LEADING RESEARCH… MEASURES THAT COUNT

Base Primary Prevention Decision ModelRole of Risk Stratification and Biomarkers in Role of Risk Stratification and Biomarkers in Prevention of Cardiovascular Disease SymposiumPrevention of Cardiovascular Disease Symposium

Stephanie EarnshawStephanie EarnshawJanuary 30, 2012January 30, 2012

Objective

• To examine the costs and outcomes associated with To examine the costs and outcomes associated with use of aspirin, statins, or a combination of aspirin use of aspirin, statins, or a combination of aspirin and statins in patients with no history of coronary and statins in patients with no history of coronary heart disease (CHD) (i.e., primary prevention patients)heart disease (CHD) (i.e., primary prevention patients)

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• Patient populationPatient population– Men and women who are candidates for primary preventionMen and women who are candidates for primary prevention– Starting age (years): 35, 45, 55, 65, and 75Starting age (years): 35, 45, 55, 65, and 75– 10-year CHD risk: 2.5%, 5%, 7.5%, 10%, 15%, and 25%10-year CHD risk: 2.5%, 5%, 7.5%, 10%, 15%, and 25%

• ComparatorsComparators– Aspirin: 81 mg per dayAspirin: 81 mg per day

– Statin: generic simvastatin, 40 mg per dayStatin: generic simvastatin, 40 mg per day

– Aspirin+statin: in the same dosages as when used separatelyAspirin+statin: in the same dosages as when used separately

– No treatmentNo treatment

• Perspective: third-party payerPerspective: third-party payer• Time horizon: 1, 2, 5, 10, 20, and 25 year and lifetimeTime horizon: 1, 2, 5, 10, 20, and 25 year and lifetime• Costs and outcomes discounted at 3% Costs and outcomes discounted at 3% (Gold et al.,

1996)

Methods

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Methods: Model Structure

44CVD = cardiovascular disease; GI = gastrointestinal.CVD = cardiovascular disease; GI = gastrointestinal.

Methods: Model Structure

• The Markov model accounted for the followingThe Markov model accounted for the following– Patients were followed year after year (cycle time = 1 year) for Patients were followed year after year (cycle time = 1 year) for

remainder of lifetimeremainder of lifetime

– Patients incurred costs and utilities associated with each health statePatients incurred costs and utilities associated with each health state

– After a CVD event, patients were assumed to receive optimal After a CVD event, patients were assumed to receive optimal secondary prevention in which they had increased costs, increased secondary prevention in which they had increased costs, increased risk for mortality, and decreased utilitiesrisk for mortality, and decreased utilities

– Patients could die at any time in the modelPatients could die at any time in the model

55

Methods: Updates Since Pignone et al, 2006 and Pignone et al, 2007

• What is different between this model and the Pignone et al, What is different between this model and the Pignone et al, 2006 and Pignone et al, 2007 analyses?2006 and Pignone et al, 2007 analyses?– Input values are updatedInput values are updated

– All costs updated to 2011 US dollarsAll costs updated to 2011 US dollars

– Efficacy data to be updated to represent more recent evidenceEfficacy data to be updated to represent more recent evidence

– Patients on aspirin may incur the additional benefit of reducing the risk of Patients on aspirin may incur the additional benefit of reducing the risk of cancer mortalitycancer mortality

– Risk of gastrointestinal bleeding (GIB) increases as patients age through Risk of gastrointestinal bleeding (GIB) increases as patients age through the modelthe model

– Patients who have a GIB and go off aspirin progress as healthy patients, Patients who have a GIB and go off aspirin progress as healthy patients, but they then have an increase risk for GIB because of historybut they then have an increase risk for GIB because of history

– Adherence can vary in the model and can affect costs and efficacy Adherence can vary in the model and can affect costs and efficacy separatelyseparately

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Methods: Overview of Model Parameters

• Baseline risk of CVD events estimated from Framingham Baseline risk of CVD events estimated from Framingham risk equations (Anderson et al., 1991)risk equations (Anderson et al., 1991)– Starting age (years): 35, 45, 55, 65, and 75Starting age (years): 35, 45, 55, 65, and 75– 10-year CHD risk: 2.5%, 5%, 7.5%, 10%, 15%, and 25%10-year CHD risk: 2.5%, 5%, 7.5%, 10%, 15%, and 25%

