Alzheimer's Disease Anti-inflammatory Prevention Trial Research Articles

Precision Medicine for Preventing Alzheimer's Disease: Analysis of the ADAPT Study.

The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was the first-ever large-scale anti-inflammatory prevention trial targeting Alzheimer's disease. The overall goal of this study was to evaluate predictive blood biomarker profiles that identified individuals most likely to be responders on NSAID treatment or placebo at 12 and 24 months. Baseline (n = 193) and 12-month (n = 562) plasma samples were assayed. The predictive biomarker profile was generated using SVM analyses with response on treatment (yes/no) as the outcome variable. Baseline (AUC = 0.99) and 12-month (AUC = 0.99) predictive biomarker profiles were highly accurate in predicting response on Celecoxib arm at 12 and 24 months. The baseline (AUC = 0.95) and 12-month (AUC = 0.9) predictive biomarker profile predicting response on Naproxen were also highly accurate at 12 and 24 months. The baseline (AUC = 0.93) and 12-month (AUC = 0.99) predictive biomarker profile was also highly accurate in predicting response on placebo. As with our prior work, the profiles varied by treatment arm. The current results provide additional support for a precision medicine model for treating and preventing Alzheimer's disease.

Follow-up evaluation of cognitive function in the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial and its Follow-up Study

ObjectiveThe Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) and Follow-up Study (ADAPT-FS) examined effects of naproxen and celecoxib on cognition in the elderly. We report here results describing trajectories of cognitive evaluation test scores. MethodsA total of 2356 participants completed baseline and at least one follow-up cognitive evaluation between 2001 and 2004. Study treatments were discontinued in 2004, but participants were followed until 2007. A total of 1537 participants were reevaluated in 2010 to 2011. Outcomes include seven cognitive evaluations administered yearly in person in ADAPT and three of these evaluations that were administered by telephone near the end of ADAPT and again in ADAPT-FS. ResultsThere were no important differences over time by treatment group on any ADAPT cognitive measure, a global composite, or the three cognitive measures reassessed in ADAPT-FS by telephone. ConclusionsTreatment for 1 to 3 years with naproxen or celecoxib did not protect against cognitive decline in older adults with a family history of AD.

Results of a follow-up study to the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT)

ObjectivesThe Alzheimer's Disease Anti-inflammatory Prevention Trial Follow-up Study (ADAPT-FS) was designed to evaluate the efficacy of naproxen and celecoxib for the primary prevention of Alzheimer's disease (AD) several years after cessation of treatment in ADAPT. MethodsADAPT was a randomized, double-masked, multicenter clinical trial of naproxen or celecoxib vs placebo (1:1:1.5 assignment ratio) at six U.S.-based clinics. The trial enrolled 2528 people between 2001 and 2004. Treatments were discontinued in December 2004 and participants were monitored regularly until 2007. In 2010 and 2011, ADAPT-FS screened 1537 participants by telephone and, if indicated, examined them in person using standardized clinical assessments. The primary outcome was time to diagnosis of AD. Death index searches were performed for participants not located. ResultsEighty-nine additional AD events were identified (24 celecoxib, 25 naproxen, and 40 placebo) yielding a total of 161 events (48 [6.6% of randomized participants] celecoxib, 43 [6.0%] naproxen, and 70 [6.5%] placebo) across ADAPT and ADAPT-FS. Adjusted hazard ratios (HRs) comparing each treatment with placebo showed no overall reduction in risk of AD: HR celecoxib vs placebo, 1.03 (95% confidence interval [CI], 0.72–1.50; P = .86); HR naproxen vs placebo, 0.92 (95% CI, 0.62–1.35; P = .66). There were 349 deaths (110 [15.2%] celecoxib, 96 [13.4%] naproxen, and 143 [13.2%] placebo). Risk of death was similar for the naproxen- and placebo-assigned groups (HR, 0.99; 95% CI, 0.76–1.28; P = .93) and slightly higher for celecoxib compared with the placebo-assigned group (HR, 1.15; 95% CI, 0.90–1.48; P = .27). ConclusionsThese results acquired during a follow-up of approximately 7 years (which included a median of less than 1.5 years of treatment) do not support the hypothesis that celecoxib or naproxen prevent AD in adults with a family history of dementia.

