A Cost-Effectiveness Analysis of Biomarkers for Risk Prediction in Atrial Fibrillation.

RATIONALE: Atrial fibrillation (AF) is associated with an increased risk of thromboembolism. This risk is currently assessed with scoring systems based on clinical characteristics. However, these tools have limited prognostic performance. Circulating biomarkers are proposed for improved prediction of major clinical events and individualization of treatments in patients with AF. OBJECTIVE: The aim was to assess the cost-effectiveness of precision medicine (PM), i.e., the use of combined biomarkers and clinical variables, in comparison to standard of care (SOC) for risk stratification in a hypothetical cohort of AF patients at risk of stroke. METHODS: A Markov cohort model was developed to evaluate the costs and quality-adjusted life-years (QALYs) of PM compared to SOC, over 20 years using a Canadian healthcare system perspective. RESULTS: PM decreased the mean per-patient overall costs by 7% ($94,932 vs $102,057 [Canadian dollars], respectively) and increased the QALYs by 12% (8.77 vs 7.68 QALYs, respectively). The calculated incremental cost-effectiveness ratio was negative, indicating that PM is an economically dominant strategy. These results were robust to one-way and probabilistic sensitivity analyses. CONCLUSION: PM compared to SOC is economically dominant and is projected to generate cost savings.

Trajectories of systemic agent use and associated depression- and anxiety-related health care costs among patients with psoriasis.

Background: Systemic treatment patterns and related mental health disorders and economic burden among patients with psoriasis are largely unknown. Objective: To assess systemic treatment patterns and associated depression and anxiety-related health care costs among patients with psoriasis initiating a conventional systemic treatment (CST). Methods: Using a retrospective cohort design with sequence and cluster analyses, we assessed systemic treatment trajectories (CST and tumor necrosis factor inhibitors or ustekinumab, [TNFi/UST]) over a 2-year period following CST initiation. We compared health care costs between trajectories using 2-part models. Results: We included 781 patients and identified 8 trajectories: persistent methotrexate users, persistent acitretin users, early CST discontinuation, late methotrexate discontinuation, switch to TNFi/UST, adding TNFi/UST, discontinuation then restart on methotrexate, and discontinuation then restart on acitretin or multiple CST switches. Overall, 165 (21%) patients incurred depression- and anxiety-related health care costs (median annual cost, CAN$56; quartiles, $14-$127). Compared with persistent methotrexate users, adding a TNFi/UST (cost ratio, 3.63; 95% CI, 1.47-5.97) and discontinuation then restart on acitretin or multiple switches between systemic agents (cost ratio, 13.3; 95% CI 5.76-22.47) had higher costs. Limitations: Trajectory misclassification may have occured. These date represent an association, and causality cannot be inferred, particularly given the risk of confounding. Conclusion: Depression- and anxiety-related health care costs were high among patients adding TNFi/UST and those discontinuing then restarting on acitretin or experiencing multiple switches between systemic agents.

Sex Differences in the Patterns of Systemic Agent use Among Patients With Psoriasis: A Retrospective Cohort Study in Quebec, Canada.

