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Drugs for Primary Prevention of Atherosclerotic

CardiovascularDisease

 An Overview of Systematic Reviews

Kunal N. Karmali, MD, MS;Donald M. Lloyd-Jones, MD, ScM; Mark A. Berendsen, MLIS;DavidC. Goff Jr, MD, PhD;

Darshak M. Sanghavi,MD; Nina C. Brown, MPH, CHES;Liliya Korenovska, PhD; Mark D.Huffman, MD, MPH

IMPORTANCE  The Million Hearts initiative emphasizesABCS (aspirin for high-risk patients,

blood pressure [BP] control, c holesterollevel management, and smoking cessation).

Evidence of the effects of drugs used to achieve ABCS hasnot been synthesized

comprehensively in the prevention of primary atherosclerotic cardiovascular disease

(ASCVD).

OBJECTIVE  To compare the efficacy and safety of aspirin, BP-lowering therapy, statins, and

tobacco cessation drugs for fataland nonfatal ASCVD outcomes in primary ASCVD

prevention.

EVIDENCE REVIEW   Structured search of the Cochrane Databaseof Systematic Reviews,

Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment

Database (HTA), MEDLINE, EMBASE, and PROSPERO International Prospective Systematic

Review Trial Registerto identify systematic reviews publishedfrom January 1, 2005, to June

17, 2015, thatreported the effectof aspirin, BP-lowering therapy, statin, or tobacco cessation

drugs on ASCVD events in individuals without prevalent ASCVD. Additional studies were

identified by searching the reference lists of included systematic reviews, meta-analyses, and

health technology assessment reports. Reviews were selected accordingto predefined

criteria and appraised for methodologic quality using the Assessmentof Multiple Systematic

Reviews (AMSTAR) tool (range, 0-11). Studies were independently reviewed for key

participant and intervention characteristics. Outcomes that were meta-analyzed in each

included review were extracted. Qualitative synthesiswas performed, and data were

analyzedfrom July 2 to August13, 2015.

FINDINGS From a totalof 1967 reports, 35 systematic reviews of randomized clinical trials

were identified, including15 reviews of aspirin,4 reviews of BP-lowering therapy, 12 reviews

of statins, and4 reviews of tobacco cessationdrugs. Methodologic quality varied, but 30

reviews hadAMSTAR ratings of 5 or higher. Compared with placebo, aspirin (relativerisk [RR],

0.90;95% CI,0.85-0.96) andstatins(RR, 0.75;95% CI,0.70-0.81) reduced therisk for

ASCVD. Compared with placebo, BP-lowering therapy reduced the risk for coronary heart

disease (RR, 0.84; 95% CI, 0.79-0.90) and stroke (RR, 0.64; 95% CI, 0.56-0.73). Tobacco

cessationdrugs increasedthe odds of continued abstinence at 6 months (odds ratio range,

1.82 [95% CI,1.60-2.06] to 2.88 [95% CI,2.40-3.47]), but thedirecteffects on ASCVD were

poorly reported. Aspirin increasedthe risk formajorbleeding (RR, 1.54; 95%CI, 1.30-1.82),

and statins did not increase overall risk for adverse effects (RR, 1.00;95% CI,0.97-1.03).

Adverse effects of BP-lowering therapy and tobacco cessation drugs were poorly reported.

CONCLUSIONS AND RELEVANCE  This overview demonstrates high-quality evidence to support

aspirin, BP-lowering therapy, and statins for primary ASCVDprevention and tobacco

cessationdrugs forsmoking cessation. Treatment effects of each drug canbe used to enrich

discussions between health care professionals and patients in primary ASCVD prevention.

 JAMA Cardiol . doi:10.1001/jamacardio.2016.0218

Published online April27, 2016.

Supplementalcontent at

 jamacardiology.com

Author Affiliations: Author

affiliations arelisted atthe endof this

article.

Corresponding Author: MarkD.

Huffman, MD,MPH, Department of 

Preventive Medicine, Northwestern

UniversityFeinberg School of 

Medicine, 680N Lake ShoreDr,

Ste 1400, Chicago,IL 60660

(m-huffman@northwestern.edu).

Clinical Review& Education

Review

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In 2011, the US Department of Health and Human Services

launchedthe MillionHearts initiative to prevent1 millionheart

attacks and strokes during 5 years.1 Million Hearts includes a

clinical emphasison ABCS,thatis, aspirinfor high-riskpatients,blood

pressure (BP)control, c holesterol level management, and smoking

cessation. Projections estimate that optimizing ABCS manage-

mentcouldreducethe burden ofatheroscleroticcardiovascular dis-

ease (ASCVD) substantially.

2

To support theMillionHearts goal andtoidentifynew models ofcare delivery andpayment, theCenterfor

Medicare & Medicaid Innovation launched the Million Hearts

Cardiovascular Risk Reduction Model in 2016, a cluster-

randomized payment model test to evaluate the effect of value-

based payment to incentivize ASCVD risk assessment and reduc-

tion. Thiseffort requires rigorousand transparent quantificationof 

the treatment effects of aspirin, BP-lowering therapy, statins, and

tobaccocessationdrugs in primaryASCVD prevention.3Despitethe

wealthofevidence-synthesisactivitieswithinindividualdrugclasses,

we arenot awareof any reports thathavesummarized theefficacy

and safety of all 4 drug classes highlighted in the Million Hearts

initiative for primary ASCVD prevention.

