Top practice-changing articles over the last two years

Scott Kaatz • Brian F. Gage

Published online: 3 March 2013

� Springer Science+Business Media New York 2013

Abstract The field of thromboembolic disease and anti-

coagulation has had critical advances since the Anticoag-

ulation Forum last met (May of 2011). We summarize our

‘‘top ten list’’ of papers that are likely to change the care of

the anticoagulated population and improve their outcomes:

(1) Patient self-management of their vitamin K antagonist

and self monitoring can decrease thromboembolic events;

(2) restarting warfarin after gastrointestinal bleeding may

decrease mortality; (3) rivaroxaban is effective in the

treatment of pulmonary embolism; either (4) apixaban or

(5) low-dose aspirin prevented recurrent venous thrombo-

embolic disease after a standard course of therapy; (6)

warfarin prevents thrombotic complications up to at least

90 days after bioprosthetic aortic valve replacement; (7)

the relative risk reduction of apixaban compared to war-

farin is similar across CHADS2 scores, but the absolute risk

reduction is higher in high-risk patients; (8) adherence to a

warfarin dose-adjustment algorithm improved time in the

therapeutic range and thromboembolic outcomes in the

RE-LY trial; (9) warfarin had little benefit (if any) over

aspirin in patients with decreased ejection fraction and

sinus rhythm; (10) adding clopidogrel to aspirin in patients

with lacunar infarcts did not reduce the risk of recurrent

stroke and increased bleeding.

Keywords Anticoagulation � Thrombosis � INR testing �Warfarin � Apixaban � Rivaroxaban

Citation: Heneghan, C., et al., Self-monitoring of oral

anticoagulation: systematic review and meta-analysis

of individual patient data. Lancet, 2012. 379(9813):

p. 322–34 [1]

Clinical question: Does patient self-monitoring of the

international normalized ratio (INR) of the prothrombin

time improve the time until death, thromboembolic event

or major hemorrhage?

Background: Capillary INR meters allow patients on

vitamin K antagonists (VKA), including warfarin, to

monitor their INRs at home or while traveling. Addition-

ally, home INR testing makes it practical to get more fre-

quent (i.e. weekly) testing. Patient self-monitoring includes

both patient self-testing (with INR results communicated to

an anticoagulation service or provider who adjusts warfa-

rin) or patient self-management whereby patients adjust

their warfarin therapy themselves. Previous systematic

reviews using traditional methodology have suggested an

improvement in the time in therapeutic range and decrease

mortality in patients who perform patient self-monitoring.

Study design: Systematic review with pooled patient-level

data.

Setting: 11 randomized clinical trials comparing patient

self-monitoring to usual care of patients on VKAs from the

United States, Germany, Austria, Canada, Denmark,

Netherlands, Spain and the United Kingdom.

Synopsis: Twenty-one trials were identified and patient

level data were obtained from 11 of the trials representing

84 % of participants. Patient self-monitoring resulted in a

49 % reduction in the time to a thromboembolic event

(hazard ratio 0.51; 95 % CI 0.13–0.85, I2 = 52.6 %); there

was no difference in major bleeding or mortality compared

S. Kaatz (&)

Hurley Medical Center, One Hurley Plaza, Flint, MI 48503, USA

e-mail: skaatz1@hurleymc.com

B. F. Gage

Washington University Medical Center, Box 8005, 660 S. Euclid

Avenue, St. Louis, MO 63110, USA

123

J Thromb Thrombolysis (2013) 35:325–332

DOI 10.1007/s11239-013-0896-x

to controls. The time in the therapeutic INR range at one

year follow up improved by 2.7 and 5.1 % in patients with

mechanical valves and atrial fibrillation, respectively, with

patient-self monitoring. Subgroups of patient’s younger

than age 55 and those with mechanical heart valves had the

greatest reduction in thromboembolic events in a priori

analyses, with numbers needed to treat of 21 (95 % CI

17–42) and 55 (95 % CI 41–116), respectively, at one year

follow up and there was no significant increase in adverse

events in patients over the age of 85.

Bottom line: Patient self-monitoring of INR values yields

small improvements in the time in the therapeutic range

without improvement in major bleeding or mortality.

Combining patient-self testing with self-management

decreases thromboembolic complications. Younger

patients and those with mechanical heart valves seem to

derive the most benefit and self-monitoring appears to be

safe when performed in the elderly.

Citation: Witt, D.M., et al., Risk of thromboembolism,

recurrent hemorrhage, and death after warfarin therapy

interruption for gastrointestinal tract bleeding. Archives

of Internal Medicine, 2012. 172(19): p. 1484–91 [2]

Clinical question: For patients that suffer a gastrointestinal

bleed while receiving warfarin, should warfarin be reini-

tiated and if so, when?

Background: Gastrointestinal (GI) bleeding while on

warfarin has an incidence of 4–5 % per year and the

decision to resume warfarin is a frequent clinical challenge.

