Case Presentation: A 76-year-old

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Coronary Stents and Chronic Anticoagulation

Angelos Sourgounis, MD; Janusz Lipiecki, MD; Ted S. Lo, MD; Martial Hamon, MD

C

ase Presentation:

A 76-year-old

man was admitted with

retroster-nal chest pain. The ECG on admission

showed inferolateral ST depression,

and troponin levels were elevated,

con-firming the diagnosis of an acute

cor-onary syndrome. The patient had a

history of hypertension and aortic

valve replacement with a metallic

bileaflet valve 7 years before. He was

being treated with warfarin and

low-dose aspirin and had an international

normalized ratio (INR) of 2.5.

Coro-nary angiography revealed a long

sub-occlusive lesion of the proximal right

coronary artery. At that point, there

was a question about the optimal

treat-ment for this patient regarding the type

of stent to be selected and the need for

future combined antiplatelet and

anti-coagulation treatment.

Percutaneous Coronary

Intervention and

Warfarin Treatment

Oral anticoagulation was routinely

used for coronary stent thrombosis

prevention during the first era of

stents.

1

_{It has since been replaced by the}

combination of aspirin and a

thienopyri-dine because studies have shown a

def-inite advantage of the antiplatelet

com-bination on coronary events

2– 4

_{and on}

reducing the risk of access-site bleeding

complications. However,

⬇

5%

5,6

_of

patients undergoing percutaneous

cor-onary intervention (PCI) also present

with an indication for oral

anticoagu-lation therapy. In such cases, the type

of stent selected; the use of oral

anti-coagulants, antiplatelets, or their

com-binations; the target INR; and the

du-ration of treatment are essential

considerations in relation to the risk of

stent thrombosis/thromboembolic

events and bleeding risk. With the

introduction and widespread use of

drug-eluting stents (DES) in recent

years and given the necessity for

longer duration of dual antiplatelet

therapy, the issue of concurrent

warfa-rin and antiplatelet therapy has become

even more important. The existing

guidelines do not offer a convincing

solution to these issues. For acute

cor-onary syndrome patients with an

indica-tion for anticoagulaindica-tion, triple therapy

(warfarin, aspirin, and clopidogrel) for

the minimum time possible and a

maintenance regimen of warfarin plus

aspirin are recommended after stent

implantation

7–9

_{; for patients with atrial}

fibrillation, double therapy of warfarin

plus clopidogrel is recommended as

maintenance.

10

_{However, these}

recom-mendations are based on a low level of

evidence. Recently, the use of bare

metal stents (BMS) was recommended

with triple therapy for 1 month,

fol-lowed by warfarin plus aspirin; DES

are to be avoided, but when they are

used, clopidogrel therapy for 1 year

was recommended.

11

_{However, these}

recommendations do not specify the

optimal treatment according to the

var-ious indications for anticoagulation or

the duration of treatment, nor do they

take into account the estimated

throm-bosis and bleeding risks.

As a result, there is a significant

variation in the regimens followed for

patients on anticoagulation who have

had a stent implanted, as was

demon-strated in a survey among

interven-tional cardiology centers worldwide.

12

Data from an acute coronary syndrome

patient registry

6

_{show that triple}

ther-apy is the most commonly used (60%

of acute coronary syndromes),

fol-lowed by double antiplatelet therapy

(used in 31%), whereas warfarin plus

aspirin or clopidogrel is used in a

minority of patients. However, no

ran-domized trial demonstrating the

effi-cacy and safety of triple therapy has

yet been conducted.

A small number of retrospective

studies have examined the safety of

triple therapy (Table 1)

13–22

_{and have}

demonstrated a significant occurrence

of major bleeding episodes, ranging

from 4.5% to 27.4% of patients. Data

From the Department of Cardiology, University Hospital of Caen, Normandy (A.S., T.S.L., M.H.); Department of Cardiology, University Hospital of Clermont-Ferrand, Clermont-Ferrand (J.L.); and INSERM U744, Institute Pasteur de Lille (M.H.), Lille, France.