Anoverviewofsystematicreviewsisanovelapproachtoappraise

andsynthesizeresultsfrom multiple systematicreviewsinto a single,

usefuldocumentthatcan be used to guide healthcare profession-

alsandpolicymakers.4-7To addressthis evidence gap,we performed

anoverviewofsystematicreviewstocomparetheefficacyandsafety

of aspirin, BP-loweringtherapy, statins, andtobacco cessation drugs

on fatal and nonfataloutcomesfor primary ASCVD prevention.

Methods

This overview followed guidelines outlined by the Cochrane

Collaboration tosynthesizethe effectsof multipleinterventions for

an overarching clinical question using datafrom publishedsystem-

atic reviews.4

We established a protocol and published it in thePROSPERO International Prospective Register of Systematic

Reviews.8 The clinical question guiding this overview is presented

inthePICOTSS( patient, i ntervention, c omparators, outcomes, t im-

ing, setting, and study design) format (Box). We also performed a

supplemental systematic review to evaluate for potential interac-

tions when combination drug therapy is used but found none (de-

tailsaboutthesearch and results areoutlined ineAppendices1 and

2 inthe Supplement).

ReviewEligibility Criteria

Weincludedsystematicreviewsofrandomizedandquasi-randomized

clinical trials comparing the pooled treatment effects of aspirin,

BP-loweringtherapy, statins, or tobacco cessation drugs against pla-ceboorusualcareinadults(18yearsofage)withoutprevalentASCVD.

Forsystematicreviewsthatincludeda combinationofindividualswith

andwithout prevalentASCVD,we included reviewsthat reportedef-

fectestimatesforparticipantsdefinedasreceivingprimaryprevention.

Whenreportsincludedprimaryandsecondarypreventionpopulations,

we included only those reportswith lessthan10% of thepopulation

with prevalent ASCVD.9 Systematic reviews or trials in which drugs

wereusedtotreatorcontrolchronicconditions(eg,Alzheimerdisease,

rheumatoidarthritis,renal disease, macular degeneration, andaortic

stenosis) were excluded.

Outcomes

The primary outcomes for our review were (1) all-cause mortality;

(2) fatal and nonfatal cardiovascular events, including myocardial

infarction andstroke (ASCVD); and(3) adverse events as reported

by the authors of included reviews. Secondary outcomes were

(1) fatal and nonfatal ischemicheart disease events,includingmyo-

cardial infarction, angina, and coronary revascularization; (2) fatal

and nonfatal cerebrovascular events, including stroke and tran-

sientischemic attack;(3) total nonfatalASCVDevents;(4) total and

low-density lipoprotein cholesterol levels; (5) systolicand diastolic

BP; (6)health-relatedqualityof lifeusing validated instruments;and

(7) directcosts.

Search Strategy

We searched the Cochrane Database of Systematic Reviews, Data-

baseof Abstractsof Reviews of Effects (DARE),Health Technology

Assessment Database (HTA), MEDLINE, EMBASE, and PROSPEROInternational Prospective Systematic Review Trial Register from

January1, 2005, toJune 17, 2015. Welimitedretrievalto Englishlan-

guage systematic reviews. One of us (M.A.B.) who was an experi-

encedinformation specialistperformed all searches. Detailed search

strategies with explanations of databases and search filters are

included in eAppendix1 in the Supplement.

We identifiedadditional eligible studies by searchingthe refer-

encelistsof includedsystematicreviews, meta-analyses,and health

technology assessment reports.We contacted study authorswhen

necessaryto identify further informationthat we mayhave missed.

StudySelectionandDataExtraction

Twoof us(K.N.K.andM.D.H.) independently performed alltasksforstudy selection, dataextraction, evidencesynthesis,and qualityas-

sessment. Any discrepancies here and throughout were resolved

through consensus or recourse to a third investigator (D.M.L.-J.).

We screened titlesand abstractsand then full textsto identify

relevant systematic reviews for inclusion. For studies that fulfilled

the inclusioncriteria,we independently abstracted key participant

and interventioncharacteristics and reported dataon prespecified

outcomes usingstandardized dataextractiontemplates.We alsoex-

tracted pooled effect estimates for outcomes that were meta-

analyzed in each included review. We reported dichotomous data

Key Points

Question   Howeffective and safeare aspirin, statins, blood

pressure (BP)–lowering therapy, and tobacco cessationdrugs for

prevention of primary atheroscleroticcardiovascular disease

(ASCVD)?

Finding Inthis overviewof systematic reviews,we show that

aspirin, statins, and BP-loweringtherapyreduce ASCVD riskby10%to 25%and tobacco cessationdrugsincrease theoddsof 

continuedsmokingabstinence by 88%to 188%. Adverse events

wereincreased withaspirin, werenot increased with statins, and

werepoorly reported among BP-loweringand tobacco cessation

drug trials.

Meaning   High-quality evidence supports use of thesedrugs for

ASCVD primary prevention and tobacco cessation.

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as risk ratios(RRs) or odds ratios(ORs)with 95%CIs. We reported

continuous data as mean differences with 95%CI.

EvidenceSynthesis

Data were analyzed from July 2 to August 13, 2015. We indepen-

dently assessed the methodologic quality of each systematic

review using the Assessment of Multiple Systematic Reviews

(AMSTAR) tool.

10

Because many systematic reviews includedinformation from overlapping trials, we did not perform a

separate meta-analysis of pooled effect estimates. Instead, we

performed a qualitative synthesis for each drug intervention and

reported the treatment effect from the most comprehensive and

highest-quality systematic reviews as recommended by the

Cochrane Collaboration and as has been performed in other

overviews.4,6,11,12

We used the Grading of Recommendations Assessment, De-

velopmentandEvaluation(GRADE)approachtoratetheoverallqual-

ityof theevidence.13 We created an adapted Summary of Findings

table based on the methods described in the  Cochrane Handbook 

for Systematic Reviews of Interventions to convey key information

about the best treatment effect for each drug intervention and

overall confidence in this estimate.4

SecondaryAnalyses

We reported results thatevaluatedpotential differences in drugef-

fects between menand womenand people with and without type

2 diabetes mellitus when these results were presented by authors

ofreviewedstudies.We wereunableto quantifydifferencesby race/

ethnicity owing to limitations of data availability and reporting.

