Simulating the impact of improved cardiovascular risk interventions on clinical and economic outcomes in Russia.

OBJECTIVES: Russia faces a high burden of cardiovascular disease. Prevalence of all cardiovascular risk factors, especially hypertension, is high. Elevated blood pressure is generally poorly controlled and medication usage is suboptimal. With a disease-model simulation, we forecast how various treatment programs aimed at increasing blood pressure control would affect cardiovascular outcomes. In addition, we investigated what additional benefit adding lipid control and smoking cessation to blood pressure control would generate in terms of reduced cardiovascular events. Finally, we estimated the direct health care costs saved by treating fewer cardiovascular events. METHODS: The Archimedes Model, a detailed computer model of human physiology, disease progression, and health care delivery was adapted to the Russian setting. Intervention scenarios of achieving systolic blood pressure control rates (defined as systolic blood pressure <140 mmHg) of 40% and 60% were simulated by modifying adherence rates of an antihypertensive medication combination and compared with current care (23.9% blood pressure control rate). Outcomes of major adverse cardiovascular events; cerebrovascular event (stroke), myocardial infarction, and cardiovascular death over a 10-year time horizon were reported. Direct health care costs of strokes and myocardial infarctions were derived from official Russian statistics and tariff lists. RESULTS: To achieve systolic blood pressure control rates of 40% and 60%, adherence rates to the antihypertensive treatment program were 29.4% and 65.9%. Cardiovascular death relative risk reductions were 13.2%, and 29.6%, respectively. For the current estimated 43,855,000-person Russian hypertensive population, each control-rate scenario resulted in an absolute reduction of 1.0 million and 2.4 million cardiovascular deaths, and a reduction of 1.2 million and 2.7 million stroke/myocardial infarction diagnoses, respectively. Averted direct costs from current care levels ($7.6 billion [in United States dollars]) were $1.1 billion and $2.6 billion, respectively.

A standardized vascular disease health check in europe: a cost-effectiveness analysis.

BACKGROUND: No clinical trials have assessed the effects or cost-effectiveness of health check strategies to detect and manage vascular disease. We used a mathematical model to estimate the cost-effectiveness of several health check strategies in six European countries. METHODS: We used country-specific data from Denmark, France, Germany, Italy, Poland, and the United Kingdom to generate simulated populations of individuals aged 40-75 eligible for health checks in those countries (e.g. individuals without a previous diagnosis of diabetes, myocardial infarction, stroke, or serious chronic kidney disease). For each country, we used the Archimedes model to compare seven health check strategies consisting of assessments for diabetes, hypertension, lipids, and smoking. For patients diagnosed with vascular disease, treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, major adverse cardiovascular events (MACE), and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). RESULTS: Compared with current care, health checks reduced the incidence of MACE (6-17 events prevented per 1000 people screened) and diabetes related microvasular complications (5-11 events prevented per 1000 people screened), and increased QALYs (31-59 discounted QALYs) over 30 years, in all countries. The cost per QALY of offering a health check to all individuals in the study cohort ranged from €14903 (France) to cost saving (Poland). Pre-screening the population and offering health checks only to higher risk individuals lowered the cost per QALY. Pre-screening on the basis of obesity had a cost per QALY of €10200 (France) or less, and pre-screening with a non-invasive risk score was similar. CONCLUSIONS: A vascular disease health check would likely be cost effective at 30 years in Denmark, France, Germany, Italy, Poland, and the United Kingdom.

