efficacy of statins for primary prevention in people at...
TRANSCRIPT
Although statins are known to improvesurvival and relevant clinical outcomesin high-risk populations,1 evidence of
their clinical benefit in lower risk populations ismore equivocal. Initially, low-risk populationswere defined by the absence of known coronaryartery disease (and their treatment was termed“primary prevention”). However, it was sub -sequently recognized that these populationsincluded both patients at very high risk of coro-nary artery disease (e.g., those with severeperipheral vascular disease) and those at verylow risk (e.g., those aged < 40 years who haveno diabetes or hypertension and have low- density lipoprotein cholesterol level of less than1.8 mmol/L). Accordingly, current guidelinesfor the use of statins are based on the projected
risk of an atherosclerotic event rather thansolely on the presence or absence of knowncoronary artery disease.2,3
Results of the recent JUPITER study (Justifi-cation for the Use of Statins in Prevention: anIntervention Trial Evaluating Rosuvastatin)4 haverenewed enthusiasm for the use of statins in peo-ple without a history of coronary artery diseaseand have generated further controversy as towhether high-potency statins such as rosuva statinand atorvastatin lead to better clinical outcomesthan low-potency statins such as prava statin, sim-vastatin, fluvastatin and lovastatin. We did a sys-tematic review of randomized trials to assess theefficacy and harms of statins in people at low car-diovascular risk, including indirect comparisonsof high-potency and low-potency statins.
Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis
Marcello Tonelli MD SM, Anita Lloyd MSc, Fiona Clement PhD, Jon Conly BA, Don Husereau BScPharm MSc,Brenda Hemmelgarn PhD MD, Scott Klarenbach MD MSc, Finlay A. McAlister MD MSc, Natasha Wiebe MMath PStat, Braden Manns MD MSc; for the Alberta Kidney Disease Network
Competing interests:Marcello Tonelli hasreceived research supportfrom Pfizer; in 2011 heserved on an advisory boardfor Merck, providing expertopinion on global chronickidney disease andcardiovascular disease.Brenda Hemmelgarn hasreceived research supportfrom Merck and Amgen.Braden Manns has receivedresearch support fromMerck Canada. Nocompeting interests declaredby the other authors.
This article has been peerreviewed.
Correspondence to:Dr. Marcello Tonelli, mtonelli-admin @med.ualberta.ca
CMAJ 2011. DOI:10.1503/cmaj.101280
ResearchCMAJ
Background: Statins were initially used to im -prove cardiovascular outcomes in people withestablished coronary artery disease, but re -cently their use has become more common inpeople at low cardiovascular risk. We did a sys-tematic review of randomized trials to assessthe efficacy and harms of statins in these individuals.
Methods: We searched MEDLINE and EMBASE(to Jan. 28, 2011), registries of health technol-ogy assessments and clinical trials, and refer-ence lists of relevant reviews. We included tri-als that randomly assigned participants at lowcardiovascular risk to receive a statin versus aplacebo or no statin. We defined low risk asan observed 10-year risk of less than 20% forcardiovascular-related death or nonfatal myo -cardial infarction, but we explored other defi-nitions in sensitivity analyses.
Results: We identified 29 eligible trials involv-ing a total of 80 711 participants. All-cause
mortality was significantly lower among pa -tients receiving a statin than among controls(relative risk [RR] 0.90, 95% confidence inter-val [CI] 0.84–0.97) for trials with a 10-year riskof cardiovascular disease < 20% [primaryanalysis] and 0.83, 95% CI 0.73–0.94, for trialswith 10-year risk < 10% [sensitivity analysis]).Patients in the statin group were also signifi-cantly less likely than controls to have nonfa-tal myocardial infarction (RR 0.64, 95% CI0.49–0.84) and nonfatal stroke (RR 0.81, 95%CI 0.68–0.96). Neither metaregression norstratified analyses suggested statistically sig-nificant differences in efficacy between high-and low-potency statins, or larger reductionsin cholesterol.
Interpretation: Statins were found to be effi-cacious in preventing death and cardiovascu-lar morbidity in people at low cardiovascularrisk. Reductions in relative risk were similar tothose seen in patients with a history of coro-nary artery disease.
Abstract
© 2011 Canadian Medical Association or its licensors CMAJ 1
See related research article by Conly and colleagues at www.cmaj.ca/lookup/doi/10.1503/cmaj.101281
Early release, published at www.cmaj.ca on October 11, 2011. Subject to revision.
Methods
We performed a systematic review of publishedand unpublished randomized controlled trialsthat compared statins with no statin or placebo.We used accepted methods for literaturesearches, article selection, data extraction andrisk-of-bias assessment. The review was reportedaccording to accepted guidelines.5,6
Literature searchWe searched MEDLINE (1950 to Jan. 28, 2011)and EMBASE (1950 to Jan. 28, 2011). Details ofthe search strategy appear in Appendix 1 (avail-able at www.cmaj.ca/lookup /suppl/doi:10.1503/cmaj.101280/-/DC1). Because of high searchyields, an update of a modified version of theNational Institute for Health and Clinical Excel-lence search7 was performed, with elimination ofstudies published before 2003. Searches werenot restricted by language (when a translatorcould be found).
We also searched registries of health technol-ogy assessments and clinical trials, conductedmanual searches of reference lists of relevantreviews, and contacted Canadian manufacturersof statins (Astra Zeneca, Merck Frosst, Pfizer,Bristol Myers Squibb, Novartis) for additionalstudies and unpublished reports of trials.
Study selection and validity assessmentWe included parallel-group randomized con-trolled trials if they included people 16 years orolder who were at low cardiovascular risk (asdefined in the next paragraph), the follow-upperiod was at least six months, and an eligiblestatin (atorvastatin, fluvastatin, lovastatin, prava -statin, rosuvastatin or simvastatin) was comparedwith no statin (placebo or standard care). We cat-egorized statins according to their pharmaco-logic effect on lowering cholesterol as either lowpotency (fluvastatin, lovastatin, pravastatin andsimva statin) or high potency (atorvastatin androsuva statin).8 To be eligible, studies also had toreport one or more of the following outcomes:all-cause mortality, unstable angina, acute myo -cardial infarction (fatal or nonfatal), stroke ortransient ischemic attack (fatal or nonfatal), sur-gical or percutaneous revascularization, length ofstay, quality of life, persistence on statin therapy,and adverse events. Trials with fewer than 30participants per study arm were excluded toimprove the efficiency of the work without anappreciable loss of power.9
Trials were considered to have enrolled par-ticipants at low cardiovascular risk if the 10-yearrisk of cardiovascular-related death or nonfatalmyocardial infarction among participants was
less than 20%,10 as assessed by extrapolation ofobserved risk in the control group of each trial.In general, this corresponded to participants whowere free from cardiovascular disease (i.e., noprior acute coronary syndrome or coronary re -vascularization, no prior ischemic stroke and noprior revascularization or loss of limb owing toperipheral arterial disease) and diabetes. Datafrom trials in which some, but not all, partici-pants had known cardiovascular disease wereincluded if the control group had a low cardio-vascular risk (as defined above).
In sensitivity analyses, we calculated the esti-mated 10-year risk of cardiovascular-related deathor nonfatal myocardial infarction for the averageparticipant in each trial, using mean baseline char-acteristics from the control group and two com-monly used formulas from D’Agostino and col-leagues11 and the Third Adult Treatment Panel.12
We also used a number of other definitions forlow risk in sensitivity analyses.
Two reviewers screened each citation. Trialsconsidered to be relevant by one or both review-ers were retrieved, and the full text was indepen-dently assessed by two reviewers for inclusion.Disagreements were resolved by a third partythrough consensus.
Two reviewers independently assessed eachstudy’s risk of bias using a condensed version ofthe Chalmers Index13 as well as other characteris-tics that influence the risk of biased estimates ofeffectiveness in meta-analyses.14–16 Disagreementswere resolved by a third party through consensus.
Data extractionOne reviewer extracted data from selected trials,and a second reviewer checked the data for accu-racy. Results of intention-to-treat analyses werecollected if reported.
We classified adverse events as serious if theywere defined as such by the primary authors or iftheir severity was unspecified but they led towithdrawal from therapy or study. We also col-lected data on the incidence of new diabetes, can-cer and rhabdomyolysis. Myocardial infarctionswere classified as fatal, nonfatal or fatal/ nonfatal;those in the fatal/ nonfatal category were fromstudies that did not specify the type of myocardialinfarction or separate totals for fatal and nonfatalmyocardial infarctions. Strokes were classified ina similar manner. Angina was classified as un -stable if defined as such by the primary authors, ifit required admission to hospital or if it necessi-tated revascularization. Angina that did not meetthese criteria was classified as “unspecified”angina. Types of revascularization in cluded coro-nary artery by pass graft surgery, percutaneouscoronary intervention, percutaneous transluminal
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coronary angioplasty, interventional vascular pro-cedure, coronary revascularization, arterial revas-cularization and coronary angioplasty. For studiesin which the number of cardiovascular-relateddeaths or nonfatal myocardial infarctions wasunclear, we contacted the original authors forinformation so that we could calculate the 10-year risk.