Differences BetweenProtocol andOverview

We revised our search strategy by using a precision-maximizing

filter after our initial search with a sensitivity- and specificity-

balancing filter produced unfeasibly large results. We also re-

strictedour retrievalto English-languagetrialsbecauseof timelimi-tationsfor projectcompletion.Last, weelectedto include systematic

reviews oftobaccocessationdrugsthat includedsome trials involv-

ing participants with known vascular disease. We made this deci-

sion because reviews addressed smoking cessationas the primary

efficacy outcome and provided limited data on cardiovascular

outcomes or mortality.

Results

Search Results

Weperformed4independentsearchesforsystematicreviewsevalu-

ating the effects of aspirin, BP-lowering therapy, statins, and to-

bacco cessation drugs in the primary prevention of ASCVD. We

presentaPRISMAstudyflowinaggregate(Figure)andbydrugclass

(eAppendix 3 in the Supplement).

Our search identified 1967 records, of which 145 were evalu-

ated as full-text articles after title and abstract screening. In total,

we selected 35 systematic reviews, available as 37reports forinclu-

sion. These consisted of 15 systematic reviews evaluating the ef-

fectofaspirin,14-294 systematicreviewsof BP-loweringtherapy,30-33

12 systematic reviews of statins,34-46 and 4 systematic reviews

of tobacco cessation drugs in a primary prevention setting.47-50

Reasons forexclusion ofeach full text reportand referencesto the

excludedstudies arepresented by drug class in eAppendix4 in the

Supplement.

Aspirin

Characteristicsof IncludedReviews

Asummaryofthe15systematicreviewsofaspirinisprovidedineAp-

pendix3inthe Supplement. Type 2 diabetes–specific treatmentef-

fects were provided in 6 reviews.18-20,24,28,29 The latestsearch ran

through 2013.17 Thereviewsincludeddatafrom6to9primarypre-

ventiontrials with95 456to 102621 participants.Trialsgenerally in-

cludedadultsaged40to70years,andtheweightedmean(SD)age

ofparticipants inthe most comprehensivereportwas57 (4)years.25

Box.PICOTSS(Patients,Interventions,Comparators, Outcomes,

Timing, Setting, andStudy Design)Format

Patients

• Adults18yearsof age

• People without prevalentASCVD

• Systematic reviews or trials that included people withAlzheimer

disease, end-stage renal disease, macular degeneration, andaortic stenosiswere excluded

Interventions

• Aspirin

• BP-lowering therapy

• Statins

• Tobacco cessationdrugs (ie, nicotine replacement therapy,

varenicline tartrate, bupropion hydrochloride)

Comparators

• Placebo

• Usual care

Outcomes

Primary

• All-cause mortality

• Fatal and nonfatal cardiovascularevents,includingmyocardial

infarction and stroke (ASCVD)

• Adverse events as reported by authors of included studies

Secondary

• Fatal and nonfatal ischemic heartdisease events, including

myocardial infarction, angina, and coronaryrevascularization

• Fatal and nonfatal cerebrovascular events, including stroke and

transient ischemicattack

• Total and nonfatal ASCVD events

• Total and low-density lipoprotein cholesterol levels

• Systolic and diastolicBP

• Health-related quality of life

• Direct costs

Timing

• Studies of any duration

Setting

• Any setting

StudyDesign

• Systematic reviews of randomized and quasi-randomized

clinical trials

Abbreviations:ASCVD, atherosclerotic cardiovascular disease;

BP, blood pressure.

Drugsfor Prevention of Atherosclerotic Cardiovascular Disease   Review   ClinicalReview& Education

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TrialQuality AssessmentandReviewQuality

Authors of included studies used a variety of criteria to judge trial

quality, including risk for bias assessments, Jadad scores,51 Delphi

process,52 andthe US Preventive Services TaskForce quality crite-

ria. Trial quality wasgenerallyassessedas high, andriskof bias was

categorized as low. Systematic review quality, as measured by

AMSTAR rating, ranged from a score of 5 of 11 to 11 of 11. The most

comprehensive and highest rated systematic review was an HTA

by Sutcliffeet al.25

EfficacyandCardiovascularBenefitsTreatment effects of aspirin on all-cause mortality, composite car-

diovascularevents,and individual componentcardiovascularevents

were broadly comparable across all systematic reviews. The sys-

tematic review by Sutcliffe et al25 reported a 6% reduction in all-

cause mortality (RR, 0.94; 95% CI, 0.88-1.00) and a 10% reduc-

tionin major cardiovascular events (RR,0.90;95% CI, 0.85-0.96).

Treatment effects on other outcomes are provided in eAppendix 3

inthe Supplement.

Systematicreviews thatreportedtype2 diabetes–specific treat-

menteffectsdemonstrated similarrelative benefitscomparedwith

thegeneral primaryprevention group;however, allof theupper 95%

CIsincluded thepossibilityof noimprovement. Sex-stratifiedanaly-

seswerereportedin4systematicreviews,14,16,27,29ofwhichonewas

an individual participant data meta-analysis of 6 primary preven-

tion aspirin trials.14 These analyses demonstrated similar reduc-

tionsin thecompositeCVD outcome inmen (RR, 0.88;95%CI, 0.78-

0.98)and women(RR,0.88;95%CI, 0.76-1.01).However, theeffects

weredrivenbyareductioninmajorcoronaryeventsinmen(RR,0.77;95%CI, 0.67-0.89) and ischemic stroke in women (RR, 0.77; 95%

CI, 0.59-0.99).

