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New anticoagulant drugs for treatment of venous thromboembolism

VIEWS: 7 PAGES: 12

									  Review        |                                                                                           doi: 10.1111/j.1365-2796.2012.02541.x



New anticoagulant drugs for treatment of venous
thromboembolism and stroke prevention in atrial fibrillation
   A. Tripodi1 & G. Palareti2
From the 1Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine, IRCCS Ca Granda Maggiore Hospital
                                                                                                                 `
Foundation and Universita degli Studi di Milano, Milano, Italy; and 2Divsion of Angiology and Blood Coagulation, S.Orsola-Malpighi University
                         `
Hospital, Bologna, Italy



Abstract. Tripodi A, Palareti G (IRCCS Ca Granda Mag-
                                        `                                    drugs such as heparins and vitamin K antago-
                                           `
giore Hospital Foundation and Universita degli Studi                         nists. The use of these drugs is, however, complex
di Milano, Milano, Italy; S.Orsola-Malpighi University                       and demanding for both patients and physicians.
Hospital, Bologna, Italy). New anticoagulant drugs                           Recently, new antithrombotic drugs that act
for treatment of venous thromboembolism and stroke                           directly by inhibiting activated coagulation factors
prevention in atrial fibrillation (Review). J Intern Med                      such as factor X or thrombin have been developed
2012; doi: 10.1111/j.1365-2796.2012.02541.x.                                 and investigated in phase III clinical trials. The
                                                                             aim of this article is to review: (i) the need to de-
Venous thromboembolism (including deep vein                                  velop new drugs; (ii) their efficacy ⁄ safety as
thrombosis and pulmonary embolism) and atrial                                demonstrated in clinical trials; (iii) the need for
fibrillation are common conditions in Western                                 laboratory monitoring and (iv) the direction
countries. The mainstay of treatment and preven-                             towards the use of these new drugs in the real-life
tion for these diseases is fast-acting anticoagulant                         clinical situation.




Introduction                                                                 treatment and prophylaxis in all the above condi-
                                                                             tions, have recently become or will soon be available.
Venous thromboembolism (VTE), including deep vein
                                                                             The aim of this article is to review the current state of
thrombosis (DVT) and pulmonary embolism (PE), oc-
                                                                             the art and to present expert opinion on what will be
curs frequently in Western countries, with an esti-
                                                                             the practical impact for their application within the
mated incidence of about 1.5 per 1000 inhabitants
                                                                             next few years.
per year [1]. DVT may progress to potentially fatal PE
and the postthrombotic syndrome [2]. VTE is a major
cause of morbidity and mortality not only in Western
                                                                             Need to develop new drugs
countries [3], as believed until recently, but also in
Asia [4]. The standard treatment for acute VTE is anti-                      Upon diagnosis, acute VTE must be promptly treated
coagulant therapy with fast-acting drugs such as un-                         with fast-acting drugs to prevent thrombus exten-
fractionated heparin (UFH), low molecular-weight                             sion. In this respect, UFH, LMWH or fondaparinux
heparin (LMWH) or the synthetic pentasaccharide                              have proved to be highly effective and safe. However,
fondaparinux, which all prevent thrombus extension                           the need for dose-adjustment (at least for UFH) based
and its consequences, followed by prophylaxis with                           on laboratory tests and the need for parenteral
vitamin K antagonists (VKAs) to prevent recurrence                           administration (intravenous or subcutaneous infu-
[5]. The fast-acting drugs are administered parenter-                        sion) make the use of these drugs challenging both for
ally and VKAs orally [5]. Another condition for which                        patients and physicians. Conversely, because of their
anticoagulation is required is the prevention of stroke                      oral route of administration, VKAs have been the
and systemic embolism in patients with nonvalvular                           agents of choice for secondary prophylaxis of VTE for
atrial fibrillation (AF) [6]. It has been estimated that                      the last 60 years.
AF affects 2.5 million individuals in the USA, includ-
ing approximately 5% of those older than 65 years                            Vitamin K antagonists are also the drugs of choice for
[7]. Finally, VKAs are used to prevent thromboembo-                          the primary prevention of stroke in patients with non-
lism in patients with mechanical prosthetic heart                            valvular AF or prosthetic heart valves. Currently,
valves [8]. A number of new drugs that may be suit-                          AF is the most important indication for VKAs,
able alternatives to the established agents, both for                        accounting for more than 50% of all patients treated


                                                                                   ª 2012 The Association for the Publication of the Journal of Internal Medicine   1
    A. Tripodi & G. Palareti
                                              |     Review: New anticoagulants for venous thromboembolism and atrial fibrillation



worldwide with these drugs. Patients treated with
                                                                                                      Coagulation Pathway           New Anticoagulant drugs
VKAs for any indication represent as many as 1.5% of
the general population in Western countries, and                                         Initiation            TF/VIIa
thus the management of VKA treatment is a challenge
                                                                                        Thrombin                                       FXa direct inhibitors
for patients, their families and the healthcare sys-                                    generation
                                                                                                        X                    IX
                                                                                                                                     (rivaroxaban, apixaban)
tems. Although the organization of the management
                                                                                                                        IXa VIIIa
of VKA treatment has received special attention in
many countries such as Italy, the Netherlands and                                                            Xa        Va
the UK with the establishment of specialized antico-                                                              II
agulation clinics, most patients worldwide are still
denied this life-saving therapy because of the per-                                     Thrombin                                    Thrombin direct inhibitors
                                                                                         activity               IIa                      (dabigatran)
ceived management difficulties and the risk of bleed-                                                        (thrombin)
ing. Furthermore, although very effective, treatment
with VKAs is complex, is associated with conspicuous
burden for the healthcare systems and is highly                                       Fig. 1 Schematic representation of the coagulation cascade
                                                                                      and coagulation factors targeted by the new drugs. TF, tissue
demanding for patients.
                                                                                      factor.

