-slides available at http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=1355(accessed September 2011)

Region Sites Patients

Middle East 8 896

Africa 20 1089

India 22 2520

China 20 1951

Asia 11 1278

17

Participating country


Dec 2012

Global AF registry: use of oral anticoagulants was low and varied between regions

CHADS2 = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke, or TIA (2);

OAC = oral anticoagulation; TIA = transient ischaemic attack


18

100

80

60

40

20

0North

America

OAC u

se, CH

AD

S2

≥ 2

(%

patients

) *P≤0.005 vs North America

SouthAmerica

WesternEurope

EasternEurope

MiddleEast

Africa India China Asia

Patients with a prior history of AF

**

*

**

*

*


Dec 2012

Global AF registry: INR control was poor and varied between countries

INR = international normalized ratio


19

100

80

60

40

20

0North

America

% p

atients

*P≤0.005 vs North America

SouthAmerica

WesternEurope

EasternEurope

MiddleEast

Africa India China Asia

Based on three most recent INR values (%)

INR >3.0 INR 2.0–3.0 INR <2.0

54

44 67 59

47 40

34

3638

* * * * * *


Dec 2012

Vitamin K antagonists

Warfarin is the most commonly used VKA

– Rapidly absorbed from the GI tract1

– High bioavailability – reaches maximal blood concentrations about 90 min after oral administration1

– t½ = 36–42 hours1

– Circulates bound to plasma proteins (mainly albumin), and accumulates in the liver, where it is metabolized1

VKAs were the mainstay of anticoagulation therapy for over 50 years2

– Historically, a key therapy for stroke prevention in AF

GI = gastrointestinal; t1/2= half-life; VKA = vitamin K antagonist

1. Ansell J et al. Chest 2008;133;160S–98S;

2. Weitz J. The 50-year quest to replace warfarin; available from: http://www.nature.com/nrd/posters/warfarin; accessed 15 August 2012

20

Dec 2012

Warfarin reduces the risk of stroke in patients with AF

Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes(ischaemic and haemorrhagic), for ischaemic stroke only, the RRR was 67% (95% CI: 54–77%) VKA = vitamin K antagonistHart RG et al. Ann Intern Med 2007;146:857–67

21

Favours warfarin Favours placebo

RRR (%)†100 –10050 0 –50

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

All trialsRRR 64%*

(95% CI: 4974%)

When only ischaemic stroke was considered, dose-adjusted warfarin was associated with a 67% RRR (95% CI: 54–77%)

Dec 2012

Challenges and limitations of VKAs

ICH = intracranial haemorrhage; VKA = vitamin K antagonist

Adapted from Connolly SJ et al. Circulation 2007;116:449–5522

Anticoagulation reversal may not improve outcomes

Narrow therapeutic window, requiring frequent monitoring

Subject to multiple food and drug interactions

Variability in dose response between individuals

Slow onset and offset of action

VKAs have many well-

documented limitations

Risk of haemorrhage (particularly ICH) is high, and outcomes are poor

Dec 2012

ICH is the most feared complication of traditional antithrombotic therapy

ICH can be life-threatening1

Traditional antithrombotics increase the risk of ICH*:1

– ASA use increases risk by 40%

– Warfarin use doubles risk (INR 2.0–3.0; rate is 0.3–0.6%/yr)

– Warfarin use also increases the severity of ICH2

*Compared with placeboASA = acetylsalicylic acid; ICH = intracranial haemorrhage; INR = international normalized ratio1. Hart RG et al. Stroke 2005;36:1588–93; 2. Fang MC et al. Stroke 2012;43:1795–9

23

Dec 2012

Therapeuticrange

1

International normalized ratio

Odds

ratio

2

15

8

10

5

0

1

3 4 5 6 7

20

Stroke

Intracranial bleed

VKAs have a narrow therapeutic window

VKAs = vitamin K antagonists

ACCF/AHA/HRS focused update guidelines: Fuster V et al. Circulation 2011;123:e269-e367; Wann LS et al. Circulation 2011;123:104–23 & Circulation 2011;123:1144–50

24

Dec 2012

Fear of bleeding is a major reason for not prescribing VKAs

Single-centre study (n=103) of reasons for not prescribing OAC (in the era prior to approval of the NOACs)

INR = international normalized ratio; NOAC = novel oral anticoagulant; OAC = oral anticoagulation; VKA = vitamin K antagonist

Pereira-da-Silva T et al. ESC 2012; Poster 1566. 25

56%

22%

10%

7%5%

High bleeding risk

Small benefit

Poor compliance

Difficulty in INR monitoring

Other

Dec 2012

Warfarin is used in only half of eligible AF patients

Go A et al. Ann Intern Med 1999;131:927–3426

Pro

port

ion o

f elig

iible

patients

usi

ng w

arf

ain

(%

)

Age (yrs)

100

<55

80

60

40

20

055–64 65–74 75–84 85

44%

58%61%

57%

35%

Overall use= 55%

(n= 11 082)

Underuse greatest in elderly patients (who are at highest

risk of stroke)