Safety, Adverse Effects,andOtherSecondaryOutcomes

Reviews varied in theirdefinitionof clinically important bleeding, but

all 15 reported increased risk for bleeding and other hemorrhagic

complications withaspirin therapy.The analysis fromthe Antithrom-

boticTrialists’ Collaboration,which accounted fordifferences in per-

son-years of follow-up and used a standardized definition for ma-

 jor ble edi ng in pool ed tri als (maj or gast roin test inal trac t and

extracranialbleeding thatwas fatal or required bloodtransfusion),

reporteda54%increasedriskformajorbleedingwithaspirintherapy

(RR, 1.54; 95% CI, 1.30-1.82) and a 32% increased risk for hemor-

rhagic stroke (RR,1.32;95% CI,1.00-1.75).14Dataon other bleeding

risks areshown in eAppendix3 in the Supplement. Dataon health-

related quality of lifeand direct costs werenot reported in theiden-

tified systematic reviews.

GRADEAssessment

We rated the quality of evidence for the effect of aspirin on all-

causemortalityasmoderate,whichwasdowngradedbecauseofim-

precisionof the treatmenteffect. Weratedthe quality of evidence

for theeffect ofaspirin on reducing majorcardiovascular eventsas

high. We also rated thequality of evidence for the effect of aspirin

on increasing majorbleeding events as high.

BP-LoweringTherapyCharacteristics of Included Reviews

We identified 4 systematic reviews of BP-lowering therapy in pri-

mary ASCVD prevention30-33; 2 of these reviews30,33 reported the

effects ofBP reductionin individualswithmild or grade1 hyperten-

sion(systolic BP, 140-149mm Hg;diastolicBP, 90-99mm Hg).Type

2 diabetes–specifictreatmenteffectswere notreported. Thelatest

searchranthrough2014andincludedindividualparticipantdatafrom

theBloodPressure LoweringTreatmentTrialists’Collaboration.33The

most comprehensive systematic reviews included 25 trials with

163 131 participants31and27 trials with108 297participants.32Only

8 trials overlapped between these 2 reviews owing to variations in

search strategies, search time frames, inclusion criteria, and classi-

ficationofprimarypreventionbyauthorsoftheincludedreviews.The

mean age of participants ranged from 30 to 80 years, and the

weighted mean age in the most comprehensive systematic review

was62years.32A summaryof systematicreviewcharacteristics and

detailed characteristics from the full data abstraction are provided

in eAppendix3 in the Supplement.

TrialQuality AssessmentandReviewQuality

Authors of included reviews used a variety of criteria to judge trial

quality, including risk of bias and GRADE assessments. These au-

thorsreportedarangeofqualityassessmentsfromverylowtohigh

Figure.PRISMA Flowchart forOverview ofSystematicReviews

of Primary PreventionDrugs

1967 Records identified

through database

screening

4 Records identified by

hand searching

258 Duplicates removed

1713 Titles or abstracts

screened

1568 Irrelevant titles

excluded

145 Full-text reports

assessed for eligibility

108 Excluded

38

23

14

10

11

7

4

1

Not primary prevention

Not systematic review

Abstract onlyNot in English

Duplicate reports

Wrong outcomes

No placebo comparison

Unavailable

37 Reports of 35 systematic

reviews included

16 Reports of 15 reviews

on aspirin4 Reports of 4 reviews

on BP-lowering therapy

13 Reports of 12 reviews

on statin4 Reports of 4 reviews on

tobacco cessation drugs

BP indicates bloodpressure.

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quality for trials evaluating the effects of calcium channel blockers

anddiuretics. The AMSTAR ratings ranged from a score of4 of 11 to

9 of11.

EfficacyandCardiovascular Benefits

Treatmenteffectsof BP-loweringtherapyon all-causemortality, com-

posite cardiovascular outcomes,and individualcomponentcardio-

vascularoutcomeswere broadly comparableacross systematic re-

views.ThesystematicreviewbyLawetal, 32themostcomprehensive

reviewincluded in ourstudy, reported an11% reductionin all-causemortality (RR, 0.89; 95% CI, 0.84-0.95), a 16% reduction in coro-

naryheartdisease events(RR,0.84; 95%CI, 0.79-0.90),and a 36%

reduction in stroke (RR, 0.64; 95% CI, 0.56-0.73). Treatment ef-

fects standardized to a 10–mm Hg reduction in systolic BP and a

5–mm Hg reductionin diastolic BP were also reported (Table).

The effects of BP-loweringtreatments in persons with mild or

grade 1 hypertension werereportedin 2 systematic reviews.31,33The

review by Sundström et al33 was an update to the review by Diao

etal30andincludedindividualparticipantdatafrom8additionaltrials

(10 comparisons) from the Blood Pressure Lowering Treatment

Trialists’Collaboration for a total of 13 trials and 15 266 participants

with grade 1 hypertension. Sundström et al33 reported a 22% re-

duction in all-causemortality (OR,0.78;95% CI, 0.67-0.92), a 14%

reduction in total cardiovascular events (OR, 0.86; 95% CI, 0.74-

1.01), a 25% reductionin cardiovascular deaths(OR, 0.75;95% CI,

0.57-0.98), and a 28%reductionin stroke (OR,0.72; 95%CI, 0.55-

0.94). Overall, cardiovascular eventrates were lowin thetrials, so

effectestimates fortotalcardiovascular eventsand coronaryevents

were imprecise.33

Type 2 diabetes–specific treatment effects were not reportedfor BP-lowering treatment. Sundström et al33 reported no interac-

tionby sexfor all-causemortality, total CVD events,coronaryheart

disease events, stroke events, or heartfailureevents,but a border-

line interaction was present for CVD mortality (OR, 0.58 [95% CI,

0.41-0.81] for men; 1.19 [95% CI, 0.74-1.91] for women; P  = .02).

