Abstract
Background
Cost-effectiveness of testing for coronary artery calcium (CAC) relative to other treatment strategies is not established in Canada.
Objectives
The purpose of this study was to evaluate the cost-effectiveness of using CAC score-guided statin treatment compared with universal statin therapy among intermediate-risk, primary prevention patients eligible for statins.
Methods
A state transition, microsimulation model used data from Canadian sources and the Multi-Ethnic Study of Atherosclerosis to simulate clinical and economic consequences of cardiovascular disease from a Canadian publicly funded health care system perspective. In the CAC score-guided treatment arm, statins were started when CAC ≥1. Outcome of interest was the incremental cost-effectiveness ratio at 5 and 10 years; an incremental cost-effectiveness ratio <$50,000 per quality-adjusted life year (QALY) gained was considered cost-effective. Sensitivity analyses examined uncertainty in model parameters.
Results
Compared with universal statin treatment at 5 and 10 years, CAC score-guided statin treatment was projected to increase mean costs by $326 (95% CI: $325-$326) and $172 (95% CI: $169-$175), increase mean QALYs by 0.01 (95% CI: 0.01-0.01) and 0.02 (95% CI: 0.02-0.02), and cost $54,492 (95% CI: $52,342-$56,816) and $8,118 (95% CI: $7,968-$8,279) per QALY gained, respectively. The model was most sensitive to statin cost, CAC testing cost, adherence to statin monitoring, and disutility associated with daily statin use. At 5 years, CAC score-guided statin treatment was cost-effective when CAC test costs ranged from $80 to $160 in different scenarios.
Conclusions
CAC score-guided statin initiation in comparison to universal statin treatment was borderline cost-neutral at 5 years and cost-effective at 10 years in statin-eligible Canadian patients at intermediate cardiovascular disease risk.
Key words: coronary artery calcium, dyslipidemia, economic evaluation, intermediate risk, primary prevention, statins
Central Illustration
Cardiovascular disease (CVD) is the leading cause of death in Canada and CVD care is estimated to cost over $20 billion per annum.1,2 About 90% of Canadians have at least 1 CVD risk factor, while 1 in 3 have at least 3 risk factors.3 For the primary prevention of CVD events, cardiologists rely heavily on traditional risk prediction models to identify patients at risk of events, and then treat according to their risk classification. The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia (CCS-GMD) recommends the initiation of statin therapy for primary prevention of CVD in intermediate-risk patients (ie, 10-year Framingham Risk Score 10.0-19.9%) with high low-density lipoprotein cholesterol (LDL-C) or other risk factors.4
When the decision to use long-term statin therapy is uncertain through patient-physician dialogue, coronary artery calcium (CAC) testing is recommended as a secondary test to reclassify risk and aid decision-making.4 CAC measurement is useful for prognostication, discrimination, calibration, and reclassification for CVD.5,6 Studies such as the MESA (Multi-Ethnic Study of Atherosclerosis) and the Heinz Nixdorf Recall Study have shown that individuals with elevated CAC scores have a 9- to 16-fold higher risk of coronary heart disease (CHD) events compared to those with a CAC score of 0.7,8 Accumulating evidence continues to establish CAC as a robust risk restratification method beyond traditional risk scores in primary prevention settings.
CAC testing is not widely used in routine clinical practice, and the cost-effectiveness of using CAC testing to guide statin therapy relative to other treatment strategies has not been established in Canada. However, analyses in other jurisdictions such as the United States are generally favorable.9, 10, 11, 12, 13, 14, 15 We therefore evaluated the cost-effectiveness of using CAC score-guided statin treatment compared with universal statin therapy among CVD-free, statin-eligible patients at intermediate risk of CVD over 5 and 10 years from a Canadian health care system perspective.
Methods
Statistical methods
Model overview
A published state-transition, microsimulation model was adapted for the current analysis using TreeAge Pro 2023.9 The model simulated the clinical and economic consequences of CVD primary prevention strategies among 10,000 intermediate-risk individuals from a Canadian publicly funded health care system perspective. The model compared 2 strategies: 1) universal statin treatment, that is, high-intensity statin treatment in all individuals, and 2) CAC score-guided statin treatment, that is, 1-time CAC testing with high-intensity statin initiation for those with CAC ≥1 and no treatment for those with CAC = 0 (Central Illustration). We simulated outcomes over 5- and 10-year time horizons. Each year of the simulation, individuals could remain CVD-free (not taking statins or taking statins), experience their first CVD event, or die from non-CVD causes (Central Illustration). CVD events included CHD (myocardial infarction, angina pectoris, and fatal CHD), stroke (ischemic/hemorrhagic stroke and transient ischemic attack), heart failure, peripheral artery disease, and percutaneous coronary intervention (Supplemental Tables 1 and 2).16 The health and economic consequences were captured by the model each year, and the simulation progressed until the first CVD event, non-CVD death, or the time horizon was reached. Health outcomes were valued as the number of averted CVD events and quality-adjusted life years (QALYs). Effectiveness of treatment, quality of life weights, and transitions probabilities were obtained from published literature, expert opinion, and analysis of MESA participants. Direct health care costs were obtained from the analysis of Alberta Administrative health data sets and published literature.
Central Illustration.
