Colbun.utalca.cl

Quantifying effect of statins on low density lipoprotein
cholesterol, ischaemic heart disease, and stroke: systematic
review and meta-analysis
M R Law, N J Wald, A R Rudnicka
Abstract
Conclusions Statins can lower LDL cholesterol
concentration by an average of 1.8 mmol/l which Objectives To determine by how much statins reduce
reduces the risk of IHD events by about 60% and serum concentrations of low density lipoprotein (LDL) cholesterol and incidence of ischaemic heart disease (IHD) events and stroke, according to drug, Introduction
Design Three meta-analyses: 164 short term
Statins are highly effective in lowering serum randomised placebo controlled trials of six statins and cholesterol concentrations and preventing ischaemic LDL cholesterol reduction; 58 randomised trials of heart disease (IHD).1–3 Three issues remain. We do not cholesterol lowering by any means and IHD events; know by how much different statins at different doses and nine cohort studies and the same 58 trials on reduce low density lipoprotein (LDL) cholesterol con- centrations. There are indications from previous Main outcome measures Reductions in LDL
studies,4 5 but there has been no systematic review of cholesterol according to statin and dose; reduction in placebo controlled trials. Secondly, the full effect of IHD events and stroke for a specified reduction in statins in preventing IHD events has not been specified. The 30% reduction shown in meta-analyses Results Reductions in LDL cholesterol (in the 164
of major randomised trials1–3 underestimates the full trials) were 2.8 mmol/l (60%) with rosuvastatin 80 effect because IHD events in the first two years (before mg/day, 2.6 mmol/l (55%) with atorvastatin 80 the full effect of reducing serum LDL cholesterol con- mg/day, 1.8 mmol/l (40%) with atorvastatin 10 centrations is achieved6) were not censored, many trials mg/day, lovastatin 40 mg/day, simvastatin 40 mg/day, used less effective statins, and trials were affected by or rosuvastatin 5 mg/day, all from pretreatment non-adherence to the allocated regimen (those on concentrations of 4.8 mmol/l. Pravastatin and statins not taking them and those on placebo taking fluvastatin achieved smaller reductions. In the 58 statins). Thirdly, there is a paradox in that meta- trials, for an LDL cholesterol reduction of 1.0 mmol/l analyses of randomised trials showed that statinsreduced the incidence of strokes by about 30%,7–10 but the risk of IHD events was reduced by 11% in the first cohort studies showed no association between serum year of treatment, 24% in the second year, 33% in years three to five, and by 36% thereafter (P < 0.001for trend). IHD events were reduced by 20%, 31%, and51% in trials grouped by LDL cholesterol reduction (means 0.5 mmol/l, 1.0 mmol/l, and 1.6 mmol/l) after We carried out three analyses. The first was a results from first two years of treatment were excluded meta-analysis of 164 short term (typically a few weeks) (P < 0.001 for trend). After several years a reduction of randomised placebo controlled trials of six statins 1.8 mmol/l would reduce IHD events by an estimated (atorvastatin, fluvastatin, lovastatin, pravastatin, simvas- 61%. Results from the same 58 trials, corroborated by tatin, and rosuvastatin (recently marketed)), used in results from the nine cohort studies, show that fixed dose.w1-w164 The meta-analysis examined the lowering LDL cholesterol decreases all stroke by 10% efficacy of reducing total and LDL cholesterol by dose for a 1 mmol/l reduction and 17% for a 1.8 mmol/l and pretreatment serum cholesterol concentrations.