Background: Sex differences exist in psoriasis manifestation and expectations from treatment with systemic agents, including, conventional systemic agents (CSA) and tumor necrosis factor inhibitors or ustekinumab (TNFi/UST). However, sex differences in patterns of systemic agent use, such as CSA discontinuation and switch from CSA to TNFi/UST have not been examined. Objectives: To assess sex differences in patterns of CSA use and identify factors associated with switch to (or add) a TNFi/UST and those associated with CSA discontinuation. Methods: We conducted a retrospective cohort study using the Quebec health administrative databases. We included patients with psoriasis initiating a CSA in 2002-2015. We excluded patients with a psoriasis diagnosis in the 3 years prior to the first diagnosis date between 2002 and 2015, and those with a systemic agent dispensation in the year prior to that date. We used Cox regression models with the Least Absolute Shrinkage and Selection Operator method to identify factors associated with Switch/add TNFi/UST, and those associated with CSA discontinuation. Separate analyses were performed for male and female patients. Results: We included 1,644 patients (55.7% females, mean age 60.3 years), among whom 60.4% discontinued their CSA and 7.4%, switched/added TNFi/UST (3.4% switched and 4.0% added) within a median of 0.78 years of follow-up. Among male and female patients, rates of Switch/add TNFi/UST per 1,000 person-year were 49.1 and 41.0 and rates of CSA discontinuation were 381.2 and 352.8. Clinical obesity in male patients (HR 3.53, 95% CI 1.20-10.35), and adjustment/somatoform/dissociative disorders (HR 3.17, 95% CI 1.28-7.85) and use of nonsteroidal anti-inflammatory drugs (HR 2.70, 95% CI 1.56-4.70) in female patients were associated with Switch/add TNFi/UST. Male patients followed by a rheumatologist (HR 0.66, 95% CI 0.46-0.94) and those with a prior hospitalization (HR 0.70, 95% CI 0.57-0.87) were at lower risk of CSA discontinuation, while those initiated on acitretin (vs methotrexate) were at higher risk to discontinue their CSA (HR 1.61, 95% CI 1.30-2.01). Female patients with rheumatoid arthritis comorbidity (HR 0.69, 95% CI 0.51-0.93), those with a dispensed lipid-lowering agent (HR 0.72, 95% CI 0.59-0.88) and hypoglycemic agent (HR 0.75, 95% CI 0.57-0.98) and those initiated on methotrexate (vs all other CSAs) were less likely to discontinue their CSA. Male and female patients entering the cohort between 2011 and 2015 were at reduced risk of CSA discontinuation compared to those entering the cohort before 2011. Conclusion: Most male and female patients discontinued their CSA within 1 year of follow-up. Our study highlighted sex differences in patients' characteristics associated with switch/add a TNFi/UST and CSA discontinuation; treatment switch and discontinuation may be indications of treatment failure in most patients.

Domperidone increases harmful cardiac events in Parkinson's disease: A Bayesian re-analysis of an observational study.

OBJECTIVES: To assess the risks of ventricular tachyarrhythmia/sudden cardiac death (VT/SCD) with domperidone use in Parkinson's disease (PD). STUDY DESIGNS AND SETTINGS: Using Bayesian methods, results from an observationalstudy were combined with prior beliefs to calculate posterior probabilities of increasedrelative risk (RR)) of VT/SCD with use of domperidone compared to non-use and ofharm, defined as risk exceeding 15%. The analyses were carried with normallydistributed priors (log (RR)): uninformative (N(0,10)) or informative (N(0.53,179)),derived from a meta-analysis (OR (95%CI):1.70 (1.47-1.97)). Sensitivity analyses used:different priors' strengths, different priors, and Bayesian meta-analysis RESULTS: The uninformative prior yielded a RR: 1.23 (95% credible interval (CrI):0.94-1.62), like the published frequentist RR: 1.22 (95% CI:0.99-1.50), with 69% probabilityof harm. With an informative prior weighted at 100%, 50% and 10%, the RR were 1.63(1.41-1.88), 1.57 (1.31-1.91) and 1.39 (1.10-1.93), respectively. The correspondingprobabilities of harm were 100%, 99%, and 94%, respectively. CONCLUSION: While both the frequentist and Bayesian approaches with anuninformative prior were unable to reach a definitive conclusion concerning thearrhythmic risk of domperidone in PD patients, the Bayesian analysis with informativepriors showed a high probability of increased risk that was robust to multiple priorsensitivity analyses.

Cost-effectiveness of low-dose colchicine after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

AIMS: In the randomized, placebo-controlled Colchicine Cardiovascular Outcomes Trial (COLCOT) of 4745 patients enrolled within 30 days after myocardial infarction (MI), low-dose colchicine (0.5 mg once daily) reduced the incidence of the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. To assess the in-trial period and lifetime cost-effectiveness of low-dose colchicine therapy compared to placebo in post-MI patients on standard-of-care therapy. METHODS AND RESULTS: A multistate Markov model was developed incorporating the primary efficacy and safety results from COLCOT, as well as healthcare costs and utilities from the Canadian healthcare system perspective. All components of the primary outcome, non-cardiovascular deaths, and pneumonia were included as health states in the model as both primary and recurrent events. In the main analysis, a deterministic approach was used to estimate the incremental cost-effectiveness ratio (ICER) for the trial period (24 months) and lifetime (20 years). Over the in-trial period, the addition of colchicine to post-MI standard-of-care treatment decreased the mean overall per-patient costs by 47%, from $502 to $265 Canadian dollar (CAD), and increased the quality-adjusted life years (QALYs) from 1.30 to 1.34. The lifetime per-patient costs were further reduced (69%) and QALYs increased with colchicine therapy (from 8.82 to 11.68). As a result, both in-trial and lifetime ICERs indicated colchicine therapy was a dominant strategy. CONCLUSION: Cost-effectiveness analyses indicate that the addition of colchicine to standard-of-care therapy after MI is economically dominant and therefore generates cost savings.

