WORKING PARTY ON DESMOPRESSIN IN THE MANAGEMENT
OF VON WILLEBRAND DISEASE:
BIOLOGICAL RESPONSE VERSUS CLINICAL EFFICACY A WORLD WIDE PROSPECTIVE OBSERVATIONAL STUDY
(On behalf of the ISTH –SSC on VWF and AICE)
LOGIN
PATIENT ENROLLMENT IS OVER: NOW, THE 24 MONTH CLINICAL PROSPECTIVE OBSERVATION STARTS
Augusto B. Federici, Christine A. Lee, Stefan Lethagen
(Co-ordinators)
Victor Blanchette, Mariana Bonduel, Giancarlo Castaman,
Alice Cohen, Elbio D’ Amico, Craig K. Kessler, David Lillicrap,
Robert R. Montgomery, Alok Shrivastava, Barbara M. Zieger
Background
Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of vasopressin originally designed for the treatment of diabetes insipidus. DDAVP increases FVIII and VWF plasma concentrations without important side effects when administered to healthy volunteers or patients with mild hemophilia and VWD [1]. The first clinical trial of DDAVP was successfully performed in 1977, with the aim to avoid the use of blood products in mild hemophilia and VWD patients who needed dental extractions and other surgical procedures [2]. Following these early observations, DDAVP has become widely used for the treatment of these diseases [3]. The obvious advantages of DDAVP is that it is relatively inexpensive and carries no risk of transmitting blood-borne viruses. DDAVP is usually administered intravenously at a dose of 0.3 m
g/Kg diluted in 50-100 ml saline infused over 30 minutes.This treatment increases plasma FVIII:C and VWF 3 to 5 times above the basal levels within 30-60 minutes. In general, relatively high FVIII/VWF concentrations last for 6 to 8 hours. Since the responses in a given patient are consistent on different occasions, a test dose of DDAVP administered at the time of diagnosis helps to establish the individual response patterns. Infusions can be repeated every 12 to 24 hours depending on the type and severity of the bleeding episode. However, several patients treated repeatedly with DDAVP become less responsive to therapy [4]. The drug is also available in concentrated forms for subcutaneous and intranasal administration, which can be convenient for home treatment. Side effects of DDAVP are usually mild tachycardia, headache, flushing: these symptoms are attributed to the vasomotor effects of the drug and can often be attenuated by slowing the rate of infusion. Hyponatremia, volume overload and seizures, especially in young children, due to the antidiuretic effects of DDAVP are relative rare [5]. Even though no thrombotic episodes have been reported in VWD patients treated with DDAVP, this drug should be used with caution in elderly patients with atherosclerotic disease, because a few cases of myocardial infarction and stroke have occurred in hemophiliacs and uremic patients given DDAVP [6, 7].
DDAVP is most effective in patients with type 1 VWD, especially those who have normal VWF in storage sites (type 1, "platelet normal" ): in these patients FVIII:C, VWF and the BT are usually corrected within 30 minutes and remain normal for 6-8 hours. In other VWD subtypes, responsiveness to DDAVP is variable: a poor and short-lasting response is observed in type 1, "platelet low". In type 2A, FVIII levels are usually increased by DDAVP but the BT is shortened in only a minority of cases [8,9]. Desmopressin is contraindicated in type 2B so far, because of the transient appearance of thrombocytopenia [10]. However, there have been reports on the clinical usefulness of DDAVP in some 2B cases [11, 12]. In type 2N relatively high levels of FVIII are observed following DDAVP, but released FVIII:C circulates for a shorter time period in patient plasma because the stabilizing effect of VWF is impaired [13]. Patients with type 3 VWD are usually unresponsive to DDAVP. The results of a recent prospective European study on the biological effects of DDAVP in severe forms of type 1 and 2 VWD are now available [14]. PK studies in normal individuals have been reported after intranasal, subcutaneous and intravenous DDAVP [15] but a few data on PK in large groups of type 1 and 2 VWD are available. Moreover, there are still open questions about the efficacy of DDAVP in repeated bleeding episodes and during surgery and no prospective studies have been organized to correlate biological response or PK analysis with clinical efficacy in different forms of type 1 and 2 VWD.
Aims of this WP
To correlate the biological response (and PK) with clinical efficacy of Desmopressin (DDAVP) in type 1 and 2 VWD patients followed by large number of Hemophilia Centers in a prospective observational study organized world wide on behalf of the ISTH-SSC on VWF
Measurable Objectives:
To evaluate the biological response in a large number (>100) of well characterized VWD patients based on a standardized protocol using intravenous desmopressin (DDAVP)
To study the PK of DDAVP in at least 30-40 selected VWD patients by monitoring VWF and FVIII:C activities for longer time
To determine the rate of clinical efficacy of DDAVP in the management of bleeding episodes and during surgery of type 1 and 2 VWD patients previously exposed to an infusion trial with this drug
Comparison between biological response and clinical efficacy in different types 1 and 2 VWD
Comparison between intravenous – subcutaneous – intranasal administration in clinical practice
The incidence of tachyphilaxis in clinical practice when repeated injections are used
The identification of specific therapeutic regimens in surgery (i.e. three days on –two days off – three days on DDAVP and every 12 versus 24 hours).