Correspondence to Professor Martial Hamon, Service des Maladies de Coeur et des Vaisseaux, Centre Hospitalier Universitaire de Caen, Avenue Côte de Nacre, 14033 Caen, Normandy, France. E-mail [email protected]

Circulationis available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.108.834861

1682

(2)

from the 3 published matched cohort

studies show that the relative risk of

major bleeding is 4 times higher with

triple therapy than with a standard

double antiplatelet regimen (Figure 1).

On the other hand, it has been recently

demonstrated that double antiplatelet

therapy is much less efficient than

warfarin alone in preventing embolic

episodes in atrial fibrillation patients.

23

Even fewer data are available on the

efficacy of triple therapy, especially in

patients with mechanical valves. Two

recent studies

18,21

_{that compared the}

efficacy of double antiplatelet therapy

with combinations, including

combi-nations with warfarin, showed

contra-dictory results in the occurrence of

major adverse cardiac events.

Assessment of

Individual Risk

Clearly, each of the possible

treat-ments has its pros and cons. The first

step in the selection of the appropriate

therapy is to assess the risk for each

individual, and balancing embolic risk

and bleeding risk is crucial in making

this decision. Recently published data

6

have suggested that cardiologists take

bleeding risk into account more than

embolic risk, which may have resulted

in underuse of warfarin. Although the

choice is often based on the subjective

empirical estimation of the treating

physician, validated schemes for

esti-mating risk are available, and their use

is encouraged. The CHADS2 score, a

well-tested scheme that has the

advan-tage of simplicity, successfully

strati-fies atrial fibrillation patients

accord-ing to risk for stroke. The CHADS2

score is calculated from 5 risk factors:

congestive heart failure, hypertension,

age

⬎

75 years, diabetes mellitus, and

prior stroke or transient ischemic attack.

Two points are given for prior stroke; all

the other risk factors are assigned 1

point. A CHADS2 score of 0 to 1

iden-tifies patients at low risk, a score of 2 to

3 marks patients at intermediate risk, and

a score of 4 to 6 indicates high-risk

patients.

24,25

Unlike atrial fibrillation, other

con-ditions put patients at a uniformly high

risk of embolism. Patients with a

me-chanical valve prosthesis have an

an-nual risk of thrombotic complications

without anticoagulation that ranges

from 10% up to 91%, depending on the

type, position, and number of

prothe-ses.

26

_{Patients who have experienced}

an episode of venous

thromboembo-lism are at an annual risk of 6% to 9%

for a subsequent episode. The required

duration of anticoagulant treatment is

3 months for an episode resulting from

transient causes and

⬎

6 months for a

recurrent or idiopathic episode.

27

_A

substantial number of patients who

Table.

Triple Therapy and Major Bleeding

Authors Year Type Patients, n Mean Age (Range), y Regimen Follow-Up, mo Major Bleeding,* % (95% CI) Orford et al13 ₂₀₀₄ _{Retr, Obs} ₆₆ _{73 (63–83)} _Triple _NA _{4.5 (0.2–11.2)}

Mattichak et al14 ₂₀₀₅ _{Retr, Obs} ₈₂ _{67 (54–80)} _Triple ₁₂ _{21.4 (13.3}_⫾_30.8)†

Khurram et al15 ₂₀₀₆ _{Retr, MC} ₂₁₄ _{69 (58–80)} _{Triple vs Asp}_⫹_Clp ₇ _{7.3 (3.0–13.1); OR, 5.4 (2.0–14.5)}

Porter et al16 ₂₀₀₆ _{Retr, Obs} ₁₈₀ _{65 (52–75.5)} _Triple ₁ _{1.6 (0.0–4.2)}

DeEugenio et al17 ₂₀₀₇ _{Retr, MC} ₁₉₄ _{70 (59–81)} _{Triple vs Asp}_⫹_Clp ₆ _{15.1 (8.7–22.9); OR, 5.0 (1.4–17.8)}

Rubboli et al19 ₂₀₀₇ _{Retr, Obs} ₄₉ _{68.5 (59–78)} _Triple ₁ _{18 (4.4–36.9)}

Karjalainen et al18 ₂₀₀₇ _{Retr, MC} ₂₃₉ _{70 (61–79)} _{Triple vs Asp}_⫹_Clp ₁₂ _{7.4 (3.0–13.2); OR, 3.3 (1.3–8.6)}

