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127

Both direct current cardioversion and pharmacologic cardioversion using

antiarrhythmic drugs expose patients to an initial short-term increase in stroke risk

from embolization secondary to resumption of normal atrial mechanical activity (see

Chapter 15, Cardiac Arrhythmias). Data from a prospective cohort study of 437

patients noted a stroke incidence of 5.3% in patients with atrial fibrillation who were

cardioverted without prior anticoagulation, but a significant reduction in stroke

incidence to 0.8% was noted if patients who had received cardioversion were

anticoagulated.

128

In addition to preventing the development of new atrial thrombi,

anticoagulation allows any thrombus that may be present to endothelialize and adhere

to the atrial wall so that the thromboembolic risk is minimized. Based on the assumed

time course of thrombus development, as well as the presumed time course of clot

endothelialization, patients who have been in atrial fibrillation for 48 hours or longer

should receive 3 weeks of therapeutic anticoagulation with warfarin to a target INR

of 2.5 (range, 2.0–3.0) before cardioversion is attempted.

127,129 Direct oral

anticoagulants such as dabigatran, rivaroxaban, and apixaban are alternative options

to warfarin therapy.

129 Despite a lower risk of stroke than that associated with atrial

fibrillation, patients with atrial flutter should be treated similarly.

Whether T.S. has been in atrial fibrillation for 48 hours is not known; therefore,

she requires a 3-week course of oral anticoagulation before cardioversion is

attempted. If T.S. cannot tolerate her heart symptoms despite control of the

ventricular response rate, her medical team might consider immediate cardioversion

without anticoagulation if transesophageal echocardiography (TEE) is used to rule

out left atrial thrombi. TEE is much more sensitive than transthoracic

echocardiography (TTE) to visualize the left atrium and the left atrial appendage.

In a clinical trial, 1,222 patients with atrial fibrillation for a duration of 2 days or

more were randomly assigned to either cardioversion guided by TEE or to

conventional anticoagulation prior to cardioversion.

130 Patients assigned to

conventional treatment and patients in the TEE group in whom thrombus was detected

received a 3-week course of warfarin before cardioversion. Patients without

detectable thrombus by TEE were cardioverted without prior anticoagulation. All

patients received 4 weeks of postcardioversion anticoagulation. Thromboembolic

rates were identical between patients who received conventional treatment and those

whose treatment was guided by TEE (0.5% vs. 0.8%, p = 0.5).

130

ANTICOAGULATION AFTER CARDIOVERSION

CASE 11-9, QUESTION 2: After 3 weeks of regular intensity warfarin therapy, T.S. is successfully

cardioverted to normalsinus rhythm. Should anticoagulation be discontinued?

Despite normalization of atrial electrical activity, restoration of effective atrial

mechanical activity after cardioversion of atrial fibrillation can be delayed for up to

3 weeks. In addition, many patients who are cardioverted successfully will revert to

atrial fibrillation during the first month. These factors contribute to the recognized

delay in stroke presentation after cardioversion in patients with atrial fibrillation.

Therefore, anticoagulation should be continued after cardioversion for a minimum 4

weeks. Longer duration of anticoagulation therapy should be based on the individual

patient’s thromboembolic risk profile.

127,129

ANTICOAGULATION FOR PAROXYSMAL, PERMANENT, OR

PERSISTENT ATRIAL FibRILLATION

CASE 11-9, QUESTION 3: Two weeks after successful cardioversion, T.S. presents to the ED with chest

palpitations and light-headedness. An ECG is performed and indicates atrial fibrillation again. What decisions

regarding anticoagulation need to be made?

Anticoagulation in Valvular Atrial Fibrillation

Atrial fibrillation secondary to valvular heart disease has historically been

recognized as a significant risk factor for stroke. Patients with atrial fibrillation who

have a history of rheumatic mitral valve disease have a 17-fold higher incidence of

stroke than in matched controls. Patients with valvular atrial fibrillation require longterm, regular intensity anticoagulation with warfarin to a target INR of 2.5 (range,

2.0–3.0) to prevent thromboembolism and stroke. DOACs have not been studied in

this patient population and should be avoided at this time.

127,129

Anticoagulation in Nonvalvular Atrial Fibrillation

Nonvalvular heart disease is the most common cause of atrial fibrillation and, like

valvular heart disease, represents a significant risk for stroke in patients with atrial

fibrillation. Five clinical trials have substantiated the role of warfarin in the primary

prevention of systemic embolization and stroke in chronic, nonvalvular atrial

fibrillation.

