Don't Stop the Statin!

Christopher P. Cannon

Disclosures

Eur Heart J. 2019;40(43):3526-3528. 

Lipid lowering with statins is one of the most beneficial therapies in cardiovascular medicine, with evidence from hundreds of randomized clinical trials, including >25 large cardiovascular outcomes trials in the Cholesterol Treatment Trialists (CTT) collaboration.[1] Benefit is seen for reducing myocardial infarction (MI), stroke, need for revascularization, cardiovascular (CV) death, and total mortality. The benefits are seen in those with prior CV events (i.e. secondary prevention) and in primary prevention. Benefit is seen across all subgroups, without any statistical interaction, including by age.[1,2]

As for all medicines, statins do have side effects, most prominent of which is myalgia.[3,4] Other side effects have been suggested, such as dementia, but refuted in large randomized trials.[3,4] The cost of statins used to be an issue, but now they are almost all generic and widely available for very low cost. Thus, a careful assessment of benefit vs. risk is very favourable on the usual metrics of CV events prevented vs. side effects.

Yet somehow, despite wide use and acceptance in the medical community, there is scepticism and resistance to use of these agents by many patients and some medical professionals. Some have claimed that statins do not work in women for primary prevention,[5] yet multiple meta-analyses document that they significantly reduce CV death, MI, stroke, and need for revascularization.[1,6]

The media have also joined in with this, with stories citing those who claim limited benefits of statins.[7] (I often wonder whether journalists have a conflict of interest in trying to attract readers—where they have to write a shocking title saying statins do not work in order to grab attention.) Books have been written on the 'cholesterol hoax' and describe a large conspiracy of companies trying to sell these drugs without merit. In the current environment with many claiming 'Fake News' in politics, these types of conspiracy stories thrive on the Internet.

Another group in which questions have been raised is the elderly. Here, there are some reasons to raise the question. Is it worth using a long-term preventive therapy in someone who is >75 years—would they live long enough to gain the benefit? There are 'competing risks' of cancer and other major diseases, whereby those would dictate prognosis and the statin therapy might be moot. There are questions cited in guidelines about the strength of the evidence.[8,9] Since most (but not all) data on this population would be derived from subgroup analyses of trials, there are not tens of thousands of patients in trials in this age category. In particular, for secondary prevention, there is strong evidence of benefit, but in primary prevention the modest number of patients enrolled has raised this question.

The CTT thus dedicated a paper to exploration of the benefit in the elderly.[2] Among 28 randomized trials, 14 483 (8%) of 186 854 participants were ≥ 75 years old at randomization. They found proportional benefit of ~24% for each mmol reduction in LDL-cholesterol (LDL-C), with no difference by age for those with prior atherosclerotic cardiovascular disease (ASCVD; i.e. secondary prevention) and a slight trend toward less benefit for those with primary prevention.[2]

A specific pooling of the two latest primary prevention trials, JUPITER and HOPE3, also found consistent benefit in those aged 70 or more.[10] They reported a 26% relative risk reduction in CV death, MI, or stroke for those ≥70 years old [hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.61–0.91; P = 0.0048]. Because the elderly have higher event rates, they would then have large absolute rate reductions and then smaller numbers needed to treat to prevent an event compared with younger patients.[10]

An important contribution to this discussion of whether benefit exists for elderly patients with statin therapy comes in the new analysis in this issue of the European Heart Journal by Giral and colleagues.[11] They conducted an observational analysis with careful statistical adjustments, looking at a 'natural experiment' comparing patients who had their statins stopped vs. those who continued. They found consistently that those who stopped had higher rates of hospitalization for CV events, i.e. ~20–30% higher (Take home figure).[11] This is consistent with what one would expect from the benefit of statins. These data are similar to those published from a nationwide cohort from Denmark.[12] In this study, early statin discontinuation increased with negative statin-related news stories (and thankfully the opposite was true for positive statin-related news stories). As seen in the current study, early statin discontinuation was associated with increased risk of MI and CV death.[12] The former US President Bill Clinton actually experienced this. As he did rehab for his knee, he exercised and lost weight, so he stopped his statin, but a few months later developed unstable angina and required coronary bypass surgery.[13]

Take home figure.

The consequences of stopping statins (reproduced from Schiele and Kristensen16; and Giral et al.11).

We also can contrast with aspirin for primary prevention, where recent trials have shown increased bleeding and no benefit in the elderly.[14] An editorialist on one of these recent aspirin studies, Dr Paul Ridker, concluded 'Thus, beyond diet maintenance, exercise, and smoking cessation, the best strategy for the use of aspirin in the primary prevention of cardiovascular disease may simply be to prescribe a statin instead'.[15]

Fortunately, for this important question, two prospective randomized trials are nearing completion. The STAREE study (NCT02099123) will examine whether atorvastatin 40 mg compared with placebo will prolong overall survival or disability-free survival in healthy elderly people (≥70 years). The SITE/SAGA study (NCT02547883) will evaluate the cost-effectiveness ratio of statin cessation in people 75 years and older who are treated in primary prevention, with mortality as a primary outcome measure.

In conclusion, we have seen from randomized trials the benefit of statins across all age groups, with perhaps a bit less direct evidence in the elderly. However, the new observational study helps reinforce the notion that continuing statins for those over the age of 75 is beneficial.

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