Cost-Effectiveness of CAC Score-Guided Vs Universal Statin Therapy in Intermediate CVD-Risk Statin-Eligible Canadians
(A) Treatment strategies. (B) Model schematic. Cost-effectiveness acceptability curves demonstrate the probability that a given strategy is the most cost-effective using a range of willingness-to-pay thresholds plotted on the horizontal axis against the probability that the intervention will be cost-effective at that threshold on the vertical axis for the (C) 5-year time horizon, (D) 10-year time horizon. CAC = coronary artery calcium; CVD = cardiovascular disease; QALY = quality-adjusted life year.
Participant sample
The simulation model was populated with a hypothetical cohort of 10,000 asymptomatic, intermediate risk, statin-eligible adults. The hypothetical cohort was constructed to replicate the age and CAC distribution observed in MESA participants (Supplemental Table 3). MESA, described elsewhere,17 is a community-based prospective cohort study of 6,814 participants from 6 different field centers in the United States with ages ranging from 45 to 84 years at the first exam. The objectives of MESA were to investigate the progression and prognostic implications of subclinical CVD. MESA was approved by the Institutional Review Boards of the participating institutions, and all participants gave written informed consent. In the current analysis, we identified 1,203 MESA participants with a CAC score who were classified as intermediate risk and statin eligible by the CCS-GMD (4): Framingham Risk Score of 10.0%-19.5%, LDL-C <5 mmol/L, no diagnosis of chronic kidney disease or diabetes, aged 45 to 75 years, no current statin use, and no prior CHD or CVD events. The University of Alberta’s Health Research Ethics Board approved this study (Pro00121056).
MESA and CVD event rates
Patient-level data from MESA were used to determine the annual probability of CVD events and non-CVD death by CAC score (measured in MESA visit 1): CAC = 0 (including scores 0.0-0.99), 1 ≤ CAC<100, and CAC ≥ 100 (Figure 1). Kaplan-Meier 5- and 10-year cumulative incidence estimates from MESA were converted to annual risk probabilities (Supplemental Table 4). The distribution of CVD event types experienced is provided in Supplemental Table 5. In a secondary analysis, only CHD events were considered (Supplemental Tables 6 and 7). To assess the generalizability of the rates derived from MESA to the population of Canada, sex-stratified all-cause mortality rates observed in the overall MESA population were compared with the expected rates based on the general population of Canada aged 45 to 84 years (Supplemental Table 8).
Figure 1.
MESA Subgroup Patient Flow Diagram
CAC = coronary artery calcium; CKD = chronic kidney disease; CVD = cardiovascular disease; FRS = Framingham Risk Score; LDL-C = low-density lipoprotein cholesterol; MESA = Multi-Ethnic Study of Atherosclerosis.
Statin treatment
The relative risk of CVD with high-intensity statin treatment was derived from a published meta-analysis of 15 trials of statin use for the primary prevention of CVD in adults (Supplemental Table 9).18 The CVD composite outcome in the meta-analysis included myocardial infarction, angina, transient ischemic attack, fatal and nonfatal stroke, revascularization, heart failure, and cardiovascular mortality. For the secondary analysis, the relative risk of CHD was derived from a Canadian meta-analysis of high-intensity statin treatment in low CVD risk patients, which was weighted using the relative frequencies of event types in MESA (Supplemental Tables 7 and 9).19 We also applied the relative risk for all-cause mortality to the risk of non-CVD death (Supplemental Table 9).19
No statin dose adjustments or tapering of statin efficacy were assumed over the duration of the model. We assumed 55% of individuals remained adherent to statins in the universal treatment arm.20 Previous studies report that patients who visualize calcium deposits in their coronary arteries have a higher likelihood of adherence to statin therapy;21, 22, 23, 24 therefore, the proportion remaining adherent to statins was increased to 65% in the CAC score-guided treatment arm.9,10 The risk of statin treatment-related adverse events (myalgia and rhabdomyolysis) was derived from published literature and patients discontinued treatment, if they experienced the adverse event.14,25
Incidental findings with CAC
CAC testing may uncover incidental noncardiac findings that warrant follow-up examinations. Studies have found that these incidental findings occur in 4% to 8% of patients. Although incidental findings could reveal early-stage cancers, studies have found that very few noncalcified lung nodules ultimately prove cancerous.26, 27, 28, 29 A sensitivity analysis included re-scanning 8% of patients in the CAC testing arm,26, 27, 28 conservatively assuming no future health or cost benefits from the follow-up scans.
Costs
All cost inputs were inflated to 2021 Canadian dollars using the Statistics Canada Consumer Price Index.30 Mean incident CVD event costs were determined from analyzing administrative provincial Ministry of Health (Alberta Health) databases and published literature (Supplemental Tables 10 to 12). CVD costs included hospitalization and ambulatory care costs and were estimated using the cost of standard hospital stay methodology.31,32 Angina costs included Community Physician billings, using the paid amount for fee-for-service physicians and for non-fee-for-service estimated shadow billing claims were used. Percutaneous coronary intervention cost was extracted from the literature. The mean cost of an incident CVD event was the weighted average using the relative frequencies of event types in MESA. We determined the average generic unit cost for high-intensity dose statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg)4,33, 34, 35 as $0.21/tablet per the Alberta Drug Formulary Drug Benefit List.34 This excludes pharmacy markups and dispensing fees (Supplemental Table 12). Based on product monographs, we assumed 1 pill daily. Patients on statin therapy were considered to warrant monitoring costs each year: 2 annual follow-up visits with the general practitioner, 2 lipid tests, and 1 liver and 1 muscle test (Supplemental Table 12). Myalgia treatment cost was equivalent to a general practitioner assessment and rhabdomyolysis treatment cost was extracted from the literature. The cost of CAC screening ($475) was extracted from a private clinic in Alberta.36 We assumed there would be 1 additional general practitioner visit after CAC screening for patients to discuss their results.
