Sumi Sood, MD

University of Michigan Hemophilia and Coagulation Disorders Program

Ann Arbor, MI

March 18, 2014

Cardiovascular Diseases in Older

Patients with Bleeding Disorders

Outline

Ischemic Heart Disease in hemophilia

Risk factors

Prevalence

Management

Preliminary findings from the ongoing

“Cardiovascular Disease in Hemophilia Study”

Non-valvular Atrial fibrillation in hemophilia

Cardiovascular disease in other bleeding

disorders

Why is this even an issue?!

Shouldn’t having a bleeding disorder protect

against cardiovascular disease including arterial

thrombosis?

No theoretical protection against atrial fibrillation

Unclear if FVIII and FIX deficiency is truly

protective against ischemic heart disease

Case #1: K.A.

59M with severe hemophilia A

Complicated by hepatitis C, hepatocellular

carcinoma, HIV

s/p cholecystectomy and mucosal resection of a

large ampullary adenoma on 1/7/14

Postop was doing well, transitioned back to his

home prophylaxis dose and transferred to rehab.

While at rehab on 2/17/14, developed a pneumonia

which required back transfer to the inpatient floor

Became hemodynamically unstable overnight with an

intermittent wide complex tachycardia requiring ICU

transfer. Intubated for respiratory failure. Had runs of VT.

Case #2: K.A., continued

Found to have biventricular heart failure with

suspected ischemic etiology

EF 20-25%

Abnormal septal motion consistent with left bundle branch

block. Severely decreased left ventricular systolic function.

Severely decreased right ventricular systolic function.

We are asked to give recommendations for

management around cardiac catheterization and

stenting if necessary

Ischemic Heart Disease (IHD)

Cardiovascular disease is the leading cause of

death in the U.S.

Disease of aging

Men with hemophilia are living longer than ever,

on par with the non-hemophiliac population

thanks to the advent of safe factor replacement

therapy

Do men with hemophilia have risk

factors for IHD?

Case-control study in the Netherlands

100 men with hemophilia

24 severe, 12 moderate, 64 mild

Mean age 47 years

Did not separate out HIV or HCV men

Compared with 200 healthy age matched male

controls

Biere-Rafi et al. TH 2011; 105: 274

Risk Factors for IHD

Risk Factor Increased in Hemophilia

Yes No Unknown

Hypertension X

Diabetes X

Renal disease X

Obesity X

Smoking X

Elevated LDL X

Reduced HDL X

HIV infection X

Hepatitis C infection X

Elevated FVIII, VWF from

factor replacement

X

Alesci 2012; Lim 2011; Foley 2010

Do men with hemophilia develop

asymptomatic atherosclerosis?

Carotid Intima Media Thickness (IMT) is a well

described measure of atherosclerosis

In several small studies, no difference in CIMT in

patients with hemophilia and VWD vs. healthy

controls; only one study with less disease

Biere-Rafi, et al. Neth J. Med 2010; 68: 207

Prevalence of IHD is controversial

Hospital discharge

data in PA 2001-2006

in men with

hemophilia, similar to

the general population

Age (years) Prevalence of IHD

admissions

< 50 1.28%

51-64 10.9%

65-74 33.6%

> 75 31.8%

Kulkarni et al. Am J. Hematol 2005.

• Hospital discharge data in the Six State Study: IHD

admissions lower in men with hemophilia vs. general

population

Ragni et al. Haemophilia 2011

U.S. Insurance Claims analysis

Pocoski et al. Haemophilia 2013

Mortality from IHD

Appears to be lower than age-matched men in

Europe, but data from the U.S. is conflicting

Biere-Rafi, et al. Neth J. Med 2010; 68: 207

Porth et al. 2005

Subtypes of IHD

Current Hypothesis

Men with hemophilia have risk factors for IHD

Can develop atherosclerosis

May have demand ischemia or NSTEMI

BUT may be less likely to have a STEMI due to

the factor deficiency

Guidelines for IHD Management

General Guidelines:

treat like age-group peers without hemophilia,

providing factor replacement therapy to help

decrease bleeding risk

Netherlands, Italy

Stable angina

If mild deficiency or using prophylaxis

ASA 81 mg

Goal trough levels > 5%

Aggressive medical management of CV risk factors

HTN control, weight loss, statins

Severe deficiency without prophylaxis,

recommend against anti-platelet therapy

Unstable angina/NSTEMI

or STEMI > 12 hours*

Antithrombotic therapy Coagulation factor replacement

First 48 hours:

