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Anticoagulation module 3: anticoagulant therapy

Module 1 explained the mechanisms and functions of haemostasis, and of the importance of the
balance between coagulation and the dual processes of inhibition and fibrinolysis. Module 2
considered the pathology of arterial thrombosis, and the use of antiplatelet agents to treat or
prevent this.
In this module, we focus on anticoagulant therapy pharmacological intervention in the
coagulation cascade. This is of central importance in treatment and prevention of thromboses
which form under conditions of low shear venous thromboembolism. In cardiology, it is used in
three main situations: atrial fibrillation (AF), acute coronary syndromes (as an adjunct to
antiplatelet agents) and heart valve disease. But before we look at these conditions, we must
review the coagulation cascade.
The coagulation pathway revisited
A simplistic view of the coagulation cascade (see figure 1) can be divided into three pathways:
The extrinsic pathway involves tissue factor and factor VII, which together form a second
complex to generate factor Xa. This is the main pathway by which coagulation is activated in
The intrinsic pathway sees coagulation factors XII, XI, IX, and VIII come together to form a
complex that results in the conversion of factor X to activated factor X (that is, factor Xa). As a
pathway for activation of coagulation this probably has minimal importance in vivo. However,
factors VIII, IX and XI have crucial roles in amplification of the cascade.
In the common pathway, factor Xa combines with factor Va to form the prothrombinase complex
that converts prothrombin into thrombin. This, in turn, generates fibrin from fibrinogen. Once
stabilised by factor XIIIa, fibrin combines with platelets (and often with red cells) to form a

This pathway also requires the presence of phospholipids (from the surface of the platelet) and
calcium. The key steps in the coagulation cascade are (a) the generation of factor Xa, and (b) the
generation of thrombin.1
Anticoagulants interfere with this process to prevent unwanted activation of the clotting cascade.
A number of agents are in use, ranging from long-established heparin, low molecular weight
heparin (LMWH) and vitamin K antagonists (VKAs) (of which warfarin is the principal agent) to the
newer, non-VKA oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban and edoxaban.
We will consider these agents and their therapeutic indications in this module. Module 4 will
look at some of the clinical aspects of their use.
Intravenous/subcutaneous anticoagulants
Heparin is a polymer of repeating disaccharide units. Unfractionated heparin (UFH), as used
pharmacologically, consists of a heterogenous mixture of chains of different lengths. Heparin
binds antithrombin, inducing a conformational change which greatly increases its ability to
inihibit factors Xa and IIa (thrombin). Heparin is rapidly cleared from the circulation by binding to
endothelium/plasma proteins, with renal excretion becoming important once this mechanism is
saturated. Although an effective anticoagulant, heparin has many undesirable features, such as
the risk of heparin induced thrombocytopenia [HIT] and the need for intensive monitoring. Long-
term use can also lead to osteoporosis. Heparin can be rapidly neutralised by protamine.

