Antidoti dei NAO (idarucizumab) e profili di sicurezza

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3. Tutte le volte che prescriviamo un farmaco anticoagulante orale nella nostra mente tracciamo un bilancio tra il rischio ischemico e il rischio emorragico del paziente, principalmente usando gli score di rischio. Questi score, benché utili, sono però tutto meno che perfetti. Rimane quindi sempre un fondo di incertezza. Curioso però è notare che la visione del profilo beneficio rischio della fibrillazione atriale non valvolare è profondamente se non diametralmente diversa se vista con l’occhio del paziente o con l’occhio del medico. Per i medici vige il principio “primum non nocere”.

4. Nel 2011 è stata pubblicata una revisione sistematica degli studi che hanno voluto verificare i criteri e le considerazioni che fanno i medici al momento di prescrivere o non prescrivere un anticoagulante orale a un paziente con FANV.

5. Ad esempio, il 98% dei medici preferisce non prescrivere il warfarin se il paziente è considerato a rischio di cadute, e il rischio di sanguinamenti è la causa principale di non prescrizione degli anticoagulanti orali tradizionali.

6. Tuttavia è stato calcolato che per perdere il beneficio associato all’anticoagulazione orale nella FANV un paziente dovrebbe cadere circa trecento volte all’anno (quasi una volta al giorno).

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8. Ma i pazienti la pensano allo stesso modo? In questo studio, a un gruppo di pazienti con FANV è stato chiesto il loro parere sul rischio ischemico e quello emorragico.

9. Quello che è emerso è che per i pazienti con FANV un beneficio accettabile per iniziare un trattamento anticoagulante è che riduca il rischio relativo del 15% e il rischio assoluto dello 0,8%.

10. Inoltre, pur di evitare uno stroke ischemico, con le sue potenziali catastrofiche conseguenze dal punto di vista della perdita di autosufficienza, i pazienti si sono detti disposti a sopportare 4,4 sanguinamenti maggiori. Quindi è molto chiaro che i pazienti concentrano la loro attenzione sul rischio ischemico, mentre i medici sono decisamente più preoccupati per il rischio emorragico.

11. I nuovi anticoagulanti orali, con il loro indiscutibilmente migliore profilo di sicurezza rispetto agli anticoagulanti tradizionali, dovrebbero aiutare molto i medici ad avere meno paura delle conseguenze emorragiche dell’anticoagulazione orale.

12. A large proportion of patients with AF do not receive appropriate anticoagulant therapy for stroke prevention.
Physicians have cited that lack of a specific antidote for any of the novel oral anticoagulants (NOACs) as being one of the barriers to use of oral anticoagulation in this patient population.
Development of a specific antidote would help to remove this barrier to therapy and help to ensure that a greater proportion of patients receive appropriate anticoagulant therapy.
Reference
Peck P. MedPage Today; April 2014: Available at http://www.medpagetoday.com/Cardiology/Prevention/45371; Accessed July 2014.

13. Molti medici si sentono più sicuri prescrivendo il warfarin perché questo trattamento prevede frequenti occasioni di controllo del paziente e, non ultimo, perché per il warfarin c’è un teorico inattivatore, la vitamina K.

14. Questa è però una falsa percezione. La vitamina K ci può mettere anche 12 ore a normalizzare la situazione coagulativa del paziente, e, in aggiunta, molti sanguinamenti maggiori avvengono con il paziente in range terapeutico.

15. Quali dovrebbero essere le caratteristiche ideali di un inattivatore di un anticoagulante orale? Deve agire immediatamente, dev’essere facile da usare, deve avere un effetto sostenuto nel tempo, non deve avere un effetto procoagulante.

16. So, the story of innovation of dabigatran etexilate has not stopped with randomized trials or real-world data. It is an ongoing journey, with the next step being the development of a specific reversal agent.
This stage of the journey began with development of the antibody fragment molecule, idarucizumab.

