Projecting effectiveness after ending a randomized controlled trial: a two-state Markov microsimulation model.

OBJECTIVE: To investigate the behavior of restricted mean survival time (RMST) and designs of a two-state Markov microsimulation model through a 2 × 4 × 2 full factorial experiment. METHOD: By projecting patient-wise 15-year-post-trial survival, we estimated life-year-gained between an intervention and a control group using data from the Cardiovascular Outcomes for People Using Anticoagulation Strategies Study (COMPASS). Projections considered either in-trial events or post-trial medications. They were compared based on three factors: (i) choice of probability of death, (ii) lengths of cycle, and (iii) usage of half-a-cycle age correction. Three-way analysis of variance and post-hoc Tukey's Honest Significant Difference test compared means among factors. RESULTS: When both in-trial events and post-trial study medications were considered, monthly, quarterly, or semiannually were not different from one other in projected life-year-gained. However, the annual one was different from the others: mean and 95 percent confidence interval 252.2 (190.5-313.9) days monthly, 251.8 (192.0-311.6) quarterly, 249.1 (189.7-308.5) semiannually, and 240.8 (178.5-303.1) annually. The other two factors also impacted life-year-gained: background probability (269.1 [260.3-277.9] days projected with REACH-based-probabilities, 227.7 [212.6-242.8] with a USA life table); half-a-cycle age correction (245.5 [199.0-292] with correction and 251.4 [209.1-293.7] without correction). When not considering post-trial medications, only the choice of probability of death appeared to impact life-year-gained. CONCLUSION: For a large trial or cohort, to optimally project life-year-gained, one should consider using (i) annual projections, (ii) life table probabilities, (iii) in-trial events, and (iv) post-trial medication use.

Cost effectiveness analysis of a fixed dose combination pill for primary prevention of cardiovascular disease from an individual participant data meta-analysis.

Background: Cardiovascular disease (CVD) continues to impart a large burden on the global population, especially in lower income countries where affordability limits the use of cardiovascular medicines. A fixed dose combination strategy of at least 2 blood pressure lowering medications and a statin with aspirin in a single pill has been shown to reduce the risk of incident CVD by 38% in primary prevention in a recent meta-analysis. We report the in-trial (median follow-up: 5 years) cost-effectiveness of a fixed dose combination (FDC) pill in different income groups based on data from that meta-analysis. Methods: Countries were categorized using World Bank economic groups: Lower Middle Income Countries (LMIC), Upper Middle Income Countries (UMIC) and High Income Countries (HIC). Country specific costs were obtained for hospitalized events, procedures, and non-study medications (2020 USD). FDC price was based on the cheapest equivalent substitute (CES) for each component. Findings: For the CES-FDC pill versus control the difference in cost was $346 (95% CI: $294-$398) per participant in Lower Middle Income Countries, $838 (95% CI: $781-$895) in Upper Middle Income Countries and $42 (95% CI: -$155 to $239) (cost-neutral) in High Income Countries. During the study period the CES-FDC pill was associated with incremental gain in quality-adjusted life years of 0.06 (95% CI: 0.04-0.08) resulting in an incremental cost-effectiveness ratio (ICER) of $5767 (95% CI: 5735-$5799), $13,937 (95% CI: $13,893-$14,041) and $700 (95% CI: $662-$738) respectively. In subgroups analyses, the highest 10 years CVD risk subgroup had ICERs of $2033, $7322 and -$6000/QALY. Interpretation: A FDC pill produced at CES costs is cost-neutral in HIC. Governments of LMI and UMI countries should assess these results based on the ICER threshold accepted in their own country and own specific health care priorities but should consider prioritizing this strategy for patients with high 10 years CVD risk as a first step. Funding: Population Health Research Institute.

The Cost-Effectiveness of Rivaroxaban Plus Aspirin Compared with Aspirin Alone in the COMPASS Trial: A US Perspective.