Data synthesis and analysisWe pooled the results using the random-effectsmodel described by DerSimonian and Laird.17
We used relative risks (RRs) to summarize di -chotomous results. We quantified statistical het-erogeneity using the I2 statistic and used “small,”“moderate” and “large” to describe values of25%, 50% and 75%.18,19 A weighted regressiontest20 was used to test for publication bias.
We used univariable and bivariable meta -regression analyses18 to examine whether the fol-lowing variables influenced the association be -tween statin use and all-cause mortality: durationof study, year of study, baseline cholesterol lev-els, observed annual cardiovascular risk in thecontrol arm, the absolute and percent change inlow-density lipoprotein cholesterol from baselinein the statin arm, the point at which low-densitylipoprotein cholesterol was measured, daily ini-tial dose of statin, potency of statin (high v. low),mean age of participants, proportion of partici-pants who were male, proportion who had dia-betes, proportion who had hypertension, andrisk-of-bias items.
The number needed to treat and the absoluterisk reduction were calculated for outcomes withstatistically significant relative risks. The numberneeded to treat indicates the number of patientswho need to be given statin treatment to preventone event and is the reciprocal of the absoluterisk reduction (difference in probabilities of anevent between treatment and control groups).21
In subgroup analyses, we examined all-causemortality and other clinical outcomes for trialsstratified by statin potency (high v. low). We alsoexplored the relative effects of statins using amethod of indirect comparison of treatments de -scribed by Bucher and colleagues,22 a techniquethat facilitates the comparison of any two statinsnot directly compared in any one study. Here, themagnitude of treatment effects (e.g., relativerisk) for the direct evidence of treatment A ver-sus B and treatment B versus C were comparedwith acquired indirect evidence of treatment Aversus C.
Analyses were conducted using RevMan Ver-sion 4.2 (The Cochrane Collaboration, 2002,Oxford, England) and Stata/MP 11.2 software(Stata Corp, 2011, College Station, Texas).
Results
Literature searchOf the 15 250 articles identified, 29 (n = 80 711)met our inclusion criteria (Figure 1).4,23–50 Atorva -statin was the study drug in six trials (n = 11 894),fluvastatin in four trials (n = 2107), lovastatin inthree (n = 15 769), pravastatin in nine (n =30 974), rosuva statin in four (n = 19 129) andsimvastatin in three (n = 838). Twenty-two of thetrials were placebo-controlled, and the remainingseven reported usual care, conventional treatment,standard treatment, no treatment or diet as thecomparators. The median year of publication was2004 (range 1991–2010). The median duration offollow-up was two years (range 0.5–5.3 years).Details of the studies are summarized in Table 1(at the end of the article).
Risk-of-bias assessmentThe 29 trials generally exhibited moderate riskof bias (Table 2, at the end of the article). Aweighted regression test20 using all-cause mortal-ity results detected no statistical evidence of pub-lication bias (bias = 0.03, p = 0.92).
Characteristics of participantsThe median age of the participants was 58 years(range 51–76), and the proportion who were
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Excluded n = 14 426 • Not relevant n = 14 388 • Not retrievable n = 6 • No translator n = 32
Excluded n = 795 • Not original research n = 292 • Not low-risk population n = 187 • No relevant outcomes n = 142 • Sample size < 30 n = 43 • No placebo or usual-care
arm n = 32 • Follow-up < 6 mo n = 32 • Multiple publication n = 30 • No statin arm n = 24 • Not an RCT n = 7 • No useable data n = 5 • Not human n = 1
Trials included in meta-analysis n = 29
Articles retrieved for detailed evaluation n = 824
Potentially relevant records identified and screened for retrieval
n = 15 250
Figure 1: Selection of studies for inclusion in the meta-analysis. RCT = random-ized controlled trial.
male ranged from 0% to 100% (median 62%).The median proportion of participants who haddiabetes was 7% (range 0%–35%), and hyper-tension 47% (range 16%–100%) (Table 1).
The baseline lipid levels in the in cluded trialswere: total cholesterol, median 6.0 (range 4.8–7.6) mmol/L; low-density lipoprotein cholesterol,median 4.0 (range 2.8–5.2) mmol/L; high-densitylipoprotein cholesterol, median 1.3 (range 1.0–1.9) mmol/L; and triglycerides, median 1.7(range 1.2–3.6) mmol/L. Seven studies reportedbaseline C-reactive protein levels: median 0.17(range 0.15–7.7) mg/dL (16.6 [range 13.8–732.4]nmol/L). The mean 10-year risk of cardiovascu-lar-related death or nonfatal myocardial infarctionwas 6% (range 0%–18%).
OutcomesTable 3 presents a summary of the relative risks(overall and stratified by high- and low-potencystatins), number needed to treat and absolute riskreduction for all outcomes.
All-cause mortalityTwenty-three trials (n = 79 495) reported all-causemortality (Figure 2). The trial-level relative riskcould not be estimated for four trials that reportedno events in either group.51 From the remaining 19trials (n = 78 321), the pooled relative risk ofdeath was significantly lower among statin recipi-ents than among controls (RR 0.90, 95% confi-dence interval [CI] 0.84–0.97; I2 = 2.0%).
In the metaregression analyses, none of thecharacteristics listed in the methods section(including baseline cholesterol levels or changein lipid levels during the trials) significantlymodified the association between statin use andall-cause mortality at the level of p < 0.05(Appendix 2, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.101280/-/DC1).
Myocardial infarctionThirteen trials (n = 48 023) reported the numberof participants with fatal, nonfatal or unspecifiedmyocardial infarctions. The pooled relative riskwas significantly lower among statin recipientsthan among controls (RR 0.63, 95% CI 0.50–0.79; I2 = 13%].
From eight trials (n = 31 424) that provideddata on fatal myocardial infarctions, we foundthat the pooled relative risk did not differ signifi-cantly between treatment groups (RR 0.96, 95%CI 0.5–1.85; I2 = 0%).
Ten trials (n = 49 222) reported nonfatalmyocardial infarctions. The pooled relative riskwas significantly lower among statin recipientsthan among controls (RR 0.64, 95% CI 0.49–0.84; I2 = 44%) (Figure 3). After removingstudies that enrolled people with prior myocar-dial infarction, we found that the point estimatewas similar to the estimate from the primaryanalysis (eight trials, n = 48 595; RR 0.64,95% CI 0.48–0.86; moderate heterogeneity [I2
= 54%]).
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Table 3: Relative risk of serious outcomes associated with the use of statins in patients at low cardiovascular risk*
Outcome Overall
RR (95% CI)
RR for high-potency statins
(95% CI)
RR for low-potency statins
(95% CI)
Number needed to treat
(95% CI)†
Absolute risk reduction, %
(95% CI)†
Death from any cause 0.90 (0.84–0.97) 0.85 (0.74–0.96) 0.90 (0.79–1.03) 239 (149–796) 0.42 (0.13–0.67)
Myocardial infarction 0.63 (0.50–0.79) 0.47 (0.31–0.71) 0.68 (0.53–0.87) 216 (160–381) 0.46 (0.26–0.63)
Fatal myocardial infarction 0.96 (0.50–1.85) 1.54 (0.61–3.89) 0.59 (0.23–1.51) – –
Nonfatal myocardial infarction 0.64 (0.49–0.84) 0.47 (0.34–0.67) 0.77 (0.59–1.00) 153 (108–343) 0.66 (0.29–0.93)
Stroke 0.83 (0.74–0.93) 0.70 (0.55–0.87) 0.89 (0.77–1.03) 291 (190–707) 0.34 (0.14–0.53)
Fatal stroke 0.91 (0.65–1.29) 0.50 (0.13–2.0) 0.95 (0.67–1.35) – –
Nonfatal stroke 0.81 (0.68–0.96) 0.51 (0.33–0.79) 0.88 (0.73–1.06) 335 (199–1592) 0.30 (0.06–0.50)
Unstable angina 0.71 (0.55–0.92) 0.73 (0.48–1.11) 0.70 (0.51–0.97) 431 (278–1563) 0.23 (0.06–0.36)
Angina, type unspecified 0.83 (0.57–1.22) 1.05 (0.12–9.23) 0.83 (0.56–1.22) – –
Revascularization 0.66 (0.57–0.77) 0.74 (0.39–1.40) 0.66 (0.55–0.78) 131 (103–193) 0.77 (0.52–0.97)
Serious adverse event 1.01 (0.96–1.07) 0.96 (0.86–1.09) 1.03 (0.98–1.10) – –
Rhabdomyolysis 1.29 (0.25–6.68) 2.99 (0.31–28.75) 0.50 (0.05–5.51) – –
Cancer 1.00 (0.93–1.08) 0.95 (0.81–1.11) 1.02 (0.93–1.11) – –
New diabetes 1.05 (0.84–1.32) 1.17 (1.04–1.32) 0.76 (0.56–1.02) – –
Note: CI = confidence interval, RR = relative risk. *Low cardiovascular risk was defined as an observed 10-year risk of less than 20% for cardiovascular-related death or nonfatal myocardial infarction. †Number needed to treat and absolute risk reduction for each outcome were calculated on the basis of the pooled risk in the control arm from all included trials. Number needed to treat and absolute risk reduction were calculated only for outcomes with a statistically significant estimate of effect.