17. Idarucizumab is a humanized antibody fragment that binds to dabigatran with a more than 350-fold higher affinity than dabigatran does to thrombin, thus preventing dabigatran from binding to thrombin and so reversing its anticoagulant effects. Humanization of the antibody fragment and the removal of the Fc region reduce the immunogenic potential of the molecule.
The antibody fragment does not bind to known thrombin substrates and has no activity in coagulation tests or platelet aggregation, and thus has no procoagulant or anticoagulant effects on its own.
Due to its intravenous application route, idarucizumab has a fast onset of action.
Idarucizumab has a half-life of approximately 6 hours. It binds rapidly to dabigatran and the antidote–dabigatran complex is eliminated quickly. This potentially allows a patient to resume dabigatran treatment soon after the bleeding event has been resolved.
Idarucizumab has no known endogenous targets. It is highly specific to dabigatran, which has no naturally occurring homologues in the human body.
Schiele et al. Blood 2013;121:3554-62
Stangier et al. OR 320; presented at ISTH 2015

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19. Idarucizumab was first tested in animal models of trauma and bleeding.
Dramatic results were seen in anaesthetized pigs where, in the presence of major trauma, idarucizumab not only reduced plasma levels of dabigatran, but substantially improved haemostasis and reduced mortality by the end of the study.1,2
In a mouse model of ICH, idarucizumab reduced haematoma volume and again reduced mortality by the end of the study.
Grottke O et al. JACC 2014;63:12(Suppl)A295, abstr 921-03
Grottke O et al. Critical Care 2014;doi:10.1186/cc13717
Veltkamp R et al. LP P4; presented at ISC 2015

20. Building on the results from animal models, idarucizumab was then assessed in a study of healthy volunteers.

21. Here are the data from a randomized, double-blind, placebo-controlled trial of 145 healthy male volunteers.
Volunteers were pretreated with dabigatran followed by infusion of idarucizumab or placebo. The figure shows clotting times assessed by the dTT assay; dosing with dabigatran prolonged clotting times, as shown by the blue line on the graph.
Upon infusion of a dose of idarucizumab, we see immediate, complete, and sustained reversal of anticoagulation, as shown by the dramatic drop of the red line on the graph. Mean clotting times were reversed to baseline immediately after end of the injection and remained low for the duration of observation. This effect was consistent for both the 2 g and 4 g doses.
The same results were also demonstrated with a 5 g dose of idarucizumab in a second study involving middle-aged (age 45–64 years) and elderly (age 65-80 years) men and women, and in individuals with mild (CrCl 60–90 mL/min) and moderate (CrCl 30–60 mL/min) renal impairment.
To date there is no report of any serious adverse effects in any volunteers exposed to idarucizumab.
Glund S et al. Lancet 2015;doi: 10.1016/S0140-6736(15)60732-2
Glund S et al. abstr. 344; presented at ASH, San Francisco CA, USA, 2014

22. Across all groups of volunteers, there were no clinically relevant drug-related adverse events and no relevant changes in any of the investigated safety parameters. Adverse events and local tolerability reactions were similar for patients receiving placebo or idarucizumab.
Idarucizumab itself has no effect on blood coagulation. As demonstrated by the endogenous thrombin potential (ETP) test, infusion of idarucizumab 8 g over 1 hour had no significant effect on thrombin peak, time to peak, lag time, and ETP area under the curve, showing no effect of idarucizumab on endogenous thrombin formation, even at very high concentrations.
Importantly, there were no adverse events indicative of immediate immunogenic reactions and no persistent newly developed antidrug antibodies were observed.
Overall, the results demonstrate that infusion of up to 8 g of idarucizumab was safe and well tolerated, both alone and in combination with dabigatran.
Glund et al. Thromb Haemost 2015;113:943–51
Glund et al. abstr. 334; presented at ASH 2014
Glund et al. Lancet 2015;doi: 10.1016/S0140-6736(15)60732-2

23. Building on the positive results with idarucizumab seen in the preclinical and human volunteer studies, idarucizumab is being investigated in RE-VERSE AD™, the first patient study of a NOAC-specific reversal agent.

