Studies on screening

The first population-based AAA screening trial was conducted in Oxford, United Kingdom, in 1988. It included 825 men aged 65-74 years, only little over half of whom attended. The prevalence of AAA was 5.4% (Collin et al.

1988). After this small non-randomised study, four RCTs followed: The Chichester trial (Chichester, United Kingdom) in 1989-1994 (Scott et al.

1995), the Viborg trial (Viborg county, Denmark) in 1994-1999 (Lindholt et al.

2005), the Western Australian trial 1996-1999 (Norman et al. 2004), and the Multicentre Aneurysm Screening Study (MASS; Portsmouth, Southampton, Winchester, and Oxford, United Kingdom) in 1997-1999 (Ashton et al. 2002).

61 The Chichester study, which was a pilot study for the much larger MASS trial, was the only one that included women as well as men. It included 15 775 patients (6 433 men) aged 65-80 years. The Viborg trial and the MASS trial were larger and included only men and younger age groups - 12 639 men aged 64-73 years and 67 800 men aged 65-75 years. The Western Australian trial included 38 480 men aged 65-83 years, with 33.4% being 75-83 years of age.

This age group was included in order for the study to have adequate power.

The AAA prevalence in men in these studies ranged from 4.4% in Viborg and 4.9% in MASS to 7.2% in Western Australia and 7.6% in Chichester. Twelve per cent of the discovered AAAs were over 55 mm in diameter upon initial scans in Viborg and MASS, but only 7% in Western Australia.

The number of elective AAA repairs was approximately 2-4 times higher in the invited groups compared to controls. Emergency procedures fell to roughly half the number seen in the control group, however. The Chichester, Viborg and MASS trials all showed a reduction in AAA-related mortality in the group that was invited to screening when compared to the control group. The relative risk reduction was 42% in Chichester and MASS, and 67% in the Viborg trial.

In the Western Australian trial, AAA-related mortality was not significantly reduced, mostly because of the high number of deaths in those that were invited but did not attend. The conclusion of the authors was that “the success of screening will depend on choosing the best target age group (probably men aged 65-74 years), excluding ineligible men, and minimising delay between becoming eligible for screening and actual screening”. In the MASS trial, the reduction in non-fatal RAAA was similar to the reduction in AAA mortality.

Long-term results are also available for the four RCT studies: 15-year follow-up for Chichester (Ashton et al. 2007), 14-year follow-up for the Viborg trial (Lindholt et al. 2010), 13-year follow-up for the MASS trial (Thompson et al. 2012), and 12.8-year follow-up for the Western Australian trial (McCaul et al. 2016). The benefit from screening could still be seen in the Chichester population after 15 years, although the reduction at 15 years in AAA-specific mortality had dropped from the 42% at 5 years to only 11% and was not statistically significant. The risk of AAA rupture increased after 10 years from the initial scan. Of the patients with a detected AAA who had died during the follow-up in the MASS trial, 58.2% had not had a RAAA or undergone AAA repair. The number of operations in the invited group was about twice as high as in the control group, and the number of emergency operations was half of the number in the control group. Thirty-day surgical mortality was 4.2%.

Repair was done with EVAR in 12.8%, with a mortality rate of 1.8%. The mortality in this later report compares favourably to the rate of 6% in the initial MASS report. The relative risk reduction for AAA-related deaths was 42% in the invited patients and 52% in those who actually attended.

Because AAA deaths are still uncommon, the absolute risk reduction was only 0.46% during the follow-up. The number of men needed to be invited to screening to prevent one death during 13 years was 216. This compares favourably to, for instance, breast cancer screening, in which the number of

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individuals needed for screening is approximately 400. All-cause mortality was reduced by 3% in the invited group (HR 0.97, 95% CI 0.95-0.99). Eight years after the initial scans, the number of RAAAs increased in the invited group, but was still lower than in the control group. Rescreening those with an aortic diameter of 25-29 mm 5 years after the initial scan was suggested (Thompson et al. 2012).

In the Viborg trial, the patients with an aortic diameter of 25-29 mm upon the initial scan were rescreened 3-5 years later, and 28% had developed an AAA, although the largest was only 48 mm in diameter. The conclusions of the Western Australian trial did not change after longer follow-up. The reduction in AAA-related mortality was only 8% even in the subgroup of 65-74 year-olds and not statistically significant. The deaths from AAA in those patients who actually attended the screening, however, were halved. The authors attributed the lack of benefit from screening to the low rate of rupture and death from AAA, the high rate of elective surgery in the control group, and the low attendance to screening (68% compared to 76.6% in Viborg and 80.3% in MASS).

During the surveillance in the Viborg study, 36% of those with an AAA of under 5 cm in the initial scan were operated on. The AAA-related risk reduction remained high at 66% after long-term follow-up. The decrease in all-cause mortality compared to the control group was 2% but not statistically significant. The same trend of roughly double the number of elective procedures and half the number of emergency procedures was also seen in the long term.

Several meta-analyses have been published on the combined data of these four RCTs. With the inclusion of the 15-year results of the Chichester trial, the 13-year results of the MASS trial, the 14-year results of the Viborg trial and the 11-year results of the Western Australian trial, the 2.7% reduction in all-cause mortality reached statistical significance (Takagi et al. 2013b). The estimated number of individuals needed to be invited to screening to save one life was 156. As AAA accounted for only 2% of the deaths in this population, it is likely that there are also other causes for the reduction in all-cause mortality besides the reduced AAA-specific mortality. It is possible that addressing cardiovascular risk factors during the screening process has a beneficial effect on mortality.

The thorough review of the RCTs and other related studies by the United States Preventive Services Task Force (USPSTF) concluded that one-time screening for 65-year-old men, especially those who have ever smoked, is effective in reducing AAA-related mortality. The original review and screening recommendation was published in 2005 and updated in 2014 (Fleming et al.

2005; Guirguis-Blake et al. 2014a; Guirguis-Blake et al. 2014b). This review, however, concluded that the effect on all-cause mortality was not statistically significant, although it was later pointed out that their rounding was incorrect and the reduction in all-cause mortality would actually reach statistical significance (Lederle 2016a). The all-cause mortality reduction remained

63 statistically significant even after including the most recent negative long-term data from the Western Australian trial (Lederle 2016b).

There are several on-going trials on AAA screening listed on ClinicalTrials.gov (January 2017). Some of these focus on screening in suspected high-incidence groups such as patients with peripheral arterial disease or carotid stenosis (NCT01248533). There is also a study looking into US in AAA screening in smoking Israeli Arab Men (NCT02306304). The population-based screening studies listed are from Norway (screening for abdominal aortic aneurysm in 65-year-old males in Oslo, NCT01248533), and Denmark (randomised preventive vascular screening trial of 65-74-year-old men in the Central region of Denmark, NCT00662490).