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CONVINCE Clinical Trial Q&A
General Questions
What is the CONVINCE trial?
CONVINCE is a randomized controlled trial aimed to assess benefits and harms of high dose hemodiafiltration as compared with high-flux hemodialysis regarding death from any cause, cause-specific mortality, cardiovascular events, hospitalizations, patient-reported outcomes, and cost-effectiveness.
What specifically did the trial assess?
The effect of high-dose hemodiafiltration (>23L / session) compared to high-flux hemodialysis on clinical outcome. 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, recurrent all-cause or infection-related hospitalizations, patient-reported outcomes and cost-effectiveness.
Who funded the trial?
The trial was funded by a grant from the European Commission Horizon 2020.
Who is involved and ran the trial?
The trial was initiated by the investigators and was designed and executed by a steering committee consisting of academic investigators and employees of dialysis providers independent of financial contributors. The scientific committee, whose membership did not include representatives of financial contributors, had final responsibility for the interpretation of the data, the preparation of the manuscript, and the decision to submit the manuscript for publication. The trial was monitored by an academic contract research organization, Julius Clinical, according to standard operating procedures.
Investigators were: Peter J. Blankestijn, M.D., Robin W.M. Vernooij, Ph.D., Carinna Hockham, Ph.D., Giovanni F.M. Strippoli, M.D., Bernard Canaud, M.D., Jorgen Hegbrant, M.D., Claudia Barth, M.D., Krister Cromm, Ph.D., Andrew Davenport, M.D., Matthias Rose, M.D., Marietta Torok, M.D., Mark Woodward, Ph.D., and Michiel L. Bots, M.D.
The authors’ affiliations are as follows: From the Department of Nephrology and Hypertension (P.J.B., R.W.M.V.) and the Julius Center for Health Sciences and Primary Care (R.W.M.V., M.L.B.), University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; George Institute for Global Health, School of Public Health, Imperial College London (C.H., M.W.), and the Department of Renal Medicine, Royal Free Hospital, Division of Medicine, University College London (A.D.) — both in London; the Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Bari, Italy (G.F.M.S.); the School of Public Health, University of Sydney (G.F.M.S.), and the George Institute for Global Health, University of New South Wales (M.W.) — both in Sydney; Montpellier University School of Medicine, Montpellier, France (B.C.); Fresenius Medical Care Deutschland, Global Medical Office, Bad Homburg, Germany (B.C., K.C.), Medical Scientific Affairs, B. Braun Avitum, Melsungen (C.B.), and Charite Universitatsmedizin Berlin, Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and the Center of Internal Medicine and Dermatology, Department of Psychosomatic Medicine, Berlin Institute of Health, Berlin (K.C.,M.R.) — all in Germany; the Division of Nephrology, Department of Clinical Sciences, Lund University, Lund ( J.H.), and Corporate Medical Office Diaverum, Malmo (M.T.) — both in Sweden;
Who were the study subjects in the trial?
Patients with kidney failure who had received high-flux hemodialysis for at least 3 months. All the patients were deemed to be candidates for a convection volume of at least 23 liters per session (as required for high dose hemodiafiltration) and were able to complete patient-reported outcome assessments. Patients were treated at 61 centers in eight European countries.
What are the results of the trial?
Please see the paper Blankestijn PJ, Vernooij RWM, Hockham C, Strippoli GFM, Canaud B, Hegbrant J, Barth C, Covic A, Cromm K, Cucui A, Davenport A, Rose M, Török M, Woodward M, Bots ML; CONVINCE Scientific Committee Investigators. Effect of Hemodiafiltration or Hemodialysis on Mortality in Kidney Failure. N Engl J Med. 2023 389 p. 700-709. doi: 10.1056/NEJMoa2304820.
What are Patient Reported Outcomes?