StrokeFourteen trials (n = 60 841) reported the num-ber of participants with fatal, nonfatal or unde-fined strokes. The pooled relative risk of strokewas significantly lower among statin recipientsthan among controls (RR 0.83, 95% CI 0.74–0.93; I2 = 0%).
Five trials (n = 36 118) reported on the risk offatal stroke; the pooled relative risk did not differsignificantly be tween treatment groups (RR 0.91,95% CI 0.65–1.29; I2 = 0%). Nine trials (n =37 333) reported the number of participants withnonfatal stroke; the pooled relative risk was sig-nificantly lower among statin recipients (relativerisk 0.81 [0.68–0.96]; I2 = 0%) (Figure 4).
Coronary revascularizationEight trials (n = 43 708) reported the number ofparticipants who underwent percutaneous or sur-
gical coronary revascularization. The incidenceof revascularization was significantly loweramong statin recipients than among controls (RR0.66, 95% CI 0.57–0.77; I2 = 7%).
Other outcomesFour trials (n = 35 017) reported on the risk ofunstable angina: the pooled relative risk was sig-nificantly lower among statin recipients thanamong controls (RR 0.71, 95% CI 0.55–0.92;I2 = 0%). Three trials (n = 9082) re ported on therisk of un specified angina: the pooled relativerisk did not differ significantly between treat-ment groups (RR 0.83, 95% CI 0.57–1.22; I2 =0%). Thirteen trials reported on the proportion ofparticipants who adhered to statin therapy (range63%–98%). Length of hospital stay, persistenceon statin therapy and quality-of-life measureswere not reported in any of the studies.
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0.1 0.2 0.5 1 2 5 10
Favours statin
Favours nostatin
High-potency statin†
RR (95% CI)
Statin No statin RR (95% CI)Study
Low-potency statin*
No. of events, n/N
33/6 5821/4603/224
106/3 3021/151
80/3 30487/2 219
631/5 1701/6070/2061/254
13/4330/414/283
55/3 8660/87
186/5 1685/700/4851/702
198/8 9019/3144/58
403/15 698
1 419/42 887
3/1 6638/4594/223
135/3 2930/154
77/3 30178/1 634
641/5 1851/6220/1020/254
12/4310/415/285
79/3 9660/93
212/5 1375/730/1190/282
247/8 9016/3255/65
475/14 902
1 518/36 608
1 016/27 189 1 043/21 706
EXCEL45
ACAPS38
KAPS41
WOSCOPS43
CAIUS42
AFCAPS/TexCAPS39
KLIS37
ALLHAT–LLT40
Bruckert et al.33
Muldoon et al.29
PHYLLIS30
PREVEND-IT31
Rejnmark et al.32
HYRIM28
MEGA24
ASCOT–LLA36
Holmberg et al.26
Bone et al.23
METEOR34
JUPITER4
LEADe46
LORD48
OverallI² = 2.0%
SubtotalI² = 0%
SubtotalI² = 18.8%
ESPLANADE49
2.78 (0.85–9.05)0.12 (0.02–0.99)0.75 (0.17–3.30)0.78 (0.61–1.01)3.06 (0.13–74.51)1.04 (0.76–1.41)0.82 (0.61–1.11)0.99 (0.89–1.09)1.02 (0.06–16.35)Not estimable
3.00 (0.12–73.30)1.08 (0.50–2.34)Not estimable
0.81 (0.22–2.97)0.71 (0.51–1.00)Not estimable
0.90 (0.79–1.03)
0.87 (0.72–1.06)1.04 (0.32–3.45)Not estimable
1.21 (0.05–29.56)0.80 (0.67–0.96)1.55 (0.56–4.31)0.90 (0.25–3.18)
0.85 (0.74–0.96)
0.90 (0.84–0.97)
Figure 2: Risk of death from any cause associated with the use of statins (versus no statins) in pa tients atlow cardiovascular risk (observed 10-year risk of cardiovascular-related death or nonfatal myocardial infarc-tion < 20%). A relative risk (RR) of less than 1.0 indicates fewer deaths with the use of statins. CI = confi-dence interval. *Lovastatin, fluvastatin, pravastatin and simvastatin. †Rosuva statin and atorvastatin. Forcomplete study names, see Box 1.
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Statin No statin RR (95% CI)Study
Low-potency statin*ACAPS38 )24.3–92.0( 00.1064/5KAPS41 )79.1–31.0( 05.0422/3WOSCOPS43 )68.0–75.0( 07.0203 3/341CAIUS42 )65.5–50.0( 15.0151/1KLIS37 )82.2–77.0( 33.1912 2/63Muldoon et al.29 elbamitse toN602/0Rejnmark et al.32 elbamitse toN14/0MEGA26 )00.1–03.0( 55.0668 3/61ESPLANADE49 )36.77–31.0( 02.378/1
)00.1–95.0( 77.0655 01/502latotbuSI² = 15.8%
High-potency statin†ASCOT–LLA36 )67.0–04.0( 55.0861 5/06METEOR34 )65.92–50.0( 12.1207/1JUPITER4 )85.0–22.0( 53.0109 8/22
)76.0–43.0( 74.0177 41/38latotbuSI² = 22.1%
)48.0–94.0( 46.0723 52/882llarevOI² = 44.3%
No. of events, n/N
5/459
267/9 965
2/15420/1 634
0/1020/41
30/3 9660/93
204/3 2936/223
RR (95% CI)0.1 0.2 0.5 1 2 5 10
108/5 137 0/282
62/8 901
170/14 320
437/24 285
Favours statin
Favours nostatin
Figure 3: Risk of nonfatal myocardial infarction associated with the use of statins (versus no statins) inpatients at low cardiovascular risk (observed 10-year risk of cardiovascular-related death or nonfatalmyocardial infarction < 20%). A relative risk (RR) of less than 1.0 indicates fewer events with the use ofstatins. CI = confidence interval. *Lovastatin, fluvastatin, pravastatin and simvastatin. †Rosuvastatin andatorvastatin. For complete study names, see Box 1.
Statin No statin RR (95% CI)Study
Low-potency statin*ACAPS38 )57.2–10.0( 41.0064/0KAPS41 )39.3–11.0( 66.0422/2WOSCOPS43 )92.1–65.0( 58.0203 3/04ALLHAT–LLT40 )11.1–27.0( 98.0071 5/651Muldoon et al.29 1/206ESPLANADE49 )36.77–31.0( 02.378/1
)60.1–37.0( 88.0944 9/002latotbuSI² = 0%
High-potency statin†Bone et al.23 )70.81–30.0( 47.0584/1
0.22 (0.01–4.57) JUPITER4 )08.0–33.0( 25.0109 8/03
)97.0–33.0( 15.0444 9/13latotbuSI² = 0%
)69.0–86.0( 18.0398 81/132llarevOI² = 0%
No. of events, n/N
3/459
228/9 355
175/5 1850/1020/93
47/3 2933/223
RR (95% CI)0.1 0.2 0.5 1 2 5 10
0/11958/8 901
60/9 085
288/18 440
Favours statin
Favours nostatin
1.49 (0.06–36.32)
LORD48 0/58 2/65
Figure 4: Risk of nonfatal stroke associated with the use of statins (versus no statins) in patients at low car-diovascular risk (observed 10-year risk of cardiovascular-related death or nonfatal myocardial infarction< 20%). A relative risk (RR) of less than 1.0 indicates fewer events with the use of statins. CI = confidenceinterval. *Lovastatin, fluvastatin, pravastatin and simvastatin. †Rosuvastatin and atorvastatin. For com-plete study names, see Box 1.
Adverse eventsTwenty-one trials (n = 47 589) reported the num-ber of participants who had serious adverseevents. The trial-level relative risk could not beestimated for four trials that reported no events ineither group. From the remaining 17 trials (n =47 021), the pooled risk of serious ad verse eventsdid not differ significantly be tween treatmentgroups (RR 1.01, 95% CI 0.96–1.07; I2 = 8%).
Ten trials (n = 45 557) reported the number ofparticipants who experienced rhabdomyolysis.From the three trials in which this outcomeoccurred (n = 34 712), the pooled risk of rhab-domyolysis did not differ significantly betweengroups (RR 1.29, 95% CI 0.25–6.68; I2 = 0%).