reduction. Estimates allow for the fact that trials The second meta-analysis was of 58 randomised trials tended to recruit people with vascular disease, among (including eight of the above 164 trials) of reducing whom the effect of LDL cholesterol reduction on serum cholesterol concentration by any means and stroke is greater because of their higher risk of IHD events to estimate the reduction in risk by LDL thromboembolic stroke (rather than haemorrhagic cholesterol reduction and duration of treatment. This stroke) compared with people in the general updates our 1994 analyses.6 12 13 In the third analysis we examined data from nine cohort studies and the 58 BMJ VOLUME 326 28 JUNE 2003
pressure, diabetes, or IHD. We excluded trials that had Table 1 Details of 164 randomised placebo controlled trials of statins and serum
no placebo group, lasted less than two weeks, used cholesterol reduction. Figures are means (90% range) unless stated otherwise variable doses (titrating), or used cholesterol lowering Treatment
drugs in combination, and trials in which the order of No of treatment groups (participants) in trials of: treatment and placebo periods in crossover trials was not randomised or patients had chronic renal failure We defined drug efficacy as the reduction in LDL cholesterol concentration for a given dose, expressed as the change in the treated group minus that in the placebo group (in crossover trials end treatment minus end placebo concentration). Methods for calculating standard errors and the statistical analyses are Serum cholesterol (mmol/l) concentrations before treatment: 58 randomised trials of serum cholesterol
reduction (by any means) and IHD events
We expanded the literature search to include methods of reduction of serum cholesterol concentrations other than statins; 33 more recent trials and 25 reported in *Number of placebo groups is same as number of trials.
19946 met inclusion criteria. We excluded trials in †Less than total of five categories because some trials compared two or more statins with same placebogroup.
which risk factors other than lipids were changed, LDLcholesterol reduction was < 0.2 mmol/l, fewer than randomised trials to determine the effect of a decrease five IHD events were recorded, or there was no in LDL cholesterol concentration on thromboembolic, untreated control group. We calculated the absolute haemorrhagic, fatal, and non-fatal stroke.
change in serum LDL cholesterol concentration in thetreatment group minus that in the placebo group. In 164 short term trials of statins and LDL cholesterol
17 of the 25 earlier trials LDL cholesterol was not reduction
measured so we used total serum cholesterol We searched Medline, Cochrane Collaboration, and concentration. We defined IHD events as IHD death or Web of Science databases (see www.smd.qmul.ac.uk/ non-fatal myocardial infarction, ignoring subsequent wolfson/bpchol for details and webextra for full list of events in an individual and excluding “silent” infarcts.
referencesw1-w164). We included all double blind trials, In each trial we determined the numbers of IHD events irrespective of participants’ age or disease. Participants and the changes in LDL cholesterol (adjusted for pla- in most trials were healthy with above average lipid cebo) separately for years one, two, three to five, and six concentrations. In some trials they had high blood or more after trial entry. We recorded disease eventsand the average reduction in LDL cholesterol concen- tration in all randomised participants regardless of compliance (assuming LDL concentration reverted to baseline when participants left the trial).
We combined the odds ratios (treated/placebo) of disease events, stratified according to duration of scheduled treatment, to yield summary estimates using a random effects model.15 After the effects of reduction in LDL cholesterol and duration of treatment weretaken into account there was no significant residual heterogeneity. We standardised each trial result to an LDL cholesterol reduction of 1.0 mmol/l by raising the observed odds ratio to the power of (1.0 divided by the observed LDL cholesterol reduction).
Nine cohort studies and 58 randomised trials of
serum cholesterol and stroke
We identified nine cohort studies of serum cholesterol
concentration and stroke that distinguished thrombo- embolic and haemorrhagic strokes using computed tomography or postmortem findings. We used Medline (1980 to October 2002; key and text words blood chol- esterol and [cerebral haemorrhage or intracranial haemorrhages or subarachnoid haemorrhage or cerebral infarction]). We determined the difference in incidence for a difference in LDL cholesterol of 1.0 mmol/l adjusted for regression and surrogate dilution Fig 1 Average reductions in LDL cholesterol concentration (95% confidence intervals) in the
164 trials according to statin and dose (not standardised to pretreatment serum cholesterol
bias.12 Data on stroke from the 58 randomised trials were combined by using a random effects model.15There was no significant heterogeneity.