Study design: Retrospective cohort study using adminis-

trative, clinical, pharmacy and anticoagulation service

databases database coupled with clinical chart review.

Setting: Large anticoagulation clinic associated with Kai-

ser Permanente Colorado.

Synopsis: 442 patients with GI bleeding while receiving

warfarin were identified from database review and the

90-day rate of thrombosis (stroke, systemic embolism or

venous thromboembolism), recurrent GI bleed and death

(from any cause) was compared for those who did and did

not resume warfarin. Hazard ratios (HR) were adjusted for

markers of severity of GI bleeding, chronic diseases,

quality of warfarin management prior to the event, demo-

graphics, low molecular weight heparin, vitamin K and

fresh frozen plasma using propensity scoring.

260 (58.8 %) patients re-started warfarin at a median of

4 days (interquartile range 2–9 days) after the GI bleed.

Ninety days after the GI bleed, patients that resumed

warfarin, compared to those that did not had less

thrombosis (0.4 vs. 5.5 % [HR = 0.05, P \ 0.001]), a

trend toward more recurrent GI bleeding (10.0 vs. 5.5 %

[HR = 1.32, P = 0.09]) and less all-cause mortality (5.8

vs. 20.3 % [HR = 0.31, P \ 0.001]). Most causes of death

were not clinically related to thrombosis and there were no

deaths from recurrent GI bleeding. Although this study

used statistical methods to decrease confounding, the lower

mortality rate in patients that resumed warfarin may reflect

a tendency to continue anticoagulation in patients who are

less sick and hence less likely to die [3].

Bottom line: In this observation study, warfarin resump-

tion was associated with less mortality and thrombosis but

a trend toward more recurrent GI bleeding. Despite the risk

of confounding in this observational study, it seems rea-

sonable to re-initiate warfarin after GI bleeding in many

patients soon after they are stabilized.

Citation: Buller, H.R., et al., Oral rivaroxaban

for the treatment of symptomatic pulmonary

embolism. N Engl J Med, 2012. 366(14):

p. 1287–97 [4]

Clinical question: In patients with acute PE, is rivarox-

aban, a new oral anticoagulant, as effective and safe as

standard therapy with enoxaparin and a vitamin K

antagonist?

Background: The American College of Chest Physicians

recommend continuation of parenteral anticoagulation with

a vitamin K antagonist for a minimum of 5 days and until

the INR is 2.0 or above for at least 24 h for the treatment of

acute pulmonary embolism (PE) [5]. A previous trial

showed rivaroxaban without parenteral anticoagulant

therapy was effective and safe for the treatment of DVT

[6]. The availability of a treatment regime that does not

require a parenteral anticoagulant or need for INR moni-

toring could simplify the treatment of PE for patients, their

caregivers and health care professionals.

Study design: Randomized, open-label, non-inferiority,

controlled trial.

Setting: 236 sites in 38 countries.

Synopsis: 4,832 patients with acute symptomatic pulmon-

ary embolism (PE) with or with deep vein thrombosis

(DVT) were randomized to rivaroxaban 15 mg twice daily

for 21 days, followed by rivaroxaban 20 mg once daily or

to standard therapy with enoxaparin overlapped with

adjusted dose vitamin K antagonist. The primary efficacy

endpoint was recurrent symptomatic venous thromboem-

bolism (VTE). The principal safety outcome was major and

clinically relevant nonmajor bleeding. Of note, use of a

326 S. Kaatz, B. F. Gage

123

parenteral anticoagulation for greater than 48 h was an

exclusion criterion for trial eligibility and 92 % of patients

randomized to rivaroxaban received at least one dose of a

parenteral anticoagulant prior to randomization.

Recurrent VTE occurred in 2.1 % of patients receiving

rivaroxaban and 1.8 % of patients receiving enoxaparin

and vitamin K antagonist, with hazard ratio of 1.12 (95 %

CI 0.75–1.68 [P = 0.003 for non-inferiority]). The prin-

cipal safety outcome occurred in 10.3 % of patients

receiving rivaroxaban and 11.4 % receiving standard

therapy (P = 0.23). Major bleeding, a secondary endpoint

was reduced with rivaroxaban (1.1 %) compared to stan-

dard therapy (2.2 %), P = 0.003.

Bottom line: For patients with PE, rivaroxaban represents

the first oral anticoagulant that does not require initial

administration of a parenteral medication.

Citation: Agnelli, G., et al., Apixaban for extended

treatment of venous thromboembolism. N Engl J Med,

2013. 368(8): p. 699–708 [7]

Clinical question: In patients with VTE who have com-

pleted 6–12 months of anticoagulation and are considered

candidates for prolonged treatment, is apixaban, a new

oral anticoagulant, effective and safe in preventing

recurrence?

Background: The American College of Chest Physicians

(ACCP) recommends at least 3 months of anticoagulation

for deep vein thrombosis (DVT) or pulmonary embolism

(PE) and if the event is unprovoked, the patient should be

evaluated for the risk–benefit ratio of extended therapy.