Dec 2012

27

Most ischaemic strokes occur in patients who are sub-optimally anticoagulated

Data from a prospective stroke registry of 597 patients with AF at high risk of stroke (*1 high-risk factor or ≥1 moderate-risk factor according to ACCP guidelines); INR = international normalized ratio

Gladstone DJ et al. Stroke 2009;40:235–40

Pre-admission medications in high-risk* AF patients admitted for first ischaemic stroke

Dec 2012

28

New-generation agents have the potential to optimize stroke protection

Developed to overcome limitations of traditional agents1

Dabigatran etexilate

Rivaroxaban and

Apixaban have been approved for stroke prevention in AF in several countries2,3

Other agents in clinical development include:

– Edoxaban (Phase III)6

1. Lip GY et al. Eur Heart J Suppl 2005;7:E21–5; 2. Pradaxa®: SmPC, 2012; 3. Xarelto®: SmPC, 2012;4. Granger CB et al. N Engl J Med 2011;365:981–92; 5. Connolly SJ et al. N Engl J Med 2011;364:806–17; 6. NCT00781391; available at www.ClinicalTrials.gov; accessed March 2012Disclaimer: Apixaban and edoxaban are not approved for clinical use in stroke prevention in AF. Rivaroxaban is approved in this indication only in the USA and EU. Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details

Dec 2012

In addition to a significant reduction in stroke/SE, haemorrhagic stroke, and ICH

Dabigatran is the only new-generation agent to also reduce the risk of ischaemic stroke vs warfarin

ICH = intracranial haemorrhage; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; SE = systemic embolism; Sup = superiority

Connolly SJ et al. N Engl J Med 2010;363:1875–6; Pradaxa®: EU SmPC, 2012Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details

29

Event rate (%/yr)Dabigatran 110 mg BID

vs warfarinDabigatran 150 mg BID

vs warfarin

D110 D150 WarfarinRR

(95% CI)P

valueRR

(95% CI)P

value

Stroke/SE 1.54 1.11 1.71<0.001

(NI)<0.001(Sup)

Ischaemic stroke 1.28 0.86 1.14 0.310.03 (Sup)

Haemorrhagic stroke

0.12 0.10 0.38<0.001

(Sup)

<0.001 (Sup)

ICH 0.23 0.32 0.76<0.001(Sup)

<0.001(Sup)

1.50 1.00.51.50 1.00.5Favours warfarin

Favoursdabigatran

Favours warfarin

Favoursdabigatran

RRR=25%

Dec 2012

0.12

0.02

0.581

0.024

0.02

Rivaroxaban reduces the risk of haemorrhagic stroke and ICH with similar rates of stroke/SE vs warfarin

HR = hazard ratio; ICH = intracranial haemorrhage; ITT = intention-to-treat; OT = on-treatment; SE = systemic embolismEnrolled patients were at moderate-to-high risk of stroke (CHADS2 score ≥2)

Patel MR et al. N Engl J Med 2011;365:883–91Disclaimer: Rivaroxaban is only approved for clinical use in stroke prevention in atrial fibrillation in the USA and EU. Please check local prescribing information for further details.

30

Event rate(per 100 patient-yrs)

Rivaroxaban Warfarin

Stroke/SE

• ITT

• OT

2.11.7

2.42.2

Ischaemic stroke 1.34 1.42

Haemorrhagic stroke 0.26 0.44

ICH 0.5 0.7

0.11.50–0.5 1.00.5

Rivaroxaban vs warfarin

HR (95% CI) P value

Favours warfarin

Favoursrivaroxaban

Dec 2012

Apixaban reduces the risk of stroke/SE, haemorrhagic stroke, and ICH vs warfarin

HR = hazard ratio; ICH = intracranial haemorrhage; SE = systemic embolism

Granger CB et al. N Engl J Med 2011;365:981–92Disclaimer: Apixaban is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only.

31

0.1

Event rate(%/yr)

Apixaban Warfarin

Stroke/SE 1.27 1.60

Ischaemic or uncertain stroke

0.97 1.05

Haemorrhagic stroke 0.24 0.47

ICH 0.33 0.80

1.50–0.5 1.00.5

0.011

0.42

<0.001

<0.001

Apixaban vs warfarin

HR (95% CI) P value

Favours warfarin

Favoursapixaban

Dec 2012

novel agents for stroke prevention in patients with atrial fibrillation

All agents at least as effective as warfarin, with lower rates of ICH

Rivaroxaban is non-inferior to warfarin for the prevention of stroke/SE with a similar rate of major bleeding

Apixaban is superior to warfarin for the prevention of stroke/SE with a lower rate of major bleeding

Dabigatran etexilate 110 mg BID is non-inferior to warfarin for the prevention of stroke/SE with a lower rate of major bleeding

Dabigatran etexilate 150 mg BID is superior to warfarin for the prevention of stroke/SE with a similar rate of major bleeding

– Only agent to significantly reduce ischaemic stroke vs warfarin

Novel oral anticoagulants represent a significant improvement in stroke prevention in AF

