Risk factor thresholds: their existence under scrutiny WaldRiskFactThr_v1.3c-sk 18/09/2018 10:44 Risk factor thresholds: their existence under scrutiny Nicholas Wald Wolfson Institute of Preventive Medicine, London Pfizer update symposium in vascular medicine Amsterdam 3rd October 2003 V1.2a assumes that is finished (1.2) and discards the spares. They are still in 1.2 V1.2 is start of work on putting them side by side V1.0 has whole collection of graphs in old order. V1.1 has spare stuff moved out to end Nicholas Wald 2003

Ischaemic Heart Disease (IHD) and stroke are responsible for about one third of all deaths in Western countries. Nicholas Wald 2003

Risk of IHD and stroke can be reduced by decreasing: LDL cholesterol proven Blood pressure proven Platelet aggregation proven Serum homocysteine probable Body mass index probable Nicholas Wald 2003

Examination of the dose-response relationship Nicholas Wald 2003

IHD and blood pressure meta-analysis WaldRiskFactThr_v1.3c-sk 18/09/2018 10:44 IHD and blood pressure meta-analysis (age 60) (age 60) M Nicholas Wald 2003 McMahon et al, Lancet 1990

Stroke & blood pressure meta-analysis WaldRiskFactThr_v1.3c-sk 18/09/2018 10:44 Stroke & blood pressure meta-analysis MacMahon et al Lancet 1990 – check spelling Nicholas Wald 2003 McMahon et al, Lancet 1990

IHD & cholesterol in a large cohort study WaldRiskFactThr_v1.3c-sk 18/09/2018 10:44 IHD & cholesterol in a large cohort study Neaton et al Arch Intern Med 1992 Nicholas Wald 2003 Neaton et al Arch Intern Med 1992

IHD & BMI in a large cohort study WaldRiskFactThr_v1.3c-sk 18/09/2018 10:44 IHD & BMI in a large cohort study Willett et al JAMA 1995 Nicholas Wald 2003 Willett et al JAMA 1995

WaldRiskFactThr_v1.3c-sk 18/09/2018 10:44 Diabetes & BMI Knowler et al Am J Epidemiol 1981 [ref 9] Nicholas Wald 2003 Knowler et al Am J Epidemiol 1981

No threshold in risk reduction Implications No threshold in risk reduction The dose-response relationship shows that a given change 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. Nicholas Wald 2003

Percentage reduction in risk for a 10 mmHg reduction in systolic blood pressure in men aged 55-64 Nicholas Wald 2003 Taken from: Prospective Studies Collaboration, Lancet 2002;360:1903

Percentage reduction in risk of IHD events for a 1 mmol/l reduction in serum cholesterol in men aged 55-64 Nicholas Wald 2003 Taken from: Prospective Studies Collaboration, Lancet 2002;360:1903

Practical implications of the straight line proportional dose-response relationships There is benefit in modifying risk factors in people at high risk, whatever the reason for the high risk and regardless of the level of the risk factor Nicholas Wald 2003

Risk reduction from risk factor modification Nicholas Wald 2003

Risk reduction from risk factor modification Nicholas Wald 2003

Risk reduction from risk factor modification Reduction in risk Reduction in risk factor Relative Absolute 1 unit (7 to 6) 50% 8 per 1000 per year 1 unit (5 to 4) 2 per 1000 per year Nicholas Wald 2003

Defining people at high risk Nicholas Wald 2003

Is it sensible to screen using risk factors such as LDL cholesterol and blood pressure? Nicholas Wald 2003

Detection Rate False Positive Rate Nicholas Wald 2003

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Combining risk factors to screen for ischaemic heart disease events Proportion of events detected (DR) for a 5% FPR apoB (or LDL cholesterol) 17% + systolic blood pressure 22% + apoA1, apo(a) 24% + smoking 27% 3 measures of all the above + smoking 28% + smoking, family history 29% Wald et al Lancet 1994;343:75-9 Nicholas Wald 2003

