[130] Evidence for statins in people over 70

13 Jun 2021 [130] Evidence for statins in people over 70

Therapeutics Letters 48, 49 and 77 summarized the effects of statins in secondary and primary prevention populations studied in randomized controlled trials (RCTs).^1,2,3 This best available evidence comes from RCTs that enrolled mostly men aged 50-70.
There is much less evidence for use of statins after age 70. Yet in 2020 47% of men and 33% of women over 70 in British Columbia took a statin. Over half such prescribing was for primary prevention.⁴ Is this supported by the best available evidence?
In 2019 we updated our general systematic review of statins for secondary prevention.⁵ In people with proven occlusive vascular disease who started treatment at a mean age of 63, statins improve survival. Over a mean of 5 years, the relative risk (RR) of death was 0.93 (95% CI 0.89 – 0.97). This equates to an absolute risk reduction (ARR) of 1.3%, number needed to treat (NNT) 77 for 5 years. Statins also reduced cardiovascular serious adverse events (total coronary and stroke events), RR 0.77 (0.74 – 0.80), ARR 4.4%, NNT 23 for 5 years. Based on this evidence, we recommend that clinicians discuss the evidence and offer statins for adults who have had a cardiovascular event.
For primary prevention (people without proven occlusive vascular disease) statins reduce serious cardiovascular adverse events in a similar age group. The RR of 0.79 (0.75 – 0.84) equates to an ARR of 1.4%, NNT 71 over a mean of 5 years. However, total serious adverse events are not reduced, RR 0.99 (0.97 – 1.02)^1,3. We thus conclude that RCT evidence does not support a net health benefit and do not recommend statins for primary prevention.
Why emphasize serious adverse events?
Serious adverse events (SAE) capture the most important outcomes and must be reported by clinical trialists to regulators. SAE are defined internationally to include any event that is life-threatening, or results in death, hospitalization, disability or permanent damage, congenital anomaly, or other important medical events.⁶ We consider SAE the best overall measure of net health benefit/harm and to be less susceptible to biases arising in clinical studies.
Are statin effects different in people over 70?
A systematic review of all RCT data for statins in people over 70 would be extremely valuable. The Cholesterol Treatment Trialists’ (CTT) Collaboration holds individual patient data from 28 RCTs that randomized 186,854 people (72% men) to statin vs. placebo, or to more vs. less intensive statin therapy, for both primary and secondary prevention. In the CTT database, mean age at randomization was 63 years; 15% of participants were 70 – 75 (mean 73) and 8% over 75 (mean 79). Median follow-up was 4.9 years (range 2 – 7 years).⁷
In 2019 the CTT reported their analysis of results in patients age 70 – 75 and over 75.⁷ The authors concluded that “statin therapy produces significant reductions in major vascular events irrespective of age”, but also that “there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease.”
However, there are at least 6 problems with the way the data are analyzed and reported:

1. The pooled results are adjusted to a “per 1 mM reduction in LDL”. Such an adjustment is not acceptable in a Cochrane review and is not in keeping with how the RCTs were designed. The adjustment to a “per 1 mM reduction in LDL” is based on the unproven assumption that effects are strongly related to LDL reduction. The HPS trial⁸ (mainly secondary prevention) tested that assumption and found it to be false (Table 1).
2. The pooled data include RCTs comparing high-dose to low-dose statins. Limiting the analysis to trials comparing a statin to a placebo is the correct systematic review method.
3. Most data were presented as major vascular events, a composite of cardiovascular serious adverse events (coronary and stroke events) and revascularizations. Revascularizations usually are not serious adverse events (by definition) and may be influenced by loss of blinding bias. They constituted 40% of the composite major vascular events.
4. Mortality (overall survival) was not reported separately for the primary and secondary prevention groups.
5. Statin effects in older men and women were not reported separately.
6. They report no absolute risk reductions or numbers needed to treat, the most relevant information for discussing effectiveness with patients.

Table 1: No association between reduction in LDL (by tertile) and reduction of major vascular events

From HPS RCT simvastatin vs. placebo in 20,563 people⁸ (mainly secondary prevention)
Can absolute benefits/harms be derived from the CTT 2019 report?
It is not possible to extract the data (events and number of people studied) from the CTT report⁷ and independent verification of the full CTT dataset has not been possible.^9-13 However, we were able to derive best estimates of the RR and ARR in people over 70 so that we could compare them with our data from previous Therapeutics Letters. Table 2 shows that the only proven benefit of statins in people over 70 is a reduction in major vascular events for secondary prevention. When this benefit is converted to ARR and revascularizations are removed, we estimate serious cardiovascular event ARR at 3-3.5% for 5 years. This is less than the ARR of 4.4% in younger adults.
Furthermore, the CTT authors made no attempt to assess age-related harms. They adopt a restricted definition of statin myopathy (muscle pain or weakness plus >10-fold elevation of plasma CK). This would exclude most patients who experience disabling pain or muscle weakness from statins. In 2014 Therapeutics Letter 89 further discussed this and other statin harms.¹⁴
Table 2: Effect estimates in people over 70 from the data provided in CTT analysis

