Periodic Reporting for period 4 - CONVINCE (The Comparison of High-Dose Heamodiafiltration (HDF) versus Haemodialyse)
Período documentado: 2022-07-01 hasta 2023-12-31
Context
End stage kidney disease (ESKD) is a serious medical condition with high mortality rates and hence with an unmet clinical need. Globally, approximately 10% of the general population suffers from a form of kidney injury of which a proportion will progress to ESKD. The survival probability at one, two and five years is around 81, 68 and 37%, respectively. Therefore, there is an unmet and urgent medical need to improve ESKD patient survival and to address Health Related Quality of Life (HRQL).
Currently there are three types of dialysis treatments: Haemodialysis (HD), peritoneal dialysis (PD) and haemodiafiltration (HDF). HD is currently the treatment of choice in 80% of ESKD patients across Europe, in absence of any current alternatives applicable for the majority of ESKD patients. CONVINCE will not focus on PD as an alternative to HD, as only a minority of patients are treated by PD in Europe, with many patients transferring to haemodialysis with time. Therefore, CONVINCE focuses on a comparison between high-dose HDF and HD, with the hypothesis that high-dose HDF will be the superior treatment and hence can become first treatment of choice in ESKD patients.
The concept of HDF is relatively simple. In HD the basic transport mechanism for removal of waste products is diffusion. HDF combines diffusion with another transport mechanism: convection. Convection is the removal of waste products diluted in an ultrafiltrate which is produced by a pressure difference over the membrane, and is replaced by “clean” replacement fluids. Extensive pre-clinical research has shown that by combining these two mechanisms, as in high-dose HDF, accumulating waste products in the body due to the failing kidneys are more effectively removed from the body. In this respect, dose, i.e. total ultrafiltered volume expressed as L/session, seems to be of crucial significance. High-dose HDF may reduce mortality in ESKD patients.
To achieve a change in clinical practice, we run a large clinical study proving HDF (cost) effectiveness compared to HD. If proven true, a substantial reduction in mortality may be achievable for 80% of the ESKD patients currently managed with HD. At the end of the study the Guideline and review bodies will be updated with the new evidence obtained.
Objectives
Haemodifiltration (HDF): Setting the novel standard treatment for ESKD patients. CONVINCE will pursue the following objectives:
1) To prove the superiority of high-dose HDF as compared to conventional guideline based HD (i.e. current standard of care) in terms of morbidity, mortality and HRQL;
2) To collect data to conduct a comprehensive economic evaluation of HDF compared to support Health Technology Assessment (HTA) considerations among Member States and healthcare to facilitate patients acceptance and uptake of high-dose HDF across Europe;
3) To develop and implement Patient Reported Outcome Measures (PROMs) and Patient Reported Experience Measures (PREMS) to capture patient satisfaction;
4) To develop best practices and new guidelines on the most effective and efficient dialysis strategy;
5) To share results in close collaboration with all stakeholders and end-users, and to establish a sound evidence- and regulatory basis for the implementation of high-dose HDF across Europe.
References
1) Brück K, Stel V, Gambaro G,et al . J Am Soc Nephrol. 2016 Jul;27(7):2135-47.
End stage kidney disease (ESKD) is a serious medical condition with high mortality rates and hence with an unmet clinical need. Globally, approximately 10% of the general population suffers from a form of kidney injury of which a proportion will progress to ESKD. The survival probability at one, two and five years is around 81, 68 and 37%, respectively. Therefore, there is an unmet and urgent medical need to improve ESKD patient survival and to address Health Related Quality of Life (HRQL).
Currently there are three types of dialysis treatments: Haemodialysis (HD), peritoneal dialysis (PD) and haemodiafiltration (HDF). HD is currently the treatment of choice in 80% of ESKD patients across Europe, in absence of any current alternatives applicable for the majority of ESKD patients. CONVINCE will not focus on PD as an alternative to HD, as only a minority of patients are treated by PD in Europe, with many patients transferring to haemodialysis with time. Therefore, CONVINCE focuses on a comparison between high-dose HDF and HD, with the hypothesis that high-dose HDF will be the superior treatment and hence can become first treatment of choice in ESKD patients.
The concept of HDF is relatively simple. In HD the basic transport mechanism for removal of waste products is diffusion. HDF combines diffusion with another transport mechanism: convection. Convection is the removal of waste products diluted in an ultrafiltrate which is produced by a pressure difference over the membrane, and is replaced by “clean” replacement fluids. Extensive pre-clinical research has shown that by combining these two mechanisms, as in high-dose HDF, accumulating waste products in the body due to the failing kidneys are more effectively removed from the body. In this respect, dose, i.e. total ultrafiltered volume expressed as L/session, seems to be of crucial significance. High-dose HDF may reduce mortality in ESKD patients.
To achieve a change in clinical practice, we run a large clinical study proving HDF (cost) effectiveness compared to HD. If proven true, a substantial reduction in mortality may be achievable for 80% of the ESKD patients currently managed with HD. At the end of the study the Guideline and review bodies will be updated with the new evidence obtained.
Objectives
Haemodifiltration (HDF): Setting the novel standard treatment for ESKD patients. CONVINCE will pursue the following objectives:
1) To prove the superiority of high-dose HDF as compared to conventional guideline based HD (i.e. current standard of care) in terms of morbidity, mortality and HRQL;
2) To collect data to conduct a comprehensive economic evaluation of HDF compared to support Health Technology Assessment (HTA) considerations among Member States and healthcare to facilitate patients acceptance and uptake of high-dose HDF across Europe;
3) To develop and implement Patient Reported Outcome Measures (PROMs) and Patient Reported Experience Measures (PREMS) to capture patient satisfaction;
4) To develop best practices and new guidelines on the most effective and efficient dialysis strategy;
5) To share results in close collaboration with all stakeholders and end-users, and to establish a sound evidence- and regulatory basis for the implementation of high-dose HDF across Europe.