Health benefits and cost-effectiveness of a hybrid screening strategy for colorectal cancer.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines recommend screening schedules for each single type of test except for concurrent sigmoidoscopy and fecal occult blood test (FOBT). We investigated the cost-effectiveness of a hybrid screening strategy that was based on a fecal immunological test (FIT) and colonoscopy. METHODS: We conducted a cost-effectiveness analysis by using the Archimedes Model to evaluate the effects of different CRC screening strategies on health outcomes and costs related to CRC in a population that represents members of Kaiser Permanente Northern California. The Archimedes Model is a large-scale simulation of human physiology, diseases, interventions, and health care systems. The CRC submodel in the Archimedes Model was derived from public databases, published epidemiologic studies, and clinical trials. RESULTS: A hybrid screening strategy led to substantial reductions in CRC incidence and mortality, gains in quality-adjusted life years (QALYs), and reductions in costs, comparable with those of the best single-test strategies. Screening by annual FIT of patients 50-65 years old and then a single colonoscopy when they were 66 years old (FIT/COLOx1) reduced CRC incidence by 72% and gained 110 QALYs for every 1000 people during a period of 30 years, compared with no screening. Compared with annual FIT, FIT/COLOx1 gained 1400 QALYs/100,000 persons at an incremental cost of $9700/QALY gained and required 55% fewer FITs. Compared with FIT/COLOx1, colonoscopy at 10-year intervals gained 500 QALYs/100,000 at an incremental cost of $35,100/QALY gained but required 37% more colonoscopies. Over the ranges of parameters examined, the cost-effectiveness of hybrid screening strategies was slightly more sensitive to the adherence rate with colonoscopy than the adherence rate with yearly FIT. Uncertainties associated with estimates of FIT performance within a program setting and sensitivities for flat and right-sided lesions are expected to have significant impacts on the cost-effectiveness results. CONCLUSIONS: In our simulation model, a strategy of annual or biennial FIT, beginning when patients are 50 years old, with a single colonoscopy when they are 66 years old, delivers clinical and economic outcomes similar to those of CRC screening by single-modality strategies, with a favorable impact on resources demand.

Modeling the impact of increased adherence to asthma therapy.

BACKGROUND: Nonadherence to medications occurs in up to 70% of patients with asthma. The effect of improving adherence is not well quantified. We developed a mathematical model with which to assess the population-level effects of improving medication prescribing and adherence for asthma. METHODS: A mathematical model, calibrated to clinical trial data from the U.S. NHLBI-funded SOCS trial and validated using data from the NHLBI SLIC trial, was used to model the effects of increased prescribing and adherence to asthma controllers. The simulated population consisted of 4,930 individuals with asthma, derived from a sample the National Asthma Survey. Main outcomes were controller use, reliever use, unscheduled doctor visits, emergency department (ED) visits, and hospitalizations. RESULTS: For the calibration, simulated outcomes agreed closely with SOCS trial outcomes, with treatment failure hazard ratios [95% confidence interval] of 0.92 [0.58-1.26], 0.97 [0.49-1.45], and 1.01 [0-1.87] for simulation vs. trial in the in placebo, salmeterol, and triamcinolone arms, respectively. For validation, simulated outcomes predicted mid- and end-point treatment failure rates, hazard ratios 1.21 [0.08-2.34] and 0.83 [0.60-1.07], respectively, for patients treated with salmeterol/triamcinolone during the first half of the SLIC study and salmeterol monotherapy during the second half. The model performed less well for patients treated with salmeterol/triamcinolone during the entire study duration, with mid- and end-point hazard ratios 0.83 [0.00-2.12] and 0.37 [0.10-0.65], respectively. Simulation of optimal adherence and prescribing indicated that closing adherence and prescription gaps could prevent as many as nine million unscheduled doctor visits, four million emergency department visits, and one million asthma-related hospitalizations each year in the U.S. CONCLUSIONS: Improvements in medication adherence and prescribing could have a substantial impact on asthma morbidity and healthcare utilization.

The impact of initial statin treatment decisions on cardiovascular outcomes in clinical care settings: estimates using the Archimedes Model.