Vitamin K antagonists have several limitations that
include a slow onset and offset of action, complex                                    The drugs that are currently close to entering the
genetic control of their effect with polymorphisms                                    market are dabigatran, rivaroxaban and apixaban.
leading to highly variable individual sensitivity and                                 The aim of this article is to review the current situa-
a narrow therapeutic window. In addition, metabo-                                     tion with respect to the results of clinical trials
lism of VKAs is affected by many factors, including                                   for treatment of acute VTE and long-term prevention
diet, drugs, hepatic dysfunction, other co-morbid                                     of recurrences as well as prevention of stroke in AF
conditions and alcohol intake. As a result of these                                   (Tables 2 and 3), and to discuss the methods that may
limitations, the dose–response relationship of VKAs                                   be employed for laboratory control of these new
is unpredictable, and therefore frequent coagula-                                     agents (Tables 4 and 5).
tion monitoring and dose-adjustment is needed to
ensure efficacy of treatment and to minimize the                                       Dabigatran
risk of bleeding complications. Furthermore, the
percentage of time spent in the therapeutic range                                     Dabigatran is an oral direct thrombin inhibitor
might be inadequate. It was recently shown that                                       (Fig. 1) that has undergone phase III, randomized,
the time within the therapeutic range was between                                     controlled clinical trials for both VTE and stroke pre-
51.5% and 62.0% in community studies, rising to                                       vention in AF. The characteristics of dabigatran are
between 59.4% and 73.3% in randomized clinical                                        summarized in Table 1, and the main clinical trial re-
trials [9]. These unsatisfactory results are of clinical                              sults are summarized in Tables 2 and 3.
relevance because an increased frequency of ad-
verse events is associated with poor anticoagula-                                     Treatment of acute VTE: the RE-COVER study
tion control [10].
                                                                                      The RE-COVER study [11] was a randomized, dou-
                                                                                      ble-blind, double-dummy, noninferiority trial that
New drugs                                                                             included a total of 2564 patients with acute VTE
The challenges posed by the established drugs (espe-                                  (encompassing proximal DVT and ⁄ or PE). After initial
cially VKAs) prompted research to develop new anti-                                   treatment with parenteral anticoagulation therapy
coagulants (Fig. 1 and Table 1) that would be equally                                 with LMWH or UFH (for a median of 9 days), patients
effective and safe, but not require laboratory monitor-                               were randomly assigned to receive dabigatran at a
ing for dose-adjustment. The results of the clinical tri-                             dose of 150 mg twice daily (b.i.d.) or dose-adjusted
als carried out to date suggest that the new drugs will                               warfarin to achieve an international normalized ratio
fulfil these expectations. However, definitive conclu-                                  (INR) of 2.0–3.0. The duration of treatment was
sions can only be drawn after they have been used to                                  6 months. The primary analysis for efficacy, accord-
treat patients in real-life situations outside clinical                               ing to the intention-to-treat principle, was based on
trials. For instance, it is likely that laboratory control                            the composite end-point of symptomatic VTE or
will be required to some extent in selected categories                                death associated with VTE in the 6 months after ran-
of patients.                                                                          domization.

2    ª 2012 The Association for the Publication of the Journal of Internal Medicine
     Journal of Internal Medicine
  A. Tripodi & G. Palareti
                               |   Review: New anticoagulants for venous thromboembolism and atrial fibrillation



Table 1 Main pharmacological
characteristics of the new drugs                         Dabigatran                   Rivaroxaban                             Apixaban
                                   Brand name            Pradaxa                      Xarelto                                 Eliquis
                                   Mechanism of          Direct, selective            Direct, selective factor                Direct, selective
                                    action                factor IIa inhibitor          Xa inhibitor                           factor Xa inhibitor
                                   Prodrug               Yes                          No                                      No
                                   Time to Cmax          2 [26]                       2–4 [30]                                1–3 [31]
                                    (hours)
                                   Half-life (hours)     12–14 [26]                   9–13 [30]                               8–15 [31]
                                   Elimination           80% renal                    1 ⁄ 3 renal                             25% renal
                                                         20% biliary                  1 ⁄ 3 renal (as inactive                75% biliary
                                                                                        metabolites)
                                                                                      1 ⁄ 3 biliary
                                   Interactions          P-glycoprotein               P-glycoprotein and                      P-glycoprotein
                                                                                      CYP3A4                                   (minimal)
                                                                                                                               and CYP3A4
                                   Effect of food        Absorption                   Absorption                              Not reported
                                                          delayed                       delayed
                                   Protein binding (%)   35                           90                                      87
                                   Dosing                b.i.d.                       o.d.                                    b.i.d.

                                   Dabigatran and rivaroxaban are P-glycoprotein substrates. Amiodarone, verapamil and
                                   clarithromycin inhibit P-glycoprotein and therefore increase the anticoagulant effect of
                                   these factor IIa ⁄ Xa inhibitors.


For the safety analysis, bleeding was classified as ma-            anticoagulation, treatment with dabigatran at the
jor, according to Schulman and Kearon [12], or non-               dose of 150 mg b.i.d. is noninferior for efficacy and at
major clinically relevant. After central adjudication,            least as safe as warfarin at the usual INR level in sub-
occurrence of the primary outcome for efficacy was                 jects with acute VTE (Table 3).
confirmed in 2.4% of all patients treated with
dabigatran and in 2.1% of patients who received
                                                                  Secondary prevention of VTE: the RE-MEDY and RE-SONATE studies
warfarin (time in therapeutic range 60%), establish-
ing the noninferiority of dabigatran versus warfarin              The preliminary results of these two studies have
(P < 0.001). A major bleeding episode occurred in                 been presented at the XXIII Congress of the Interna-
1.6% and 1.9% of patients in the dabigatran and war-              tional Society on Thrombosis and Haemostasis, held
farin groups, respectively [hazard ratio (HR) 0.82;               in Kyoto in July 2011. In the double-blind, noninferi-
95% confidence interval (CI), 0.45–1.48]. The most                 ority RE-MEDY study [13], 2856 patients who had re-
frequent major bleeding event in the dabigatran                   ceived 3–12 months of anticoagulant therapy after a
group was gastrointestinal (n = 9). Intracranial                  VTE episode were randomly assigned to treatment
haemorrhage occurred in three patients treated with               with dabigatran 150 mg b.i.d. or warfarin (INR 2.0–
warfarin and in none receiving dabigatran. Major or               3.0) for an additional period of 6–36 months.
clinically relevant nonmajor bleeding was detected in
5.6% of patients in the dabigatran group and in 8.8%              Safety outcomes were bleeding events, acute coro-
in the warfarin group (HR, 0.63; 95% CI, 0.47–0.84;               nary syndromes and other adverse events. Recur-
P = 0.002). In total, 9.0% of patients in the dabigatran          rent symptomatic VTE occurred in 1.8% and 1.3%
group and 6.8% in the warfarin group had an adverse               of patients treated with dabigatran and warfarin,
event that led to discontinuation of the study drug               respectively (HR 1.44; 95% CI 0.78–2.64; P = 0.03
(HR, 1.33; 95% CI, 1.01–1.76; P = 0.05).                          for noninferiority). Major bleeding occurred in 0.9%
                                                                  and 1.8% of dabigatran- and warfarin-treated pa-
In conclusion, the results of the RE-COVER study                  tients, respectively (HR 0.52; 95% CI, 0.27–1.01).
showed that, after an initial few days of parenteral              Any bleeding occurred in 19% of patients receiving