Trajectories of Preparation for Future Care Among First-Degree Relatives of Alzheimer's Disease Patients: An Ancillary Study of ADAPT

This study examines the longitudinal patterns of Preparation for Future Care (PFC), defined as Awareness, Avoidance, Gathering Information, Decision Making, and Concrete Plans, in first-degree relatives of people with Alzheimer's disease (AD). Eight time points across 6.5 years from a subsample of adults aged 70 years and older who were participating in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) were analyzed using latent growth modeling. Baseline attitudes toward planning for future care and demographic variables functioned as predictors in the conditional analyses. Awareness, Gathering Information, Decision Making, and Concrete Planning increased across time, but Avoidance did not. Covariates were more often associated with the initial levels of planning behavior than with change across time. Women engaged in more initial Decision Making than men. Education was associated with more initial Gathering Information, Decision Making, and less Avoidance. Favorable attitudes toward planning were more predictive of baseline Awareness, Gathering Information, Avoidance, and less so for Decision Making or Concrete Planning. Older adults with an elevated risk for AD increase in positive PFC behaviors gradually across time. Demographic characteristics and attitudes predict initial levels of planning, making it possible to identify individuals who might need help progressing to more advanced levels of planning. Future studies are needed to understand rates of change in planning behaviors.

Extended results of the Alzheimer's disease anti‐inflammatory prevention trial

Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2,528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ(1-42.) Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairment--no dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B2 (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F2-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F2-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F2-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older.

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Alzheimer's Disease Anti-Inflammatory Prevention Trial: Design, methods, and baseline results

Background The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was designed to address whether non-steroidal anti-inflammatory drugs (NSAIDs) can prevent or delay the onset of Alzheimer's disease (AD). Methods ADAPT was a randomized, double-placebo-controlled, multicenter chemoprevention trial conducted at six U.S. dementia research clinics. At entry, participants were required to test “normal” on a battery of cognitive tests and to be age 70+ with a family history of Alzheimer-like dementia. Persons were randomly assigned to 200 mg b.i.d. celecoxib (Celebrex, Pfizer), 220 mg b.i.d. naproxen sodium (Aleve, Bayer), or placebo. The primary outcome measure was AD. Secondary outcome measures were cognitive decline and measures related to safety of the treatments when used long term. ADAPT was designed to detect a 30% reduction in AD incidence with 80% power. The estimated sample size requirement was 2,625. Results Enrollment began in March 2001 and ended in December 2004 when treatments were suspended because of concerns regarding cardiovascular safety of the treatments. Followup ranged from 1 to 46 months. The achieved enrollment was 2,528. Recruitment was achieved primarily via mailings to people aged 70+ living in the catchment areas of the six field sites.

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Large Studies Provide Clues to Alzheimer's Risk, Prevention

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessLarge Studies Provide Clues to Alzheimer's Risk, PreventionJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:4 Jul 2008https://doi.org/10.1176/pn.43.13.0018aIn 1994 some 1,000 older Catholic priests, nuns, and brothers signed up for a mission that had nothing to do with saving souls but plenty to do with saving minds.The mission, headed by David Bennett, M.D., director of the Rush University Alzheimer's Disease Center, was called the Rush Religious Orders Study. Subjects were evaluated medically, neurologically, cognitively, and psychologically, both at the start of the study and annually thereafter. Differences between those who develop Alzheimer's and those who do not are being analyzed to identify factors that might predict subsequent susceptibility to Alzheimer's.During the past few years, the study has identified several putative Alzheimer's risk factors. One is rapidly progressing Parkinson's disease (Psychiatric News, June 20, 2003). Another is an enduring tendency to experience negative emotions (Psychiatric News, July 20, 2007). yet a third is depression.And now still more results from the study, published in the April Archives of General Psychiatry, go a step further by suggesting that depression is truly a risk factor for Alzheimer's and not the result of the disease itself.In this phase of the study, 917 subjects without Alzheimer's were evaluated annually for 13 years to determine both whether they were depressed and whether they might be developing Alzheimer's. Of the 917 subjects, 190 developed the illness during this time span. Consistent with earlier findings in this cohort, having more depressive symptoms at the start of the study was linked with an increased risk of developing Alzheimer's. However, Bennett and his coworkers did not find that the subjects who developed Alzheimer's experienced an increase in depressive symptoms during the four years or so leading up to the onset of their Alzheimer's. So depressive symptoms indeed seem to be a risk factor for Alzheimer's rather than an early sign of its pathological process, Bennett and his colleagues concluded.Yet if, as these data imply, depressive symptoms are a risk factor for Alzheimer's, how might they be contributing to the risk? Since major depression has been linked with brain atrophy, such atrophy in turn might make the brain more susceptible to Alzheimer's, Bennett and his team speculated. Understanding the means by which depression preps the brain for Alzheimer's might lead to some way of preventing Alzheimer's, they suggested.Meanwhile, two other groups of scientists have been looking into whether nonsteroidal anti-inflammatory drugs (NSAIDs) might do so.In the first study, Steven Vlad, M.D., of Boston University and coworkers evaluated prescription NSAID use by some 49,000 veterans who had developed Alzheimer's and by some 197,000 veterans who had not. The NSAID classes assessed included arylpropionic acids such as ibuprofen or naproxen, enolic acids such as piroxicam, COX-2 inhibitors such as celecoxib, nonacetylated salicylates such as salsalate, and high-dose aspirin.The researchers found that the odds of developing Alzheimer's decreased with longer NSAID use. Compared with persons not using NSAIDs, the odds of getting Alzheimer's decreased from 0.98 among those with use for one year or less to 0.76 for those using NSAIDs for more than five years. However, the researchers found that the protective effect did not seem to be identical for each NSAID. Some, such as ibuprofen, showed clear protective effects; others, such as the COX-2 inhibitors, did not, and in yet others the effect on Alzheimer's risk was unclear. The results appeared in the May 6 Neurology.In the second study, Barbara Martin, Ph.D., of Johns Hopkins University and her colleagues allocated some 2,100 subjects aged 70 years or older and with a family history of Alzheimer's to one of three treatment arms—200 mg of celecoxib twice daily, 220 mg of naproxen twice daily, or a placebo. The researchers followed the subjects for three years to see whether those getting either celecoxib or naproxen were better protected against Alzheimer's than those getting a placebo.The answer was no, the researchers found. In fact, there was weak evidence that the cognitive function of the naproxen group was inferior to that of the placebo group. Thus, neither celecoxib nor naproxen appears to shield people against Alzheimer's, Martin and her group concluded in their study report, which was posted May 12 on the Archives of Neurology Web site.All three studies were financed by the National Institutes of Health.An abstract of “Change in Depressive Symptoms During the Prodromal Phase of Alzheimer Disease” is posted at<http://archpsyc.ama-assn.org/cgi/content/abstract/65/4/439>. An abstract of “Protective Effects of NSAIDs on the Development of Alzheimer Disease” is posted at<www.neurology.org/cgi/content/abstract/70/19/1672>. An abstract of “Cognitive Function Over Time in the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT)” is posted at<http://archneur.ama-assn.org/cgi/content/abstract/2008.65.7.nct70006v1>.▪ ISSUES NewArchived