The patient experienced health status was a secondary outcome of the CONVINCE study. Participating study centers collected patient-reported health information on disease specific symptoms based on the Kidney Disease Quality of Life Instrument (KDQOLTM) symptom list, as well as generic health aspects using instruments from the Patient-Reported Outcome Measurement Information System (PROMIS®) assessing eight health domains. For seven health domains (physical function, fatigue, sleep disturbance, depression, anxiety, pain interference, and ability to participate in social roles and activities) as well as a single item measuring pain intensity
Why are Patient Reported Outcomes important?
There is increasing awareness in the nephrology and elsewhere in medicine, that the question “what does the patient feel or experience” is of crucial importance. In fact, these aspects should be a central focus of our activities. We have collected an enormous amount of data on these “patient reported outcomes”. We expect to be able to report the results later this year.
Why are CONVINCE outcomes meaningful? What makes it different to other studies?
This is the first time since many many years that a meaningful improvement of the dialysis treatment itself is established. Also, in this trial we prove that adding another mechanism of treatment (convection) to the every-day standard HD is of clinical relevance. Actually, we think that these aspects are really cool! We are rather confident that this trial will be considered as landmark paper by the community for many years.
How was CONVINCE designed and why does the design overcome insufficiencies of prior HDF trials?
CONVINCE was designed as randomized controlled trial. We increased the likelihood of an unbiased effect estimate through the trial design, which included complete mortality follow-up, no-censoring alive, and competing-risk statistical analyses.
How does it compare to prolonged i.e. daily, night time HD?
That is a very good question. It is important to realize that we show that in the presently accepted organizational standard (i.e. 3 times weekly 4 hours treatment) we can offer a better result. This does not say anything about prolonged versions of HD.
Consortium
Is this the definitive HDF trial? Is it generalizable to other settings?
Features to support generalizability include a pragmatic trial design without numerous exclusion criteria. However, our inclusion criteria may have resulted in a trial population that was healthier than the general hemodialysis population in Europe and in the United States. Also, we did not collect data regarding race or ethnic group among our European patients, so our findings may not be generalizable to non-White patients with kidney failure.
Selection by the treating physician to enroll patients who were likely to reach a convection volume of at least 23 liters during each session, an indication that these patients had relatively good vascular access. Furthermore, patients were expected to complete outcome assessments. But, an overall lower risk of death among the trial patients as such does not invalidate our findings of an association between hemodiafiltration and a reduction in death from any cause.
What additional studies are being planned in terms of real world evidence?
Indeed, we are working on conducting emulation trials.
How is this study different from previous studies on HDF?
The intervention is high dose HDF. We added patient reported outcomes. Furthermore, CONVINCE was broadly multicenter, pragmatic with complete follow-up, no censoring alive, and competing risk analyses, and has large sample size.
Is there an ethical obligation for clinicians to consider or implement HDF?
There is not.
Will this change the Cochrane analysis on HDF vs HD which says that most of data is low quality?
Indeed it does. This is a high quality RCT, addressing a evidence gap. Also, we will update the Cochrane review with recent published trials, including CONVINCE to expand the evidence.
How will the trial impact vulnerable populations – those with cardiovascular disease, cognitive impairments?
We need to validate earlier analyses from Kruijsdijk R et al using CONVINCE information show which groups of patients will and will not benefit most. [Van Kruijsdijk RCM, et al Personalizing treatment in end-stage kidney disease: deciding between haemodiafiltration and haemodialysis based on individualized treatment effect prediction. Clin Kidney J. 2022 Jun 20;15(10):1924-1931. doi: 10.1093/ckj/sfac153. PMID: 36158156; PMCID: PMC9494541.]
Can I generalize CONVINCE results to my country/ my clinical practice?
Yes indeed for hemodialysis patients of whom it is expected that they can achieve a convective volume of > 23 L per session.
Features to support generalizability include a pragmatic trial design without numerous exclusion criteria. However, our inclusion criteria may have resulted in a trial population that was healthier than the general hemodialysis population in Europe and in the United States. We did not collect data regarding race or ethnic group among our European patients, so our findings may not be generalizable to non-White patients with kidney failure.
Which countries were involved?
Spain, Portugal, UK, France, Germany, The Netherlands, Romania, Hungary
My patients are old and frail. I doubt that HDF would have a large effect on mortality in my patients.