24. RE-VERSE AD™ is a Phase III case series investigating the reversal of the anticoagulant effects of dabigatran by intravenous administration of idarucizumab 5 g to patients receiving dabigatran in two major subgroups: patients who have uncontrolled bleeding judged by the physician to require a reversal agent, and patients who require emergency surgery or procedure for a condition other than bleeding.
RE-VERSE AD™ is recruiting around the world in a highly efficient manner. It will provide data on anticoagulation reversal in patients undergoing urgent surgery and patients experiencing uncontrolled or life-threatening bleeding, and as such is truly representative of clinical practice.
Pollack C et al. Thromb Haemost 2015;114:198–205

25. RE-VERSE AD™ is highly unusual for a Phase III trial, in that there are no restrictions to enrolment. Any patient who is deemed to require urgent reversal of anticoagulation for emergency surgery or life-threatening bleeding is eligible to enter this study.
Clearly there will be patients with such advanced trauma, or such severe underlying illnesses, that even after full reversal of anticoagulant therapy, it will be impossible to treat the cause of the bleeding and prevent adverse outcomes, including death. Nevertheless, such patients will be recruited into RE-VERSE AD™, enabling the results of this study to truly apply to the diverse range of emergencies seen in emergency departments around the world.
1. Pollack C et al. Thromb Haemost 2015;114:198–205
2. Clinicaltrials.gov identifier NCT02104947
3. ClinicalTrials.gov identifier NCT02329327

26. The primary outcome measure of RE-VERSE AD™ is the reversal of the anticoagulant effect of dabigatran, as assessed by the dTT and ECT coagulation assays.
Clinical endpoints are included in the secondary outcome measures. In Group A, time to cessation of bleeding will be recorded, where possible. In Group B, surgeons will rate haemostasis during the surgical procedure, as normal or as mildly, moderately, or severely abnormal.
Other secondary efficacy endpoints include: assessment of TT and activated partial prothrombin time (aPTT); plasma concentrations of total and unbound dabigatran and idarucizumab; proportion of patients achieving complete normalization of dTT or ECT in the first 4 hours; severity of bleeding before and at several time points after treatment; for patients with ICH, CT scans at or near baseline and at 24 hours will be compared with estimate blood volumes; Modified Rankin Score and Glasgow Coma Scale will also be analysed.
Safety assessments include: AEs, serious AEs, immune reactions, reactions that could be caused by antidrug antibodies (ADAs); formation of ADAs; thrombotic events; deaths.
There is a strong rationale for choosing pharmacological reversal of anticoagulation as the primary endpoint rather than a clinical assessment. It is anticipated that the patients enrolled will be a very heterogeneous group, potentially including a large proportion of patients with complex co-existing medical conditions, which may have little or nothing to do with their anticoagulant status. Thus, achievement of haemostasis will depend on a wide variety of factors other than reversal of anticoagulation, such as severity of the presenting injury or the patient’s underlying illnesses. Laboratory anticoagulation parameters were chosen as the primary endpoint as these are directly correlated with patients’ coagulation status.
Pollack C et al. N Engl J Med 2015;373:511–520
Pollack C et al. Thromb Haemost 2015;114:198–205

27. Before we describe some of the results from RE-VERSE AD™, let’s reiterate the key features of the study design.
RE-VERSE AD™ is a single-arm, open-label study. The study does not have a control group because currently there is no proven reversal agent available against which to compare idarucizumab. In addition, based on the impressive data available from the volunteer studies, it seemed clear that there was no good rationale to perform a study that randomized patients to standard of care plus placebo.
RE-VERSE AD™ has broad inclusion criteria and minimal exclusion criteria. This allows enrolment of even severely ill patients with immediately life-threatening conditions, reflecting real-world emergency medicine.
The primary endpoint of RE-VERSE AD™ is pharmacological reversal of anticoagulation. Idarucizumab was designed to reverse dabigatran’s anticoagulant effect, allowing the physician to address the presenting emergency in the manner in which they would address it in the absence of anticoagulation.
Pollack C et al. N Engl J Med 2015;373:511–520
Pollack C et al. Thromb Haemost 2015;114:198–205

