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CLINICIAN UPDATE

Oral Anticoagulation for Acute Coronary Syndromes


Marc A. Brouwer, MD; Freek W.A. Verheugt, MD, PhD

T
he following 2 case presentations illustrate the range to 3) was started in addition to aspirin (80 mg daily) as a
of considerations when formulating plans for oral strategy for secondary prevention of death, (re)infarction, and
anticoagulation in patients with acute coronary stroke.
syndromes.
Background
Case A Notwithstanding the improvements in the secondary preven-
A 59-year-old patient presented within 5-hours of the onset of tion of acute coronary syndromes, death and (re)infarction
an electrocardiographic wave segment (ST) elevation anterior occur in ⬇10% to 15% of patients in the 4 to 6 weeks after
myocardial infarction and was treated with the accelerated
presentation despite the use of aspirin. Interestingly, in-
dose regimen of alteplase, adjunctive unfractionated heparin,
creased activity of the coagulation cascade has been reported
aspirin, and a ␤-blocker. The maximum isoenzyme of creat-
up to 6 months after the index event.1 In addition, raised
ine kinase with muscle and brain subunits was ⬎10 times the
concentrations of factor VII are associated with both initial
upper limit of normal. At day 4, echocardiography revealed a
mass suggestive of a mural left ventricular thrombus and and recurrent ischemic events.2 These observations stimu-
important apical wall motion abnormalities. ACE inhibition lated renewed interest in the potential benefit of oral
therapy was initiated. To reduce the risk of systemic emboliza- anticoagulants.
tion, heparinization with a target activated partial thromboplastin The INR has replaced the nonstandardized prothrombin
time of 1.5 to 2.0 times control was started, followed by 6 time and quick tests,3 and INR monitoring by patients is now
months of dose-adjusted warfarin, target international normal- a new feature in clinical practice.4,5 Several trials have
ized ratio (INR) 2.5 to 3.5 (Table 1). evaluated a combined regimen of aspirin with dose-adjusted
coumarins,6 –10 2 of which also addressed the direct compar-
Case B ison of both agents alone.9,10 In view of these developments,
A 66-year-old diabetic patient, taking aspirin daily because of the present report forms an update on the role of oral
a prior transient ischemic attack, presented with chest pain at anticoagulation therapy in acute coronary syndromes with the
rest and dynamic ST depression ⬎1 mm. He recovered from emphasis on secondary prevention and its additional effect in
the acute phase after treatment with low-molecular-weight combination with aspirin.
heparin, nitroglycerine, aspirin, and ␤-blocker therapy. Car-
diac markers remained negative. During the convalescence Pathophysiological Rationale
period, no recurrent chest pain occurred, and exercise testing The process of coronary thrombosis can be divided into 3
was negative with respect to symptoms and electrocardio- major steps: (1) vascular injury with exposure of the throm-
graphic signs of ischemia. Before discharge, dose-adjusted
bogenic subendothelial surface; (2) adhesion and aggregation
medium-intensity oral anticoagulation therapy (target INR, 2
of platelets; and (3) formation of a fibrin-rich clot.
Exposure of subendothelial collagen not only activates
From the Heartcenter, Department of Cardiology, University Medical platelets but also the coagulation system (Figure 1). As a
Center Nijmegen, the Netherlands.
result, prothrombin is cleaved into thrombin by prothrombi-
Correspondence to Freek W.A. Verheugt, MD, PhD, FAHA, FACC,
Heartcenter, 540 Department of Cardiology, PO Box 9101, University nase (factor Xa, Va, and phospholipids). Thrombin is a potent
Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands. E-mail platelet activator, a process not inhibited by aspirin or
f.verheugt@cardio.umcn.nl
clopidogrel. In addition, thrombin activates important cofac-
(Circulation. 2002;105:1270-1274.)
© 2002 American Heart Association, Inc. tors (V and VIII) for coagulation and is the key factor in the
Circulation is available at http://www.Circulationaha.org process of fibrin clot formation. Not only does it cleave
DOI: 10.1161/hc1102.105594 fibrinogen into fibrin, it also activates factor XIII, which
1270
Brouwer and Verheugt Oral Anticoagulation for Acute Coronary Syndromes 1271