O2-01-02: Onset of Alzheimer's dementia occurs commonly without prior cognitive impairment: Results from the Alzheimer's disease anti-inflammatory prevention trial (ADAPT)

O2-01-02: Onset of Alzheimer's dementia occurs commonly without prior cognitive impairment: Results from the Alzheimer's disease anti-inflammatory prevention trial (ADAPT)

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ADAPT: The Wrong Way to Stop a Clinical Trial

In an accompanying article published in PLoS Clinical Trials, the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) Research Group report the cardiovascular outcomes from their study [1]. The circumstances surrounding the termination of ADAPT were unusual and provide an important lesson for all clinical trialists, demonstrating the importance of following rigorous procedures for prematurely stopping clinical trials. In this case, stopping the trial before its intended completion resulted in data that cannot be reliably interpreted. On September 30, 2004, Merck withdrew rofecoxib (Vioxx) from the market after the trial's data safety and monitoring board (DSMB) recommended termination of a placebo-controlled study of this agent in the prevention of colon polyps [2]. The reason for study termination was a statistically significant increase in adverse cardiovascular outcomes. On December 17, 2004, Pfizer announced that termination of a trial of celecoxib (Celebrex) in colon polyp prevention, because it also showed statistically significant evidence for increased cardiovascular event rates [3]. The results of these two trials were subsequently published in February 2005 in the New England Journal of Medicine [4,5]. The revelations about increased cardiovascular events with these “coxibs” generated enormous public attention and concern. However, in both cases, the decision-making leading to trial discontinuation was handled appropriately through the regular reviews conducted by an independent DSMB. Three days following the announcement of the termination of the celecoxib colon polyp prevention study, the National Institute of Health (NIH), issued a press release entitled “Use of Non-Steroid Anti-Inflammatory Drugs Suspended in Large Alzheimer's Disease Prevention Trial” [6]. The NIH press release stated that “data from the ADAPT trial indicated an apparent increase in cardiovascular and cerebrovascular events among participants taking naproxen when compared to placebo.” In the press release, NIH Director Dr. Elias Zerhouni stated that “this step is being taken as a precautionary measure to ensure the safety of the study's participants” and that “the investigators made their decision based on the risk/benefit analysis specific to this trial.” Shortly following the NIH announcement, the Food and Drug Administration (FDA) issued a public statement that “based on emerging information from a long-term prevention trial, the risk of cardiovascular and cerebrovascular events may increase among patients taking naproxen” [7]. These announcements generated front-page headlines such as “Heart Risk Seen in Naproxen” (Wall Street Journal), “Tough Choice: Pain or Risk” (USA Today), and “Patients, Doctors Agonize over Risks of Painkiller (Los Angeles Times) [8]. Occurring immediately following the revelations about rofecoxib and celecoxib, the naproxen announcement generated considerable public apprehension [8]. Physicians received many urgent calls from worried patients. However, there was a major problem with the naproxen warning: it was not based upon the application of standard procedures for stopping an ongoing clinical trial. During the subsequent FDA hearings to set policy on nonsteroidal anti-inflammatory agents (NSAIDs) and COX-2 inhibitors, I described the warnings about naproxen as “the medical equivalent of yelling ‘fire' in a crowded auditorium” [9].

