A strategy to reduce cardiovascular disease by more than 80%
N J Wald, professor1, M R Law,
professor1
1 Department of Environmental and Preventive
Medicine, Wolfson Institute of Preventive Medicine, Barts and the London, Queen
Mary's School of Medicine and Dentistry, University of London, London EC1M 6BQ
Objectives To determine the combination of drugs and vitamins,
and their doses, for use in a single daily pill to achievea large
effect in preventing cardiovascular disease with minimaladverse
effects. The strategy was to simultaneously reducefour
cardiovascular risk factors (low density lipoprotein cholesterol,
blood pressure, serum homocysteine, and platelet function)regardless
of pretreatment levels.
Design We quantified the efficacy and adverse effects of the proposed
formulation from published meta-analyses of randomisedtrials and
cohort studies and a meta-analysis of 15 trialsof low dose (50-125
mg/day) aspirin.
Outcome measures Proportional reduction in ischaemic heart disease
(IHD) events and strokes; life years gained; and prevalenceof
adverse effects.
Results The formulation which met our objectives was: a statin(for example, atorvastatin (daily dose 10 mg) or simvastatin
(40 mg)); three blood pressure lowering drugs (for example,a
thiazide, a
blocker, and an angiotensin converting enzymeinhibitor), each at
half standard dose; folic acid (0.8 mg);and aspirin (75 mg). We
estimate that the combination (whichwe call the Polypill) reduces
IHD events by 88% (95% confidenceinterval 84% to 91%) and stroke by
80% (71% to 87%). One thirdof people taking this pill from age 55
would benefit, gainingon average about 11 years of life free from an
IHD event orstroke. Summing the adverse effects of the components
observedin randomised trials shows that the Polypill would cause
symptomsin 8-15% of people (depending on the precise formulation).
Conclusion The Polypill strategy could largely prevent heartattacks and stroke if taken by everyone aged 55 and older and
everyone with existing cardiovascular disease. It would beacceptably
safe and with widespread use would have a greaterimpact on the
prevention of disease in the Western world thanany other single
intervention.
Heart attacks, stroke, and other preventable cardiovasculardiseases
kill or seriously affect half the population of Britain.Western diet
and lifestyle have increased the population levelsof several of the
causal "risk factors," and their combinedeffects have made the
diseases common. Cardiovascular diseasecan be avoided or delayed,
but the necessary changes to Westerndiet and lifestyle are not
practicable in the short term. Randomised trials show that drugs to lower three
risk factors—lowdensity lipoprotein (LDL) cholesterol,1 blood pressure,2–6 and platelet function (with aspirin)78—reduce the incidence of ischaemic
heart disease (IHD) events and stroke.Evidence that lowering serum
homocysteine (with folic acid)reduces the risk of these diseases is
largely observationalbut still compelling.910
Drug treatment to prevent IHD events and stroke has generallybeen
limited to single risk factors, to targeting the minorityof patients
with values in the tail of the risk factor distribution,and to
reducing the risk factors to "average" population values.This policy
can achieve only modest reductions in disease.11
A large preventive effect would require intervention in everyoneat
increased risk irrespective of the risk factor levels; intervention
on several reversible causal risk factors together; and reducing
these risk factors by as much as possible.11
We describe a strategy to prevent cardiovascular disease basedon
these three principles12 and quantify the
overall preventiveeffect. We show that a daily treatment, the
Polypill, comprisingsix components, each lowering one of the above
four risk factors,would prevent more than 80% of IHD events and
strokes, witha low risk of adverse effects. This strategy would be
suitablefor people with known cardiovascular disease and for
everyoneover a specified age (say 55), without requiring risk
factorsto be measured.
We identified categories of drugs or vitamins used to modifyLDL
cholesterol, blood pressure, homocysteine, and plateletfunction. For
LDL cholesterol, statins are the drugs of choice.11314 For lowering blood
pressure, we considered all fivemain categories of drugs: thiazides,
blockers,
angiotensinconverting enzyme (ACE) inhibitors, angiotensin II
receptorantagonists, and calcium channel blockers.13 Serum homocysteineis most effectively
reduced by folic acid; vitamins B-6 andB-12 have relatively small
effects.15 Aspirin is the mostwidely
used and least expensive antiplatelet agent.
