A randomised clinical trial with two parallel groups will be conducted at the Ophthalmology Department of the Complejo Hospitalario de Navarra in Spain. Clinical management of the patients will be performed according to local current clinical practice except in the experimental group, where oral anticoagulant therapy will not be interrupted before surgery. Patients will be stratified according to the oral anticoagulant they are taking (direct or indirect anticoagulation).
Main objective: To compare haemostasis-related perioperative complications of PPV in patients maintaining oral anticoagulant therapy before surgery compared to patients who interrupt this therapy before PPV.
- To compare changes in the visual results three months after PPV in patients who maintain anticoagulant therapy with respect to those who interrupt this therapy before surgery.
- To compare the incidence of systemic thromboembolic events after PPV in those patients who maintain anticoagulant therapy compared to those who interrupt this therapy before surgery.
We hypothesise that anticoagulant therapy maintenance before PPV is not associated with a significant increase in perioperative complications compared to those cases in which this therapy is interrupted before surgery, and that the postoperative visual results are not inferior in those cases in which anticoagulant therapy is maintained compared to those cases in which such therapy is interrupted before surgery.
Participants, recruitment methods and procedures
Patients with a possible clinical indication for PPV identified by any ophthalmologist in the reference area are referred to be evaluated by the vitreoretinal surgeons of the Ophthalmology Department in the Complejo Hospitalario de Navarra, who will confirm the surgical indication, in addition to assessing the medical status and checking the treatments in each case. The surgeon in charge will invite all subjects receiving OAT with a clinical indication for PPV to participate in the study. The purposes, methods, objectives and possible risks associated with the study will be suitably explained to them. A patient information sheet and an informed consent form (ICF) will be subsequently provided. A specific consent form for the surgery will also be provided to participants. The schedule of enrolment, interventions and assessments is summarized in Figs. 1 and 2. A screening visit will be scheduled for patients who decide to participate in the study. In that visit, the inclusion and exclusion criteria will be assessed (see Table 1), and patients will be informed of the group they are to be assigned to, together with the date of the operation. A description of the surgical procedure will also be provided during the screening visit. They will also be scheduled to attend anaesthesia consultation. If the anaesthetist considers that there is a circumstance that contraindicates the interruption of anticoagulant treatment, the patient will be excluded from the trial. After PPV, they will be followed up in order to assess complications, adverse effects and visual acuity for three months.
Upon completion of the screening assessment, participants who satisfy all the inclusion criteria and none of the exclusion criteria will be randomly assigned to the intervention and control groups in a 1:1 allocation ratio. Randomisation will be stratified by oral anticoagulation type: direct anticoagulation, which includes dabigatran, rivaroxaban, apixaban or edoxaban, and indirect anticoagulation, which includes acenocumarol. Randomisation assignment will be computer-generated using the ‘randomizr’ library of the R statistical program R 3.4.0, with a complete randomising method based on permutations that guarantees balanced groups. The allocation sequence will be generated by the Methodology Unit of Navarrabiomed. Randomisation will be requested to the Clinical Trials Platform (CTP) of Navarrabiomed by the investigator responsible for patient recruitment. In return, CTP will send to this investigator an answer form by email that includes a randomisation number and the assigned treatment for this patient. Then, the investigator responsible for patient recruitment will give the information about treatment allocation to the anesthetist, who will inform to the patient. Throughout the study, the randomisation will be conducted by the CTP and the randomisation list will be kept by the CTP team along the duration of the study. Randomisation will be conducted without any influence of the investigators. The surgeons in charge, who will measure the outcomes, will be blinded. The data analyst will also be blinded, whereas participants and the rest of investigators will not be blinded. Unblinding will not be allowed in any circumstance.
Control group (standard of care): Anticoagulant therapy will be interrupted before surgery and patients will receive the substitutive treatment with subcutaneous enoxaparine in accordance with the currently employed protocol in the hospital.
To establish substitution therapy, the thrombotic risk of patients is evaluated, taking into account their clinical characteristics. Their renal function is also evaluated by measuring the glomerular filtration rate. In patients undergoing treatment with acenocumarol, if the thrombotic risk is low, they will be treated with enoxaparin 40 mg/24 h; if the thrombotic risk is high and the glomerular filtration rate is less than 30 ml / min, they will be treated with enoxaparin 40 mg/24 h; and if the thrombotic risk is high and the glomerular filtration rate is greater than 30 ml/min, they will be treated with enoxaparin 40 mg/12 h. In patients undergoing treatment with the new direct action oral anticoagulants, if the glomerular filtration rate is less than 50 ml/min or if the thrombotic risk is high, the treatment is replaced 5 days before with enoxaparin 40 mg/24h. If the glomerular filtration rate is greater than 50 ml/min and the thrombotic risk is low, anticoagulant treatment is suspended without the need for substitution treatment.
Intervention group: Oral anticoagulant therapy will not be interrupted. Patients will continue their regular oral anticoagulant therapy before and after surgery.