Cardiovascular and Cerebrovascular Events in the Randomized, Controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT)

Objectives:The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was designed to evaluate the conventional NSAID naproxen sodium and the selective COX-2 inhibitor celecoxib for primary prevention of Alzheimer's dementia (AD). On 17 December 2004, after the Adenoma Prevention with Celecoxib (APC) trial reported increased cardiovascular risks with celecoxib, the ADAPT Steering Committee suspended treatment and enrollment. This paper reports on cardiovascular and cerebrovascular events in ADAPT.Design:ADAPT is a randomized, placebo-controlled, parallel chemoprevention trial with 1–46 mo of follow-up.Setting:The trial was conducted at six field sites in the United States: Baltimore, Maryland; Boston, Massachusetts; Rochester, New York; Seattle, Washington; Sun City, Arizona; and Tampa, Florida.Participants:The 2,528 participants were aged 70 y and older with a family history of AD.Interventions:Study treatments were celecoxib (200 mg b.i.d.), naproxen sodium (220 mg b.i.d.), and placebo.Outcome measures:Outcome measures were deaths, along with nonfatal myocardial infarction (MI), stroke, congestive heart failure (CHF), transient ischemic attack (TIA), and antihypertensive treatment recorded from structured interviews at scheduled intervals. Cox proportional hazards regression was used to analyze these events individually and in several composites.Results:Counts (with 3-y incidence) of participants who experienced cardiovascular or cerebrovascular death, MI, stroke, CHF, or TIA in the celecoxib-, naproxen-, and placebo-treated groups were 28/717 (5.54%), 40/713 (8.25%), and 37/1070 (5.68%), respectively. This yielded a hazard ratio (95% confidence interval [CI]) for celecoxib of 1.10 (0.67–1.79) and for naproxen of 1.63 (1.04–2.55). Antihypertensive treatment was initiated in 160/440 (47.43%), 147/427 (45.00%), and 164/644 (34.08%). This yielded hazard ratios (CIs) of 1.56 for celecoxib (1.26–1.94) and 1.40 for naproxen (1.12–1.75).Conclusions:For celecoxib, ADAPT data do not show the same level of risk as those of the APC trial. The data for naproxen, although not definitive, are suggestive of increased cardiovascular and cerebrovascular risk.

Primary prevention trials in Alzheimer disease

Many new treatments under development for Alzheimer disease (AD) will be disease-modifying rather than symptomatic. Clinical evaluation of these treatments will require primary and secondary prevention trials. We describe some of the methodologic challenges in designing primary prevention trials for AD and illustrate these with examples from the ADAPT (Alzheimer Disease Anti-Inflammatory Prevention Trial) Study and GEM (Ginkgo in Evaluation of Memory) Study. Primary prevention trials for AD present many design challenges. In most situations, secondary prevention trials provide the most feasible first step toward primary prevention.

The Cardiovascular Toxicity of Selective and Nonselective Cyclooxygenase Inhibitors: Comparisons, Contrasts, and Aspirin Confounding

The premature suspension of the Alzheimer Disease Anti-inflammatory Prevention (ADAPT) and the Adenoma Prevention with Celecoxib (APC) trials prompted intense review of the cardiovascular safety profile of selective and nonselective cyclooxygenase (COX) inhibitors. This article reviews the current state of selective COX-2 inhibitors, discusses the mechanistic evidence underlying the cardiovascular risk associated with selective COX-2 inhibition, outlines the pharmacodynamics of aspirin effects on platelets and the interference of propionic acid derivatives (ibuprofen and naproxen) with these effects, and poses that aspirin confounding may have led to the erroneous conclusion of naproxen-associated adverse cardiovascular outcomes in the ADAPT trial. Finally, recommendations regarding selective COX-2 inhibitors and appropriate timing of aspirin coadministration with traditional NSAIDs are proposed in relevance to patient safety and future trial design.

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Double placebo design in a prevention trial for Alzheimer's disease

The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) is designed to compare two nonsteroidal anti-inflammatory agents against placebo. A placebo control for two active treatments can be achieved in several ways, each of which may have different implications for the logistics of drug supply, enrollment, adherence to treatment, and the validity of specific treatment comparisons. The authors outline the placebo designs considered in ADAPT, discuss their advantages and disadvantages, and provide their rationale for and the consequences of the selection of the double placebo design.