                                                                        ª 2012 The Association for the Publication of the Journal of Internal Medicine   3
                                                                                                                         Journal of Internal Medicine
    A. Tripodi & G. Palareti
                                              |     Review: New anticoagulants for venous thromboembolism and atrial fibrillation



Table 2 Phase III clinical trials to assess the efficacy and safety                     VTE was observed in 0.4% of patients treated with da-
of treatment with the new drugs                                                        bigatran and 5.6% of those treated with placebo (HR
                                                                                       0.08; 95% CI 0.02–0.25; P < 0.0001). There were two
Study                        Clinical condition                       Reference
                                                                                       major bleeding episodes (both gastrointestinal;
Dabigatran                                                                             0.39%) in the dabigatran group and none in the pla-
    RE-COVER                 Treatment of acute VTE                   [11]             cebo group. Clinically, relevant nonmajor bleeding
    RE-MEDY and              Secondary prevention                     [13]             occurred in 5.3% and 1.8% of patients treated with
    RE-SONATE                 of VTE                                                   dabigatran and placebo, respectively (HR 2.9; 95%
                                                                                       CI, 1.5–5.6; P = 0.001). The rate of cardiovascular
    RE-LY                    Treatment of patients                    [15]
                                                                                       events was not different in the two groups. It was con-
                              with nonvalvular AF                                      cluded that extended treatment with dabigatran was
Rivaroxaban                                                                            highly effective in reducing the rate of VTE recur-
    EINSTEIN                 Treatment of acute DVT                   [19]             rences compared with placebo, and was associated
    programme                                                                          with only a low risk of major bleeding (Table 3).
    Rocket AF                Stroke prevention in                     [20]
                              patients with                                            Treatment of patients with nonvalvular AF: the RE-LY study
                              nonvalvular AF                                           The RE-LY study was a noninferiority trial in which
Apixaban                                                                               18 113 patients with AF were randomly assigned to
    ARISTOTLE                Stroke prevention in                     [21]             two fixed doses of dabigatran (110 mg or 150 mg
                              patients with                                            b.i.d.), administered in a blinded manner, or to open-
                                                                                       label use of warfarin [15]. The median duration of fol-
                              nonvalvular AF
                                                                                       low-up was 2 years. The primary efficacy outcome
    AVERROES                 Stroke prevention in                     [25]             was stroke or systemic embolism, and the main out-
                              patients with                                            come for safety was major bleeding. Amongst the ma-
                              nonvalvular AF                                           jor bleeding episodes, other events that were consid-
    Amplify VTE              Treatment of acute VTE                   (Both studies    ered life-threatening were symptomatic intracranial
    programme                 (AMPLIFY CV 185056)                       are ongoing)
                                                                                       bleeding, decrease in haemoglobin level of at least
                                                                                       5 g dL)1, haemorrhage requiring transfusion of at
                             Secondary prevention of
                                                                                       least four units of blood or inotropic agents or events
                              VTE (AMPLIFY-EXT                                         necessitating surgery.
                              CV 185057)
                                                                                       With regard to the study population, the mean patient
VTE, venous thromboembolism. AF, atrial fibrillation. DVT,                              age was 71 years, and 63.6% were men. Half of all pa-
deep vein thrombosis.                                                                  tients had received long-term therapy with VKAs. The
                                                                                       mean CHADS2 score was 2.1. Aspirin was used dur-
                                                                                       ing the treatment period in about 20% of patients in
treatment with dabigatran and in 26% of those                                          all the three groups. The mean percentage of time
receiving warfarin (HR 0.71; 95% CI, 0.61–0.83).                                       within the therapeutic range for warfarin (INR 2.0–
Higher rates of acute coronary syndromes were ob-                                      3.0) was 64%.
served in patients treated with dabigatran com-
pared with those treated with warfarin (0.9% vs.                                       Stroke or systemic embolism occurred at a rate of
0.2%; P = 0.02). It was concluded that dabigatran                                      1.69% per year in patients receiving warfarin and
was as effective as warfarin for the extended treat-                                   1.53% and 1.11% per year, respectively, in those trea-
ment of VTE; dabigatran was associated with a re-                                      ted with 110 or 150 mg dabigatran. Both doses of da-
duced risk of bleeding but an increased incidence                                      bigatran were noninferior to warfarin (P < 0.001), but
of acute coronary events (Table 3).                                                    the latter was also superior (RR versus warfarin 0.66;
                                                                                       95% CI 0.53–0.82; P < 0.001). Amongst other out-
In the double-blind RE-SONATE study [14], 1343 pa-                                     comes, the rate of myocardial infarction was found to
tients with VTE who had completed 6–18 months of                                       be significantly higher in the 150 mg dabigatran
anticoagulant therapy were randomly assigned to                                        group (0.74% per year) than in the warfarin group
receive dabigatran 150 mg b.i.d. or placebo for a fur-                                 (0.53% per year; RR 1.38; 95% CI, 1.00–1.91;
ther 6 months. Patients with a clear indication to                                     P = 0.048). However, after a subsequent revision of
continue anticoagulation were not eligible. Recurrent                                  the database, new events were detected, adjudicated