Pharmacologically pertinent period of effect (PPPE).

BACKGROUND: The period of time during which a patient is exposed to a drug does not necessarily correspond to the period during which the drug produces the adverse effect under consideration. We propose the term Pharmacologically pertinent period of effect (PPPE) to address this time window. We explored the PPPE in light of the rofecoxib saga. METHODS: We identified the observational database studies of rofecoxib at doses 25 and 50 mg daily and thromboembolic events. We also obtained the Kaplan-Meier curves of Vioxx Gastrointestinal Outcomes Research trial (VIGOR) and Adenomatous Polyp Prevention on Vioxx (APPROVE) trials. RESULTS: We found seven observational studies with nine analyses. All the studies only looked at current exposure. At the dose of 25 mg, only three of nine analyses were barely statistically significant. At the dose of 50 mg, the risk ratios were much higher. The visual inspection of the Kaplan-Meier curves shows that in the APPROVE trial (25 mg), the placebo and rofecoxib curves start separating to become statistically significantly different only after 36 months. In contrast the VIGOR (50 mg), curves start separating very early and the divergence increases after 8 months. DISCUSSION: The 50 mg observational studies, looking at current exposure, correctively identified the almost immediate increase in risk evident in the VIGOR Kaplan-Meier curves. The absence of an immediate increase in risk shown by the APPROVE trial was also correctively identified by most observational 25 mg studies. To our knowledge no observational study was done on the long-term cardiac toxicity of the 25-mg dose. It would thus appear that the two doses of rofecoxib have different PPPEs.

Value of a Hypothetical Pharmacogenomic Test for the Diagnosis of Statin-Induced Myopathy in Patients at High Cardiovascular Risk.

We recently conducted two economic evaluations of a hypothetical pharmacogenomic test for statin-induced myopathy (SIM) in patients at high cardiovascular risk. Although the models differed in modeling technique and data inputs, both yielded similar results. We believe our approach to assessing the economic value of a diagnostic test was highly advantageous as it characterized the complete range of false-negative and false-positive test outcomes. We used a broad interpretation of test parameters that reflected physician and patient behavioral responses to the test results and accounted for patient adherence to treatment. Both economic evaluations indicated that a highly accurate pharmacogenomic test for SIM would provide a positive incremental net monetary benefit (INMB) for a provincial payer in Canada. However, the value of the test would depend on its ability to accurately diagnose patients when they experience musculoskeletal pain symptoms and guide patients with a test result indicating no SIM to adhere to treatment. Interestingly, our results indicated that a highly inaccurate test would still yield a positive INMB. We found this surprising result was driven by the imbalance of the risk of cardiovascular events outweighing the risk of rhabdomyolysis in patients at high cardiovascular risk. A highly accurate pharmacogenomic test for SIM in patients at high cardiovascular risk would provide economic value for payers. However, the economic and clinical value of the test would depend on the credibility of the test results and their success in influencing patients without SIM to adhere to therapy.

Long-term Mortality After Acute Kidney Injury in the Pediatric ICU.

OBJECTIVES: (1) To evaluate the association between acute kidney injury (AKI) in the PICU and long-term mortality and (2) to determine the extent to which adding the urine output (UO)-defined AKI alters the association. METHODS: A 2-center retrospective cohort study of children (≤18 years old) admitted to the PICU between 2003 and 2005 for noncardiac surgery, with follow-up until 2010. Patients with end stage renal disease, no provincial health insurance number, who died during hospitalization, or could not be linked to administrative data were excluded. One hospitalization per patient was included. AKI was defined by using serum creatinine criteria and/or UO criteria. Mortality was ascertained by using administrative data. Cox regression analysis was performed to evaluate the association between AKI and long-term mortality. RESULTS: The study population included 2041 patients (55.7% male, mean admission age 6.5 ± 5.8 years). Of 2041 hospital survivors, 9 (0.4%) died within 30 days, 51 (2.5%) died within 1 year, and 118 (5.8%) died within 5 to 7 years postdischarge. AKI was independently associated with 5- to 7-year mortality (adjusted hazard ratio [95% confidence interval]: 3.10 [1.46-6.57] and 3.38 [1.63-7.02], respectively). Including UO did not strengthen the association. CONCLUSIONS: AKI is associated with 5- to 7-year mortality. Because this is an observational study we cannot determine if AKI is causative of mortality or of the pathophysiology. However, patients with AKI represent a high-risk group. It is reasonable that these patients be considered for targeted follow-up until future researchers better elucidate these relationships.