Health-related quality of life
Age-specific health-related quality of life was assessed using utilities, which range from 0 (death) to 1 (perfect health), derived from published literature (Supplemental Table 13). Reductions in utility due to the consumption of a daily statin and statin-induced myalgia and rhabdomyolysis were included.9,37 CVD utility reductions were condition-specific losses weighted using the relative frequencies of event types in MESA.38,39 CAC testing entails exposure to modest doses of ionizing radiation (∼1 mSv); therefore, lifetime cancer risk and the associated probability of mortality were represented by weighted probabilities of sex-specific utility.40,41
Model validation
We validated the model by comparing the expected CVD time-to-event data from MESA to the predicted CVD events from the microsimulation model, assuming patients were not treated with a statin (Supplemental Figure 1). The model also produced a consistent mean age and percentage of CAC scores with the MESA participants. To ensure the model produced stable estimates, we examined outcomes when varying the number of individuals simulated from 2,000 to 10,000; no substantial differences were observed.
Base-case analysis
Our analyses followed best practices for cost-effectiveness analysis recommended by the Consolidated Health Economics Evaluation Reporting Standards (Supplemental Table 14).42 We used a Canadian publicly funded health care system perspective and future costs and QALYs were discounted at a 1.5% rate based on the Canadian guidelines.43 The base-case cost and QALY projections for each treatment arm were calculated as the mean of 10,000 patients in the hypothetical cohort. The incremental cost-effectiveness ratio (ICER) was calculated using the difference in direct health care costs divided by the difference in QALYs. In Canada, there is no formal cost-effectiveness threshold. However, the Canadian Agency for Drugs and Technologies in Health often cites a threshold of CAD$50,000 per QALY as a benchmark.43,44 Therefore, we used this commonly accepted threshold (strategy is cost-effective if ICER <50,000/QALY gained). We also calculated the incremental number of incident CVD events avoided.
Sensitivity analyses
Assumptions and uncertainty in the base-case analysis were assessed by conducting a series of sensitivity analyses. One-way and 2-way sensitivity analyses varied key model parameters independently and jointly, respectively, over a range of plausible values while holding all other parameters constant. In addition, we performed a threshold analysis to determine the CAC testing cost that would result in CAC score-guided statin treatment becoming cost-effective/cost-saving in both time horizons. Lastly, we performed a probabilistic sensitivity analysis to assess uncertainty in model parameters by drawing 1,000 random samples for each model parameter from prespecified distributions and repeating the simulation for each parameter set.45 We used beta distributions for probabilities and utilities, lognormal distribution for relative risks, and gamma distributions for costs. The distributions used published or calculated standard errors and 95% CI when available; otherwise, input parameters were varied by 20%.
Results
Base-case analysis
Over 5 years, the model projected that universal statin treatment would avert an average of 27 CVD events per 10,000 individuals compared with CAC score-guided statin treatment (Table 1) and the mean age was 62 years old. Relative to universal statin treatment, CAC score-guided statin treatment was estimated to increase mean direct health care costs by $326 and, due to reduced pill-taking disutility and fewer treatment-related adverse events, increase mean QALYs by 0.01 per patient, resulting in an ICER of $54,492/QALY gained (Table 1). At a willingness-to-pay threshold of $50,000/QALY, CAC score-guided statin treatment was cost-effective in 42% of the iterations (Central Illustration). CAC score-guided statin treatment was dominated by universal statin treatment (ie, CAC score-guided treatment cost more and was less effective) when considering the cost per CVD event avoided.
Table 1.
Base-Case Cost Utility Analysis for CVD Outcome Over 5- and 10-Year Time Horizon
| Universal Statin Treatment | CAC Score-Guided Statin Treatment | CAC-Guided vs Universal Statin Treatment | |
|---|---|---|---|
| Base-case assumptions: 5-y time horizon | |||
| CVD events (per 10,000 individuals) | 336 (301-371) | 363 (327-399) | 27 (26-27) |
| QALYsa | 3.93 (3.92-3.94) | 3.94 (3.93-3.95) | 0.01 (0.01-0.01) |
| Direct health care costsa (2021 CAD) | 1,207 (1,129-1,286) | 1,533 (1,455-1,611) | 326 (325-326) |
| Probability cost-effective at $50,000 per QALYb or ICERa ($ per QALY gained) | 58%b | 42%b | $54,492a ($52,342-$56,816) |
| Base-case assumptions: 10-y time horizon | |||
| CVD events (per 10,000 individuals) | 732 (683-781) | 810 (758-861) | 78 (75-80) |
| QALYsa | 7.21 (7.18-7.24) | 7.23 (7.20-7.26) | 0.02 (0.02-0.02) |
| Direct health care costsa (2021 CAD) | 2,496 (2,397-2,594) | 2,667 (2,566-2,769) | 172 (169-175) |
| Probability cost-effective at $50,000 per QALYb or ICERa ($ per QALY gained) | 38%b | 62%b | $8,118a ($7,968-$8,279) |
CAC = coronary artery calcium; CAD = coronary artery disease; CVD = cardiovascular disease; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year.