BMJ VOLUME 326 28 JUNE 2003
Table 2 Absolute reductions* (mmol/l) (with 95% confidence intervals) and percentage reductions† in serum LDL cholesterol
concentration according to statin and daily dose (summary estimates from 164 randomised placebo controlled trials)
Daily dose (mg)
*Absolute reductions are standardised to usual serum LDL cholesterol concentration of 4.8 mmol/l before treatment (mean concentration in trials).
†Percentage reductions are independent of pretreatment LDL cholesterol concentration; 95% confidence intervals on percentage reductions can be derived bydividing those on absolute reductions by 4.8.
In these 164 trials atorvastatin and rosuvastatin Table 3 Reduction in risk (95% confidence intervals) of
were taken in the morning but the other statins in ischaemic heart disease events* for 1.0 mmol/l decrease in the evening. In four randomised comparisons in three serum LDL cholesterol concentration, according to number of trialsw77 w137 w153 the average reduction was 0.20 mmol/l smaller with morning dose than with evening dose Year in trial
% Reduction in risk
(95% confidence interval 0.05 mmol/l to 0.44 mmol/l smaller). Doubling the dose has a similar effect (about 0.20 mmol/l) and so would counter this. The greater effect of evening dose arises because of short biologicalhalf life (peak cholesterol synthesis occurs at night).
*IHD death and non-fatal myocardial infarction.
Atorvastatin and rosuvastatin have longer half lives and avoid this problem; lipid changes with atorvastatin 164 short term trials of statins and LDL cholesterol
were similar with morning and evening dose.17 reduction
The reductions in total and LDL cholesterol Table 1 shows details of the 164 trials. There were concentrations were highly correlated across trials about 24 000 treated and 14 000 placebo participants (r=0.83). On average, a reduction in LDL cholesterol of 1.0 mmol/l was associated with a total cholesterol reduction of 1.20 mmol/l (1.10 mmol/l to 1.31 mmol/ Figure 1 shows the dose-response relations for the l). If only total serum cholesterol reduction were five statins across the doses tested (2.5-80 mg/day). The measured, we would expect the absolute reduction in straight lines fit the data well. With simvastatin the lin- LDL cholesterol to be 17% less (1.0 minus 1.0/1.20).
ear trend is unconvincing above 20 mg/day, but one The reduction in VLDL cholesterol was on average study (excluded from our meta-analysis because it had 10% of the reduction in LDL cholesterol shown in no placebo group) confirmed greater efficacy at higher table 2. Statins increased HDL cholesterol by 0.07 mmol/l (0.06 mmol/l to 0.08 mmol/l) on average, with Table 2 shows the estimated reductions in LDL chol- esterol, according to statin and dose, calculated from thestraight lines and standardised to the average pretreat- 58 trials of serum cholesterol reduction and IHD
ment LDL cholesterol concentration in these trials (4.8 mmol/l; about the average in people having an IHD These 58 trials included 76 359 participants allocated event). Rosuvastatin 5 mg/day, atorvastatin 10 mg/day, treatment and 71 962 controls, with 5440 and 7102 and lovastatin or simvastatin 40 mg/day reduced LDL IHD events respectively: 52% of participants had cholesterol concentrations by about 35% (1.8 mmol/l), known vascular disease on entry. See webextra tables A but fluvastatin and pravastatin produced smaller reductions even at the highest doses tested (80 mg/day).
