Population models of health impact of combination polypharmacy

Population models of health impact of combination polypharmacy Global Summit on Combination Polypharmacy for CVD, 25 th September 2012 Dr Mark Huffman Northwestern University, Chicago Charity No: 1110067 Particular thanks to: Simon Capewell, Don Lloyd-Jones, Earl Ford, Martin O Flaherty, Darwin Labarthe, Julia Critchley, Iain Buchan et al, Katie Huffman

This talk Recent US CHD/CVD mortality trends Looking for explanations Building a CHD policy model- IMPACT Using the model to explain past trends Exploring potential polypharmacy contributions Implications for future CVD strategies

US Trends in age-adjusted CHD mortality rates: men & women aged 35 years Ford & Capewell JACC 2007 50 2128 1000 900 800 Per 100,000 population 700 600 500 400 300 200 100 0 Women Men 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 Year

International mortality trends 1 968-2008 men, coronary heart disease [CHD] Source:BHF Heartstats (WHO statistics Men aged 35-74, Standardised)

International mortality trends 1 968-2003 men, coronary heart disease [CHD] Why have CHD mortality rates halved? Source:BHF Heartstats (WHO statistics Men aged 35-74, Standardised)

Aim Our IMPACT CHD Model To explain falls in CHD mortality in recent decades in USA & elsewhere Ford et al NEJM 2007 356 2388

What is modelling?

What is modelling? a simplification of reality

What is modelling? a simplification of reality Visit Australia!

Data INPUT Logic OUTPUT

IMPACT Model is comprehensive Main Components F RISK FACTORS Cholesterol Blood Pressure Smoking Blood Pressure BMI & Diabetes Physical Activity Patient Groups Age & Sex AMI Angina Heart Failure 2' Prevention 50 TREATMENTS CABG/PTCA Medical Therapy surgery OUTCOMES Death Survival Ford et al NEJM 2007 356 2388

Large evidence base for CHD treatments: RCTs & meta-analyses Acute Myocardial Infarction (AMI) Secondary Prevention Chronic Angina & Unstable Angina CABG surgery & Angioplasty (PTCA) Hypertension Heart Failure Hyperlipidaemia Smoking cessation Ford et al NEJM 2007 356 2388

Evidence base: Meta-analyses & RCTs Example: Initial treatments for AMI TREATMENT Relative Risk Reduction (95% CI) First author (year) Thrombolysis 26% (15-37) Primary angioplasty Aspirin 32% (5-50) 15% (11-19) Beta-blockers 4% (-8, 15) ACE-I 7% (2-11) Estess et al 2002, FTT 1997 Cucherat et al 2003 Antithrombotic Trialists Collaboration 2002 Freemantle et al 1999 Latini et al 1998 Ford NEJM 2007; 356: 2388.

Treating individual CHD patients - impact on population CHD mortality: US example AMI: Aspirin, Men 55-64 years Patients Treatment Relative 30d Case Deaths prevented eligible uptake risk Fatality or postponed (DPP) reduction a x b x c x d = a x b x c x d 102,000 X 84% x 0.15 x 0.05 = 640 SOURCES NHDS Paper ATC Medicare MEPS audits Meta-analyses Ford et al NEJM 2007

Sensitivity analyses Brigg s Analysis of Extremes method (using minimum & maximum plausible values) US example AMI Aspirin Men 55-64 years Patients Treatment Relative Case Deaths prevented eligible uptake risk Fatality or postponed reduction (DPP) a x b x c x d = a x b x c x d Best Estimate 102,000 X 84% x 0.15 x 0.05 = 640 Minimum 90,000 X 75% x 0.11 x 0.03 = 230 Maximum 110,000 X 95% x 0.19 x 0.07 = 1390 Ford et al NEJM 2007

Explaining the fall in CHD deaths in USA 1980-2000 CHD deaths NEJM 2007; 356: 2388. 341, 745 fewer deaths in 2000 1 980 2000

10000-10000 - 30000-50000 Explaining the fall in CHD deaths in USA 1980-2000 : RESULTS CHD deaths NEJM 2007; 356: 2388 Risk Factors worse + 1 7% Risk Factors better - 61 % 341, 745 fewer deaths in 2000 1 980 2000 Treatments - 47%

10000-10000 - 30000-50000 Explaining the fall in CHD deaths in USA 1980-2000 : RESULTS NEJM 2007; 356: 2388. CHD deaths 341, 745 fewer deaths in 2000 1 980 2000 Risk Factors worse + 1 7% Obesity (increase) + 7% Diabetes (increase) + 1 0% Risk Factors better - 61 % Population BP fall - 20% Smoking - 1 2% Cholesterol (diet) - 24% Physical activity - 5% Treatments - 47% AMI treatments - 1 0% Secondary prevention - 11% Heart failure - 9% Angina: CABG & PTCA - 5% Hypertension therapies - 7% Statins (primary prevention) - 5% Unexplained - 9%

What if more patients were treated with combination therapy? US treatment rates, 2000 AMI 2 prevention after MI 2 prevention after revasc. Chronic stable angina Primary prevention Aspirin, % 84 38 40 43 -- B-blocker, % 16 29 33 -- -- ACE-I, % 21 26 26 -- -- Statin, % -- 36 38 39 16 Deaths prevented or postponed if 1980 CHD trends persisted 8,870 17,740 5,330 2,040 16,580 Am J Cardiol 2007; 356: 2388.