Mean value based on microsimulations of 10,000 individuals.
Mean value based on microsimulation of 1,000 trials and 2,000 samples.
When extending the time horizon to 10 years, universal statin treatment was projected to prevent 78 CVD events per 10,000 individuals compared with CAC score-guided statin treatment. CAC score-guided statin treatment was estimated to increase mean costs by $172 and mean QALYs by 0.02 compared with universal statin treatment, resulting in an ICER of $8,118/QALY (cost-effective in 62% of the iterations) (Central Illustration, Table 1). Similar results were seen in the secondary analysis that only considered CHD (Supplemental Table 15).
Sensitivity analysis
The model findings were sensitive to statin costs, CAC testing costs, statin monitoring adherence, and the disutility of a daily statin (Table 2, Supplemental Table 16). When CAC testing costs were ≤$150 and ≤$280, CAC score-guided statin treatment was estimated to dominate universal statin treatment (ie, CAC score-guided statin treatment cost less and gained more QALYs) over the 5- and 10-year time horizons, respectively. At 5 years, when annual statin costs were $100 and $150, CAC score-guided statin treatment was dominant when CAC testing cost ≤$160 and ≤$220, respectively. When there was no disutility associated with a statin, universal statin treatment was dominant. A scenario analysis of MESA events associated with an extreme case of a White race intermediate-risk group was conducted to assess sensitivity to race. In the 5-year time horizon, the difference in costs ($326 vs $280) and QALYs (0.01 vs 0.01) were similar between our base-case intermediate-risk group and the White intermediate-risk group, respectively. Similar patterns are seen in the 10-year time horizon.
Table 2.
Sensitivity and Scenarios Analyses
| Analysis | ICER ($/QALY) |
|---|---|
| 5-y time horizon | |
| Base-case | $54,492 |
| CAC test cost | |
| $150 | CAC score-guided dominates |
| $265 | $19,302 |
| $350 | $33,546 |
| Annual statin drug cost | |
| $50 | $58,056 |
| $100 | $51,290 |
| $150 | $44,525 |
| CAC test cost when annual statin drug cost = $100 | |
| $160 | CAC score-guided dominates |
| $220 | $8,560 |
| $300 | $21,966 |
| CAC test cost when annual statin drug cost = $150 | |
| $160 | CAC score-guided dominates |
| $220 | CAC score-guided dominates |
| $300 | $15,200 |
| Proportion adhering to the annual statin monitoring | |
| 0% | $77,666 |
| 50% | $66,079 |
| CAC test cost when 50% adhere to annual statin monitoring | |
| $80 | CAC score-guided dominates |
| $180 | $16,646 |
| $250 | $28,376 |
| Excluding disutility from a daily statin tablet consumption | Universal treatment dominates |
| Disutility of myalgia increased by 20% | $54,492 |
| Disutility of rhabdomyolysis decreased by 20% | $54,492 |
| Disutility of CVD events increased by 20% | $51,519 |
| CVD event costs increased by 30% | $50,746 |
| Incidental noncardiac findings from CAC testing included | $57,401 |
| Patients do not visit GP after CAC screening for results interpretation | $48,127 |
| All-cause mortality relative risk reduced by 20% | $66,447 |
| Alternative disutility value (0.001) from a daily statin tablet consumption | $94,681 |
| 100% compliance of statin treatment (adherence) | $25,540 |
| MESA event rates of White race only | $39,977 |
| 10-y time horizon | |
| Base-case | $8,118 |
| CAC test cost | |
| $280 | CAC score-guided dominates |
| $350 | $2,350 |
| $400 | $4,570 |
| Annual statin drug cost | |
| $50 | $10,243 |
| $100 | $6,209 |
| $150 | $2,174 |
| Proportion adhering to the annual statin monitoring | |
| 0% | $21,954 |
| 50% | $15,036 |
| CAC test cost when 50% adhere to annual statin monitoring | |
| $150 | CAC score-guided dominates |
| $180 | $1,081 |
| $250 | $4,392 |
| Excluding disutility from a daily statin tablet consumption | Universal treatment dominates |
| Disutility of myalgia increased by 20% | $8,118 |
| Disutility of rhabdomyolysis decreased by 20% | $8,118 |
| Disutility of CVD events increased by 20% | $7,821 |
| CVD event costs increased by 30% | $8,473 |
| Incidental noncardiac findings from CAC testing included | $8,939 |
| Patients do not visit GP after CAC screening for results interpretation | $6,321 |
| All-cause mortality relative risk reduced by 20% | $8,125 |
| Alternative disutility value (0.001) from a daily statin tablet consumption | $16,097 |
| 100% compliance of statin treatment (adherence) | CAC dominates |
| MESA event rates of White race only | $6,610 |
Detailed results including mean, incremental, and uncertainty intervals for costs and QALYs are shown in Supplemental Table 16. Strategies labeled as “dominates” means the strategy is lower in costs and higher in QALYs; thus; superior in comparison to the other strategy.