We need to validate earlier analyses from Kruijsdijk R et al using CONVINCE information show which groups of patients will and will not benefit most. [Van Kruijsdijk RCM, et al Personalizing treatment in end-stage kidney disease: deciding between haemodiafiltration and haemodialysis based on individualized treatment effect prediction. Clin Kidney J. 2022 Jun 20;15(10):1924-1931. doi: 10.1093/ckj/sfac153. PMID: 36158156; PMCID: PMC9494541.]
Did CONVINCE also investigate QoL related aspects?
The patient experienced health status was a secondary outcome of the CONVINCE study. Participating study centers collected patient-reported health information on disease specific symptoms based on the Kidney Disease Quality of Life Instrument (KDQOLTM) symptom list, as well as generic health aspects using instruments from the Patient-Reported Outcome Measurement Information System (PROMIS®) assessing eight health domains. For seven health domains (physical function, fatigue, sleep disturbance, depression, anxiety, pain interference, and ability to participate in social roles and activities) as well as a single item measuring pain intensity. Analyses on these topics follow.
Should the outcomes matter to me as a practitioner, and should I change the way I currently treat my patients? Can I put catheter patients on HDF?
Yes, indeed for hemodialysis patients of whom it is expected that they can achieve a convective volume of > 23 L per session.
Features to support generalizability include a pragmatic trial design without numerous exclusion criteria. However, our inclusion criteria may have resulted in a trial population that was healthier than the general hemodialysis population in Europe and in the United States. We did not collect data regarding race or ethnic group among our European patients, so our findings may not be generalizable to non-White patients with kidney failure.
Is HVHDF – as delivered in CONVINCE study centres – also applicable in a normal dialysis set-up? If yes, how can I implement it into daily routine?
Yes, indeed for hemodialysis patients of whom it is expected that they can achieve a convective volume of > 23 L per session.
Are high substitution volumes easy to achieve in clinical routine and what is the preferred mode of delivery (pre-/ post)?
In CONVINCE we were able to reach high volume in over 90% of participants on HDF in post-dilution.
Why is HDF better than hi flux HD – what’s the biological basis?
The results of previous pharmacologic intervention studies involving patients with kidney failure have often been neutral. Possibly, such results have to do with the fact that an intervention that is targeted to modify a single mechanism or intervention late in the patient-treatment pathway is not sufficiently powerful or protective to mitigate risk and to change clinical outcome in patients with multiple coexisting illnesses. Hemodiafiltration is a general and nonselective intervention that potentially involves multiple mechanisms, including increased removal of uremic toxins and other physiologic processes. What mechanisms contribute most, is not known.
Medical – General
Can I expect further results from CONVINCE regarding ESA-savings?
No, unfortunately not. We have no data on that because we have not collected info on the dosage of ESA
Does HDF help to overcome hypersensitivity reactions in HD patients?
Not known
On your data, should everybody now move to HDF? If Yes Why?
We have shown a 23% benefit in terms of survival within a relatively short time window of 2.5 years. This means that for those on hemodialysis and in whom a 23L per session HDF dose is likely to be achievable should indeed be considered for a change.
Of course we realize that guideline bodies, health care authorities, health care funding bodies, professional and patient organizations and others now need to review and consider this new information and decide on the place of HDF in every day clinical practice. We very much understand that these processes take some time. But we do feel that our findings allow for a much wider acceptance of HDF.
Of course we have to also see what our patient reported outcome analyses will tell us about their experience and wait for the cost effectiveness analyses.
Who should receive HDF – all or only selected patients?
CONVINCE has been conducted in patients on hemodialysis, of whom the treating physician expected that a high dose HDF could be reached, and who were willing and capable of completing the PRO questionnaire. So there may be a selection of the more healthier patients than all hemodialysis patients seen by the nephrologist .
Please note that there were no safety concerns for HDF compared to HD, so boldly put ‘is does not seem to harm patients, so they may only benefit.