Healthcare Utilization after Acute Kidney Injury in the Pediatric Intensive Care Unit.

BACKGROUND AND OBJECTIVES: Little is known about the long-term burden of AKI in the pediatric intensive care unit. We aim to evaluate if pediatric AKI is associated with higher health service use post-hospital discharge. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective cohort study of children (≤18 years old) admitted to two tertiary centers in Montreal, Canada. Only the first admission per patient was included. AKI was defined in two ways: serum creatinine alone or serum creatinine and/or urine output. The outcomes were 30-day, 1-year, and 5-year hospitalizations, emergency room visits, and physician visits per person-time using provincial administrative data. Univariable and multivariable Poisson regression were used to evaluate AKI associations with outcomes. RESULTS: A total of 2041 children were included (56% male, mean admission age 6.5±5.8 years); 299 of 1575 (19%) developed AKI defined using serum creatinine alone, and when urine output was included in the AKI definition 355 of 1622 (22%) children developed AKI. AKI defined using serum creatinine alone and AKI defined using serum creatinine and urine output were both associated with higher 1- and 5-year hospitalization risk (AKI by serum creatinine alone adjusted relative risk, 1.42; 95% confidence interval, 1.12 to 1.82; and 1.80; 1.54 to 2.11, respectively [similar when urine output was included]) and higher 5-year physician visits (adjusted relative risk, 1.26; 95% confidence interval, 1.14 to 1.39). AKI was not associated with emergency room use after adjustments. CONCLUSIONS: AKI is independently associated with higher hospitalizations and physician visits postdischarge.

A Discrete Event Simulation Model to Assess the Economic Value of a Hypothetical Pharmacogenomics Test for Statin-Induced Myopathy in Patients Initiating a Statin in Secondary Cardiovascular Prevention.

BACKGROUND: Statin (HMG-CoA reductase inhibitor) therapy is the mainstay dyslipidemia treatment and reduces the risk of a cardiovascular (CV) event (CVE) by up to 35%. However, adherence to statin therapy is poor. One reason patients discontinue statin therapy is musculoskeletal pain and the associated risk of rhabdomyolysis. Research is ongoing to develop a pharmacogenomics (PGx) test for statin-induced myopathy as an alternative to the current diagnosis method, which relies on creatine kinase levels. The potential economic value of a PGx test for statin-induced myopathy is unknown. METHODS: We developed a lifetime discrete event simulation (DES) model for patients 65 years of age initiating a statin after a first CVE consisting of either an acute myocardial infarction (AMI) or a stroke. The model evaluates the potential economic value of a hypothetical PGx test for diagnosing statin-induced myopathy. We have assessed the model over the spectrum of test sensitivity and specificity parameters. RESULTS: Our model showed that a strategy with a perfect PGx test had an incremental cost-utility ratio of 4273 Canadian dollars ($Can) per quality-adjusted life year (QALY). The probabilistic sensitivity analysis shows that when the payer willingness-to-pay per QALY reaches $Can12,000, the PGx strategy is favored in 90% of the model simulations. CONCLUSION: We found that a strategy favoring patients staying on statin therapy is cost effective even if patients maintained on statin are at risk of rhabdomyolysis. Our results are explained by the fact that statins are highly effective in reducing the CV risk in patients at high CV risk, and this benefit largely outweighs the risk of rhabdomyolysis.

Rationale, design, and preliminary results of the Quebec Warfarin Cohort Study.

