Clinicians have been eagerly awaiting results of the enormous Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study, which may determine whether amyloid scans will be covered by insurance. Preliminary findings previously indicated that such scans do sway diagnoses and treatment plans when used for patients with uncertain etiology. At the 11th Clinical Trials on Alzheimer’s Disease conference, held October 24–27 in Barcelona, Spain, Gil Rabinovici of the University of California in San Francisco presented final results for this aspect of the study. In a cohort of 11,409 people, clinicians changed treatment plans for two-thirds of them after seeing amyloid PET scans, he reported. This is well over the study’s endpoint of 30 percent. Yet the positive finding does not guarantee insurers will cover the scans. For payers, a crucial question is whether those treatment changes improved the health of participants, and IDEAS researchers are still collecting data on that. They will get that answer in 2019.
- IDEAS study finds amyloid PET scans change treatment plans in two-thirds of cases.
- Answer not yet in on how this affects patient health.
- Automated CSF assays roughly equal PET for diagnostic accuracy.
Even so, Rabinovici believes amyloid scans have shown their clinical worth. “This is the strongest Phase 4 data to date supporting the use of amyloid PET,” he told the audience in Barcelona.
Another issue for payers is cost-effectiveness. An amyloid PET scan runs thousands of dollars, far exceeding the cost of lumbar punctures or blood draws. In the past, cerebrospinal fluid tests have had too much variance to make good diagnostics, but with the advent of automated assays and certified reference materials, measurements are becoming more reliable. In Barcelona, several groups reported that automated CSF measures agree closely with amyloid scan results, suggesting that these markers could reduce the need for amyloid scanning in clinical diagnostics.
The Centers for Medicare & Medicaid Services (CMS) supports the IDEAS study under its coverage with evidence development mechanism (Apr 2015 news). IDEAS was planned as a four-year, $100 million study of 18,200 Medicare recipients seen at doctor’ offices around the U.S. It finished enrolling in January 2018, ahead of schedule and under budget. IDEAS admitted people who met the appropriate-use criteria for amyloid scanning by having measurable cognitive impairment but an uncertain diagnosis (Jan 2013 conference news). At the 2017 AAIC in London, Rabinovici presented findings from the first third of this cohort (Aug 2017 conference news).
At CTAD, Rabinovici showed data for the whole cohort. IDEAS’ first aim was to see if amyloid scanning affected treatment. Clinicians first developed a treatment plan without knowing the patient’s amyloid status, then revisited it once they knew. Researchers registered 16,008 people for this part of the study. (The remaining participants are registered for the second part of the study, which looks at health outcomes after a year.) Rabinovici noted a large number of dropouts. About 2,000 people did not show up for their amyloid scans, another 1,800 skipped their post-PET visits, and about 800 more were disqualified for various violations of study protocol. This left 11,409 participants for analysis. Dropouts did not differ significantly from people who remained in the study, Rabinovici said.
Among the 11,409 participants, 60 percent were clinically diagnosed with mild cognitive impairment, the others with dementia. Their average age was 75. Scans determined that 55 percent of the MCI group were amyloid-positive, as were 70 percent of those with dementia.
Physicians adjusted their diagnoses after seeing scans. A quarter of the cohort were initially deemed to have AD but changed to a non-AD diagnosis, and another 11 percent started with a different diagnosis but later told they had AD. Overall, among all those with a positive amyloid scan, AD diagnoses jumped from 80 to 96 percent, while in the amyloid-negative group, they fell from 72 percent to 10 percent. As in the preliminary findings, scans had their largest effect in ruling out AD.
Treatment plans changed accordingly for about 60 percent of people with MCI, and 64 percent of those with AD. Most often, the changes involved prescription of the approved Alzheimer’s drugs, acetylcholinesterase inhibitors and memantine. Clinicians typically added these drugs after seeing a positive scan, with their use climbing from 40 to 82 percent in the MCI group and from 63 to 91 percent in the dementia group. Clinicians were much less likely to cancel prescriptions, with only a small drop in AD drug use after PET imaging.
Doctors changed other medications in about a quarter of the cohort, and recommended counseling for safety and long-term care planning in a quarter of participants as well. Clinicians reported that the PET result drove these decisions 87 percent of the time.
In addition, doctors cut plans for additional testing and imaging by half after seeing scans. The scan data also refined referrals for AD clinical trials. Although physicians referred slightly fewer people, the percentage of those who were amyloid-positive jumped from 66 to 93. This may result in fewer screen failures in those trials, Rabinovici said in his talk.
