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Statins benefit those at much lower CV risk - 2 Lancet articles below
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"The Cholesterol Treatment Trialists' (CTT) Collaboration previously reported meta-analyses of individual data from 170000 individuals in 21 trials of standard statin regimens versus control and five trials of more intensive versus less intensive regimens.1 That report showed that lowering of LDL cholesterol by 1 mmol/L with a standard statin regimen reduced the incidence of major vascular events (defined as non-fatal myocardial infarction or coronary death, any stroke, or coronary revascularisation procedure) by around a fifth, and that further reductions in LDL cholesterol with more intensive statin regimens yielded further reductions in risk. There was no evidence that lowering of LDL cholesterol increased the risk of non-vascular death or of cancer, even in participants with baseline LDL cholesterol less than 2 mmol/L (in whom LDL cholesterol was reduced from about 1.7 mmol/L [65 mg/dL] to 1.3 mmol/L [50 mg/dL]).2
In those analyses, reduction of LDL cholesterol with a statin in participants with no previous history of vascular disease reduced the risk of major vascular events by about a fifth,1 but there remains uncertainty about whether statin therapy is of overall net benefit in primary prevention.3-5This question is important because, although individuals without previous vascular disease are at lower absolute risk, at least half of all vascular events occur among them.6 The availability of individual participant data from each trial within the CTT database (allowing the inclusion of information from both primary prevention trials and low-risk participants in other trials) allows a more complete assessment of the effects of lowering of LDL cholesterol in low-risk people than was possible in previous meta-analyses of published data"
theheart.org May 16, 2012 Sue Hughes
Oxford, UK - New data from an individual patient meta-analysis of 27 large statin trials shows that statin treatment is clearly beneficial in much lower-risk patients than are currently recommended for such therapy in most guidelines [1].
And authors of an accompanying comment suggest that with this new data, everyone over 50 should now be eligible for statin treatment.
The meta-analysis, published online May 16, 2012 in the Lancet, was conducted by the Cholesterol Treatment Trialists' (CTT) Collaborators. They analyzed data from 175 000 individuals and grouped participants into five baseline categories of cardiovascular risk. Outcomes were studied in trials comparing statin with no statin treatment and of more vs less intensive statin regimens.
Results showed that statins reduced the risk of serious vascular events by around 21% for each 1-mmol/L reduction in LDL cholesterol in each of the five baseline risk groups, including those people with the lowest risk of vascular disease.
Benefits greatly exceeded harms
One of the senior authors on the paper, Prof Colin Baigent (Clinical Trial Service Unit, Oxford, UK), commented to heartwire: "Last year Cochrane published a review of statins in primary prevention that was somewhat unclear in its conclusions. They showed that although there was a clear reduction in mortality with statins, they were uncertain about adverse effects. We wanted to clarify the situation, so we looked at all the available individual patient data from all trials that included low-risk patients. As well as all the primary-prevention trials, these include some trials where both primary- and secondary-prevention patients were included, such as the Health Protection Study. This was a much more thorough analysis than the Cochrane review, which only had access to the overall trial results."
Baigent continued: "We found the relative reduction in risk of cardiovascular events with a statin is just as good in the lowest-risk group as in higher-risk groups. Even in the very lowest-risk group studied (those with a risk below 10% in 10 years), the benefits greatly exceeded the harms."
Primary prevention is obviously needed.
"Half of cardiac deaths happen in people who have not previously had heart disease, so there is a limit to what can be achieved just with secondary prevention. So primary prevention is obviously needed. The question is where we set the threshold. And our data suggest this should be lowered to a risk of 10% over 10 years."
Baigent believes the decision on whether to take a statin needs to be made on the basis of risk of the patient rather than on their cholesterol level. "Typically, at the moment, the public and many doctors think that statins are necessary only if a patient has high cholesterol. But the preferable view would be that a statin is needed if you are at any increased risk of heart disease."
A statin is needed if you are at any increased risk of heart disease.