The ACCP guidelines suggest patients with first proximal

unprovoked DVT or PE and low or moderate risk of

bleeding should receive extended anticoagulant therapy

[5].

Study design: Randomized, double-blind, controlled trial.

Setting: 328 sites in 28 countries.

Synopsis: 2,486 patients with VTE who had completed

6–12 months of standard anticoagulation treatment and for

who there was clinical equipoise regarding continuation of

anticoagulant therapy were randomized to apixaban 2.5 mg

twice a day, 5.0 mg twice a day or placebo for 12 months.

The primary outcome was recurrent VTE or death from any

cause and the primary safety outcome was major bleeding.

During the 1-year active study period, 3.8, 4.2 and

11.6 % of patients receiving apixaban 2.5 mg twice a day,

5 mg twice a day or placebo had a primary event

(P \ 0.001 for each dose of apixaban compared to pla-

cebo). Of note, 13 (1.5 %), 20 (2.5 %) and 19 (2.3 %)

patients were lost to follow-up and all were counted as

having a primary event. Symptomatic recurrent VTE or

death related to VTE occurred in 1.7, 1.7 and 8.8 % of

patients receiving 2.5 mg apixaban, 5 mg apixaban

or placebo (P \ 0.001 for each dose of apixaban vs.

placebo).

Major bleeding occurred in 0.2, 0.1 and 0.5 % and major

or clinically relevant nonmajor bleeding occurred in 3.2,

4.3 and 2.7 % of patients receiving apixaban 2.5 mg, 5 mg

or placebo respectively (P not significant for any compar-

ison). There was an increase in clinical relevant nonmajor

bleeding with apixaban 5 mg compared to placebo

(RR = 1.82, 95 % CI 1.05–3.18).

Bottom line: One year of extended treatment of VTE with

2.5 or 5 mg twice daily apixaban after an initial

6–12 months of standard anticoagulation reduced the risk

of recurrent VTE by approximately 80 % without a sig-

nificant increase in bleeding. This reduction in recurrence

compared to placebo is consistent with extended treatment

of VTE with other anticoagulants (see Table 1).

Citation: Brighton, T.A., et al., Low-dose aspirin

for preventing recurrent venous thromboembolism.

N Engl J Med, 2012. 367(21): p. 1979–87 [8]

Clinical question: In patients with first unprovoked VTE

who are a high risk of recurrence, is aspirin effective and

safe in preventing recurrent VTE?

Background: Antiplatelet prophylaxis, although contro-

versial, has been shown to be effective in primary pro-

phylaxis of VTE in hospitalized surgical and medical

patients [9]. In addition, aspirin reduces the risk of non-

fatal myocardial infarction, non-fatal stoke or death in high

risk patients [10].

Study design: Randomized, double-blind, controlled trial.

Setting: Australia, New Zealand, Singapore and Argentina.

Synopsis: 822 patients with first symptomatic proximal

unprovoked VTE who had completed initial anticoagula-

tion with a heparin and vitamin K antagonist or another

anticoagulant were randomized to 100 mg of aspirin or

placebo and followed for up to 4 years. The primary out-

come was recurrent VTE which was defined as objectively

confirmed DVT, nonfatal PE or fatal PE. Pre-specified

secondary outcomes were major vascular events (a com-

posite of VTE, myocardial infarction, stroke or cardio-

vascular death) and a measure of the net clinical benefit of

a reduction in the rate of the composite of VTE, myocardial

infarction, stoke, major bleeding or death from any cause.

The primary safety outcome was bleeding, either major or

Top practice-changing articles 327

123

clinically relevant nonmajor bleeding. The inclusion cri-

teria, randomized treatments and outcomes were harmo-

nized with the WARFASA trial [11] to facilitate pooling of

the data.

During a median follow up of 37 months, the rate of

recurrent VTE was 4.8 % per year with aspirin and 6.5 %

per year with placebo (P = 0.09). Aspirin reduced the

secondary outcome of major vascular events compared to

placebo (5.2 vs. 8.0 % per year; P = 0.01). There was no

statistically significant difference in major or nonmajor

clinically relevant bleeding with aspirin or placebo (1.1 vs.

0.6 % per year, P = 0.22).

When pooled with the WARFASA trial [11], aspirin

reduced recurrent VTE by 32 % (P = 0.007), major vas-

cular events by 34 % (P = 0.002) but tended (P = 0.31)

to increase clinically relevant bleeding.

Bottom line: After standard initial treatment of first non-

provoked VTE, aspirin reduces the risk of recurrent VTE,

although the relative effect was not as large as one might

expect with warfarin or new oral anticoagulants (Table 1).

Aspirin should be considered in patients who are likely to

benefit from prolonged antithrombotic therapy after non-

provoked VTE if they cannot or do not continue on an

anticoagulant.