Safety, AdverseEffects,andOtherSecondaryOutcomes

Only 1 systematic review30 reported an increased risk for treat-

ment withdrawals owing to adverse events, and this was derived

from1 trial (RR4.80, 95%CI 4.14-5.57).However, therisk of biasfor

Table.SummaryofKeyFindings for theEffect ofDrugsfor Primary Prevention

of AtheroscleroticCardiovascular Diseases

Outcomes Risk, RR or OR (95% CI)Quality of Evidence(GRADE)a Comment

Aspirin

All-cause mortality RR, 0.94 (0.88-1.00) Moderate Downgraded owingto imprecision

Major cardiovascular events RR, 0.90 (0.85-0.96) High NA

Adverse effects (major bleeding) RR, 1.54 (1.30-1.82) High NA

BP-lowering therapies

All-cause mortality RR, 0.89 (0.84-0.95) High NA

CHD events RR, 0.84 (0.79-0.90) High NA

CHD events standardized toa BP reduction of 10/5 mm Hg

RR, 0.79 (0.72-0.86) High NA

Stroke events RR, 0.64 (0.56-0.73) High NA

Stroke events standardized toa BP reduction of 10/5 mm Hg

RR, 0.54 (0.45-0.65) High NA

Adverse effects(treatment withdrawal)

RR, 4.80 (4.14-5.57) Low Downgraded owingto study limitationsand inconsistency

Statins

All-cause mortality OR, 0.86 (0.79-0.94) High NA

Major cardiovascular events RR, 0.75 (0.70-0.81) High NAMajor vascular events per 40.6 mg/dLof LDL cholesterol level reduction

RR, 0.75 (0.70-0.80) High NA

CHD events RR, 0.73 (0.67-0.80) High NA

Stroke events RR, 0.78 (0.68-0.89) High NA

Adverse effects

All RR, 1.00 (0.97-1.03) Moderate Downgraded owingto indirectnessof evidence

Type 2 diabetes RR, 1.18 (1.01-1.39) Moderate Downgraded owingto indirectnessof evidence

Tobacco cessation drugs

Nicotine replacement therapy,continuous smoking abstinence at ≥6 mo

OR, 1.84 (1.71-1.99) Moderate Downgraded owingto study limitations

Bupropion hydrochloride, continuous

smoking abstinence at ≥6 mo

OR, 1.82 (1.60-2.06) Moderate Downgraded owing

to study limitationsVarenicline tartrate, continuoussmoking abstinence at ≥6 mo

OR, 2.88 (2.40-3.47) High NA

Abbreviations: BP, bloodpressure;

CHD,coronary heartdisease;

GRADE,Gradingof RecommendationsAs sessment,

Development, and Evaluation;

LDL, low-density lipoprotein;

NA,not applicable; OR,oddsratio;

RR, risk ratio.

SI conversion factor: To convert LDL

cholesterol to millimoles perliter,

multiply by 0.0259.

a Highindicatesfurther researchis

very unlikely tochange our

confidencein theestimateof effect;

moderate, further research is likely

tohavean importanteffect onour

confidencein theestimateof effect

andmay changetheestimate; and

low, furtherresearch is very likelyto

have an importanteffect onour

confidencein theestimateof effect

andis likelyto changetheestimate.

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this outcome was high. The updated search by Sundström et al33

noted that data on treatmentwithdrawal were limited but equally

common in the active and control groups when available. Data on

health-related quality of life and direct costs were not reported in

any review.

GRADEAssessment

WeratedthequalityofevidencefortheeffectofBP-loweringtherapyon reducing all-causemortality, coronary heartdisease,and stroke

as high. We rated the quality of evidence for the effect of BP-

lowering therapy on treatment withdrawals as low, downgraded

because of study limitations and inconsistency.

Statins

Characteristicsof IncludedReviews

Weidentified 13 reports of 12 systematicreviewsof trials that inves-

tigatedthe effects of statinsin primary prevention.34-46 Type2dia-

betes–specifictreatment effects werereportedin 3 reviews,36,39,41

and sex-specific treatment effects were reported in 3 systematic

reviews.34,37,43 The latestsearch ranthrough 2012.45

The 2 most comprehensive reviews included 18 to 20 primary

prevention trials involving 56 934 to 63 899 participants.42,45 Themean ageof participantsgenerally rangedfrom50 to75 years,and

mean age in the most comprehensive review was 57 years.45 Two

reports fromthe Cholesterol Treatment Trialists’ Collaboration37,38

wereincludedin ouroverview. Oneof thesereportedtreatmentef-

fectsfor 70 025 participants without prevalent vascular disease,37

andtheotherreportedtreatmenteffectsfor53 152participants with

a 5-year predicted risk for a major vascular event of 10% or less

(>90% without prevalent vascular disease).38 A summary of sys-

tematic review characteristics is provided in eAppendix 3 in the

Supplement.