He added that everyone is supposed to have a vascular check in middle age, and the current recommendation in the UK is that if they are found to have a risk of a cardiovascular event of more than 20% over 10 years they should be offered a statin. "But we found in this current meta-analysis that the benefits of statins are still obvious at a risk level of 10% over 10 years, and even below that."
At present in the UK, five million patients take statins, and another five million are eligible to take them but are not receiving them, Baigent reported. "If the threshold were reduced to a cardiac risk of 10% over 10 years, an additional five million people would be eligible to receive these drugs. Simvastatin is off patent and atorvastatin is now coming off patent, so this will not be an expensive exercise. It is right and proper that there is an assessment of safety, but we have now done that and shown the benefits to greatly outweigh the risks. If the threshold were lowered to 10%, we could avoid 10 000 events, including 2000 deaths every year."
If the threshold was lowered to 10%, we could avoid 10 000 events, including 2000 deaths every year.
Asked if everyone should just receive a statin at a certain age, Baigent said this was one possibility. "It is up to the guidelines committees to decide on the strategy. We have called for NICE to reconsider the threshold they recommend for statin treatment. All we are saying is that we should at least treat everyone with a risk of 10% or more over 10 years. But we actually showed benefit in patients with a lower risk than this. People can be educated about risk. Everybody knows their age and if they are overweight, smoke, or don't exercise enough. It's not difficult to find out your cholesterol, blood pressure, family history, or whether you are diabetic. These things then should then trigger the thought that you might be able to benefit from a statin."
Statins for everyone over 50?
In the comment article, Drs Shah Ebrahim and Juan P Casas (London School of Hygiene and Tropical Medicine, UK) suggest that as most people older than 50 years are likely to be at a >10% 10-year risk of a cardiovascular event, it would be more pragmatic to use age as the only indicator for statin prescription, which would avoid the costs of vascular screening checks.
Major results for the new meta-analysis showed that statin treatment reduced the risk of major vascular events by 21% per 1.0-mmol/L reduction in LDL, and this was largely irrespective of age, sex, baseline LDL cholesterol, previous vascular disease, and baseline cardiovascular risk. The proportional reduction in major vascular events was at least as big in the two lowest-risk categories as in the higher-risk categories.
There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1.0-mmol/L LDL-cholesterol reduction 1.00, 95% CI 0.96-1.04), cancer mortality (RR 0.99, 95% CI 0.93-1.06), or other nonvascular mortality.
What about side effects?
In terms of side effects, the data show that there was a small increased risk of myopathy (excess incidence of about 0.5 per 1000 over five years) and rhabdomyolysis (excess incidence of about 0.1 per 1000 over five years). There was also an increase of hemorrhagic strokes per 1.0-mmol/L LDL-cholesterol reduction of about 0.5 per 1000 people treated over five years. But the authors write that "this was outweighed by the reduction in ischemic stroke (as well as the reduction in other occlusive vascular events and deaths) even in individuals whose five-year risk of major vascular events is lower than 5%."
They also report an absolute excess of diabetes associated with statin treatment of about 0.1% per year. But they estimate that the increased risk of cardiovascular events associated with this excess in diabetes is more than 50 times smaller than the absolute benefit observed with statin therapy in low-risk patients.
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The Lancet, Early Online Publication, 17 May 2012
Statins for all by the age of 50 years?
Shah Ebrahim a, Juan P Casas a b
In The Lancet, the Cholesterol Treatment Trialists' (CTT) Collaborators report a relative risk reduction on statins of about 20% (RR 0.79, 95% CI 0.77-0.81) for major vascular events per 1 mmol/L reduction in LDL cholesterol across different levels of cardiovascular risk.1 Men and women, old and young, and people with and without cardiovascular disease all benefit. These findings confirm the efficacy of statins for primary prevention, resolving concerns about possible serious adverse effects and potential sources of bias in randomised trials.2 The report extends findings to lower levels of cardiovascular disease risk than is recommended by existing guidelines in the USA, Europe, and the UK, and shows that benefits of statins outweigh any conceivable serious adverse effects. The study raises questions for clinical practice. Are the opportunity costs in primary care acceptable? Can LDL cholesterol reductions of 1 mmol/L be sustained in routine primary care? Are statins cost effective for patients at low cardiovascular disease risk?
