Impact of anti-rheumatic treatment on the individual components of the ACR composite score in patients with rheumatoid arthritis: real-world data.

OBJECTIVES: Standard criteria for measuring treatment efficacy in patients with rheumatoid arthritis (RA) include American College of Rheumatology (ACR) response rates, which require meeting a threshold of ≥20/50/70% improvement in several physician- and patient-reported measures. We aimed to evaluate the impact of csDMARDs, TNF inhibitors (TNFi), and tofacitinib (TOFA) on ACR components in real-life practice. METHODS: Clinical data of RA patients with a CDAI >10 at the time they started a treatment were pooled from two registries: Ontario Best Practices Research Initiative (OBRI) and RHUMADATA. Endpoints included proportions of patients achieving: ACR20/50/70 responses, ≥20/50/70% improvements and mean percentage improvement in individual ACR components at Month 6. We also adjusted for potential confounders to compare impact of these medications on outcomes of interest. RESULTS: A total of 669 patients were included (csDMARD, n=157, TNFi, n=252; TOFA, n=260). An overall higher proportion in all three-medication groups achieved ≥20/50/70% improvement in primary ACR components vs. secondary components. Among secondary components, ≥20/50/70% improvement rates were numerically highest for PhGA and lowest for HAQ-DI and pain. Among ACR20/50/70 responders for all medications, the mean percentage improvement was more than 80% for primary components, and ranged from 30% to 80% for secondary components. A significantly lower proportion of patients in TNFi group achieved to at least 50% improvement in pain compared to TOFA after adjusting. CONCLUSIONS: In this real-world practice, physician-reported measures contribute slightly more to overall ACR20/50/70 responses. Pain was the most important factor in achieving an ACR50 TOFA users, possibly reflecting the different effects of JAKi on pain.

Which advanced treatment should be used following the failure of a first-line anti-TNF in patients with rheumatoid arthritis? 15 years of evidence from the Quebec registry RHUMADATA.

BACKGROUND: Since 2000, advanced therapies (AT) have revolutionized the treatment of moderate to severe rheumatoid arthritis (RA). Randomized control trials as well as observational studies together with medication availability often determine second-line choices after the failure of first Tumor Necrosis Factor inhibitors (TNFi). This led to the observation that specific sequences provide better long-term effectiveness. We investigated which alternative medication offers the best long-term sustainability following the first TNFi failure in RA. METHODS: Data were extracted from RHUMADATA from January2007. Patients were followed until treatment discontinuation, loss to follow-up, or November 25, 2022. Kaplan-Meier and Cox regression models were used to compare discontinuation between groups. Missing data were imputed, and propensity scores were computed to reduce potential attribution bias. Complete, unadjusted, and propensity score-adjusted imputed data analyses were produced. RESULTS: 611 patients (320 treated with a TNFi and 291 treated with molecules having another mechanism of action (OMA)) were included. The mean age at diagnosis was 44.5 and 43.9 years, respectively. The median retention was 2.84 and 4.48 years for TNFi and OMAs groups. Using multivariable analysis, the discontinuation rate of the OMA group was significantly lower than TNFi (adjHR: 0.65; 95% CI: 0.44-0.94). This remained true for the PS-adjusted MI Cox models. In a stratified analysis, rituximab (adjHR: 0.39; 95% CI: 0.18-0.84) had better retention than TNFi after adjusting for patient characteristics. CONCLUSION: Switching to an OMA, especially rituximab, in patients with failure to a first TNFi appears to be the best strategy as a second line of therapy.

Residual Disease Activity in Canadian Patients With Psoriatic Arthritis Treated With Advanced Therapies: Results From a Multiregistry Analysis (UNISON-PsA).

OBJECTIVE: Although patient outcomes in psoriatic arthritis (PsA) have improved with the advent of advanced therapies, there remains a high unmet need to treat residual disease activity. The objective of the current study was to quantify residual disease activity and burden of disease in Canadian patients with PsA. METHODS: This was a multiregion, observational, retrospective analysis of patient data extracted from the Rhumadata and the International Psoriasis and Arthritis Research Team (IPART) registries, analyzing deidentified data from patients who had initiated advanced therapy for the treatment of PsA between January 2010 and December 2019. The primary endpoint was the proportion of patients failing to achieve minimal disease activity (MDA) within 6 months; secondary endpoints included clinical and patient-reported burden of disease. Descriptive statistics included summaries by region, treatment class, and number of prior advanced therapies. RESULTS: One thousand five hundred ninety-six patients were included. The proportions of patients who failed to achieve MDA within 6 months of an advanced therapy were 64.8% in Ontario, 68.3% in Western Canada, 74.8% in Quebec, and 75% in the Atlantic/East region. Failure to achieve MDA was higher among patients receiving an IL-17i compared with a TNFi in all regions except the Atlantic/East. Between 73.2% and 78.6% of patients reported pain at 6 months, and continuing functional impairment varied from 24% in the West to 83.3% in the Atlantic/East. CONCLUSION: There is substantial burden and unmet need for improved therapies for Canadians with PsA. There is a wide regional variation in outcomes that requires further assessment.