Ten trials (n = 62 547) reported the number ofparticipants in whom cancer was diagnosed, andfour trials (n = 31 818) reported the proportionwith new diabetes. The pooled risk of cancer didnot differ significantly between groups (RR 1.00,95% CI 0.93–1.08; I2 = 0%), nor did the pooledrisk of diabetes (RR 1.05, 95% CI 0.84–1.32),although heterogeneity between studies in thelatter analysis was large (I2 = 64%).
Subgroup and sensitivity analysesIndirect comparisons between high- and low-potency statins did not show a significant differ-ence in the risk of all-cause mortality (RR forhigh- v. low-potency statins: 0.94, 95% CI 0.79–1.13), fatal or nonfatal myocardial infarction(RR 0.69, 95% CI 0.43–1.12) or stroke (RR0.79, 95% CI 0.61–1.02).
The sensitivity analyses, many of which usedalternative definitions of low cardiovascular risk,showed findings that were consistent with theresults of the primary analysis across a wide varietyof assumptions and conditions (Appendices 3 and4, available at www .cmaj .ca /lookup /suppl/doi:10.1503 /cmaj .101280 / -/DC1). In particular, use ofestimates rather than observed data to classify trialswith respect to 10-year cardiovascular risk led tosimilar conclusions regarding the efficacy of statinsin re ducing all-cause mortality. In addition, whenlow cardiovascular risk was defined as a 10-yearrisk of cardiovascular-related death or nonfatalmyocardial infarction of less than 10%, the pooledrelative risk was similar to that of the primaryanalysis (RR 0.83, 95% CI 0.73–0.94). The pooledrelative risk of all-cause mortality among statinrecipients was statistically significant in virtually allof the sensitivity analyses (28 of 33). In addition,the point estimate for the pooled relative risk wasrelatively stable in these analyses (range 0.78–0.93,as compared with the point estimate of 0.90 in theprimary analysis), except for one analysis thatincluded trials with a follow-up period shorter thanthe median of two years (pooled RR 0.99).
InterpretationWe found that the use of statins by people at lowcardiovascular risk reduced the relative risk ofdeath from any cause by 10%. Treatment withstatins also reduced the risk of stroke, myocardialinfarction, unstable angina and coronary revascu-larization to an extent similar to that seen in trialsinvolving patients with coronary artery disease.52
In a meta-analysis of the efficacy and safetyof statins among patients with coronary arterydisease, the number needed to treat was 86 toprevent a single death from any cause and 62 toprevent a single nonfatal myocardial infarction.52
The corresponding numbers needed to treatamong people at low cardiovascular risk by ourprimary definition were 239 and 153, whichreflect the generally low rates of vascular eventsin this population. Because statins might be usedindefinitely to reduce cardiovascular risk, theabsolute benefit may in crease (accompanied bycorresponding decreases in the number neededto treat) with longer durations of treatment, al -though this remains speculative.
Although we sought information from all tri-als on outcomes associated with serious harmfrom statins, information on serious adverseevents was available for only 59% (47 589/80 711) of the trial participants. This low propor-tion is consistent with previously documenteddeficiencies in re porting harm among participantsin randomized controlled trials.53,54 Our experi-ence with soliciting this information from investi-gators revealed a lack of clarity among trialauthors regarding how serious adverse eventswere re ported in published reports. Be cause therisk of serious morbidity would be expected todecline among statin users, our finding of a lackof significant difference in the rate of seriousadverse events between treatment groups and ournonsignificant estimate of elevated risk amongstatin users should be interpreted with caution. Acomplete analysis of published and unpublisheddata from individual patients on the effect ofstatins among low-risk patients would be a usefuladdition to the literature, but it would requirecooperation among the various stakeholders.
Our metaregression and indirect comparisonsdid not show statistically significant differencesin the efficacy of high- and low-potency statins.However, metaregression has relatively low sta-tistical power. The as-yet unproven potential forhigh-potency statins to prevent cardiovascularoutcomes more effectively must be balancedagainst their higher costs compared with low-potency statins. The recent availability of generic(lower cost) atorvastatin makes this issue of par-ticular importance for decision-makers and third-party payers.
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8 CMAJ
Unlike a recent systematic review that in -cluded statin trials involving both low- and high-risk people,55 we did not find a significantly in -creased risk of new diabetes among low-riskstatin users, perhaps because of differences instudy populations or statistical power. If such aneffect exists, this would be expected to furtherre duce the absolute benefit of statin treatment inlow-risk populations over the long term.
Our findings also differ from those of anotherre cently published systematic review of 11 trialsinvolving 65 229 people without cardiovasculardisease that found no evidence of a benefit ofstatin use on all-cause mortality.56 The authorsreported a relative risk reduction for all-causemortality that was similar to ours (9% v. 10%),but their estimate was less precise, leading to a95% CI that crossed unity (0.83–1.01). Eight tri-als in that review were included in ourstudy.4,24,28,31,36,39,40,43 However, we included an addi-tional 11 trials that reported on all-cause mortal-ity, and we excluded 2 trials57,58 that exclusivelyenrolled participants with a diagnosis of diabetesat baseline. A third study included in the priorreviews was excluded from our study becausethe 10-year risk for cardiovascular-related deathor nonfatal myocardial infarction was greaterthan 20%.59
Strengths and limitationsThis is an up-to-date, comprehensive systematicreview of the clinical implications of statin useamong people at low cardiovascular risk. We in -cluded studies in which participants were consid-ered to be at low risk according to an accepteddefinition — a 10-year incidence of less than 20%for cardiovascular-related death or nonfatalmyocardial infarction.10 We excluded trials thatpredominantly enrolled people at higher cardio-vascular risk, such as those with diabetes or priorcardiovascular events. Therefore, our relative riskestimates were unlikely to be influenced byhigher-risk subgroups within the trial populations.
Our analysis has limitations. First, as with allmeta-analyses, our conclusions are limited bythe availability of individual trials. We cannotexclude the possibility of publication bias, al -though it seems unlikely that there are unidenti-fied trials large enough to influence the directionor significance of our findings.
Second, although we used accepted tech-niques for metaregression in an attempt to iden-tify factors associated with greater or lesser ben-efit from statin use among low-risk participants,statistical power for these analyses was relativelylow given the number of available trials.
Third, the duration of all trials was relativelyshort given that people at low cardiovascular risk
might require treatment with statins for decades. Fourth, we used the number needed to treat to
summarize the benefits of statins across differentanalyses. Whether the number needed to treat isappropriate for use in meta-analyses is contro-versial; however, we believe that the simplicityand transparency of this method outweigh itspotential disadvantages.21,60
Fifth, although we reported a wide range ofclinically relevant outcomes as specified in ourprotocol, the definition for some (e.g., unstableangina) will have varied across trials.
Sixth, in an attempt at unbiased identificationof people at low cardiovascular risk, we based ourinclusion criterion on the observed incidence ofevents among placebo recipients, anticipating thatclinicians could apply our findings in practice byusing their risk prediction instrument of choice toidentify patients with an estimated 10-year risk ofless than 20% for cardiovascular-related death ornonfatal myocardial infarction. Because risk pre-diction tools may overestimate true rates of eventsin contemporary practice, we re peated analysesafter including only trials with an estimated 10-year risk of less than 20% based on mean partici-pant characteristics and two widely used riskequations;11,12 we reached similar conclusions.
Finally, given that most of the trials includedin our review were at moderate risk of bias, wecannot exclude the possibility that other factorsbesides statin use may have influenced the ob -served differences in health outcomes betweentreatment groups.
ConclusionBoth low- and high-potency statins were effica-cious in preventing death and cardiovascular-related morbidity in people at low risk of car -diovascular events (whose 10-year risk ofcardiovascular-related death or nonfatal myocar-dial infarction is less than 20%), most of whomdid not have a history of coronary artery diseaseor diabetes. However, the number needed to treatto prevent one adverse outcome was relativelyhigh for any statin. Whether high-potency statinsimprove outcomes to a greater extent than low-potency statins is uncertain based on current data.
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46. Feldman HH, Doody RS, Kivipelto M, et al. Randomized con-trolled trial of atorvastatin in mild to moderate Alzheimer dis-ease: LEADe. Neurology 2010;74:956-64.
47. Chan KL, Teo K, Dumesnil JG, et al. Effect of lipid lowering withrosuvastatin on progression of aortic stenosis: results of the AorticStenosis Progression Observation: Measuring Effects of Rosuva -statin (ASTRONOMER) Trial. Circulation 2010;121:306-14.
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50. Yun KH, Shin IS, Park EM, et al. Effect of additional statin ther-apy on endothelial function and prognosis in patients withvasospastic angina. Korean Circ J 2008;38:638-43.
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52. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety ofcholesterol-lowering treatment: prospective meta-analysis ofdata from 90 056 participants in 14 randomised trials of statins.Lancet 2005;366:1267-78.
53. Chan AW, Hrobjartsson A, Haahr MT, et al. Empirical evidencefor selective reporting of outcomes in randomized trials: compar-ison of protocols to published articles. JAMA 2004;291:2457-65.