BACKGROUND: Rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily was shown to be better than aspirin 100 mg daily for preventing cardiovascular (CV) death, stroke or myocardial infarction in patients with either stable coronary artery disease (CAD) or peripheral artery disease (PAD). The cost-effectiveness of this regimen in this population is essential for decision-makers to know. METHODS: US direct healthcare system costs (in USD) were applied to hospitalized events, procedures and study drugs utilized by all patients. We determined the mean cost per participant for the full duration of the trial (mean follow-up of 23 months) plus quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) over a lifetime using a two-state Markov model with 1-year cycle length. Sensitivity analyses were performed on the price of rivaroxaban and the annual discontinuation rate. RESULTS: The costs of events and procedures were reduced for Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) patients who received rivaroxaban 2.5 mg orally (BID) plus acetylsalicylic acid (ASA) compared with ASA alone. Total costs were higher for the combination group ($7426 versus $4173) after considering acquisition costs of the study drug. Over a lifetime, patients receiving rivaroxaban plus ASA incurred $27,255 more and gained 1.17 QALYs compared with those receiving ASA alone resulting in an ICER of $23,295/QALY. ICERs for PAD only and polyvascular disease subgroups were lower. CONCLUSION: Rivaroxaban 2.5 mg BID plus ASA compared with ASA alone was cost-effective (high value) in the USA. COMPASS ClinicalTrials.gov identifier: NCT01776424.

Clinical outcomes and cost implications of routine early PCI after fibrinolysis: one-year follow-up of the Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) study.

BACKGROUND: In patients with ST-elevation myocardial infarction treated with fibrinolysis, routine early percutaneous coronary intervention (r-PCI) improves clinical outcomes at 30 days compared with a more standard approach of performing early PCI only for failed fibrinolysis (s-PCI). METHODS: We report prespecified secondary clinical outcomes and cost implications of r-PCI compared with s-PCI from the Canadian TRANSFER-AMI trial. Average cost per patient in each arm was calculated based on a microcosting approach. Bootstrap method (5,000 samples) was used to calculate standard errors and 95% CI. RESULTS: At 1 year, rates of death or reinfarction (10.3% vs 11.6%, P = .50), hospital readmission (15.4% vs 16.5%, P = .64) and subsequent revascularization after index hospitalization (6.9% vs 8.7%, P = .30) were similar between the r-PCI and s-PCI arms. The difference in cost per patient between r-PCI and s-PCI was CAD $1,003 (95% CI, -$247 to $2,211). Since a greater proportion of patients were transported by air (vs land) in the r-PCI arm (9.4% vs 3%), and the ratio of abciximab to eptifibatide use was higher in the r-PCI arm compared with s-PCI (2:1 vs 4:5), we undertook additional post hoc cost scenario analyses. In a scenario where patients are transported by land only and eptifibatide is used as the sole GPIIb/IIIa inhibitor, the difference in cost per patient between r-PCI and s-PCI was estimated to be CAD $108 (95% CI, -$1,114 to $1,344). CONCLUSIONS: At 1 year, there is no difference in the clinical composite outcome of death or reinfarction between r-PCI and s-PCI strategies. Greater cost with r-PCI, although statistically insignificant, is economically important.

The impact of statistical properties of incremental monetary net benefit and incremental cost-effectiveness ratio on health economic modeling choices.

INTRODUCTION: There is controversy on whether to use incremental monetary net benefit (INMB) or incremental cost-effectiveness ratio (ICER) in health economic evaluations alongside randomized controlled trials. We studied the impact of restricted mean survival time (RMST) on the long-term projection of INMB and ICER. METHODS: We analyzed the unbiasedness and efficiency of ICER and INMB by (1) deriving the metrics' expected values and variances based on theoretical probability distributions, (2) simulating their 15-year post-trial projections based on between-arm-RMST-gained through a 2 × 4 × 2 factorial experiment of Markov 2-state microsimulations. Simulations and comparison were run on the data from the Cardiovascular Outcomes for People Using Anticoagulation Strategies Study (COMPASS). RESULTS: Our simulation findings using RMST showed that ICER was more efficient than INMB, regardless of disease populations, time horizon, modeling choices, and underlying probability distributions of incremental mean cost and effect. ICER had a small variance and thus showed its robustness to the choices of models. CONCLUSION: INMB's variance varies with a willingness-to-pay (WTP) threshold quadratically while ICER's variance with a WTP threshold value quadratically while ICER's variance with incremental-mean-cost quadratically. A simple and naïve model can sufficiently estimate ICER. Future metrics are expected to be health-economic-meaningful, unambiguous, unbiased, efficient, and statistical-inference-friendly.