Discontinuation of tofacitinib and TNF inhibitors in patients with rheumatoid arthritis: analysis of pooled data from two registries in Canada.

OBJECTIVES: The similarity in retention of tumour necrosis factor inhibitors (TNFi) and tofacitinib (TOFA) was previously reported separately by the Ontario Best Practices Research Initiative and the Quebec cohort Rhumadata. However, because of small sample sizes in each registry, we aimed to confirm the findings by repeating the analysis of discontinuation of TNFi compared with TOFA, using pooled data from both these registries. DESIGN: Retrospective cohort study. SETTING: Pooled data from two rheumatoid arthritis (RA) registries in Canada. PARTICIPANTS: Patients with RA starting TOFA or TNFi between June 2014 and December 2019 were included. A total of 1318 patients were included TNFi (n=825) or TOFA (n=493). OUTCOME MEASURES: Time to discontinuation was assessed using Kaplan-Meier survival and Cox proportional hazards regression analysis. Propensity score (PS) stratification (deciles) and PS weighting were used to estimate treatment effects. RESULTS: The mean disease duration in the TNFi group was shorter (8.9 years vs 13 years, p<0.001). Prior biological use (33.9% vs 66.9%, p<0.001) and clinical disease activity index (20.0 vs 22.1, p=0.02) were lower in the TNFi group.Discontinuation was reported in 309 (37.5%) and 181 (36.7%) TNFi and TOFA patients, respectively. After covariate adjustment using PS, there was no statistically significant difference between the two groups in discontinuation due to any reason HR=0.96 (95% CI 0.78 to 1.19, p=0.74)) as well as discontinuation due to ineffectiveness only HR=1.08 (95% CI 0.81 to 1.43, p=0.61)).TNFi users were less likely to discontinue due to adverse events (AEs) (adjusted HRs: 0.46, 95% CI 0.29 to 0.74; p=0.001). Results remained consistent for firstline users. CONCLUSIONS: In this pooled real-world data study, the discontinuation rates overall were similar. However, discontinuation due to AEs was higher in TOFA compared with TNFi users.

Heterogeneity in Patient Characteristics and Differences in Treatment Across 4 Canadian Rheumatoid Arthritis Cohorts.

OBJECTIVE: To compare clinical characteristics and treatment of patients with rheumatoid arthritis (RA) across 4 Canadian cohorts. METHODS: The 4 longitudinal cohorts included the following: the Canadian Early Arthritis Cohort (CATCH; n = 2878), Ontario Best Practices Research Initiative (OBRI; n = 3734), RHUMADATA (Quebec, n = 2890), and the Rheum4U Precision Health Registry (Calgary, Alberta, n = 709). Data were from cohort inception (range 1998-2016) to 2020. Clinical characteristics and drug treatments were summarized descriptively. RESULTS: In total, 10,211 patients with RA were included. The percentage of patients who entered the cohort with early RA (2 yrs of disease at enrollment) ranged from 29% (Rheum4U) to 100% (CATCH). Mean age (55 yrs), sex (74% female), and seropositivity (69%) were similar between cohorts. At the time of initial disease-modifying antirheumatic drug (DMARD) use, median Disease Activity Score in 28 joints (DAS28) varied, ranging from 2.99 (Rheum4U) to 5.19 (CATCH), but were more similar at the time of the first DMARD switch (range 3.57-5.03), first biologic (bDMARD) or targeted synthetic DMARD (tsDMARD) use (range 4.01-4.67), and second bDMARD or tsDMARD (range 3.71-4.39). The initial DMARD was most commonly methotrexate, either in monotherapy (32%, range 18-40%) or dual therapy (34%, range 29-42%). The first DMARD switch was to another DMARD monotherapy in 20% (range 10-32%), dual therapy in 49% (range 39-56%), and bDMARD or tsDMARD in 24% (range 15-28%). The first bDMARD was an anti-tumor necrosis factor in 79% (range 78-82%). CONCLUSION: Canadian RA cohorts demonstrate some heterogeneity in treatment, which could reflect differences in inclusion criteria, calendar year, or regional differences. This project is a first step toward conducting harmonized analyses across Canadian RA cohorts.