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55. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incidentdiabetes: a collaborative meta-analysis of randomised statin tri-als. Lancet 2010;375:735-42.
56. Ray KK, Seshasai SR, Erqou S, et al. Statins and all-cause mor-tality in high-risk primary prevention: a meta-analysis of 11 ran-domized controlled trials involving 65,229 participants. ArchIntern Med 2010;170:1024-31.
57. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary pre-vention of cardiovascular disease with atorvastatin in type 2 dia-betes in the Collaborative Atorvastatin Diabetes Study (CARDS):multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96.
58. Knopp RH, d’Emden M, Smilde JG, et al. Efficacy and safety ofatorvastatin in the prevention of cardiovascular end points in sub-jects with type 2 diabetes: the Atorvastatin Study for Preventionof Coronary Heart Disease Endpoints in non-insulin-dependentdiabetes mellitus (ASPEN). Diabetes Care 2006;29:1478-85.
59. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderlyindividuals at risk of vascular disease (PROSPER): a randomisedcontrolled trial. Lancet 2002;360:1623-30.
60. McAlister FA. The “number needed to treat” turns 20 — andcontinues to be used and misused. CMAJ 2008;179:549-53.
Affiliations: From the Department of Medicine (Tonelli,Lloyd, McAlister), University of Alberta, Edmonton, Alta.;the Department of Community Health Sciences (Clement,Hemmelgarn, Manns), University of Calgary, Calgary, Alta.;the Alberta Kidney Disease Network (Tonelli, Lloyd, Conly,
Hemmelgarn, Klarenbach, Wiebe, Manns), Calgary/Edmon-ton, Alta.; the Department of Epidemiology and CommunityMedicine (Husereau, Klarenbach, Wiebe), University ofOttawa, Ottawa, Ont.; and the Department of Medicine(Hemmelgarn, Manns), University of Calgary, Calgary, Alta.The complete list of members of the Alberta Kidney DiseaseNetwork is available at www.akdn.info.
Contributors: All the authors contributed to the conceptionand design. Marcello Tonelli, Fiona Clement, Braden Manns,Anita Lloyd and Jonathan Conly contributed to the acquisi-tion of data and drafted the report. All of the authors con-tributed to the analysis and interpretation of data, criticallyrevised the report for important intellectual content andapproved the final version submitted for publication.
Funding: This study was jointly funded by the CanadianAgency for Drugs and Technology in Health and the AlbertaHeritage Foundation for Medical Research InterdisciplinaryTeam Grants Program (which supports the InterdisciplinaryChronic Disease Collaboration). The study sponsors had norole in the design of the study, the collection, analysis orinterpretation of data, the writing of the report or the decisionto submit the article for publication.
Acknowledgements: The authors thank Dr. Steven Grover forhis helpful comments on an earlier draft of this manuscript.
Marcello Tonelli, Finlay McAlister and Braden Manns aresupported by Alberta Innovates — Health Solutions (formerlythe Alberta Heritage Foundation for Medical Research(AHFMR) Health Scholar Awards. Brenda Hemmelgarn andScott Klarenbach were supported by Population Health Investi-gator Awards from Alberta Innovates — Health Solutions. Marcello Tonelli was supported by a Government of CanadaResearch Chair in the optimal care of people with chronic kid-ney disease. Fiona Clement was supported by a postdoctoralfellowship award from the Canadian Health Services ResearchFoundation and AHFMR. Marcello Tonelli, Brenda Hemmel-garn, Scott Klarenbach, Finlay McAlister and Braden Mannswere supported by an alternative funding plan from the Govern-ment of Alberta and the Universities of Alberta and Calgary.
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Box 1: Full names of trials included in the meta-analysis
• ACAPS: Asymptomatic Carotid Artery Progression Study
• AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study
• ALLHAT–LLT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
• ASCOT–LLA: Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm
• ASTRONOMER: Aortic Stenosis Progression Observation: Measuring the Effects of Rosuva statin
• CAIUS: Carotid Atherosclerosis Italian Ultrasound Study
• ESPLANADE: European Study for Preventing by Lipid-lowering Agents aNd ACE-inhibition DialysisEndpoints
• EXCEL: Expanded Clinical Evaluation of Lovastatin Study
• HYRIM: Hypertension High-Risk Management Trial
• JUPITER: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuva -statin
• KAPS: Kuopio Atherosclerosis Prevention Study
• KLIS: Kyushu Lipid Intervention Study
• LEADe: Lipitor’s Effect in Alzheimer’s Dementia
• LORD: Lipid Lowering and Onset of Renal Disease
• MEGA: Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese
• METEOR: Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin
• PHYLLIS: Plaque Hypertension Lipid-Lowering Italian Study
• PREVEND-IT: Prevention of Renal and Vascular Endstage Disease Intervention Trial
• UK-HARP-I: First United Kingdom Heart and Renal Protection
• WOSCOPS: West of Scotland Coronary Prevention Study
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CMAJ 11
Tab
le 1
: Des
crip
tio
n o
f st
ud
ies
incl
ud
ed in
th
e sy
stem
atic
rev
iew
(p
art
1 o
f 3)
Stu
dy,
yea
r,
loca
tio
n
Pop
ula
tio
n
Sam
ple
siz
e in
st
atin
/no
-sta
tin
g
rou
ps
(mea
n
follo
w-u
p, y
r)
Stat
in a
nd
st
arti
ng
d
ose
, mg
/d
Car
dio
vasc
ula
r h
isto
ry (
%)
10-y
r ri
sk o
f N
FMI o
r C
V
dea
th in
co
ntr
ols
, %
D’A
go
stin
o C
VD
ris
k,*
%
DM
H
TN, %
Mea
n TC
, LD
L-C
, H
DL-
C a
nd
TG
le
vels
, mm
ol/L
M
ean
age,
yr
(% m
ale)
AST
RO
NO
MER
47
2010
C
anad
a
Men
an
d w
om
en 1
8–82
yr;
asy
mp
tom
atic
mild
to
m
od
erat
e ao
rtic
ste
no
sis
(max
imu
m a
ort
ic v
alu
e ve
loci
ty 2
.5–4
m/s
); n
o C
AD
, CV
D, P
VD
or
dia
bet
es
134/
135
(3.5
) R
osu
vast
atin
40
N
A
16
15
0 NR
5.
3 3.
2 1.
6 1.
3
58
(62)
ESPL
AN
AD
E49
2010
It
aly
>16
yr;
BP
>14
0/90
mm
Hg
or
con
com
itan
t an
tih
yper
ten
sive
th
erap
y; 2
4-h
ou
r p
rote
inu
ria
per
sist
entl
y >
1 g
(la
ter
chan
ged
to
> 0
.5 g
) af
ter
2-m
o
was
ho
ut
from
pre
vio
us
trea
tmen
t w
ith
RA
S in
hib
ito
rs
or
stat
ins;
no
evi
den
ce o
f u
rin
ary
trac
t in
fect
ion
s o
r h
eart
fai
lure
87/9
3 (0
.5)
Flu
vast
atin
40
–80
NR
0
18
17
N
R
5.6
3.6
1.2
1.4
51
(76)
LEA
De46
20
10
10 c
ou
ntr
ies
Men
an
d w
om
en 5
0–90
yr;
dia
gn
osi
s o
f p
rob
able
A
lzh
eim
er d
isea
se; t
akin
g d
on
epez
il 10
mg
fo
r ≥
3 m
o; L
DL-
C 2
.5–3
.5 m
mo
l/L u
nle
ss D
M p
rese
nt
(LD
L-C
2.
5–3.
5 m
mo
l/L, b
loo
d s
ug
ar s
tabl
e an
d H
bA
1C <
10%
);
no
clin
ical
ly s
ign
ific
ant
or
un
stab
le m
edic
al c
on
dit
ion
314/
325
(1.4
) A
torv
asta
tin
80
N
A
13
28
NR
N
R
5.8
3.7
1.6
1.5
74
(48)
LOR
D48
2010
A
ust
ralia
18–8
5 yr
wit
h c
hro
nic
kid
ney
dis
ease
(SC
r >
120
µm
ol/L
); a
ll le
vels
of
pro
tein
uri
a an
d s
eru
m
cho
lest
ero
l; n
o p
revi
ou
s lip
id-l
ow
erin
g th
erap
y
58/6
5 (2
.5)
Ato
rvas
tati
n
10
NR
12
26
8 NR
5.
6 3.
4 1.
2 2.
3
60
(65)
JUPI
TER
4 20
08
26 c
ou
ntr
ies
Men
≥ 5
0 yr
an
d w
om
en ≥
60
yr; n
o h
isto
ry o
f C
VD
; LD
L-C
< 3
.4 m
mo
l/L, T
G <
5.6
mm
ol/L
, hig
h-s
ensi
tivi
ty
CR
P ≥
2.0
mg
/dL;
no
pre
vio
us/
curr
ent
use
of
lipid
-lo
wer
ing
ther
apy
8901
/890
1 (m
edia
n 1
.9)
Ro
suva
stat
in
20
NA
6
22
0 NR
4.
