Perioperative Oral Eltrombopag Versus Intravenous Immunoglobulin In Patients With Immune Thrombocytopenia: A Non-Inferiority, Multicenter, Randomized Trial

Medic with test tubeOne of the many challenges that patients with immune thrombocytopenia (ITP) face with low-platelet counts is how best to prepare for planned major or minor surgeries. This is especially true for patients who require major surgery because even ITP patients who are stable with counts of 50-75,000 may need a boost in order to safely undergo surgery. With ITP, platelet transfusions will be very short-lived in their effects so they can be used for an emergency but are not good as a “maintenance” treatment designed to last for several days to 1-2 weeks. There is controversy about the use of steroids not only because they might predispose to an infection but also, they could interfere with wound healing. This is controversial only in the sense of not knowing how significant an effect (for example) a one-week course of prednisone would have on healing or on increasing the risk for infection. Therefore, in part because IVIG has the most rapid onset of action but also because of its perceived anti-infection role, IVIG is often used as a pre-treatment to produce a rapid rise in platelet count. However, its effects are transient, and there can be infusion reactions and aseptic meningitis although these are generally infrequent and could be ameliorated or prevented if steroids are given alongside IVIG. Recently, IVIG has been in short supply because of all the increased uses of it. Furthermore, the COVID pandemic has decreased plasma donations so the shortage may be aggravated in the coming months.

As a result, alternative options are in demand. One such alternative option under consideration includs eltrombopag, a thrombopoietin receptor agonist. There have been at least five single arm trials of eltrombopag and romiplostim (the other TPO agonist that has been approved since 2008 in the United States and elsewhere, now worldwide). In order to determine if eltrombopag would hold up as well as IVIG in elevating platelet count to reach targets for surgery one of PDSA’s medical advisors, Dr. Donald Arnold and the McMaster group put together a number of Canadian centers to conduct a randomized parallel arm, open-label, non-inferiority trial of perioperative management for patients with ITP comparing IVIG and eltrombopag.

In this trial, adult patients over the age of 18 years who had either primary or secondary ITP with a platelet count less than 100,000 for major surgery or 50,000 for minor surgery were recruited from eight participating hospitals in Ontario, Canada. They were recruited between June 5, 2013 – March 7, 2019. Patients were randomly assigned into either the IVIG group (36 individuals) where they received 1g/kg or 2g/kg of according to local protocols a week before their procedure, or the eltrombopag group (38 individuals) who received an oral dose of 50mg daily starting 21 days before their procedure. The eltrombopag dose was monitored by weekly counts and could be increased to 75mg daily either after 1 or 2 weeks of treatment if the platelet increase was deemed insufficient. The goal was to safely reach a platelet target of 90,000 for major surgery and at least 45,000 for minor surgery, before and during one week after the procedure. Patients were followed for 1-2 months post-surgery.

There was an intention-to-treat (ITT) analysis created for both drug groups which consisted of all participants who were assigned to each group, and there was a per-protocol analysis (PP) for both drug groups which included only those who took the drug as per protocol. If participants dropped out of the study, or needed amendments to the drug dose, they were not included in the PP group. Results revealed that in the ITT group, perioperative platelet target counts (for the day of surgery and 1 week afterward) were reached for 79% in the eltrombopag group, and 61% in the IVIG group; in the latter most of the failures were for counts that had fallen by the end of the week after surgery rather than not achieving the target count on the day of surgery. In the PP group, perioperative platelet targets were reached in 78% of those receiving eltrombopag, and 63% of those receiving IVIG. Two serious adverse events were noted in the eltrombopag group, and five serious ones in the IVIG group, all related to complications of the patients surgery. There were two cases of thrombosis but the one in the eltrombopag group appeared to be related to the use of eltrombopag whereas the one in the IVIG group was 30 days after infusion and attributed to the surgery itself.

In conclusion, while eltrombopag may increase the risk for thrombosis, perioperative treatment of ITP can be expanded beyond the use of IVIG.

Comments from PDSA’s Medical Advisors:

This study is timely, however not without a few weaknesses and limitations. One such weakness includes a somewhat controversial way of defining what constitutes a ‘major’ vs ‘minor’ surgical procedure. In addition, the one or two IVIG doses provided were given seven days prior to surgery instead of one-three days prior to the scheduled procedure which is more ideal. This could explain perhaps why there was a loss of response to the IVIG one week following the surgery which could have been prevented if the timing of the IVIG had been different. Currently, when preparing a patient for an upcoming surgery choosing the best treatment depends on timing. If the procedure is urgent and scheduled within one-five days than IVIG would be preferred to eltrombopag which would require more time to affect the platelet count. It isn’t clear, however, how best to treat in preparing for a surgery that is ten-twelve days away instead of three weeks away. An underlying issue is that platelet count thresholds chosen for given procedures are generally quite arbitrary and it is unclear if treatment was required in the first place when the average platelet count was 40,000 before treatment for procedures such as dental extraction, colonoscopy, skin biopsy, or cataract surgery. Thus other alternatives such as perhaps tranexamic or epsilon amino caproic acid could have been considered for some of these indications. Finally, this study did not include a steroid comparator.