Ruiz-Nodar et al21 ₂₀₀₈ _{Retr, Obs} ₄₂₆ _{71.5 (63–80)} _{Triple, Warf}_⫹_Antiplat ₂₀ _{15.2 (10.5–20.6)}

Rogacka et al22 ₂₀₀₈ _{Retr, Obs} ₁₂₇ _{70 (61–79)} _Triple ₂₁ _{5.4 (2–10.1)}

Manzano-Fernandez et al20

2008 Retr, Obs 104 72 (64–80) Triple, Warf_⫹Antiplat, Asp_⫹Clp

12 27.4 (19.3–36.2) Retr indicates retrospective; Obs, observational; MC, matched cohort; Asp, aspirin; Clp, clopidogrel; OR, odds ratio; Warf, warfarin; and Antiplat, antiplatelet. *Midpoint-adjusted Wald interval.

†Transfusions.

Figure 1.Major bleeding in matched cohort trials. Warf indicates warfarin; Asp, aspirin, Clop, clopidogrel, and RR, relative risk.

(3)

undergo PCI with stent implantation

after an acute myocardial infarction

develop left ventricular thrombus and

are at increased risk of embolism (6%

to 12% annually), so anticoagulation

therapy is recommended for at least 3

months for these patients.

28

The next step in risk assessment is

to estimate the bleeding risk of the

patient. Major bleeding in patients

un-der anticoagulant treatment is not rare;

the yearly incidence of intracranial

hemorrhage was reported to be 0.3% in

an elderly population.

29

_Risk

stratifica-tion schemes developed so that

indi-vidual bleeding risk can be objectively

estimated

30 –32

_{include the Outpatient}

Bleeding Risk Index, which classifies

patients into 3 risk categories; 1 point

is applied for age

⬎

65 years, 1 point

for history of stroke, and 1 point for

history of gastrointestinal bleeding; an

additional point is applied if any one of

the following conditions exists:

ane-mia (hematocrit

⬍

30%), renal

dys-function (creatinine

⬎

15 mg/L), or

dia-betes.

30

_{A score of 0 is defined as low}

risk, 1 to 2 as intermediate risk, and 3 to

4 as high risk for bleeding. This index

has been prospectively validated and

shown to achieve acceptable

discrimina-tion among the categories of risk.

32,33

Finally, the selection of the

appro-priate therapy is influenced by the

estimated restenosis risk, which

deter-mines whether a DES is necessary.

The clinical, lesion, and procedural

variables that define high risk for

re-stenosis after BMS implantation are

well established

34

_{; however, the}

con-comitant treatment with warfarin urges

less liberal use of DES for restenosis

prevention because of the risk of

in-creased bleeding inherent in

anticoag-ulation treatment.

Therapeutic Options

Triple Therapy

The combined use of warfarin, aspirin,

and clopidogrel is, in theory, the

op-tion that ensures the best protecop-tion

against embolic episodes and stent

thrombosis. Only 2 studies have

pro-vided data on the efficacy of triple

therapy, showing that its stroke rate is

comparable to that on warfarin

mono-therapy; substantially more data are

available on major bleeding caused by

the triple combination. Using data

from the 3 matched cohort studies

(Figure 1), one can estimate that,

add-ing warfarin to standard double

anti-platelet therapy, the number needed to

harm for 1 year inducing a major

bleeding episode was 14. An indirect

comparison with the protection

pro-vided can be done using data from the

Atrial Fibrillation Clopidogrel Trial

With Irbesartan for Prevention of

Vas-cular Events (ACTIVE W) study,

23

accepting similar rates of stroke for

triple therapy and warfarin

mono-therapy. In the ACTIVE W trial, the

number needed to treat to prevent a

stroke with warfarin compared with

dual antiplatelet therapy was 100. This

comparison strongly discourages the

extensive use of triple therapy and

urges careful selection of patients, but

it probably also urges limiting the

du-ration of this treatment.