Table 3 shows the reduction in IHD events by dura- Rosuvastatin 10 mg/day, atorvastatin 20 mg/day, and tion of treatment; each trial result is standardised to a lovastatin or simvastatin 80 mg/day reduced concentra- reduction in LDL cholesterol of 1.0 mmol/l (about the tions by about 45% (2.1 mmol/l) and rosuvastatin average reduction in the trials). In the first year the 80 mg/day by about 60% (2.8 mmol/l).
reduction was 11%, in the second 24%, and in the first Statins significantly lowered LDL cholesterol from and second years combined 13%. Data from 12 trials all pretreatment concentrations. The absolute reduc- with event numbers published for the first two years tions (in mmol/l) were greater in those with higher but not the first and second years separately yielded a pretreatment concentrations. The percentage reduc- similar result. The reduction in the third, fourth, and tions were independent of pretreatment concentra- fifth years combined was 33%, and the sixth and subse- tions and therefore more generalisable, but we adopted quent years was 36%. After standardisation for absolute reductions because the relations with disease reduction in LDL cholesterol and duration of events were quantified by using absolute cholesterol treatment, risk reduction was similar for fatal and non- reductions.6 If the pretreatment concentration was fatal IHD events, for different methods of reducing 1 mmol/l higher (5.8 mmol/l), LDL cholesterol reduc- serum cholesterol (fibrates, resins, niacin, statins, or tion was on average 0.28 mmol/l greater. No effect of dietary change), and in participants with and without age was apparent, but there was little variation in aver- known IHD on entry (showing that the proportional risk reduction model applies regardless of initial risk).
BMJ VOLUME 326 28 JUNE 2003
Thrombo-embolic stroke
No of events Relative risk
Eastern Collaborative Research Groupw202 60 750 Korea Medical Insurance Corporationw208 114 973 All studies
Haemorrhagic stroke
Relative risk
No of events All
Eastern Collaborative Research Groupw202 60 750 Korea Medical Insurance Corporationw208 114 973 All studies
Fig 2 Relative risk (95% confidence intervals) for thromboembolic and haemorrhagic strokes (subarachnoid (SAH) and intracerebral
haemorrhage (ICH)) for 1.0 mmol/l decrease in LDL cholesterol concentration from cohort studies in which different types of stroke were
distinguished
Table 4 shows the combined effect of duration of 15% (6% to 21%) decrease in thromboembolic stroke treatment and reduction in LDL cholesterol directly.
(P < 0.001) and a 19% (10% to 29%) increase in haem- The trials tend to cluster into three groups, with mean orrhagic stroke (P < 0.001). The similar relative risk reductions of LDL cholesterol of 0.5 mmol/l (n=21), estimates for subarachnoid (1.16) and intracerebral 1.0 mmol/l (n=24), and 1.6 mmol/l (n=5). Across these haemorrhage (1.22) justify combining them as “haem- groups, the greater the reduction in LDL cholesterol the greater the reduction in IHD events. With a reduc- The opposing effects of thromboembolic and tion in LDL cholesterol of around 1.6 mmol/l the haemorrhagic stroke explain the absence of an associ- reduction in IHD events after two or more years’ treat- ation between serum cholesterol and stroke in a meta- analysis of 45 cohort studies.11 Death from the twotypes of stroke cancelled each other because the 45 Serum cholesterol and stroke
cohort studies generally recorded only fatal stroke and at age 60 (the average in the studies) about half of fatal Figure 2 shows the relative risk of thromboembolic and strokes are thromboembolic and half are haemor- haemorrhagic stroke for a 1.0 mmol/l decrease in LDL rhagic.18 w210-w214 These data also show that at age 60, cholesterol concentration from each of the nine cohort 76% of non-fatal strokes are thromboembolic and 24% studies that distinguished the two. Overall there was a haemorrhagic, and 71% of all strokes are thromboem-bolic and 29% haemorrhagic18 (the difference fromfatal stroke explained by the greater chance of dying Table 4 Reduction (%) in risk of ischaemic heart disease events (relative odds
from a haemorrhagic stroke). Application of the reduction) in 49 randomised trials* according to number of years in trial at time of change in risk for type of stroke to these percentages event and reduction in LDL cholesterol concentration yields an expected decrease in non-fatal stroke (per 1 LDL cholesterol reduction (mmol/l)
P value (test for
mmol/l reduction in LDL cholesterol) of 7% (a 15% Year in trial
0.2-0.7*
0.8-1.4†
≥1.5‡
decrease in 76% plus a 19% increase in 24%). Similarly the expected decrease for all stroke is 6%.