Cost-utility analysis of second-line therapy with rituximab compared to tumour necrosis factor inhibitors in rheumatoid arthritis.

OBJECTIVE: To compare direct costs and treatment utility associated with the second-line therapy with rituximab and tumour necrosis factor inhibitors (TNFis) (adalimumab, etanercept, and infliximab) in patients with Rheumatoid Arthritis (RA) using data from a prospective registry. METHODS: Health Assessment Questionnaire Disability Index (HAQ-DI) scores and RA-related healthcare resource utilization data (biologic agents and visits to rheumatologists) were extracted from a registry (Quebec, Canada) for patients with RA (n = 129) who had to discontinue a first-line TNFi and were treated with rituximab, adalimumab, etanercept, or infliximab as the second-line therapy between January 2007 and May 2016. A decision analytic model followed patients for 1 and 6 years. Treatment utility was measured as quality-adjusted life-years (QALYs) gained, which were calculated from HAQ-DI scores observed over the follow-up time. Quebec 2020 unit costs (Canadian Dollars, $) were used to value healthcare resource consumption. A probabilistic sensitivity analysis was performed with 10,000 Monte Carlo simulations to assess uncertainty around point-estimates of cost-utility. RESULTS: Over 1-year, rituximab and etanercept resulted in the effectiveness of 0.80 QALYs gained at the cost of $14,291and $18,880, respectively, and were dominant (i.e. associated with lower costs and more QALYs gained) compared to adalimumab (0.79 QALYs, $18,825) and infliximab (0.76 QALYs, $20,158). Over 6-years, rituximab (4.42 QALYs, $82,402) was dominant compared to adalimumab (4.30 QALYs, $101,420), etanercept (4.02 QALYs, $99,191), and infliximab (3.71 QALYs, $100,396). In the probabilistic analysis, rituximab was dominant over adalimumab, etanercept, and infliximab with the probability of 0.51, 0.62, and 0.65, respectively. CONCLUSION: Real-world data revealed differences between alternative biologic agents used as the second-line therapy in terms of both treatment costs for the healthcare system and utility of treatment for patients. Therefore, new guidelines on the order of selecting and switching biologic agents should be explored.

Persistence rates of abatacept and TNF inhibitors used as first or second biologic DMARDs in the treatment of rheumatoid arthritis: 9 years of experience from the Rhumadata® clinical database and registry.

BACKGROUND: Treatment persistence is an important consideration when selecting a therapy for chronic conditions such as rheumatoid arthritis (RA). We assessed the long-term persistence of abatacept or a tumor necrosis factor inhibitor (TNFi) following (1) inadequate response to a conventional synthetic disease-modifying antirheumatic drug (first-line biologic agent) and (2) inadequate response to a first biologic DMARD (second-line biologic agent). METHODS: Data were extracted from the Rhumadata® registry for patients with RA prescribed either abatacept or a TNFi (adalimumab, certolizumab, etanercept, golimumab, or infliximab) who met the study selection criteria. The primary outcome was persistence to abatacept and TNFi treatment, as first- or second-line biologics. Secondary outcomes included the proportion of patients discontinuing therapy, reasons for discontinuation, and predictors of discontinuation. Persistence was defined as the time from initiation to discontinuation of biologic therapy. Baseline characteristics were compared using descriptive statistics; cumulative persistence rates were estimated using Kaplan-Meier methods, compared using the log-rank test. Multivariate Cox proportional hazard models were used to compare the persistence between treatments, controlling for baseline covariates. RESULTS: Overall, 705 patients met the selection criteria for first-line biologic agent initiation (abatacept, n = 92; TNFi, n = 613) and 317 patients met the criteria for second-line biologic agent initiation (abatacept, n = 105; TNFi, n = 212). There were no clinically significant differences in baseline characteristics between the treatments with either first- or second-line biologics. Persistence was similar between the first-line biologic treatments (p = 0.7406) but significantly higher for abatacept compared with TNFi as a second-line biologic (p = 0.0001). Mean (SD) times on first-line biologic abatacept and TNFi use were 4.53 (0.41) and 5.35 (0.20) years, and 4.80 (0.45) and 2.82 (0.24) years, respectively, as second-line biologic agents. The proportion of patients discontinuing abatacept and TNFi in first-line was 51.1% vs. 59.5% (p = 0.1404), respectively. In second-line, it was 57.1% vs. 74.1% (p = 0.0031). The main reasons for stopping both treatments were inefficacy and adverse events. CONCLUSIONS: Abatacept and TNFi use demonstrated similar persistence rates at 9 years as a first-line biologic agent. As a second-line biologic agent, abatacept had better persistence rates over a TNFi.