Warfarin Plus Aspirin

The combination of warfarin plus

as-pirin has been studied much more

ex-tensively, although the studies were

done before the introduction of latest

generation of stents, including DES. A

meta-analysis of these studies

demon-strated the superiority of double

anti-platelet therapy over warfarin plus

as-pirin in patients with an end point of

death, myocardial infarction, or need

for revascularization, whereas there

was no significant difference in the

occurrence of stent thrombosis and

major bleeding.

35

_{However, an}

ad-justed indirect meta-analysis based on

a much larger number of patients and

more recent studies

36

_{showed that the}

combination of warfarin plus aspirin

with a target INR of 2 to 3 was as

efficient as aspirin plus clopidogrel in

preventing major adverse events in

patients recovering from an acute

cor-onary syndrome. The combination of

aspirin and warfarin was associated

with a lower risk of stroke but

in-creased risk of major bleeding. The

number needed to harm to cause a

major bleeding episode is 77 compared

with 14 with triple therapy. However,

the 2 recent trials that provided data on

the efficacy of this combination

spe-cifically in PCI patients showed a high

incidence of stent thrombosis (15.2%)

and unscheduled PCI (17.2%),

respec-tively, mainly during the first month of

treatment. However, the studies

in-cluded a small number of patients.

18,37

Warfarin Plus Clopidogrel

Limited data are available on the

safety and efficacy of this

combina-tion. In the 2 studies that have

ad-dressed the combination,

18,37

_it

pre-sented common major bleeding

complications (11.1%) but good

effi-cacy against stroke (0% to 4.4%) and

stent thrombosis (0%). However,

be-cause these data were derived from a

small number of patients, further

stud-ies are needed to clarify the issue and

to support the use of this combination.

Aspirin Plus Clopidogrel

The efficacy of the antiplatelet

combi-nation against stent thrombosis is well

established, especially in the case of

DES. In addition, experts suggest

war-farin treatment when the risk of stroke

is

⬎

2%; for lower-risk patients, the

benefits from stroke prevention are

counterbalanced by the increased

bleeding risk, so it is logical to suggest

this combination only to patients with

a CHADS2 score of 0 to 1. In a

recently published study,

38

_patients

with atrial fibrillation and a CHADS2

score of 1 had a yearly stroke risk of

1.25% while taking aspirin plus

clopi-dogrel, which can be considered

ac-ceptable, considering the high bleeding

risk of other options.

Incorporating the existing data, we

provide an algorithm for appropriate

treatment selection in various

situa-tions in Figure 2.

Other Considerations

Acute Coronary Syndromes

According to current guidelines,

aspi-rin treatment is recommended

defini-tively for acute coronary syndrome

(4)

patients whether or not they underwent

PCI. Clopidogrel is recommended for

at least 12 months, especially in the

case of coronary stenting. However, in

the case of coronary stenting with

BMS, the gain from prolonged

clopi-dogrel treatment in patients at

interme-diate or high risk for bleeding can be

assumed to be neutralized by the

in-creased bleeding complications;

there-fore, we suggest the same strategy as

for elective PCI for these patients.

Access-Site Selection

It is generally accepted that coronary

angiography and PCI can be safely

performed by femoral access after

dis-continuing warfarin and achieving an

INR of

⬍

1.5.

39

_{Manual-pressure}

he-mostasis and artery closure devices

have been used during diagnostic

an-giography with a low incidence of

bleeding complications in fully

antico-agulated patients.

40,41

_{However, the}

usual strategy is to withhold warfarin

before transfemoral PCI and to restart

after the procedure using intravenous

heparin or low-molecular-weight

hep-arin as a bridge until adequate

antico-agulation with warfarin is

reestab-lished in patients at high risk for

embolism. Many of the bleeding

com-plications are reported to happen

dur-ing this crossover period from heparin

to oral anticoagulation.

16

_{The radial}

approach has also been used

success-fully for coronary angiography with no

incidence of major bleeding

complica-tions in fully anticoagulated

pa-tients

42,43

_and

_has

_consistently

achieved fewer bleeding complications

during PCI compared with the femoral

approach.

44,45

_{Compared with the}

ra-dial approach, femoral access has been

a strong predictor of access-site

com-plications after PCI in patients treated

with warfarin.

46

_{The possibility of}

per-forming PCI by the radial approach

without withholding warfarin, thereby

avoiding bleeding or thrombotic

com-plications during the crossover period,

makes the radial approach the first

choice for these patients, especially

during emergency procedures.

