Efficacy of LDL-lowering therapy in elderly, both in primary and secondary prevention combined has shown a significant lower CV-risk. Direct evidence of efficacy of reducing cardiovascular risk in primary prevention in patients ≥75 years alone, still remains rare in results of RCTs [1-3]. Although RCTs are considered as most reliable study designs to prove a causal relationship of efficacy, data are too limited to do a reliable assessment in this specific population of elderly patients above the age of 75 years without cardiovascular disease at baseline. The ongoing STAREE trial will determine whether results of efficacy will be as strong in not fragile elderly above 70 years without cardiovascular disease as in elderly in secondary prevention. In addition, it will evaluate CVD-free survival and disability free survival and therefore give more insight in the net benefit of statin treatment [20].

Other study designs however, e.g. (retrospective) cohorts, showed more clear results in this particular age group without established CVD. Despite the potential risk of bias due to unknown confounders and confounding by indication in these study designs, it allows an evaluation of large amount of routine clinical practice patients. Additionally, circumstantial evidence strengthens results of previously described cohorts. In a primary prevention cohort of participants ≥75 years, discontinuation of statin was associated with a 33% increased risk for cardiovascular event hospital admission [14]. Therefore, evidence of efficacy of LDL-lowering therapy in elderly for primary prevention points into the direction of benefit. Conclusively, LDL-lowering therapy may need a more prominent role in primary prevention in elderly than currently advised in guidelines and weigh heavier in physician-patient discussion.

However, beneficial risk ratios of CV-risk reduction are not similar to absolute benefit of treatment.

Apart from efficacy, patient may decide to refrain from treatment based on alleged side-effects, due to the widespread negative news of statins. However, results of RCTs never showed any causal relationship. Age is found to be a risk factor to develop myopathy and rhabdomyolysis but the main cause may not be statin-treatment itself, but a higher risk due to drug-drug interaction and different pharmacokinetics and- dynamics in the elderly which leads to these otherwise very rare side effects.

However, LDL-lowering treatment (statin) is associated with a higher risk of new-onset Diabetes. In absolute numbers, this means one additional case of diabetes in every 498 patients versus one prevented cardiovascular event for 155 patients treated (each year). Furthermore, patients who developed DM type 2 while receiving treatment had a lower rate of macro- and micro vascular complication. The benefit of preventing a CV-event therefore seems to outweigh the risk at new-onset (mild) Diabetes [8,10].

From patients’ registries and surveys, muscle-related symptoms are responsible for statin discontinuation, switching or non-adherence. Although this problem reflects a problem in daily practice, a plausible explanation is that physicians or patients wrongfully link muscle-discomfort (which is more prevalent in elderly) to statin-treatment. Therefore, quit or switch treatment without a justified reason while at the same time increasing the nocebo effect during rechallenge. Fear of side-effects therefore may be overrated [13].

A helpful tool to quantify the CV-risk in an individual is presented on U-prevent.com [21]. When using the elderly risk score, this tool sketches the 10-year CV-risk without treatment. The elderly risk score was specifically developed for elderly patients, as using the general SCORE-model (whole population) tended to overestimate the 10-year risk in elderly patients. This tool can estimate the influence of LDL-lowering therapy in CV-risk reduction in terms of absolute risk reduction and NNT over a certain timespan. Because statins in primary prevention are estimated to take two to five years to be effective, life expectancy should be enough to be able to benefit from treatment [12]. Therefore, the CV life-time risk and CV life-time risk model may be more useful. The LIFE-CVD model (also available on u- prevent.com) is the most suitable in this case (among all others options based on patient characteristics). Using the LIFE-CVD model provides even more accurate predictions of long-term risk as it also takes competing mortality into account. These life time predictions and hazard ratios from the trials together, can be used to estimate the absolute benefit in CVD-free life years gained after treatment initiation.

If we use this LIFE-CVD model for our patient, the 10-year risk of development of CVD is 20%. It shows a life-time risk of 22% without treatment. With statin therapy (atorvastatin 20mg 1dd), a 6.7% reduction in CV-risk can be expected with 15 number needed to treat. The lifetime benefit is estimated to be approximately +1 year of CVD-free survival.

Because this tool is helpful to quantify life time benefit of treatment and estimates CV-risk reduction for10 years, it can be used during physician-patient discussion. However, it is a estimation and should not be leading subject of the discussion.

Strengths and Limitations

Because this review mostly evaluated outcomes of systematic reviews with large meta-analysis, it was hard to maintain a structured overview of patient characteristics, e.g., diabetic or non-diabetic, frail or vital. To obtain more patient specific results, a new IPD meta-analyses might have been better.

Although data of CTT (which is an IPD) was used, too little data of primary prevention was available to do a reliable assessment. Additionally, an IPD of side-effects could also be useful.

This review mainly focuses on statins because its current position as cornerstone in treatment of LDL- lowering. Nowadays there are other drugs available that can reduce LDL sufficiently with a different pathway, e.g., PCSK-9 inhibition. These drugs have not been assessed in this study, but might offer a greater benefit/risk ratio in the future. The same applies for Ezetimibe treatment. Although the EWTOPIA study had its limitations, it showed that Ezetimibe succeeded in reducing CV-risk and is not associated with adverse events. Current guidelines advise to consider adding Ezetimibe to current statin treatment, only when target LDL-levels are not achieved by statin treatment [16]. Further trials might help to evaluate effectiveness of single-ezetimibe treatment and might offer a greater absolute benefit for the elderly in the future.

In conclusion, direct evidence from RCTs remain scarce, but other study designs give indication that LDL-lowering therapy is effective and beneficial in the elderly in primary prevention. The STAREE trial will hopefully present more direct evidence of efficacy and disability free survival in this specific population and should give more certainty. If life-expectancy is long enough and the patients feels comfortable after the shared decision, together with the fact there is no evidence of a causal relationship with side-effects, the absolute benefit seems to outweighs the risks.