12 Aug 2016

Results of the six-year Prevention of Dementia by Intensive Vascular Care (PreDIVA) trial, presented at the Alzheimer’s Association International Conference, held July 22-28 in Toronto, indicated that the multi-domain intervention aimed at reducing cardiovascular risk factors had no overall benefit. The incidence of all-cause dementia recorded in the intervention arm matched that in control group. “The main conclusion is that this type of intervention for this primary outcome in this study group does not show an effect,” said Edo Richard, University of Amsterdam, who presented the data.

However, he told Alzforum that this interpretation lacks nuance. “We also saw in per-protocol subgroup analysis that the intervention seemed more effective in people who had untreated hypertension at baseline,” he said. People with high blood pressure who stuck to the trial regimen over the six to eight years of follow-up reduced their risk of dementia by 46 percent.

Researchers at AAIC urged caution in interpreting the subgroup analysis. “It would have been nice if this trial had clearly shown a positive response, but we need to keep the many methodological issues in mind,” said Miia Kivipelto, Karolinska Institute, Stockholm. “We need to learn more about prevention trials, including what is the right type of intervention, how much should be given to make a difference and when, and who stands get the most benefit,” she told Alzforum. Some took the results to mean that broadly targeting populations with modest interventions may not the best way to prevent dementia.

PreDIVA is one of several trials testing multi-domain interventions and the first to suggest any effect in reducing dementia incidence. Participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), run by Kivipelto, and in the Multidomain Alzheimer’s Prevention Trial (MAPT) being run in France gained modest improvements in cognition, but it remains unclear if those will translate to protection against Alzheimer’s disease or other dementias (see Nov 2015 conference news). 

Together with principal investigator Willem van Gool, Richard, and co-investigator and Eric Moll van Charante designed PreDIVA to test interventions that could be easily adopted by routine clinical practices. All interventions were carried out at general health-care facilities in the Netherlands. The study recruited 3,526 volunteers, age 70-78, to one of 116 clinics that were cluster randomized to standard care or vascular care. At 63 of them, nurses assessed 1,853 volunteers for cardiovascular risk factors during routine visits (three per year), gave tailored advice on healthy lifestyle, and optimized treatments for hypertension, dyslipidemia, and type 2 diabetes, if necessary. At another 53 clinics, 1,601 people received standard care over the length of the trial. For primary outcomes the researchers measured dementia incidence and disability according to the Academic Medical Center Linear Disability Score (ALDS). The trial design and outcome were published online in The Lancet on July 26.

Overall, the intervention failed to reduce dementia incidence, with 121 cases in the intervention group (6.5 percent) and 112 in the control (7 percent). Likewise, no difference in disability emerged, with mean ALDS scores in both groups being 85.7 at the end of the trial. The hypertension effect surfaced in a per-protocol analysis, in which investigators limited the treatment group to people who had attended at least two-thirds of their planned visits, and restricted the control group to those who had attended less than three unplanned doctor visits for cardiovascular risk management. Richard explained that extra visits would in essence move people from the placebo to the treatment arm. “We wanted to examine why we might not see a treatment effect, so we left those people out,” he said.

The per-protocol analysis turned up an effect in people who had untreated hypertension at baseline. If they were randomized to treatment, their dementia incidence was 4.8 percent versus 6.9 percent in the control arm. It dropped to 4.3 percent in patients who strictly adhered to the intervention for the duration of the trial. Compared with the control group, that drop in incidence was statistically significant. “When you think that the control group is already getting good care, seeing a difference in the treatment group is actually a very positive signal,” suggested Kivipelto. She said the data bodes well for countries where hypertension is not routinely treated.

It is unclear what led to the reduction in dementia incidence. While the intervention very slightly reduced blood pressure in the overall treatment group by 2.1 mmHg compared to the control group, data on blood pressure for the per-protocol analysis has not been released yet. Richard told Alzforum that this data is being analyzed.