Citation: Merie, C., et al., Association of warfarin

therapy duration after bioprosthetic aortic valve

replacement with risk of mortality, thromboembolic

complications, and bleeding. JAMA, 2012. 308(20):

p. 2118–25 [12]

Clinical question: For how long should warfarin therapy

be continued after placement of a bioprosthetic aortic

valve?

Background: Current guidelines recommend life-long

therapy with a vitamin K antagonist plus low-dose aspirin

after placement of a mechanical heart valve. Previously,

guidelines advocated for 3 months of therapy with a vita-

min K antagonist after placement of any bioprosthetic

heart valve, [13] but newer guidelines recommend anti-

platelet therapy if the prosthetic heart valve is in the aortic

position [14].

Study design: A retrospective cohort study of 4,075

patients who had a bioprosthetic aortic valve placed during

the period 1997–2009. Using administrative data from the

Danish National Patient Registry, the investigators used

Poisson regression to quantify the risks thrombotic and

hemorrhagic events, stratified by duration of warfarin

therapy.

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328 S. Kaatz, B. F. Gage

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Setting: Denmark.

Synopsis: The 4,075 patients had a median duration of

6.57 years of claims data. The mean age was 74.6 years

and 41 % were female. Adjusted relative risks (RRs) for

thrombotic events were significantly greater for patients

who were not prescribed warfarin: RR was 2.46 for stroke

and 2.93 for (other) thromboembolic events. However,

these RRs appeared time dependent, with warfarin being

protective even 90–180 days after bioprosthetic aortic

valve replacement (AVR). During this period, the mortality

rate was 3.4 % with warfarin and 5.4 % without it. Use of

warfarin during this interval did not appear to elevate the

rate of bleeding, but the use of administrative claims

obfuscated an accurate assessment of bleeding.

The RR of cardiovascular death in patients who were not

prescribed warfarin was 7.61 for days 30–89 days after

AVR and 3.51 for days 90–179 days after AVR. Based on

this observation, the authors advocate extending warfarin

therapy until 6 months after AVR. However, Figure 2 of

the article shows that mortality rates with aspirin therapy

were similar to those with warfarin therapy, at least

beginning on day 90 after AVR.

Bottom line: Warfarin appears highly beneficial for at least

89 days after bioprosthetic AVR. During days 90–179 after

implantation, either warfarin or aspirin appear beneficial.

Citation: Lopes, R.D., et al., Efficacy and safety

of apixaban compared with warfarin according to patient

risk of stroke and of bleeding in atrial fibrillation:

a secondary analysis of a randomized controlled trial.

Lancet, 2012. 380(9855): p. 1749–58 [15]

Clinical question: Does the benefit of apixaban over

warfarin for patients with atrial fibrillation (AF) depend on

risks of stroke or hemorrhage?

Background: Like rivaroxaban, apixaban is an oral factor

Xa inhibitor approved for stroke prophylaxis in patients

who have AF. The Apixaban for Reduction in Stroke and

Other Thromboembolic Events in atrial fibrillation (ARIS-

TOTLE) trial was a multi-centered, double-blind random-

ized control trial of apixaban (5 mg bid in most patients)

vs. warfarin therapy adjusted to an INR of 2–3. In ARIS-

TOTLE, apixaban reduced the risk of adverse events: the

RR was 0.69 for major bleeding, 0.92 for ischemic or

uncertain type of stroke, and 0.89 for mortality [16].

Study design: Post-hoc analysis of data from the ARIS-

TOTLE trial.

Setting: Patients (median age 70 years; 35 % female) from

39 countries who had AF and at least 1 additional risk

factor for stroke—i.e., CHADS2 (congestive heart failure,

hypertension, age C 75, diabetes, stroke or transient

ischemic attack) score C 1. The average time in range in

patients randomized to warfarin was 62 %.

Synopsis: Although ARISTOTLE was not designed to test

for an interaction between stroke and bleeding risk and

treatment arm, the size of that study (N = 18,201) allows

for worthwhile test of interaction. This analysis found no

significant interaction between and risk of stroke and the

efficacy of apixaban, as quantified by the hazard ratio.

Likewise, there was no interaction between the risk of

bleeding and the safety of apixaban.

The analysis also provides data stratified by CHADS2

score so that clinicians can calculate absolute risk reduc-

tions. For patients with a CHADS2 score of 1 or 2, apix-

aban had an absolute risk reduction of 0.13 % stroke or

systemic embolism per year, for a number needed to treat

of 770 versus warfarin. For patients with a CHADS2 score

of 3 or more, apixaban had an absolute risk reduction of

0.85 % in stroke or systemic embolism, for a number

needed to treat of 118 versus warfarin.

Bottom line: The relative risk reductions of apixaban were

not modified by underlying risks of stroke or of hemorrhage.

However, the absolute risk reductions of these adverse

events were proportional to baseline risks; consequently, the

benefits of apixaban were modest in patients at modest risk of

stroke and larger in patients at high risk of stroke.