Low molecular weight heparin

Several of the problems with UFH have been resolved by the development of a cleaner form,
low molecular weight heparin (LMWH), by depolymerisation of heparin. The shorter chain means
that principal anticoagulant activity is by anti Xa activity, but there is some residual antithrombin
activity also the several different LMWHs available differ in their ratio of anti Xa to antithrombin
activity, according to their chain length.
LMWHs have much more predictable anticoagulant activity, so that monitoring is usually not
required. LMWH also has a much lower incidence of HIT.
The main disadvantage of LMWHs is their greater reliance on renal excretion (although this varies
between agents) making them unsuitable for use in severe renal impairment. LMWH also has a
longer half life than UFH, and cannot be completely neutralised by protamine (although again
this varies between agents), which can make the management of bleeding challenging.2
Differences between UFH and LMWHs are shown in table 1.
This may be described as a super-LMWH, being an engineered pentasaccharide that very
precisely and reversibly binds the active site of factor Xa, providing very efficient inhibition.2
Other advantages are its inactivity towards platelets, and, with no activity against thrombin, that
it has very predictable anticoagulant activity.
A relatively long plasma half-life of 1421 hours permits once-daily injection. There is a rapid
onset of action, with a peak activity reached in two hours, and no interactions with aspirin,
warfarin or digoxin have been noted. Thrombocytopenia occurs even less commonly than with
LMWH. In almost all cases, fondaparinux need not be routinely monitored in the laboratory.
Clearance is reduced in renal impairment; no reversal agent is available.
Fondaparinux has had a key role in the management of acute coronary syndromes since the
OASIS-5 trial showed similar efficacy with reduced bleeding and lower mortality compared to
Direct thrombin inhibitors (DTIs)
These operate by inhibiting the action of thrombin directly, that is (unlike heparin),
independently of antithrombin. Bivalirudin is a hirudin, named after an anticoagulant purified
from the mouthpart of a leech (see figure 2). Another parenteral hirudin, lepirudin, was recently
discontinued by its manufacturer.
Direct thrombin inhibitors (DTIs)
These operate by inhibiting the action of thrombin directly, that is (unlike heparin),
independently of antithrombin. Bivalirudin is a hirudin, named after an anticoagulant purified
from the mouthpart of a leech (see figure 2). Another parenteral hirudin, lepirudin, was recently
discontinued by its manufacturer.
Argatroban is a synthetic, reversible, direct thrombin inhibitor. It has a short half life (50 minutes)
and minimal renal clearance. Its main use is in the specialist management of acute HIT.4
Bivalirudin is an option instead of a heparin in patients with acute coronary syndromes having
percutaneous coronary intervention (PCI) as an adjunct to aspirin and clopidogrel, and is
approved by the National Institute for Health and Care Excellence (NICE) for patients with ST-
elevation MI having PCI.5 Bivalirudin also has an important but specialist role in cardiac surgery
in patients with a history of HIT, who cannot receive heparin.4
Dabigatran (discussed below) is an orally available direct thrombin inhibitor.
Monitoring intravenous/subcutaneous anticoagulants
UFH must be monitored in each patient using the activated partial thromboplastin time (APTT).
Argatroban is also monitored by the APTT.
One of the major advantages of LMWHs and fondaparinux is that they do not routinely require
monitoring. However, in cases where it is felt necessary to measure the degree of
anticoagulation with these agents (for instance in patients with poor renal function, or with
recurrent thrombosis despite anticoagulation) this can be done by measuring the anti Xa activity.
Anticoagulant monitoring will be considered further in module 4.