The incidence of hyponatremia, volume overload, seizure in VWD patients after DDAVP
The risk of thrombotic events especially in older VWD patients
Recommendations and guidelines for DDAVP treatment in type 1 and 2 VWD.
Methods:
Design of the study
: This is a prospective observational study on the clinical use of DDAVP in the management of type 1 and 2 VWD patients. Aims of this study is to compare biological response (Part A) and PK (Part B) versus clinical efficacy (Part C) of DDAVP. Therefore, since DDAVP is not effective in all VWD patients, enrollment in the clinical efficacy study (Part C of the Protocol) is allowed only after the standardized infusion trial with DDAVP.
Inclusion criteria of patients with VWD. We would like to include well characterized VWD patients with all type 1 and 2 (including 2B if treatment with DDAVP is allowed in any Center), with the widest range of age (from young children to senior adults).
Exclusion criteria. Patients should be excluded from the study in the following cases: a) Acquired von Willebrand Syndrome; b) Additional congenital and acquired defects of platelet function (ex, Acquired Storage Pool defect + VWD); c) use of anti-inflammatory drugs that may affect platelet function within the previous 15 days; d) previous history of seizures in the family; e) recent serious cardiovascular episodes (Acute myocardial infarction and stroke) in the VWD patient.
Computerized Data Base and Case Reported Forms (CRF). A computerized CRF is prepared to collect standardized information about VWD diagnosis, biological response to DDAVP (Infusion trial and PK), types and sides of bleeding episodes, types and sides of surgeries, number and days of infusions, types of side effects, additional comments (see CRF enclosed)
Criteria for VWD Diagnosis. Diagnosis of type 1 and 2 VWD should be correctly performed by the participating center following recommendations provided by the ISTH-SSC on VWF. If available, molecular diagnosis (mutations) should be also reported to confirm classification in a specific VWD type. In a few patients, to be considered undefined because of a difficult diagnosis, plasma samples should be kept and sent, upon request by the Center, to a more experienced laboratory. All these difficult diagnosis will be confirmed by the Steering Committee by using clinical and laboratory data.
Criteria for a standardized Infusion trial with DDAVP: All VWD patients enrolled in this prospective study must be exposed, after signing an informed consent, to the standardized infusion trial with DDAVP. This infusion trial for biological response must be performed in the absence of bleeding or surgery always before using DDAVP in clinical practice. The trial must be performed in 30 minutes with an intravenous 0.3 m
g/Kg of DDAVP diluted in 50-100 ml of saline. Since the infusion must be standardized, only intravenous injections are considered (not subcutaneous or intranasal). Factor VIII/VWF activities must be measured before and 0.5, 1, 2 and 4 hours after the start of DDAVP infusion; bleeding time or PFA-100 (especially in pediatric patients) must be performed before and after 2 hours from the start of infusions, only for the infusion trial.
Calculation of the half-life of VWF and FVIII:C following DDAVP (PK study): In a smaller number (30-40) of well characterized patients (also molecular diagnosis is required), the VWF and FVIII half-lives will be calculated. The decision for the enrollment in the PK study should be made after sending detailed data of the patient selected to the coordinators. More sampling are in fact required to calculate the FVIII/VWF parameters: a first baseline (1 hour before injection), a second baseline (just before DDAVP injection) and 0.5 (immediately at the end of injection), 1, 2, 4, 6, 8, 12, 24 hours after the start of intravenous DDAVP infusion (baseline). Prof. Sven Bjorkman of the University of Uppsala, expert on PK studies, will join the Coordinators to organize this part of the study and evaluate the results, following the example of previous studies [15].
Definition of biologic responsiveness: VWD patients should be considered responsive to DDAVP when after two hours from baseline they show increases of baseline levels of FVIII:C and VWF:RCo or VWF:CB by at least three times, with levels of at least 30 U/dL and bleeding time of 12 minutes or less (Criteria derived from previous protocol, as reported in reference n. 15). Compared to that previous protocol, to allow a correct evaluation of PK in this current study, the two hours are considered here from baseline. Moreover we have introduced the PFA:100 in case BT cannot be performed and VWF:CB in case VWF:RCo is not available in the laboratory of the Center (see CRFs in detail).
Ethical Approval, Informed Consent and Insurance to Patients. VWD patients should be enrolled after obtaining the Ethical approval from the Institutional Regulatory Board of the Participating Centers. The informed consent will be submitted to the IRB in the original language of the country and should inform the patients stating that this Study is not sponsored by any Pharmaceutical Company.