28. RE-VERSE AD™ was started in April 2014, and is currently recruiting at more than 500 sites in more than 35 countries around the world.
Interim results from the first 90 patients to be enrolled were presented at the ISTH annual congress in Toronto, 2015, and published in the June 2015 issue of the New England Journal of Medicine. Let’s now take a look at these results, which included 51 patients in Group A and 39 patients in Group B.
Pollack C et al. Presented at ISTH 2015
Pollack C et al. N Engl J Med 2015;373:511–520

29. The patients enrolled in RE-VERSE AD™ so far are generally elderly with moderate renal impairment. Median age was 76.5 years and median CrCl was 57.6 mL/min.
Twelve patients with severely impaired renal function (CrCl Note that elevated values for dTT or ECT were observed at study baseline for most, but not all, patients in Groups A and B. It is only these patients with elevated clotting tests at baseline in whom we can assess reversal of anticoagulation after administration of idarucizumab.
In addition, enrolled patients typically presented between 12 and 24 hours after their last dose of dabigatran. Approximately two-thirds of the patients were taking the lower dose of dabigatran (110 mg BID or 75 mg BID), reflecting the elderly population. Most patients were using dabigatran for stroke prevention in AF.
Patients enrolled in Group A of RE-VERSE AD™ had major bleeding events, such as ICH and GI bleeding. Of these 51 patients, 16 were haemodynamically unstable with ongoing blood loss when they entered the study.
Patients enrolled in Group B required a variety of emergency procedures, the most common including repair of bone fractures and gall bladder surgery.
Pollack C et al. N Engl J Med 2015;373:511–520

30. These figures show the primary endpoint of RE-VERSE AD™ – reversal of dabigatran anticoagulation – for the Group A patients, who have uncontrolled bleeding.
The results show immediate reversal of anticoagulation after administration of the first idarucizumab vial, demonstrated by both the dTT and ECT assays, and sustained through 24 hours in most patients.
The median maximum percentage reversal within 4 hours was 100%. Looking at normalization of individual coagulation tests, dTT was normalized in 98% of evaluable patients, while ECT was normalized in 89% of evaluable patients.
Data are presented as box and whisker plots where the top and bottom of the rectangles reflect the 75th and 25th percentiles, respectively; the horizontal lines within the rectangles reflect the 50th percentile; the lines above and below the rectangles reflect the 90th and 10th percentiles, respectively; and the dots above and below the lines indicate the 95th and 5th percentiles, respectively.
Pollack C et al. N Engl J Med 2015;373:511–520

31. These figures show the primary endpoint of RE-VERSE AD™, for the Group B patients, who required urgent reversal of anticoagulation for emergency surgery or procedures.
Again, the results show immediate reversal of anticoagulation after administration of the first idarucizumab vial, demonstrated by both the dTT and ECT assays, and sustained through 24 hours in most patients.
The median maximum percentage reversal was 100%. Looking at normalization of individual coagulation tests, dTT was normalized in 93% of evaluable patients, while ECT was normalized in 88% of evaluable patients.
In both Groups A and B, similar results were obtained with the aPTT and TT tests.
Data are presented as box and whisker plots where the top and bottom of the rectangles reflect the 75th and 25th percentiles, respectively; the horizontal lines within the rectangles reflect the 50th percentile; the lines above and below the rectangles reflect the 90th and 10th percentiles, respectively; and the dots above and below the lines indicate the 95th and 5th percentiles, respectively.
Pollack C et al. N Engl J Med 2015; 373:511–520