Oral anticoagulants
Warfarin inhibits the enzyme vitamin K epoxide reductase. This prevents the recycling of vitamin
K, which is essential for carboxylation of several clotting factors. Without this carboxylation they
will not function. Factors affected by warfarin are factors II, VII, IX and X; it also reduces levels of
protein C and protein S. For those in whom warfarin is contra-indicated, perhaps by intolerance or
allergy, alternative VKAs are available: acenocoumarol and phenidione.
Warfarin is a long-established and effective anticoagulant, which is safe in renal impairment, and
has established reversal agents available (prothrombin complex concentrate for emergency
reversal, vitamin K for reversal over hours). However, there are a number of problems associated
with its use, including its numerous drug interactions, a narrow therapeutic window with
requirement for frequent monitoring blood tests, and the long time (days) taken to reach a
therapeutic level. Practical issues relating to warfarin use are discussed in modules 4 and 5.
Non-vitamin K antagonist oral anticoagulants (NOACs)
Previously known as novel or new oral anticoagulants, not all these agents are really new
anymore (dabigatran obtained its US licence in 2010). This has led to them being renamed, e.g.
by NICE as non-vitamin K antagonist oral anticoagulants. The International Society for
Thrombosis and Haemostasis, however, recently suggested a change of name to DOACs,6 in
recognition of their mode of action: direct inhibition of one clotting factor, rather than
interference with the metabolism of several, as warfarin does.
In fact the grouping is somewhat false, as the agents do not share the same mechanism of
action: three are inhibitors of factor Xa (rivaroxaban, apixaban and edoxaban) while dabigatran
inhibits thrombin. What they share, however, are rapid onset of action from oral administration,
and predictable pharmacokinetics such that monitoring of anticoagulant effect is not routinely
Discussion of drug dosing below is for the atrial fibrillation indication. Always consult up to date
product literature or the British National Formulary for prescribing information.
Dabigatran is an oral direct thrombin inhibitor. It has rapid absorption (within two hours) and
distribution with an estimated half-life of 1318 hours. Nearly 80% is excreted unchanged by the
kidneys, so that half life can be significantly prolonged in renal impairment, and dabigatran is
contraindicated in severe renal impairment (creatinine clearance <30 ml/min).
Although drug interactions are few, dabigatran is a substrate for the efflux transporter P-
glycoprotein (P-gp), so that levels of dabigatran are increased by P-gp inhibitors. Some of these
interactions are potentially highly significant in cardiac patients: strong P-gp inhibitors
(ketoconazole, cyclosporine, itraconazole and dronedarone) are contraindicated with dabigatran,
while moderate inhibitors (amiodarone, verapamil, quinidine, clarithromycin and ticagrelor)
should be used with caution.
A reduced dose is suggested by the manufacturer for elderly patients, patients with renal
impairment, patients on one of the drugs listed above, or other patients felt to be at high risk of
This was the first selective oral direct factor Xa inhibitor on the market.7 It inhibits both free and
clot bound factor Xa, and, unlike heparin, does not depend on antithrombin for its action. It
achieves peak plasma levels in two hours and has a half-life of 513 hours longer in elderly
subjects and those with renal impairment. Rivaroxaban is dosed once daily.
Excretion is approximately one third renal a dose reduction is recommended with creatinine
clearance 1549 ml/min, and the drug contraindicated below 15 ml/min. A further one third of
rivaroxaban is metabolised by the liver via CYP3A4, with the final third excreted through the gut
via P-gp. Inhibitors of both CYP3A4 and P-gp might therefore be expected to raise rivaroxaban
levels, and certain drugs (such as azole antifungals, and HIV protease inhibitors) are
contrainidicated. Full information can be found in the rivaroxaban SPC.
Apixabans mechanism of action and metabolism is much as for rivaroxaban, except that,
although its half life is between 914 hours it is dosed twice daily. It has the least dependence on
renal excretion of the NOACS at 25%, but shares rivaroxabans dependence on metabolism by
The manufacturer recommends a dose reduction for patients with creatinine clearance 1529
ml/min, and also for patients with serum creatinine 1.5 mg/dL (133 micromol/l) associated with
age 80 years or body weight 60 kg. Apixaban is contraindicated at creatinine clearance <15
ml/min see SPC for further details.
Another inhibitor of factor Xa, Edoxaban is newly licensed in Europe, but has been licensed in
Japan since 2012. It is dosed once daily, with a half life of 1014 hours. 50% is renally excreted,
with the rest excreted via P-gp it has the least CYP3A4 interaction of all the Xa inhibitiors. As for
rivaroxaban, dose reduction is recommended at 1549 ml/min, and the drug contraindicated
below 15 ml/min. A lower dose is also recommended for patients <60 kg, and those taking P-gp
The relevant profiles of these four NOACs are shown in table 2.8

