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Meta-analysis: Lowering LDL-C levels using statins reduces major vascular events regardless of baseline risk
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Annals of Internal Medicine Oct 16 2012
Meera Jain, MD; and Mark Rosenberg, MD
Cholesterol Treatment Trialists' (CTT) Collaborators. 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. Lancet. 2012;380:581-90
Abstract
Question: Does lowering low-density lipoprotein cholesterol (LDL-C) levels using statin therapy reduce major vascular events in low-risk patients?
Scope: Included studies evaluated statin therapy, included ≥ 1 intervention intended to lower LDL-C levels, enrolled ≥ 1000 patients, scheduled treatment for ≥ 2 years' duration, reported results by 2009, and provided individual patient data by June 2011. Outcomes included a composite of major vascular events (MVEs) (major coronary event [nonfatal myocardial infarction or coronary death], coronary revascularization, or stroke).
Methods: Individual patient meta-analysis of 22 trials comparing statin with control therapy (n = 134 537, mean age 63 y, 71% men, median follow-up in survivors 4.8 y) and 5 trials comparing more with less intensive statin therapy (n = 39 612, mean age 62 y, 81% men, median follow-up in survivors 5.1 y). Data were analyzed using an intention-to-treat approach and in subgroups based on baseline 5-year MVE risk (< 5%, ≥ 5% to < 10%, ≥ 10% to < 20%, ≥ 20% to < 30%, and ≥ 30%).
Main results: Individual patient meta-analysis showed that using statins to lower LDL-C levels by 1 mmol/L (39 mg/dL) reduced MVEs regardless of baseline risk level (Table).
Conclusion: Lowering low-density lipoprotein cholesterol levels using statins reduces major vascular events compared with control regardless of baseline risk level.
Individual patient meta-analysis of statin therapy vs control or more vs less intensive statin therapy*
Commentary
This most recent meta-analysis by the Cholesterol Treatment Trialists' (CTT) Collaborators reports relative risks (RRs) for MVEs with statins in all patients, including Òlow-riskÓ patients. Although useful, baseline risk and absolute risk reduction (ARR) are important considerations. In primary prevention, baseline cardiac risk among patients can vary greatly. Using the Adult Treatment Panel III online calculator (1), 10-year coronary heart disease risk may be 1% in a 50-year-old healthy woman, 7% in a 50-year-old man, and ≥ 16% in a 50-year-old man who smokes. Statins are considered safe, with low levels of myopathy, rhabdomyolysis, and diabetes; however, myalgia is common, and there are worrisome case reports of statin-associated cognitive decline (2-4). All risks, even uncommon ones, become more important when considering population treatment of patients at lowest risk; ARR is lower while harm remains constant. For example, in a hypothetical patient with a low 5-year MVE risk of 1.0%, statin therapy would lower risk to 0.79% (RR reduction 21% for a 1-mmol/L [39-mg/dL] LDL-C reduction and ARR 0.21%). Treatment of 1000 such patients over 5 years would prevent 2 MVEs, with the tradeoff of myalgia in 100 patients (2) and diabetes in 4 (4). It should be noted that CTT participants in the lowest risk group had a 5-year MVE risk of 3%, which is higher than in our example.
Although it is appropriate to emphasize reducing cardiovascular risk at a population level, we must be careful not to overmedicalize the general population. At a public health level, broadening the net too wide for statins can distract from such beneficial activities as tobacco prevention and cessation programs and measures to promote healthy lifestyle through diet and physical activity. We do not recommend statins for everyone by 50 years of age, as some may be considering, but rather advocate using estimates of individual cardiac risk, personal preferences, costs, and risk for side effects in deciding to initiate statins for primary prevention.
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The Lancet, 11 August 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=134 537; mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin (n=39 612; 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 170 000 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
Results
Individual participant data were available from 27 trials in 174 149 participants. 22 trials compared a standard statin regimen versus control (134 537 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).
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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 175 000 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.
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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 guideline might need to be reconsidered.
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