4    ª 2012 The Association for the Publication of the Journal of Internal Medicine
     Journal of Internal Medicine
  A. Tripodi & G. Palareti
                                  |   Review: New anticoagulants for venous thromboembolism and atrial fibrillation



Table 3 Main conclusions of phase III clinical trials

Study                                  Conclusion                                                                                       Reference
Dabigatran
  RECO-VER (treatment                  After parenteral anticoagulation, dabigatran 150 mg b.i.d is                                     [11, 12]
   of acute VTE)                        noninferior for efficacy and at least as safe as VKAs
  RE-MEDY (secondary                   Dabigatran is as effective as VKAs in the extended treatment of                                  [13]
   prevention of VTE)                   VTE. It is associated with a reduced risk of bleeding, but an
                                        increased incidence of acute coronary events
  RE-SONATE                            Extended treatment with dabigatran is highly effective in                                        [14]
   (secondary prevention                reducing the rate of recurrence compared to placebo and is
   of VTE)                              associated with a low risk of major bleeding
  RE-LY (stroke                        Dabigatran 110 mg b.i.d. is as effective as VKAs with lower rates                                [15, 16]
   prevention in AF)                    of major bleeding. Dabigatran 150 mg b.i.d. is associated with
                                        lower rates of stroke and systemic embolism, but similar rates of
                                        major haemorrhage. Dabigatran 110 and 150 mg are associated
                                         with lower rates of ICH than VKAs
Rivaroxaban
  Acute DVT Study                      Rivaroxaban 15 mg b.i.d. for the first 3 weeks, followed by                                       [17]
   (treatment of DVT)                   20 mg o.d. thereafter provides an effective and safe,
  Acute PE Study                        single-drug approach to the initial and continued                                               (Study ongoing)
   (treatment of PE)                    treatment of VTE
  Continued Treatment                                                                                                                   [17]
   Study (secondary
   prevention of VTE)
  ROCKET AF (stroke                    Rivaroxaban 20 (or 15) mg o.d. is noninferior to VKAs in patients                                [18]
   prevention in AF)                    with moderate-to-high risk of stroke. There is no difference in
                                        rates of major and clinically relevant nonmajor bleeding between
                                        treatments. ICH occurs less frequently with rivaroxaban
                                        than VKAs
Apixaban
  ARISTOTLE (stroke                    Apixaban 5 (or 2.5) mg b.i.d. is superior to VKAs and is associated                              [19]
   prevention in AF)                    with less bleeding and lower mortality. Apixaban 5 (or 2.5) mg is
                                        associated with a lower rate of ICH than VKAs
  AVERROES (stroke                     Apixaban 5 (or 2.5) mg b.i.d. given to patients who cannot take                                  [23]
   prevention in AF)                    VKAs is more effective than aspirin, without increasing the risk
                                        of major bleeding or ICH

VTE, venous thromboembolism. AF, atrial fibrillation. DVT, deep vein thrombosis. PE, pulmonary embolism. ICH, intracranial
haemorrhage. VKA, vitamin K antagonist.


in a blinded fashion and in accordance with the study                  related to myocardial ischaemia were not increased
protocol, and the significant difference regarding the                  [17]. However, it should be noted that treatment with
rates of myocardial infarction was no longer evident                   dabigatran was found to be associated with a signifi-
[16]. After a further recent revision of the RE-LY re-                 cantly increased odds ratio (1.33; 95% CI 1.03–1.71)
sults, it was found that there was a nonsignificant in-                 for myocardial infarction or acute coronary syndrome
crease in myocardial infarction with dabigatran com-                   in a recent meta-analysis of seven randomized trials
pared with warfarin and that other clinical events                     [18].

                                                                             ª 2012 The Association for the Publication of the Journal of Internal Medicine   5
                                                                                                                              Journal of Internal Medicine
    A. Tripodi & G. Palareti
                                              |     Review: New anticoagulants for venous thromboembolism and atrial fibrillation



Table 4 Situations that may require laboratory control of the                          110 mg b.i.d. was equally effective, but was
new drugs                                                                              associated with significantly lower rates of major
                                                                                       bleeding, including intracranial bleeding. At a dose of
Emergency presentation with thrombotic or haemorrhagic
                                                                                       150 mg b.i.d., dabigatran was associated with lower
events                                                                                 rates of stroke, systemic embolism and intracranial
Need for immediate reversal of anticoagulation                                         bleeding, but similar rates of other major haemor-
Previously unrecognized renal failure                                                  rhage (Table 3).
Liver failure
Suspicion of or known interaction with other drugs                                     Rivaroxaban
                                                                                       Rivaroxaban is an oral direct factor Xa inhibitor
                                                                                       (Fig. 1), and phase III, randomized, controlled clinical
                                                                                       trials have been conducted for both VTE and stroke
With regard to safety, the rate of major bleeding was                                  prevention in AF. The main characteristics of rivarox-
3.36% per year in the warfarin group, 2.71% per year                                   aban are summarized in Table 1, and the clinical
in the 110 mg dabigatran group (RR 0.80; 95% CI,                                       trials results are summarized in Tables 2 and 3.
0.69–0.93; P = 0.003) and 3.11% per year in the
150 mg dabigatran group (RR 0.93; 95% CI, 0.81–
                                                                                       Treatment of acute DVT: the EINSTEIN programme
1.07; P = 0.31). Of particular interest are the lower
rates of intracranial bleeding recorded in patients                                    The EINSTEIN programme consists of three random-
who received dabigatran: 0.74% per year in the war-                                    ized trials of rivaroxaban: the Acute DVT Study and
farin group and 0.23% and 0.30% per year in the                                        the Acute PE Study, for the acute treatment of pa-
110 mg and 150 mg dabigatran groups, with an RR                                        tients with symptomatic DVT or PE, respectively, and
of 0.31 and 0.40 (both P < 0.001), respectively. The                                   the Continued Treatment Study for prolonged treat-
rate of major gastrointestinal bleeding was signifi-                                    ment of patients after therapy for acute DVT or PE.
cantly higher with dabigatran at the 150 mg dose                                       The results of the Acute DVT Study and Continued
(1.51% per year) than with warfarin (1.02% per year;                                   Treatment Study have been recently reported by
P < 0.001). With regard to other adverse events, dys-                                  Bauersachs et al. [19], whereas the Acute PE Study is
pepsia was the most frequent in the dabigatran                                         ongoing.
groups (>11% with either dose) and significantly
more frequent than in the warfarin group (P < 0.001).                                  The Acute DVT Study was an open-label, event-dri-
Liver enzymes were not abnormally elevated more                                        ven, randomized, noninferiority trial that compared
frequently with dabigatran, at either dose, than with                                  oral rivaroxaban alone [15 mg b.i.d. for 3 weeks, fol-
warfarin.                                                                              lowed by 20 mg once daily (o.d.)] with standard anti-
                                                                                       coagulation treatment (subcutaneous enoxaparin
In conclusion, the RE-LY study performed in patients                                   followed by VKA therapy to a target INR of 2.0–3.0) for
with AF confirmed that, compared with standard                                          3, 6 or 12 months in patients with acute, symptom-
treatment with warfarin, dabigatran at a dose of                                       atic DVT and without symptomatic PE. After the com-