58 trials of cholesterol reduction by any means and disease *21 trials, mean reduction 0.5 mmol/l.
†24 trials, mean reduction 1.0 mmol/l.
‡5 trials, mean reduction 1.6 mmol/l.
Fifty six of the 58 trials reported on deaths from stroke §Excludes 8 trials that lasted less than one year.
(though in 21 trials none occurred) and 40 reported on BMJ VOLUME 326 28 JUNE 2003
Table 5 Change in risk of stroke (relative odds reduction) for 1.0 mmol/l reduction in LDL cholesterol in randomised trials and
estimates from analysis of cohort studies (fig 2) according to whether trial participants had known vascular disease on entry and
whether stroke was thromboembolic or haemorrhagic and fatal or non-fatal
Randomised trials
Estimated % change in risk
Estimated % change in risk in
Category
No of trials
No of events
cohort studies† (95% CI)
All stroke in people with known vascular disease All stroke in people without known vascular disease *P<0.001.
†Trials in which there were similar numbers of strokes in patients with and without vascular disease on entry are omitted, except one in which separate numberswere available.w168‡From data in figure 2 (taking account where necessary of proportions of non-fatal and all strokes that are thromboembolic and haemorrhagic).
§Meta-analysis of 45 cohort studies11 (in which nearly all strokes recorded were fatal) gave similar result (2, −1 to 6).
non-fatal strokes (in 10 none occurred) (see webextra would, therefore, be greater if events occurring in the Table 5 shows the main results on stroke from ran- Adverse effects
domised trials and the above expected results from the Forty eight of the 164 trials of statins and LDL choles- nine cohort studies, standardised to an LDL choles- terol reported the number of participants with one or terol reduction of 1.0 mmol/l. Stroke risk in all the more symptoms possibly caused by the drug trials was reduced by 20% on average (P < 0.001), but (1063/14197 allocated to statins and 923/10568 this varied. In people without known vascular disease allocated to placebo). Meta-analysis of these data the reduction was the same ( − 6%)as that expected showed no excess risk in people allocated to statins. On from cohort studies, but in people with known vascular average 1% fewer treated patients than placebo disease it was higher ( − 22% v − 6%; P < 0.001). This patients reported symptoms (95% confidence interval difference probably arises because thromboembolic 3% fewer to 1% more in treated patients). The stroke is common in people with vascular disease so prevalence of each of 12 specific symptoms, including more of their strokes will be thromboembolic. Results muscle pain and various gastrointestinal symptoms, from the six randomised trials in people with known was similar in treated and placebo patients, even for the vascular disease that distinguished the two types of highest daily dose tested (80 mg for all six statins). The stroke confirmed this: 91% of the strokes in the upper confidence limits excluded the possibility that placebo groups were thromboembolic (700/773) and statins caused any symptom in more than 2% of treated 9% haemorrhagic, whereas in the stroke registry stud- ies in people the same age without known vascular dis- The only known serious adverse effects of statins ease 71% of strokes were thromboembolic and 29% are rhabdomyolysis and liver failure from hepatitis.
haemorrhagic.w210-w214 Reduction in LDL cholesterol The absolute risks are low. In the trials of statins and concentration prevents thromboembolic but not adverse events, with about 35 000 people and 158 000 haemorrhagic strokes, accounting for the greater than person years of observation in both treated and expected effect of treatment in people with vascular placebo groups (see webextra table A), rhabdomyolosis disease. This also explains the greater than expected was diagnosed (variable criteria) in eight treated and reduction in non-fatal stroke in shown table 5 ( − 23% v five placebo patients, none with serious illness or death.
