The sensational mid-term results of the EndoVascular Aneurysm Repair (EVAR) 1 and EVAR 2 trials, presented at an extra special meeting of the UK Endovascular Forum, at the Belfry, and at the Society for Vascular Surgery (SVS), in Chicago, IL, and in The Lancet, have been overshadowed by the conflicting message from the Dutch Randomised Endovascular Aneurysm Management (DREAM) trial, published in the New England Journal of Medicine (NEJM) a week earlier.
Despite the four-year results of the EVAR trials receiving acclaim from both sides of the Atlantic, the pre-emptive publication of the two-year DREAM Trial results in the NEJM received greater publicity. However, Dr Wesley Moore, from the UCLA, described the EVAR 1 trial as “a landmark trial” which should have been done in the US. During the first session where both trials results were presented at the SVS, he commented that the interpretation of the findings of the smaller DREAM trial was “totally negative.” The articles in the Wall Street Journal and other news media had caused many concerned patients who had undergone EVAR to call their physicians, because the message of the DREAM Trial was that the benefit of EVAR was limited to one-year only. In comparison results of the EVAR trials, which were properly powered to assess long-term outcomes including the impact of EVAR in terms of all cause mortality and aneurysm-related mortality, showed that the initial benefits of endovascular repair are maintained at four years for low risk patients. Yet for high risk patients endovascular aneurysm repair offers no benefit.
The EVAR trials consist of two separate randomised controlled trials for patients fit for open repair (EVAR 1) or unfit/high risk (EVAR 2) totalling 1,420 patients making it the largest study of its kind globally. The multi-centred trials are run from Charing Cross Hospital, Hammersmith Hospitals NHS Trust, Imperial College London, UK, in collaboration with another 41 centres nationwide. Commenting on the EVAR presentation, Professor Peter Littlejohns, Medical Director of the National Institute of Clinical Excellence (NICE) said that if scientific work was always of such high quality, NICE could disband.
EVAR 1 was the first to compare the two key surgical techniques and has been successful in recruiting a large numbers of patients (1,082) and experts to take part. Following that, the new EVAR technique became the first choice procedure of surgeons by default, making it of great interest to both the national and international medical communities, and giving rise to many imitators.
Results of the £1.7 million EVAR trials, commissioned by the NHS Health Technology Assessment (HTA) programme, in the UK, show that the 3% operative mortality benefit of EVAR over open repair (OR) is maintained in this four year follow-up. In contrast to OR, which imposes a significant period of recovery in intensive care, EVAR can be carried out under local anaesthetic with a very much shorter hospital stay. However, EVAR is a developing technology and is associated with increased surveillance needs, NHS costs and the risk of further procedures, including conversion to OR.
In the high risk patients (people who were unfit for an OR) for whom EVAR was originally developed, there was no demonstrable benefit in terms of either mortality or quality of life, and 7% of patients died in the first 30 days after the elective operation.
“The EVAR trial results will affect clinical practice at once,” said Professor Roger Greenhalgh, lead applicant and chair of the Trial Management Committee. “There will be cautious enthusiasm for the use of EVAR in low risk patients but personally I shall not offer EVAR in high risk patients.”
In comparison, the DREAM trial concluded the EVAR benefits are limited to one-year. Lead investigators were Drs Jan Blankensteijn and Dr Monique Prinssen of the University Medical Center, Utrecht, the Netherlands. The DREAM trial found 30-day operative mortality was 4.6% in the open repair group (eight of 174 patients) and 1.2% in the endovascular repair group (two of 171 patients). DREAM recruits patients with aneurysms larger than 5.0cm and EVAR, larger than 5.5cm.
The DREAM Trial reported that two years after randomisation, cumulative survival was similar in both groups, at 89.6% with open repair and 89.7% with endovascular repair. Aneurysm-related deaths occurred in 5.7% of the open repair group and 2.1% of the endovascular repair group, with the advantage of the endovascular approach entirely due to events in the peri-operative period, with no significant difference in subsequent aneurysm-related mortality.
The DREAM trial results were presented as a setback for endovascular aneurysm repair. In an attempt to account for their findings, the researchers suggest: “The survival advantage resulting from a less-invasive approach to aneurysm repair may largely be based on postponing death among higher-risk patients from the peri-operative period to the subsequent months.” They add: “Another possible explanation for the convergence of survival curves is the failure of endovascular repair to prevent rupture of the aneurysm.”
However, the DREAM is a much smaller trial and under-recruited. It included 351 patients diagnosed with an AAA of at least 5cm in diameter and were considered suitable candidates for both techniques. EVAR 1 is a much larger trial (1,082 patients) and over-recruited. DREAM used composite endpoints of 30 day mortality and morbidity, while EVAR was powered on the single endpoint of mortality.
Dr Frank Lederle, Professor of Medicine at the Minneapolis VA Medical Center and trial coordinator of the US Open Versus Endovascular Repair (OVER) trial, commented in an article accompanying the publication of the DREAM trial results, “the primary endpoint of the DREAM trial was 30 day outcomes and it was not powered to assess long-term outcomes (with only 38 deaths overall).” Whereas, the EVAR 1 trial is assessing long-term outcomes including all cause mortality and aneurysm-related mortality.
Regarding the EVAR trials, the investigators added that further investigations were taking place, in particular sub-group and rupture analysis. All EVAR trial patients are due to be followed until at least 2010 so long-term results will be available in due course.
Concluding, Greenhalgh said, “When we first mentioned the trial in 1996, there were three possible outcomes regarding the trials; if open repair wins it will be the end of EVAR; if EVAR wins, there will be caution; and a draw would validate EVAR. These results validate the use of EVAR in fit patients. An important minority of patients are anatomically unsuited for EVAR in our current state of knowledge and therefore surgeons must still be trained to do open aneurysm repair. Vascular specialists of the future will need operative and catheter skills to be able to manage all problems.”
An accompanying comment featured in The Lancet by Jack L Cronenwett, from the Dartmouth-Hitchcock Medical Center, concluded that the current results from the EVAR 1 trial have shifted the choice point slightly toward the endovascular option, but ultimate clarity will await the long-term results of this trial.
Professor Janet Powell, member of the Trial Management Committee added, “If the patient is high risk, the emphasis should be to get the patient fit enough first rather than perform early EVAR.”
After witnessing the presentation of the EVAR results at the SVS, Juan Parodi, the founding father of EVAR, commented, “The EVAR trials are impeccable. As for EVAR 2, after 15 years of treating high risk patients with EVAR, I realised that a multi-disciplinary group to optimise clinical condition should be the priority before intervention. In addition, it is necessary to have a variety of devices to hand to achieve the best results. My learning curve over 15 years has indicated ever lower operative mortality and rupture rate approaching zero.”