8 2.
8 1.
3 1.
3
66
(62)
Yu
n e
t al
.50
2008
K
ore
a
Ch
est
pai
n a
t re
st; n
o s
ign
ific
ant
CA
D; n
o a
cute
MI
wit
hin
6 m
o; n
o p
revi
ou
s co
ron
ary
inte
rven
tio
n
37/3
7 (0
.5)
Ro
suva
stat
in
10
NR
0
18
9 51
5.
0 3.
0 1.
2 1.
7
57
(48)
Bo
ne
et a
l.23
2007
U
SA
Post
men
op
ausa
l wo
men
40–
75 y
r, L
DL-
C ≥
3.4
< 4
.9
mm
ol/L
; no
his
tory
of
dia
bet
es o
r C
HD
48
5/11
9 (1
) A
torv
asta
tin
10
, 20,
40
, 80
NA
0
15
0 NR
6.
3 4.
0 1.
5 1.
6
59
(0)
MET
EOR
34
2007
U
SA
Men
40–
70 y
r an
d w
omen
55–
70 y
r; L
DL-
C <
4.1
mm
ol/L
, H
DL-
C ≤
1.6
mm
ol/L
, TG
< 5
.7 m
mol
/L; 1
0-yr
ris
k of
CA
D
even
ts <
10%
; no
evid
ence
of
CAD
or
othe
r pe
riph
eral
at
hero
scle
roti
c di
seas
e; n
o pr
evio
us r
evas
cula
riza
tion
; no
dia
bet
es
702/
282
(2)
Ro
suva
stat
in
40
NA
0
14
0 28
5.
9 4.
0 1.
3 1.
4
57
(60)
MEG
A24
2006
Ja
pan
Men
an
d p
ost
men
op
ausa
l wo
men
40–
70 y
r; T
C 5
.69–
6.98
mm
ol/L
; no
his
tory
of
CH
D o
r st
roke
38
66/3
966
(5.3
) Pr
avas
tati
n
10–2
0 N
A
2
18
21
42
6.3
4.1
1.5
1.4
58
(31)
Der
nel
lis e
t al
.35
2005
G
reec
e
Ad
ult
s w
ith
CRP
0.8
–1.3
mg
/dL;
at
leas
t o
ne
epis
od
e o
f PA
F o
n a
mb
ula
tory
mo
nit
ori
ng
40
/40
(0.5
) A
torv
asta
tin
20
–40
NR
0
20
20
65
5.
8 4.
0 1.
2 N
R
52
(65)
Research
12 CMAJ
Tab
le 1
: Des
crip
tio
n o
f st
ud
ies
incl
ud
ed in
th
e sy
stem
atic
rev
iew
(p
art
2 o
f 3)
Stu
dy,
yea
r,
loca
tio
n
Pop
ula
tio
n
Sam
ple
siz
e in
st
atin
/no
-sta
tin
g
rou
ps
(mea
n
follo
w-u
p, y
r)
Stat
in a
nd
st
arti
ng
d
ose
, mg
/d
Car
dio
vasc
ula
r h
isto
ry (
%)
10-y
r ri
sk o
f N
FMI o
r C
V
dea
th in
co
ntr
ols
, %
D’A
go
stin
o
CV
D r
isk,
* %
D
M
HTN
, %
Mea
n TC
, LD
L-C
, H
DL-
C a
nd
TG
le
vels
, mm
ol/L
M
ean
age,
yr
(% m
ale)
Di L
ullo
et
al.25
20
05
Ital
y
Men
an
d w
om
en 1
8–80
yr;
mild
/mo
der
ate
CR
F fo
r ≥
5 yr
; CR
P 3–
14 m
g/d
L, T
C 6
.5–9
.1 m
mo
l/L, H
DL-
C 1
.3–1
.8
mm
ol/L
, LD
L-C
2.6
–4.9
mm
ol/L
, TG
1.8
–5.1
mm
ol/L
; no
d
iag
no
sis
of
seve
re h
eart
fai
lure
or
fam
ilial
h
yper
cho
lest
ero
lem
ia; n
o c
ard
iac
illn
ess
80/5
0 (0
.7)
Flu
vast
atin
XL
80
NA
0
32
35
65
7.
6 4.
0 1.
7 2.
6
59
(54)
Ho
lmb
erg
et
al.26
20
05
Swed
en
≥ 18
yr;
GFR
< 3
0 m
L/m
in p
er b
od
y su
rfac
e ar
ea o
f
1.73
m2
70/7
3 (1
.8)
Ato
rvas
tati
n
10
NR
0
40
31
N
R
5.8
3.5
1.1
2.4
69
(69)
HY
RIM
28
2005
N
orw
ay
Dru
g-t
reat
ed h
yper
ten
sive
men
40–
75 y
r; T
C 4
.5–8
m
mo
l/L, T
G <
4.5
mm
ol/L
; no
sym
pto
mat
ic C
VD
, CH
F,
typ
e I D
M o
r h
isto
ry o
f co
ron
ary
inte
rven
tio
n
283/
285
(4)
Flu
vast
atin
† 40
N
A
8
26
NR
10
0 5.
9 3.
9 1.
3 1.
8
57
(100
)
UK
-HA
RP-
I27
2005
U
K
Men
an
d w
om
en ≥
18
yr; 1
) p
re-d
ialy
sis
wit
h P
Cr
or
SCr
≥ 1.
7 m
g/d
L; u
nd
er d
ialy
sis;
or
fun
ctio
nin
g
ren
al t
ran
spla
nt,
an
d 2
) n
o d
efin
ite
ind
icat
ion
or
con
trai
nd
icat
ion
fo
r ch
ole
ster
ol-
low
erin
g t
her
apy
or
ASA
224/
224
(1)
Sim
vast
atin
† 20
V
ascu
lar
dis
ease
‡ (9
) 9
22
12
N
R
5.2
3.2
1.0
2.1
53
(79)
Mu
ldo
on
et
al.29
20
04
USA
Hyp
erch
ole
ster
olem
ic m
en a
nd
wo
men
35–
70 y
r;
LDL-
C 4
.1–5
.7 m
mo
l/L; n
o C
AD
, str
oke
, dia
bet
es o
r cu
rren
t lip
id-l
ow
erin
g m
edic
atio
n
206/
102
(0.5
) Si
mva
stat
in
10, 4
0 N
A
0
15
0 NR
6.
8 4.
7 1.
3 1.
7
54
(48)
PHY
LLIS
30
2004
It
aly
Men
an
d p
ost
men
op
ausa
l wo
men
45–
70 y
r; u
ntr
eate
d
or
un
con
tro
lled
HTN
, hyp
erch
ole
ster
ole
mia
, as
ymp
tom
atic
car
oti
d a
ther
osc
lero
sis;
no
pre
vio
us
CV
A e
ven
ts; L
DL-
C 4
.14–
5.17
mm
ol/L
, TG
≤
3.39
mm
ol/L
254/
254
(2.6
) Pr
avas
tati
n†
40
NA
5
21
N
R
100
6.8
4.7
1.4
1.6
58
(40)
PREV
END
-IT31
20
04
Net
her
lan
ds
28–7
5 yr
; per
sist
ent
mic
roal
bu
min
uri
a; B
P
< 1
60/1
00 m
m H
g w
ith
ou
t u
se o
f an
tih
yper
ten
sive
m
edic
atio
n; T
C <
8 m
mo
l/L (
< 5
mm
ol/L
if p
revi
ou
s M
I); n
o u
se o
f lip
id-l
ow
erin
g m
edic
atio
n
433/
431
(3.8
) Pr
avas
tati
n†
40
MI (
1)
CV
A (
1)
PVD
(1)
11
14
3 NR
5.
8 4.
1 1.
0 1.
4
51
(65)
Rej
nm
ark
et a
l.32
2004
D
enm
ark
Hea
lth
y, p
ost
men
op
ausa
l wo
men
< 7
6 yr
; no
pre
vio
us
stat
in u
se w
ith
in 2
yr
41/4
1 (1
.5)
Sim
vast
atin
40
N
A
0
15
NR
N
R
6.5
4.0
1.9
1.2
64
(0)
ASC
OT–
LLA
36
2003
Eu
rop
e
Men
an
d w
om
en 4
0–79
yr;
TC
≤ 6
.5 m
mo
l/L;
no
t ta
kin
g li
pid
-lo
wer
ing
ther
apy;
≥ 3
CV
D r
isk
fact
ors
; no
pre
vio
us
MI o
r h
eart
fai
lure
5168
/513
7 (m
edia
n 3
.3)
Ato
rvas
tati
n
10
Stro
ke/T
IA (
10)
PVD
(5)
O
ther
CV
D (
4)
11
42
25
80
5.5
3.4
1.3
1.7
63
(81)
Bru
cker
t et
al.33
20
03
Fran
ce, I
taly
, Sp
ain
, Bel
giu
m,
Isra
el
Men
and
wom
en 7
0–85
yr;
pri
mar
y hy
perc
hole
ster
olem
ia
(TC
≥ 6.