What if more patients were treated with combination therapy? 60%+ uptake AMI 2 prevention after MI 2 prevention after revasc. Chronic stable angina Primary prevention Aspirin, % 84 60 60 60 -- B-blocker, % 60 60 60 -- -- ACE-I, % 60 60 60 -- -- Statin, % -- 60 60 60 60 Deaths prevented or postponed if 1980 CHD trends persisted 11,790 (33%) 43,615 (146%) 9,605 (80%) 2,630 (29%) 35,890 (116%) Am J Cardiol 2007; 356: 2388.

What if treatment rates were increased to 60%? Am J Cardiol 2007; 356: 2388.

CHD Deaths Prevented or Postponed: Trends vs. Treatment in 1 and 2 Prev. Am J Prev Med 2010; 39:228.

IMPACT MODEL LIMITATIONS Assumes that RCT efficacy = effectiveness Data patchy ~ especially women & elderly Model explains 91% fall (9% not explained) Therefore Sensitivity Analyses & Validation are key NEJM 2007; 356: 2388.

Explaining CHD mortality fall USA 1980-2000 Sensitivity Analysis: % contributions to mortality reduction

Comparisons with other studies % CHD mortality falls attributed to: NEJM 2007 356 2388 updated

100000 90000 80000 70000 60000 50000 40000 30000 20000 10000 0 US IMPACT Model Fit in specific age groups (Columns = Observed fall in deaths ; Diamonds = Best Estimates, Bars = minimum and maximum estimates,) Deaths prevented or postponed 100000 90000 80000 70000 Men Women 60000 50000 40000 30000 20000 10000 0 35-44 45-54 55-64 65-74 75-84 85+ 35-44 45-54 55-64 65-74 75-84 85+ NEJM 2007; 356: 2388.

IMPACT: Explaining past trends Large CHD mortality falls in Western countries Reductions in major risk factors often played a bigger role than medical therapies Increased treatment coverage has substantial potential for CHD prevention Comprehensive CHD strategy important: active promotion of primary prevention particularly diet & tobacco control also maximise effective treatments & secondary prevention in eligible patients

Quantifying the fall in CHD mortality due to aspirin treatment. Using the IMPACT Model in USA & beyond Conclusions 1 CHD mortality: big falls in USA, UK & elsewhere 50%-75% due to risk factor reductions 25%-50% due to evidence-based therapies Gains from therapies could double if treatment uptake reached 60%

Quantifying the fall in CHD mortality due to aspirin treatment. Using the IMPACT Model in USA & beyond Conclusions 2?? CHD mortality: big falls in USA, UK & elsewhere 50%-75% due to risk factor reductions 25%-50% due to evidence-based therapies Gains from therapies could double if treatment uptake reached 60% small reductions in risk factors could halve CHD deaths in US, UK & elsewhere

Fall in CHD Mortality: 1 vs. 2 Prevention Risk factor Absolute decline in population risk In healthy individuals (1 prevention) Cholesterol 0.32 mmol/l 107,300 (67,090-151,575) In CHD patients (2 prevention) 22,210 (11,780-33,330) Totals 129,510 34% 7% Systolic blood pressure 4.86 mmhg 97,555 (64,420-135,285) 34,330 (18,290-40,360) 131,885 31% 11% Am J Prev Med 2010; 39:228.

IMPACT vs. Wald/Law: Differences in relative decreases for CHD death Aspirin 15% IMPACT Wald/Law Notes (ATC) Statin 23% BP lowering drugs (CTT) 13% to 29% (Law, 2003) 32% (23%-40%) 61% (51%-71%) per (1.8 mmol/l reduction) One drug: 19% (17-21%) Two drugs: 34% (29-40%) Three drugs: 46% (39-54%) with SBP by ~9.1mmHg, DBP by ~5.5 mmhg 2003 meta-analysis Based on differences at age 60-69 years using cohort data Based on differences at age 60-69 years using cohort data

β Coefficients = % fall in CHD mortality per unit decrease in risk factors (from meta-analyses & cohorts, Ford et al, NEJM 2007 356 : 2388 Cholesterol lowering PSC 2007 Reduction in CHD deaths 5mg/dl mean pop cholesterol 5% Blood pressure PSC Lancet 2003 1 mmhg Systolic BP 5% Obesity Bogers, 2008 1 Kg/M 2 BMI 2.5% Smoking InterHEART, 2004 1% Smoking prevalence 1% Diabetes InterHEART, 2004 1% diabetic population 2% Physical Activity InterHEART, 2004 1% inactive population 0.3% Ford et al NEJM 2007