Hypomagnesemia During Teriparatide Treatment in Osteoporosis: Incidence and Determinants.

In our clinical experience, we have encountered patients who developed hypomagnesemia after the introduction of teriparatide. Some trials have reported hypomagnesemia as an adverse event during teriparatide treatment, but this issue had never been studied specifically. Our objective was twofold: 1) determine the incidence of hypomagnesemia (serum magnesium <0.7 mmol/L) associated with teriparatide in a retrospective cohort and 2) identify the predisposing factors to hypomagnesemia in this cohort. We reviewed the files of 53 patients treated for severe osteoporosis with teriparatide for 6 to 24 months between May 2008 and January 2016. Serum magnesium levels were measured at 0, 3, 6, 12, 18, and 24 months. In the full cohort, we observed an average decrease of serum magnesium of 0.075 mmol/L, 0.069 mmol/L, 0.085 mmol/L, 0.086 mmol/L (p < 0.001) at 3, 6, 12 months, and at the end of the treatment, respectively. The cumulative incidence of hypomagnesemia during treatment with teriparatide was 35.9% (19 patients). Patients' older age (71.1 versus 65.1 years; p = 0.05) and lower baseline level of magnesium before teriparatide treatment (0.81 mmol/L versus 0.85 mmol/L; p = 0.03) were significant risk factors for teriparatide-induced hypomagnesemia. The average decrease of serum magnesium was greater in the patients who developed hypomagnesemia compared with normomagnesemic patients at 3 months (0.110 mmol/L versus 0.054 mmol/L; p = 0.02), 6 months (0.139 mmol/L versus 0.036 mmol/L; p < 0.001), and 12 months (0.156 mmol/L versus 0.048 mmol/L; p < 0.001). Serum calcium, creatinine, and parathyroid hormone remained normal throughout the treatment period. We observed a statistically significant decrease in the serum magnesium levels in patients treated with teriparatide for severe osteoporosis. Older age and lower baseline magnesium were significant determinants of hypomagnesemia. Closer monitoring of serum magnesium level should be considered in these patients. © 2018 American Society for Bone and Mineral Research.

Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer.

PURPOSE: Prostate cancer aggressiveness and appropriate therapy are routinely determined following biopsy sampling. Current clinical and pathologic parameters are insufficient for accurate risk prediction leading primarily to overtreatment and also missed opportunities for curative therapy. EXPERIMENTAL DESIGN: An 8-biomarker proteomic assay for intact tissue biopsies predictive of prostate pathology was defined in a study of 381 patient biopsies with matched prostatectomy specimens. A second blinded study of 276 cases validated this assay's ability to distinguish "favorable" versus "nonfavorable" pathology independently and relative to current risk classification systems National Comprehensive Cancer Network (NCCN and D'Amico). RESULTS: A favorable biomarker risk score of ≤0.33, and a nonfavorable risk score of >0.80 (possible range between 0 and 1) were defined on "false-negative" and "false-positive" rates of 10% and 5%, respectively. At a risk score ≤0.33, predictive values for favorable pathology in very low-risk and low-risk NCCN and low-risk D'Amico groups were 95%, 81.5%, and 87.2%, respectively, higher than for these current risk classification groups themselves (80.3%, 63.8%, and 70.6%, respectively). The predictive value for nonfavorable pathology was 76.9% at biomarker risk scores >0.8 across all risk groups. Increased biomarker risk scores correlated with decreased frequency of favorable cases across all risk groups. The validation study met its two coprimary endpoints, separating favorable from nonfavorable pathology (AUC, 0.68; P < 0.0001; OR, 20.9) and GS-6 versus non-GS-6 pathology (AUC, 0.65; P < 0.0001; OR, 12.95). CONCLUSIONS: The 8-biomarker assay provided individualized, independent prognostic information relative to current risk stratification systems, and may improve the precision of clinical decision making following prostate biopsy.

Estimating the benefits of patient and physician adherence to cardiovascular prevention guidelines: the MyHealthCheckup Survey.