Cost Implications of Left Atrial Appendage Occlusion During Cardiac Surgery: A Cost Analysis of the LAAOS III Trial.

Background The LAAOS III (Left Atrial Appendage Occlusion Study) clinical trial demonstrated that concomitant left atrial appendage (LAA) occlusion leads to a lower risk of ischemic stroke or systemic embolism compared with no occlusion in participants with atrial fibrillation and a CHA2DS2-VASc score of ≥2 undergoing cardiac surgery for another indication. We report the cost implications of concomitant LAA occlusion during cardiac surgery. Methods and Results Using LAAOS III data, we compared the costs (in US dollars) associated with LAA occlusion to no occlusion from the perspective of the Centers for Medicare and Medicaid Services. We calculated the average cost per participant during the trial by applying Medicare reimbursement costs to cardiovascular events for all trial participants. We conducted sensitivity analyses, varying the cost of stroke ±25% and occlusion technique use. Cost neutrality was defined as a mean cost difference within ±5% of the cost per participant in the no-occlusion group. Total study cost per participant was $3878 in the LAA occlusion group and $4490 in the no-occlusion group, a mean difference of -$612 (95% CI, -$1276 to $45). The main drivers of cost savings were fewer stroke events during the trial (mean difference of -$1021). In sensitivity analyses, LAA occlusion was cost saving for suture and stapler techniques but more expensive with closure device. Conclusions Concomitant LAA occlusion was cost saving for participants in LAAOS III. Our findings support concomitant LAA occlusion as an economically dominant strategy for patients with atrial fibrillation and a CHA2DS2-VASc score of ≥2 undergoing cardiac surgery.

The cost-effectiveness of rivaroxaban with or without aspirin in the COMPASS trial.

AIMS: The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial demonstrated that rivaroxaban 2.5 mg BID with aspirin 100 mg was more effective than aspirin 100 mg daily alone for the prevention of cardiovascular (CV) death, stroke, or myocardial infarction in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). We aimed to examine the cost-effectiveness of rivaroxaban using patient-level data from the COMPASS trial. METHODS AND RESULTS: We performed an in-trial analysis and extrapolated our results for 33 years using a two-state Markov model with a 1-year cycle length. Hospitalization events, procedures, and study drugs were documented for patients. We applied country-specific (Canada, France, and Germany) direct healthcare system costs (in USD) to healthcare resources consumed by patients. Average cost per patient during the trial (mean follow-up of 23 months), quality-adjusted life years (QALYs), and lifetime cost-effectiveness were calculated. Costs of events and procedures were reduced with rivaroxaban 2.5 mg BID with aspirin. The addition of rivaroxaban 2.5 mg BID increased total costs for the combination group. Over a lifetime horizon (in trial +33 years), rivaroxaban plus aspirin was associated with 1.17 QALYs gained, yielding an incremental cost-effectiveness ratio (ICER) of $3946/QALY, $9962/QALY, and $10 264/QALY in Canada, France, and Germany, respectively. PAD and polyvascular disease subgroups had lower ICERs. CONCLUSION: Rivaroxaban 2.5 mg twice daily plus aspirin compared with aspirin alone reduces direct healthcare costs. After acquisition costs of rivaroxaban, the lifetime cost-effectiveness of 2.5 mg twice daily plus aspirin is highly cost-effective in Canada, France, and Germany.(COMPASS ClinicalTrials.gov identifier: NCT01776424).