• GIB and myopathy risks were obtained from a review of the GIB and myopathy risks were obtained from a review of the literatureliterature– Based on age; risks increased as patients aged through modelBased on age; risks increased as patients aged through model– Slight increased risk of mortality due to GIB and myopathySlight increased risk of mortality due to GIB and myopathy

• Treatment efficacy: relative risks were obtained from Treatment efficacy: relative risks were obtained from published meta-analyses and clinical trialspublished meta-analyses and clinical trials– AspirinAspirin

• Decreased risk of myocardial infarction (MI) (differ by gender)Decreased risk of myocardial infarction (MI) (differ by gender)• Decreased risk of CHD death (differ by gender)Decreased risk of CHD death (differ by gender)• Decreased risk of cancer mortalityDecreased risk of cancer mortality• Increased risk of combined stroke (differ by gender)Increased risk of combined stroke (differ by gender)• Increased risk of GIBIncreased risk of GIB

77

Methods: Overview of Model Parameters

• Treatment efficacy: relative risks were obtained from Treatment efficacy: relative risks were obtained from published meta-analyses and clinical trials (continued)published meta-analyses and clinical trials (continued)– StatinStatin

• Decreased risk of MIDecreased risk of MI

• Decreased risk of CHD deathDecreased risk of CHD death

• Decreased risk of combined strokeDecreased risk of combined stroke

• Increased risk of myopathyIncreased risk of myopathy

– Aspirin+statinAspirin+statin

• Efficacy among treatments is independentEfficacy among treatments is independent

• All-cause population mortality from National Vital StatisticsAll-cause population mortality from National Vital Statistics– Age and gender-specific and mortality increases as patients ageAge and gender-specific and mortality increases as patients age

• Costs and utilities were obtained from the published literatureCosts and utilities were obtained from the published literature

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Methods: Model Parameters—Efficacy

99

ParameterParameter

Base-CaseBase-CaseValue Value

(Range(Rangeaa)) SourceSource

Aspirin

GIB RR (no history of GIB)

2.0 Hernandez et al. (2006)

GIB RR (history of GIB) 10.0 Hernandez et al. (2006)

Angina RR 1.0 (0.80, 1.20) Assumption

Stroke RR (males) 1.06 (0.91, 1.24)

Sanmuganathan et al. (2001)

Stroke RR (females) 0.76 (0.63, 0.93)

Ridker et al. (2005)

MI RR (males) 0.70 (0.62, 0.79)

Sanmuganathan et al. (2001)

MI RR (females) 1.01 (0.84, 1.21)

Ridker et al. (2005)CI = confidence interval; RR = relative risk.CI = confidence interval; RR = relative risk.aa Range: 95% CI or estimate of plausible range. Range: 95% CI or estimate of plausible range.

Methods: Model Parameters—Efficacy

1010

ParameterParameter

Base-CaseBase-CaseValue Value

(Range(Rangeaa)) SourceSource

Statin

GIB RR 1.00 Assumption

Myopathy 0.001 (0.0005, 0.05)

Graham et al. (2004)

Angina RR 0.68 (0.49, 0.95)

Downs et al. (1998)

Stroke RR 0.85 (0.57, 1.28)

White et al. (2000); Briel et al. (2004)

MI RR 0.70 (0.68, 0.79)

Pignone et al. (2000)

aa Range: 95% CI or estimate of plausible range. Range: 95% CI or estimate of plausible range.

Methods: Model Parameters—Mortality

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ParameterParameterBase-CaseBase-Case

Value (RangeValue (Rangeaa)) SourceSource

Absolute increase in mortality due to having hemorrhagic stroke

0.37 Roger et al. (2011)

Absolute increase in death due to GIB

0.00001(0.000001, 0.0001)

Expert clinical opinion

Myopathy 0.00001(0.000001, 0.000100)

Graham et al. (2004)

No treatment

CHD Death RR 1.0 Assumption

Aspirin

CHD death RR (males) 0.87 (0.70, 1.09) Hayden et al. (2002)

CHD death RR (females)

1.00 (0.80, 1.20) Assumptionaa Range: 95% CI or estimate of plausible range. Range: 95% CI or estimate of plausible range.