BACKGROUND: The management of cardiovascular risk factors such as hypertension and dyslipidemia is poorly described in many communities, and the benefits associated with tighter control remain unknown. We used data from the 2007 MyHealthCheckup survey to document the treatment gaps and estimated the potential benefits of better adherence to recommended guidelines. METHODS: Cardiovascular risk factors, lifestyle habits, and prescribed medications were evaluated among Canadian adults recruited primarily in pharmacies. The Cardiovascular Life Expectancy Model was used to estimate the potential benefits of optimally treating hypertension or dyslipidemia (defined as not smoking, regular physical activity, an acceptable body weight, and maximal medication as needed). RESULTS: Among 2674 screened individuals, 1266 (47%) were receiving pharmacotherapy for either dyslipidemia or hypertension, including 772 (61%) and 656 (63%), respectively, who remained above treatment targets. Among those above lipid or blood pressure targets, 27% and 22%, respectively, were optimally treated. The average increased life expectancy or life-years gained associated with making appropriate lifestyle changes included 2.2 to 4.7 years from smoking cessation, 0.7 to 1.1 years from regular exercise, and 0.4 to 0.7 years from weight reduction. The life-years gained following better risk factor treatment included maximal pharmacotherapy for elevated blood pressure (0.6-0.8), low-density lipoprotein cholesterol (0.5-0.6), and the ratio of total cholesterol to high-density lipoprotein cholesterol (0.3-0.4). Years of life free of cardiovascular disease would be similarly increased. CONCLUSIONS: Better treatment of cardiovascular risk factors could result in a substantial reduction in morbidity and mortality among Canadians. Given current physician prescribing and patient habits, lifestyle modification should be considered a priority before additional medications are prescribed.

Discussing coronary risk with patients to improve blood pressure treatment: secondary results from the CHECK-UP study.

OBJECTIVES: Hypertension is common among patients with dyslipidemia but is often poorly treated. The objective of this analysis was to evaluate how a decision aid, used by primary care physicians to improve lipid therapy, impacted on the treatment of hypertension. STUDY DESIGN: Data were analyzed from patients enrolled in a randomized trial focusing primarily on the treatment of dyslipidemia. Patients received usual care or a coronary risk profile every three months to monitor the risk reduction following lifestyle changes and/or pharmacotherapy to treat dyslipidemia. Hypertension management was assessed based on a post hoc analysis of individuals whose blood pressure exceeded current national hypertension guidelines. RESULTS: There were 2,631 subjects who completed the study. Among 1,352 patients without diagnosed hypertension, 30% were above target on at least three consecutive visits. Among 1,279 individuals with known hypertension, 69% were above target on at least two consecutive visits. Overall, patients receiving risk profiles were more likely to receive appropriate antihypertensive therapy (OR = 1.40, 95% CI 1.11-1.78) compared to those receiving usual care. After adjustment for inter-physician variability and potential confounders, the use of the risk profile was associated with an increased likelihood of starting therapy (OR = 1.78, 95% CI 1.06-3.00) or modifying therapy (OR = 1.40, 95% CI 1.03-1.91). CONCLUSIONS: In this clinical trial of dyslipidemia management, inadequately controlled hypertension was common, occurring in nearly 50% of individuals. Ongoing coronary risk assessment was associated with more appropriate blood pressure management. Cardiovascular risk assessment decision aids should be further evaluated in a randomized trial of hypertension therapy.

Preventing cardiovascular disease among Canadians: is the treatment of hypertension or dyslipidemia cost-effective?

BACKGROUND AND OBJECTIVES: The direct health care costs associated with treating hypertension and dyslipidemia continue to grow in most western countries, including Canada. Despite the proven effectiveness of hypertension and lipid therapies to prevent cardiovascular disease, the cost-effectiveness of long-term primary prevention, as currently advocated by Canadian treatment guidelines, remains to be determined. METHODS: Therapeutic efficiency, defined as person-years of treatment per year of life saved (YOLS) and the cost-effectiveness of treatment were estimated for groups of Canadian adults, 40 to 74 years of age. The clinical indications for treatment were based on the Canadian national guidelines in 2005. Analyses focused on those without cardiovascular disease or diabetes using risk factor data from the Canadian heart health surveys and drug data from a national study, the MyHealthCheckUp survey. The expected impact of therapy was based on published results: statins would result in a 40% drop in low-density lipoprotein cholesterol and a 6% increase in high-density lipoprotein cholesterol, while hypertension therapy would result in a 6.4% drop in systolic and a 5.6% drop in diastolic blood pressure. RESULTS: The estimated daily cost of statins was $1.98 versus $1.72 for antihypertensives. Overall, 2.33 million patients would be treated with lipid therapy and 2.34 million with antihypertensives. The average cost-effectiveness of lipid therapy would be approximately $16,700 per YOLS while hypertension therapy would be approximately $37,100 per YOLS. Lifelong lipid and hypertension therapy would be associated with 1.1 million and 472,000 life years saved at a national cost of $18.3 billion and $17.5 billion, respectively. However, hypertension treatment for some groups of Canadians appeared relatively expensive (more than $50,000 per YOLS) including men or women younger than 50 years of age. Despite attractive cost-effectiveness ratios, treatment appeared relatively inefficient (person-years of treatment per YOLS more than 100 years) for statin therapy among women younger than 50 years of age, and hypertension treatment for women younger than 60 years of age and men younger than 50 years of age. CONCLUSIONS: Given Canadian guidelines, the treatment of dyslipidemia or hypertension in primary prevention appears economically attractive overall. However, for some groups of individuals, the forecasted future benefits appear to be relatively small given the many years of treatment that are required.