Citation: Van Spall, H.G., et al., Variation in warfarin

dose adjustment practice is responsible for differences

in the quality of anticoagulation control between centers

and countries: an analysis of patients receiving warfarin

in the randomized evaluation of long-term

anticoagulation therapy (RE-LY) trial. Circulation, 2012.

126(19): p. 2309–16 [17]

Clinical question: Did compliance with the warfarin dos-

ing algorithm in RE-LY correlate with improved INR

response as measured by the total time in range (TTR)?

(Table 2).

Table 2 Warfarin dosing algorithm in RE-LY [17]

INR Dose change

B1.5 ?15 %

1.51–1.99 ?10 %

2.0–3.0 No change

3.01–3.99 -10 %

4.0–4.99 Hold, then -10 %

5.0–8.99 Hold, then -15 %

Top practice-changing articles 329

123

Background: RE-LY was a multi-centered, randomized

trial of 18,113 patients with nonvalvular atrial fibrillation

who were randomized to one of two doses of dabigatran or

to open-labeled warfarin adjusted to an INR of 2–3

(2.0–2.5 in Japan). Overall, 150 mg of dabigatran (taken

twice daily) reduced the rate of strokes or systemic

embolism, and 110 mg of dabigatran (taken twice daily)

had a similar stroke rate but fewer major bleeds than

warfarin [18].

Study design: Post-hoc analysis of data from 6022 RE-LY

participants randomized to warfarin.

Setting: Patients (mean age 72 years; 37 % female) from

44 countries who had AF and at least one additional risk

factor for stroke. The TTR averaged 64 %.

Synopsis: Countries whose doses were compliant with the

RE-LY algorithm had better TTR. Each 10 % increase in a

center’s compliance was associated with a 6 % increase in

TTR. Although the correlation by country was strong

(R2 = 0.65 %), it was driven, in part, by one outlier: a country

that had \ 30 % compliance with the dosing algorithm and a

TTR of \ 40 %. Overall compliance with the dosing algo-

rithm averaged 62 % but was lower in Southeast and Eastern

Asia, where lower INR values where more frequent.

In addition to TTR, clinical outcomes were better at

centers that had greater compliance with the dosing algo-

rithm: Each 10 % increase in compliance was associated

with an 8 % decrease in rate of the composite clinical

outcome (P = 0.05). There was no correlation between a

center’s compliance with the warfarin algorithm and out-

comes in patients taking dabigatran, suggesting that algo-

rithm compliance was not confounded by quality of care.

The dosing algorithm differs from other recommenda-

tions in two ways: First, many recommendations do not

advocate for a warfarin dose adjustment when the INR

values are slightly out of range, [19] especially if the

patient was previously therapeutic on the current dose [20].

Second, several experts would decrease the warfarin dose

by more than 10–15 % for INR values of 4 or more [19].

Bottom line: The analysis validates the effectiveness of the

RE-LY algorithm, but the 62 % compliance demonstrates

that local RE-LY investigators often made other dose

adjustments.

Citation: Homma, S., et al., Warfarin and aspirin

in patients with heart failure and sinus rhythm. N Engl J

Med, 2012. 366(20): p. 1859–69 [21]

Clinical question: As compared to aspirin, does warfarin

reduce the rate of ischemic stroke, intracerebral hemor-

rhage and death in patients with heart failure?

Background: In trials of patients with atrial fibrillation,

anticoagulants halved the risk of ischemic stroke vs aspirin

[22, 23]. However, in a prior multi-centered study of

patients with sinus rhythm and a low ejection fraction,

warfarin did not reduce the rate of stroke [24].

Study design: This was a double-blind, randomized con-

trolled trial in 168 centers. Blinding was maintained in the

warfarin arm by performing sham INR monitoring. Patients

were randomized to aspirin (325 mg/d) or to warfarin with

a target INR of 2.0–3.5. Despite this relatively wide target

INR range, the TTR averaged 63 %.

Setting: Patients (N = 2,305) with left ventricle ejection

fraction \ 35 % were recruited from 11 countries. Their

mean age was 61 years, 80 % of participants were male,

and half were from North America. Mean ejection fraction

was 25 %, and 13 % of participants had previously had a

stroke or TIA. They were followed for 1–6 years (mean

follow up, 3.5 years).

Synopsis: Overall, there was no significant benefit of

warfarin on the composite outcome (ischemic stroke,

intracerebral hemorrhage and death) or on the rate of

hospitalization. However, the efficacy of warfarin therapy

became significant over time (P = 0.046 for the interaction

between efficacy and time). Furthermore, the annual rate of

ischemic stroke was 1.36 % with aspirin and 0.72 % with

warfarin (P = 0.005). A meta-analysis of all 4 trials of

warfarin for patients in sinus rhythm and a low ejection

fraction had similar findings: Compared with aspirin,

warfarin reduced the rate of (ischemic or hemorrhagic)

stroke by 41 %, but doubled the risk of major hemorrhage

(relative risk = 1.95) [25].