TABLE 1. Established Indications for Oral Anticoagulant IX, and X fall after ⬇4 days. This underscores the possibility
Therapy and Recommended Therapeutic Range of a procoagulant effect developing in a patient early after
Indications Target INR initiation or termination of oral anticoagulant therapy. Ab-
sorption of warfarin from the gastrointestinal tract is rapid,
Prophylaxis of venous thrombosis
with a high bioavailability. The drug circulates bound to
Treatment of venous thrombosis
plasma proteins with subsequent accumulation and metabo-
Treatment of pulmonary embolism lization in the liver. Accordingly, dietary aspects related to
Prevention of systemic embolism INR 2.0–3.0 increased or decreased intake of the fat-soluble vitamin K,
Atrial fibrillation gastrointestinal malabsorption, and hepatic dysfunction are
Tissue heart valves some of the factors that can interfere with the response to oral
Valvular heart disease anticoagulation therapy. Various drugs can cause interactions
Acute myocardial infarction* or affect metabolic clearance of warfarin. A common inter-
INR 2.5–3.5 action is with antibiotics, some potentiating (trimethoprim
Mechanical prosthetic valves (high risk)
and metronidazole) and others inhibiting (rifampicin) antico-
Bileaflet mechanical valve in aortic position INR 2.0–3.0
agulant efficacy. Important for in-hospital and outpatient care
Table modified from Hirsh et al. Chest. 2001;119:85–215.
in cardiology is amiodarone, which potentiates anticoagulant
*As demonstrated in case A.
activity.14,15 Nonsteroidal anti-inflammatory drugs14,15 and
high doses of aspirin (⬎1 g/d) plus high-intensity warfarin
results in improved clot strength with more resistance to
have been associated with an increased bleeding risk.16
endogenous and exogenous fibrinolysis.
Given the extent of drug interactions and range of genetic
In view of the above, an antithrombotic regimen of both
factors impacting drug disposition, interindividual and intra-
antiplatelet and antithrombin therapy could potentially have
individual variability in anticoagulant efficacy and safety is
an additional impact when compared with a regimen of
not surprising. However, monitoring was standardized with
antiplatelet therapy alone (Figure 1). This favors the combi-
the introduction of the INR, and results became internation-
nation of aspirin with either unfractionated heparin, low-
ally exchangeable and comparable.3 Both efficacy and safety
molecular-weight heparin, or a direct antithrombin in the
were found to depend on the intensity of anticoagula-
initial hospital treatment phase in patients with acute coro-
tion14,15,17 and the maximum time spent in the target range.15
nary syndromes.11–13 After hospital discharge, recurrent is-
This, in turn, relates to the frequency of monitoring,15 which
chemic events are not infrequent, and in light of the demon-
emphasizes the future potential of self-monitoring.4,5 In view
strated persistent increased coagulant activity, prolonged oral
of these developments and the lower daily doses of aspirin
anticoagulation after hospitalization might be beneficial.
presently prescribed, new studies in the primary and second-
Pharmacology ary prevention of acute coronary syndromes were initiated,
Oral anticoagulants such as warfarin act through interference addressing not only the efficacy of a combined regimen with
with the vitamin K– dependent production of coagulation different intensities of anticoagulation but also the direct
factors II, VII, IX, and X, which are produced by the liver comparison of warfarin versus aspirin alone.
(Figure 2). In addition, proteins C and S, regulatory antico-
agulants, are also produced in a biologically less-active form Clinical Efficacy
after warfarin treatment. Based on their half-lives, concentra- Primary Prevention
tions of protein C and factor VII are the first to drop, within Dose-adjusted low-intensity warfarin (target INR, 1.3 to 1.8)
24 hours of initiation of therapy, whereas levels of factors II, has been shown to reduce the risk of ischemic heart disease to