− 7%; P < 0.001) as most non-fatal strokes are Raised serum creatine kinase activity ( ≥ 10 times the thromboembolic. The absence of a material reduction “upper limit of normal,” used to recognise rhabdomy- in fatal stroke in the trials corroborates the cohort olysis) was reported in 55 treated patients (0.17%) and 43 placebo patients (0.13%); muscle symptoms were The 20% reduction in stroke for a 1.0 mmol/l present in 13 and 4 respectively. From the first market- reduction in LDL cholesterol concentration is there- ing of statins in 1987 to May 2001 the Food and Drug fore specific to these trial populations in which 80% of Administration recorded 42 deaths from rhabdomy- all strokes were in people with known vascular disease.
olysis attributable to statins (other than cerivastatin, In the general population, stroke registry data indicate which was not used in these trials) in the United that about 25% of first strokes are in people with States,19 a rate of one per 10 million prescriptions dis- known vascular disease.w217-w219 Therefore a reduction of pensed19 or (as a prescription is typically for one 1.0 mmol/l in LDL cholesterol would reduce stroke in month’s supply20) about one per million person years the general population by 10% (25% of the 22% reduc- of use. There were no cases of liver failure in the trials.
tion in people with known vascular disease and 75% of Raised alanine aminotransferase activity ( ≥ 3 times the the 6% reduction in people without known vascular upper limit of normal, used to recognise hepatitis) was reported in 449 treated (1.3%) and 383 placebo Three large trials showed little or no reduction patients (1.1%) (see webextra table A). From 1987 to in incidence of stroke until the second year, as for May 2000 the Food and Drug Administration recorded IHD.w165 w184-w187 The reductions in all stroke, thrombo- 30 cases of liver failure attributable to statins,21 again embolic stroke, and non-fatal stroke shown in table 5 about one per million person years of use.
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Table 6 Percentage reduction (95% confidence interval) in risk of ischaemic heart disease events in randomised trials (excluding first
two years of treatment) compared with expected reductions from cohort study data6
Mean reduction
Total no of
Reduction in risk of IHD events
Serum cholesterol reduction (mmol/l)
(mmol/l)
Observed in trial data
Expected from cohort study data*
*At age 60 years (average age at which ischaemic heart disease events occurred).
Table 7 Expected % decrease in incidence of ischaemic heart disease events for specified decreases in serum cholesterol according
to age at event, based on 10 largest cohort studies of serum cholesterol and ischaemic heart disease6
LDL cholesterol reduction (mmol/l)*
Age (years)
*Decreases in incidence follow from linear dose-response relation indicating constant proportional change in risk for specified change in cholesterol. Thus at age 60years relative risk for decrease of 1.0 mmol/l is 0.59 (41% decrease), therefore 0.591.4 = 0.48 (52% decrease) for 1.4 mmol/l decrease.
