After years of uncertainty, meta-analysis finds statins benefit all ages

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StatinA new analysis of clinical trials reverses current thinking on giving statins to most people over 75, finding that the cholesterol-lowering drugs benefit all ages with minimal risk, found the international Cholesterol Treatment Trialists’ Collaboration. The UK Royal College of GPs said it was “particularly reassuring” to see evidence of the benefit of statins in over-75s, although some patients would not want to be on long-term medication.

“There has been a longstanding controversy over whether statins are effective and safe in the elderly,” said the University of Oxford’s Colin Baigent, a member of the Cholesterol Treatment Trialists’ Collaboration, an international group of doctors and researchers who conducted the analysis.

“I think the debate about whether statins are associated with particular hazards has got out of control,” Baigent said, “and it’s blinding us to the clear evidence of benefit that we already have.”

The report says the Cholesterol Treatment Trialists’ Collaboration has been studying statins since 1995. In its newest meta-analysis, the group looked at 23 randomised controlled trials and another five that investigated intensive vs standard statin therapy. There were over 185,000 people with an average age of 63 in those trials. Almost 15,000 were over 75.

Although the analysis found a slight dip in benefit for the oldest patients, it wasn’t enough to keep the researchers from recommending the use of statins for people who, “simply because of their age, are at higher risk of cardiovascular disease,” said Baigent, who directs the Medical Research Council Population Health Research unit at the University of Oxford. “If this was a policy that was adopted more widely,” Baigent said, “this could prevent many thousands of deaths per year in the UK alone and many more deaths worldwide.”

The report says in an related editorial, Bernard Cheung, a professor at the University of Hong Kong, agreed. “The present meta-analysis makes a case to reduce LDL cholesterol in people at risk of cardiovascular events regardless of age,” Cheung said, “provided that the benefits outweigh the risks and the patient accepts long term treatment.”

Cardiovascular disease and stroke hit the elderly the hardest, yet some doctors have been reluctant to prescribe risk-reducing drugs called statins, the report quotes Baigent as saying, because of inconclusive evidence of the benefits for anyone over 75. That thinking, Baigent said, had been fuelled by poor-quality studies with known flaws. When only large, randomised clinical trials were reviewed, the benefits for the elderly are clear.

“We found statin therapy reduces the risk of major vascular events by about 20 percent for every millimoles per litre reduction in LDL, or bad, cholesterol,” Baigent said, “and it’s effective throughout the age range, including in those over 75.”

In the US, cholesterol is measured by milligrams of cholesterol per decilitre of blood; in the UK, Canada and Europe, it’s measured by millimoles per litre. Current US guidelines recommend that anyone at risk for cardiovascular disease keep that bad cholesterol under 100 mg/dL or 2.6 mmol/L. Those with signs of disease should strive for levels below 70 mg/dL or 1.8 mmol/L.

The report says cardiologist Dr Kevin Campbell, who was not involved with the analysis, said it is not surprising that the elderly saw fewer positive results from use of the drugs. “Statins protect us from cardiovascular events over time,” Campbell said. “Over the long haul, those over 75 do not have the same ‘longevity’ as those who are younger.

“Nonetheless, those in that age group should be considered for statin therapy,” Campbell said. “As always, the risks must not outweigh the benefits when choosing any treatment – particularly in elderly populations who may be more prone to side effects.”

 

BBC News reports that the Royal College of GPs welcomed the research and said it was “particularly reassuring” to see evidence of the benefit of statins in over-75s. Professor Martin Marshall, vice-chair of the college, said some patients would not want to be on long-term medication.

“But GPs are highly trained to prescribe and will only recommend the drugs if they think they will genuinely help the person sitting in front of them, based on their individual circumstances – and after a frank conversation about the potential risks and benefits.”

Summary
Background: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages.
Methods: In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups.
Findings: 14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence.
Interpretation: Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials.

Authors
Colesterol Treatment Trialists’ Collaboration

CNN report
BBC News report
The Lancet article summary


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