Table 5 Main laboratory tests to assess the anticoagulant effect of the new drugs

Test                                                             Characteristics                                                        Reference
Dabigatran
    Prothrombin time                                             Linear dose–response, not very responsive to increasing dosage         [26]
    Activated partial thromboplastin time                        Nonlinear dose–response, adequately responsive to increasing dosage    [26]
    Dilute thrombin time                                         Linear dose–response, adequately responsive to increasing dosage       [26]
    Ecarin clotting time                                         Linear dose–response, adequately responsive to increasing dosage       [26]
Rivaroxaban
    Prothrombin time                                             Linear dose–response, adequately responsive to increasing dosage       [28]
    Activated partial thromboplastin time                        Linear dose–response, adequately responsive to increasing dosage       [28]
    Anti-factor Xa activity                                      Linear dose–response, adequately responsive to increasing dosage       [27]



6    ª 2012 The Association for the Publication of the Journal of Internal Medicine
     Journal of Internal Medicine
  A. Tripodi & G. Palareti
                                     |   Review: New anticoagulants for venous thromboembolism and atrial fibrillation



pletion of 6–12 months of treatment, patients with                 get INR 2.0–3.0) [20]. The median duration of expo-
DVT or PE were included in the Continued Treatment                 sure to treatment was 590 days, and the median fol-
Study, a double-blind, randomized, superiority study               low-up period was 707 days. The primary efficacy
that compared rivaroxaban alone (20 mg o.d.) with                  end-point was the composite of stroke (either ischae-
placebo for an additional 6 or 12 months. The pri-                 mic or haemorrhagic) and systemic embolism. The
mary efficacy outcome for both studies was recurrent                principal safety end-point was a composite of major
VTE. The principal safety outcome was major bleed-                 and nonmajor clinically relevant bleeding events.
ing or clinically relevant nonmajor bleeding in the ini-
tial treatment study and major bleeding in the study               The median patient age was 73 years and 60.3% of
of continued treatment.                                            participants were male patients. Patients were at
                                                                   moderate-to-high risk of stroke; only those with a
In the Acute DVT Study, which included 3449 pa-                    CHADS2 score of ‡2 (mean score of 3.5) were in-
tients, the primary efficacy outcome occurred in                    cluded in the study. Previous use of VKAs was re-
2.1% of patients who received rivaroxaban and in                   ported by 62.4% of patients and about one-third of
3.0% of those who received LMWH+VKAs; time in                      the patients also took aspirin at some time during
the therapeutic range for warfarin was 57.7% and                   the study. In warfarin-treated patients, INR values
the HR was 0.68 (95% CI 0.44–1.04; P < 0.001 for                   were within the therapeutic range, an average of
noninferiority). With regard to safety, major or clini-            55% of the time.
cally relevant nonmajor bleeding occurred in 8.1%
of patients treated with either rivaroxaban or stan-               In the per-protocol population, primary outcome
dard therapy (HR for rivaroxaban, 0.97; 95% CI,                    events occurred at a rate of 1.7% per year in the riva-
0.76–1.22; P = 0.77). The outcome of a net clinical                roxaban group and 2.2% per year in the warfarin
benefit occurred in 2.9% of patients in the rivarox-                group (HR 0.79; 95% CI 0.66–0.96; P < 0.001 for non-
aban group and 4.2% in the standard therapy                        inferiority). In the intention-to-treat analysis, pri-
group (HR 0.67; 95% CI, 0.47–0.95; P = 0.03).                      mary efficacy events occurred at a rate of 2.1% per
There were no differences in other adverse events                  year in rivaroxaban-treated patients and 2.4% per
between the two groups.                                            year in the warfarin group (HR 0.88; 95% CI 0.74–
                                                                   1.03; P < 0.001 for noninferiority and P = 0.12 for
A total of 1197 patients were enrolled in the Contin-              superiority).
ued Treatment Study. Outcome events occurred in
1.3% of patients in the rivaroxaban group and 7.1%                 With regard to safety, the rates of major bleeding
in the placebo group (HR 0.18; 95% CI, 0.09–0.39;                  were not different in the rivaroxaban- and warfa-
P < 0.001; relative risk reduction 82%). The principal             rin-treated patients (3.6% and 3.4%, respectively);
safety outcome of major bleeding occurred in four pa-              the rates of major and clinically relevant nonmajor
tients (0.7%) in the rivaroxaban group and in none in              bleeding were also similar in the two groups (14.9%
the placebo group (P = 0.11). However, major or clini-             and 14.5% per year). Intracranial haemorrhage oc-
cally relevant nonmajor bleeding occurred in 6.0%                  curred less frequently in rivaroxaban-treated pa-
and 1.2% in the rivaroxaban and placebo groups,                    tients than in those receiving warfarin (0.5% vs.
respectively (P < 0.001).                                          0.7% per year, respectively; HR 0.67; CI 0.47–0.93;
                                                                   P = 0.02). The effect of rivaroxaban when compared
From the results of both studies it appears that oral              to warfarin did not differ across quartiles of the
rivaroxaban, at a dose of 15 mg b.i.d. for the first                percentage of time of INR within the therapeutic
3 weeks followed by 20 mg o.d. thereafter, can pro-                range according to study centre. There were no dif-
vide an effective, safe, single-drug approach to the ini-          ferences in serious adverse events between the two
tial and continued treatment of VTE (Table 3).                     treatment groups.