Figure 1. Thrombus formation and pharmacologi-


cal interventions in the coagulation cascade. Tis-
sue injury not only induces subendothelial adhe-
sion (vWF, GP Ib, GP Ia/IIa) and aggregation of
platelets (fibrinogen, GP IIb/IIIa), but also activates
the coagulation cascade. Activation of the extrinsic
and intrinsic coagulation pathways results in the
thrombin-induced formation of a fibrin-rich clot.
Fibrin cross-linking by factor XIII improves clot-
strength. Whereas oral anticoagulants interfere
with the production of coagulation factors, other
agents inhibit the action of activated clotting fac-
tors. vWF indicates von Willebrand factor; PT, pro-
thrombin (II); T, thrombin (IIa); OAC, oral antico-
agulants; UFH, unfractionated heparin; and
LMWH, low-molecular-weight heparin.
1272 Circulation March 19, 2002

placebo-controlled randomized trials in the early 1990s un-


equivocally demonstrated the efficacy of full-intensity anti-
coagulation (INR, 2.8 to 4.2) at the cost of a 4-fold increased
risk of major bleeding.17,20,21

Monotherapy Versus Aspirin


Given its ease of administration and favorable safety profile,
aspirin has become the initial antithrombotic agent of choice
in acute coronary syndromes. Meta-analysis of the few small
trials comparing moderate-to-high intensity anticoagulation
Figure 2. Oral anticoagulants: mechanism of action. Coumarins versus aspirin did not demonstrate a difference in efficacy,
inhibit the conversion of vitamin K epoxide (Vit.KO) to its whereas bleeding was lower with aspirin.17 Interestingly, the
reduced form (Vit.KH2) through interference with 2 reductases:
KO-reductase and K-reductase. Subsequent insufficient ASPECT-2 (target INR, 3 to 4) and WARIS-2 (target INR,
␥-carboxylation results in coagulation factors with impaired bio- 2.8 to 4.2) trials both reported that full-intensity anticoagu-
logical function. Most of the impact is exerted through inhibition lation as monotherapy was superior to aspirin alone in the
of the coumarin-sensitive KO-reductase. As K-reductase is rela-
tively coumarin resistant, dietary aspects and administration of
secondary prevention of death, (re)infarction, and stroke.9,10
vitamin K (Vit.K1) are interfering factors. Adapted from Ansell et Thus, high-intensity oral anticoagulation seems an effective
al.15 alternative for aspirin in the setting of well-organized fre-
quent INR monitoring.
an extent similar to 75 mg of aspirin. Interestingly, warfarin
Combination Therapy Versus Aspirin Alone
(mean INR, 1.5) primarily reduced fatal events and aspirin Oral anticoagulation therapy at medium-high and low inten-
primarily reduced nonfatal myocardial infarction. The com- sity combined with aspirin has been tested (Table 2). A
bination of warfarin and aspirin had additional beneficial combination of medium-high intensity oral anticoagulation
impact but increased fatal strokes and minor bleeding. The plus aspirin seems promising,17 whereas fixed-dose, low
use of either agent alone was associated only with more intensity does not improve clinical outcome.22 Since the start
minor bleeding.18 Similar to primary prevention studies with of the new millennium, 4 trials with a target INR ⬎2 have
aspirin,19 the benefit of oral anticoagulant therapy in primary been completed, 3 involving patients with myocardial infarc-
prevention is confined to high-risk men, with little data tion8 –10 and 1 that primarily included patients with unstable
available for women. angina.6 APRICOT-2 and ASPECT-2 were performed in the
Netherlands8,9 and WARIS-2 was performed in Norway,10
Secondary Prevention countries that are known for the high quality of their
Monotherapy Versus Control anticoagulation clinics. ASPECT-2 was unfortunately prema-
Oral anticoagulation is one of the oldest strategies for turely discontinued because of slow recruitment. Although
secondary prevention of ischemic heart disease. After a large underpowered, a significant clinical benefit for the combined
number of controlled trials in the 1960s, 2 large double-blind antithrombotic regimen (INR, 2.4) was observed when com-