CAC = coronary artery calcium; CVD = cardiovascular disease; GP = general practitioner; ICER = incremental cost-effectiveness ratio; MESA = Multi-Ethnic Study of Atherosclerosis; QALY = quality-adjusted life year.
In the probabilistic sensitivity analysis, CAC score-guided statin treatment was projected to accumulate mean (95% uncertainty interval) costs of $1,546 ($1,541-$1,552) and 3.936 (3.936-3.937) QALYs, and universal statin treatment $1,225 ($1,219-$1,231) and 3.932 (3.931-3.933) QALYs at 5 years (Central Illustration, Supplemental Table 17, Supplemental Figure 2). The estimated ICER for CAC score-guided vs universal statin treatment was $77,572/QALY gained. At 10 years, similar patterns were projected but with reduced incremental costs and increased incremental QALYs, resulting in an ICER for CAC score-guided vs universal statin treatment of $8,607/QALY gained.
Discussion
In this study, we used participant-level analysis of the MESA cohort and adapted a published computer simulation model to project the cost-effectiveness of using CAC scores to guide statin treatment compared with universal statin treatment among patients in Canada at intermediate CVD risk recommended statins by the CCS-GMD guidelines. Compared with universal statin treatment at 5 years, CAC score-guided statin treatment was estimated to cost $54,000 per QALY gained, above commonly accepted thresholds for cost-effectiveness. However, at 10 years, CAC score-guided statin treatment was cost-effective, costing an estimated $8,000 per QALY gained. The results were sensitive to the cost of CAC screening, statin medication costs, and reductions in quality of life due to daily statin taking, that is, disutility.
To our knowledge, this is the first study to examine the cost-effectiveness of using CAC testing to guide statin treatment in intermediate-risk patients in Canada recommended statin therapy for primary CVD prevention by the CCS-GMD guidelines. Our results are similar to other analyses in different countries. Hong et al10 estimated that CAC strategies in the United States would be dominant when statin costs per year were between USD $150 and $500/year or when CAC testing was USD $50. They did not find substantial influence of the intensity of statin therapy. In our analysis, we chose to study only high-intensity statins as treatment goals in Canada are to achieve a 50% lowering of LDL-C after statin initiation. Similar to our results, Hong et al showed that in the absence of disutility associated with daily statin therapy, a treat all strategy was dominant. This finding was consistent and robust regardless of the manner in which the disutility was derived. Other studies examining the cost-effectiveness of CAC score-guided statin treatment found it to be cost-effective when CAC testing costs range from USD $50 to $200,9, 10, 11,14,46,47 a range compatible with the findings of the current analysis.
We believe that these analyses underscore the importance of having access to CAC to ensure that the clinician-patient discussion48 can lead to therapeutic decisions that are as individualized as possible within the relevant socioeconomic treatment setting and context of the patient’s perception of the negative impact of long-term or lifelong statin therapy. It is also important, however, that practitioners recognize the large body of evidence showing that statins are both safe and effective and should not promote or advocate avoidance of statins in patients who would benefit from lipid-lowering therapy.18,49 Additionally, a growing body of evidence has emerged to substantiate that the perception of disutility may be related to nocebo effects.50, 51, 52
Study Limitations
There are limitations to this study. Cost-effectiveness models are based on assumptions about the underlying data and the experience of individuals in clinical practice. First, our analysis only considered the first CVD event and did not include the long-term downstream consequences occurring after an event, such as increased treatment and health care costs and decreased quality of life. Second, there are no population-level CAC score data from Canada nor are there CVD event and non-CVD death rates by CAC score. Therefore, we derived these model parameters from a subset of MESA participants who had CAC testing. MESA is a U.S.-based cohort study and has a different racial/ethnic and socioeconomic composition than the population in Canada. However, we found that all-cause mortality rates observed in the overall MESA population were similar to the expected rates derived from the general population in Canada. In addition, we found that race between the populations did not have a significant impact on this analysis, possibly due to the intermediate-risk population already have a higher risk of CVD. Third, our model assumed the effectiveness of statin therapy did not vary by CAC score and had a consistent effect over the time periods evaluated. However, evidence shows that the effectiveness of lipid-lowering therapy may grow over time.49,50 Fourth, the costs of CVD events may be underestimated as we did not include direct and indirect management costs such as drugs, laboratory tests, and loss of productivity. However, we conducted a scenario analysis where we increased the CVD event costs by 20% and this did not affect our conclusions substantially. Fifth, the cost of statins may have been underestimated as we did not include pharmaceutical markups and dispensing fees. However, we did conduct extensive sensitivity analyses to assess the impact of this. Sixth, the risk of developing lifetime cancer from CAC screening could be overestimated, especially in the 5-year time horizon; patients could potentially develop cancer due to CAC screening many years after the screening takes place and possibly even die of other causes before it develops. However, this did not have major impacts on the model results. Seventh, the mean age from the MESA participants in the subanalysis were 62 years old. A lower age group or a higher age group may potentially lead to different results. Lastly, we did not consider other CVD prevention treatment modalities such as antihypertensive treatment, aspirin, or emerging non-statin lipid-lowering drugs that might be relevant to treat the intermediate-risk group (these are generally costlier and/or less accessible). However, since our study focused on the decision strategy of statin initiation, these other treatment strategies were considered beyond the scope of our study.