Bottom line: Although WARCEF found no benefit of

warfarin therapy on the primary outcome, warfarin lowered

the risk of ischemic stroke and a modest net benefit

emerged after 4 years of therapy. However, the annual

reduction in ischemic stroke was only 0.64 % and warfarin

doubled the risk of major hemorrhage.

Citation: Benavente, O.R., et al., Effects of clopidogrel

added to aspirin in patients with recent lacunar stroke.

N Engl J Med, 2012. 367(9): p. 817–25 [26]

Clinical question: As compared to aspirin alone, does the

combination of aspirin plus clopidogrel reduce the rate of

stroke in patients with recent symptomatic lacunar infarcts?

Background: Lacunar strokes are noncortical infarcts that

occur in small vessels and result in motor and/or sensory

deficits, ataxia, or dysarthria. To prevent recurrence, the

standard treatment is antiplatelet therapy with aspirin,

clopidogrel, or aspirin plus dipyridamole. Clopidogrel plus

330 S. Kaatz, B. F. Gage

123

aspirin is more effective than aspirin alone in patients with

an acute coronary syndrome [27] and probably in patients

who have atrial fibrillation [28], but the combination nearly

doubles the risk of major hemorrhage compared to single

antiplatelet therapy [28, 29].

Study design: SPS3 was a double-blind, randomized

controlled trial in 81 centers. All patients received aspirin

(325 mg/d) and were randomized to either clopidogrel

(75 mg/d) or placebo. The primary endpoint was any

stroke. The trial was terminated prematurely based on the

second interim analysis, which revealed futility and

increased mortality in patients randomized to dual anti-

platelet therapy.

Setting: Patients (N = 3,020) with a prior lacunar stroke

on magnetic resonance imaging were recruited from 9

countries. Their mean age was 63 years, 63 % of partici-

pants were male, 75 % had hypertension, 37 % had dia-

betes, and 65 % were from North America. They were

followed for an average of 3.4 years.

Synopsis: Annual rates of recurrent stroke (any ischemic

stroke or intracranial hemorrhage, including subdural

hematomas) were similar: 2.7 % with aspirin and 2.5 %

with aspirin plus clopidogrel (P = 0.48). For ischemic

stroke the hazard ratio tended to favor dual therapy (the HR

was 0.82) but the 95 % CI was wide (0.63–1.09). The

annual rate of major hemorrhage was 2.1 % with dual

antiplatelet therapy versus 1.1 % with aspirin alone

(P \ 0.001). Although not a primary endpoint, mortality

was significantly (P = 0.004) greater in patients receiving

dual antiplatelet therapy with a HR of 1.52.

Bottom line: Just as the MATCH trial found no benefit of

dual antiplatelet therapy vs. clopidogrel after a recent

ischemic stroke or TIA, [29] SPS3 found no benefit of dual

antiplatelet therapy vs. clopidogrel after a lacunar stroke.

The 1.52-fold increased mortality with dual therapy might

have been due to chance, but the nearly doubling of major

hemorrhages with dual antiplatelet therapy is consistent

with prior trials. Thus, aspirin plus clopidogrel are not

indicated after a lacunar stroke or TIA.

References

1. Heneghan C, Ward A, Perera R, Bankhead C, Fuller A, Stevens

R, Bradford K, Tyndel S, Alonso-Coello P, Ansell J, Beyth R,

Bernardo A, Christensen TD, Cromheecke ME, Edson RG,

Fitzmaurice D, Gadisseur AP, Garcia-Alamino JM, Gardiner C,

Hasenkam JM, Jacobson A, Kaatz S, Kamali F, Khan TI, Knight

E, Kortke H, Levi M, Matchar D, Menendez-Jandula B, Rakovac

I, Schaefer C, Siebenhofer A, Souto JC, Sunderji R, Gin K,

Shalansky K, Voller H, Wagner O, Zittermann A (2012)

Self-monitoring of oral anticoagulation: systematic review and

meta-analysis of individual patient data. Lancet 379(9813):

322–334. doi:10.1016/S0140-6736(11)61294-4

2. Witt DM, Delate T, Garcia DA, Clark NP, Hylek EM, Ageno W,

Dentali F, Crowther MA (2012) Risk of thromboembolism,

recurrent hemorrhage, and death after warfarin therapy interrup-

tion for gastrointestinal tract bleeding. Arch Intern Med

172(19):1484–1491. doi:10.1001/archinternmed.2012.4261

3. Brotman DJ, Jaffer AK (2012) Resuming anticoagulation in the

first week following gastrointestinal tract hemorrhage: should we

adopt a 4-day rule? Arch Intern Med 172(19):1492–1493.

doi:10.1001/archinternmed.2012.4309

4. Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF,

Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen

A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F,

Gallus AS, Raskob GE, Schellong S, Segers A (2012) Oral riv-

aroxaban for the treatment of symptomatic pulmonary embolism.