Methods: Model Parameters—Mortality

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ParameterParameterBase-CaseBase-Case

Value (RangeValue (Rangeaa)) SourceSource

Aspirin (continued)

All-cause death RR when aspirin used in secondary prevention

0.85 (0.80, 0.90) He et al. (1998)

All cancers 0.78 (0.70, 0.87) Rothwell et al. (2011)

Colorectal cancer 0.60 (0.45, 0.81)

Statins

CHD death RR (males) 0.89 (0.81, 0.98) Mills et al. (2008)

CHD death RR (females)

0.89 (0.81, 0.98) Assumed to be same as males

Cancer mortality 1.0 Assumption

aa Range: 95% CI or estimate of plausible range. Range: 95% CI or estimate of plausible range.

Methods: Model Parameters—Mortality

1313

ParameterParameterBase-CaseBase-Case

Value (RangeValue (Rangeaa)) SourceSource

Hazard ratios

After MI 3.7 (3.0, 4.7) Lampe et al. (2000)

After angina 3.0 (2.1, 4.2) Lampe et al. (2000)

After stroke 2.3 (1.0, 4.6) Dennis et al. (1993)

aa Range: 95% CI or estimate of plausible range. Range: 95% CI or estimate of plausible range.

Methods: Model Parameters—Annual Costs

1414

ParameterParameter

Base-Base-Case Case ValueValue SourceSource

Aspirin drug costs

$9.12 Walgreens.com

Statin drug costs

$48.55 Generic price at Target.com

Healthy, on aspirin

$71.01 Ingenix RBRVS (2011): assume 1 physician visit

Healthy, on statins

$163.43 Ingenix RBRVS (2011): assume 1 physician visit + an additional physician visit and a lipid panel

GIB, acute care $16,025 2008 HCUP data set; Friedman et al. (2002)

Myopathy $17,799 2008 HCUP data set; Friedman et al. (2002)

GIB and myopathy, ongoing care

$71.01 Assumption

HCUP = Healthcare Cost and Utilization ProjectHCUP = Healthcare Cost and Utilization ProjectNote: All costs were inflated to 2011 dollars using the Medical Consumer Price Index when appropriateNote: All costs were inflated to 2011 dollars using the Medical Consumer Price Index when appropriate

Methods: Model Parameters—Annual Costs

1515

ParameterParameter

Base-Base-CaseCaseValueValue SourceSource

Angina, acute care

$14,638 2008 HCUP data set; Friedman et al. (2002)

Angina, ongoing carea

$6,698 Russell et al. (1998)

MI, acute care $36,129 2008 HCUP data set; Friedman et al. (2002)

MI, ongoing carea

$3,425 AHA (2002); Russell et al. (1998)

Stroke, acute care

$25,992 2008 HCUP data set; Friedman et al. (2002)

Stroke, ongoing care

$2,001 AHA (2002); Ingenix RBRVS (2011)

Note: All costs were inflated to 2011 dollars using the Medical Consumer Price Index when appropriateNote: All costs were inflated to 2011 dollars using the Medical Consumer Price Index when appropriateaa Costs of ongoing care included physician visits, institutionalization, and acute care for a percentage of Costs of ongoing care included physician visits, institutionalization, and acute care for a percentage of patients who experienced subsequent events, as appropriatepatients who experienced subsequent events, as appropriate

Methods: Model Parameters—Utilities

1616

ParameterParameterBase –CaseBase –Case

Value (RangeValue (Rangeaa)) SourceSource

Healthy 1.0 Assumption

Taking medications 1.0 (0.985, 1.0) Expert opinion

GIB 0.94 (0.88, 1.00) Augustovski et al. (1998)

Myopathy 0.97 (0.94, 1.00) Assumptiona

Post GIB and myopathy

1.000 Assumption

Angina 0.929 (0.923, 1.00) Nease et al. (1995)

Post angina 0.997 (0.997, 1.00) Nease et al. (1995)

MI 0.87 (0.82, 0.92) Tsevat et al. (1993)

Post MI 0.91 (0.86, 0.96) Tsevat et al. (1993) aaWe assume individuals with myopathy to have a lower utility than that of a healthy individual, but We assume individuals with myopathy to have a lower utility than that of a healthy individual, but higher than one with GI bleed. Thus, we assume a utility of (1-0.94)/2 = 0.97higher than one with GI bleed. Thus, we assume a utility of (1-0.94)/2 = 0.97