Why did the intervention not work overall? Richard attributes this, at least partly, to high-quality health care in the Netherlands. Other researchers agreed that trying to reduce dementia by improving care in a country that already has top-quality medicine presents a challenge. This is especially true against the backdrop of falling incidence in many developed nations, which may be due to an overall improvement in lifestyle and health, including cardiovascular health (see Apr 2016 news; Feb 2016 news). In fact, Richard said that the new incidence data that has emerged since PreDIVA was designed suggest the trial was underpowered. “We would actually need a much larger sample size to see a difference,” he said.

How does this data inform population-based intervention trials going forward? In an accompanying Lancet commentary, Lon Schneider, University of Southern California, Los Angeles, questioned the value of the population-based approach. “Providing modestly enhanced care to non-selected or non-targeted patients already connected to a medical practice, and identifying and trying to mitigate risk, does not seem to be effective or to reduce overall dementia,” he wrote. He suggested focusing intervention on people at high risk, not the general population.

Richard partially agrees with this. He said biomarkers such as amyloid PET or CSF analytes are a way to select for at-risk people, but are unsuitable for this type of intervention. “Selection should be based on readily obtainable clinical data, such as hypertension or family history,” he said. Schneider agreed, but cautioned that just surveying for undiagnosed high blood pressure and then ensuring it was treated might not necessarily get the same result as in the multi-domain PreDIVA because the context of the therapy is very different. He noted that in a multi-domain trial subjects may also be quitting smoking, or getting diabetes treatment. “If you just treat for hypertension, you might not get similar results,” he said. “We would need to do that kind of trial.” In the Systolic Blood Pressure Intervention Trial (aka SPRINT), treating older adults who are about the same age as those in PreDIVA reduced cardiovascular events such as stroke and heart attack but did not measure any cognitive outcomes (see Williamson et al., 2016).  

Richard has teamed up with Kivipelto and MAPT investigators Bruno Vellas and Sandrine Andrieu at the University of Toulouse to pool PreVIVA, FINGER, and MAPT data. “The goal is to see what we can learn from these trials and to use that going forward,” said Richard. Kivipelto coordinates MIND AD, a multimodal intervention trial based on the FINGER design but targeting people with prodromal AD, i.e., more cognitively impaired than participants in FINGER. It includes sites in Finland, France, Germany, and Sweden. MIND AD begins in September with a six-month pilot study to optimize protocols. The full study will run two years.

Richard, Kivipelto, and the MAPT investigators also collaborate on the Healthy Ageing through Internet Counselling in the Elderly (HATICE) trial, which aims to improve cardiovascular health through interactive Internet counseling. HATICE recruited 2,700 people in Finland, France, and the Netherlands, and will run for 18 months. “This is a very large proof-of-concept trial,” said Richard. “If we can improve cardiovascular risk profiles, which should reduce the risk for cardiovascular diseases and for cognitive decline and dementia, then we will have to test in a much larger study to see if it can lead to prevention,” he said. He believes it will be feasible to do this on a very large scale because volunteers will not need to come to a research clinic so long as they have an Internet connection. “It’s the next step in the pragmatic design of implementable interventions,” he said.—Tom Fagan

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References

News Citations

1. Health Interventions Boost Cognition—But Do They Delay Dementia? 27 Nov 2015
2. Dementia Incidence in Britain Dropped, Mostly in Men 21 Apr 2016
3. Falling Dementia Rates in U.S. and Europe Sharpen Focus on Lifestyle 12 Feb 2016

Paper Citations

1. Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, Fine LJ, Haley WE, Hawfield AT, Ix JH, Kitzman DW, Kostis JB, Krousel-Wood MA, Launer LJ, Oparil S, Rodriguez CJ, Roumie CL, Shorr RI, Sink KM, Wadley VG, Whelton PK, Whittle J, Woolard NF, Wright JT Jr, Pajewski NM, SPRINT Research Group. Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial. JAMA. 2016 Jun 28;315(24):2673-82. PubMed.

External Citations

1. MIND AD
2. HATICE

Further Reading

No Available Further Reading