The Polypill: a new approach to the prevention and ... · The Polypill: a new approach to the...

The Polypill: a new approach to the prevention and treatment of

cardiovascular disease

The Heinrich-Heine UniversitaetDusseldorf

24 November 2004

Nicholas WaldWolfson Institute of Preventive Medicine

University of London

Declaration of interest

Nicholas Wald and Malcolm Law have applied for patents for the Polypill (granted in UK) and for trademark

protection

Ischaemic Heart Disease (IHD) and stroke are responsible for about one third of all deaths in Western countries.

Risk of IHD and stroke can be reduced by decreasing:

LDL cholesterol provenBlood pressure provenPlatelet aggregation provenSerum homocysteine probable

Methionine

Homocysteine

MTHFR

Homocysteine and MTHFR(Methylenetetrahydrofolate reductase)

TT is 2.7µmol/L higher than CC

Common: about 10% are homozygous for the genetic variant

MTHFR

Methionine

Homocysteine

Genetic Variant

Homocysteine level is 2.7μmol/L higher

Methionine

Homocysteine

Normal

MTHFR

Homocysteine and MTHFR(Methylenetetrahydrofolate reductase)

Mendelian Randomisation:Evidence that homocysteine (Hcy) is a cause of IHD

Similar (14%) lower incidence observed in cohort studies for the same homocysteine difference

Randomised trial (Conventional Randomisation)

Treatment Placebo

IHD incidence IHD incidence

Natural randomised trial (Mendelian Randomisation)

MTHFR

46 Studies 35,000 subjects

Higher IHD incidence (16%)

Lower IHD incidence

MTHFR

Examination of the dose-response relationship

IHD & cholesterol in a large cohort study

4 5 6 7

0.75

1

1.5

2

3Mortality per 1000 per year

Serum cholesterol (mmol/l)Neaton et al Arch Intern Med 1992

70 80 90 100 110

0.330.5

1

23

Relative risk

Usual diastolic BP (mmHg)

IHD and blood pressure meta-analysis

(age 60) McMahon et al, Lancet 1990

5 10 20 40

0.25

0.5

1.0

2.0

4.0Relative risk

Serum homocysteine (mol/L)Wald et al, Arch Internal Med 1998; 158: 862 – 7

IHD & serum homocysteine in the BUPA study

Stroke & blood pressure meta-analysis

McMahon et al, Lancet 1990

70 80 90 100 110

0.25

0.5

1.0

2.0

4.0Relative risk

Diastolic BP (mm Hg)

No threshold – the lower the blood pressure the lower the risk

70 80 90 100 110

0.25

0.5

1.0

2.0

4.0Relative risk


Stroke & blood pressure meta-analysis

McMahon et al, Lancet 1990

70 80 90 100 110

0

1

2

3

4Relative risk


No threshold – the lower the blood pressure the lower the risk

Concealed

Constant proportional change in risk for a given change in risk factor

Revealed

4 5 6 71

2

4

8

16

Risk factor (arbitrary units)

Ris

k of

dis

ease

(per

100

0 pe

r yea

r)

Implications of the constant proportional risk reduction from risk factor modification

Implications of the constant proportional risk reduction from risk factor modification

4 5 6 71

2

4

8

16

Risk factor (arbitrary units)

Ris

k of

dis

ease

(per

100

0 pe

r yea

r)

Reduction in riskReduction in risk factor Relative Absolute1 unit (7 to 6) 50% 8 per 1000 per year1 unit (5 to 4) 50% 2 per 1000 per year8 x

Diabetic

A given reduction in a risk factor reduces the risk of disease by a constant proportion of the existing risk irrespective of the starting level of the risk factor or of the existing risk.

Practical implications of the straight line proportional dose-response relationship

What is the effect of lifestyle changes on these risk factors?