The cost implications of a polypill for primary prevention in the TIPS-3 trial.

AIMS: The International Polycap Study 3 (TIPS-3) trial demonstrated that a polypill containing cholesterol- and multiple blood-pressure-lowering drugs reduces cardiovascular events by 20% compared with placebo in people without cardiovascular disease. The polypill plus aspirin led to a 31% relative risk reduction in cardiovascular disease events compared with double placebo. We report regional variations in costs and affordability of a polypill based on the TIPS-3 trial. METHODS AND RESULTS: Countries were categorized using World Bank economic groups: lower-middle-income, upper-middle-income, and high-income countries. Country-specific costs were obtained for hospitalization events, procedures, and non-study medications (2019 US dollars). Polypill price was based on the cheapest equivalent substitute (CES) for each component. For the polypill vs. placebo, the difference in cost over the 4.6 years of the trial was $291 [95% confidence interval (CI): $243-339] per participant in lower-middle-income countries, $1068 (95% CI: $992-1144) in upper-middle-income countries, and $48 (95% CI: -$271 to $367) in high-income countries. Results were similar for the polypill plus aspirin vs. a double placebo. In both cases, the polypill was affordable in all groups using monthly household capacity to pay or a threshold of 4% of the gross national income per capita. CONCLUSION: The use of a polypill (CES) in TIPS-3 increases costs in lower-middle-income countries and upper-middle-income countries but is affordable in countries at various economic levels and is cost neutral (dominant) in high-income countries.

The Cost Implications of Dabigatran in Patients with Myocardial Injury After Non-Cardiac Surgery.

BACKGROUND: The Management of Myocardial Injury after Non-Cardiac Surgery (MANAGE) trial demonstrated that dabigatran 110 mg twice daily was more effective than placebo in preventing the primary composite outcome of vascular mortality, non-fatal myocardial infarction, non-hemorrhagic stroke, peripheral arterial thrombosis, amputation and symptomatic venous thromboembolism in patients with myocardial injury after non-cardiac surgery (MINS). The cost implications of dabigatran for this population are unknown but are important given the significant clinical implications. METHODS: Hospitalized events, procedures, and study and non-study medications were documented. We applied Canadian unit costs to healthcare resources consumed for all patients in the trial, and calculated the average cost per patient in Canadian dollars for the duration of the study (median follow-up of 16 months). A sensitivity analysis was performed using only Canadian patients, and subgroup analyses were also conducted. RESULTS: The total study cost for the dabigatran group was $9985 per patient, compared with $10,082 for placebo, a difference of - $97 (95% confidence interval [CI] - $2128 to $3672). Savings arising from fewer clinical events and procedures in the dabigatran 110 mg twice-daily group were enough to offset the cost of the study drug. In Canadian patients, the difference was $250 (95% CI -$2848 to $4840). Both differences were considered cost neutral. Dabigatran 110 mg twice daily was cost saving or cost neutral in many subgroups that were considered. CONCLUSION: Dabigatran 110 mg twice daily was cost neutral for patients in the MANAGE trial. Our cost findings support the use of dabigatran 110 mg twice daily in patients with MINS. TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT01661101.

The cost implication of primary prevention in the HOPE 3 trial.