PURPOSE: Many patients treated for dyslipidemia do not achieve recommended cholesterol goals despite the widespread availability of effective statins. Pharmaceutical claims show a strong tendency for patients to remain on their initially assigned treatment. With computer simulations, the impact of initial statin treatment decisions on medium- and long-term cardiovascular outcomes were examined. PATIENTS AND METHODS: Using the Archimedes Model, three treatment scenarios were simulated. Patients initiated treatment with simvastatin (20, 40, or 80 mg), atorvastatin (10, 20, 40, or 80 mg), or rosuvastatin (10, 20, or 40 mg), and periodically intensified treatment. The simulated population consisted of 50,025 patients, aged 45-70 years, with low-density lipoprotein cholesterol exceeding goal. The proportion of patients initiating each dose was calibrated to United States pharmacy claims. Patients not reaching goal intensified the dose of their current statin or switched to an appropriate dose of rosuvastatin at rates matching pharmacy claims. Biomarkers and major adverse cardiovascular events (MACE) were tracked for 10 years and several high-risk subpopulations were analyzed. Statin models used biomarker effects from the STELLAR (Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin) trial and outcomes data from various trials. RESULTS: Initiating therapy with rosuvastatin reduced MACE more than simvastatin or atorvastatin. The 5- year relative risk of MACE was 0.906 (95% confidence interval: 0.888-0.923; P < 0.001) for initial treatment with atorvastatin rather than simvastatin, 0.831 (0.812-0.850; P < 0.001) for rosuvastatin rather than simvastatin, and 0.918 (0.898-0.938; P < 0.001) for rosuvastatin rather than atorvastatin. Subgroups with higher MACE incidence experienced greater absolute benefit. CONCLUSION: Considering observed rates of treatment intensification, initial treatment choices appear to significantly impact medium- and long-term cardiovascular risk. Patients at high cardiovascular risk are good candidates for aggressive initial therapy.

Comparing the effectiveness of rosuvastatin and atorvastatin in preventing cardiovascular outcomes: estimates using the Archimedes model.

OBJECTIVE: This study used simulation to compare the effectiveness of rosuvastatin 20 mg vs atorvastatin 40 mg, and rosuvastatin 40 mg vs atorvastatin 80 mg in preventing MACE in a range of patient populations with varying baseline cardiovascular risk. RESEARCH DESIGN AND METHODS: The Archimedes Model was used to simulate head-to-head clinical trials in nine patient populations: Framingham Risk Score (FRS)≥5%, 5-10%, 10-20%, >20%, EURO-SCORE≥5% and >10%, diagnosed diabetes, secondary prevention (history of myocardial infarction or stroke, CVD), and acute coronary syndrome (ACS). Simulated patients, aged 45-70 at trial start, were based on the NHANES 1999-2006. Treatments were modeled using results from the STELLAR, JUPITER, CARDS, ASCOT-LLA, and TNT trials. Treatment models were confirmed using trial validations. RESULTS: Comparing rosuvastatin 20 mg vs atorvastatin 40 mg, the 5-year numbers needed to treat to prevent one MACE event (NNT) were 525, 70, and 55 for the FRS≥5%, CVD, and ACS groups, respectively. Comparing rosuvastatin 40 mg vs atorvastatin 80 mg the corresponding NNT values were 468, 63, and 51. The 20-year relative risks of MACE in the FRS≥5% population were 0.907 (0.901-0.913) for rosuvastatin 20 mg vs atorvastatin 40 mg and 0.892 (0.884-0.901) for rosuvastatin 40 mg vs atorvastatin 80 mg. The relative risks were similar for the remaining populations. CONCLUSIONS: This study found that rosuvastatin 20 mg and 40 mg lowers the risk of MACE more than atorvastatin 40 mg and atorvastatin 80 mg. While simulation models cannot replace real-world clinical trials, this study bridges gaps in the evidence, and identifies high risk cohorts that would likely see additional benefit from treatment with rosuvastatin rather than atorvastatin.

Health and economic outcomes for exenatide once weekly, insulin, and pioglitazone therapies in the treatment of type 2 diabetes: a simulation analysis.