TrialQuality AssessmentandReviewQuality

Theauthorsof included reviews reported thattrialsgenerally hadalow risk of bias, but many were funded by pharmaceutical

companies.45 The AMSTAR ratings rangedfrom a score of 5 of 11 to

11 of 11. The most comprehensive and highest rated systematic

reviewwas by Taylor et al.45

EfficacyandCardiovascularBenefits

Treatmenteffects of statins on all-cause mortality,total CVDevents,

myocardial infarction, and stroke were broadly comparable across

all systematic reviews. The systematic review by Taylor et al45 re-

ported a 14% reduction in all-cause mortality (OR, 0.86; 95% CI,

0.79-0.94), a 25% reduction in major cardiovascular events (RR,

0.75;95% CI,0.70-0.81),and reductionsin fatal andnonfatal coro-

naryheartdisease andstroke events.45Themean(SD)baselinelow-

density lipoprotein cholesterol level in the Cholesterol Treatment

Trialists’ Collaborationtrials was143.1(27.1) mg/dL(to convertto mil-

limoles per liter, multiply by 0.0259),and themean (SD)difference

in low-density lipoprotein cholesterol levels between participants

in the statin regimen and controls was 41.8 mg/dL. Treatment ef-

fects standardized per 40.6–mg/dL reduction in levels of low-

density lipoprotein cholesterol were also reported by the Choles-

terol Treatment Trialists’Collaboration38 forall-causemortality(RR,

0.91;95% CI,0.85-0.97) and major vascularevents (RR,0.75; 95%

CI, 0.70-0.80).

Effects of statin treatment in participants with diabetes were

reported in 3 systematic reviews36,39,41 and demonstrated similar

proportional benefits compared with the general primary preven-

tion group. Sex-specific treatment effects were also reported in 3

systematic reviews,34,37,43 of which one was an individual partici-

pant data meta-analysis.37 After adjusting for baseline differences

in prognostic characteristics and 5-year vascular risk, no sex-

specific heterogeneity was seen.

37

Additional statin treatmenteffects are provided in eAppendix3 in the Supplement.

Safety, Adverse Effects,andOtherSecondaryOutcomes

Data on adverse effects of statin treatment were included in

7 systematic reviews andincludedrisks for cancer, elevation of cre-

atine kinase levels, rhabdomyolysis, elevation of liver enzyme lev-

els, hemorrhagic stroke, type 2 diabetes, and serious adverse

effects.34,35,37,38,42,45,46 Taylor et al45 reported no evidence of in-

creased riskfor overalladverse effects (defined as cancers,myalgia

andrhabdomyolysis, type2 diabetes, hemorrhagicstroke,and other

adverse effects leading to treatment discontinuation) among indi-

viduals treated withstatinscompared withcontrol or placebo (RR,

1.00; 95% CI, 0.97-1.03). However, the risk for the individual out-

come oftype 2 diabetes for those treated with statinsincreased by

18% (RR, 1.18; 95% CI, 1.01-1.39).

Data on health-related quality of life were not reported. Data

on cost-effectiveness were reported in Taylor et al45 from 3 statin

trials, all demonstrating cost-effectiveness of statin therapy in pri-

maryprevention. In theWest of ScotlandCoronaryPreventionStudy

(WOSCOPS), statin treatmentled to 2460 years of life at £8121 (or

$12 788)per life-yeargained.In theJustification forthe Useof Stat-

insin Primary Prevention: anInterventionTrialEvaluatingRosuvas-

tatin (JUPITER) trial, statin therapy had a cost-effectiveness of 

£25 796 (or $40 315) per quality-adjusted life-year. Last, in analy-

ses from the Collaborative Atorvastatin Diabetes Study (CARDS),

Taylor et al45 reported an incremental cost-effectiveness ratio of 

£2320 (or $3626) per quality-adjusted life-year at 10 years.

GRADEAssessment

We rated thequality of evidence for theeffect of statins on reduc-

ingthe riskfor all-causemortality, majorcardiovascularevents, coro-

nary heart disease events, and stroke as high. We rated thequality

of evidence for the safety of statins as moderate, downgraded

because of the indirectness of evidence.

TobaccoCessationDrugs

Characteristics of Included Reviews

We included 4 systematic reviews of tobacco cessationdrugs.47-50

None ofthe reviewsdifferentiated between trialsthat includedpar-

ticipants withand withoutprevalentvasculardisease.Moreover, the

reviews reported limited information about the effects of tobacco

cessationdrugs oncardiovascularoutcomesor riskfactors. Thepri-

mary efficacy outcome for most reviews was continuous smoking

cessation at 6 months. Type 2 diabetes–specificor sex-specifictreat-

ment effects were not reported. The latest search ran through

2012.48Themean ageamong participants in the mostcomprehen-

sive systematic reviewwas 57 years.48

The most comprehensive systematic review was an overview

of several Cochrane systematic reviews by Cahill et al48 that ad-

dressed drugtherapyfor smoking cessation. Thisoverview synthe-

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sized informationfrom267trialsof 101804 participants.Amongthe

trials, 150 assessed nicotine replacement therapy, 72 trials as-

sessedantidepressants (primarily bupropion hydrochloride), and24

trials assessed nicotine receptor partial agonists (primarily vareni-

cline tartrate). A summary of systematic review characteristics is

provided in eAppendix3 in the Supplement.

TrialQuality AssessmentandReviewQuality

Authors reported that trials of nicotine replacement therapy and

bupropiondid notclearlydescribemethodsof randomization or al-

location concealment andwere thereforeat high risk of bias. Trials

of varenicline were more contemporary and generally at lower risk

of bias, although they were industry funded.48 The AMSTAR rat-

ings rangedfrom 7 of 11 to 11 of 11,and thehighestrated systematic

reviewwas by Cahill et al48 (eAppendix 3 in the Supplement).