Pars plana vitrectomy (PPV)
Patients will undergo PPV with the 23 or 25 gauge technique and under retrobulbar anaesthesia. PPV may be associated with facoemulsification or scleral buckling if there is a clinical indication. Blood pressure will be measured before retrobulbar anaesthesia in all the patients. Before the surgery, the anaesthetist in charge will verify that the patient has performed the anticoagulant procedure to which he or she was assigned. International Normalised Ratio (INR) will be measured in those patients under treatment with acenocumarol. Retrobulbar anaesthesia will be performed according to the common technique of injecting bupivacaine 0.5% or a mixture of bupivacaine 0.5% and lidocaine 2% with a 25 gauge retrobulbar needle. Epinephrine will not be used. The volume of anaesthetic injected will be 7 millilitres and the injection may be repeated whenever the surgeon considered it necessary. Apart from retrobulbar anaesthesia, parenteral anxiolytics and analgesics may be administered before or during surgery. Concomitant care or interventions other than usual clinical practice are not expected.
Primary and secondary endpoints
The primary endpoint is the presence of any of the following complications i) retrobulbar or peribulbar haemorrhage after local anaesthesia (preoperative complication), ii) choroidal haemorrhage or incoercible haemorrhage in the anterior chamber or vitreous cavity during surgery (intraoperative complications) and iii) during the first two weeks after surgery, anterior chamber haemorrhage, vitreous haemorrhage, intraretinal haemorrhage or choroidal haemorrhage (postoperative complications). These haemorrhagic complications can be divided according to their clinical relevance into major (choroidal haemorrhage and retrobulbar or peribulbar haemorrhage) and minor (anterior chamber haemorrhage, vitreous haemorrhage and intraretinal haemorrhage). The secondary endpoints are i) a change in the corrected visual acuity after surgery (measured as the difference between baseline and three months after surgery, in the decimal scale and converted into logMAR scale) ii) thromboembolic events during the first three months after surgery, and iii) other surgical procedure related complications during the first three months after surgery.
All adverse events and serious adverse events, which might be related to the study procedures, will be recorded, investigated and notified to the regulatory authorities and to the ethics committee by the researchers during the study period, in accordance with Clinical Trials Directive 2001/20/EC.
Finalisation or interruption of the study
The trial will be considered finished when all the patients have concluded the follow-up period. It may be interrupted under any of the following situations:
- Impossibility of recruiting the number of patients previously determined.
- Noncompliance with the requisites of the protocol.
- Noncompliance with the rules of clinical practice or current legislation.
- Appearance of unexpected risks that are unacceptable for patients.
Considering that there is no difference in the probability of not having complications between the standard therapy (anticoagulants interruption) and the experimental therapy (no interruption of anticoagulants), and assuming a 95% confidence level and a 96% probability of not having complications, 48 patients are required in each branch (n=48x2) in order to have a 80% probability that the upper limit of the confidence interval (CI) excludes a difference of over 10% in favour of the standard group. Calculations performed with Sealed Envelope Ltd.
A description of the socio-demographic and clinical characteristics of the patients involved in this trial will be performed, for the complete sample and for each group, using a mean with standard deviation or median with interquartile range for the quantitative variables, and using frequencies and percentages for the categorical variables. These characteristics will be compared between the control and experimental groups using parametrical tests, such as the Student t- test and X2 test, or non-parametrical tests, such as the Mann Witney or Fisher tests. If any of the variables differs significantly between groups, this will be taken into account when comparing the outcomes. The incidence of haemorrhage (pre, intra and postoperative) and other categorical secondary variables such as complications three months after surgery, both for the total sample and for each group, will be estimated by means of sample proportion with a 95% confidence interval and from baseline to three months after surgery will be compared between groups using parametrical or non-parametrical tests, such as the Student t and Mann Whitney tests, depending on normality. If any socio-demographic or clinical characteristic differs between groups, lineal and logistic regression models will be used to compare the outcomes between groups, including them as covariates, which will provide adjusted Odds Ratios for the intervention, together with 95% confidence intervals. Sensitivity analyses will also be performed excluding patients with proliferative vitreoretinopathy or proliferative diabetic retinopathy, patients for whom scleral buckling procedures have been placed, and patients under treatment with acetylsalicylic acid to account for the possible bias induced after having included them. Additionally, a multivariate analysis including age and treatment with acetylsalicylic acid will also be performed to account for possible differences in the distribution of these variables among groups. SPSS software version 21.0 will be used to perform the analysis.
The Steering committee will consist of the Principal Investigator and his research collaborators, which includes clinicians with expertise in ophthalmology. They will be responsible for the recruitment, data collection and completion of Case Report Forms (CRFs). They will also perform assessments to guarantee adherence to the study protocol. Trial management and data verification will be carried out from the center's Clinical Trials Platform of Navarrabiomed and data analysis will be conducted by the Unit of Methodology of Navarrabiomed.
This clinical trial was approved by the local ethics committee (Comité Ético de Investigación con medicamentos de Navarra, Health Department of Navarre Government) and was authorised by the Spanish Agency of Medicines and Medical Devices. This study will be performed in accordance with the standard of Good Clinical Practice (GCP) and with the current European and Spanish laws that are applicable. The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH (International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use)/ GCP, and applicable regulatory requirements.