BACKGROUND: Patients with type 2 diabetes (T2DM) are at risk of long-term vascular complications. In trials, exenatide once weekly (ExQW), a GLP-1R agonist, improved glycemia, weight, blood pressure (BP), and lipids in patients with T2DM. We simulated potential effects of ExQW on vascular complications, survival, and medical costs over 20 years versus standard therapies. PATIENTS AND METHODS: The Archimedes model was used to assess outcomes for ~25,000 virtual patients with T2DM (NHANES 1999-2006 [metformin ± sulfonylureas, age 57 years, body mass index 33 kg/m(2), weight 94 kg, duration T2DM 9 years, hemoglobin A1c [A1C] 8.1%]). The effects of three treatment strategies were modeled and compared to moderate-adherence insulin therapy: advancement to high-adherence insulin at A1C ≥ 8% (treat to target A1C < 7%) and addition of pioglitazone (PIO) or ExQW from simulation start. ExQW effects on A1C, weight, BP, and lipids were modeled from clinical trial data. Costs, inflated to represent 2010 $US, were derived from Medicare data, Drugstore.com, and publications. As ExQW was investigational, we omitted ExQW, PIO, and insulin pharmacy costs. RESULTS: By year 1, ExQW treatment decreased A1C (~1.5%), weight (~2 kg), and systolic BP (~5 mmHg). PIO and high-adherence insulin decreased A1C by ~1%, increased weight, and did not affect systolic BP. After 20 years, A1C was ~7% with all strategies. ExQW decreased rates of cardiovascular and microvascular complications more than PIO or high-adherence insulin versus moderate-adherence insulin. Over 20 years, ExQW treatment resulted in increased quality-adjusted life-years (QALYs) of ~0.3 years/person and cost savings of $469/life-year versus moderate adherence insulin. For PIO or high-adherence insulin, QALYs were virtually unchanged, and costs/life-year versus moderate-adherence insulin increased by $69 and $87, respectively. CONCLUSIONS: This long-term simulation demonstrated that ExQW treatment may decrease rates of cardiovascular and some microvascular complications of T2DM. Increased QALYs, and decreased costs were also projected.

Impact of comorbidity on colorectal cancer screening cost-effectiveness study in diabetic populations.

BACKGROUND: Although comorbidity has been shown to affect the benefits and risks of colorectal cancer (CRC) screening, it has not been accounted for in prior cost-effectiveness analyses of CRC screening. OBJECTIVE: To evaluate the impact of diagnosis of diabetes mellitus, a highly prevalent comorbidity in U.S. adults aged 50 and older, on health and economic outcomes of CRC screening. DESIGN: Cost-effectiveness analysis using an integrated modeling framework. DATA SOURCES: Derived from basic and epidemiologic studies, clinical trials, cancer registries, and a colonoscopy database. TARGET POPULATION: U.S. 50-year-old population. TIME HORIZON: Lifetime. PERSPECTIVE: Costs are based on Medicare reimbursement rates. INTERVENTIONS: Colonoscopy screening at ten-year intervals, beginning at age 50, and discontinued after age 50, 60, 70, 80 or death. OUTCOME MEASURES: Health outcomes and cost effectiveness. RESULTS OF BASE-CASE ANALYSIS: Diabetes diagnosis significantly affects cost-effectiveness of CRC screening. For the same CRC screening strategy, a person without diabetes at age 50 gained on average 0.07-0.13 life years more than a person diagnosed with diabetes at age 50 or younger. For a population of 1,000 patients diagnosed with diabetes at baseline, increasing stop age from 70 years to 80 years increased quality-adjusted life years (QALYs) gained by 0.3, with an incremental cost-effectiveness ratio of $206,671/QALY. The corresponding figures for 1,000 patients without diabetes are 2.3 QALYs and $46,957/QALY. RESULTS OF SENSITIVITY ANALYSIS: Cost-effectiveness results are sensitive to cost of colonoscopy and adherence to colonoscopy screening. LIMITATIONS: Results depend on accuracy of model assumptions. CONCLUSION: Benefits of CRC screening differ substantially for patients with and without diabetes. Screening for CRC in patients diagnosed with diabetes at age 50 or younger is not cost-effective beyond age 70. Screening recommendations should be individualized based on the presence of comorbidities.