Over- and undercoagulation with warfarin are associated with hemorrhagic and thromboembolic events, respectively. Genetic and clinical factors affect warfarin response, and the causes of this variability remain unclear. We present descriptive statistics and test for predictors of poor anticoagulation control. The Quebec Warfarin Cohort (QWC) comprises 1059 new warfarin users, with prospective follow-up using telephone questionnaires every 3 months for 1 year, and using healthcare administrative databases (RAMQ and Med-Echo) for 5 years prior to cohort entry and up to 10 years following active patient participation. Genetic material was collected, and genotyping of CYP2C9 and VKORC1 genes was conducted. Measured outcomes included the percentage of time patients spent within therapeutic range, anticoagulation control, warfarin dose, bleeding, and thromboembolic events. We report baseline characteristics and outcomes after 1 year of follow-up. Poor anticoagulation control was defined as time in therapeutic range <60% in the 3- to 12-month interval. Participants had a mean age of 71 years, and 62% were men. The most common indication for warfarin was atrial fibrillation (87%). Mean time in therapeutic range was 56% (±25%) in the 3 months following warfarin initiation, and 70% (±21%) in the 3- to 12-month interval. During follow-up, the rate of stroke or systemic embolism was 1.8 events per 100 person-years; for major bleeding events, 3.3 events per 100 person-years. Independent predictors of poor anticoagulation control were chronic kidney disease, heart failure, dyslipidemia, and age. The QWC represents a good research cohort to investigate clinical and genetic factors in a warfarin-anticoagulated population.

The impact of renal protection clinics on prescription of and adherence to cardioprotective drug therapy in chronic kidney disease patients.

Background: The aim of this study was to assess the impact of follow-up in renal protection clinics on the prescription of and adherence to cardioprotective drugs in patients with chronic kidney disease (CKD). Methods: We studied stage 4 and 5 CKD patients who initiated follow-up in three renal protection clinics. The prescription pattern of antihypertensive agents (AHA) and lipid-lowering agents (LLAs) was measured as the percentage of patients who are prescribed the agents of interest at a given time. Adherence to drug therapy was defined as the percentage of days, during a pre-defined observation period, in which patients have an on-hand supply of their prescribed medications. Results: A total of 259 CKD patients were enrolled and followed for up to 1 year after referral to renal protection clinics. There was a significant increase in the prescription of angiotensin-converting enzyme inhibitors (34-39%), angiotensin II receptor blockers (11-14%), beta-blockers (40-51%), calcium channel blockers (62-74%), diuretics (66-78%) and LLAs (39-47%) during follow-up in the renal protection clinic compared with baseline (P-values <0.01 for all comparisons). The proportions of patients with good (≥ 80%) and poor (< 80%) adherence to AHA (P = 0.41) and LLAs (P = 0.11) were similar in the year preceding and the year following the first visit to the renal protection clinics. Conclusion: Our results suggest that referral and follow-up in a renal protection clinic may increase the prescription of cardioprotective agents in CKD patients, but does not appear to improve adherence to these medications.

Cost-Effectiveness Analysis of Fosfomycin for Treatment of Uncomplicated Urinary Tract Infections in Ontario.

Background and Objective. Bacterial resistance to antibiotics traditionally used to treat uncomplicated urinary tract infections (uUTIs) is rising in Canada. We compared the cost-per-patient in Ontario of including fosfomycin (an antibiotic with a low resistance profile) as an option for first-line empirical treatment of uUTIs with current cost of treatment with sulfonamides, fluoroquinolones, and nitrofurantoin. Methods. A decision-tree model was used to perform a cost-minimization analysis. All possible outcomes of a uUTI caused by bacterial species treated with either sulfonamides, fluoroquinolones, nitrofurantoin, or fosfomycin were included. Results. In the base case analysis, the cost-per-patient for treating uUTI with fosfomycin was $105.12. This is similar to the cost-per-patient for each of the other currently reimbursed antibiotics (e.g., $96.19 for sulfonamides, $98.85 for fluoroquinolones, and $99.09 for nitrofurantoins). The weighted average cost-per-patient for treating uUTI was not substantially elevated with the inclusion of fosfomycin in the treatment landscape ($98.41 versus $98.29 with and without fosfomycin, resp.). The sensitivity analyses revealed that most (88.34%) of the potential variation in cost was associated with the probability of progressing to pyelonephritis and hospitalization for pyelonephritis. Conclusion. Fosfomycin in addition to being a safe and effective agent to treat uUTI has a low resistance profile, offers a single-dose treatment administration, and is similar in cost to other reimbursed antibiotics.

Use of Continuous Exposure Variables when Examining Dose-Dependent Pharmacological Effects - Application to the Association between Exposure to Higher Statin Doses and the Incidence of Diabetes.