127,129,131 All five trials compared warfarin with a placebo and were

terminated before completion because of the substantial benefit of warfarin. In

comparison with a placebo, warfarin significantly reduced the risk of stroke from

approximately 5% per year to approximately 2% per year, with an average relative

risk reduction of 67%. Based on the results of these trials, long-term anticoagulation

with warfarin to a goal INR of 2.5 (range, 2.0–3.0) is recommended in patients like

T.S., who have atrial fibrillation secondary to nonvalvular heart disease.

127,129,131

Several clinical trials have attempted to define the comparative efficacy of

warfarin versus aspirin in the prevention of stroke associated with atrial

fibrillation.

127,129,132 Compared with a placebo or

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control, aspirin decreases the risk of stroke in patients with atrial fibrillation.

However, that reduction is not as substantial as the reduction seen with warfarin. In

clinical trials comparing warfarin and aspirin, the risk reduction associated with

warfarin is significantly larger than that of aspirin. However, aspirin may be

appropriate in certain patients at low risk for stroke associated with atrial fibrillation

based on individualized risk assessment using the CHADS2 and CHA2 DS2

-VASc

score (Table 11-9). The CHADS2 score is currently endorsed by ACCP whereas the

CHA2DS2VASc score is endorsed by the American Heart Association/American

College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) and the European

Society of Cardiology (ESC) (see Chapter 15, Cardiac Arrhythmias).

Subsequent trials have confirmed the superiority of warfarin over the combination

of aspirin plus clopidogrel for stroke prevention in atrial fibrillation, and the

increased risk of intracranial hemorrhage when aspirin and clopidogrel are

combined.

133,134

Direct Oral Anticoagulants

The direct thrombin inhibitor (dabigatran) and direct factor Xa inhibitors

(rivaroxaban, apixaban, and edoxaban) have all been compared to warfarin for

stroke prevention in patients with nonvalvular atrial fibrillation.

135–138

Patient-specific characteristics such as age, renal function, weight, concomitant

medications, and past medical history should be considered when selecting the most

appropriate anticoagulant for initial therapy. Cost, insurance coverage and patient

preference with regard to number of daily doses, frequency of monitoring, etc. must

also be taken into account

139

(see Chapter 15, Cardiac Arrhythmias).

The decision to continue long-term anticoagulation with warfarin in T.S. should be

based on an evaluation of the likelihood that her atrial fibrillation will become

chronic with a paroxysmal, persistent, or permanent presentation, as well as an

assessment of her risk of stroke compared with her risk of anticoagulant-associated

bleeding complications. Because of her age and history of hypertension (CHADS2

score of 2 and CHA2DS2

-VASc score of 3), the appropriate strategy should be longterm anticoagulation, either with warfarin at a goal INR of 2.5 (range, 2.0–3.0) or

full-dose DOAC therapy.

Cardiac Valve Replacement

MECHANICAL PROSTHETIC VALVES

CASE 11-10

QUESTION 1: P.B., a 59-year-old woman with a history of rheumatic mitral valve disease, has undergone

mitral valve replacement. A St. Jude (bileaflet mechanical) valve has been implanted, and heparin therapy is

initiated postoperatively. Does P.B. require continued anticoagulation with warfarin?

Mechanical prosthetic valves confer a significant thromboembolic risk by

providing a foreign surface in contact with blood components on which platelet

aggregation and thrombus formation can occur. Valvular thrombosis can impair the

integrity of valve function and can lead to embolization with systemic manifestations,

including stroke.

140 The incidence of thromboembolic complications depends on the

type of artificial valve (caged ball [Starr-Edwards] > tilting disk [Medtronic-Hall;

Bjork-Shiley] > bileaflet [St. Jude]), as well as the anatomic position of the

replacement (dual valve replacement > mitral > aortic).

141

Long-term anticoagulation is required in patients with mechanical valve

replacement because it significantly reduces the risk of stroke and other

manifestations of systemic embolization (Table 11-9). Trials comparing different

intensities of oral anticoagulation with warfarin in mechanical valve replacement

helped identify the intensity of anticoagulation that protects against thromboembolic

risk, while reducing the incidence of hemorrhagic complications.

142 Patients with a

mechanical aortic valve replacement (AVR) (St. Jude bileaflet or tilting disc) in the

aortic position should receive long-term anticoagulant therapy with warfarin to a

target INR of 2.5 (range, 2.0–3.0).

140,143 For all other mechanical valve types in the

aortic position, and for any mechanical mitral valve replacement (MVR), chronic

warfarin therapy with a target INR of 3.0 (range, 2.5–3.5) is recommended. The

concurrent use of low-dose aspirin (81 mg daily) is recommended for patients with

mechanical mitral or aortic valve at low-bleeding risk.