                                                                   In conclusion, the study showed that a fixed dose of
Treatment of patients with nonvalvular AF: the ROCKET AF study
                                                                   rivaroxaban given on a daily basis was noninferior to
The ROCKET AF study was a multicentre, random-                     adjusted-dose warfarin in patients with nonvalvular
ized, double-blind, double-dummy, event-driven trial               AF at moderate-to-high risk of stroke. There were no
in which 14 264 patients with AF were randomly as-                 significant differences in rates of major and clinically
signed to receive fixed-dose rivaroxaban 20 mg o.d.                 relevant nonmajor bleeding between the two treat-
(or 15 mg o.d. in patients with a creatinine clearance             ments. Intracranial bleeding occurred less frequently
of 30 to 49 mL min)1) or adjusted-dose warfarin (tar-              in rivaroxaban-treated patients (Table 3).

                                                                        ª 2012 The Association for the Publication of the Journal of Internal Medicine   7
                                                                                                                         Journal of Internal Medicine
    A. Tripodi & G. Palareti
                                              |     Review: New anticoagulants for venous thromboembolism and atrial fibrillation



Apixaban                                                                              Apixaban in patients with AF: the AVERROES study
Apixaban is an oral direct factor Xa inhibitor (Fig. 1)                               It is well known that VKA therapy is effective for
that has undergone phase III randomized clinical tri-                                 prevention of cardioembolism in patients with AF.
als for stroke prevention in AF. The main characteris-                                However, its use is limited by many factors and at
tics of apixaban are summarized in Table 1, and the                                   least one-third of AF patients who are at risk of
results from these clinical trials are summarized in                                  complications does not receive VKA therapy, or
Tables 2 and 3.                                                                       discontinue treatment [22]. Despite the fact that
                                                                                      aspirin is not, or only slightly, effective [23] in
                                                                                      reducing thromboembolic complications in these
Treatment of patients with nonvalvular AF: the ARISTOTLE study
                                                                                      patients, it is largely used to treat those, especially
The ARISTOTLE study was a double-blind, double-                                       the elderly people, who for various reasons are not
dummy study in which 18 201 patients with nonval-                                     suitable for VKA therapy [24].
vular AF were randomly assigned to treatment with
apixaban 5 mg b.i.d. or dose-adjusted warfarin (INR                                   The AVERROES study [25] was designed to deter-
2.0–3.0) [21]. A lower apixaban dose (2.5 mg b.i.d.)                                  mine the efficacy and safety of apixaban at a dose of
was used in patients with at least two of the following                               5 mg b.i.d. (2.5 mg in 6% of patients), compared with
criteria: age ‡80 years, body weight £60 kg and ser-                                  aspirin at a dose of 81 to 324 mg o.d., for the treat-
um creatinine level ‡1.5 mg dL)1. The median follow-                                  ment of patients with nonvalvular AF for whom VKA
up duration was 1.8 years. The median age of study                                    therapy was considered unsuitable. Of the 5599 pa-
participants was 70 years; 35.3% were women and                                       tients enrolled, 40% had previously received but dis-
the mean CHADS2 score was 2.1. Approximately,                                         continued VKA treatment, 42% of them because the
57% of patients had previously received VKA treat-                                    INR could not be maintained in the therapeutic range.
ment. The median time spent within the therapeutic                                    The treating physician had established that INR mea-
INR range in the warfarin group was 66.0%.                                            surements could not be regularly obtained in 43% of
                                                                                      the other patients enrolled. VKA therapy was consid-
Primary outcome events (stroke or systemic embo-                                      ered to be unsuitable for 21% of patients because the
lism) occurred at a rate of 1.27% per year in the apix-                               risk of stroke was only moderate (CHADS2 score of 1).
aban group and 1.60% per year in the warfarin group                                   In addition, 15% of patients did not want to take
(HR 0.79; 95%; CI 0.66–0.95; P < 0.001 for noninferi-                                 VKAs. The mean duration of follow-up was 1.1 years.
ority and P = 0.01 for superiority). The rates of death
from cardiovascular and noncardiovascular causes                                      The rates of primary outcome events were 1.6% per
and of myocardial infarction were lower (although not                                 year in patients treated with apixaban and 3.7% per
statistically significantly different) in the apixaban                                 year in those assigned to aspirin (HR 0.45, 95% CI
group compared with the warfarin group. Major                                         0.32–0.62; P < 0.001). The rate of major bleeding was
bleeding occurred at a rate of 2.13% per year in the                                  1.4% per year in patients taking apixaban and 1.2%
apixaban group and 3.09% per year in the warfarin                                     per year amongst those taking aspirin (HR 1.13; 95%
group (HR 0.69; 95% CI, 0.60–0.80; P < 0.001). The                                    CI, 0.74–1.75; P = 0.57). An intracerebral haemor-
rate of intracranial haemorrhage was 0.33% per year                                   rhage occurred in six and nine patients receiving
in the apixaban group and 0.80% per year in the war-                                  apixaban and aspirin, respectively. In an on-treat-
farin group (HR 0.42; 95% CI 0.30–0.58; P < 0.001).                                   ment analysis, whilst patients were receiving the
Furthermore, the rate of any bleeding was 25.8% per                                   study treatment, major bleeding events occurred at a
year in the warfarin group and 18.1% per year in the                                  rate of 1.4% and 0.9% per year in the apixaban and
apixaban group, with an absolute reduction of 7.7                                     aspirin groups, respectively (HR 1.54; 95% CI, 0.96–
percentage points (P < 0.001). The overall rates of                                   2.45; P = 0.07). Serious adverse events occurred sig-
serious adverse events were not different in the two                                  nificantly less frequently in the apixaban than in the
treatment groups.                                                                     aspirin group (22% vs. 27%; P < 0.001).