The choices of statin and of the categories and doses of blood
pressure lowering drugs were determined from the meta-analysisof
short term randomised trials in our companion papers.116 The dose of folic acid was the minimum needed to
ensurethe maximum reduction in serum homocysteine.1517 The longterm
effect of a specified absolute reduction in LDL cholesterol,blood
pressure, and homocysteine expressed as the proportionalreduction in
the incidence of IHD events and stroke was takenfrom published
sources that were based on systematic reviewsof cohort studies.191418 Cohort studies show long termeffects
because the observed differences in risk factors between individuals will have
existed for decades.2 Predictions from
the cohort studies on LDL cholesterol and blood pressure in preventing disease
have been corroborated by results of randomisedtrials, and both
cohort studies and trials have shown thata specified reduction in
blood pressure or serum cholesterolproduces a constant proportional
reduction in risk that isindependent of the initial value of the
risk factor.1341114 The average age at which
cardiovascular event occurredin the studies was around 60-65 years.
Platelet function is difficult to quantify, and there is inadequate evidence
on its association with ischaemic heart disease andstroke. We
therefore used direct evidence from randomised trialsof the effects
of aspirin on disease events. Since the necessaryinformation on
stroke and adverse effects with low dose aspirinwas not available
from published meta-analyses, we conductedone. The efficacy of low
dose aspirin (50-125 mg/day) is similarto that of higher doses
(160-1500 mg/day),8 so we analysed
only trials of low dose aspirin. We identified trials of ≥6 months' duration
from previous meta-analyses,78
from Medline(using the search term "aspirin" in all fields and
publicationtype "clinical trial"), and the Cochrane Collaboration
andWeb of Science databases. This yielded 15 trials: four werein healthy adults, nine in people with a history of IHD, and
two in people with atrial fibrillation. We determined the average
proportional reduction in IHD events and stroke, and the prevalence
and incidence of adverse effects.
We calculated the combined effect of changing the four risk
factors (the effect of the Polypill) by multiplying the relative
risks associated with each. We calculated the years of lifegained
without a heart attack or stroke if people without aprevious
cardiovascular event used the Polypill from age 55.We used a simple
Markov model incorporating the probabilitiesof three factors—a fatal
or non-fatal IHD event or stroke(from an analysis of registry data4), dying from another cause(from 1999
England and Wales mortality data), and remainingalive without a
vascular disease event—stratified by sexand age by year. We then
estimated the numbers of events duringeach subsequent year of life
for 100 men and 100 women, andcompared these numbers with those
calculated from otherwiseidentical groups not taking the Polypill.
From this we determinedthe extra years of event-free life gained by
taking the Polypill.
Efficacy Table 1 shows the effects of the individual agents. By useof statins, LDL cholesterol concentration can be reduced byan
average of 1.8 mmol/l. Atorvastatin 10 mg taken at any timeof day or
simvastatin (or lovastatin) 40 mg taken in the eveningor 80 mg taken
in the morning after about two years of treatmentcan reduce the
incidence of IHD events at age 60 by an estimated 61%.1
Higher doses produce little further gain. The overallreduction in
stroke from an LDL cholesterol reduction of 1.8mmol/l is about 17%.1 This estimate takes account of the reduction
in risk of stroke in people with and without existing vascular
disease (35% v 11%, a difference which arises because a stroke
in people with vascular disease is more likely to be thromboembolic,
and statins prevent thromboembolic, but not haemorrhagic, stroke)and
also takes account of the proportion of first strokes thatoccur in
people with known vascular disease (25%)1 (25% of35% plus 75% of 11% making 17%).