Why combining risk factors is less effective than one would think DR for a 5% FPR LDL cholesterol 17% Systolic BP 17% What would the DR be if we used both? 17% + (17% of 83%) = 31% But the FPR would increase to about 10%. If FPR kept at 5%, DR = 22% Instead of 17% for one alone. Nicholas Wald 2003

Is it sensible to screen using risk factors such as LDL cholesterol and blood pressure? - NO Nicholas Wald 2003

Is it sensible to screen by asking people if they have a history of cardiovascular disease? - YES Nicholas Wald 2003

History of cardiovascular disease About 50% of IHD deaths and about 65% of stroke deaths occur in individuals who have had a previous stroke or heart attack. They have a much higher risk than others. Their risk of dying is about 5% per year. Nicholas Wald 2003

Is it sensible to screen using age alone? - YES Nicholas Wald 2003

IHD and stroke deaths (England and Wales 1997) Screening using age Age 55 and over Age under 55 IHD and stroke deaths (England and Wales 1997) Nicholas Wald 2003

WaldRiskFactThr_v1.3c-sk 18/09/2018 10:44 Prospective Studies Collaboration: blood pressure and ischaemic heart disease C Lancet 2002;360:1903 Nicholas Wald 2003

Prospective Studies Collaboration: blood pressure and stroke WaldRiskFactThr_v1.3c-sk 18/09/2018 10:44 Prospective Studies Collaboration: blood pressure and stroke D Lancet 2002;360:1903 Nicholas Wald 2003

Using risk factors 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 treatment by about five years. Nicholas Wald 2003

Second Joint Task force on prevention of CHD Existing atherosclerotic disease Adults with CHD risk  20% over ten years Try “lifestyle” change to achieve: BP < 140/90, cholesterol < 5 mmol/l If the lifestyle changes do not achieve this, use drugs. BUT about 50% of people over 55 have BP > 140/90 and about 90% of people over 55 have cholesterol > 5 mmol/l Nicholas Wald 2003 Wood et al, Atherosclerosis, 140 (1998): 199-270

If 10% of people can lower their blood pressure by lifestyle changes and 10% of people can lower their serum cholesterol in this way then 40% and 80% respectively would require drugs. What proportion of people would require drugs on account of either blood pressure or serum cholesterol? 88% The proposed screening would identify about 90% of people aged 55 and over as needing drugs – so why not give them to all? Nicholas Wald 2003

Guidance on Guidelines Guidelines like this are not effective We need simpler, more effective guidelines. Nicholas Wald 2003

Wolfson Guidelines on Cardiovascular Disease Prevention Lifestyle changes for all Drugs for all with cardiovascular disease Drugs for all above a given age (55) Avoid testing and monitoring Nicholas Wald 2003

What drugs? Nicholas Wald 2003

Effect of medical intervention (pills) Approximate risk factor reduction Reduction in risk IHD Stroke LDL cholesterol Statin 1.8 mmol/L 61% 17% Blood pressure Half standard dose of 3 from: – Thiazide – β-blocker – ACE-inhibitor or ARB – Calcium channel blocker 10.7 mm Hg diastolic 46% 63% Serum homocysteine Folic acid 3 µmol/L 16% 24% Platelet aggregation Aspirin – 32% Combined effect 88% 80% Nicholas Wald 2003 150/90

WaldRiskFactThr_v1.3c-sk 18/09/2018 10:44 Put all six drugs into one daily pill. Deleted for short version Nicholas Wald 2003

anyone under 55 with a history of cardiovascular disease Prevention strategy A single Polypill per day composed of six active ingredients, to be taken by: all aged 55 or more anyone under 55 with a history of cardiovascular disease without medical examination. Nicholas Wald 2003

Conclusion The Polypill represents a radical departure from current practice in the prevention of cardiovascular disease. Probably no other preventive method or treatment would have as great an impact on public health in the Western world. Nicholas Wald 2003