Physicians find it helpful to consider benefit and clinical effort needed in terms of the numbers needed to treat for 5 years. The CTT analysis predicts that six and 15 major vascular events would be avoided per 1000 people treated for 5 years in the two lowest baseline risk categories, respectively, giving numbers needed to treat of 167 and 67. These figures look encouraging and are similar to those for treatment of mild hypertension,3 which is widely accepted as a primary care task. However, half of men older than 50 years and 30% of women older than 60 years have a 10-year risk of cardiovascular disease equal to or higher than 20% in England, the present threshold for treatment.4 Adoption of a lower, 10% or more, threshold would classify 83% of men older than 50 years and 56% of women older than 60 years as needing a statin (Health Survey for England, 2003;5 Reecha Sofat, personal communication). Currently, UK primary care struggles to treat patients with prevalent cardiovascular disease,6 or to use high-dose statins after acute coronary syndromes.7
In primary care, long-term reductions of the order of 1 mmol/L LDL cholesterol might be difficult to achieve. 2-year adherence rates to statins in people without evidence of cardiovascular disease might be as low as 25%,8 and use of lower than optimum doses of statins seems to be resistant to an audit-education intervention for doctors.6 The CTT analyses provide reassurance for general practitioners to prescribe higher doses of statins to achieve greater benefit, and dissipate uncertainty about any potential serious adverse risks of statins, which might account for prescription of lower than optimum doses.
Low-cost generic statins are now widely available (figure) and cost-effectiveness studies show that statins are cost-saving in the USA, even in people at low predicted risk of coronary heart disease. To gain maximum effect from use of statins, 64 million people in the USA (just under half of the population older than 35 years) would need to be put on treatment at a cost of US$2800 per QALY gained.8 These cost-effectiveness estimates are likely to be better for more potent statins and in lower cost health services.
Translation of the CTT findings into practice will necessitate more affordable ways to identify individuals for treatment and keep them on optimum regimens. Because most people older than 50 years are likely to be at greater than 10% 10-year risk of cardiovascular disease, it would be more pragmatic to use age as the only indicator for statin prescription, as was originally proposed for the polypill.10 This approach would avoid the costs, ranging from 7 to more than 700 per patient screened, of vascular screening checks recently implemented in the UK.11 In low-income and middle-income countries, as they rapidly go through epidemiological transition, efforts to detect risk factors for cardiovascular disease using similar medical models are increasing, resulting in the same issues of volume of work and costs involved. In Latin America, 61% of men older than 55 years and 65% of women older than 60 years have a 10-year Framingham risk score for cardiovascular disease equal to or higher than 10% (Bautista L, personal communication).
An additional challenge is that identification of a new and larger proportion of the population for statin treatment could shift attention from existing high-risk groups (particularly those with established cardiovascular disease) that benefit most, in absolute terms, from statins, and in whom underuse of statins is still far too common.12
So should the UK National Institute for Health and Clinical Excellence (NICE) reconvene its guidelines development group urgently in view of these new findings? NICE guidance on statins was reissued in 2010 and is reconsidered every 2 years, so incorporation of these findings would fit neatly.13 Whether populations will be well served by present pharmacologically dominated research findings for lifestyle-related diseases is debatable. A change in the edible oil import policy from palm to soya oil rewarded the people of the small island of Mauritius with a 0.8 mmol/L reduction in total cholesterol at no cost and without the need to medicate the whole population with statins.14 But political will is needed to include health as well as fiscal outcomes in strategic decision making-something that does not seem to be on the agendas of richer countries or multinational corporations.15
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The Lancet, Early Online Publication, 17 May 2012
The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials
Summary
Background
Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain.
Methods
This meta-analysis included individual participant data from 22 trials of statin versus control (n=134537; mean LDL cholesterol difference 1.08 mmol/L; median follow-up 4.8 years) and five trials of more versus less statin (n=39612; difference 0.51 mmol/L; 5.1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1.0 mmol/L LDL cholesterol reduction was estimated.