Concern over hazards from serum cholesterol and rosuvastatin is relatively untested. As moderate reduction was resolved by earlier studies.9 13 Data from doses of statins substantially reduce the risk of IHD the 58 randomised trials of cholesterol reduction and events it may be prudent to select commonly used disease events confirm this. The odds ratios (treated/ doses of the older drugs for general use. This would placebo) for a 1.0 mmol/l decrease in serum also be cheaper, as simvastatin comes off patent in cholesterol were 0.87 (0.73 to 1.03; 675 deaths) for cir- 2003 and lovastatin is already off patent. At doses of 40 culatory diseases other than IHD and stroke, 1.06 (0.96 mg/day these drugs lower LDL cholesterol by 1.8 to 1.16; 2293 deaths) for cancer, 0.94 (0.72 to 1.23; 324 mmol/l, which can reduce IHD events at age 60 years deaths) for injuries and suicide, and 0.88 (0.78 to 1.01; by 61% (51% to 71%). This is about double the 1363 deaths) for diseases other than circulatory currently recognised preventive effect of 30%.1–3 Reasons for underestimation of effect on IHD
Why are the current estimates of effect so low? Firstly,
Discussion
five of the seven largest statin trials used pravastatin,which is relatively less effective (table 2). Secondly, risk Randomised trials show directly that a reduction in falls relatively little within the first two years, and inclu- LDL cholesterol of 1.6 mmol/l halves the risk of IHD sion of these early events underestimates the events after two years and that this reduction can be preventive effect. Thirdly, a particular problem for the achieved with low doses of some statins (for example, statin trials was the extent to which the intention to simvastatin 20 mg/day, table 2). Certain statins achieve treat analysis underestimated the true preventive phar- larger reductions (for example, 2.6 mmol/l with atorv- macological effect because of non-adherence to the astatin 80 mg/day and 2.8 mmol/l with rosuvastatin 80 protocol (treated patients not taking their tablets and mg/day), which would lead to greater reductions in placebo patients taking statins). This last problem was IHD events, but the corresponding risk reduction can- partially overcome by relating the reduction in disease not be quantified directly from randomised trials as no events to the average LDL cholesterol reduction in all trial achieved so large a reduction. This can be randomised participants (treated and placebo). In this determined from cohort studies of cholesterol and way non-adherence to the protocol was reflected in IHD if cohort studies accurately predicted trial results.
both a smaller than expected difference in LDL Table 6 shows the reduction in IHD events in the cholesterol concentration and a smaller than expected trials after the exclusion of data from the first two years difference in the number of IHD events between the and those expected from cohort study results.6 two groups. While this yields an accurate estimate of Observed trial and expected cohort study results are the risk reduction for the observed difference in LDL close, showing that cohort study data can be used to cholesterol it underestimates the effect of a given dose predict risk reduction from lowering LDL cholesterol.
The similarity between trial and cohort study data, andthe similar reductions in risk (given cholesterol reduc- Effects of LDL cholesterol reduction on stroke
tion) with different methods of lowering cholesterol, The estimated overall reduction in stroke of 10% (rela- indicate that the reduction in risk is directly tive risk 0.90) for a 1.0 mmol/l reduction in LDL chol- attributable to cholesterol reduction; there is no need esterol is equivalent to a 17% (9% to 25%) reduction in stroke for a 1.8 mmol/l reduction LDL cholesterol, Table 7 shows the reductions in IHD events at readily achievable with a statin (as 0.901.8/1 = relative risk different ages predicted from the cohort studies.6 At of 0.83). In people with existing vascular disease the age 60 years a 2.2 mmol/l reduction in serum LDL reduction is 36% (0.781.8 = 0.64) The interpretation of cholesterol concentration (attainable by using atorva- the cohort study result showing a higher incidence of statin 40 mg/day, lovastatin 80 mg/day, or rosuvastatin haemorrhagic stroke for a lower LDL cholesterol con- 20 mg/day) would reduce the risk of IHD by nearly centration is uncertain. Too few haemorrhagic strokes 70%. However, adverse effects are also dose related,19 were identified in the randomised trials to resolve the BMJ VOLUME 326 28 JUNE 2003
Competing interests: NW and ML have filed a patent What is already known on this topic
application on the formula of a combined pill to simultaneouslyreduce four cardiovascular risk factors.
Statins lower LDL cholesterol, but the size of thereduction according to statin and dose is uncertain LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease.
JAMA 1999;282:2340-6.
Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary Statins prevent heart disease, but meta-analyses of prevention of coronary heart disease: meta-analysis of randomised trials.
randomised trials have underestimated their effect Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD.
Cholesterol reduction yields clinical benefit. Impact on statin trials. Circu- The effect of statins on risk of stroke is uncertain Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy What this study adds
study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvas-tatin in patients with hypercholesterolemia (the CURVES Study). Am J Simvastatin 40 mg/day, lovastatin 40 mg/day, and Schectman G, Hiatt J. Dose-response characteristics of cholesterol- atorvastatin 10 mg/day lower LDL cholesterol by lowering drug therapies: implications for treatment. Ann Intern Med about 37% from all pretreatment concentrations Law MR, Wald NJ, Thompson SG. By how much and how quickly doesreduction in serum cholesterol concentration lower risk of ischaemic These interventions reduce the risk of ischaemic heart disease? BMJ 1994;308:367-72.