We are currently performing an in-depth analysis on the generalizability of the findings, but more importantly, we are conducting analyses to explore which patients benefit more / most (in terms of better survival) of a HDF switch.
Our subgroup analyses in model hint towards that already: those without a previous history of cardiovascular disease, without diabetes, and with fistula access. But a final appropriate statistical analyses is needed.
Is the selection of everybody with a good fistula your take?
Usually dialysis staff feels that patients need to have an adequate vascular access in order to have HDF. In CONVINCE over 80% had a native fistula. But about 14 % had a catheter. So having a catheter is not an absolute contra indication.
Is it not only the characteristics of the study population? > 65, no difference between diabetic and non-diabetic, no benefit when already cardiovascular events?
We are conducting analyses to explore which patients benefit more / most (in terms of better survival) of a HDF switch.
In an earlier analyses combining the data from 4 RCts, we indicated that patients who benefitted most from haemodiafiltration were younger, less likely to have diabetes or a cardiovascular history and had higher serum creatinine and albumin levels. That was based on HDF versus HD and not on high dose HDF.
Are you suggesting to wait for a KDIGO guideline revision? Also in the light of the British study coming along?
The way treatment changes is indeed through providing evidence like CONVINCE, but also the UK HDF study, then have the guideline committees evaluate the totality of the evidence and judge about statement on the initiation of (high dose) HDF.
23% survival benefit sounds a lot, but is only relative mortality risk. What is your view?
Indeed, 23% is a relative measure. So the event rate went from 21.9% to 17.3% in a time period of 2.5 years. 4.6% reduction in absolute terms; roughly speaking does this mean that we need to treat 22 patients to prevent 1 death.
For a treatment that is similar from an organizational point of view to the established treatment (hemodialysis), this is quite impressive.
COVID did have an impact, how much? Also in the light of COVID we need to wait for the next study?
COVID came along during the conduct of the trial. COVID was not anticipated. Patients on dialysis had an increased risk of getting COVID, and perhaps also dying from COVID. For obvious reasons, we had no a-priori hypothesis on how COVID would affect our trial.
It is important to realize that in the mortality analyses we can not make the distinction between death due to COVID or death from any cause in a COVID positive patient.
We are currently looking into the matter in a very detailed manner.
Are there real world data comparison on the way?
There are several large observational type data sets which indeed also suggest a beneficial effect for HDF. It is also interesting to see that results of the present study are comparable to an earlier meta-analysis that we did on the data of the four earlier trials. Altogether it is fair to say that multiple earlier datasets seem to support the present findings.
Indeed, one approach is mimic the CONVINCE trial using real world data.
Let us than look at the possible selection steps: selection by the treating physician; actually inviting of the patient; decline of the patient to participate.
RWD will take away these potential effects, but probable not aspects of patients involved in that patient are able to achieve a high dose of 23L or above.
So yes, emulation trials will indeed overcome some of the potential issue. And yes, they are on the way.
What is your view on the costs versus the benefit?
Years ago HDF was considered more expensive and more complex to deliver. Today, most modern dialysis machines and modern water treatment facilities are suitable to deliver HDF. Costs may differ between geographies and between the type of contracts you have with suppliers. But our take on it is that HDF will be very cost effective when compared to the present day standard HD. We will do a formal cost effectiveness analysis.
The second one is about sustainability of high volume HDF in terms of water consumption, electrolytes, power... etc
That is a very good point! When we started the study this question was not on our agenda. But indeed, there is increasing awareness of the environmental impact of HD. We have no data on the environmental impact of HDF. But it seems fair to say that it will not be lower. Presently, we are looking in to the question whether the environmental impact of HDF could be comparable to HD. Subsequent steps should be to address the question how reduce the environmental impact of both.
What is the suggestion when 23 liter can’t be achieved?
Please do realize that the number of 23 L/session was the lower end of the highest tertile in our previous meta-analysis (Peters et al NDT 2016). There is no high level scientific reasoning behind this number. Most likely, it represents a continuum, i.e. the higher volume the better. There seems to be a dose response relationship here. Where to plateau of this effect is, nobody knows.