EfficacyandSmoking Cessation

The overview by Cahill et al48 reported treatment effects of to-

bacco cessation drugs on 6 months of continuous smoking absti-

nence,which wasprimarilyverifiedby biochemicalmeans. Theover-

view reported that nicotine replacement therapy, bupropion, and

varenicline allincreased theodds ofsmokingcessationat 6 months

compared withplacebo(OR fornicotine replacement therapy, 1.84

[95%CI, 1.71-1.99];OR forbupropion, 1.82 [95%CI, 1.60-2.06]; and

OR forvarenicline, 2.88 [95% CI,2.40-3.47]). Cahill et al48 also re-

ported the effects of a limited number of tobacco cessation drugs

on CVDevents. However, individual studieswere underpowered for

this end point, events were poorly reported, and many trials in-

cludedparticipantswith prevalent CVD.Treatmentestimatesfor bu-

propion and varenicline for smoking cessationoutcomes are listed

ineAppendix 3 inthe Supplement.

Safety, Adverse Effects,andOtherSecondaryOutcomes

Cahill et al48 also reported the effects of tobacco cessation drugs

onseriousadverseeventsforalimitednumberoftherapies.Fornico-tinereplacement therapy, limitedinformationon seriousadverse ef-

fects was reported in trials.48 Data for bupropion and varenicline

werereported (RR,1.29[95% CI,0.99-1.69]and 1.06[95% CI,0.72-

1.55], respectively).Data on health-relatedquality of lifeand direct

costs were not reported.

GRADEAssessment

Weratedthequalityofevidencefortheeffectofvareniclineonsmok-

ingcessation as high andthe quality ofevidence forthe effect ofbu-

propion and nicotine replacement therapy on smoking cessation as

moderate, downgraded because of study limitations. We rated the

qualityof evidence forthe safetyof tobacco cessationdrugsas mod-

erate,downgradedbecauseofindirectnessofevidence.Weratedthequality of evidence for the effect of tobacco cessation drugs on all-

cause mortality and cardiovascular outcomes as low, downgraded

becauseof study limitations,inconsistency, and imprecision.

Discussion

Principal Findings

We performed an overviewof systematic reviews thatsynthesized

evidence ofthe efficacy andsafetyof drugs that canbe used inpri-

maryASCVDpreventiontoachievetargetssetbytheMillionHearts

initiative and that will be used in theMillion Hearts Cardiovascular

RiskReduction model. High-quality evidencesuggeststhat aspirin,

BP-lowering therapy, and statins reduce the risk for ASCVDevents

from10%to25%amongindividualswithoutprevalentASCVD.High-

quality evidence also suggests that BP-lowering therapy and stat-

ins reduce the risk for all-cause mortality by 11% and 14%, respec-

tively. No heterogeneity in treatment effect was found amongsubgroupsof individuals with type 2 diabetes orby sex. Moderate-

to high-quality evidence suggests thattobacco cessation drugs in-

creasethe odds of continued abstinence by 88% to 188%, butthe

directeffects oncardiovasculareventsare uncertain. A summaryof 

findings is presentedin theTable.

Adverse effects of drug therapy were not reported or were

poorly reported in many systematic reviews, and many authors of 

theincluded reviewsnotedunderreporting ofadverseeventsin the

individualtrials.Our searchdemonstrated high-quality evidence that

aspirin increasesthe riskfor major bleeding by 54%and moderate-

quality evidence that statins do notincrease theoverallrisk for ad-

verse events, butthe risk fortype 2 diabetes was increasedamong

individualstakingstatins.AdverseeffectsofBP-loweringtherapyand

tobacco cessation drugs were poorly reported.

Strengths

Our overview has several strengths. First, we focused this evi-

dence synthesis on systematic reviews and meta-analyses of ran-

domized clinical trials, because randomized clinical trials represent

thehighest-quality evidenceto determinethe effectsof healthcare

interventions.Second,weusedacomprehensive,transparentsearch

strategy to identify studies and followeda prespecifiedprotocol to

guideour evidence synthesis, noting anydeviations fromprotocol.

Third, we performedall title screening,data extraction, andquality

assessments in duplicate to minimize potential bias in generation

of this overview. Fourth, we used a validated instrument (the

AMSTAR tool) to assess the methodologic quality of included sys-tematic reviews and factored this quality assessment to guide our

conclusions regarding the effects of pharmacologic interventions.

Thissystematic process, withstudy quality assessmentusing stan-

dardized tools, could be used as a potential model for more rapid

development of trustworthy guidelines.

Limitations

Our overview alsohas importantlimitationsto acknowledge. First,

wedid not retrievedatafromprimary trialsandthereforewere lim-

itedtotheinformationandjudgmentsoftheauthorswhowrotethe

systematic reviews. Selection criteria, search strategies, and defi-

nitions ofprimarypreventionoftenvaried betweenreviews,and au-

thors of theincluded reviews oftenused differentcriteriato define

primary prevention, which ledto differentnumbersof trials forsys-

tematic reviewsof thesamedrug.Second,our conclusions werelim-

ited by the available data. Although data were generally well re-

portedfordrug efficacy, limitedinformationwas reportedon safety,

particularly for BP-lowering therapy and tobacco cessation drugs.

Third, we hadlimited ability to comment onthe potentialof differ-

ential treatmenteffectsby race/ethnicity. Nevertheless,severalre-

views noted consistent proportional treatment effects regardless

of baseline characteristics, suggesting that treatment effect does

not demonstrate heterogeneity. Fourth, our treatment effect

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estimates werelimited bytheshort-termhorizonof theclinical trials.