Findings
Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0.79, 95% CI 0.77-0.81, per 1.0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1.0 mmol/L reduction from lowest to highest risk: 0.62 [99% CI 0.47-0.81], 0.69 [99% CI 0.60-0.79], 0.79 [99% CI 0.74-0.85], 0.81 [99% CI 0.77-0.86], and 0.79 [99% CI 0.74-0.84]; trend p=0.04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0.57, 99% CI 0.36-0.89, p=0.0012, and 0.61, 99% CI 0.50-0.74, p<0.0001) and in coronary revascularisations (RR 0.52, 99% CI 0.35-0.75, and 0.63, 99% CI 0.51-0.79; both p<0.0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1.0 mmol/L LDL cholesterol reduction 0.76, 99% CI 0.61-0.95, p=0.0012) was also similar to that seen in higher risk categories (trend p=0.3). In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1.0 mmol/L LDL cholesterol reduction 0.85, 95% CI 0.77-0.95) and all-cause mortality (RR 0.91, 95% CI 0.85-0.97), and the proportional reductions were similar by baseline risk. There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1.0 mmol/L LDL cholesterol reduction 1.00, 95% CI 0.96-1.04), cancer mortality (RR 0.99, 95% CI 0.93-1.06), or other non-vascular mortality.
Interpretation
In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.
Funding
British Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.
Introduction
The Cholesterol Treatment Trialists' (CTT) Collaboration previously reported meta-analyses of individual data from 170000 individuals in 21 trials of standard statin regimens versus control and five trials of more intensive versus less intensive regimens.1 That report showed that lowering of LDL cholesterol by 1 mmol/L with a standard statin regimen reduced the incidence of major vascular events (defined as non-fatal myocardial infarction or coronary death, any stroke, or coronary revascularisation procedure) by around a fifth, and that further reductions in LDL cholesterol with more intensive statin regimens yielded further reductions in risk. There was no evidence that lowering of LDL cholesterol increased the risk of non-vascular death or of cancer, even in participants with baseline LDL cholesterol less than 2 mmol/L (in whom LDL cholesterol was reduced from about 1.7 mmol/L [65 mg/dL] to 1.3 mmol/L [50 mg/dL]).2
In those analyses, reduction of LDL cholesterol with a statin in participants with no previous history of vascular disease reduced the risk of major vascular events by about a fifth,1 but there remains uncertainty about whether statin therapy is of overall net benefit in primary prevention.3-5 This question is important because, although individuals without previous vascular disease are at lower absolute risk, at least half of all vascular events occur among them.6 The availability of individual participant data from each trial within the CTT database (allowing the inclusion of information from both primary prevention trials and low-risk participants in other trials) allows a more complete assessment of the effects of lowering of LDL cholesterol in low-risk people than was possible in previous meta-analyses of published data.3, 4
Methods
Trials
The methods of the CTT collaboration have been described in detail elsewhere.1, 7, 8 In the present analyses, a trial was eligible if it reported by the end of 2009 and provided data before June, 2011, and met three criteria: (1) it included at least one intervention whose main effect was to lower LDL cholesterol concentration; (2) it was unconfounded with respect to this intervention (ie, no other differences in risk factor modification between the treatment groups were intended); and (3) it recruited at least 1000 participants with scheduled treatment duration of at least 2 years. The main outcomes of interest were major vascular events, major coronary events (defined as non-fatal myocardial infarction or coronary death), stroke (subdivided by type), coronary revascularisation procedures, cancers, and cause-specific mortality.
Statistical analysis
Two different Cox proportional hazards models were developed to allow risk to be modelled separately in trials of statin versus control (22 trials; model 1) and in trials of more versus less intensive statin regimens (five trials; model 2). Both models incorporated terms derived from characteristics measured at the time of randomisation, terms that modelled average differences in risk between trials (as well as within specific periods of time within each trial), and interaction terms (appendix pp 1-2). On the basis of these risk prediction models, participants in both treatment groups of each study were assigned to one of five baseline categories of 5-year risk of a major vascular event: <5%; ≥5% to <10%; ≥10% to <20%; ≥20% to <30%; or ≥30%. Further details of model development are shown in the appendix pp 15-16.