Reversal of NOACs
A reversal agent for dabigatran idarucizumab is now licensed in the US and Europe. For the Xa
inhibitors, reversal agents are in the late stages of development, and can be expected to be
available soon.
Idarucizumab is a fully humanised monoclonal antibody fragment, which binds dabigatran and
nullifies its anticoagulant activity. The RE-VERSE AD trial, a phase 3 trial of efficacy of
idarucizumab, is still ongoing, but interim results were published recently which showed
impressive correction rates of both laboratory parameters and bleeding.9
Andexanet alfa is a recombinant, modified factor Xa molecule with no pro-coagulant activity,
which binds and inactivates all Xa inhibitors. Phase 2 trials have yielded promising results, and
phase 3 trials are underway. This agent may also be useful in the reversal of low molecular
weight heparins (as discussed above, these mostly target factor Xa, and are incompletely
reversed by the available antidote, protamine).
Andexanets manufacturer, Portola Pharmaceuticals, has provided a video illustrating its
mechanism of action:https://www.portola.com/clinical-development/andexanet-alfa-prt4445-fxa-
Other reversal agents in development include Ciraparantag (PER 977). This is a small molecule
which can bind inhibitors of both factor IIa and factor Xa in effect a universal NOAC reversal
Pending licensing of these agents, the British Committee for Standards in Haematology have
issued guidance on the management of bleeding in patients on all anticoagulants, including
NOACs.10 In an emergency, prothrombin complex concentrate is suggested based on limited
data from animal and human studies. Expert help should be sought early, and local guidance
Figure 3 demonstrates how the NOACs act on the coagulation pathway.
Indications for anticoagulation in cardiology
These can be grouped into three areas: acute coronary syndromes (ACS), non-valvular AF, and
diseases of the heart valves.
Heart valves
Where patients with valvular heart disease require anticoagulation, this should usually be with a
vitamin K antagonist none of the NOACs is licensed for valvular AF, and none has been shown
to be adequate for the anticoagulation of patients with mechanical heart valves. The RE-ALIGN
study of dabigatran versus warfarin for this indication was terminated early due to an excess of
both thrombotic complications and bleeding in the dabigatran group.11
Anticoagulation for patients with valvular heart disease is considered in detail in another BJC
Learning module, Heart valve disease module 7: antithrombotic therapy for valvular heart

Acute coronary syndromes

As discussed in module 1, while platelets are of primary importance in initiating arterial
thromboses, both platelets and the clotting cascade are closely linked, so that both are involved
in the formation of all clots. Accordingly, although antiplatelet agents are of central importance in
the management of acute coronary syndromes (see module 2), anticoagulants are also used in
this critical situation to further suppress thrombus formation.

The specialist management of acute coronary syndromes will not be discussed further here:
readers are referred to excellent guidelines from the European Society for Cardiology (ESC), and
NICE. As discussed above, options are low molecular weight heparin or fondaparinux, with the
evidence from OASIS-5 perhaps favouring fondaparinux. UFH or bivalirudin are options for
patients undergoing PCI; fondaparinux is not recommended in patients with ST-elevation MI
undergoing primary PCI after an excess of procedure-related complications was noted in the
OASIS-6 trial.3,12,13
Atrial fibrillation
One of the main risks in AF is cardioembolic stroke. Overall, AF brings a 5% risk of stroke per year
but not all patients have the same risk. Risk can be greatly reduced by anticoagulation but as
anticoagulation carries a risk of bleeding, it is important to have some means of identifying which
patients will, on balance, benefit from anticoagulation i.e. in which patients does the benefit of
anticoagulation outweigh the risks.
Risk assessment
The CHA2DS2-VASc score14 is currently the most widely used tool for estimating stroke risk in AF
(see table 3), and is the scoring system recommended by both the ESC and NICE in their recent
guidelines.15,16 It represents a refinement of the previous CHADS2 system, particularly in that it
defines a group of genuinely low risk patients (score 0 out of 9) who seem to have a very low risk
of stroke, and whom the risk of anticoagulation is probably not justified. Annual stroke risk in a
large Swedish validation cohort study was 0.2% (score 0) to 12.2% (score 9).17
Both ESC and NICE guidelines advise anticoagulation (in the absence of a contraindication) in
patients with a score of 2 or more, and suggest considering it even in patients with a score of 1
(unless the only risk factor is female sex).
An assessment of bleeding risk should also be undertaken before advising on anticoagulation.
Probably the most widely used is the HAS-BLED score (see table 4) this is recommended by
both NICE and ESC guidelines, but it is worth remembering that it was designed, and validated,
using cohorts of patients taking vitamin K antagonists:
ESC guidelines advise caution with anticoagulation with a score of 3 or more (bleeding risk
approximately 3.7 per 100 patient years). However, each case should be considered individually,
with a full discussion of risks and benefits, and taking into account each patients perspective.
Importantly, several of these factors are correctable, and attention should be paid to this to
ensure anticoagulation can be offered more safely.
Web-based calculators are available which can be used to calculate both CHA2DS2-VASc and
HAS-BLED scores.
Choice of anticoagulation in AF