N Engl J Med 366(14):1287–1297. doi:10.1056/NEJMoa1113572

5. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H,

Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F,

Crowther M, Kahn SR, American College of Chest Physicians

(2012) Antithrombotic therapy for VTE disease: antithrombotic

therapy and prevention of thrombosis, 9th ed: American College

of Chest Physicians evidence-based clinical practice guidelines.

Chest 141(2 Suppl):e419S–e494S. doi:10.1378/chest.11-2301

6. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus

H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE,

Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H,

Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral

rivaroxaban for symptomatic venous thromboembolism. N Engl J

Med 363(26):2499–2510. doi:10.1056/NEJMoa1007903

7. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M,

Porcari A, Raskob GE, Weitz JI (2013) Apixaban for extended

treatment of venous thromboembolism. N Engl J Med 368(8):

699–708. doi:10.1056/NEJMoa1207541

8. Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Oc-

kelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes

J (2012) Low-dose aspirin for preventing recurrent venous

thromboembolism. N Engl J Med 367(21):1979–1987.

doi:10.1056/NEJMoa1210384

9. Antiplatelet Trialists’ Collaboration (1994) Collaborative over-

view of randomised trials of antiplatelet therapy–III: reduction in

venous thrombosis and pulmonary embolism by antiplatelet pro-

phylaxis among surgical and medical patients. BMJ 308(6923):

235–246

10. Antithrombotic Trialists C (2002) Collaborative meta-analysis of

randomised trials of antiplatelet therapy for prevention of death,

myocardial infarction, and stroke in high risk patients. BMJ

324(7329):71–86

11. Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E,

Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR,

Grandone E, Prandoni P (2012) Aspirin for preventing the

recurrence of venous thromboembolism. N Engl J Med

366(21):1959–1967. doi:10.1056/NEJMoa1114238

12. Merie C, Kober L, Skov Olsen P, Andersson C, Gislason G, Skov

Jensen J, Torp-Pedersen C (2012) Association of warfarin therapy

duration after bioprosthetic aortic valve replacement with risk of

mortality, thromboembolic complications, and bleeding. JAMA

308(20):2118–2125. doi:10.1001/jama.2012.54506

13. Bonow RO, Carabello BA, Kanu C, De Leon AC Jr, Faxon DP,

Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT,

O’Rourke RA, Otto CM, Shah PM, Shanewise JS, Smith SC Jr,

Jacobs AK, Adams CD, Anderson JL, Antman EM, Faxon DP,

Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW,

Nishimura R, Page RL, Riegel B (2006) ACC/AHA 2006

guidelines for the management of patients with valvular heart

disease: a report of the American College of Cardiology/

Top practice-changing articles 331

123

American Heart Association task force on practice guidelines

(writing committee to revise the 1998 guidelines for the man-

agement of patients with valvular heart disease): developed in

collaboration with the Society of Cardiovascular Anesthesiolo-

gists: endorsed by the Society for Cardiovascular Angiography

and Interventions and the Society of Thoracic Surgeons. Circu-

lation 114(5):e84–e231. doi:10.1161/circulationaha.106.176857

14. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH (2012)

Antithrombotic and thrombolytic therapy for valvular disease:

antithrombotic therapy and prevention of thrombosis, 9th ed:

American College of Chest Physicians evidence-based clinical

practice guidelines. Chest 141(2 Suppl):e576S–e600S. doi:

10.1378/chest.11-2305

15. Lopes RD, Al-Khatib SM, Wallentin L, Yang H, Ansell J, Bahit

MC, De Caterina R, Dorian P, Easton JD, Erol C, Ezekowitz JA,

Gersh BJ, Granger CB, Hohnloser SH, Horowitz J, Hylek EM,

McMurray JJ, Mohan P, Vinereanu D, Alexander JH (2012)

Efficacy and safety of apixaban compared with warfarin according

to patient risk of stroke and of bleeding in atrial fibrillation: a

secondary analysis of a randomised controlled trial. Lancet

380(9855):1749–1758. doi:10.1016/S0140-6736(12)60986-6

16. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM,

Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit

MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D,

Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG,

Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-

Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wal-

lentin L (2011) Apixaban versus warfarin in patients with atrial

fibrillation. N Engl J Med. doi:10.1056/NEJMoa1107039

17. Van Spall HG, Wallentin L, Yusuf S, Eikelboom JW, Nieuwlaat

R, Yang S, Kabali C, Reilly PA, Ezekowitz MD, Connolly SJ

(2012) Variation in warfarin dose adjustment practice is

responsible for differences in the quality of anticoagulation

control between centers and countries: an analysis of patients

receiving warfarin in the randomized evaluation of long-term

anticoagulation therapy (RE-LY) trial. Circulation 126(19):