AIMS: The Heart Outcomes Prevention Evaluation-3 (HOPE-3) found that rosuvastatin alone or with candesartan and hydrochlorothiazide (HCT) (in a subgroup with hypertension) significantly lowered cardiovascular events compared with placebo in 12 705 individuals from 21 countries at intermediate risk and without cardiovascular disease. We assessed the costs implications of implementation in primary prevention in countries at different economic levels. METHODS AND RESULTS: Hospitalizations, procedures, study and non-study medications were documented. We applied country-specific costs to the healthcare resources consumed for each patient. We calculated the average cost per patient in US dollars for the duration of the study (5.6 years). Sensitivity analyses were also performed with cheapest equivalent substitutes. The combination of rosuvastatin with candesartan/HCT reduced total costs and was a cost-saving strategy in United States, Canada, Europe, and Australia. In contrast, the treatments were more expensive in developing countries even when cheapest equivalent substitutes were used. After adjustment for gross domestic product (GDP), the costs of cheapest equivalent substitutes in proportion to the health care costs were higher in developing countries in comparison to developed countries. CONCLUSION: Rosuvastatin and candesartan/HCT in primary prevention is a cost-saving approach in developed countries, but not in developing countries as both drugs and their cheapest equivalent substitutes are relatively more expensive despite adjustment by GDP. Reductions in costs of these drugs in developing countries are essential to make statins and blood pressure lowering drugs affordable and ensure their use. CLINICAL TRIAL REGISTRATION: HOPE-3 ClinicalTrials.gov number, NCT00468923.

A UMLS-based spell checker for natural language processing in vaccine safety.

BACKGROUND: The Institute of Medicine has identified patient safety as a key goal for health care in the United States. Detecting vaccine adverse events is an important public health activity that contributes to patient safety. Reports about adverse events following immunization (AEFI) from surveillance systems contain free-text components that can be analyzed using natural language processing. To extract Unified Medical Language System (UMLS) concepts from free text and classify AEFI reports based on concepts they contain, we first needed to clean the text by expanding abbreviations and shortcuts and correcting spelling errors. Our objective in this paper was to create a UMLS-based spelling error correction tool as a first step in the natural language processing (NLP) pipeline for AEFI reports. METHODS: We developed spell checking algorithms using open source tools. We used de-identified AEFI surveillance reports to create free-text data sets for analysis. After expansion of abbreviated clinical terms and shortcuts, we performed spelling correction in four steps: (1) error detection, (2) word list generation, (3) word list disambiguation and (4) error correction. We then measured the performance of the resulting spell checker by comparing it to manual correction. RESULTS: We used 12,056 words to train the spell checker and tested its performance on 8,131 words. During testing, sensitivity, specificity, and positive predictive value (PPV) for the spell checker were 74% (95% CI: 74-75), 100% (95% CI: 100-100), and 47% (95% CI: 46%-48%), respectively. CONCLUSION: We created a prototype spell checker that can be used to process AEFI reports. We used the UMLS Specialist Lexicon as the primary source of dictionary terms and the WordNet lexicon as a secondary source. We used the UMLS as a domain-specific source of dictionary terms to compare potentially misspelled words in the corpus. The prototype sensitivity was comparable to currently available tools, but the specificity was much superior. The slow processing speed may be improved by trimming it down to the most useful component algorithms. Other investigators may find the methods we developed useful for cleaning text using lexicons specific to their area of interest.

Cost implication of an early invasive strategy on weekdays and weekends in patients with acute coronary syndromes.

BACKGROUND: Early invasive intervention is associated with shorter length of stay (LOS) and similar outcomes in a delayed strategy in lower-risk patients with non-ST segment elevation acute coronary syndromes (NSTEACS), but is superior in higher-risk patients. However, early invasive intervention might be constrained by the need to mobilize the on-call team on weekends. We evaluated costs associated with an early vs delayed invasive intervention strategy, including patients who present on weekends. METHODS: Health care utilization was extracted from the Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial for Canadian patients from case report forms. Only direct costs were considered and only hospitalization events were included. Canadian unit costs were applied to health care resources consumed for all patients. Sensitivity and subgroup analyses were performed. RESULTS: Early invasive intervention reduced LOS costs by $2808 (95% confidence interval [CI], $4,629-$987). Total costs per Canadian patient for early invasive intervention were $16,579 (95% CI, $14,949-$18,209) compared with $19,517 (95% CI, $17,897-$21,136) for the delayed invasive approach. This resulted in a savings of $2938 (95% CI, $5236-$640). Findings were confirmed using bootstrap simulation. Sensitivity analyses confirmed savings regardless of proportion of cases done on weekends. All subgroup costs favoured early intervention. CONCLUSIONS: Early invasive strategy was cost-saving, even on weekends, for Canadian NSTEACS patients because of significant LOS savings. Because many high-risk NSTEACS patients receive delayed intervention because of weekend catheterization laboratory status, these findings support opening catheterization laboratories on weekends to facilitate the use of early invasive intervention.