In conclusion, the study showed that a fixed dose of                                   In conclusion, the study showed that, in comparison
apixaban (given b.i.d.) in patients with AF was supe-                                 with aspirin, apixaban substantially reduced the risk
rior to warfarin in preventing stroke or systemic                                     of thromboembolic complications in patients with AF
embolism and was associated with less bleeding                                        for whom VKA therapy is unsuitable, without
(including intracranial bleeding) and lower mortality                                 increasing the risk of major or intracranial bleeding
(Table 3).                                                                            (Table 3).


8    ª 2012 The Association for the Publication of the Journal of Internal Medicine
     Journal of Internal Medicine
   A. Tripodi & G. Palareti
                                          |   Review: New anticoagulants for venous thromboembolism and atrial fibrillation



Treatment of VTE: the AMPLIFY programme                                 information is currently available on the effect of
                                                                        these drugs in this setting as the presence of chronic
Two clinical trials are ongoing to assess the efficacy
                                                                        liver failure has been one of the exclusion criteria for
and safety of apixaban in subjects with VTE. The dou-
                                                                        most of the clinical trials so far carried out. (v) Suspi-
ble-blind, double-dummy AMPLIFY CV 185056
                                                                        cion of or known interaction with other drugs.
study is enrolling patients with acute DVT and ⁄ or PE
                                                                        Although very few interactions have hitherto been re-
who are randomly assigned to receive apixaban 5 mg
                                                                        ported, the possibility of drug interactions cannot be
b.i.d. or warfarin (INR 2.0–3.0) for 6 months. The en-
                                                                        excluded a priori; therefore, laboratory control may
rolment of 5400 patients is expected to be complete in
                                                                        occasionally be needed in this situation (Table 4).
July 2012.

For the AMPLIFY-EXT CV 185057, enrolment was                            Potentially useful tests
completed in July 2011. The study included patients
                                                                        On the basis of limited experience, it appears that
with a recent VTE episode who received a first stan-
                                                                        most of the global and some specific tests can be used
dard anticoagulation course for 6–12 months. After
                                                                        to evaluate the anticoagulant effect of the new drugs
this period, patients were randomly assigned to re-
                                                                        (Table 5).
ceive placebo or apixaban for 1 year; those treated
with apixaban were further randomly assigned to re-
ceive 2.5 or 5 mg b.i.d. apixaban in a double-blind                     Dabigatran
fashion. The follow-up of patients is ongoing.
                                                                        To date, the following tests have been evaluated with
                                                                        regard to dabigatran. (i) Activated partial thrombo-
Laboratory control of new drugs                                         plastin time (APTT). This test showed a relatively poor
                                                                        dose–response linearity and an intermediate respon-
Clinical trials with dabigatran, rivaroxaban and apix-                  siveness to increasing dose [26]. Different results
aban have been designed with a fixed dosage without                      have been obtained depending on the reagents used.
any laboratory control. Indeed, these drugs have                        Hence, it is anticipated that standardization across
proved to be effective and safe for the investigated                    laboratories will be difficult. As a consequence, man-
conditions (see above) and, therefore, strict labora-                   agement of patients cannot be generalized on the ba-
tory control and ⁄ or dose adjustment are not required                  sis of the test results. (ii) Thrombin clotting time (TT).
[24, 25]. However, it should be recognized that pa-                     Preliminary evaluations have shown that this test
tients enrolled in clinical trials are highly selected,                 has excellent linearity, but excessive responsiveness
and therefore it is possible that they do not represent                 to increasing dose [26]. It is anticipated that stan-
the general population encountered in the real-life                     dardization across laboratories will be an issue. (iii)
clinical situation. Thus, laboratory monitoring might                   Prothrombin Time (PT). Good linearity but poor
be needed, at least to some extent. Although experi-                    responsiveness has been reported for PT [26]; it is
ence is still limited, as these drugs are not yet used on               also anticipated that standardization will be difficult.
a large scale, we can start to consider the most appro-                 (iv) Ecarin clotting time (ECT). This test has shown
priate strategy for laboratory control of these new                     good linearity and excellent responsiveness. How-
drugs on the basis of current knowledge [26].                           ever, standardization can be a problem due to the
                                                                        type ⁄ concentration of phospholipids and purity of
                                                                        the snake venoms used for testing. (v) Others. In the-
Situations requiring laboratory control
                                                                        ory the thrombin generation test could be useful;
The following situations may require laboratory con-                    however, at present the method is too complex for
trol. (i) Emergency presentation with thrombotic or                     daily routine use.
haemorrhagic events. The treating physician may
need to know whether the adverse events are due to
                                                                        Rivaroxaban and apixaban
over- or under-dosage of the drug. (ii) Need for imme-
diate reversal of anticoagulation. Laboratory control                   The following tests may be useful to evaluate the anti-
may be needed to judge objectively whether or not                       coagulant effects of rivaroxaban and apixaban. Most
reversal has been achieved. (iii) Previously unrecog-                   of the currently available information focuses on riva-
nized renal failure. The kidney is the main route of                    roxaban; however, it is likely that results will also be
excretion for some of these drugs. Therefore, labora-                   valid for apixaban. (i) Anti-factor Xa activity. In theory
tory control may be needed to identify drug accumu-                     this should be the test of choice [27]; however, it is not
lation in cases of renal failure. (iv) Liver failure. No                readily available in an emergency. As a result of the