Approximate risk factor reduction

LDL cholesterol 0.3 mmol/L

Blood pressure 2.5 mm Hg diastolic

Serum homocysteine 3%

Platelet aggregation –

Effect of lifestyle changes


Reduction in risk

IHD StrokeLDL cholesterol 0.3 mmol/L 14% 3%

Blood pressure 2.5 mm Hg diastolic 11% 19%

Serum homocysteine 3% 3% 2%

Platelet aggregation – – –



Reduction in risk

IHD StrokeLDL cholesterol 0.3 mmol/L 14% 3%

Blood pressure 2.5 mm Hg diastolic 11% 19%

Serum homocysteine 3% 3% 2%

Platelet aggregation – – –

Combined effect 26% 23%


Is medical intervention more effective?

Absolute reductions are standardised to usual serum LDL cholesterol concentration of 4.8mmol/L before treatment (mean concentration in trials).

Absolute reductions in serum LDL cholesterol concentration according to statin and daily dose (summary estimates from

164 randomised placebo controlled trials)

Daily dose (mg)

5 10 20 40 80

Statin Reduction (mmol/L)

Atorvastatin 1.5 1.8 2.1 2.4 2.6

Rosuvastatin 1.8 2.1 2.3 2.6 2.8

Simvastatin 1.1 1.3 1.5 1.8 2.0

Percentage reductions are independent of pre-treatment LDL cholesterol concentrations.

Percentage reductions in serum LDL cholesterol concentration according to statin and daily dose (summary estimates from 164 randomised placebo controlled trials)

Daily dose (mg)

5 10 20 40 80

Statin Reduction (%)

Atorvastatin 31 37 43 49 55

Rosuvastatin 38 43 48 53 58

Simvastatin 23 27 32 37 42

StrokeIHD

from meta-analyses of 10 largest cohort studies and 58 trials

from 164 placebo-controlled trials

17%61%1.8 mmol/L(70 mg/dL)

Statin(e.g. atorvastatin 10 mg/day or simvastatin 40 mg/day)

Reduction (after 2 years) in:

Reduction inLDL cholesterol

LDL cholesterol

Reduction in risk of IHD events in 58 randomised trials (excluding first two years of treatment) compared with

expected reductions from cohort study data

% reduction in IHD events (95% CI)LDL cholesterol reduction (mmol/L)

Mean reduction (mmol/L)

IHD events

Observed in trial data

Expected from cohort study data*

0.2 0.5 2311 20 (7 to 31) 23 (20 to 26)0.8 1.0 3556 32 (27 to 36) 41 (37 to 45)≥1.5 1.6 705 51 (42 to 58) 57 (52 to 61)

At age 60 years (average age at which IHD events occurred)

BP lowering drugs

DoseDiastolic BP reduction 95% confidence interval

Half standard 4.4 4.2 – 4.6

Standard 5.5 5.4 – 5.7

Twice standard 6.5 6.3 – 6.7

Half v. standard dose – 20% less

Meta-analysis of 354 randomised trials

Mean starting blood pressure 154/97

Half standard dose

Reduction in diastolic blood

pressure

1 drug 3.7 mmHg

2 drugs 7.3 mmHg

3 drugs 10.7 mmHg

from meta-analysis of 354 placebo-

controlled trials

Blood pressure

Starting blood pressure 150/90

Half standard dose

Reduction in diastolic blood

pressure

Reduction in:

IHD Stroke

1 drug 3.7 mmHg 19% 29%

2 drugs 7.3 mmHg 34% 49%

3 drugs 10.7 mmHg 46% 63%

from meta-analysis of 354 placebo-

controlled trials

from meta-analysis of 61 cohort studies

supported by 69 trials

Starting blood pressure 150/90

Blood pressure

Men 5,400 Women 1,700

Men 83,000

Stroke

IHD

4% 96%

Women 90,000

Age

IHD and stroke deaths (England and Wales 1997)

Age under 55

Age 55 and over

0

24

68

10

1214

1618

20

0- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85- 90- 95-

Persons without a history of IHD or stroke

England and Wales 1998

Age

Perc

enta

ge

images/009/red.xls

0

24

68

10

1214

1618

20

0- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85- 90- 95-

Death from IHD or stroke

ONS 1998

Age

Perc

enta

ge

England and Wales 1998


0

2

4

6

8

10

12

14

16

18

20

0 5- 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95

Age 55

Age as a screening test for ischaemic heart disease and stroke

0- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85- 90- 95-

Perc

enta

ge

DR= 96%

FPR=20%

Death from IHD or stroke


Age

40 60 80 100 120

Diastolic Blood Pressure (mmHg)