Aspirin does reduce stroke risk to a small extent in AF (approximately 20%), but is much less
effective than warfarin (approximately 70% risk reduction). Moreover, there is a growing body of
evidence that the inferior efficacy of aspirin is not compensated for by a lower bleeding risk,
especially in elderly patients.19,20 Aspirin is therefore not recommended as stroke prevention in
current guidelines, except in patients who refuse anticoagulation.

WarfarinWarfarins efficacy and safety depend crucially on how well-controlled the INR is (see
module 4). NICE advise regular review, and consideration of switching to a DOAC if the time in
therapeutic range (TTR) is <65%.
Dabigatran was compared to warfarin for the prevention of stroke in AF in the RELY trial (see
figure 4).21 Over 18,000 patients received 110 mg or 150 mg of dabigatran twice a day, or
warfarin to target INR 2.5. Yearly rates of the primary outcome (stroke or systemic embolus) were
1.69% in the warfarin group, and 1.53% and 1.11% in the dabigatran 110 mg and 150 mg groups
respectively, the latter being significantly lower than the warfarin result.

Figure 4. KaplanMeier curve for the primary outcome of stroke or systemic embolism

The rate of the primary side effect of major bleeding was 3.36%, 2.71% and 3.11% respectively.
Therefore dabigatran 110 mg bd was equally as efficacious as warfarin but had a better safety
profile in terms of major bleeding, whereas the 150 mg dose twice a day was superior to warfarin
in terms of stroke prevention but had similar rates of bleeding. Closer scrutiny of the trial data
shows that rates of intracranial haemorrhage were lower with dabigatran even at the higher
dose. The higher dose of dabigatran was, however, associated with significantly more
gastrointestinal bleeds than warfarin.
One other result of concern was a small increase in rates of myocardial infarction in both
dabigatran groups, which was statistically significant for the 150 mg dose. This was, however,
not replicated in a real-world post-marketing study conducted by the US FDA.22

Figure 5. KaplanMeier curve for the primary efficacy outcome of stroke and non-
central nervous system embolism
Rivaroxaban was also compared to warfarin for the prevention of stroke in AF. The ROCKET-AF7
trial (see figure 5) randomly assigned over 14,000 patients to rivaroxaban 20 mg once daily or
to dose-adjusted warfarin, finding rates of stroke or systemic embolism to be 1.7% and 2.2%
respectively, whilst the major and minor bleeding events were 14.9% and 14.5% respectively (all
differences not significant). However, there were significantly fewer fatal bleeds and cases of
intracranial haemorrhage in those taking rivaroxaban, but again more gastrointestinal bleeding.
In the ARISTOTLE trial (see figure 6),23 apixaban was compared to warfarin for stroke
prevention in over 18,000 patients with AF and at least one additional risk factor for stroke. After
1.8 years of follow up, yearly rates of the primary end point (any stroke, or systemic embolism)
were 1.27% on apixaban and 1.6% on warfarin (p=0.01). Furthermore, apixaban was associated
with significantly fewer cases of major bleeding and fewer haemorrhagic strokes (both p<0.001).
Rates of gastrointestinal bleeding were the same.