Unfractionated heparin with a bolus

(or LMWH)

Goal factor level 60-80%

For the next 4 weeks:

Dual antiplatelet therapy

(ASA and clopidogrel)

Goal trough factor level 30%

Indefinitely:

Baby ASA daily Goal trough factor level 5%

*Consider avoiding PCI

Consider CI rather than

bolus therapy

Recommend PPI with

dual antiplt therapy

Avoid DDAVP

STEMI: primary PCI indicated General recommendations:

Bare metal stents (less duration dual anti-platelet tx)

Radial artery access (vs. femoral)

Peak factor level ≥ 80% for the procedure

Manucci et al. Blood 2009; 114: 5256

STEMI: post PCI therapy

Antithrombotic therapy Coagulation factor replacement

First 12-24 hours:

None

GPIIb/IIIa inhibitors

UFH or LWMH

Goal trough factor level 50%

Goal peak factor level 80%

Goal peak factor level 60-80%

For the next 4 weeks:

Dual antiplatelet therapy

(ASA and clopidogrel)

Goal trough factor level 30%

Indefinitely:

Baby ASA daily Goal trough factor level 5%

Tuinenburg et al. Haemophilia 2013

On 5 year re-evaluation of the Dutch protocol: 9 procedures in 6 patients, most mild

• Can consider DES if baseline factor level > 25%

• Avoid stronger anti-platelet agents

Cardiovascular Disease in Hemophilia

Study

CDC funded cross-sectional study administered

through ATHN

Goal is to enroll 200 men with moderate or severe

hemophilia, ages 54-73

Aims:

To determine:

the prevalence of risk factors for IHD

The prevalence of IHD

Compare to a national U.S. database (ARIC database)

To describe AE related to antithrombotic therapy

Preliminary data as of 2/14

127 subjects enrolled at 19 centers

Striking prevalence of renal insufficiency, with 30% of patients having an abnormally elevated creatinine and 23% with eGFR< 60 ml/min/1.73 m2.

Table 1: Demographics N (%)

Moderate Hemophilia

Severe Hemophilia

52 (42%)

72 (58%)

Mean age (y, SD)

54-63 years

64-72 years

61 (4.9)

85 (68%)

40 (32%)

Race

Caucasian

African-American

Asian

110 (88%)

14 (11%)

1 (1%)

HTN 76 (61%)

DM 29 (23%)

Dyslipidemia 40 (32%)

Hep C positive 90 (72%)

HIV positive 34 (27%)

Abnormal renal function 65 (60%)

Recommendations for K.A.

Peak factor level ≥ 80% for the procedure

Radial artery access

Bare metal stents if needed

Further recommendations to follow pending the results

of the cardiac catheterization

Follow-up for K.A.

He was clinically recovering and was tired of

procedures.

Follow-up TTE 3/5/14 more consistent with stress

induced cardiomyopathy

Left ventricular systolic dysfunction appears mild.

Normal right ventricular systolic function.

Transferred back to rehab 3-8-14

Cardiac catheterization deferred for now; outpatient

cardiology follow-up pending

Case #2: U.L.

51M with mild hemophilia A

baseline FVIII level 8%, no history of an inhibitor.

History of a traumatic hemarthrosis as a child,

otherwise rare bleeding and no serious bleeds.

Recently developed palpitations and found to be

in atrial fibrillation.

- He is interested in elective cardioversion

Question for us: can he safely be anticoagulated

with a cardioversion?