* Primary/secondary not reported separately
Lack of evidence for people over 70 is the basis for two new large RCTs
The publicly funded Australian STAREE trial, commenced in 2015, aims to enrol 18,000 participants over 70, randomized to atorvastatin 40mg/d or placebo. By June 2021, enrolment had surpassed 10,500, of whom over 8,000 had already been randomized. The primary outcome is time to death, dementia, or disability or time to a major fatal or non-fatal cardiovascular event.¹⁵
In 2020 the United States National Institute on Aging began the PREVENTABLE RCT. By May 2021, out of a planned 20,000 community-dwelling adults over 75 (without clinically evident CV disease, disability, or dementia), 896 had been randomized to atorvastatin or placebo.¹⁶ Planned follow-up is an estimated median of 3.8 years. Results of these trials have been delayed by COVID-19, but should clarify whether benefits of statins outweigh harms for primary prevention in people 70 and over.
Conclusions

• Statins have not been proven to increase survival in the combined primary and secondary prevention population of people over 70.
• Statins have not been proven to reduce serious cardiovascular events in primary prevention in people over 70.
• Statins reduce serious cardiovascular events for secondary prevention in people over 70, but the relative and absolute benefit is less than in younger people.
• More evidence should be available within 4-7 years.

The Therapeutics Letter is a member of the International Society of Drug Bulletins (ISDB), a world-wide network of independent drug bulletins that aims to promote international exchange of quality information on drugs and therapeutics.

References

1. Therapeutics Initiative. Do statins have a role in primary prevention? Therapeutics Letter. Apr-Jun 2003; 48:1-2. https://ti.ubc.ca/letter48
2. Therapeutics Initiative. Statin’s benefit for secondary prevention confirmed. What is the optimal dosing strategy? Therapeutics Letter. Jul-Sep 2003; 49:1-2. https://ti.ubc.ca/letter49
3. Therapeutics Initiative. Do statins have a role in primary prevention? An update. Therapeutics Letter. Mar-Apr 2010; 77:1-2. https://ti.ubc.ca/letter77
4. Therapeutics Initiative. Pharmacoepidemiology Working Group analysis of BC Ministry of Health linked databases (unpublished). 2020.
5. Wright JM. Is there Evidence for Starting or Continuing Statins in People over 70? Recorded video of October 5, 2019 live presentation to Therapeutics Initiative Annual Best Evidence course. https://ti.ubc.ca/2020/02/04/is-there-evidence-for-starting-or-continuing-statins-in-people-over-70/
6. U.S. Food and Drug Administration. What is a serious adverse event? US FDA 2016. https://www.fda.gov/safety/reporting-serious-problems-fda/what-serious-adverse-event/
7. 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. Lancet 2019; 393(10170):407–15. DOI: 10.1016/S0140-6736(18)31942-1
8. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002; 360(9326):7-22. DOI: 10.1016/S0140-6736(02)09327-3
9. Parish E, Bloom T, Godlee F. Statins for people at low risk. BMJ 2015; 351:h3908. DOI: 10.1136/bmj.h3908
10. Godlee F. Statins: we need an independent review. BMJ 2016; 354:i4992. DOI: 10.1136/bmj.i4992
11. Krumholz H. Statins evidence: when answers also raise questions. BMJ 2016; 354:i4963 DOI: 10.1136/bmj.i4963
12. Abramson J, Furberg C, Jewell N, Wright JM. Questioning statin therapy for older patients. Lancet 2020; 395(10240):1831-2. DOI: 10.1016/S0140-6736(19)33156-3
13. Fulcher J, Keech A, Simes J, Baigent C, Collins R. Questioning statin therapy for older patients – Authors’ reply. Lancet 2020; 395(10240):1832-3. DOI: 10.1016/S0140-6736(19)33159-9
14. Therapeutics Initiative. Statins: Proven and Associated harms. Therapeutics Letter. April-May 2014; 89:1-2. https://ti.ubc.ca/letter89
15. ClinicalTrials.Gov. A Clinical Trial of STAtin Therapy for Reducing Events in the Elderly (STAREE). 2020. https://clinicaltrials.gov/ct2/show/NCT02099123 See also: https://www.monash.edu/medicine/staree/home
16. ClinicalTrials.Gov. Pragmatic Evaluation of Events And Benefits of Lipid-lowering in Older Adults (PREVENTABLE). 2020. https://clinicaltrials.gov/ct2/show/NCT04262206 See also: https://www.preventabletrial.org/home.cfm