Figure 6. KaplanMeier curve for the primary efficacy outcome of stroke or systemic
In the ARISTOTLE trial (see figure 6),23 apixaban was compared to warfarin for stroke
prevention in over 18,000 patients with AF and at least one additional risk factor for stroke. After
1.8 years of follow up, yearly rates of the primary end point (any stroke, or systemic embolism)
were 1.27% on apixaban and 1.6% on warfarin (p=0.01). Furthermore, apixaban was associated
with significantly fewer cases of major bleeding and fewer haemorrhagic strokes (both p<0.001).
Rates of gastrointestinal bleeding were the same.
he ENGAGE AF-TIMI 48 trial (see figure 7) randomised over 21,000 patients with non-valvular AF
and a CHADS2 score of 2 or more to one of two dose regimens of edoxaban, or warfarin. The
higher dose regimen showed a trend towards superiority over warfarin in terms of the primary
outcome (any stroke or systemic embolus). Bleeding (including major, life-threatening and
intracranial bleeding) was significantly lower with edoxaban, with the exception of
gastrointestinal bleeding which was significantly more common.24 Based on these results, the
higher dose regimen was licensed: 60 mg once daily is the standard dose, with 30 mg used for
patients with low weight, renal impairment, or on potent P-gp inhibitors.

Figure 7. KaplanMeier curve for the primary efficacy outcome of stroke or systemic
Which drug to choose for stroke prevention?

Based on this data, all four NOACs are now approved by NICE as an option for stroke prevention
within their licensed indications (i.e. non-valvular AF with one or more risk factors for stroke).
Given their equivalent or superior efficacy, with apparently superior safety, ESC guidelines advise
choosing a NOAC first line, in the absence of contraindication (see figure 8). NICE have
suggested that a NOAC might be preferred if a patients time in therapeutic range on warfarin is
Trial data will only be a part of the decision-making process. Patients should be involved; some
will not wish to switch, or be nervous of new medications. Financial considerations will also play a
part. In the UK, some Clinical Commissioning Groups (CCGs) have sought to limit use of NOACs to
reduce cost.25 While NOACs are considerably more expensive than warfarin, it is likely that this
cost will be at least partially offset by the improved efficacy and safety (with consequently
reduced costs of stroke care/management of bleeding), and by reduced monitoring costs. NICE
have undertaken a number of costing analyses:
Economic analyses have also been undertaken in other healthcare settings.26 NOACs have not
been directly compared in head-to-head trials, and direct comparison between trials is difficult,
as the risk profile of patients in each trial was different (for example the mean CHADS2 score of
patients in the RE-LY study was 2.1, compared to 3.47 in the ROCKET-AF trial).
Other issues which should be considered are the twice-daily dosing of dabigatran and apixaban;
the greater reliance on renal excretion of dabigatran; and drug interactions (as discussed above).
Local policies should be followed where these exist.

Figure 8. Oral anticoagulation for stroke prevention

Cardioversion of AF

schaemic stroke rates following cardioversion are between 5 and 7% in non-anticoagulated

patients, which can be reduced to 0.5 to 1.6% with warfarin.24 Current ESC guidelines advise
anticoagulation with an INR of 23 for at least three weeks before and four weeks after
cardioversion.16 Based on analysis of data on over 1,200 patients who underwent cardioversion
during the RE-LY trial, dabigatran appears to be as safe and effective as warfarin, and is
approved by ESC as an option.16
Since these guidelines were published, a similar analysis of data from the ARISTOTLE trial
(apixaban) has been performed,27 and a randomised trial of rivaroxaban versus warfarin for
cardioversion published (EX-VeRT28). Again this shows similar efficacy and safety to warfarin,
including in the context of early cardioversion with the use of transoesophageal
echocardiography to exclude thrombus.
Strict compliance with treatment is crucial if NOACs are to be used pre-cardioversion, as
adequacy of anticoagulation cannot be confirmed by measurement of INR, as it can with
warfarin. However, it is likely that local protocols will begin to adopt NOACs for this indication.
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All available from http://journal.publications.chestnet.org/issue.aspx?
journalid=99&issueid=23443 (accessed 14/02/13)
Online resources
The Scottish Medicine Consortium: http://www.scottishmedicines.org.uk
The British National Formulary: http://www.bnf.org
The National Institute for Health and Clinical Excellence (NICE): http://www.nice.org.uk
Further reading
Hicks T, Stewart F, Eisinga A. NOACs versus warfarin for stroke prevention in patients with AF: a
systematic review and meta-analysis. Open Heart 2016;3:e000279.