Crouse JR, Byington RP, Furberg CD. HMG-CoA reductase inhibitor heart disease events at age 60 by an estimated 61% therapy and stroke risk reduction: an analysis of clinical trials data.
in the long term, with little reduction in the first Atherosclerosis 1998;138:11-24.
year but a 51% reduction by the third year Blauw GJ, Lagaay AM, Smelt AHM, Westendorp RGJ. A meta-analysis ofrandomised, placebo controlled, double-blind trials with HMG-CoAreductase inhibitors. Stroke 1997;28:946-50.
The interventions reduce the overall risk of stroke Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol loweringwith statin drugs, risk of stroke, and total mortality. JAMA 1997;278:313- by 17%, preventing thromboembolic but not 10 Bucher HC, Griffith LE, Guyatt GH. Effect of HMGcoA reductase inhibi- tors on stroke. Ann Intern Med 1998;128:89-95.
11 Prospective Studies Collaboration. Cholesterol, diastolic blood pressure and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts.
uncertainty. An increased risk cannot be excluded, but this should not preclude the use of statins in the 12 Law MR, Wald NH, Wu T, Hackshaw A, Bailey A. Systematic underestimation of association between serum cholesterol concentration prevention of cardiovascular disease.
and ischaemic heart disease in observational studies: data from the BUPAstudy. BMJ 1994;308:363-6.
Conclusions
13 Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. BMJ 1994;308:373–9.
Statins can reduce IHD events by an estimated 61%.
14 Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination They reduce stroke by 17%, preventing non-fatal treatment with blood pressure lowering drugs: analysis of 354randomised trials. BMJ 2003; to go in same issue strokes with little effect on the risk of fatal stroke. Any 15 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials possible excess of haemorrhagic stroke is greatly outweighed by the protective effect against IHD events 16 Ose L, Davidson MH, Stein EA, Kastelein JJP, Scott RS, Hunninghake DB, et al. Lipid-altering efficacy and safety of simvastatin 80mg/day: long-term experience in a large group of patients with hypercholest-erolemia. Clin Cardiol 2000;23:39-46.
We thank the following authors for unpublished data from 17 Cilla DD, Gibson DM, Whitfield LR, Sedman AJ. Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to nor- trials: V Athyros (GREACEw173), M Bortolini and P Serruys mocholesterolemic subjects in the morning and evening. J Clin Pharma- (LIPSw174), A Tonkin and A Kirby (LIPIDw183), T Pedersen and T Cook (4Sw156), and G Steiner (DAISw200), as well as the authors 18 Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke acknowledged in our earlier paper.6 We also thank Leo Kinlen and its pathological types: results from an international collaboration.
International Stroke Incidence Collaboration. Stroke 1997;28:491-9.
19 Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomy- Contributors: MRL, NJW, and ARR wrote the paper. MRL and olysis. N Engl J Med 2002;346:539-40.
ARR abstracted the data. ARR carried out the statistical 20 Wysowski DK, Kennedy DL, Gross TP. Prescribed use of cholesterol- analyses. All authors interpreted the results. MRL is guarantor.
lowering drugs in the United States, 1978 through 1988. JAMA1990;263:2185-8.
Funding: ARR was supported by an NHS research and develop- 21 Food and Drug Administration, Center for Drug Evaluation and ment programme award. The guarantor accepts full responsibil- Research. Statins and hepatotoxicity. www.fda.gov/ohrms/dockets/ac/ ity for the conduct of the study, had access to the data, and 00/backgrd/3622b2b_safety_review.pdf (accessed 8 Apr 2003).
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