References
1) Brück K, Stel V, Gambaro G,et al . J Am Soc Nephrol. 2016 Jul;27(7):2135-47.
The project has faced challenges in the recruitment of patients for the clinical trial. The COVID-19 pandemic challenged the project even further. Some sites had recruitment issues and were discontinued. The start-up processes in other locations had delays. This was due in part to the acquisition of ethics approval and lower than anticipated numbers of eligible patients. In response, we added additional sites in existing countries, and added Romania to the recruiting countries. The recruitment period was extended and the final inclusion was 1360 patients, exceeding our adjusted target for 80% power. An extension of 12 months was granted to the project. This was necessary to maintain the initially planned 24-month minimum follow-up. The last follow-up was done in March 2023.
We conducted a pragmatic, multinational, randomized, controlled trial involving patients with kidney failure who had received HDF for at least 3 months. All the patients were deemed to be candidates for a convection volume of at least 23 liters per session and were able to complete patient-reported outcome assessments. The patients were assigned to receive HDF or continuation of conventional HD. The primary outcome was death from any cause. Key secondary outcomes were cause-specific death, a composite of fatal or nonfatal cardiovascular events, kidney transplantation, and recurrent all-cause or infection-related hospitalizations. A total of 1360 patients underwent randomization where 683 received HDF and 677 received HD, with median follow-up of 30months. Death occurred in 118 patients (17.3%) in the HDF group and in 148 patients (21.9%) in the HD group. In patients with kidney failure resulting in kidney-replacement therapy, the use of HDF resulted in a lower risk of death from any cause than conventional HD.
The main outcome paper was published in June 2023. The results were announced simul on the same day during the ERA meeting. A dissemination and communication plan was prepared and press releases took place. The patient reported outcome results were submitted in January 2024. The economic evaluation will be submitted in spring 2024. Eight abstracts based on the results were submitted to ERA 2024. New initiatives as spin off of CONVINCE have been launched.
We conducted a pragmatic, multinational, randomized, controlled trial involving patients with kidney failure who had received HDF for at least 3 months. All the patients were deemed to be candidates for a convection volume of at least 23 liters per session and were able to complete patient-reported outcome assessments. The patients were assigned to receive HDF or continuation of conventional HD. The primary outcome was death from any cause. Key secondary outcomes were cause-specific death, a composite of fatal or nonfatal cardiovascular events, kidney transplantation, and recurrent all-cause or infection-related hospitalizations. A total of 1360 patients underwent randomization where 683 received HDF and 677 received HD, with median follow-up of 30months. Death occurred in 118 patients (17.3%) in the HDF group and in 148 patients (21.9%) in the HD group. In patients with kidney failure resulting in kidney-replacement therapy, the use of HDF resulted in a lower risk of death from any cause than conventional HD.
The main outcome paper was published in June 2023. The results were announced simul on the same day during the ERA meeting. A dissemination and communication plan was prepared and press releases took place. The patient reported outcome results were submitted in January 2024. The economic evaluation will be submitted in spring 2024. Eight abstracts based on the results were submitted to ERA 2024. New initiatives as spin off of CONVINCE have been launched.
The key question of CONVINCE now is whether HDF will replace standard HD as the new “standard” of treatment. For that, the following elements are essential: cumulative meta-analysis, evidence supporting patient outcomes for HDF, healthcare policy/reimbursement aligning with evidence.
Over the past months, meta-analyses have been published, indicating superiority of HDF over HD. Additional evidence shows that survival benefit gradually increases with increasing achieved convective volume. The results on PRO’s have shown that in certain domains of quality of life, HDF is superior to standard HD. Furthermore, the CONVINCE trial has found no safety concern when applying HDF. Cost-effectiveness analyses based on our data are under way.
Next steps should be taken by our peers by defining guidelines and best practice documents, when results on PROs and costs are published.
Key steps to implement HDF will include:
-further increasing the use of HDF seems simple to establish in centers that already use it
-in centers that wish to start a HDF program, investments may be necessary in hardware. The CONVINCE trial and subsequent meta-analyses may help to decide to make these investments.
-education of the dialysis staff is necessary on how to implement high dose HDF. This is simple to organize given the available practical guidelines.
The full impact of the CONVINCE trial will become clearer in the coming years. However, it is important to realise that this trial for the first time in decades proposes a change in the dialysis process itself, which turns out to be clinically relevant. It is already clear from the several comments received, that the trial is already considered of high significant in nephrology and that this will likely remain so for the coming (many) years.
Over the past months, meta-analyses have been published, indicating superiority of HDF over HD. Additional evidence shows that survival benefit gradually increases with increasing achieved convective volume. The results on PRO’s have shown that in certain domains of quality of life, HDF is superior to standard HD. Furthermore, the CONVINCE trial has found no safety concern when applying HDF. Cost-effectiveness analyses based on our data are under way.
Next steps should be taken by our peers by defining guidelines and best practice documents, when results on PROs and costs are published.
Key steps to implement HDF will include:
-further increasing the use of HDF seems simple to establish in centers that already use it
-in centers that wish to start a HDF program, investments may be necessary in hardware. The CONVINCE trial and subsequent meta-analyses may help to decide to make these investments.
-education of the dialysis staff is necessary on how to implement high dose HDF. This is simple to organize given the available practical guidelines.
The full impact of the CONVINCE trial will become clearer in the coming years. However, it is important to realise that this trial for the first time in decades proposes a change in the dialysis process itself, which turns out to be clinically relevant. It is already clear from the several comments received, that the trial is already considered of high significant in nephrology and that this will likely remain so for the coming (many) years.