Determining the cost-effectiveness of preventing cardiovascular disease: are estimates calculated over the duration of a clinical trial adequate?

BACKGROUND: Economic analyses of randomized clinical trials often focus only on the results that are observed during the study. However, for many preventive interventions, associated costs and benefits will accrue over a patient's remaining lifetime. To determine the importance of the chosen time horizon, the cost-effectiveness (C/E) of ramipril therapy was calculated and compared in the Heart Outcomes Prevention Evaluation (HOPE), the Microalbuminuria, Cardiovascular, and Renal Outcomes in HOPE (MICRO-HOPE) and the Acute Infarction Ramipril Efficacy (AIRE) study versus the entire life expectancy (L/E) of potential patients. METHODS: The Cardiovascular Disease Life Expectancy model, a validated Markov model, was calibrated to accurately forecast the results of each trial. These results were then extrapolated over the remaining L/E of hypothetical patients 55 to 75 years of age. The predicted change in L/E and associated direct health care costs for Canadians were calculated and discounted 3% annually. RESULTS: In HOPE, the forecasted increased L/E averaged 0.06 years during the five-year study versus 1.3 years over the remaining years of L/E. The associated C/E of ramipril was $15,000 per year of life saved (YOLS) over the study duration and $8,500/YOLS over the remaining lifetime. For hypothetical patients, the C/E of ramipril over 4.5 years ranged from $6,700/YOLS to more than $58,300/YOLS and was lowest among elderly men. When the remaining L/E was considered, the C/E of ramipril was similar for men and women of all ages, ranging from $8,100/YOLS to $10,200/YOLS. The analyses of MICRO-HOPE and AIRE provided similar results. CONCLUSION: The estimated efficacy and associated C/E of ramipril in HOPE, MICRO-HOPE and the AIRE study is extremely sensitive to the selected time horizon. Economic analyses beyond the duration of randomized clinical trials are required to fully evaluate the potential costs and benefits of long-term preventive therapies.

Estimating the cost effectiveness of ramipril used for specific clinical indications: comparing the outcomes in four clinical trials with a common economic model.

BACKGROUND AND OBJECTIVES: Economic analyses of drug therapies are highly dependent on the clinical indications for treatment. The cost effectiveness of ramipril has been evaluated in numerous studies, usually based on the results of one specific clinical trial. We estimated the cost effectiveness of this drug across a range of currently accepted therapeutic indications, using a single health economic model and adjusted for quality of life, to compare the different outcomes observed in four clinical trials. METHODS: The cardiovascular life expectancy model, a validated Markov model, was calibrated to accurately forecast the results of four trials including AIRE, HOPE, Micro-HOPE, and REIN. We then extrapolated these results over the remaining life expectancy of the patients enrolled in each study and adjusted for the quality of life associated with the observed outcomes. The cost per quality-adjusted life-year (QALY) was then calculated from the perspective of the Canadian healthcare system incorporating the estimated direct healthcare costs associated with treatments and outcomes. RESULTS: After discounting all costs and outcomes 3% annually, the benefits associated with ramipril ranged from 0.74 QALYs in the AIRE study to 1.22 QALYs in Micro-HOPE. Treatment was estimated to be cost-saving for some patient groups, such as those in REIN. The highest cost-effectiveness ratio was observed among individuals enrolled in HOPE ($Can20 000 per QALY in 2002). CONCLUSION: Treatment with ramipril appears to be economically attractive across a wide range of patient groups, including those with increased coronary risk and/or diabetes mellitus (HOPE and Micro-HOPE), those with congestive heart failure (AIRE), and those with non-diabetic nephropathy (REIN).

Patient knowledge of coronary risk profile improves the effectiveness of dyslipidemia therapy: the CHECK-UP study: a randomized controlled trial.