TABLE 2. Randomized Aspirin-Controlled Studies of Oral Anticoagulation in Addition to Aspirin After Acute Coronary Syndromes
1° End Point
INR INR ASA Dose, Fup,
Study Year n Target Reached mg ASA⫹OAC ASA RR P mo
Angiographic % (Re)occlusion
Williams23 1997 57 2.0–2.5 2.0 150 4% 33% NA 0.02* 3
APRICOT-28 2000 308 2.0–3.0 2.6 80 18% 30% 0.60 (0.39–0.93) 0.02 3
Clinical % Mortality, (re)MI, stroke
CARS22 1997 8803 1 mg QD 8.8% 1.03 (0.87–1.22) 0.74 14
80 vs 160 8.6%
3 mg QD 8.4% 0.95 (0.81–1.12) 0.57 14
CHAMP7 1999 5059 1.5–2.5 1.8 80 vs 160 17.6%† 17.3%† 0.98 (0.87–1.11) 0.76 33
ASPECT-29 2000 668 2.0–2.5 2.4 80 5.1% 9.2% 0.55 (0.31–0.98) ⬍0.05 12
OASIS-26 2001 3712 2.0–2.5 NP Not specified 7.6% 8.3% 0.90 (0.72–1.14) 0.40 5
Good compliers 1821 6.1% 8.9% 0.68 (0.48–0.95) 0.02
Poor compliers 1891 9.0% 7.8% 1.17 (0.86–1.60) 0.33
WARIS-210 2001 2414 2.0–2.5 2.2 75 vs 160 15.0% 20.0% 0.71 (0.58–0.86) ⬍0.01 48
Unpublished data are shown as presented at the respective congresses (see References) and are preliminary results. See References for full trial names. n indicates
number of patients randomized; INR, international normalized ratio; ASA, aspirin; OAC, oral anticoagulation; 1° End Point, primary end point; RR, relative risk; Fup,
follow-up period; Good/poor compliers, oral anticoagulation use in ⬎ or ⬍70% patients at 35 days; NA, not applicable; and NP, not published.
*P value by Fisher exact test.
†Mortality, primary end point.
Brouwer and Verheugt Oral Anticoagulation for Acute Coronary Syndromes 1273