Gastric Protection

Proton pump inhibitors are used in

acute coronary syndrome patients

con-sidered at high risk for hemorrhage

47

despite the absence of a randomized

trial evaluating their usefulness after

PCI. However, on the basis of data

from a case-control study

48

_{and the}

documented effectiveness of

esome-prazole in reducing bleeding caused by

antiplatelet medications,

49

_proton

pump inhibition can be recommended

for patients at medium or high risk for

bleeding. Omeprazole has been shown

to potentiate the anticoagulant action

of warfarin

50

_{and to decrease the}

inhib-itory effect of clopidogrel on

plate-lets

51

_{; therefore, its use has to be}

un-dertaken with caution in this category

of patients.

52

Optimal Level of Anticoagulation

Dual treatment with warfarin and

aspi-rin has been shown to be favorable

compared with aspirin monotherapy

only in patients under tight INR

con-trol and an aim of 2 to 3.

53

_{In the}

Coronary stent and need for chronic anticoagulation What is the embolic risk?

What is the bleeding risk? High (>=6%) or

Medium (3-5%)

Low (<3%)

Avoid DES

Warf+Asp+Clop 1 month*; then Warf+Asp definitively† Consider CABG

Avoid DES if possible If BMS: Warf+Asp+Clop 1month; then Warf+Asp definitively† If DES: Warf+Asp+Clop 12 months; then Warf+Asp definitively

If BMS: Warf+Asp+Clop 1month‡; then Warf+ Asp definitively† If DES: Warf+Asp+Clop 12 months; then Warf+Asp definitively High Medium Low

If BMS: Asp+Clop for 1 month, then Asp+ Warf

If DES: Asp+Clop 12 months,

then Asp+Warf Figure 2.Flow chart for the selection of

appropriate treatment. Abbreviations as in Figure 1. *Consider adding PPI to any com-bination that includes aspirin. †Alternatively, warfarin_⫹clopidogrel (less evidence for this combination). ‡For acute coronary syn-drome, warfarin_⫹aspirin_⫹clopidogrel 12 months, then warfarin⫹aspirin.

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studies that have provided relevant

data, most major bleeding events

oc-curred at INR levels

⬍

3.

13,17,20

_{For the}

duration of concurrent antiplatelet

ad-ministration, an INR target of 2 to 2.5

under close observation seems to be

the best choice. When warfarin therapy

is required for a short period of time

(eg, venous thromboembolism, left

ventricular thrombus), PCI should be

postponed, if possible, until

comple-tion of warfarin therapy.

Prosthetic Valves

Current guidelines recommend

vita-min K antagonists plus low-dose

aspi-rin for patients with mechanical valves

and coronary disease. However,

long-term triple therapy could increase

bleeding complications to

unaccept-able levels, especially when a high

INR target (

ⱖ

3) is needed because of

valve or patient characteristics.

Al-though there are no data available that

address this specific subgroup of

pa-tients, it seems appropriate to shorten

the duration of triple therapy as much

as possible and to restrict the use of

DES only to patients at low calculated

risk for bleeding and with an INR of

no more than 2.5.

How Should We Manage

Our Example Patient?

Having taken into account the patient’s

age and the necessity of anticoagulant

treatment, we performed PCI with a

BMS. Triple therapy and a proton

pump inhibitor were prescribed for 1

month, followed by warfarin with an

INR target of 2.5 and aspirin 75 mg

indefinitely.

Conclusions

Available data show a remarkably

in-creased rate of major bleeding

compli-cations during prolonged treatment

with warfarin, aspirin, and

thienopyri-dine. This strongly suggests limiting

the time of its administration as much

as possible, especially in patients with

a high profile for bleeding risk. This

might be accomplished in the future by

using stents that recruit endothelial

progenitor cells and accelerate

endo-thelialization. A combination of

war-farin and 1 antiplatelet agent seems to

be a better choice for long-term

treat-ment after stent implantation,

balanc-ing the risks of thromboembolic events

and stent thrombosis with the risk of

major bleeding. Randomized trials in

progress are expected to further clarify

this issue.

Disclosures

None.

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