Table 1 Effects of
the Polypill on the risks of ischaemic heart disease
(IHD) and stroke after two years of treatment at age
55-64
The five main categories of blood pressure lowering drugs (thiazide,
blockers, ACE inhibitors, angiotensin II receptor antagonists,and
calcium channel blockers), and the individual drugs withinthe
categories, produce similar reductions in blood pressure,given dose
as a ratio of standard dose.16 A combination ofthree drugs from different categories in low dose has greater efficacy and
fewer adverse effects than using one or two drugsin standard dose.16 The blood pressure reduction with three
drugs in combination at half standard dose is about 11 mm Hg
diastolic, reducing the incidence of IHD events by 46% and stroke by 63%.1617
The maximum effect of folic acid, achieved at a dose of about0.8
mg/day,1518 lowers serum
homocysteine by 3 µmol/l(about 25%) and reduces IHD events by about
16% and strokeby 24%.9
Figure 1 shows our meta-analysis of the 15 randomised
trialsof low dose aspirin (50-125 mg/day). IHD events were reducedby 32% and strokes by 16% (details in web table A). As with
statins, aspirin may have a larger preventive effect in peoplewith
occlusive vascular disease than in those without suchdisease; the
three trials of people without disease indicatea non-significant 9%
reduction in risk of stroke (web tableA).
Fig 1 Relative
risks (95% confidence intervals) of ischaemic heart
disease events and all strokes (fatal and non-fatal) in
15 randomised trials of low dose aspirin
Table 1 shows that changing all four risk factors
togetherreduces the risk of IHD events by 88% and stroke by 80%.
Theseresults are obtained from the product of the relative riskestimates relating to interventions on each risk factor, which
is the complement of the proportion of events prevented; thus,
preventing, say, 61% is equivalent to a relative risk of 0.39.The
following example illustrates the calculation. The relativerisks of
an IHD event for the four interventions in table 1are 0.39, 0.54, 0.84, and 0.66, the product of which yieldsa
combined relative risk of 0.12 or an 88% preventive effect(if 100
people who would have had IHD events without interventionwere
treated, statins would prevent 61 of the 100 events, leaving39; 46%
of these would be prevented with blood pressure lowering drugs, leaving 21; 16%
of these would be prevented with folicacid, leaving 18; and 34% of
these would be prevented withaspirin, leaving 12; 88% have thus been
prevented). Reducingone risk factor has a similar proportional
effect on risk irrespectiveof the level of other risk factors, as
confirmed by cohortstudies and randomised trials.19–22 For example, trialsof LDL cholesterol reduction show similar proportional reductionsin risk in people with high and low blood pressure and in people taking
and not taking aspirin.2021
Other than the statin (in respect of IHD), omitting a single
component has a relatively minor impact on the combined effectof the
residual components, illustrating the robustness ofthe Polypill
concept. Compared with the reductions in IHD eventsand stroke of 88%
and 80% respectively with all six components,the reductions were 86%
and 74% without folic acid, 85% and73% without one blood pressure
lowering drug (two instead ofthree), and 83% and 77% without
aspirin. So, for example, aspirinprevents 32% of IHD events when
used alone but prevents onlyan additional 5% of the original number
of expected eventswhen added to the other components in the
combination.
Table 2 shows the expected proportion of people who would
avoidan IHD event or stroke by taking the Polypill from age 55 and,in those, the average number of event-free life years gained.
The estimates take account of deaths from causes other thanIHD and
stroke. About a third of people taking the Polypillwould benefit. On
average each will gain 11-12 years of lifefree from a heart attack
or stroke. The gain in life is substantialat all ages.
Table 2 Expected
benefits in 100 men and 100 women without a known
vascular disease who start taking the Polypill at age
55. Calculations are based on a Markov model and allow
for other causes of death
Adverse effects Table 3 summarises the extracranial adverse effects of lowdose aspirin from our meta-analysis of 15 randomised trials.Table 4 uses these data together with those published in ourcompanion papers116
to show the proportions of people reportingsymptoms attributable to
any of the components of the Polypill(percentage with symptoms in
treated groups minus percentage in placebo groups in trials). If we included the
three classesof blood pressure lowering drugs with the lowest
prevalenceof adverse effects (thiazide, angiotensin II receptor
antagonist,and calcium channel blocker16)
in a Polypill formulation,8% would be expected to have symptoms
attributable to one ormore of the six components of the pill, mostly
due to aspirin.If we used the three least expensive blood pressure
loweringdrugs (a thiazide, a blocker, and an ACE inhibitor) instead,a Polypill including these would cause symptoms in about 15%of
people taking the pill.