Criteria for enrolment into the prospective clinical observational study (efficacy): Only patients who have been exposed previously to DDAVP trial (Part A) can be enrolled into the prospective observational clinical study of DDAVP (Part C, Efficacy Study) because this protocol explore biological response versus clinical efficacy of DDAVP. During each DDAVP infusion for bleeding or surgery, only FVIII:C and VWF:RCo or VWF:CB should be measured before and two hours after DDAVP injection (not BT or PFA) when patients are hospitalized. In case of home therapy, no tests will be performed and response will be evaluated only clinically, based on description of symptoms reported by patients to the hematologists of the participating Center.
Registration of Bleeding episodes and surgeries. The participating Hemophilia Centers will enroll into the Study any type 1 and 2 VWD patient who requires DDAVP treatments for bleeding episodes, surgeries or invasive procedures. All the data will be reported in specific CRF prepared by the Coordinators (see enclosures). These CRF will be also computerized and will be available electronically in a specific web site to be linked to the ISTH Web site (www.ddavp-in-vwd.com) and to the web site (www.ddavp-in-vwd.it) Italian Association of Hemophilia Centers (AICE) .
Criteria for definition of Clinical Response. The clinical effects of DDAVP will be evaluated by using the same evaluation scale used for concentrates in patients with congenital bleeding disorders. Excellent response: stop of bleeding and no bleeding during surgery after less than three injections of DDAVP alone; Good response: stop of bleeding and no bleeding during surgery after more than three injections of DDAVP or DDAVP with antifibrinolytic agents; Poor response: stop of bleeding and no bleeding during surgery after DDAVP followed by FVIII/VWF concentrates. The loss of blood during surgery will be evaluated directly by the surgeon and indirectly by the actual reduction of haemoglobin.
Collection of results and analysis of the data: the results obtained by each Hemophilia Center will be collected electronically by the Coordinators by and data analyzed with the help of a statistician and PK expert appointed by the Coordinators.
Preparation of the Guidelines: Results obtained after analysis will be discussed by the Members of the Steering Committee who will prepare guidelines for the use of Desmopressin in VWD to be officially approved by the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis.
Expected Results:
Comparison between biological response and clinical efficacy of DDAVP in type 1 and 2 VWD patients.
Number of repeated doses of DDAVP for bleeding episodes or surgeries
Identification of the possible causes of DDAVP failures: VWD types, repeated injections, side effects
Type of major and minor side effects
Recommendations: specific DDAVP regimens according to types of VWD, of bleeding episodes, of surgeries
Participants to the Study:
This study was proposed originally by several members of the ISTH-SSC on VWF and was approved in its revised version during the last ISTH-SSC in Birmingham. The same protocol has been extended by the two Italian Members (Federici & Castaman) of the Steering Committee to the hematologists of the Italian Association of Hemophilia Centers (AICE), as a continuation of the previous Italian national registry on VWD. Therefore this study is now organized on behalf of ISTH-SSC on VWF and AICE, as reported in the CRF. Colleagues of other countries are encouraged to extend this protocol to their national hemophilia organizations, because it might be interesting to compare the use of DDAVP in different countries world-wide.
Besides the members of this Steering Committee who will contact the hemophilia centers in their countries, all the hematologists expert in VWD management who regularly follow at least 50 VWD cases are invited to participate in the study. The protocol and computerized CRF will be available by a web site (www.ddavp-in-vwd.com), linked to the ISTH web site and by another web site (www.ddavp-in-vwd.it), linked to the web site of Italian Association of Hemophilia Centers organizations involved in this study.
To have access to the study protocol and CRF, a specific procedure to obtain official authorization to participate will be required by contacting the coordinators. Authorship of the possible publications derived from this study will be decided by the Steering Committee and based on the actual contribution of each colleague (number of VWD cases enrolled in the study).
Sequential procedures to correctly enroll VWD patients in the study :
Make a complete diagnosis of type 1 and 2 VWD (if available, molecular analysis can confirm phenotypic diagnosis)
Inform extensively the patient by using also the information sheet and obtain the signature in written informed consent
Organize the DDAVP infusion trial in all patients (biological response) when the patient is not bleeding or under surgery: follow the instructions on timing
If the patient is selected for a PK study, send a message to the coordinators and, after approval, follow the instruction on the different timing
When laboratory and clinical data are available, classify the patient as responsive or unresponsive to DDAVP: see criteria
Once classified, the patients should be followed for at least two years
Register the DDAVP treatments used during the bleeding episodes, dental extractions or surgeries and invasive procedures by collecting all the data reported in the CRFs.
Test FVIII:C and VWF activity (VWF:RCo or VWF:CB) only before DDAVP and after two hours from baseline when patients are hospitalized. Register clinical data only when patients are not hospitalized
Introduce data in the computerized CRFs on line when episodes are complete and laboratory data available.
Make an update report on cases from the same Center every four months
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