BACKGROUND: Despite increasing evidence that treating dyslipidemia reduces cardiovascular events, many patients do not achieve recommended lipid targets. METHODS: To determine whether showing physicians and patients the patient's calculated coronary risk can improve the effectiveness of treating dyslipidemia in a primary care setting, patients were randomized to receive usual care or ongoing feedback regarding their calculated coronary risk and the change in this risk after lifestyle changes, pharmacotherapy, or both to treat dyslipidemia. Outcomes, based on intention-to-treat analysis, included changes in blood lipid levels, coronary risk, and the frequency of reaching lipid targets. RESULTS: Two hundred thirty primary care physicians enrolled 3,053 patients. After 12 months of follow-up, 2,687 patients (88.0%) remained in the study. After adjustment for baseline lipid values, significantly greater mean reductions in low-density lipoprotein cholesterol levels and the total cholesterol to high-density lipoprotein cholesterol ratio were observed in patients receiving risk profiles (51.2 mg/dL [to convert to millimoles per liter, multiply by 0.0259] and 1.5, respectively) vs usual care (48.0 mg/dL and 1.3, respectively), but the differences were small (-3.3 mg/dL; 95% confidence interval [CI], -5.4 to -1.1 mg/dL; and -0.1; 95% CI, -0.2 to -0.1, respectively). Patients in the risk profile group were also more likely to reach lipid targets (odds ratio, 1.26; 95% CI, 1.07 to 1.48). A significant dose-response effect was also noted when the impact of the risk profile was stronger in those with worse profiles. CONCLUSIONS: Discussing coronary risk with the patient is associated with a small but measurable improvement in the efficacy of lipid therapy. The value of incorporating risk assessment in preventive care should be further evaluated.

Preventing cardiovascular disease among Canadians: what are the potential benefits of treating hypertension or dyslipidemia?

BACKGROUND: Treatments for hypertension and dyslipidemia to prevent the development of cardiovascular disease compete for the same finite number of health care dollars. Therefore, the potential benefits of treating Canadians without cardiovascular disease or diabetes who would currently be targeted by the national treatment guidelines were estimated and compared. STUDY DESIGN: Canadian Heart Health Surveys data were used to estimate the number of Canadians requiring intervention. The Cardiovascular Life Expectancy Model, a previously validated Markov model, was used to calculate the increased life expectancy and decreased morbidity associated with treating risk factors to target. RESULTS: Among 8.44 million adults 40 to 74 years of age without cardiovascular disease or diabetes, it was estimated that approximately 2.33 million would require treatment for dyslipidemia and 2.34 million for hypertension. The estimated Framingham 10-year coronary risk averaged 12.4% versus 9.6%, respectively. Treating dyslipidemia was associated with an average increased life expectancy of 1.67 years and 1.81 years of life free of cardiovascular disease. Treating hypertension was expected to increase life expectancy by 0.94 years and years of life free of cardiovascular disease by 1.29 years. The population benefits associated with treating dyslipidemia or hypertension would be 2.5 million and 1.4 million person years of life saved, respectively. Overall, the person years of treatment required to save one year of life was estimated to average 20 years for dyslipidemia therapy and 38 years for hypertension. CONCLUSIONS: The potential benefits associated with treating hypertension or dyslipidemia to prevent cardiovascular disease are substantial. However, compared with hypertension guidelines, dyslipidemia guidelines target higher-risk patients. Accordingly, given the relative efficacy of each treatment, the forecasted benefits associated with treating dyslipidemia are substantially greater than those associated with hypertension therapy.

Do the benefits of finasteride outweigh the risks in the prostate cancer prevention trial?

PURPOSE: The Prostate Cancer Prevention Trial demonstrated that finasteride could reduce the incidence of prostate cancer by 25%. However, its use was also associated with an increased risk of high grade cancer resulting in uncertainty surrounding the net benefits of therapy. MATERIALS AND METHODS: We used the Montreal Prostate Cancer Model, a validated Markov model of prostate cancer progression, to compare the forecasted survival in treated and untreated men. The conditions of the model were varied to reflect different assumptions about whether the cancer grade difference observed in the PCPT was real or a treatment associated artifact, and whether cancers detected on end of study biopsies were clinically significant. RESULTS: For a hypothetical cohort of 1,000, 62-year-old men treated with finasteride, an increased survival of 140 life-years (0.14 years per individual) is forecasted if all diagnosed cancers are considered. If tumor grade differences are held to be artifactual, the forecasted benefits increase to 200 life-years. However, if the tumor grade difference is real and only clinically detected cancers are considered, estimated increased survival is only 20 life-years (0.02 years per individual). CONCLUSIONS: The primary prevention of prostate cancer with finasteride looks promising. However, at the present time it should only be considered with caution until we have answered critical questions surrounding the difference in cancer grade observed in the PCPT and the clinical significance of cancers detected on protocol directed end of study biopsies.

The prevalence of erectile dysfunction in the primary care setting: importance of risk factors for diabetes and vascular disease.