Methods: Model Parameters—Utilities

1717

ParameterParameterBase –CaseBase –Case

Value (RangeValue (Rangeaa)) SourceSource

Stroke 0.61 (0.48, 0.83) Augustovski et al. (1998)

Post stroke 0.830 Gore et al. (1995)

Death 0.0 Assumption

Methods: Outcomes Presented by the Model

• Costs: drug, other medical, and totalCosts: drug, other medical, and total• Life-yearsLife-years• Quality-adjusted life-years (QALYs) Quality-adjusted life-years (QALYs) • Number of eventsNumber of events

– Myopathy due to statinMyopathy due to statin– GIB due to aspirinGIB due to aspirin– First MIFirst MI– First anginaFirst angina– First strokeFirst stroke– CHD deathCHD death– All-cause deathAll-cause death

1818

Methods: Outcomes Presented by the Model

• Cost-effectiveness ratiosCost-effectiveness ratios– Incremental cost per QALYIncremental cost per QALY

– Incremental cost per life-yearIncremental cost per life-year

• Sensitivity analysesSensitivity analyses– One-way (tornado diagrams)One-way (tornado diagrams)

– Probabilistic (scatter-plot and cost-effectiveness acceptability Probabilistic (scatter-plot and cost-effectiveness acceptability curves)curves)

1919

Results: 45 Year Old Men with 7.5% 10 Year CHD Risk

2020

45 year old 45 year old man with 7.5% man with 7.5% 10 year CHD 10 year CHD risk aspirin risk aspirin versus no versus no treatment treatment comparison: comparison: statin price at statin price at $0.133/day, $0.133/day, time time horizon=10 horizon=10 years, no years, no cancer cancer mortality mortality benefit when benefit when using aspirinusing aspirin

Preliminary Results

Clinical Events (per 1,000): 45 Year Old Men with 7.5% 10 Year CHD Risk-Aspirin vs No Treatment

OutcomeOutcome AspirinAspirin No TreatmentNo Treatment

MI 24.43 34.58

CHD death 8.54 9.75

Angina 35.81 35.63

Stroke 7.61 7.15

GIB 17.95 8.96

Myopathy 0 0

All deaths 83.26 84.97

Preliminary Results

Results: 55 Year Old Women with 7.5% 10 Year CHD Risk

2222

55 year old 55 year old woman with woman with 7.5% 10 year 7.5% 10 year CHD risk statin CHD risk statin versus no versus no treatment treatment comparison: comparison: statin price at statin price at $0.133/day, $0.133/day, time time horizon=10 horizon=10 years, no years, no cancer mortality cancer mortality benefit when benefit when using aspirinusing aspirin

Preliminary Results

Clinical Events (per 1,000): 55 Year Old Women with 7.5% 10 Year CHD Risk-Statin vs No Treatment

OutcomeOutcome StatinStatin No TreatmentNo Treatment

MI 15.68 22.11

CHD death 5.37 5.96

Angina 27.03 39.28

Stroke 8.98 10.44

GIB 13.36 13.22

Myopathy 9.18 0

All deaths 116.64 118.72

Preliminary Results

Sensitivity Analysis: Time Horizon

Time HorizonTime Horizon ICER (MenICER (Menaa)) ICER (WomenICER (Womenbb))

10 years -$22,570 $44,357

20 years -$13,702 $7,650

Lifetime -$5,645 $2,595

aa45 year old men, 7.5% 10 year CHD risk, aspirin vs no treatment45 year old men, 7.5% 10 year CHD risk, aspirin vs no treatmentbb55 year old women, 7.5% 10 year CHD risk, statin vs no treatment55 year old women, 7.5% 10 year CHD risk, statin vs no treatment

Preliminary Results

Sensitivity Analysis: Statin Cost

45 Year Old Men with 7.5% 10 Year CHD Risk-Aspirin vs No Treatment45 Year Old Men with 7.5% 10 Year CHD Risk-Aspirin vs No Treatment