In 2012, the RE-ALIGN trial was halted early after demonstrating a significant

increase in thromboembolic events such as valve thrombosis, myocardial infarction,

transient ischemic attack and stroke as well as significant increase in bleeding when

taking dabigatran versus warfarin in patients with mechanical prosthetic valves.

144

Based on these results as well as case reports reporting valve thrombosis following

transition from warfarin to dabigatran, the FDA issued a MedWatch safety alert

recommendation that dabigatran should not be used in any patient with a mechanical

heart valve. Subsequently, dabigatran’s product information was also updated to

include this contraindication. Based on the results of this trial, it is unlikely any other

DOAC will be tested in the population; thus, all DOACs should not be used in

patients with mechanical prosthetic valves. Therefore, P.B. would be required to

continue warfarin indefinitely to reduce the risk of stroke and other systemic

embolism.

BIOPROSTHETIC VALVES

CASE 11-11

QUESTION 1: E.F., an 82-year-old woman with a history of symptomatic aortic stenosis, has received a

bioprosthetic (mammalian) aortic valve replacement. Is anticoagulant therapy required in E.F.?

Prosthetic heart valves extracted from mammalian sources (porcine or bovine

xenografts, homografts) are significantly less thrombogenic than mechanical

prosthetic valves. The period of greatest thromboembolic risk appears to be during

the first 3 months after implantation. Therefore, anticoagulation with warfarin to an

INR goal of 2.5 (range, 2.0–3.0) is recommended for 3 to 6 months following

implantation of a bioprosthetic aortic or mitral valve in patients at low risk of

bleeding (Table 11-9). After this period, long-term aspirin therapy (75–100 mg) is

indicated.

140,143 Alternatively, treatment with only aspirin 75 to 100 mg daily is also

reasonable in patients with a bioprosthetic aortic or mitral valve. More about E.F.’s

bleeding risk would need to be determined, however due to her age, long-term

aspirin therapy only may be reasonable.

140 Transcatheter aortic valve replacement

(TAVR) is a new technique that avoids the open chest approach. Initially,

clopidogrel 75 mg daily for the first 3 to 6 months, followed by long-term aspirin

was recommended following TAVR. However, the most recent AHA/ACC

guidelines recommend either warfarin with a goal INR of 2.5 (range, 2.0–3.0) for at

least 3 months or clopidogrel 75 mg daily for the first 6 months following TAVR in

addition to life-long aspirin 75 to 100 mg daily.

143

BRIDGE THERAPY

Management of Anticoagulation Around Invasive

Procedures

CASE 11-12

QUESTION 1: L.P. is a 48-year-old woman with a history of valvular heart disease and a St. Jude mitral

valve replacement. She is adequately anticoagulated with warfarin 7.5 mg once daily to a goal INR range of 2.5

to 3.5. Recently, she has complained of episodic rectal bleeding and is scheduled for a colonoscopy in several

weeks. Her gastroenterologist calls the anticoagulation clinic to determine the most appropriate plan for reversal

of her warfarin before the procedure. What are the options?

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p. 202

When an invasive procedure is planned, it is often necessary to reverse the effects

of warfarin to minimize the risk of bleeding complications associated with the

procedure, which can be worsened by the presence of an anticoagulant. It can take

several days for the anticoagulant effect of warfarin to be reversed after

discontinuation of the drug, but in that period of time, a patient may be at risk for

thromboembolic complications associated with underanticoagulation. Bridge therapy

is the term that refers to the use of a relatively short-acting injectable anticoagulant

(UFH, LMWH) as a substitute for warfarin before and immediately after an invasive

procedure to shorten the period of time a patient is without any anticoagulation.

145

Because UFH and LMWH have shorter elimination half-lives than warfarin, they can

be stopped just before the invasive procedure without increasing the risk of bleeding

associated with the procedure. The last dose of LMWH and SC UFH should be given

at least 24 hours before the scheduled procedure, whereas IV UFH infusions are

discontinued 6 hours before the procedure. The timing of the last dose of LMWH may

need to be extended based on a patient’s renal function because it is renally

eliminated. Because of their faster onsets of effect, these agents are resumed after

invasive procedures once hemostasis is achieved to establish an immediate degree of

anticoagulation. Resumption of therapeutic injectable anticoagulants after a highbleeding risk surgery should be delayed until at least 48 to 72 hours postoperatively,

whereas patients undergoing lower-bleeding risk procedures can be restarted 24

hours later. Warfarin is resumed simultaneously, and the bridging anticoagulant is

continued until the INR reaches the therapeutic range.