Analyses included all participants who were randomly assigned to treatment groups, irrespective of whether they received their allocated treatment (ie, intention-to-treat). Analyses of the effects on disease rates within each trial are derived from the logrank (o-e) statistic and its variance (v) for first events. Meta-analyses were weighted by the absolute LDL cholesterol difference in that trial at 1 year (d mmol/L), and are reported as effects per 1.0 mmol/L reduction in LDL cholesterol. In a meta-analysis of several trials, the log of the rate ratio (RR) per 1.0 mmol/L was calculated as S/V with variance 1/V (and hence, for example, with 95% CI of S/V±1.96/√V), where S is the sum over all trials of d(o-e) and V is the sum over all trials of d2v. For most subgroup analyses, the weight for a particular subgroup was the LDL cholesterol difference observed in the whole trial, but analyses by baseline LDL cholesterol concentration used LDL weights specific to a particular subgroup of a particular trial.1 In trials comparing more versus less intensive statin therapy, the relevant baseline lipid values were those achieved on the less intensive regimen. In three of these trials,9-11 however, any statin therapy was stopped before randomisation, so we estimated their relevant baseline values by multiplying the values at the randomisation visit (ie, off statin treatment) by the mean proportional reduction observed at 1 year in participants allocated the less intensive regimen.1 Proportional risk reductions in different subgroups were compared by standard χ2 tests for heterogeneity or, where appropriate, trend. To allow for multiple testing by subdivisions, only overall summary rate ratios have 95% CIs; all other rate ratios have 99% CIs. Analyses used SAS version 9.1 (SAS Institute, Cary, NC, USA), Stata version 11.2 (StataCorp, TX, USA), and R version 2.11.1.
Role of the funding sources
The funding sources had no involvement in the study design, data collection, analysis and interpretation, the writing of the report, or the decision to submit for publication. The writing committee had full access to all data and accepts full responsibility for the content of this report.
Results
Individual participant data were available from 27 trials in 174149 participants. 22 trials compared a standard statin regimen versus control (134537 participants; mean baseline LDL cholesterol 3.70 [SD 0.7] mmol/L; mean difference at 1 year 1.08 mmol/L; median follow-up duration in survivors 4.8 years)12-33 and five trials assessed a more intensive versus a less intensive statin regimen (39 612 participants; mean baseline LDL cholesterol 2.53 [SD 0.6] mmol/L; mean difference at 1 year 0.51 mmol/L; median follow-up duration in survivors 5.1 years).9-11,34,35 Individual participant data were unavailable from only two eligible trials in 6331 higher-risk patients with pre-existing vascular disease (SPARCL36 and GREACE37).
The baseline prognostic factors that were strong predictors of major vascular event risk (ie, at the 1% significance level) were broadly similar in the trials of statin versus control and the trials of more versus less intensive statin regimens (appendix pp 1-2). Predicted risk compared well with observed risk for each trial, as well as within each 5-year risk group (appendix p 3). When trials were ordered by their median 5-year predicted risk of a major vascular event, the five trials with the lowest median predicted risks (all <10%) were primary prevention trials (table 1).13, 15, 22, 29, 31 By contrast, almost all participants with predicted 5-year risk of 20% or higher were recruited into trials in patients with a definite history of vascular disease.12,14,16-19,25,28 The predicted 5-year risk of a major vascular event was also 20% or higher in most dialysis patients.26, 30 In two trials in patients with heart failure,32, 33 there was a high risk of sudden death, but such deaths were categorised differently, with a much smaller proportion of such deaths thought to be due to coronary occlusion in the GISSI-HF trial33 than in CORONA;32 this difference is the main reason why the predicted 5-year risk of major vascular events was more than twice as high in CORONA (23%) as in GISSI-HF (10%).