Rabinovici noted that this study represented real-world specialty care, a middle ground between primary care and select tertiary academic centers. Participants were seen at 595 dementia clinics nationwide; about 80 percent of these were private practices. That said, the study was limited by recruiting a fairly homogenous population that was 88 percent white and highly educated, with 44 percent having a college degree. By design, the study only analyzed the benefit of PET scanning for people with measurable cognitive impairment and atypical presentations. To address these shortcomings, Rabinovici said that IDEAS researchers were discussing a proposed follow-on study with the CMS. IDEAS2 would enroll people with typical AD and earlier-stage disease, and would strive to recruit more under-represented participants (Oct 2018 conference news). The new study will also collect DNA and plasma samples and store them in a biorepository, Rabinovici told the audience.
In the meantime, PET scans remain uncovered by most insurance companies, and thus unaffordable for many patients. Could CSF biomarkers fill the gap? In Barcelona, Samantha Burnham of Commonwealth Scientific and Industrial Research Organisation in Canberra, Australia, suggested they eventually will. She presented data from 202 participants in the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, 70 percent of whom were cognitively healthy. All underwent lumbar punctures and PET scans with either PiB, florbetapir, or flutemetamol. CSF was analyzed by Elecsys automated assays in Gothenburg, Sweden. Amyloid scans flagged 42 percent of the cohort as amyloid-positive, and CSF biomarker ratios—whether of total tau/Aβ42, p-tau/Aβ42, or Aβ42/40—agreed with the scans 90 percent of the time. Each of the three ratios gave an AUC of 0.94. Single biomarkers performed less well, with an Aβ42 cutoff agreeing with scans only 81 percent of the time.
Timo Grimmer of the University of Munich showed similar data coming from the Phase 3 CREAD studies of the therapeutic antibody crenezumab. In these trials, 109 people, whose average age was 70 and CDR 0.5 to 1, participated in a sub-study directly comparing CSF and PET. They underwent florbetapir scanning and donated CSF for analysis by Elecsys. Similar to the AIBL data, Aβ42 alone agreed with PET scans 85 percent of the time. There were 16 people with discordant findings; nine were CSF-positive and PET-negative, while seven were CSF-negative and PET-positive. As in the AIBL study, tau/Aβ42 ratios performed better, giving 90 percent concordance with PET.
Another presentation, from Alberto Lleó of the Hospital de Sant Pau in Barcelona, compared florbetapir PET to a different automated platform, the LUMIPULSE system from Fujirebio Inc. The researchers analyzed 94 people from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort, whose average age was 73 and whose diagnoses ranged from cognitively normal to dementia. Amyloid scans were positive in 63 percent. As in the other studies, CSF ratios gave high agreement with scans, from 86 to 88 percent, while single biomarkers performed less well.
Other new studies add to these data. Researchers at Washington University in St. Louis recently reported that CSF ratios determined by Elecsys can discriminate PiB-positive and PiB-negative people (Schindler et al., 2018). Likewise, researchers led by Oskar Hansson at Lund University, Sweden, found that CSF cutoffs determined in the BioFINDER cohort agreed with PET imaging in the ADNI cohort 90 percent of the time, and predicted cognitive decline over the next two years (Hansson et al., 2018). Furthermore, Hansson and other PET experts agree that semiquantitative analyses of PET scans agree with visual reads only 90 percent of the time, suggesting that CSF biomarkers are already pushing against the ceiling of current amyloid PET scan accuracy.—Madolyn Bowman Rogers
- $100M IDEAS: CMS Blesses Study to Evaluate Amyloid Scans in Clinical Practice
- HAI—Amyloid Imaging in the Clinic: New Guidelines and Data
- In Clinical Use, Amyloid Scans Change Two-Thirds of Treatment Plans
Conference Coverage Series Citations
- Schindler SE, Gray JD, Gordon BA, Xiong C, Batrla-Utermann R, Quan M, Wahl S, Benzinger TL, Holtzman DM, Morris JC, Fagan AM. Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement. 2018 Mar 2; PubMed.
- Hansson O, Seibyl J, Stomrud E, Zetterberg H, Trojanowski JQ, Bittner T, Lifke V, Corradini V, Eichenlaub U, Batrla R, Buck K, Zink K, Rabe C, Blennow K, Shaw LM, Swedish BioFINDER study group, Alzheimer's Disease Neuroimaging Initiative. CSF biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018 Mar 1; PubMed.