NIH/NIA – Clinical Trial on Effects of Statins in Older Adults without Clinical Cardiovascular Disease (U19 Clinical Trial Required)

August 13, 2018 by School of Medicine Webmaster

Although statins have been shown to be effective in preventing cardiovascular events in persons with existing cardiovascular disease (CVD) and in persons up to age 75 who are free of CVD, there is significant uncertainty about the risks and benefits of statin treatment in adults over age 75 without CVD, especially those with common age-related conditions (multimorbidity, cognitive and physical decline, and polypharmacy). The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on the Treatment of Blood Cholesterol indicate that there are few data to assess the benefits and risks of statins therapy in individuals over age 75 without CVD. In its 2016 report, the US Preventive Services Task Force agrees with this assessment: “…the current evidence is insufficient to assess the balance of benefits and harms of initiating statin use in adults 76 years and older.” Both the ACC/AHA and the US Preventive Services Task Force list randomized trials to assess the overall benefits and risks of statins in adults over 75 years of age without clinical CVD as a high-priority research area.

Issues regarding statin use in persons over 75 years without clinical cardiovascular diseases, and the possible value of one or more clinical trials to address these issues, were discussed in detail at the NIA-sponsored workshop “Opportunities for Trials on Effects of Statins in Primary Prevention in Older Adults” in August 2017. Workshop participants included experts in geriatrics, cardiology, pharmacology, biostatistics, and related fields. Several other federal agencies were represented, including the Veterans’ Administration, National Cancer Institute and National Heart, Lung and Blood Institute (NHLBI). The review of data presented at the workshop indicated that existing evidence is not sufficient to inform administration of statins to adults 75 years of age and older without clinical cardiovascular disease.

Results of several meta-analyses of randomized controlled trials show that statin therapy is associated with significant reduction in the risk of major incident CVD events in persons over 70 years of age. However, trials informing these meta-analyses did not enroll significant numbers of participants aged over 75 (the mean age of patients included in the meta-analyses was approximately 74 years), and rarely included those older than 80 years. Given the relationship between elevated serum LDL cholesterol and incident CVD risk declines with advancing age, questions remain regarding the size of potential incident CVD risk reduction with statin therapy, if any, at these older ages. In these older age groups, the most common CVD event will likely be heart failure. The majority of these heart failure cases will likely be non-reduced ejection fraction type. Compared to the prevention of myocardial infarction, there is little clinical trial evidence regarding the primary prevention of preserved ejection fraction heart failure in any age group. Furthermore, none of the statin trials on CVD outcomes were sufficiently powered to assess the effects of statins on other important outcomes for older adults such as dementia, functional status, quality of life, incident diabetes or adverse muscular effects. Finally, one of the most important limitations of the existing statins’ trials is that elderly who were enrolled in these trials differ markedly from ‘real world’ older patients, who often have some physical and cognitive challenges, multiple chronic conditions and take numerous medications, and are seen daily in physicians’ clinical practices.

Based on data from primarily younger persons on statins’ cardiovascular effects, it has been estimated that statin therapy in adults over age 75 without clinical cardiovascular disease could prevent large numbers of cardiovascular events. However, a small to moderate increase in risk for disability or cognitive impairment could offset these cardiovascular benefits. Cardiac biomarkers have predicted the absolute magnitude of cardiovascular benefit from statins and cardiovascular risk in older individuals, and therefore possibly could identify subgroups with superior benefit to harm ratios. Additionally, there remains significant uncertainty about the extent and severity of statin-associated muscle symptoms and how they affect muscle strength, physical activity, performance, and falls in persons age 75 and above.

Data regarding the potential cognitive benefits and risks of statins in older adults is also inconclusive. A recent systematic review and meta-analysis of cognitive test data from clinical trials shows no significant adverse effects of statins on all tests of cognition in either cognitively normal participants or those with Alzheimer’s disease despite post-marketing report of statin-related impaired cognition. A Cochrane Review published in 2016 found no evidence that statins given late in life to people at risk for vascular disease prevents cognitive decline or dementia. It is important to note that those at high risk for cognitive impairment, including the very elderly, were not included in significant numbers in these clinical trials assessing the potential effect of statins on incident and/or worsening dementia.