pared with aspirin alone.9 In APRICOT-2, designed and to 3-fold increased risk of minor and major bleeding, without
powered as angiographic follow-up trial, the combined anti- an increased risk of intracerebral hemorrhage.6 –10
thrombotic regimen (INR, 2.6) produced a 40% reduction in A less frequently observed side effect is skin necrosis
3-month reocclusion after successful fibrinolytic therapy. attributable to thrombosis of the venules and capillaries
Similar findings were observed in a smaller, more heteroge- within the subcutaneous fat. An abrupt drop in protein C
neous group of patients after acute coronary syndromes. levels or a preexisting deficiency is responsible for the
Clinical outcome, the secondary end point, was also signifi- procoagulant response seen in the first 3 to 8 days after
cantly improved.8,23 The larger WARIS-2 trial (INR, 2.2) initiation of therapy.14,15 It should be noted that oral antico-
confirmed these observations over a 4-year follow-up period, agulants are associated with an increased risk of fetal central
with a reduction in the combined end point of death, rein- nervous system and bone abnormalities, bleeding, and fetal
farction, and stroke from 20% to 15%.10 OASIS-2 was death. For most pregnant women requiring anticoagulant
performed worldwide and showed a nonsignificant 10% therapy, unfractionated heparin and subcutaneous low-
reduction for the combined strategy.6 When OASIS-2 was molecular-weight heparin are safe alternatives.14,15
reanalyzed, stratified by countries with good compliance to
anticoagulation therapy, a marked clinical benefit was appar- Recommendations
ent (Table 2). The largest worldwide trial after myocardial Irrespective of the indication, dose-adjusted, frequently mon-
infarction to date, CHAMP, was aimed at a target INR of 1.5 itored, and individually tailored therapy is a prerequisite for
to 2.5 and was neutral. In this trial, with a mean INR of 1.8, optimal oral anticoagulation. Primary prevention can be
most patients had an INR near the lowest target intensity.7 considered in high-risk patients with nonmodifiable risk
In aggregate, the available data suggest that in a setting of factors or risk factors that are not easily controlled, aiming at
good compliance and well-organized INR monitoring, addi- a target INR of 1.5.18 In patients with an acute coronary
tion of oral anticoagulation (INR, ⬎2.0) to aspirin seems syndrome, oral anticoagulation should be prescribed for
beneficial. More insight into the efficacy and safety of a established indications (eg, case A,15 Table 1) in the absence
regimen with a target of 1.5 to 2.5 will be provided by the of contraindications.
LOWASA study, which is enrolling ⬎5000 patients in Secondary prevention of coronary events attributable to
Sweden. recurrent thrombosis is a major component of management of
patients after presentation with an acute coronary syndrome.
Clinically Observed Mechanism of Benefit Given its ease of administration, predictable safety, and
The controlled trials of warfarin as a single agent showed proven efficacy, aspirin should be the preferred agent for this
marked reductions in death, (re)infarction, and stroke, respec- indication.19 In clinical settings with a good infrastructure,
tively.17 As for the direct comparison with aspirin, or a full-intensity oral anticoagulation (target INR, 2.8 to 4.2) is
specification of the efficacy of the combined regimen, an an effective alternative, with ample evidence-based sup-
updated meta-analysis including final data of the unpublished port.9,10,17 If aspirin is contraindicated, oral anticoagulation is
trials is warranted. The fact that oral anticoagulants take 2 to the only effective alternative long-term antithrombotic regi-
4 days to become therapeutically effective is an important men evaluated to date in patients after ST elevation myocar-
clinical consideration. Timing of initiation of oral anticoag- dial infarction. Although both low-molecular-weight heparin
ulation and the antithrombotic regimen administered during and clopidogrel in addition to aspirin have been proven safe
the acute phase therefore must take into account such phar- in the long-term treatment of patients after a non-ST elevation
macological factors. acute coronary syndrome,25,26 only clopidogrel proved to be
of additional benefit. In cases of aspirin intolerance, 75 mg
Adverse Events clopidogrel once daily seems a practical long-term alterna-
In patients taking oral anticoagulants, the initiation or with- tive. With respect to the long-term benefits of clopidogrel,27
drawal of concurrent medications must be reviewed by a direct comparisons with oral anticoagulation, both as single
health care professional, preferably a member of a dedicated agents and in addition to aspirin, have not been performed to
anticoagulation service committed to close communication date. We believe this is an important area for future trials.
with the patient. The most frequent complication is bleeding, Data on the combination of moderate intensity anticoagu-
which is related to the intensity of anticoagulation14,15,17 and lation (target INR, 2 to 3) with aspirin seem promising,6,8 –10,17
is more frequent when oral anticoagulation is used in patients but routine implementation in general cannot yet be recom-
with cerebrovascular or peripheral disease.24 High-risk sub- mended in uncomplicated patients (eg, case B). Combination
groups are those with a history of gastrointestinal bleeding, therapy can certainly be considered in individual (high-risk)
stroke, hypertension, impaired renal function, and anemia. cases; in that case, the recommended aspirin dose is 80 mg
Whether increased age is an independent risk factor or daily7–10,22 to be taken along with moderate-intensity oral
whether bleeding is primarily a result of comorbid factors anticoagulation. Definition of the optimal duration of therapy
remains an issue of controversy. Irrespective of age, bleeding and identification of subsets of patients with the optimal
episodes should trigger a search for a possible underlying risk-benefit profile are relevant clinical issues. A practical
occult lesion, which may be malignant.14,15 With respect to aspect of concern is the fact that even in countries with an
the safety of a combined regimen of aspirin and dose-adjusted established good quality anticoagulation service infrastruc-
oral anticoagulation therapy, the different studies report a 2- ture and high short-term compliance, ⬇20% to 25% of
1274 Circulation March 19, 2002

patients discontinue therapy within 6 months, and only a 13. The Global Use of Strategies to Open Occluded Coronary Arteries
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heparin for the treatment of acute coronary syndromes. N Engl J Med.
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Chest. 2001;119:22S–38S.
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16. Chesebro JH, Fuster V, Elveback LR, et al. Trial of combined warfarin
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