Thus,wemayhaveunderestimatedthepotentialaddedbenefitsand

risks of sustained treatment. Fifth, our overview does not include

evidence from recent trials like the Japanese Primary Prevention

Project (JPPP)53 or cost-effectiveness analyses of long-term statin

usefromtheWOSCOPS.54However,inclusionofthesestudieswould

not have changed our overall conclusions. For example, the point

estimatefor treatment effect fromlow-doseaspirinin theJPPP trialwas similar to our reported effect, althoughwith wider confidence

intervals (hazard ratio, 0.94; 95% CI, 0.77-1.15), and primary pre-

vention statin therapy was also shown to be cost-effective at 15

yearsof follow-up. Finally, our overview does not provide informa-

tion onthe added effects of lifestyleinterventions such as diet, ex-

ercise, andweightloss in combination withdrug therapy. However,

essentially all included clinical trials of ASCVD prevention included

background recommendations of therapeutic lifestyle change in

combination with study drugs.

Conclusions

This overview of systematic reviews demonstrates high-quality

evidenceto supportaspirin, BP-loweringtherapy, andstatins forpri-mary ASCVD prevention and tobacco cessationdrugs for smoking

cessation. The overview provides reliable, evidence-based pooled

estimates for these interventions on the lowered risk for primary

ASCVD events and best-available evidence for the effect of 

tobacco cessation drugs on continuous abstinence at 6 months.

These treatment effects can be used to enrich discussions

between health care professionals and patients.

ARTICLE INFORMATION

Accepted for Publication: February 10,2016.

Published Online: April27, 2016.

doi:10.1001/jamacardio.2016.0218 .

Author Affiliations: Division of Epidemiology,Departmentof Preventive Medicine,Northwestern

UniversityFeinberg School of Medicine,Chicago,

Illinois (Karmali, Lloyd-Jones, Huffman); Division of 

Cardiology, Department of Medicine,Northwestern

UniversityFeinberg School of Medicine,Chicago,

Illinois (Karmali, Lloyd-Jones, Huffman); Galter

Health Sciences Library, NorthwesternUniversity

FeinbergSchool of Medicine,Chicago,Illinois

(Berendsen); Colorado School of PublicHealth,

Universityof Colorado Anschutz Medical Center,

Aurora (Goff);Center forMedicare& Medicaid

Services, Baltimore,Maryland(Sanghavi,Brown);

TheMITRE Corporation, McLean, Virginia

(Korenovska);Associate editor, JAMA Cardiology 

(Huffman).

Author Contributions: Drs Karmali and Huffman

had fullaccessto all the datain the study and take

responsibility fortheintegrity ofthe data andthe

accuracy of the data analysis.

 Study concept and design: Karmali, Lloyd-Jones,

Berendsen,Goff,Sanghavi,Brown, Huffman.

 Acquisition, analysis, or interpretation of data:

Karmali, Berendsen, Korenovska,Huffman.

Drafting of the manuscript: Karmali, Lloyd-Jones,

Berendsen, Huffman.

Critical revision of the manuscriptfor important 

intellectual content: Karmali, Lloyd-Jones, Goff,

Sanghavi, Brown, Korenovska,Huffman.

 Statistical analysis: Karmali, Korenovska,Huffman.

Obtained funding: Goff, Lloyd-Jones.

 Administrative, technical, or material support:

Karmali, Berendsen, Brown, Korenovska, Huffman.

 Study supervision: Sanghavi, Brown, Huffman.

Conflict of Interest Disclosures: All authors have

completedand submitted theICMJE Form for

Disclosureof PotentialConflicts of Interest.Dr

Huffman reports receivinggrants fromthe Center

for Medicare & Medicaid Innovation (CMMI) via

subcontractfrom TheMITRE Corporation during

theconductof thestudy andgrantsfrom World

HeartFederation outside the submitted workand

serving as an associateeditorfor JAMA Cardiology 

and thecoordinating editor of the Cochrane Heart

GroupUS Satellite.Dr Lloyd-Jonesreportsreceiving

grantsfromthe CMMI viasubcontractfromThe

MITRECorporationduring the conduct of thestudy.

No other disclosureswere reported.

Funding/Support: This study wassupported bythe

CMMIthroughwork conducted undercontract No.

HHSM-500-2012-00008I.

Roleof Funder/Sponsor:Thisstudy was

performedto provide a synthesisof available

evidence to support development of a longitudinal

cardiovascular risk calculator that willbe used in the

Million Hearts Cardiovascular Risk Reduction

Model. TheCMMI provided an initial descriptionof 

keyquestions. However, thefinal protocol was

developedindependentlyby the authors. The

authors weresolely responsiblefor data collection,

management, analysis, and interpretation.

Members of CMMIand TheMITRE Corporation

revieweda draft version of a full, more detailed

report, andthe final version used bythe group

explicitlyaddressedcomments and suggestions

provided.Final interpretationof the data,including

 judgments of evidence quality,was solely the

responsibility of the authors. Thesponsorhad norole in thereviewor approval ofthe manuscript.

The sponsor wasinvolved in thedecision tosubmit

themanuscriptfor publicationin  JAMA Cardiology 

to provide transparency regardingthe evidence

basefor thenew cardiovascular riskcalculator.

Disclaimer: DrHuffman is anassociateeditor of 

 JAMA Cardiology butwas notinvolved in the

editorialreview orthe decision toaccept the

manuscriptfor publication.

Additional Contributions: Janet S. Wright, MD,

Million Hearts initiative,Centersfor Disease Control

and Prevention, provided inputin preparingthis

manuscript.She received no compensation for this

role.

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