5 m
mol
/L, T
G ≥
4.6
mm
ol/L
, LD
L-C
≥ 4.
1 m
mol
/L
afte
r di
etar
y in
teve
ntio
n); n
o sy
mpt
om
atic
CH
F, h
isto
ry
of M
I, an
gina
or
stro
ke
607/
622
(1)
Flu
vast
atin
XL
80
CH
F (0
.4)
TIA
(2)
2
33
7 56
7.
3 5.
2 1.
4 1.
5
76
(25)
Research
CMAJ 13
Tab
le 1
: Des
crip
tio
n o
f st
ud
ies
incl
ud
ed in
th
e sy
stem
atic
rev
iew
(p
art
3 o
f 3)
Stu
dy,
yea
r,
loca
tio
n
Pop
ula
tio
n
Sam
ple
siz
e in
st
atin
/no
-sta
tin
g
rou
ps
(mea
n
follo
w-u
p, y
r)
Stat
in a
nd
st
arti
ng
d
ose
, mg
/d
Car
dio
vasc
ula
r h
isto
ry (
%)
10-y
r ri
sk o
f N
FMI o
r C
V
dea
th in
co
ntr
ols
, %
D’A
go
stin
o C
VD
ris
k,*
%
DM
H
TN, %
Mea
n TC
, LD
L-C
, H
DL-
C a
nd
TG
le
vels
, mm
ol/L
M
ean
age,
yr
(% m
ale)
ALL
HA
T–LL
T40
2002
C
anad
a, U
SA,
Puer
to R
ico
, V
irg
in Is
lan
ds
Ag
e ≥
55 y
r; s
tag
e I o
r II
HTN
; ≥ 1
ad
dit
ion
al C
HD
ris
k fa
cto
r; f
asti
ng
LD
L-C
3.1
–4.9
mm
ol/L
(if
no
kn
ow
n C
HD
) o
r 2.
6–3.
3 m
mo
l/L (
if k
no
wn
CH
D);
fas
tin
g T
G <
3.9
m
mo
l/L
5170
/518
5 (4
.8)
Prav
asta
tin
20
-40
CH
D (
14)
18
36
35
100
5.8
3.8
1.2
1.7
66
(51)
KLI
S37
2000
Ja
pan
Men
45–
75 y
r; p
rim
ary
hyp
erch
ole
ster
ole
mia
(TC
≥ 5
.69
mm
ol/L
) in
at
leas
t tw
o m
easu
rem
ents
; no
his
tory
of
MI
or
coro
nar
y b
ypas
s su
rger
y
2219
/163
4 (5
) Pr
avas
tati
n
10–2
0 N
A
3
33
23
43
6.4
4.3
1.3
1.9
58
(100
)
Bak
et
al.44
19
98
Net
her
lan
ds
Men
40–
70 y
r; T
C 6
.5–8
mm
ol/L
, TG
≤ 4
mm
ol/L
; no
CV
D;
no
pri
or
use
of
lipid
-lo
wer
ing
dru
gs
106/
109
(0.5
) Pr
avas
tati
n†
20
NA
0
24
N
R
NR
7.
3 5.
2 1.
1 2.
1
55
(100
)
AFC
APS
/Tex
CAPS
39
1998
U
SA
Men
45–
73 y
r an
d po
stm
enop
ausa
l wom
en 5
5–73
yr;
no
hist
ory
of M
I, an
gina
, cla
udic
atio
n, C
VA
or
TIA
; TC
4.65
–6.8
2 m
mol
/L, L
DL-
C 3.
36–4
.91
mm
ol/L
, HD
L-C
≤ 1.
16 m
mol
/L f
or
men
and
≤ 1
.22
for
wom
en, T
G ≤
4.5
3 m
mo
l/L
3304
/330
1 (5
.2)
Lova
stat
in
20–4
0 N
A
7
28
4 22
5.7
3.9
1.0
1.8
58
(85)
CA
IUS42
19
96
Ital
y
Men
an
d w
om
en 4
5–65
yr;
th
ree
bas
elin
e d
eter
min
atio
ns
of
LDL-
C 3
.88–
6.47
mm
ol/L
an
d T
G <
2.8
2 m
mo
l/L; n
o C
AD
; at
leas
t o
ne
caro
tid
art
ery
lesi
on
d
etec
ted
by
ult
raso
un
d im
agin
g
151/
154
(3)
Prav
asta
tin
40
N
A
4
18
0 NR
6.
8 4.
7 1.
4 1.
6
55
(53)
KA
PS41
1995
Fi
nla
nd
Men
44–
65 y
r; L
DL-
C >
4.2
5 m
mo
l/L, T
C <
8.0
mm
ol/L
, B
MI <
32
kg/m
2 , ALT
/AST
≤ 1
.5-f
old
th
e la
bo
rato
ry u
pp
er
no
rmal
lim
it
224/
223
(3)
Prav
asta
tin
40
M
I (8)
13
29
2 33
6.
7 4.
9 1.
2 1.
7
57
(100
)
WO
SCO
PS43
1995
Sc
otl
and
Men
45–
64 y
r; h
yper
cho
lest
ero
lem
ia (
LDL-
C 4
.5–
6 m
mo
l/L);
no
his
tory
of
MI o
r o
ther
ser
ious
illn
ess
3302
/329
3 (4
.9)
Prav
asta
tin
40
V
ascu
lar
dis
ease
**
(16)
17
31
1 16
7.0
5.0
1.1
1.8
55
(100
)
AC
APS
38
1994
U
SA
Men
an
d w
om
en 4
0–79
yr;
ear
ly c
aro
tid
ath
ero
scle
rosi
s;
mo
der
atel
y el
evat
ed L
DL-
C; n
o h
isto
ry o
f st
roke
, TIA
, an
gin
a o
r M
I
460/
459
(2.8
) Lo
vast
atin
† 20
–40
NA
8
21
2 29
6.
1 4.
0 1.
3 3.
6
62
(52)
EXC
EL45
1991
U
SA
Men
an
d w
om
en (
po
stm
eno
pau
sal o
r su
rgic
ally
ste
rile
) 18
–70
yr; f
asti
ng
pla
sma
TC 6
.2–7
.6 m
mo
l/L, L
DL-
C ≥
4.1
m
mo
l/L; n
o u
nst
able
med
ical
co
nd
itio
ns,
imp
aire
d
hep
atic
or
ren
al f
un
ctio
n
6582
/166
3 (0
.9)
Lova
stat
in
20, 4
0,
80
CH
D (
29)
13
21
NR
40
6.
7 4.
7 1.
2 1.
8
56
(59)
Not
e: A
LT =
ala
nine
am
inot
rans
fera
se, A
SA =
ace
tyls
alic
ylic
aci
d, A
ST =
asp
arta
te a
min
otra
nsf
eras
e, B
MI =
bod
y m
ass
ind
ex, B
P =
blo
od p
ress
ure,
CA
D =
co
rona
ry a
rter
y di
seas
e, C
HD
= c
oron
ary
hea
rt d
isea
se, C
HF
= co
nges
tive
hea
rt
failu
re, C
RF =
chr
onic
ren
al f
ailu
re, C
RP =
C-r
eact
ive
pro
tein
, CV
= c
ardi
ovas
cula
r, C
VA
= c
ereb
rova
scu
lar a
ccid
ent,
CV
D =
car
dio
vasc
ula
r d
isea
se, D
M =
dia
bete
s m
ellit
us, G
FR =
glo
mer
ula
r fi
ltra
tion
rat
e, H
DL-
C =
high
-den
sity
lipo
pro
tein
ch
ole
ster
ol, H
TN =
hyp
erte
nsio
n, L
DL-
C =
low
-den
sity
lip
opro
tein
cho
lest
erol
, MI =
myo
card
ial i
nfar
ctio
n, N
A =
not
app
licab
le, N
FMI =
no
nfat
al m
yoca
rdia
l inf
arct
ion,
NR
= no
t re
port
ed, P
AF
= p
arox
ysm
al a
tria
l fib
rilla
tion
, PCr
= p
lasm
a cr
eati
nine
, PV
D =
per
iphe
ral v
ascu
lar
dise
ase,
SCr
= s
erum
cre
atin
ine,
TC
= to
tal c
hol
este
rol,
TG =
tri
glyc
erid
es, T
IA =
tra
nsie
nt is
chem
ic a
ttac
k, U
K =
Uni
ted
Kin
gdom
, USA
= U
nite
d St
ates
of
Am
eric
a. F
or c
ompl
ete
stud
y na
mes
, see
Box
1.