Estimating health and economic benefits from using prescription omega-3 fatty acids in patients with severe hypertriglyceridemia.

Patients with increased triglyceride levels compared to those with normal levels are at higher risk for coronary heart disease. In patients with severe (≥500 mg/dl) hypertriglyceridemia (SHTG), clinical trials have demonstrated that prescription ω-3 fatty acids (P-OM3s) 4 g/day can decrease triglyceride levels by 45%. However, the precise health and economic benefits of decreasing SHTG with P-OM3 are unknown. We used the previously validated Archimedes model to simulate a 20-year trial involving subjects 45 to 75 years old with SHTG. The trial consisted of an intervention arm (P-OM3 4 g/day) and a control arm. Simulation results for the control arm indicated that subjects with SHTG are at about 2 times higher risk for myocardial infarction than those with normal triglyceride levels. Using estimates from previous epidemiologic studies and meta-analyses with OM3s, the model predicted 29% to 36% decreases in various measurements of adverse cardiac events for the intervention arm. The model also predicted a decrease in ischemic stroke of 24% (95% confidence interval 15 to 33). For the 20-year simulated trial, the cost per quality-adjusted life-year gained for the currently available P-OM3 approved by the Food and Drug Administration was $47,000. Results remained robust under different clinical assumptions. In our model P-OM3 was effective in decreasing triglyceride levels and cardiovascular disease risk in patients with SHTG. In conclusion, P-OM3 medication is cost effective in our simulated trial and comparable to other cost-effective cardiovascular interventions.

Cost-effectiveness of chemoprevention of breast cancer using tamoxifen in a postmenopausal US population.

BACKGROUND: Previous cost-effectiveness analyses of tamoxifen therapy account for breast cancer risk reduction during active treatment but not for its persistent protective effect after active treatment. METHODS: A detailed, continuous time, mathematical model of breast cancer and healthcare processes was used to simulate a postmenopausal population aged <55 years in a virtual trial comparing tamoxifen treatment with no treatment for lifetime follow-up. Unlike previous work, the current model of tamoxifen therapy is based on a meta-analysis of 4 randomized, placebo-controlled chemoprevention trials with breast cancer risk reduction continuing for 10 years after treatment termination. Cancer incidence and survival data were derived from Surveillance, Epidemiology and End Results statistics. Noncancer disease incidences, quality-adjusted life year (QALY) utility weights, and costs were derived from the literature. RESULTS: Tamoxifen treatment (vs no treatment) saved 29 QALYs in a population of 1000 postmenopausal women aged <55 years with an additional cost of $333,000 over the population's lifetime (average cost-effectiveness ratio, $11,530 per QALY). Tamoxifen therapy, compared with no treatment, was cost saving when higher risk populations were targeted (5-year risk ≥1.66%). The cost-effectiveness results were sensitive to parameters that characterized menopausal symptoms and adverse side effects of tamoxifen. CONCLUSIONS: The current results indicated that tamoxifen chemoprophylaxis for postmenopausal women aged <55 years is a cost-effective health policy that reduces breast cancer incidence and improves life expectancy. Focusing on a postmenopausal population aged <55 years minimized the threat of adverse events associated with tamoxifen.

Modeling the effects of omalizumab over 5 years among patients with moderate-to-severe persistent allergic asthma.

