Fifteen-year follow-up results of the UK endovascular aneurysm repair trial 1 (EVAR 1), published online in The Lancet on 12 October 2016, show higher rates of aneurysm-related and total mortality during the last eight years of follow-up for patients who had EVAR than those who had open repair. However, over the whole follow-up of the trial the mean total and aneurysm-related mortality rates were not significantly different between groups. The investigators note that “the significant late divergence of the survival curves in favour of open repair can be partly explained through greater increase in late mortality from aneurysm-related deaths in the EVAR group”. They add that the loss of early EVAR survival benefit, followed by inferior late survival benefit and durability compared with open repair, needs to be addressed by lifelong surveillance of EVAR and prompt reintervention if necessary. The 15-year results were first presented at the Charing Cross Symposium in April 2016.
The EVAR 1 randomised controlled trial previously reported aneurysm-related mortality and total mortality up to 10 years of follow-up, at which point no difference was reported between endovascular and open abdominal aneurysm repair, “but the problem of secondary sac rupture after EVAR was emerging”, according to the researchers Rajesh Patel, Michael J Sweeting, Janel T Powell and Roger M Greenhalgh (on behalf of the EVAR trial investigators). The original trial protocol stated that if concerns became apparent about the durability of EVAR, the trial should be extended to address the issue. EVAR 1 is the first randomised controlled trial to report follow-up longer than 10 years of EVAR vs. open repair.
EVAR 1 enrolled 1,252 patients who were aged 60 years or older between 1 September 1999 and 31 August 2004, from 37 hospitals in the UK. Patients were offered enrolment if they had an aortic aneurysm of at least 5.5cm in diameter (assessed with CT) and were deemed fit for open repair. As of 1 September 2009, 711 patients with a mean age of 80 years were reported alive and under follow-up in EVAR 1 (357 in the EVAR group and 354 in the open repair group). Due to non-proportional hazards during the first eight years of follow-up, the investigators analysed data by splitting follow-up into four time groups: from randomisation to six months, six months to four years, four years to eight years, and after eight years’ follow-up.
During 9,968 person-years of follow-up 910 deaths occurred, 101 (11%) of which were aneurysm-related. Overall aneurysm-related mortality was 1.1 deaths per 100 person-years in the EVAR group and 0.9 deaths per 100 person-years in the open repair group (adjusted HR 1.31, 95% CI 0.86–1.99, p=0.21). For total mortality, the study recorded 9.3 deaths per 100 person-years in the EVAR group and 8.9 deaths per 100 person-years in the open repair group (adjusted HR 1.11, 95% CI 0.97–1.27, p=0.14).
The researchers noted evidence of deviation from proportional hazards assumption for aneurysm-related mortality (p<0.0001), with a significant early benefit of EVAR during the first six months after randomisation (p=0.031), counteracted by an increase in aneurysm-related mortality after four years (p=0.05), the difference being most significant after eight years (p=0.0064). Additionally, they reported deviation from the proportional-hazards assumption for total mortality (p=0.0232), with a significant early benefit of EVAR during the first six months after randomisation (p=0.06), similar mortality between the groups from six months to eight years, but after eight years a significant increase in patient mortality in the EVAR group (p=0.048). Kaplan-Meier aneurysm-related mortality curves crossover between six years and eight years and total mortality curves diverge after 10 years. Survival was not significantly improved in EVAR compared with open repair (median 8.7 years in the EVAR group vs. median 8.3 years in open-repair group; log-rank p=0.49).
In terms of causes of death, overall, rupture after aneurysm repair resulted in 31 deaths in the EVAR group and five in the open repair the group. Overall there was no difference in cancer-related mortality between the groups (adjusted HR 1.09, 95% CI 0.84–1.40, p=0.53), although an increase was recorded in the EVAR group after eight years (adjusted HR 1.87, 95% CI 1.19–2·96, p=0.0072).
Per-protocol analysis was of 598 patients in the EVAR group and of 567 patients in the open repair group, and again strongly showed the benefit of EVAR during the first six months, counteracted by an increase in aneurysm-related mortality at all subsequent time periods, the increase being proportionately greater than for the analysis by randomised group. Overall aneurysm-related mortality was significantly higher in the EVAR group (1.0 per 100 person-years) than in the open repair group (0.6 per 100 person-years; adjusted HR 1.76, 95% CI 1.07–2.89, p=0.026). Total mortality was not significantly higher in the EVAR group at 9.1 per 100 person-years than in the open repair group at 8.4 per 100 person-years (adjusted HR 1.14, 95% CI 0.99–1.31, p=0.07).