2309–2316. doi:10.1161/circulationaha.112.101808

18. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J,

Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S,

Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener

HC, Joyner CD, Wallentin L (2009) Dabigatran versus warfarin

in patients with atrial fibrillation. N Engl J Med 361(12):

1139–1151. doi:10.1056/NEJMoa0905561

19. Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs

MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH (2012)

Evidence-based management of anticoagulant therapy: anti-

thrombotic therapy and prevention of thrombosis, 9th ed:

American College of Chest Physicians evidence-based clinical

practice guidelines. Chest 141(2 Suppl):e152S–e184S. doi:

10.1378/chest.11-2295

20. Banet GA, Waterman AD, Milligan PE, Gatchel SK, Gage BF

(2003) Warfarin dose reduction vs watchful waiting for mild ele-

vations in the international normalized ratio. Chest 123(2):499–503

21. Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger

RS, Teerlink JR, Ammon SE, Graham S, Sacco RL, Mann DL,

Mohr JP, Massie BM, Labovitz AJ, Anker SD, Lok DJ, Poni-

kowski P, Estol CJ, Lip GY, Di Tullio MR, Sanford AR, Mejia V,

Gabriel AP, del Valle ML, Buchsbaum R (2012) Warfarin and

aspirin in patients with heart failure and sinus rhythm. N Engl J

Med 366(20):1859–1869. doi:10.1056/NEJMoa1202299

22. Hart RG, Pearce LA, Aguilar MI (2007) Adjusted-dose warfarin

versus aspirin for preventing stroke in patients with atrial fibril-

lation. Ann Intern Med 147(8):590–592

23. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn

S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J,

Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan

RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH,

Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M,

O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S (2011)

Apixaban in patients with atrial fibrillation. N Engl J Med

364(9):806–817. doi:10.1056/NEJMoa1007432

24. Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG,

Ezekowitz M, Jafri SM, Krol WF, O’Connor CM, Schulman KA,

Teo K, Warren SR (2009) Randomized trial of warfarin, aspirin,

and clopidogrel in patients with chronic heart failure: the warfarin

and antiplatelet therapy in chronic heart failure (WATCH) trial.

Circulation 119(12):1616–1624. doi:10.1161/circulationaha.108.

801753

25. Kumar G, Goyal MK (2012) Warfarin versus aspirin for pre-

vention of stroke in heart failure: a meta-analysis of randomized

controlled clinical trials. J Stroke Cerebrovasc Dis. doi:10.1016/

j.jstrokecerebrovasdis.2012.09.015

26. Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey

CS, Pearce LA (2012) Effects of clopidogrel added to aspirin in

patients with recent lacunar stroke. N Engl J Med 367(9):

817–825. doi:10.1056/NEJMoa1204133

27. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL,

Diaz R, Commerford PJ, Valentin V, Yusuf S (2003) Effects of

aspirin dose when used alone or in combination with clopidogrel

in patients with acute coronary syndromes: observations from the

clopidogrel in unstable angina to prevent recurrent events

(CURE) study. Circulation 108(14):1682–1687. doi:10.1161/

01.cir.0000091201.39590.cb

28. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M,

Chrolavicius S, Yusuf S (2009) Effect of clopidogrel added to

aspirin in patients with atrial fibrillation. N Engl J Med

360(20):2066–2078. doi:10.1056/NEJMoa0901301

29. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L,

Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ (2004) Aspirin

and clopidogrel compared with clopidogrel alone after recent

ischaemic stroke or transient ischaemic attack in high-risk

patients (MATCH): randomised, double-blind, placebo-con-

trolled trial. Lancet 364(9431):331–337. doi:10.1016/s0140-

6736(04)16721-4

30. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR,

Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian

JA (1999) A comparison of 3 months of anticoagulation with

extended anticoagulation for a first episode of idiopathic venous

thromboembolism. N Engl J Med 340(12):901–907. doi:10.1056/

NEJM199903253401201

31. Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS,

Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG,

Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP,

Bounameaux H, Glynn RJ (2003) Long-term, low-intensity

warfarin therapy for the prevention of recurrent venous throm-

boembolism. N Engl J Med 348(15):1425–1434. doi:10.1056/

NEJMoa035029

32. Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H

(2003) Secondary prevention of venous thromboembolism with

the oral direct thrombin inhibitor ximelagatran. N Engl J Med

349(18):1713–1721. doi:10.1056/NEJMoa030104

33. Buller HR, Cohen AT, Davidson B, Decousus H, Gallus AS, Gent

M, Pillion G, Piovella F, Prins MH, Raskob GE (2007) Extended

prophylaxis of venous thromboembolism with idraparinux.

N Engl J Med 357(11):1105–1112. doi:10.1056/NEJMoa067703

34. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H,

Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber

SZ, (2013) Extended use of dabigatran, warfarin, or placebo in

venous thromboembolism. N Engl J Med 368(8):709–718. doi:

10.1056/NEJMoa1113697

332 S. Kaatz, B. F. Gage

123