OBJECTIVE: Omalizumab is a monoclonal antibody indicated for adults and adolescents with moderate-to-severe persistent allergic asthma whose symptoms are inadequately controlled with inhaled corticosteroids. Omalizumab has been demonstrated to improve health outcomes of asthmatic patients as compared to placebo. However, to date, the trials conducted have been relatively short (less than 1 year) and have been restricted to a limited set of patients who met the clinical study criteria. This study examined the expected effects of omalizumab over 5 years on a representative sample of all patients eligible for omalizumab in the US. METHODS: The Archimedes Asthma Model was used to simulate the following treatment scenarios for US patients age 12 and older with moderate-to-severe persistent allergic asthma: (1) Current asthma treatment (CAT) (treatment according to National Heart, Lung, and Blood Institute (NHLBI) guidelines, without use of omalizumab, and with adherence levels as observed in the National Asthma Survey); (2) Guideline asthma treatment (GAT) without omalizumab (NHLBI guidelines without use of omalizumab, assuming perfect adherence); (3) GAT plus omalizumab; and (4) GAT plus omalizumab with steroid reduction. The simulation was run for 5 years. MAIN OUTCOME MEASURES: Symptom days, asthma exacerbations, emergency room/urgent care (ER/UC) visits, hospitalizations, and medication use. RESULTS: For the full simulated population of omalizumab-eligible patients, the simulation forecasted that omalizumab would decrease cumulative exacerbations by 30%, ER/UC visits by 37%, and hospitalizations by 38% over 5 years. Among responders to omalizumab, assuming that 60.5% of patients respond, the results suggest that omalizumab would decrease cumulative exacerbations by 50%, ER/UC visits by 62%, and hospitalizations by 63% over 5 years. In addition, the simulation predicted that omalizumab would allow 45% of patients who are taking more than the minimum steroid dose to reduce their steroid dose, while maintaining similar asthma control as achieved in the GAT plus omalizumab arm (no steroid dose reduction) and better asthma control than following treatment protocols that do not include omalizumab. CONCLUSION: Based on the results of this simulation, omalizumab is effective for those who respond, reducing serious events by more than 50% among the responder group, while also allowing many patients to reduce their steroid dose.

Age at initiation and frequency of screening to detect type 2 diabetes: a cost-effectiveness analysis.

BACKGROUND: No clinical trials have assessed the effects or cost-effectiveness of sequential screening strategies to detect new cases of type 2 diabetes. We used a mathematical model to estimate the cost-effectiveness of several screening strategies. METHODS: We used person-specific data from a representative sample of the US population to create a simulated population of 325,000 people aged 30 years without diabetes. We used the Archimedes model to compare eight simulated screening strategies for type 2 diabetes with a no-screening control strategy. Strategies differed in terms of age at initiation and frequency of screening. Once diagnosed, diabetes treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, myocardial infarction, stroke, and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). FINDINGS: Compared with no screening, all simulated screening strategies reduced the incidence of myocardial infarction (3-9 events prevented per 1000 people screened) and diabetes-related microvascular complications (3-9 events prevented per 1000 people), and increased the number of QALYs (93-194 undiscounted QALYs) added over 50 years. Most strategies prevented a significant number of simulated deaths (2-5 events per 1000 people). There was little or no effect of screening on incidence of stroke (0-1 event prevented per 1000 people). Five screening strategies had costs per QALY of about US$10,500 or less, whereas costs were much higher for screening started at 45 years of age and repeated every year ($15,509), screening started at 60 years of age and repeated every 3 years ($25,738), or a maximum screening strategy (screening started at 30 years of age and repeated every 6 months; $40,778). Several strategies differed substantially in the number of QALYs gained. Costs per QALY were sensitive to the disutility assigned to the state of having diabetes diagnosed with or without symptoms. INTERPRETATION: In the US population, screening for type 2 diabetes is cost effective when started between the ages of 30 years and 45 years, with screening repeated every 3-5 years. FUNDING: Novo Nordisk, Bayer HealthCare, [corrected] and Pfizer.