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Time to benefit

The evidence base

A preventive medication does not work on the day it is taken. It works over years, by shifting the odds of an event that would have happened later. If the person taking it does not have those years, the arithmetic changes — and so does the answer.

The idea

Time to benefit is the interval a treatment needs before enough events have been prevented for the benefit to be measurable. It is a property of the drug and the population, not of the individual — but it becomes an individual question the moment someone’s expected remaining life is shorter than it.

This is what STOPPFrail exists for: deprescribing criteria for older adults with limited life expectancy who are approaching the end of life, where a preventive drug’s time to benefit can exceed the years available to benefit from it.

The statin numbers

The clearest published figures are for statins in primary prevention. A survival meta-analysis of eight randomized primary-prevention trials covering 65,383 adults, mean ages 55 to 69, with mean follow-up of two to six years, estimated:

  • 2.5 years (95% CI 1.7 to 3.4) to prevent one major adverse cardiovascular event per 100 patients treated.
  • 1.3 years (95% CI 1.0 to 1.7) per 200 treated.
  • 0.8 years (95% CI 0.5 to 1.0) per 500 treated.

Two things must travel with those numbers. First, the analysis covers ages 50 to 75 — applying the 2.5-year figure to a 90-year-old is an extrapolation and should be named as one. Second, and more importantly: only one of the eight studies showed that statins decreased all-cause mortality, and the authors state plainly, “There is no evidence of a mortality benefit.”

A different way to express the same thing

A meta-analysis of 16 randomized statin trials modeled the average postponement of death attributable to treatment within trial follow-up at 12.6 days (95% postponement interval 7.1 to 18.0) — 10.2 days in primary prevention and 17.4 days in secondary prevention. The authors proposed this framing specifically because it is more intuitive than relative risk reduction.

It is also easy to misuse. That figure is postponement achieved within roughly two to six years of trial follow-up. It is not a lifetime estimate, and “statins only add 12 days to your life” would misrepresent the paper.

Where time to benefit is decisive

The one randomized trial that tested statin discontinuation in this situation enrolled 381 adults with an estimated life expectancy between one month and one year, on a statin for at least three months, with recent deterioration in functional status and no recent active cardiovascular disease. Mean age was 74.1; 48.8% had cancer and 22.0% were cognitively impaired.

Death within 60 days occurred in 23.8% of those who stopped and 20.3% of those who continued (90% CI for the difference −3.5% to 10.5%, p = 0.36). The trial did not meet its noninferiority endpoint and should not be described as having proven noninferiority. Quality of life was better in the discontinuation group (mean McGill score 7.11 versus 6.85, p = 0.04), and cardiovascular events were few in both arms — 13 versus 11. The authors concluded that stopping “is safe and may be associated with benefits including improved QOL, use of fewer nonstatin medications,” and called for “thoughtful patient-provider discussions regarding the uncertain benefit.”

The population these questions matter most for

Applying STOPPFrail to 464 applications for long-term nursing care found 274 (64.3%) eligible, median age 83, of whom 250 (91.2%) had at least one potentially inappropriate medication. The three most common categories were medications without a clear indication (47.0%), long-term high-dose proton pump inhibitors (31.4%) and statins (29.6%).

How to use this without turning it into a rule

Time to benefit is a way of framing a conversation, not a threshold that triggers an action. Life expectancy estimates in individuals are imprecise, and being wrong about one in the pessimistic direction has consequences. The honest use is the one the trial authors themselves proposed: a prompt for a discussion about whether a particular preventive medication is still serving this particular person’s goals.

Before you read on

Never stop or change a prescribed medication without speaking to your own prescriber. Several of the classes described on this site rebound, or cause a withdrawal syndrome, when they are stopped abruptly, and some have to be reduced gradually over weeks or months under supervision. Nothing here is advice about your own medication, and nothing here is a reason to change anything on your own.

Common questions

Should someone with a short life expectancy stop their preventive medications?

That is a conversation with their own prescriber, informed by what the drug is for, how long it takes to help, and what the person wants. The one randomized trial in this situation found stopping a statin did not increase 60-day mortality and was associated with slightly better quality of life — but it did not meet its noninferiority endpoint, and it studied a specific population with a stated prognosis. Statins in the very old.

Does time to benefit apply to all medications?

It applies to preventive ones — treatments given now to avoid an event later. It does not apply to symptom control. A drug relieving pain, breathlessness or agitation works today and its value does not depend on prognosis at all. Confusing the two categories is how time-to-benefit reasoning gets misapplied. Reducing medication burden.

Back to the evidence base.

References

  1. Yourman LC, Cenzer IS, Boscardin WJ, et al. Evaluation of Time to Benefit of Statins for the Primary Prevention of Cardiovascular Events in Adults Aged 50 to 75 Years: A Meta-analysis. JAMA Internal Medicine. 2021;181(2):179–185. PMID 33196766 · DOI 10.1001/jamainternmed.2020.6084.
  2. Hansen MR, Hróbjartsson A, Pottegård A, et al. Postponement of Death by Statin Use: a Systematic Review and Meta-analysis of Randomized Clinical Trials. Journal of General Internal Medicine. 2019;34(8):1607–1614. PMID 31073857 · DOI 10.1007/s11606-019-05024-4.
  3. Kutner JS, Blatchford PJ, Taylor DH, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA Internal Medicine. 2015;175(5):691–700. PMID 25798575 · DOI 10.1001/jamainternmed.2015.0289.
  4. Curtin D, Gallagher P, O’Mahony D. Deprescribing in older people approaching end-of-life: development and validation of STOPPFrail version 2. Age and Ageing. 2021;50(2):465–471. PMID 32997135 · DOI 10.1093/ageing/afaa159.
  5. Lavan AH, O’Mahony D, Gallagher P. STOPPFrail (Screening Tool of Older Persons’ Prescriptions in Frail adults with a limited life expectancy) criteria: application to a representative population awaiting long-term nursing care. European Journal of Clinical Pharmacology. 2019;75(5):723–731. PMID 30685856 · DOI 10.1007/s00228-019-02630-3.
  6. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. The Lancet. 2019;393(10170):407–415. PMID 30712900 · DOI 10.1016/S0140-6736(18)31942-1.

Bibliographic records on this page were retrieved from PubMed. Every reference links to its DOI or PubMed record.

Written and medically reviewed by Dr. Gurpreet Singh Padda, MD, MBA, MHP, founder and medical director of DWARAA. Last reviewed . This page is educational. DWARAA does not prescribe, deprescribe, diagnose or treat.