Conclusions
In a computer-simulated Canadian population of statin-eligible adults without a history of CVD and at intermediate risk of CVD as identified by Canadian dyslipidemia guidelines, CAC score-guided vs universal statin treatment was estimated to be borderline cost-neutral at 5 years. CAC score-guided treatment would be cost-effective if CAC cost ranged from $80 to $160. At 10 years, CAC score-guided treatment was estimated to be cost-effective. Health care decision-makers should ensure that equitable access to CAC testing is available to inform clinician-patient statin treatment decisions.
PERSPECTIVES.
COMPETENCY IN MEDICAL KNOWLEDGE: CAC score-guided vs universal statin treatment was borderline cost-neutral at 5 years and cost-effective at 10 years at a cost-effectiveness threshold of $50,000 per QALY gained.
TRANSLATIONAL OUTLOOK: Wider access to low-cost CAC screening is needed in Canada for those in the intermediate-risk population.
Funding support and author disclosures
Funding was provided by the CardioRisk Clinic Grant/Vancouver Hospital Foundation. MESA was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute (Bethesda, Maryland), and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS) (Bethesda, Maryland). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Acknowledgments
The authors thank the other investigators, the staff, and the participants of the MESA study for their invaluable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. This paper has been reviewed and approved by the MESA Publications and Presentations Committee. This study is based in part on data provided by Alberta Health and Alberta Health Services. We thank the Customer Relationship Management and Data Access Unit at Alberta Health for creating the linked database. The interpretation and conclusions are those of the researchers and do not represent the views of the Government of Alberta. Neither the Government of Alberta nor Alberta Health express any opinion in relation to this study.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental tables and figures, please see the online version of this paper.
Supplemental data
References
- 1.IHME Institute for health metrics and evaluation. 2015. http://www.healthdata.org/canada
- 2.Public Health Agency of Canada About heart diseases and conditions. Six types of cardiovascular disease. 2017. http://www.phac-aspc.gc.ca/cd-mc/cvd-mcv/cvd-mcv-eng.php
- 3.Smith E.R. The Canadian heart health strategy and action plan. Can J Cardiol. 2009;25:451–452. doi: 10.1016/s0828-282x(09)70116-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Pearson G.J., Thanassoulis G., Anderson T.J., et al. Canadian cardiovascular society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults. Can J Cardiol. 2021;37:1129–1150. doi: 10.1016/j.cjca.2021.03.016. [DOI] [PubMed] [Google Scholar]
- 5.Sarwar A., Shaw L.J., Shapiro M.D., et al. Diagnostic and prognostic value of absence of coronary artery calcification. J Am Coll Cardiol Img. 2009;2:675–688. doi: 10.1016/j.jcmg.2008.12.031. [DOI] [PubMed] [Google Scholar]
- 6.Polonsky T.S., McClelland R.L., Jorgensen N.W., et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA. 2010;303:1610–1616. doi: 10.1001/jama.2010.461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Silverman M.G., Blaha M.J., Krumholz H.M., et al. Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the Multi-Ethnic Study of Atherosclerosis. Eur Heart J. 2014;35:2232–2241. doi: 10.1093/eurheartj/eht508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Mahabadi A.A., Möhlenkamp S., Moebus S., et al. The Heinz Nixdorf recall study and its potential impact on the adoption of atherosclerosis imaging in European primary prevention guidelines. Curr Atheroscler Rep. 2011;13:367–372. doi: 10.1007/s11883-011-0199-7. [DOI] [PubMed] [Google Scholar]
- 9.Roberts E.T., Horne A., Martin S.S., et al. Cost-effectiveness of coronary artery calcium testing for coronary heart and cardiovascular disease risk prediction to guide statin allocation: the Multi-Ethnic Study of Atherosclerosis (MESA) PLoS One. 2015;10 doi: 10.1371/journal.pone.0116377. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hong J.C., Blankstein R., Shaw L.J., et al. Implications of coronary artery calcium testing for treatment decisions among statin candidates according to the ACC/AHA cholesterol management guidelines. J Am Coll Cardiol Img. 2017;10:938–952. [Google Scholar]
- 11.Pletcher M.J., Pignone M., Earnshaw S., et al. Using the coronary artery calcium score to guide statin therapy: a cost-effectiveness analysis. Circ Cardiovasc Qual Outcomes. 2014;7:276–284. doi: 10.1161/CIRCOUTCOMES.113.000799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Venkataraman P., Kawakami H., Huynh Q., et al. Cost-effectiveness of coronary artery calcium scoring in people with a family history of coronary disease. J Am Coll Cardiol Img. 2021;14:1206–1217. doi: 10.1016/j.jcmg.2020.11.008. [DOI] [PubMed] [Google Scholar]