Table 4 Prevalence
of participants in randomised trials reporting symptoms
attributable to the Polypill components (in doses
specified in table 1)
Of all the components, aspirin has the most serious adverse
effects, mainly due to haemorrhage (table B on bmj.com).
Inour meta-analysis of the trials of low dose aspirin the increasein haemorrhagic stroke (table A on bmj.com)
was exceededby the reduction in thrombotic strokes, producing an
overall16% reduction in stroke. There was no excess risk of fatalextracranial haemorrhage, with 13 and 15 deaths in the aspirin
and placebo groups respectively in about 17 000 people in each(table
B on bmj.com), and an excess risk of major
non-fatalextracranial haemorrhage (mainly gastric) of 1.2 per 1000
personyears (see table 3).
The Polypill strategy, based on a single daily pill containingsix
components as specified, would prevent 88% of heart attacksand 80%
of strokes. About 1 in 3 people would directly benefit,each on
average gaining 11-12 years of life without a heartattack or stroke
(20 years in those aged 55-64).
We are confident that the estimated effect is accurate. Thereis
substantial evidence on the individual components of thePolypill,
both for risk factor reduction and disease reduction.Extensive
evidence exists that reducing the four risk factorsby any means
lowers the risk of cardiovascular disease. Theconsistency between
evidence from observational studies and trials is persuasive. The estimates of
efficacy are robust toimprecision in the separate estimates of the
effect of theindividual components because overestimates will tend
to cancelunderestimates. Even if each estimate of the effect of
reductionin risk factors on reducing IHD events were 10% too high
(sothat in table 1, 61% became 55%, etc) the
combined preventiveeffect of 88% would only be reduced to 84%.
The percentage reduction in stroke will be greater for non-fatal
than fatal events (about 82% and about 75%, respectively) because
statins and aspirin have different effects on thrombotic and
haemorrhagic stroke and haemorrhagic strokes are more oftenfatal.
Who should take the Polypill
In people with a previous heart attack or a stroke, withoutany
treatment, cardiovascular disease mortality is about 5%per year for
life.23 About half of all cardiovascular deathsoccur in individuals with a previous myocardial infarctionor
cerebral thrombosis. All such individuals should be offered treatment to reduce
the reversible risk factors and would benefitfrom the Polypill.
Patients with angina pectoris, transientischaemic attacks,
peripheral arterial disease, and diabetesmellitus should also
consider taking the Polypill.
Among people without existing disease, the most discriminatory
screening factor is age. As 96% of deaths from ischaemic heart
disease or stroke occur in people aged 55 and over, treatingeveryone
in this group would prevent nearly all such deaths.Using different
age cut-offs for men and women, or smokersand non-smokers, or
combining several risk factor values withage and sex to produce
individual estimates of overall riskwould add little discrimination
and would probably not justifythe added complexity and cost.
Figure 2 illustrates this with serum cholesterol, blood
pressure, and serum homocysteine. Thesefactors, though
aetiologically important, are poor predictorsof future
cardiovascular disease events.112425 There islittle separation between the
distributions of the risk factorsin people who over a specified
period do or do not have a diseaseevent. With such closely
overlapping distributions there areno cut-off levels that include
most people who will have diseaseevents but few of those who will
not have them. Cut-off levelsthat identify the 5% of the unaffected
population who have themost extreme values of the risk factors
identify only about15% of the disease events (24% for blood pressure
and stroke).The screening performance of cardiovascular risk factors
incombination is little better.22
Fig 2 Relative
distributions of risk factors in men who subsequently
died of ischaemic heart disease or stroke and in men who
did not. Gaussian distribution fitted to data from a
cohort of 22 000 men followed prospectively for 10 years
(the BUPA study)42225
The best approach is therefore to treat people with known occlusive vascular
disease and everyone aged about 55 or over. There isno need to
measure the four risk factors before starting treatment,because
intervention is effective whatever the initial levelsof the risk
factors,11 nor to monitor the effect of the
treatment,because fluctuations within individuals tend to mask
variationsbetween individuals in the systematic effects of the
interventions.