Among the 22 trials of statin versus control, the observed annual major vascular event rate ranged from 0.6% in the lowest predicted risk category to 9.5% in the highest risk category, whereas in trials of more versus less intensive statin therapy (which were undertaken solely in patients with previous coronary disease) the observed annual event rate varied between 3.7% and 10.7% across the categories studied (table 2). In both sets of trials, the achieved reduction in LDL cholesterol at 1 year with statin therapy or more intensive statin therapy was greater in people with higher predicted 5-year risk of major vascular events (appendix p 4).
Among all 27 trials, statins reduced the risk of major vascular events by 21% per 1.0 mmol/L LDL cholesterol reduction (RR 0.79, 95% CI 0.77-0.81, p<0.0001), with separately significant proportional reductions in each risk group (figure 1). In particular, there were significant reductions in major vascular event risk in each of the two lowest risk categories (RR per 1.0 mmol/L LDL cholesterol reduction 0.62, 99% CI 0.47-0.81, for 5-year predicted risk <5%, and 0.69, 99% CI 0.60-0.79, for 5-year predicted risk ≥5% to <10%; both p<0.0001; figure 1). These results were qualitatively similar after exclusion of five trials12, 15, 22, 24, 31 that ended early on the advice of their data monitoring committees (data not shown). The proportional reductions in major vascular events per 1.0 mmol/L LDL cholesterol reduction in the two lowest risk categories seemed to be at least as large as for other participants (figure 1), even after further stratification by age and sex (appendix p 6) or by baseline LDL cholesterol (appendix p 7).
The reductions in risk of major vascular events among the two categories of participant at lowest risk reflected reductions in major coronary events (RR per 1.0 mmol/L LDL cholesterol reduction 0.57, 99% CI 0.36-0.89, p=0.0012, and 0.61, 99% CI 0.50-0.74, p<0.0001), mainly non-fatal myocardial infarction, and in coronary revascularisations (RR 0.52, 99% CI 0.35-0.75, and 0.63, 99% CI 0.51-0.79; both p<0.0001), that were at least as large as those seen in higher risk participants (trend p=0.02 for major coronary events and p=0.03 for coronary revascularisations; figure 1, appendix p 8). The reduction in stroke risk per 1.0 mmol/L LDL cholesterol reduction (RR 0.85, 95% CI 0.80-0.89) was similar at all levels of baseline major vascular event risk (trend p=0.3; figure 1). In particular, the reduction in stroke risk in those with predicted 5-year major vascular event risk lower than 10% (ie, the two lowest risk groups combined; RR 0.76, 99% CI 0.61-0.95; p=0.0012) was similar to that seen in higher risk categories. The proportional reductions in ischaemic stroke (RR per 1.0 mmol/L LDL cholesterol reduction 0.79, 95% CI 0.74-0.85) and in strokes of unknown cause (RR 0.87, 95% CI 0.79-0.97) were similar irrespective of baseline major vascular event risk, and there was no evidence that the RR for haemorrhagic stroke (1.15, 95% CI 0.97-1.38) varied by baseline risk (appendix p 9). Separate analyses of major vascular events and its components in the trials that tested statin versus control and the trials that tested more versus less intensive statin regimens are shown in the appendix pp 10-11.
For participants with previous vascular disease, the proportional reductions in major vascular event risk were broadly similar irrespective of predicted risk of these events (figure 2). In participants with no history of vascular disease, the proportional reduction in major vascular events was at least as large in the two lowest risk groups (RR per 1.0 mmol/L LDL reduction 0.61, 99% CI 0.45-0.81, and 0.66, 99% CI 0.57-0.77) as in those at higher risk. Further exclusion from these lowest risk groups of participants with diabetes or chronic kidney disease had little effect on the proportional reductions in major vascular events (RR per 1.0 mmol/L LDL cholesterol reduction 0.63, 99% CI 0.46-0.85, for 5-year predicted risk <5%; 0.64, 99% CI 0.54-0.76, for 5-year predicted risk ≥5% to <10%). The LDL-weighted proportional reduction in major coronary events in participants with no history of vascular disease was also at least as large in the two lowest risk groups as in those at higher risk (appendix p 12).