NIH Launches Trial of Rigel Drug for Severe COVID-19 and Octapharma launches trial for intravenous immunoglobulin (IVIG) as Potential Treatment for COVID-19

COVID-19 Test test tubeWhile COVID-19 is still a growing concern, the race to find an effective antiviral treatment and an effective and safe vaccine remains a very high priority. In the interim, two therapies well known among patients with immune thrombocytopenia (ITP) are now being considered as possible treatments for fighting COVID-19 or at least some of its symptoms. These two treatments are Tavalisse, also known as fostamatinib, and intravenous immunoglobulin, or IVIG.

Fostamatinib Trial
A new randomized, placebo-controlled phase 2 trial with Rigel pharmaceuticals has launched through the National Institutes of Health (NIH) to evaluate the safety of fostamatinib in treating COVID-19 patients. This spleen tyrosine kinase (SYK) inhibitor that has been approved for use in the USA and Europe in adults who have persistent or chronic ITP, and have failed to respond to at least one other available ITP therapy. Earlier this year, Rigel pharmaceuticals also announced a phase 2 trial with Imperial College London to evaluate the efficacy of fostamatinib in the treatment of respiratory complications caused by COVID-19.

In ITP, fostamatinib inhibits the SYK signaling pathway thus preventing platelet destruction by activated macrophages in the immune system. By inhibiting SYK pathways, inflammation and thrombosis are both known to be reduced as well. In severely affected COVID-19 patients, fostamatinib is believed likely to interrupt immunoreceptor signaling in parts of the immune system including neutrophil extracellular traps (NETs), a major mechanism of thrombosis, and to block cytokine release thus reducing the hyperinflammation caused by the SARS Cov2 virus on the lungs and other major organ systems in critically ill COVID-19 patients. Rigel pharmaceuticals hopes to enroll 60 patients from the NIH and a number of other sites with the primary goal of evaluating its safety and efficacy in treating severe cases of COVID-19, and intends to complete the trial within two or three months. The trial in London lead by another PDSA medical advisor, Nichola Cooper, hopes to compare fostamatinib to another medication, Jakafi, which blocks signaling through the Jak-Stat pathways, a different pro-inflammatory pathway.

IVIG trial
A randomized, blinded phase 3 trial has been initiated through Octapharma AG, a Swiss pharmaceutical company, and the University of California to assess the impact of using IVIG in patients with severe COVID-19 symptoms who require hospitalization. This trial is based on an earlier non-blinded pilot study conducted in China where IVIG was provided to declining patients with COVID-19 and other pre-existing conditions. The observation in this retrospective, non-randomized setting was that those patients did better than those who had severe symptoms from COVID-19 and did not receive the therapy. It is now well-established that there is currently no antibody to the COVID-19 virus in IVIG. Rather like fostamtinib but in a different not completely understood pathway, IVIG is primarily thought to have anti-inflammatory effects. In fact, that pilot study revealed the use of IVIG resulted in a reduced hospital admission, improvement in overall oxygen levels, and removal from medical ventilation. Octapharma indicated IVIG calms the immune system by reducing the intensity of the ‘cytokine storm’ leading to a better recovery from the COVID-19 virus.

While different from covalescent plasma therapy, which uses antibodies specifically from individuals who have recovered from COVID-19, IVIG also contains antibodies as it’s a human derived blood product. As more recoveries are made from those exposed to the virus, it is hoped that IVIG will not only benefit COVID-19 patients by calming the immune system, but also by providing COVID-19 antibodies directly through the use of IVIG. Whether IVIG in the future or specific hyperimmune anti-COVID-19 preparations will be the optimal vehicles (or the combinations of recombinant anti-COVID-19 antibodies in trials) to deliver antibody to COVID-19 remains to be seen.

Octapharma has also partnered with companies to develop a plasma derived hyperimmune anti-SARS-CoV-2 polyclonal immunoglobulin therapy for treating individuals with serious complications secondary to COVID-19.

Comments from PDSA’s Medical Advisors:

The use of fostamatinib as an anti-inflammatory treatment is of great interest. Studies directed against IL-6 or its receptor or using TNF antagonists have failed to demonstrate the expected benefits of amelioration of cytokine storm. Thus a different anti-inflammatory might be perfect. Syk is a central enzyme in one of the critical inflammatory pathways. It is required for signaling from all Fc receptors. Therefore blocking it might provide an important way to ameliorate the cytokine storm seen in sick patients with COVID19. Its anti-thrombotic properties are likely also beneficial in this setting given the degree of hypercoagulability seen in infected patients.

IVIG has been known to have immunomodulatory properties for many years. Exactly which ones are clinically important has never been well-established since literally dozens have been shown. Whether there are anti-cytokine antibodies or one of many other possibilities is of interest if the immunomodulatory effects are confirmed clinically. Since there are other benefits in ITP such as increasing the platelet count in autoantibody settings and to provide anti-pathogen antibodies, the threshold to define efficacy may be lower.


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