                                                                              ª 2012 The Association for the Publication of the Journal of Internal Medicine   9
                                                                                                                               Journal of Internal Medicine
     A. Tripodi & G. Palareti
                                              |     Review: New anticoagulants for venous thromboembolism and atrial fibrillation



large between-reagent variability, it is anticipated                                   However, according to both patients and physicians,
that standardization will be difficult to achieve. (ii) PT.                             for many years there has been a real need for a sub-
Good linearity and responsiveness have been shown                                      stantial improvement in anticoagulant treatment
with PT [28]. Results are dependent on the type of                                     with new drugs, possibly free from some of the limita-
thromboplastin used for testing, but evidence has                                      tions of VKAs and heparins. As shown in this review,
been provided that standardization across reagents                                     the oral direct thrombin or factor Xa inhibitors are in
is feasible by employing an international sensitivity                                  the advanced phase of clinical investigation with a
index (ISI) based on plasma supplemented with                                          number of phase III clinical trials having demon-
increasing doses of rivaroxaban [29]. This index (ISI-                                 strated their efficacy and safety for prolonged treat-
rivaroxaban) was successfully used to convert PT ra-                                   ments. One of these drugs, dabigatran, is already
tio into INR calibrated for rivaroxaban (INR-rivarox-                                  available for chronic clinical use in some countries,
aban) [29], which proved effective in minimizing be-                                   whereas others are expected to become available
tween-thromboplastin variability [29]. (iii) APTT. This                                soon for stroke prevention in AF patients and for
test has excellent linearity, but poor responsiveness                                  treatment of VTE.
to increasing dose [28], and standardization will be
difficult. (iv) HepTest. Good linearity and excellent                                   We believe that the use of these new drugs is an
responsiveness have been shown [28] but standardi-                                     important step towards an easier, effective and safe
zation could be an issue. (v) Dilute Russell viper ve-                                 long-term anticoagulant treatment, which will enable
nom test. This test also has good linearity and respon-                                effective antithrombotic treatment even in those
siveness [28]. Standardization might be an issue                                       patients in whom an adequate anticoagulation is
because of the variety of phospholipids and purity of                                  currently denied due to the limitations of VKAs. How-
snake venom used for testing. (vi) Others. Other tests,                                ever, some aspects of the use of these new drugs re-
for example using portable coagulometers with test                                     quire careful consideration before they are intro-
strips calibrated in terms of INR valid for patients on                                duced for broad clinical use. Some of these drugs
VKAs and thrombin generation tests, have been pro-                                     (although to different degrees) are excreted via the
posed [28] but their advantages compared with previ-                                   kidney (see Table 1). This indicates a potential risk of
ous tests have not been investigated.                                                  drug accumulation in patients with renal failure, sug-
                                                                                       gesting the need for dosage reduction and ⁄ or thera-
                                                                                       peutic monitoring. This is important especially in the
Recommended tests
                                                                                       elderly people in whom close clinical control and fre-
Based on the aforementioned considerations and the                                     quent renal function assessment is highly advisable.
present limited experience, we recommend ECT or di-                                    Although lower with the new drugs than with VKAs,
lute TT for dabigatran and the PT for rivaroxaban and                                  there is still some risk of drug–drug interactions. Fur-
apixaban. The ECT and dilute TT are simple, readily                                    thermore, previous experience with a different agent
available tests that can be run using a standard coag-                                 (ximelagatran) suggests that it is advisable to collect
ulometer; the PT is also a simple and readily available                                long-term data on the safety of these drugs, For in-
test. Furthermore, we recommend that results for                                       stance, clearance of apixaban is mainly hepatic (@
these tests should be expressed as the ratio                                           75%) and caution should be used in patients with li-
(patient ⁄ normal) of the clotting time. In particular, PT                             ver dysfunction.
results should be expressed as the clotting time ratio
(patient ⁄ normal), or INR valid for this drug. Expres-                                Whichever drug is used, good patient compliance is of
sion of the results as an INR valid for patients on VKAs                               paramount importance for an effective and safe anti-
is strongly discouraged as it was shown that this dra-                                 coagulant treatment. Poor compliance, however, can
matically increases the between-reagent variability                                    be even more serious with the new drugs than with
[29].                                                                                  VKAs. Indeed, whilst the anticoagulant effect of VKAs
                                                                                       lasts for several days, the relatively rapid offset of ac-
                                                                                       tion of the new drugs may result in a rapid and com-
Future directions
                                                                                       plete lack of anticoagulant protection in patients who
Until now, VKAs have been the only oral agents avail-                                  forget their medication for only 1 or 2 consecutive
able for long-term anticoagulation and are therefore                                   days. Furthermore, in contrast to VKA therapy, where
widely used for prevention of thromboembolic com-                                      an erratic compliance to the treatment can be de-
plications and for treatment in many clinical condi-                                   tected in a timely manner due to repeated clinic visits
tions that involve a large and increasing number of                                    and INR determinations, the absence of periodic vis-
patients.                                                                              its with the new drugs may reduce the attention to ad-

10    ª 2012 The Association for the Publication of the Journal of Internal Medicine
      Journal of Internal Medicine
  A. Tripodi & G. Palareti
                              |   Review: New anticoagulants for venous thromboembolism and atrial fibrillation



here to therapy. The use of the new drugs requires           and the recent approval by the US Food and Drug
maximum effort to ensure adherence to treatment              Administration as well as other regulatory agen-
and to develop interventions to maintain good com-           cies, they can be prescribed for treatment and
pliance during long-term therapy.                            prophylaxis of thrombotic events, thus opening a
                                                             new era in antithrombotic treatment for millions
The new drugs do not need routine coagulation moni-          of patients worldwide. However, because results
toring, which is an important and favourable charac-         from clinical trials cannot be easily generalized to
teristic. However, there are instances when the drug         the real-life situation, these new drugs must un-
effect may need to be evaluated (see Table 4).               dergo close scrutiny in phase IV clinical trials to
                                                             establish their efficacy and safety.
Potential differences between the results obtained in
clinical trials and the effects of the new drugs in the
real-life clinical situation should be carefully as-         Conflict of interest statement
sessed with specifically designed postmarketing               No conflict of interest was declared.
studies. The phase III clinical studies of these drugs,
in general, included only highly selected patients and
important groups were excluded, particularly the el-         References
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                                              |     Review: New anticoagulants for venous thromboembolism and atrial fibrillation



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12    ª 2012 The Association for the Publication of the Journal of Internal Medicine
      Journal of Internal Medicine

								
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