In all participants, there was a proportional reduction in vascular mortality of 12% per 1.0 mmol/L LDL cholesterol reduction (RR 0.88, 95% CI 0.84-0.91; figure 3), which was chiefly attributable to reductions in coronary deaths of 20% (RR 0.80, 95% CI 0.76-0.85) and in other cardiac deaths of 8% (RR 0.92, 95% CI 0.87-0.98; appendix p 13). There were too few deaths among the lower risk participants to allow reliable direct assessment of the effects of statin therapy (appendix p 13). However, the LDL-weighted proportional reductions seemed similar in each risk category both for the aggregate of all vascular deaths (trend p=0.7; figure 3) and for each specific cause of vascular death (all trend p=NS; appendix p 13), and there was no significant trend towards an increase in non-vascular mortality in those at lower risk (trend p=0.9; figure 3). In participants with no history of vascular disease, reduction of LDL cholesterol with statin therapy reduced the risk of vascular mortality (RR per 1.0 mmol/L reduction 0.85, 95% CI 0.77-0.95, p=0.004; figure 3) and, since there was no increase in the risk of non-vascular causes of death (RR 0.97, 95% CI 0.88-1.07; figure 3), reduced the risk of all-cause mortality (RR 0.91, 95% CI 0.85-0.97, p=0.007; appendix p 14). These mortality benefits remained even after further exclusion of participants with diabetes or chronic kidney disease at baseline (vascular death, RR 0.80, 95% CI 0.67-0.95; any death, 0.87, 95% CI 0.78-0.95). There was no evidence of an increase in cancer incidence (RR per 1.0 mmol/L LDL reduction 1.00, 95% CI 0.96-1.04) or of cancer death (RR 0.99, 95% CI 0.93-1.06) at any level of major vascular event risk (figure 4).
Discussion
The most recent CTT meta-analysis of individual participant data from randomised trials showed that lowering of LDL cholesterol with standard statin regimens safely reduced the 5-year incidence of major coronary events, coronary revascularisations, and ischaemic strokes by about one fifth per 1.0 mmol/L reduction in LDL cholesterol, and that additional reductions in LDL cholesterol obtained with more intensive statin regimens further reduced the incidence of these major vascular events.1 The present results show that reduction of LDL cholesterol with statin therapy significantly reduced the risk of major vascular events in individuals with 5-year risk lower than 10% (in whom the mean risks were 2.6% for major coronary events plus 3% for other major vascular events), even in those with no previous history of vascular disease, diabetes, or chronic kidney disease (panel).
Panel
Research in context
Systematic review
Lowering of LDL cholesterol with a statin reduces the risk of myocardial infarction, coronary death, ischaemic stroke, and coronary revascularisation by about one fifth per 1 mmol/L LDL cholesterol reduction in a wide range of people.1 However, tabular meta-analyses of people at low risk of these events, studied predominantly in primary prevention trials, have concluded that statin therapy might not result in worthwhile net benefit in this group.3, 4
Interpretation
Individual participant data in the Cholesterol Treatment Trialists' Collaboration of 27 trials involving 175000 participants showed that statin therapy reduces the risk of major vascular events (non-fatal myocardial infarction, coronary death, coronary revascularisation, or stroke) in people with 5-year risk of such an event lower than 10% (and, separately, in those at 5-year risk <5%), and in these people each 1.0 mmol/L reduction in LDL cholesterol produces 11 fewer major vascular events per 1000 treated over 5 years, a benefit that greatly exceeds any known hazards of statin therapy.
