Posted by Liset Pengel on June 27, 2011
At the Centre for Evidence in Transplantation (CET) we have been rating the methodological quality of randomised controlled trials (RCTs) published since 2004. The quality score is a composite score assessing allocation concealment, intention to treat (ITT) analysis and the Jadad scale which comprises items on the adequate description of randomisation, double blinding and withdrawals. The quality scores are available through the Transplant Library.
We have applied the strict definition of ITT, namely that analysis should be based on all patients randomised. Recently, this definition of ITT has stirred a discussion among some of the authors whose trials we have assessed and among ourselves on how this item should be interpreted when assessing trials for their quality.
Randomisation of patients at the start of a trial ensures that known and unknown prognostic factors are balanced between groups. This is the strength of an RCT. An ITT analysis maintains this balance as all randomised patients are included when analysing the results of a trial. The ITT also ensures that the power of the study is preserved.
However, an ITT analysis gives rise to concern when patients drop out or there are deviations from the study protocol. In the case of patient dropout and thus missing data an ITT analysis can only be carried out with a complete data set. This can be achieved by imputing data using techniques such as last observation carried forward or replacing missing values with mean change scores. But these imputations are subject to certain assumptions and may introduce a bias. In the case of deviations from the study protocol participants are often excluded from the analysis, for example participants who did not receive a transplant or participants who did not take (a minimal amount of) the study drug. However, following the ITT these patients should still be included because the balance between randomised groups is no longer maintained when patients are excluded. Excluding patients also affects the power of the study.
The 2010 CONSORT statement (http://www.consort-statement.org/) acknowledges these difficulties when deciding how to handle the ITT and therefore an ITT analysis is no longer requested when reporting a trial. Instead it is now required that authors provide a detailed description of whether the analysis was by original assigned group and which patients were included in each of the analyses (this information is also clearly identified in a flow chart).
The CET will follow the approach outlined in the new CONSORT statement. Instead of assessing whether a trial was based on the ITT we will rate the statistical analysis of trials as one of four different analysis strategies:
These ratings will be available in the Transplant Library from September 2011.
Posted by Simon Knight on June 22, 2011
The MRC centre for transplantation are running a 2 day course entitled “Frontiers in Transplantation: Clinical Excellence Through Innovation” in London on the 8-9 September 2011. This two-day course is for Medical and Surgical trainees, Transplant Physicians, Surgeons or nurses, allied health professionals and scientists interested in translational transplantation biology.
The course will cover recent developments in basic transplantation immunology alongside the latest cutting-edge clinical research, with an emphasis on the ‘bench-to-bedside’ strategies being pursued within the MRC Centre for Transplantation at Guy’s Hospital and King’s College London. There will be a number of distinguished speakers to speak on exciting and important areas in translational transplantation biology.
For more information or to register for the course, visit the King’s College London website.
Posted by Simon Knight on June 18, 2011
I read with some interest a case series in this month’s AJT from a group in India, reporting an initial experience of laparoscopic kidney transplantation (AJT 2011; 11: 1320). Modi and colleagues provide the rationale that transplant patients are at increased risk of wound related complications (due to renal failure and immunosuppression) and so a laparoscopic approach may reduce the risk of such complications. The manuscript reports four technically successful deceased donor kidney transplants via a transperitoneal laparoscopic approach. Compared to open transplants of the paired kidney from the same donor, warm ischaemic time and total operative time were significantly longer in the laparoscopic patients, but with a reduction in overall wound length from 18.4 to 11 cm.
Whilst performing a renal transplant laparoscopically is clearly an impressive technical feat, I remain unconvinced about the merits of such a procedure. As the accompanying editorial in AJT points out, whilst there is a reduction in total wound length with the laparoscopic approach, the new procedure requires that the peritoneum is breached, increasing the risk of bowel trauma and postoperative ileus. Minimal incision open techniques have been previously described that allow for similar overall incision length without peritoneal breach. Modi and colleagues do not report any data regarding post-operative pain, ileus, wound complications or length of hospital stay.
Another consideration is of patient safety. Vessels are isolated and controlled with slings rather than clamps, and of course there is no direct access to the kidney on reperfusion to deal with any reperfusion bleeding increasing the risk of substantial blood loss. Whilst blood loss in the four patients described here was comparable, a much larger series would be required to prove that this technique is safe.
My major concern, however, is the significantly longer warm ischaemic times with the laparoscopic technique. Prolonged warm ischaemia is associated with increased risk of delayed graft function and poorer long-term outcomes, and so any new procedure for implantation must minimise warm ischaemia to allow the optimum long-term outcomes, particularly in light of the shortage of donor organs.
What Modi and colleagues have presented is a proof of concept; an impressive technical achievement which I suspect in the course of time will prove to offer very limited clinical benefit. If they are serious about pursuing this technique, their next step must be a formal randomised controlled trial with adequate follow-up to compare outcomes with a traditional open technique.