BACKGROUND: Many observational studies have found an association between the exposure to statins and the increased risk of diabetes, mostly through the use of intent-to-treat (ITT) like exposure measure (EM). ITT like EM may not adequately reflect the mechanism of action by which statins could cause diabetes. OBJECTIVES: To determine if continuous EMs can more accurately reflect the mechanism of action by which statins and incidence of diabetes would be associated than ITT like EM. METHODS: We obtained a cohort of 404,129 diabetes-free incident statin users from the Québec public drug insurance plan. Patients dispensed with a drug used in the treatment of diabetes or diagnosed with diabetes within 2-years follow-up were defined as cases. Controls were randomly matched to each case on the index date. Three EMs were tested. EM 1: exposure to a high versus low dose statin at baseline (ITT like); EM 2: cumulative standardized statin dose (cSSD) at the index date; and EM 3: cSSD in the 180 days prior to the index date. The optimal EM was selected based upon each model's Akaike's information criterion (AIC). Conditional logistic regressions were used to calculate conditional OR and model AIC. RESULTS: All three EMs identified an increased risk of diabetes among patients exposed to higher statin doses. Model AIC identified EM 3 as the best EM for this association. CONCLUSIONS: Our results indicate that higher statin doses increase the risk of diabetes but favour a cumulative reversible diabetogenic effect of statins.

Economic Evaluation of a Pharmacogenomics Test for Statin-Induced Myopathy in Cardiovascular High-Risk Patients Initiating a Statin.

BACKGROUND: Statins are the mainstay hypercholesterolemia treatment and reduce the risk of cardiovascular events in patients. However, statin therapy is often interrupted in patients experiencing musculoskeletal pain or myopathy, which are common in this patient group. Currently, the standard tests for diagnosing statin myopathies are difficult to interpret. A pharmacogenomics (PGx) test to diagnose statin-induced myopathy would be highly desirable. METHODS: We developed a Markov state model to assess the cost-effectiveness of a hypothetical PGx test, which aims to identify statin-induced myopathy in high-risk, secondary prevention cardiovascular patients. The alternative strategy hypothesized is that physicians or patients interrupt the statin therapy in the presence of musculoskeletal pain. Our model includes health states specific to the PGx test outcome which assesses the impact of test errors. RESULTS: Assuming a perfect test, the results indicate that the PGx test strategy dominates when the test costs less than CAN$356, when the strategy is cost neutral. These results are robust to deterministic and probabilistic sensitivity analyses. CONCLUSION: Our base-case results show that a PGx test for statin-induced myopathy in a high-risk, secondary prevention of a cardiovascular event population would be a dominant solution for a test cost of CAN$356 or less. Furthermore, the modelling of the complete range of diagnostic test outcomes provide a broader understanding of the economic value of the pharmacogenomics test.

A model to assess the cost-effectiveness of pharmacogenomics tests in chronic heart failure: the case of ivabradine.

Pharmacogenomics (PGx) tests have the potential of improving the effectiveness of expensive new drugs by predicting the likelihood, for a particular patient, to respond to a treatment. The objective of this study was to develop a pharmacoeconomic model to determine the characteristics and the cost-effectiveness of a hypothetical PGx test, which would identify patients who are most likely to respond to an expensive treatment for chronic heart failure. For this purpose, we chose the example of ivabradine. Our results suggest that the use of a PGx test that could select a subgroup of patients to be treated with an expensive drug has the potential to provide more efficient drug utilization.

Maximal expected benefits from lowering cholesterol in primary prevention for a high-risk population.

AIMS: The objective of this study was to estimate the maximal clinical benefit that could be reasonably expected from a cholesterol-lowering intervention. MATERIALS AND METHODS: We used a hypothetical population at high risk of cardiovascular disease events from three risk assessment models including the Framingham risk function, the Score Canada and the Pooled Cohort Risk Assessment Equations. Our source population were all 55-year-old smoking men with diabetes, hypertension and low HDL. From this population, we identified two different subpopulations named "high" and "low", referring to their cholesterol levels which were set at 8.60 and 4.14 mmol/L respectively. Both subpopulations were identified for each risk assessment model in order to estimate the maximal impact of lowering cholesterol on cardiovascular disease events. RESULTS: Our extrapolations estimated that the maximal theoretical efficacy of a cholesterol-lowering intervention corresponds to a risk ratio ranging between 0.46 and 0.66 over a 10-year period. The number of events prevented during this period were between 21 and 29 per 100 patients which corresponds to a number needed to treat varying from 3.47 to 4.76. CONCLUSIONS: Our estimation showed the maximal clinical benefit that could be reasonably expected by an intervention that would lower total cholesterol in high-risk patients.