Adverse effects
The Polypill may not be suitable for some people. blockersare
unsuitable for people with asthma, and some people areintolerant of
aspirin. Monitoring to prevent rare serious adverseeffects of
treatment might be considered, measuring serum creatinekinase and
transaminase (for rhabdomolysis and hepatitis causedby statins) and
serum potassium and creatinine (for acute renalfailure caused by ACE
inhibitors and angiotensin II receptorantagonists). However, the
value of such monitoring is uncertain. The complications are rare, it is not
known whether monitoringwill avoid them, and the tests lack
specificity, so the increasedrisk of cardiovascular disease after
stopping the drug in peoplepositive on monitoring may outweigh any
benefit.
What
is already known on this topic
Four risk factors (LDLcholesterol, blood
pressure, homocysteine, and platelet function)that can be reduced by drugs or vitamins account
for most cardiovasculardisease
Apart from aspirin, the use of such agents has
focusedon people with high levels of the
risk factor
What this studyadds
Intervening on all four risk factors reduces heart
attacksand strokes by over 80%
To achieve this large effect in a
population requires a combination treatment taken by
everyoneabove a specified age (say 55) and
younger people with a clinicalhistory of
occlusive arterial disease
A combination pill containingsix active
components could be widely used
Each componenthas been used in medical
practice for more than 10 years with
substantial evidence on safety and efficacy
Cost and acceptability
A low cost Polypill could use generic components that are notsubject
to patent protection (simvastatin (from mid-2003),
hydrochlorothiazide, atenolol, enalapril, folic acid, and aspirin).
This formulation does not have the lowest rate of adverse effects,
but even if about 10% of people were intolerant of the formulationit
would still have considerable public health merit. Those found to be intolerant
could be prescribed alternatives to avoidthe side effects.
Controlled trials of different formulationsof the Polypill would
provide direct estimates of acceptability.
Conclusions
The preventive strategy outlined is radical. But a formulationthat
prevented all cancer and was safe would undoubtedly bewidely used,
and one that prevented more than 80% of cardiovasculardisease would
be even more important, because such deaths aremore common than
cancer deaths. It is time to discard the viewthat risk factors need
to be measured and treated individuallyif found to be "abnormal."
Instead it should be recognisedthat in Western society the risk
factors are high in us all,so everyone is at risk; that the diseases
they cause are commonand often fatal; and that there is much to gain
and littleto lose by the widespread use of these drugs. No other
preventivemethod would have so great an impact on public health in
theWestern world.
We thank Joan Morris and Alicja Rudnicka for statistical help,and Leo Kinlen, Jeffrey Aronson, Mark Caulfield, David Collier,
James Haddow, and Frank Speizer for their helpful commentson drafts
of this paper. This paper is based on a lecture givenby Nicholas
Wald on 18 September 2000 at a meeting in Israelof the Israel
National Institute for Health Services Policyand Health Services
Research.
Contributors: The paper was written by NW and ML. NW generatedthe idea for the Polypill, which was developed jointly withML.
NW is guarantor.
Funding: None.
Competing interests: The authors have filed a patent
applicationon the formulation of the combined pill described here
(applicationNos GB 0100548.7 and GB 008791.6, priority date 10 April
2000)and a trademark application for the name Polypill.
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Abstract
Introduction
blocker, and an angiotensin converting enzyme inhibitor), each at
half standard dose; folic acid (0.8 mg); and aspirin (75 mg). We
estimate that the combination (which we call the Polypill) reduces
IHD events by 88% (95% confidence interval 84% to 91%) and stroke by
80% (71% to 87%). One third of people taking this pill from age 55
would benefit, gaining on average about 11 years of life free from an
IHD event or stroke. Summing the adverse effects of the components
observed in randomised trials shows that the Polypill would cause
symptoms in 8-15% of people (depending on the precise formulation).
Further tables
appear on 