Patients on no treatment progress to CVD events quicker than patients on aspirin. Patient in the post Patients on no treatment progress to CVD events quicker than patients on aspirin. Patient in the post CVD event health states are on optimal secondary prevention of aspirin+statins. As a result, as no CVD event health states are on optimal secondary prevention of aspirin+statins. As a result, as no treatment patients go on secondary prevention, the costs for these patients increase which causes the treatment patients go on secondary prevention, the costs for these patients increase which causes the difference in costs between treating with aspirin and no treatment increasedifference in costs between treating with aspirin and no treatment increase

Preliminary Results

Sensitivity Analysis: Statin Cost

55 Year Old Women with 7.5% 10 Year CHD Risk-Statin vs No Treatment55 Year Old Women with 7.5% 10 Year CHD Risk-Statin vs No Treatment

Preliminary Results

Sensitivity Analysis: Disutility for Taking a Pill

45 Year Old Men with 7.5% 10 Year CHD Risk-Aspirin vs No Treatment45 Year Old Men with 7.5% 10 Year CHD Risk-Aspirin vs No Treatment

As the disutility associated with taking a pill increase (i.e., utility of taking a pill decreases) treating with As the disutility associated with taking a pill increase (i.e., utility of taking a pill decreases) treating with aspirin is less effective than no treatment. Thus, the denominator of the ICER becomes smaller and aspirin is less effective than no treatment. Thus, the denominator of the ICER becomes smaller and the ultimate ICER becomes more negative (i.e., the difference in costs do not change)the ultimate ICER becomes more negative (i.e., the difference in costs do not change)

Preliminary Results

Sensitivity Analysis: Disutility for Taking a Pill

55 Year Old Women with 7.5% 10 Year CHD Risk-Statin vs No Treatment55 Year Old Women with 7.5% 10 Year CHD Risk-Statin vs No Treatment

Preliminary Results

Sensitivity Analysis: 45 Year Old Men with 7.5% 10 Year CHD Risk

2929

One-way sensitivity analyses: 45-year-old man with a 10-year 7.5% coronary heart disease risk, statin cost = One-way sensitivity analyses: 45-year-old man with a 10-year 7.5% coronary heart disease risk, statin cost = $0.133 and no cancer mortality benefit for aspirin: Aspirin vs no treatment$0.133 and no cancer mortality benefit for aspirin: Aspirin vs no treatment

Preliminary Results

Sensitivity Analysis: 55 Year Old Women with 7.5% 10 Year CHD Risk

3030

One-way sensitivity analyses: 55-year-old woman with a 10-year 7.5% coronary heart disease risk, statin One-way sensitivity analyses: 55-year-old woman with a 10-year 7.5% coronary heart disease risk, statin cost = $0.133 and no cancer mortality benefit for aspirin: Statin vs no treatmentcost = $0.133 and no cancer mortality benefit for aspirin: Statin vs no treatment

Preliminary Results

Sensitivity Analysis: 45 Year Old Men with 7.5% 10 Year CHD Risk

3131

Probabilistic sensitivity analyses: 10,000 runs of a 45-Probabilistic sensitivity analyses: 10,000 runs of a 45-year-old man with a 10-year 7.5% coronary heart disease year-old man with a 10-year 7.5% coronary heart disease risk, statin cost = $0.133 and no cancer mortality benefit for risk, statin cost = $0.133 and no cancer mortality benefit for aspirin: Aspirin vs no treatmentaspirin: Aspirin vs no treatment

% Cost Saving: 95.3%% Cost Saving: 95.3%% Cost Effective: 99.1%% Cost Effective: 99.1%

Preliminary Results

Sensitivity Analysis: 55 Year Old Women with 7.5% 10 Year CHD Risk

3232

Probabilistic sensitivity Probabilistic sensitivity analyses: 10,000 runs of a 55-analyses: 10,000 runs of a 55-year-old woman with a 10-year year-old woman with a 10-year 7.5% coronary heart disease 7.5% coronary heart disease risk, statin cost = $0.133 and risk, statin cost = $0.133 and no cancer mortality benefit for no cancer mortality benefit for aspirin: Statin vs no treatmentaspirin: Statin vs no treatment

% Cost Saving: 5.8%% Cost Saving: 5.8%% Cost Effective: 54.3%% Cost Effective: 54.3%

Preliminary Results

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