The Elderly on Primary-Prevention Statins: No Survival Gains in ALLHAT-LLT

Fran Lowry

May 23, 2017

CHICAGO, IL — Statins for primary prevention do not lower the risk of death, whether cardiovascular or from any cause, when given to people aged 65 years or older with CV risk factors, suggests a secondary analysis of a major trial that caused a stir 15 years ago[1].

The ALLHAT-LLT trial had randomized >10,000 people aged >55 with dyslipidemia and hypertension but no clinical heart disease to receive open-label pravastatin 40 mg/day or usual care. In its 2002 publication[2], the trial famously saw no significant mortality reduction for the statin after 6 years, nor an improvement in fatal or nonfatal coronary heart disease events. 

The results were similar in the new post hoc analysis of the trial focusing on the 2867 participants aged 65 years and older, as a whole and by the two age groups 65 to 74 years and >75 years, according to a report published May 22, 2017 in JAMA Internal Medicine with lead author Dr Benjamin H Han (New York University Langone School of Medicine, NY).

Although no significant outcomes differences were seen between the two randomized groups in any of the age categories, there was a trend (P=0.07) for increased all-cause mortality on the statin in the oldest age group.

As Han pointed out for heartwire from Medscape, the overall trial had well-recognized limitations. For example, the statin was given on an open-label basis. Also, it has been long noted that the ALLHAT-LLT usual-care group could receive statins at the physicians' discretion, which could potentially blur any differences in treatment outcomes.

Calls for Caution

"I would be very cautious in drawing any real conclusions from this study, as the study was not specifically designed to study statins in older adults, so all of the analyses are underpowered. None of their major conclusions were statistically significant," according to Dr Ann Marie Navar (Duke Clinical Research Institute, Durham, NC), who isn't connected with the ALLHAT-LLT report.

"Most statin trials have shown no difference in mortality, but [they showed] that statins do reduce the risk of coronary heart disease, a trend also seen in this secondary analysis," Navar told heartwire by email.

"The trend toward increasing mortality is certainly provocative but really needs to be explored in a trial specifically designed to test this issue." 

The post hoc analysis included 1467 participants who had been randomized to pravastatin; their mean age was 71.3, and 48% were women. Their mean LDL-C level was 147.7 mg/dL at baseline and 109.1 mg/dL after 6 years.

The 1400 participants in the usual-care group had a mean age of 71.2 years, and 51% were female. Their mean LDL-C level was 147.6 mg/dL at baseline and 128.8 mg/dL after 6 years.

For all patients over the age of 65 who took pravastatin, the hazard ratio for all-cause mortality was 1.18 (95% CI 0.97–1.42, P=0.09) compared with the usual-care group. It was 1.08 (95% CI 0.85–1.37, P=0.55) for the 65–74 group and 1.34 (95% CI 0.98-1.84 P=0.07) for those aged 75 and older. Nor were there significant HRs for the secondary CHD end points.

In multivariate analysis, the corresponding HRs were 1.15 (95% CI 0.94–1.39) for 65 and older, 1.05 (95% CI 0.82–1.33) for those 65 to 74, and 1.36 (95% CI, 0.98-1.89) for 75 and older. The prospectively defined covariates included age, sex, race/ethnicity, primary-prevention aspirin use, smoking history, type 2 diabetes, body mass index, and systolic and diastolic blood pressures.

The Issues

"We are seeing a lot more older adults being put on statins for primary prevention, but the problem is, the evidence for doing so is limited," Han said.

"As geriatricians, we emphasize that treatment recommendations really need to be individualized with patients and need to also take into account not just what their cardiovascular risk is, but what their life expectancy is, what other competing risks they may have, and what their functional status and everyday activities are," Han observed.

Moreover, "for older adults, taking another medicine every day for the rest of your life isn't a small thing, especially if you have other chronic conditions, and right now we don't have any evidence that there's any benefit to doing so if you do not have any history of cardiovascular disease."

An editor's note accompanying the ALLHAT-LLC report points out the potential risks of extending statins to groups that may be unlikely to benefit clinically[3]. For example, statin therapy may be associated with myopathy, myalgias, muscle weakness, and arthropathies, notes Dr Gregory Curfman (Harvard Medical School, Boston, MA).

"These disorders may be particularly problematic in older people and may contribute to physical deconditioning and frailty. Statins have also been associated with cognitive dysfunction, which may further contribute to reduced functional status, risk of falls, and disability," he writes.

"The combination of these multiple risks and the ALLHAT-LLT data showing that statin therapy in older adults may be associated with an increased mortality rate should be considered before prescribing or continuing statins for patients in this age category."

Is There a "Point of No Return"?

"It takes decades for the plaque to build up in the arteries that eventually causes strokes and heart attacks. Data from thousands of adults studied in clinical trials show us that statins, when started early, can interrupt or slow down that process," according to Navar.

But, "we don't know if there is a 'point of no return' where it's too late to start a statin, and ALLHAT was not designed to answer that question. We need a large randomized trial to really know how effective statins are when started in older adults without cardiovascular disease," she said.

"There is a lot of negative press about statins, and I really worry about the effect of studies like these on the public's perception. This study was a secondary analysis of a trial that was not designed to study the effect of statins in older adults," Navar observed.

"Data from thousands of adults in multiple randomized trials have shown that statins prevent heart disease and do not kill people. I hope that the media, in the never-ending search for clickbait, doesn't overemphasize the statistically nonsignificant mortality trend and lead people who are known to benefit to discontinue their statins."

The study was funded by the National Heart Lung & Blood Institute. Study medications were contributed by Pfizer, AstraZeneca, and Bristol-Myers Squibb, and financial support was provided by Pfizer. The study authors and Curfman report no relevant financial relationships. Navar reported research support from the National Institutes of Health, Amgen, and Sanofi & Regeneron Pharmaceuticals and serving as a consultant for Amgen and Sanofi.

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