- 13.Sniderman A.D., Thanassoulis G., Lawler P.R., Williams K., Furberg C.D. Comparison of coronary calcium screening vs broad statin therapy for patients at intermediate cardiovascular risk. Am J Cardiol. 2012;110:530–533. doi: 10.1016/j.amjcard.2012.04.025. [DOI] [PubMed] [Google Scholar]
- 14.Galper B.Z., Wang Y.C., Einstein A.J. Strategies for primary prevention of coronary heart disease based on risk stratification by the ACC/AHA lipid guidelines, ATP III guidelines, coronary calcium scoring, and C-reactive protein, and a global treat-all strategy: a comparative--effectiveness modeling study. PLoS One. 2015;10 doi: 10.1371/journal.pone.0138092. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Venkataraman P., Neil A.L., Mitchell G.K., et al. The cost-effectiveness of coronary calcium score-guided statin therapy initiation for Australians with family histories of premature coronary artery disease. Med J Aust. 2023;218:216–222. doi: 10.5694/mja2.51860. [DOI] [PubMed] [Google Scholar]
- 16.D’Agostino R.B., Sr., Vasan R.S., Pencina M.J., et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117:743–753. doi: 10.1161/CIRCULATIONAHA.107.699579. [DOI] [PubMed] [Google Scholar]
- 17.Bild D.E., Bluemke D.A., Burke G.L., et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol. 2002;156:871–881. doi: 10.1093/aje/kwf113. [DOI] [PubMed] [Google Scholar]
- 18.Chou R., Cantor A., Dana T., et al. Statin use for the primary prevention of cardiovascular disease in adults: updated evidence report and systematic review for the US preventive services task force. JAMA. 2022;328:754–771. doi: 10.1001/jama.2022.12138. [DOI] [PubMed] [Google Scholar]
- 19.Tonelli M., Lloyd A., Clement F., et al. Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. CMAJ. 2011;183:E1189–E1202. doi: 10.1503/cmaj.101280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Shah P.K. Screening asymptomatic subjects for subclinical atherosclerosis: can we, does it matter, and should we? J Am Coll Cardiol. 2010;56:98–105. doi: 10.1016/j.jacc.2009.09.081. [DOI] [PubMed] [Google Scholar]
- 21.Kalia N.K., Miller L.G., Nasir K., Blumenthal R.S., Agrawal N., Budoff M.J. Visualizing coronary calcium is associated with improvements in adherence to statin therapy. Atherosclerosis. 2006;185:394–399. doi: 10.1016/j.atherosclerosis.2005.06.018. [DOI] [PubMed] [Google Scholar]
- 22.Taylor A.J., Bindeman J., Feuerstein I., et al. Community-based provision of statin and aspirin after the detection of coronary artery calcium within a community-based screening cohort. J Am Coll Cardiol. 2008;51:1337–1341. doi: 10.1016/j.jacc.2007.11.069. [DOI] [PubMed] [Google Scholar]
- 23.Nasir K., McClelland R.L., Blumenthal R.S., et al. Coronary artery calcium in relation to initiation and continuation of cardiovascular preventive medications. Circ Cardiovasc Qual Outcomes. 2010;3:228–235. doi: 10.1161/CIRCOUTCOMES.109.893396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Whelton S.P., Nasir K., Blaha M.J., et al. Coronary artery calcium and primary prevention risk assessment: what is the evidence? an updated meta-analysis on patient and physician behavior. Circ Cardiovasc Qual Outcomes. 2012;5:601–607. doi: 10.1161/CIRCOUTCOMES.112.965566. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Conly J., Clement F., Tonelli M., et al. Cost-effectiveness of the use of low- and high-potency statins in people at low cardiovascular risk. CMAJ. 2011;183:E1180–E1188. doi: 10.1503/cmaj.101281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Machaalany J., Yam Y., Ruddy T.D., et al. Potential clinical and economic consequences of noncardiac incidental findings on cardiac computed tomography. J Am Coll Cardiol. 2009;54:1533–1541. doi: 10.1016/j.jacc.2009.06.026. [DOI] [PubMed] [Google Scholar]
- 27.Schragin J.G., Weissfeld J.L., Edmundowicz D., Strollo D.C., Fuhrman C.R. Non-cardiac findings on coronary electron beam computed tomography scanning. J Thorac Imaging. 2004;19:82–86. doi: 10.1097/00005382-200404000-00004. [DOI] [PubMed] [Google Scholar]
- 28.Horton K.M., Post W.S., Blumenthal R.S., Fishman E.K. Prevalence of significant noncardiac findings on electron-beam computed tomography coronary artery calcium screening examinations. Circulation. 2002;106:532–534. doi: 10.1161/01.cir.0000027136.56615.de. [DOI] [PubMed] [Google Scholar]
- 29.Sripariwuth A., Kruamak T., Xu B. Contemporary narrative review: a clinically oriented interpretation of incidental radiological findings for common cardiovascular computed tomography scans. AME Med J. 2022;7:9. [Google Scholar]
- 30.Statistics Canada Table 18-10-0006-01 consumer price index, monthly, seasonally adjusted. 2023. https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1810000601
- 31.Kaul P., Klassen N., Dover D.C., et al. Prevalence of cardiovascular disease in a population-based cohort of high-cost healthcare services users. CJC Open. 2022;4:180–188. doi: 10.1016/j.cjco.2021.09.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Sandhu R.K., Tran D.T., Sheldon R.S., Kaul P. A population-based cohort study evaluating outcomes and costs for syncope presentations to the Emergency Department. J Am Coll Cardiol EP. 2018;4:265–273. doi: 10.1016/j.jacep.2017.09.003. [DOI] [PubMed] [Google Scholar]