Given that increased age, comorbidities and functional limitations are strong risk factors for side effects, older adults’ life expectancy could be substantially shorter than the time to benefit for a preventive intervention. Thus, administration of statins may expose participants to immediate risks with little likelihood of them surviving long enough to benefit from treatment. A related issue is the persistence of statins’ benefits and under what conditions might statins continue to reduce risk after stopping therapy. In one clinical trial, adherence to treatment as measured by LDL reductions declined after the first year, but statin’s beneficial effect increased over time in that incident CVD risk reduction remained significantly lower for five years. This phenomenon raises the question about maintenance of statin therapy in the very old, e.g., whether nonagenarians, or those with a limited life expectancy, who take statins need to continue to do so, particularly in light of the fact that their physiologic status may have changed markedly since they began taking statins, resulting in a higher risk versus benefit ratio.

In summer 2017, participants in NIA’s workshop “Opportunities for Trials on Effects of Statins in Primary Prevention in Older Adults” concluded that limited data exist on comprehensive clinical and patient-centered outcomes (e.g., functional status, independence, quality of life, statin-related symptoms) in persons aged 75 years and older to evaluate the net benefit or harm in this population among existing studies. Given the increasing population aged 75 years and older, there is a critical need for a clinical trial of statin therapy in ‘real world’ older adults without known cardiovascular disease, incorporating outcomes of clinical and patient relevance. These trials are necessary to best inform decisions on initiation of statin treatment in older patients, taking into account risks, comorbidities, and preferences to provide optimal patient-oriented care.

Scope of Research Requested

NIA, NHLBI and NINDS request applications for a pragmatic trial from a network or consortium of health care delivery systems (HCS), which together cover most of the geographic regions of the United States, and a data coordinating center to assess the overall risks and benefits of statins in adults ≥ 75 years without clinical cardiovascular disease. Specifically, the proposed trial should be designed to:

  • Be conducted in a real-life healthcare delivery system setting (see “Introduction to pragmatic clinical trials” and “Rethinking Clinical Trials: A Living Textbook of Pragmatic Trials“).
  • Have broad inclusion criteria and use minimization, stratification or another technique to ensure enrollment of a high number of women, minorities, participants with frailty, mobility limitations, cognitive impairment, comorbidities and very old adults.
  • Test the effects of moderate- to high-intensity statin (legally marketed in the US and approved by the FDA) vs placebo administered for up to five years in a blinded fashion by the health care providers (members of the HCS participating in the trial).
  • Test the effects of interventions on the universal primary health outcome of survival free of dementia and persistent physical disability.
  • Test the effects of interventions on a secondary composite cardiovascular outcome. The secondary composite cardiovascular outcome should include acute myocardial infarction, stroke, and heart failure and may include other cardiovascular components such as to death attributed to cardiovascular disease, urgent revascularization, and acute coronary syndrome requiring hospitalization. Characterization of the type of heart failure as well as stroke subtype should be considered.
  • Assess the effects of interventions on exploratory outcomes, including but not limited to health-related quality of life, muscle-related symptoms, incident diabetes, hospitalization for any cause, medication adherence, and major sources of health care resource utilization.
  • Ascertain the outcomes in a cost-efficient manner with a high degree of accuracy.
  • Have sufficient power to assess the effects of interventions with high degree of confidence. The applicants are strongly encouraged to propose a trial that has a 90% power to assess the effects of interventions on both primary and secondary outcomes. Sample size calculations should be designed to accommodate high crossover rates between study treatment groups.
  • Obtain biological samples so that analysis of biomarkers predictive of harms and benefits is feasible in the future.
  • Periodically obtain sufficient number of biological samples to assess the difference in the serum LDL-cholesterol levels between the two trial arms.
  • Include pre-specified analyses with adequate power to assess treatment risks and benefits in important subgroups (e.g., men/women, older/younger, differing baseline health status, differing ethnicity).

Deadline:  November 17, 2018 (letters of intent); December 17, 2018 (full proposals)


Filed Under: Funding Opportunities