Hyperbaric oxygen therapy in acute ischemic stroke: a review.

Stroke, also known as cerebrovascular disease, is a common and serious neurological disease, which is also the fourth leading cause of death in the United States so far. Hyperbaric medicine, as an emerging interdisciplinary subject, has been applied in the treatment of cerebral vascular diseases since the 1960s. Now it is widely used to treat a variety of clinical disorders, especially hypoxia-induced disorders. However, owing to the complex mechanisms of hyperbaric oxygen (HBO) treatment, the therapeutic time window and the undefined dose as well as some common clinical side effects (such as middle ear barotrauma), the widespread promotion and application of HBO was hindered, slowing down the hyperbaric medicine development. In August 2013, the US Food and Drug Administration declared artery occlusion as one of the 13 specific indications for HBO therapy. This provides opportunities, to some extent, for the further development of hyperbaric medicine. Currently, the mechanisms of HBO therapy for ischemic stroke are still not very clear. This review focuses on the potential mechanisms of HBO therapy in acute ischemic stroke as well as the time window.

The cost implications of off-pump versus on-pump coronary artery bypass graft surgery at one year.

BACKGROUND: The purpose of this study was to determine the cost implications of the Coronary Artery Bypass Graft Off or On Pump Revascularization Study (CORONARY) at 1 year. METHODS: Country-specific healthcare costs were obtained from public databases or local experts from each country in the CORONARY trial. Purchasing power parities were applied to these costs of consumed healthcare resources. Analyses of subgroups included in the CORONARY clinical trial were also conducted. Costs are reported in US dollars. RESULTS: After 1 year, the total cost per patient in the off-pump coronary artery bypass graft surgery (CABG) arm was $9,650 ($9,216 to $10,285) compared with $9,583 ($9,239 to $9,988) for the on-pump CABG arm; that resulted in a nonsignificant increase of $68 (-$575 to $710). Similar findings were noted for various subgroups. There were also no differences due to late conversions. CONCLUSIONS: The CORONARY trial demonstrated that off-pump CABG was clinically as safe and effective as on-pump CABG with no difference in costs. Thus, the decision as to which method to choose is free from costs considerations and should be based on patient preference and surgeon expertise (Coronary Artery Bypass Graft [CABG] Off or On Pump Revascularization Study [CORONARY]; clinicaltrials.gov NCT00463294).

The cost implications of an early versus delayed invasive strategy in Acute Coronary Syndromes: the TIMACS study.

BACKGROUND: The Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial demonstrated that early invasive intervention (within 24 hours) was similar to a delayed approach (after 36 hours) overall but improved outcomes were seen in patients at high risk. However, the cost implications of an early versus delayed invasive strategy are unknown. METHODS AND RESULTS: A third-party perspective of direct cost was chosen and United States Medicare costs were calculated using average diagnosis related grouping (DRG) units. Direct medical costs included those of the index hospitalization (including clinical, procedural and hospital stay costs) as well as major adverse cardiac events during 6 months of follow-up. Sensitivity and sub-group analyses were performed. The average total cost per patient in the early intervention group was lower compared with the delayed intervention group (-$1170; 95% CI -$2542 to $202). From the bootstrap analysis (5000 replications), the early invasive approach was associated with both lower costs and better clinical outcomes regarding death/myocardial infarction (MI)/stroke in 95.1% of the cases (dominant strategy). In high-risk patients (GRACE score ≥141), the net reduction in cost was greatest (-$3720; 95% CI -$6270 to -$1170). Bootstrap analysis revealed 99.8% of cases were associated with both lower costs and better clinical outcomes (death/MI/stroke). LIMITATIONS: We were unable to evaluate the effect of community care and investigations without hospitalization (office visits, non-invasive testing, etc). Medication costs were not captured. Indirect costs such as loss of productivity and family care were not included. CONCLUSIONS: An early invasive management strategy is as effective as a delayed approach and is likely to be less costly in most patients with acute coronary syndromes.