50 70 90 110

The Dietary and Nutritional Survey of British Adults, 1987

Age 60 Not on Polypill

Presentations\images\001\Diasoff2 cmd

40 60 80 100 120


50 70 90 110


Age 60 On Polypill

The Dietary and Nutritional Survey of British Adults, 1987Presentations\images\001\Diason2 cmd

40 60 80 100 120


50 70 90 110

Age 20


Age 60 On Polypill

The Dietary and Nutritional Survey of British Adults, 1987Presentations\images\001\Diasall2 cmd

1 2 4 6 8 10

LDL Cholesterol (mmol/L)

3 5 7

Health Survey of England, 1994


Presentations\images\001\Choloff2 cmd

Age 60 On Polypill

1 2 4 6 8 10


3 5 7



Presentations\images\001\Cholon2 cmd

1 2 4 6 8 10


3 5 7

Age 20



Age 60 On Polypill

Presentations\images\001\Cholall2 cmd

Guidelines

British Hypertension SocietyGuidelines 2004 (Simplified)

Reassess 5 yearlyReassess yearlyTreatTreatTreat

Diabetes orCVD 10-year risk

≥20%

≥160/100

130 - 13985 - 89

140 - 15990 - 99

160 -179100 - 109

Lifestyle advice Lifestyle advice

<140/90

Other

140 - 15990 - 99

Lifestyle advice Measure again

Measure BP

≥180/110 <130/85

BMJ Vol 328: 634-640, 13 March 2004

1000Age

55-64

100CVD

10 yrs

900Unaffected

40

225

40%

Using BHSguidelines

Application of BHS Guidelines in people aged 55-64

+ve

20

0

Treat

Treat

CVD events

20%

Overall reduction in CVD events

Risk in positives: 40225+40

= 15%

Risk in remainder: 60675+60

= 8%

25%

60% missed

1000Age

55-64

100CVD

10 yrs

900Unaffected

Using BHSguidelines

40%

25%

+ve

40

22565-74

200

800

60%

50%400

12020

0

Treat

CVD events

20%

Overall reduction in CVD events

Treat

60

30%

Risk in remainder: 60675+60

= 8%80

400+80= 17%

Application of BHS Guidelines in people aged 65-74

Risk in positives: 40225+40

= 15%120

400+120= 23%

Age 55-64 Age 65-74

There is little point in estimating a person’s risk using blood pressure, serum cholesterol and smoking habits because those who are thereby “positive”, but “negative” on the basis of their age alone, would anyway become “positive” when they are a few years older.

It is not worth the considerable cost and effort simply to delay the start of treatment.

Using risk factors

Guidance on Guidelines

We need simpler, more effective guidelines.

Proposed Guidelines on Cardiovascular Disease Prevention

1. Lifestyle changes for all

2. Combination drug treatment for all with cardiovascular disease or diabetes

3. Combination drug treatment for all above a given age (55)

4. Less testing and monitoring

Age 55 - 65 - 75 - 85 -No. of persons with IHD event or stroke delayed or avoided 7 11 13 6

No. of men with IHD event or stroke delayed or avoided in 100 without a previous IHD event or stroke who start

taking the Polypill from age 55

Prevention strategy

• all aged 55 or more • anyone under 55 with a history of

cardiovascular disease or diabetes

A single Polypill per day composed of six active ingredients, to be taken, without medical examination, by:

Conclusion

• The Polypill approach represents a departure from current practice in the prevention of cardiovascular disease.

• It is much simpler and much more effective than conventional cardiovascular screening strategies.

• It ensures that those who stand to benefit from treatment receive it.

The Polypill: a new approach to the prevention and ... · The Polypill: a new approach to the...

Documents

Transcript of The Polypill: a new approach to the prevention and ... · The Polypill: a new approach to the...