BACKGROUND: The prevalence of erectile dysfunction (ED) and associated risk factors has been described in many clinical settings, but there is little information regarding men seen by primary care physicians. We sought to identify independent factors associated with ED in a primary care setting. METHODS: We surveyed a cross-sectional sample of 3921 Canadian men, aged 40 to 88 years, seen by primary care physicians. Participants completed a full medical history, physical examination, and measurement of fasting blood glucose and lipid levels. We used the International Index of Erectile Function to define ED as a score of less than 26 on the erectile function domain. RESULTS: The overall prevalence of ED was 49.4%. The presence of cardiovascular disease (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.16-1.81; P<.01) or diabetes (OR, 3.13; 95% CI, 2.35-4.16; P<.001) increased the probability of ED after adjustment for other confounders. Among those individuals without cardiovascular disease or diabetes, the calculated 10-year Framingham coronary risk (OR, 1.03 per 1% increase; 95% CI, 1.02-1.05; P<.001) and fasting blood glucose levels (OR, 1.14 per 18-mg/dL [1-mmol/L] increase; 95% CI, 1.04-1.24; P<.01) were independently associated with ED. Erectile dysfunction was also independently associated with undiagnosed hyperglycemia (OR, 1.46; 95% CI, 1.02-2.10; P = .04), impaired fasting glucose (OR, 1.26; 95% CI, 1.08-1.46; P = .004), and the metabolic syndrome (OR, 1.45; 95% CI, 1.24-1.69; P<.001). CONCLUSIONS: Cardiovascular disease, diabetes, future coronary risk, and increasing fasting glucose levels are independently associated with ED. It remains to be determined if ED precedes the development of these conditions.

Cost-effectiveness of lipid-lowering treatment according to lipid level.

BACKGROUND: Recent studies suggest that the benefit of lipid-lowering treatment for the primary and secondary prevention of cardiovascular disease (CVD) extends to individuals with average cholesterol levels, to women and to the elderly. However, the proportion of the general population for which treatment is cost-effective has not been evaluated. OBJECTIVES AND METHODS: Using data provided by the Canadian Heart Health Survey, the level of CVD risk was estimated for a random sample of the total population. A cost-effectiveness ratio for simvastatin was then calculated for each individual in the sample. Lastly, the proportion of the total population for which lipid-lowering therapy would be cost-effective for primary and secondary prevention of CVD was estimated according to total cholesterol (TC) levels. RESULTS: Among the surveyed individuals who were 30 to 74 years of age, 2212 had CVD and 12,982 did not. Among those with a TC level higher than 6.2 mmol/L, the proportions of individuals for which lipid-lowering therapy was cost-effective (at a level of less than 50,000 dollars per year of life saved) were 85.6% of men and 28.7% of women for primary prevention, and 99.8% of men and 86.1% of women for secondary prevention. The estimated cost of one year of lipid-lowering treatment for all individuals in the population with a TC level higher than 6.2 mmol/L and for all individuals regardless of TC levels for whom treatment would be cost-effective was $1 billion and 3.9 billion dollars, respectively. CONCLUSIONS: Lipid-lowering treatment for CVD prevention is cost-effective for a high proportion of the population, even for primary prevention. As a result, the cost of population-wide treatment for only one year is high even among individuals with a TC level higher than 6.2 mmol/L. Such costs should be considered in health care policy decisions.

Impact of dyslipidemia associated with Highly Active Antiretroviral Therapy (HAART) on cardiovascular risk and life expectancy.

We investigated the effect of dyslipidemia associated with highly active antiretroviral therapy on cardiovascular risk and life expectancy among patients who had the human immunodeficiency virus. Dyslipidemia estimates were based on results from a phase 2 randomized trial that compared lipid changes after 32 weeks of therapy with atazanavir with those with nelfinavir (each in combination with stavudine and lamivudine). The resultant increased coronary risk was estimated using Framingham risk equations, and change in life expectancy (after adjustment for mortality due to human immunodeficiency virus) was based on the cardiovascular life expectancy model, which is based on a published Markov's model. Levels of total cholesterol and low-density lipoprotein cholesterol increased significantly more among patients who used nelfinavir (+24% and +28%) than among those who used atazanavir (+4% and +1%). This dyslipidemia increased the risk of coronary disease by 50% over 10 years. The absence of dyslipidemia was estimated to preserve life expectancy 0.15 to 1.53 additional years depending on a patient's age, gender, and other risk factors. There are increasing reports of dyslipidemia and cardiovascular events associated with highly active antiretroviral therapy. Significant increases in blood lipid levels observed with some protease inhibitors are associated with an increase in calculated 10-year coronary risk. Accordingly, minimizing dyslipidemia associated with highly active antiretroviral therapy may preserve life expectancy among adults who have the human immunodeficiency virus.