32. Now let’s look at the levels of circulating unbound dabigatran before and after administration of idarucizumab.
Unbound sum dabigatran levels were below 20 ng/mL, a dabigatran level that produces little or no anticoagulant effect, in 99% of the patients immediately after idarucizumab infusion and stayed below 20 ng/mL in 93% of the patients at 12 hours after idarucizumab infusion and 79% of patients at 24 hours.
In samples collected after the first vial of idarucizumab, unbound dabigatran concentrations were above 20 ng/mL in only one patient. This patient had extremely high concentrations of unbound dabigatran (>1000 ng/mL) at study baseline. Based on stoichiometry, the total number of idarucizumab molecules would not be sufficient to neutralize all dabigatran molecules in this particular instance.
Subsequent increases in dabigatran levels occurred 12 and 24 hours after idarucizumab administration in 6 and 16 patients, respectively. This may reflect redistribution of extravascular dabigatran into the intravascular compartment. Since idarucizumab is cleared rapidly, the returning dabigatran may be detected after 12 hours. Whether this effect is clinically relevant depends on the individual patient situation.
Pollack C et al. N Engl J Med 2015; 373:511–520

33. The benefits of pharmacological reversal of dabigatran anticoagulation in RE-VERSE AD™ were confirmed by favourable clinical endpoints.
In Group A, bleeding assessment was possible in 38 patients. Among these patients, investigator-reported median time to bleeding cessation was 11.4 hours. In 13 patients, the time to bleeding cessation could not be ascertained, 3 of these patients had no baseline bleeding assessment.
In Group B, 36 patients underwent their planned surgery. Of these, intraoperative haemostasis was reported as normal in 92% of the patients (that is, as if they were not receiving anticoagulation), as mildly abnormal in two patients, and as moderately abnormal in one patient. Three patients did not undergo their planned interventions: one patient with intentional overdosing of dabigatran, in whom planned dialysis could be averted, and two patients whose clinical condition was too unstable to proceed with the intervention.
Pollack C et al. N Engl J Med 2015; 373:511–520

34. Consistent with the results in healthy volunteers, RE-VERSE AD™ revealed no safety concerns and no evidence of prothrombotic or immunogenic effects after idarucizumab administration.
Importantly, there were no adverse events consistent with hypersensitivity to idarucizumab administration in the patients included so far in RE-VERSE AD™.
Thrombotic events were reported in 5 patients, none of whom were receiving antithrombotic therapy when the event occurred. One event, a DVT with PE, occurred 48 hours after idarucizumab application. The other events occurred from 7 to 26 days after idarucizumab administration. In the absence of a control group, thrombotic events are difficult to distinguish from prothrombotic events that might be a direct result of stimulation of the coagulation cascade by the reversal agent. However, the absence of a temporal proximity between treatment and event (earliest event 48 hours after idarucizumab) and the fact that none of these patients were anticoagulated at the time of event makes prothrombotic effects of idarucizumab very unlikely.
There were 18 deaths overall, 9 each in Groups A and B. Mortality during the study reflected the severe morbidity of the enrolled patients: deaths within 96 hours of treatment appeared to be related to progression of the original reason for emergency admission (2 with septic shock, 3 with ICH, and 1 each with multi-organ failure, haemodynamic collapse, respiratory failure, and cardiac arrest), while all later deaths appeared to reflect comorbidities (e.g. congestive heart failure, Parkinson’s disease, cardiac arrest, and progression of malignancy).
Pollack C et al. N Engl J Med 2015; 373:511–520

35. In conclusion, the results of RE-VERSE AD™ have so far confirmed that idarucizumab provides immediate and complete reversal of dabigatran anticoagulation in clinical practice.
In this cohort of elderly dabigatran-treated patients with multiple underlying illnesses who presented with life-threatening emergencies, administration of idarucizumab 5 g provided immediate and complete pharmacological reversal of anticoagulation as demonstrated by the dTT or ECT assays in up to 98% of patients.
The secondary clinical endpoints confirmed the effective reversal of anticoagulation, with normal intraoperative haemostasis reported in 92% of patients undergoing procedures and cessation of bleeding within an average of 12 hours for patients presenting with uncontrolled bleeds.
No safety concerns have been identified so far, with no immunogenic reactions and a low incidence of thrombotic events occurring only in patients not resuming anticoagulation.
Pollack C et al. N Engl J Med 2015; 373:511–520

36. The innovation that has driven the development of idarucizumab has led to this molecule being at the most advanced stage of clinical development of any anticoagulant reversal agent.

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