*Hyp
erte
nsi
on
is a
ssu
med
to
be
trea
ted
, un
less
incl
usi
on
cri
teri
a in
dic
ated
un
trea
ted
or
un
con
tro
lled
hyp
erte
nsi
on
, or
no
use
of
anti
hyp
erte
nsi
ve m
edic
atio
ns.
†F
acto
rial
des
ign
: sta
tin
tre
atm
ent
gro
up
s co
mb
ined
, co
ntr
ol g
rou
ps
com
bin
ed.
‡In
clu
des
an
gin
a, m
yoca
rdia
l in
farc
tio
n, r
evas
cula
riza
tio
n, s
tro
ke a
nd
per
iph
eral
art
eria
l dis
ease
. **
Incl
ud
es a
ng
ina,
inte
rmit
ten
t cl
aud
icat
ion
, str
oke
, tra
nsi
ent
isch
emic
att
ack
and
ab
no
rmal
ity
on
ele
ctro
card
iog
ram
.
Research
14 CMAJ
Tab
le 2
: Ris
k-o
f-b
ias
asse
ssm
ent
of
stu
die
s in
clu
ded
in t
he
syst
emat
ic r
evie
w
St
ud
y d
esig
n St
atis
tica
l an
alys
is
Pres
enta
tio
n o
f re
sult
s
Stu
dy
Des
crip
tio
n o
f p
arti
cip
ant
sele
ctio
n
Co
nce
alm
ent
of
allo
cati
on
to
tre
atm
ent*
Des
crip
tio
n
of
ther
apeu
tic
reg
imen
Was
tri
al
des
crib
ed a
s d
ou
ble
-blin
d?*
Was
blin
din
g
asse
ssm
ent
des
crib
ed?/
W
as d
ou
ble
-blin
din
g
met
ho
d a
pp
rop
riat
e?
Wer
e w
ith
dra
wal
s an
d d
rop
ou
ts
rep
ort
ed?*
Was
sa
mp
le s
ize
calc
ula
tio
n
des
crib
ed?
Was
des
ign
des
crib
ed a
s in
ten
tio
n-t
o-
trea
t?
Was
th
is a
p
relim
inar
y an
alys
is/W
as
tria
l sto
pp
ed
earl
y?
Wer
e ad
vers
e ev
ents
re
po
rted
?
Was
d
iscu
ssio
n ad
equ
ate?
So
urc
e o
f fu
nd
ing
*
AST
RO
NO
MER
47
Ad
equ
ate
Ad
equ
ate
Ad
equ
ate
Yes
Y
es/Y
es
Yes
Y
es
Yes
N
o/N
R
Yes
Y
es
Mix
ed
ESPL
AN
AD
E49
Ad
equ
ate
Ad
equ
ate
Ad
equ
ate
No
N
A/N
A
Yes
Y
es
Yes
N
o/N
R
Yes
Y
es
Mix
ed
LEA
De46
A
deq
uat
e A
deq
uat
e A
deq
uat
e Y
es
Yes
/Yes
Pa
rtia
l Y
es
Yes
N
o/N
R
Yes
Y
es
Priv
ate
LOR
D48
Ad
equ
ate
Ad
equ
ate
Ad
equ
ate
Yes
N
o/N
A
Part
ial
Yes
Y
es
No
/NR
Y
es
Yes
M
ixed
JUPI
TER
4 A
deq
uat
e A
deq
uat
e A
deq
uat
e Y
es
Yes
/Yes
N
o
Yes
Y
es
No
/Yes
Y
es
Yes
Pr
ivat
e
Yu
n e
t al
.50
Ad
equ
ate
Un
clea
r Pa
rtia
l Y
es
No
/NA
Pa
rtia
l N
o
No
N
o/N
R
Yes
Y
es
Fou
nd
atio
n
Bo
ne
et a
l.23
Ad
equ
ate
Un
clea
r A
deq
uat
e Y
es
Yes
/Yes
Y
es
Yes
Y
es
No
/NR
Y
es
Yes
Pr
ivat
e
MET
EOR
34
Ad
equ
ate
Un
clea
r A
deq
uat
e Y
es
No
/NA
Y
es
Yes
Y
es
No
/NR
Y
es
Yes
Pr
ivat
e
MEG
A24
Ad
equ
ate
Un
clea
r A
deq
uat
e N
o
NA
/NA
Y
es
Yes
Y
es
No
/NR
Y
es
Yes
M
ixed
Der
nel
lis e
t al
.35
Ad
equ
ate
Un
clea
r A
deq
uat
e N
o
NA
/NA
Y
es
No
Y
es
No
/NR
Y
es
Yes
N
R
Di L
ullo
et
al.25
A
deq
uat
e U
ncl
ear
Ad
equ
ate
No
N
A/N
A
No
N
o
No
N
o/N
R
Yes
Y
es
NR
Ho
lmb
erg
et
al.26
A
deq
uat
e U
ncl
ear
Ad
equ
ate
No
N
A/N
A
Yes
N
o
No
N
o/N
R
Yes
Y
es
Pub
lic
HY
RIM
28
Ad
equ
ate
Un
clea
r A
deq
uat
e Y
es
No
/NA
N
o
No
Y
es
No
/NR
Y
es
Yes
M
ixed
UK
-HA
RP-
I27
Ad
equ
ate
Ad
equ
ate
Ad
equ
ate
Yes
Y
es/Y
es
Yes
Y
es
Yes
N
o/N
R
Yes
Y
es
Priv
ate
Mu
ldo
on
et
al.29
A
deq
uat
e U
ncl
ear
Ad
equ
ate
Yes
Y
es/Y
es
Yes
Y
es
No
N
o/N
R
No
N
A
Pub
lic
PHY
LLIS
30
Ad
equ
ate
Un
clea
r A
deq
uat
e Y
es
No
/NA
Pa
rtia
l Y
es
Yes
N
o/N
R
Yes
Y
es
Priv
ate
PREV
END
-IT31
A
deq
uat
e U
ncl
ear
Ad
equ
ate
Yes
Y
es/Y
es
Yes
Y
es
Yes
N
o/N
R
No
N
A
Mix
ed
Rej
nm
ark
et a
l.32
Ad
equ
ate
Ad
equ
ate
Ad
equ
ate
Yes
Y
es/Y
es
Yes
Y
es
Yes
N
o/N
R
Yes
Y
es
Pub
lic
ASC
OT–
LLA
36
Ad
equ
ate
Un
clea
r A
deq
uat
e Y
es
Yes
/Yes
Y
es
Yes
Y
es
No
/Yes
Y
es
No
Pr
ivat
e
Bru
cker
t et
al.33
A
deq
uat
e U
ncl
ear
Ad
equ
ate
Yes
N
o/N
A
Yes
N
o
Yes
N
o/N
R
Yes
Y
es
Priv
ate
ALL
HA
T–LL
T40
Ad
equ
ate
Ad
equ
ate
Ad
equ
ate
No
N
A/N
A
Yes
Y
es
Yes
N
o/N
R
Yes
Y
es
Mix
ed
KLI
S37
Ad
equ
ate
Ad
equ
ate
Ad
equ
ate
No
N
A/N
A
No
Y
es
No
N
o/N
R
Yes
Y
es
Priv
ate
Bak
et
al.44
A
deq
uat
e U
ncl
ear
Ad
equ
ate
Yes
Y
es/Y
es
Part
ial
No
Y
es
No
/NR
Y
es
Yes
Pr
ivat
e
AFC
APS
/Tex
CA
PS39
A
deq
uat
e U
ncl
ear
Ad
equ
ate
Yes
Y
es/Y
es
Part
ial
Yes
Y
es
No
/NR
Y
es
Yes
Pr
ivat
e
CA
IUS42
A
deq
uat
e A
deq
uat
e A
deq
uat
e Y
es
Yes
/Yes
Pa
rtia
l Y
es
Yes
N
o/N
R
Yes
Y
es
Mix
ed
KA
PS41
Ad
equ
ate
Un
clea
r A
deq
uat
e Y
es
Yes
/Yes
Y
es
No
Y
es
No
/NR
Y
es
Yes
M
ixed
WO
SCO
PS43
Ad
equ
ate
Un
clea
r A
deq
uat
e Y
es
No
/NA
Pa
rtia
l N
o
Yes
N
o/N
R
Yes
Y
es
Priv
ate
AC
APS
38
Ad
equ
ate
Un
clea
r A
deq
uat
e Y
es
No
/NA
N
o
Yes
Y
es
No
/NR
Y
es
Yes
M
ixed
EXC
EL45
Ad
equ
ate
Un
clea
r A
deq
uat
e Y
es
No
/NA
Y
es
No
Y
es
No
/NR
Y
es
Yes
Pr
ivat
e
No
te: N
A =
no
t ap
plic
able
, NR
= n
ot
rep
ort
ed, m
ixed
= p
ub
lic a
nd
pri
vate
so
urc
es o
f fu
nd
ing
. *I
tem
s h
ave
emp
iric
al e
vid
ence
.