During 9,715 person-years of follow-up, 258 graft-related reinterventions were undertaken in 165 patients in the EVAR group and 105 were performed in 74 patients in the open repair group, with higher rates to first reintervention in the EVAR group. The reintervention rate was significantly higher in the EVAR group for any reintervention and serious reinterventions in the first four years and for life-threatening reinterventions (including conversion to open repair, repeat EVAR and treatment of graft infection) in the follow-up of six months to four years and after eight years. Even after two-year or five-year follow-up without any life-threatening reintervention, new life-threatening reinterventions occurred at any time up to 15 years of follow-up. The relative difference in reintervention rate between the groups was highest from six months to four years after randomisation, particularly for the most serious reinterventions. A similar pattern, by timepoint, was observed for second and subsequent reinterventions.
Discussing the 15-year results, the investigators write, “Our long-term results showed aneurysm-related and total mortality are greater in late follow-up for patients who had EVAR than those who had open repair, but over the whole follow-up the mean total and aneurysm-related mortality were not significantly different between groups. The significant late divergence of the survival curves in favour of open repair can be partly explained through greater increase in late mortality from aneurysm-related deaths in the EVAR group.”
Total and aneurysm-related mortality were lower in patients who received EVAR in the first six months. However, after this time deaths in the EVAR group increased, and after eight years of follow-up both total and aneurysm-related mortality were significantly higher in the EVAR group than in the open repair group. After the first six months, the increased aneurysm-related deaths in the EVAR group were predominantly from secondary sac rupture. Over the whole follow-up, two aneurysm-related deaths followed reintervention, but the 31 deaths from secondary sac rupture were partly due to not having underlying causes of sac expansion from endoleak corrected. Of patients allocated to open repair, five secondary ruptures occurred, of which four were originally assigned to open repair but received EVAR, and the last secondary rupture occurred more than eight years after the open repair procedure. Secondary sac rupture is much more common after EVAR, occurring at any period after the procedure, whereas sac rupture after open repair is rare and tends to occur in late follow-up.
The rate of reintervention was higher in the EVAR group at all follow-up timepoints. The investigators say that these late reinterventions included those with a high severity score, “indicating that it was not safe to stop follow-up for patients with EVAR”. They add, however, that in this trial some patients were discharged from surveillance and therefore lost the option of planned reintervention. With a mean age of 74 years at randomisation, there could have been some pressing clinical reasons not to reintervene for some patients after long-term follow-up because of old age and frailty. A criticism of earlier reports from this trial that not all incision-related reinterventions, after open repair, were reported was addressed in this long-term follow-up.
Limitations of this trial include that devices we used were implanted between 1999 and 2004 and newer devices since then might be expected to have better results; imaging has improved since 2004; the original protocol was for annual follow-up by CT scan but in the later stages many of the patients in the EVAR group were followed up with ultrasonography. This change from CT to ultrasonography was affected by increasing concern about radiation exposure. Moreover, imaging follow-up declined over time, particularly for the patients in the open repair group. Consequently, reinterventions became less likely once surveillance ceased.
“We cannot assume that follow-up practice is the same in the rest of the world as it is in the UK where many patients were discharged from surveillance after several years. Since the patients in the EVAR group had more diligent follow-up than those in the open repair group, aneurysm-related mortality might have been underestimated in the open repair group, although this factor does not affect our findings for total mortality,” they write.
The investigators add that to maintain the initially better results of EVAR future challenges include the need to halt the dilating disease process and the need to use devices that allow for this inevitable dilating process over the years. They write, “The long-term results of this study can act as a benchmark against which new endovascular technologies for aneurysm repair can be compared with at each timepoint. In the meantime, surveillance must be addressed in clinical guidelines: to be diligent, regular, easy, and avoid CT scan if possible, and perhaps concentrate on the sac diameter after EVAR either by ultrasonography or novel implantable sensor devices.”
The study was funded by the National Institute (NIHR) for Health Research Health Technology Assessment programme (HTA) and Camelia Botnar Arterial Research Foundation.