32

BID = twice daily; ICH = intracranial haemorrhage; SE = systemic embolism

Dec 2012

ESC 2012 focused update: antithrombotic therapygeneral recommendations (1)

Camm AJ et al. Eur Heart J 2012;33:2719–4733

Recommendation Class Level

Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except those (both male and female) who are at low risk (aged <65 years and lone AF), or with contraindications

I A

Choice of antithrombotic therapy should be based upon the absolute risks of stroke/thromboembolism and bleeding and the net clinical benefit for a given patient

I A

CHA2DS2-VASc score is recommended as a means of assessing stroke risk in nonvalvular AF

I A

In patients with a CHA2DS2-VASc score of 0 (i.e. aged <65 years with lone AF) who are at low risk, with none of the risk factors, no antithrombotic therapy is recommended

I B

Dec 2012

ESC 2012 focused update: antithrombotic therapygeneral recommendations (2)

*Pending approval; INR = international normalized ratio; OAC = oral anticoagulation; VKA = vitamin K antagonist



In patients with CHA2DS2-VASc score ≥2, OAC therapy with:

• a dose-adjusted VKA (INR 2–3); or

• a direct thrombin inhibitor (dabigatran etexilate); or

• an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*)

… is recommended unless contraindicated

I A

In patients with CHA2DS2-VASc score 1, OAC therapy with:

• a dose-adjusted VKA (INR 2–3); or

• a direct thrombin inhibitor (dabigatran); or


… should be considered, based upon an assessment of the risk of bleeding complications and patient preferences

IIa A

Dec 2012

ESC 2012 focused update: choice of oral anticoagulant

*Pending approval; INR = international normalized ratio; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist; Camm AJ et al. Eur Heart J 2012;33:2719–47

35


When adjusted-dose VKA (INR 2–3) cannot be used in a patient with AF where an OAC is recommended, due to difficulties in keeping within therapeutic anticoagulation, experiencing side effects of VKAs, or inability to attend/undertake INR monitoring, one of the NOACs, either:



… is recommended

I B

When OAC is recommended, one of the NOACs, either: in:



… should be considered rather than adjusted-dose VKA (INR 2–3) for most patients with nonvalvular AF, based on their net clinical benefit

IIa A

Dec 2012

ESC 2012 focused update: dosing of NOACs

BID = twice daily; CrCl = creatinine clearance; OD = once daily



When dabigatran is prescribed, a dose of 150 mg BID should be considered for most patients in preference to 110 mg BID, with the latter dose recommended in:

• elderly patients, age ≥80 years

• concomitant use of interacting drugs (e.g. verapamil)

• high bleeding risk (HAS-BLED score ≥3)

• moderate renal impairment (CrCl 30–49 mL/min)

IIa B

Where rivaroxaban is being considered, a dose of 20 mg OD should be considered for most patients in preference to 15 mg OD, with the latter dose recommended in:

• high bleeding risk (HAS-BLED ≥3)

• moderate renal impairment (CrCl 30–49 mL/min)

IIa C

Dec 2012

ESC 2012 focused update: NOACs in patients with renal impairment

CrCl = creatinine clearance; NOAC = novel oral anticoagulant



Baseline and subsequent regular assessment of renal function (by CrCl) is recommended in patients following initiation of any NOAC, which should be done annually but more frequently in those with moderate renal impairment where CrCl should be assessed 2–3 times per year

IIa A

NOACs (dabigatran, rivaroxaban, and apixaban) are not recommended in patients with severe renal impairment (CrCl <30 mL/min)

III A

Dec 2012

The importance of ischaemic stroke prevention in patients with AF – summary

AF increases the risk of stroke1

Most strokes associated with AF are ischaemic2

– Likely to result in permanent disability or death3

Traditional agents for stroke prevention in AF have limitations, including the risk of ICH4

– Many patients receive suboptimal anticoagulation3

Goal of antithrombotic therapy in AF should be to prevent ischemic stroke and minimize the risk of haemorrhagic stroke (ICH)

New-generation OACs could optimize stroke protection in AF

– Dabigatran, rivaroxaban and apixaban all significantly reduce the risk of haemorrhagic stroke and ICH vs warfarin4–7

– Only dabigatran 150 mg BID significantly reduced the risk of ischaemic stroke vs warfarin4,5

ICH = intracranial haemorrhage; OACs = oral anticoagulants

1. Savelieva I et al. Ann Med 2007;39:371–91; 2. Andersen KK et al. Stroke 2009;40:2068–72; 3. Gladstone DJ et al. Stroke 2009;40:235–40; 4. Hart RG et al. Stroke 2005;36:1588–93; 4. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 5. Connolly SJ et al. N Engl J Med 2010;363:1875–6; 6. Granger CB et al. N Engl J Med 2011;365:981–92;7. Patel MR et al. N Engl J Med 2011;365:883–91

38

Dec 2012

Thank you

39

Documents

Stroke Risk in AF - IJN Collegeijncollege.edu.my/PDF/Dr -SurinderAnticoagulation WKS...Stroke Risk in AF Who and When to give OACs Dr. Surinder Kaur Khelae, MBBS, MRCP, FHRS Consultant