The estimated absolute reduction in major vascular events in participants with 5-year risk of these events lower than 10% was around 11 per 1000 over 5 years for each 1.0 mmol/L reduction in LDL cholesterol (4.1% statin or more intensive statin regimen vs 5.2% control or less intensive regimen). Modern statin regimens, however, can often reduce LDL cholesterol by more than 1 mmol/L,38, 39 which would yield even larger absolute reductions in major vascular events. The avoidance of life-threatening or potentially disabling events in apparently healthy low-risk people might be deemed worthwhile provided that they are not accompanied by any definite hazard that is of comparable severity. Although there was no evidence of any increased risk of death from non-vascular causes or of cancer in those at low risk (which is consistent with previous detailed analyses of the effect of statins on cancer2), several known or potential hazards of statin therapy need to be considered when estimating the net effects of statin therapy in people at lowest risk.
First, statin therapy is associated with a small increased risk of myopathy (excess incidence of about 0.5 per 1000 over 5 years) and, more rarely, of rhabdomyolysis (excess incidence of about 0.1 per 1000 over 5 years).38 The risks of myopathy are dose-related but, with the exception of simvastatin 80 mg daily (or lower doses in Asian populations), intensive statin regimens have not been shown to result in substantial myopathy risks.38 Second, the most recent CTT report raised the possibility that statin therapy might increase the risk of haemorrhagic stroke.1 The present analyses suggest that the annual excess risk of haemorrhagic strokes per 1.0 mmol/L LDL cholesterol reduction might be of the order of 0.5 per 1000 people treated over 5 years (appendix p 9), although it might be higher in populations in which haemorrhagic stroke accounts for a higher proportion of strokes (eg, Asian populations40). But, since statin therapy produced a clear reduction in overall stroke that was independent of predicted risk, such an increase in haemorrhagic stroke risk would typically be outweighed by the reduction in the risk of ischaemic stroke (as well as the reduction in other occlusive vascular events and deaths) even in individuals whose 5-year risk of major vascular events is lower than 5%. Third, recent meta-analyses have suggested that statin therapy might be associated with a proportional increase in the diagnosis of diabetes mellitus of about 10%41 and that more intensive statin therapy produces a bigger increase.42
The observed incidence of diabetes recorded in the primary prevention trials was about 5% over 5 years, so the absolute excess was about 0.1% per year.41 If new diagnoses of diabetes were associated with an immediate doubling in cardiovascular risk43 in individuals with 5-year risk of major vascular events lower than 10%, then the expected effect would be only about 0.2 fewer events avoided per 1000 individuals treated over 5 years. Such an effect is more than 50-times smaller than the absolute benefit observed with statin therapy in such individuals (about 11 fewer major vascular events per 1000 treated over 5 years per 1.0 mmol/L reduction in LDL cholesterol; see figure 5 for absolute benefits corresponding to particular reductions in LDL cholesterol in individuals at different levels of major vascular event risk). Moreover, long-term follow-up of statin trials has shown that the absolute reductions in major vascular events increase while the statin treatment is continued1 and that these benefits persist for at least 5 years after the treatment has stopped, with no evidence of any adverse effects emerging with extended follow-up.44-47 These findings would suggest that any long-term effects of any small excesses in haemorrhagic strokes and in diagnoses of diabetes are not associated with long-term effects on major vascular events that are sufficiently large to outweigh the persistent benefits of statin therapy.
The observed event rates shown in the figures for each risk category can be readily compared with risk thresholds used in treatment guidelines. For example, under present guidelines, including those of the Adult Treatment Panel III,48, 49 the Fourth Joint Task Force of the European Society of Cardiology,50 the Task Force for the management of dyslipidaemias of the European Society of Cardiology and the European Atherosclerosis Society,51 and the UK National Institute of Clinical Excellence,52 people with 5-year risk of major vascular events lower than 10% (ie, the lowest two categories of risk in these analyses) would typically not be judged suitable for statin treatment (table 3, appendix p 5). Judgments about the appropriateness of widespread prescription of statins for the primary prevention of vascular events in patients at lower risk also depend on the cost effectiveness of such a strategy, which in turn depends on the local availability and cost of therapy. Generic statin interventions, if effective, are likely to be cost-effective in individuals at annual vascular disease risk down to at least about 1%.53-55 The present report shows that statins are indeed both effective and safe for people with 5-year risk of major vascular events lower than 10% and, therefore, suggests that these guidelines might need to be reconsidered.
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