Atrial fibrillation

Arrhythmia where the atria contract in an irregular and

disorganized manner

this leads the blood to pool and form clots

Associated with increased risk of stroke

In the absence of evidence that persons with

hemophilia are protected from cardiac embolism,

need to consider how to handle anticoagulation, both

around cardioversion and long term

Rhythm versus rate control:

No significant difference in CV mortality or occurrence of

stroke. Better QOL with rhythm control

No data in hemophilia

AF: Long term anticoagulation strategies

Manucci et al. Blood 2009; 114: 5256

AF: Baseline Factor levels >5%

Manucci et al. Blood 2009; 114: 5256 *Or NOAC, esp in FIX deficiency

Recommended trough level

> 5% > 30% > 5%

CHADS2 Score Risk Factor Points

CHF 1

HTN 1

Age ≥ 75 years 1

DM 1

Prior stroke or TIA 2

*

Gage et al. JAMA 2001; 285: 2864

AF: Baseline level < 5%

Manucci et al. Blood 2009; 114: 5256

Recommended trough level

0 > 5% 0

Management of cardioversion

Manucci et al. Blood 2009; 114: 5256

Management of cardioversion

Manucci et al. Blood 2009; 114: 5256

Antithrombotic

therapy

Coagulation

factor

replacement

First 5 days:

UFH or LMWH Goal trough factor

level 80%

For the next 4 weeks:

VKA or NOAC Goal trough factor

level 30%

Indefinitely:

Long term therapy

as per risk

stratification

Recommendations for U.L.’s elective

cardioversion:

Antithrombotic

therapy

Coagulation factor

replacement

First 5 days:

UFH or LMWH Goal trough factor level

80%

For the next 4 weeks:

VKA or NOAC Goal trough factor level

30%

Indefinitely:

Long term therapy as

per risk stratification:

low dose ASA

Goal trough level 5%

• Check a TEE

Case #2: U.L.

Followup is pending-his procedure is scheduled

for next week.

Valve replacement

Tissue valves recommended to avoid long-term

anticoagulation

Replace clotting factors 100% preoperatively and

continue for at least 10 days

Anti-coagulate with LMWH BID for 10 days ->

transition to warfarin for 3 months

Goal trough level > 30% while on anticoagulation

therapy

Cardiovascular disease in other

bleeding disorders

Women develop IHD at a slightly later age than

men (50s for men and 60s for women)

Little is known in other bleeding disorders

In VWD

CV risk factors: increased HTN in Type 3 VWD

compared to healthy controls

Asymptomatic atherosclerosis is present

Sramek et al. Circulation 2004

Reduced prevalence of arterial

thrombosis in VWD Sanders et. al. studied 635 adult patients with VWF levels ≤ 30 U dL,

aged 16-85 years, in a Dutch cross-sectional study 29 arterial thrombotic events occurred in 21 patients (3.3%).

The prevalence of cardiovascular disease in VWD was lower than in the general population SMR 0.60 (95% CI, 0.32-0.98) for coronary heart disease

SMR 0.40 (95% CI, 0.13-0.83) for acute MI

SMR 0.65 (95% CI, 0.12-1.59) and 0.33 (95% CI, 0.06-0.80) for ischemic stroke

Quereshi et al. performed a single center case-control retrospective study in the U.S. 198 patients with VWD, 86% Type 1, ICD-9 identified OR 0.28 (95% CI 0.12-0.64, p= 0.002) for CAD

OR 0.28 ((5% CI 0.10-0.77, p= 0.01) for cerebrovascular disease No protection from venous thrombosis

Little is known about management strategies Qureshi et al. TR 2012

Sanders et al. JTH 2013

Cardiovascular disease in other

bleeding disorders

Is the protection from arterial disease in VWD

related to the platelet defect? VWF levels?

Other open questions:

Do patients with functional platelet defect develop

arterial thrombosis? Can they ever receive anti-

platelet agents?

Management of patients with inhibitors?

Thank you!

Any questions?