The cost of clopidogrel use in atrial fibrillation in the ACTIVE-A trial.

BACKGROUND: The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events-Aspirin (ACTIVE-A) demonstrated that in patients with atrial fibrillation unsuitable for vitamin K antagonist (VKA) therapy, a combination of clopidogrel and aspirin reduced stroke risk by 28% but increased major hemorrhage risk by 57%. This analysis examined cost implications of adding clopidogrel to aspirin (C+A) for ACTIVE-A patients. METHODS: Health care use was extracted for each patient. We considered only direct costs and included only hospitalization events. We used Canadian unit costs for the health care resources consumed and Canadian list price of brand clopidogrel. Costs, in 2008 Canadian dollars, were discounted at 3% per year. RESULTS: C+A reduced costs of health care use components except for the study medication. Stroke prevention resulted in important cost savings that offset the cost of clopidogrel. Total costs per patient for C+A were $14,132 (95% confidence interval [CI], $13,445-$14,842), compared with $13,756 (95% CI, $13,032-$14,544) for aspirin alone, resulting in incremental cost of $376 (95% CI, -$645 to $1397) for C+A, confirmed through bootstrap simulation. Estimates were sensitive to the price of clopidogrel, varying from cost savings to a significant increase. CONCLUSION: C+A in patients unsuitable for VKA therapy is cost neutral (following our predefined conditions) as cost of clopidogrel is offset by prevention of costly strokes. These findings support the use of C+A in ACTIVE-A patients for whom VKA therapy is unsuitable.

The cost implications of the use of telmisartan or ramipril in patients at high risk for vascular events: the ONTARGET study.

BACKGROUND: The recently published ONTARGET trial found that telmisartan was non-inferior to ramipril in reducing CV death, MI, stroke, or heart failure in patients with vascular disease or high-risk diabetes. The cost implications of ramipril and telmisartan monotherapy use based on the ONTARGET study are reported here. METHODS AND RESULTS: Only healthcare system costs were considered. Healthcare resource utilization was collected for each patient during the trial. The authors obtained country-specific unit costs to the different healthcare care resources consumed (i.e., hospitalizations events, procedures, non-study, and study drugs) for all enrolled patients. Purchasing power parities were used to convert country-specific costs into US dollars (US$ 2008). The total undiscounted costs of the study for the telmisartan group was $12,762 per patient and is higher than the ramipril group at $12,007 per patient, an un-discounted difference of $755 (95% confidence interval [CI], $218-$1292); The discounted costs for the telmisartan group was $11,722 compared with $11,019 for the ramipril group; a difference of $703 (95% CI, $209-$1197). The difference in costs is exclusively related to the acquisition cost of telmisartan over generic ramipril. LIMITATIONS: This analysis only considered direct healthcare system costs. Costs accrued outside the hospital were not collected. Combination therapy was excluded since it would likely be more expensive than ramipril alone, with no additional benefit and a risk of some harm. CONCLUSIONS: Based on these results, it is suggested that for the ONTARGET patients, the use of telmisartan instead of ramipril increases costs by 6.3%. These findings suggest that the choice to put patients on telmisartan should be justified based on the patient?s susceptibility to specific adverse events to minimize the cost implications.

Concept negation in free text components of vaccine safety reports.

Large amounts of information are locked up in free text components of clinical reports. Surveillance systems that monitor adverse events following immunizations (AEFI) can utilize these components after concept extraction using natural language processing (NLP). Specifically, our method for the identification and filtering of negated concepts using the Unified Medical Language System (UMLS) potentially improves the quality of AEFI surveillance systems.