- 33.Pignone M. Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease. UpToDate. 2018. https://www.uptodate.com/contents/low-density-lipoprotein-cholesterol-lowering-therapy-in-the-primary-prevention-of-cardiovascular-disease
- 34.Alberta Ministry of Health Alberta interactive drug benefit list (iDBL). Alberta blue cross. 2023. https://www.ab.bluecross.ca/dbl/idbl_main1.php
- 35.Chou R., Dana T., Blazina I., Daeges M., Jeanne T.L. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US preventive services Task Force. JAMA. 2016;316:2008–2024. doi: 10.1001/jama.2015.15629. [DOI] [PubMed] [Google Scholar]
- 36.MIC medical imaging. CT - computed tomography. MIC. 2017. https://www.mic.ca/for-patients/procedure-information/ct-computed-tomography/
- 37.Lee K.K., Cipriano L.E., Owens D.K., Go A.S., Hlatky M.A. Cost-effectiveness of using high-sensitivity C-reactive protein to identify intermediate- and low-cardiovascular-risk individuals for statin therapy. Circulation. 2010;122:1478–1487. doi: 10.1161/CIRCULATIONAHA.110.947960. [DOI] [PubMed] [Google Scholar]
- 38.Di Tanna G.L., Urbich M., Wirtz H.S., et al. Health state utilities of patients with heart failure: a systematic literature review. Pharmacoeconomics. 2021;39:211–229. doi: 10.1007/s40273-020-00984-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Betts M.B., Rane P., Bergrath E., et al. Utility value estimates in cardiovascular disease and the effect of changing elicitation methods: a systematic literature review. Health Qual Life Outcomes. 2020;18:251. doi: 10.1186/s12955-020-01407-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Richardson L. Radiation exposure and diagnostic imaging. J Am Acad Nurse Pract. 2010;22:178–185. doi: 10.1111/j.1745-7599.2010.00494.x. [DOI] [PubMed] [Google Scholar]
- 41.Kim K.P., Einstein A.J., Berrington de González A. Coronary artery calcification screening: estimated radiation dose and cancer risk. Arch Intern Med. 2009;169:1188–1194. doi: 10.1001/archinternmed.2009.162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Husereau D., Drummond M., Augustovski F., et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 explanation and elaboration: a report of the ISPOR CHEERS II Good Practices Task Force. Value Health. 2022;25:10–31. doi: 10.1016/j.jval.2021.10.008. [DOI] [PubMed] [Google Scholar]
- 43.Canada’s Drug and Health Technology Agency Guidelines for the economic evaluation of health technologies: Canada — 4th edition. CADTH. 2017. https://www.cadth.ca/guidelines-economic-evaluation-health-technologies-canada-4th-edition
- 44.Fontrier A.-M., Kanavos P. Do reimbursement recommendations by the Canadian Agency for Drugs and Technology in Health Translate into coverage decisions for orphan drugs in the Canadian Province of Ontario? Value Health. 2023;26:1011–1021. doi: 10.1016/j.jval.2023.02.013. [DOI] [PubMed] [Google Scholar]
- 45.Briggs A.H., Weinstein M.C., Fenwick E.A.L., et al. Model parameter estimation and uncertainty analysis: a report of the ISPOR-SMDM modeling good Research practices task force Working Group-6. Med Decis Making. 2012;32:722–732. doi: 10.1177/0272989X12458348. [DOI] [PubMed] [Google Scholar]
- 46.van Kempen B.J.H., Spronk S., Koller M.T., et al. Comparative effectiveness and cost-effectiveness of computed tomography screening for coronary artery calcium in asymptomatic individuals. J Am Coll Cardiol. 2011;58:1690–1701. doi: 10.1016/j.jacc.2011.05.056. [DOI] [PubMed] [Google Scholar]
- 47.van Kempen B.J.H., Ferket B.S., Steyerberg E.W., Max W., Myriam Hunink M.G., Fleischmann K.E. Comparing the cost-effectiveness of four novel risk markers for screening asymptomatic individuals to prevent cardiovascular disease (CVD) in the US population. Int J Cardiol. 2016;203:422–431. doi: 10.1016/j.ijcard.2015.10.171. [DOI] [PubMed] [Google Scholar]
- 48.Spatz E.S., Montori V.M. Primary prevention with statins: strategies to support shared decision-making. Curr Cardiovasc Risk Rep. 2017;11:29. [Google Scholar]
- 49.Collins R., Reith C., Emberson J., et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532–2561. doi: 10.1016/S0140-6736(16)31357-5. [DOI] [PubMed] [Google Scholar]
- 50.Wang N., Woodward M., Huffman M.D., Rodgers A. Compounding benefits of cholesterol-lowering therapy for the reduction of major cardiovascular events: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2022;15 doi: 10.1161/CIRCOUTCOMES.121.008552. [DOI] [PubMed] [Google Scholar]
- 51.Gupta A., Thompson D., Whitehouse A., et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind Placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017;389:2473–2481. doi: 10.1016/S0140-6736(17)31075-9. [DOI] [PubMed] [Google Scholar]
- 52.Pedro-Botet J., Rubiés-Prat J. Statin-associated muscle symptoms: beware of the nocebo effect. Lancet. 2017;389:2445–2446. doi: 10.1016/S0140-6736(17)31163-7. [DOI] [PubMed] [Google Scholar]
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