Tailoring Antiplatelet Therapy Intensity to Ischemic and Bleeding Risk.

BACKGROUND: Balancing ischemic and bleeding risk is an evolving framework. METHODS AND RESULTS: Our objectives were to simulate changes in risks for adverse events and event-driven costs with use of ticagrelor or prasugrel versus clopidogrel according to varying levels of ischemic and bleeding risk. Using the validated PARIS risk functions, we estimated 1-year ischemic (myocardial infarction or stent thrombosis) and bleeding (Bleeding Academic Research Consortium types 3 or 5) event rates among PARIS study participants who underwent percutaneous coronary intervention with drug-eluting stent implantation for an acute coronary syndrome and were discharged with aspirin and clopidogrel (n=1497). Simulated changes in adverse events with ticagrelor or prasugrel were calculated by applying treatment effects from randomized trials for a 1-year time horizon. Event costs were estimated using National Inpatient Sample data. Net costs were calculated between antiplatelet therapy groups according to level of ischemic and bleeding risk. After weighting events for quality-of-life impact, we calculated event rates and costs for risk-tailored treatment versus clopidogrel under multiple drug pricing assumptions. One-year rates (per 1000 person-years) for ischemic events were 12.6, 24.1, and 66.1, respectively, among those at low (n=630), intermediate (n=536), and high (n=331) ischemic risk. Analogous bleeding rates were 11.0, 23.9, and 66.2, respectively, among low (n=728), intermediate (n=634), and high (n=135) bleeding risk patients. Mean per event costs were $22 174 (ischemic) and $12 203 (bleeding). When risks for ischemia matched or exceeded bleeding, simulated utility-weighted event rates favored ticagrelor/prasugrel, whereas clopidogrel reduced utility-weighted events when bleeding exceeded ischemic risk. One-year costs were sensitive to drug pricing assumptions, and risk-tailored treatment with either agent progressed from cost incurring to cost saving with increasing generic market share. CONCLUSIONS: Tailoring antiplatelet therapy intensity to patient risk may improve health utility and could produce cost savings in the first year after percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00998127.

Cost implications of intraprocedural thrombotic events and bleeding in percutaneous coronary intervention: Results from the CHAMPION PHOENIX ECONOMICS Study.

BACKGROUND: Despite improvements in percutaneous coronary intervention (PCI), intraprocedural thrombotic events (IPTE) and bleeding complications occur and are prognostically important. These have not been included in prior economic studies. METHODS: PHOENIX ECONOMICS was a substudy of the CHAMPION PHOENIX trial, evaluating cangrelor during PCI. Hospital bills were reviewed from 1,171 patients enrolled at 22 of 63 US sites. Costs were estimated using standard methods including resource-based accounting, hospital billing data, and the Medicare fee schedule. Bleeding and IPTE, defined as abrupt vessel closure (transient or sustained), new/suspected thrombus, new clot on wire/catheter, no reflow, side-branch occlusion, procedural stent thrombosis or urgent need for CABG were identified. Costs were calculated according to whether a complication occurred and type of event. Multivariate analyses were used to estimate the incremental costs of IPTE and postprocedural events. RESULTS: IPTE occurred in 4.3% and were associated with higher catheterization laboratory and overall index hospitalization costs by $2,734 (95%CI $1,117, $4,351; P = 0.001) and $6,354 (95% CI $4,122, $8,586; P < 0.001), respectively. IPTE were associated with MI (35.4% vs. 3.6%; P < 0.001), out-of-laboratory stent thrombosis (4.2% vs. 0.1%; 0 = 0.005), ischemia driven revascularization (12.5% vs. 0.3%; P < 0.001), but not mortality (2.1% vs. 0.2%; P = 0.12) vs. no procedural thrombotic complication. By comparison, ACUITY minor bleeding increased hospitalization cost by $1,416 (95%CI = 312, $2,519; P = 0.012). ACUITY major bleeding increased cost of hospitalization by $7,894 (95%CI $4,154, $11,635; P < 0.001). CONCLUSIONS: IPTE and bleeding complications, though infrequent, are associated with substantial increased cost. These complications should be collected in economic assessments of PCI.

Cost-effectiveness analysis of 30-month vs 12-month dual antiplatelet therapy with clopidogrel and aspirin after drug-eluting stents in patients with acute coronary syndrome.

Continuation of dual antiplatelet therapy (DAPT) beyond 1 year reduces late stent thrombosis and ischemic events after drug-eluting stents (DES) but increases risk of bleeding. We hypothesized that extending DAPT from 12 months to 30 months in patients with acute coronary syndrome (ACS) after DES is cost-effective. A lifelong decision-analytic model was designed to simulate 2 antiplatelet strategies in event-free ACS patients who had completed 12-month DAPT after DES: aspirin monotherapy (75-162 mg daily) and continuation of DAPT (clopidogrel 75 mg daily plus aspirin 75-162 mg daily) for 18 months. Clinical event rates, direct medical costs, and quality-adjusted life-years (QALYs) gained were the primary outcomes from the US healthcare provider perspective. Base-case results showed DAPT continuation gained higher QALYs (8.1769 vs 8.1582 QALYs) at lower cost (USD42 982 vs USD44 063). One-way sensitivity analysis found that base-case QALYs were sensitive to odds ratio (OR) of cardiovascular death with DAPT continuation and base-case cost was sensitive to OR of nonfatal stroke with DAPT continuation. DAPT continuation remained cost-effective when the ORs of nonfatal stroke and cardiovascular death were below 1.241 and 1.188, respectively. In probabilistic sensitivity analysis, DAPT continuation was the preferred strategy in 74.75% of 10 000 Monte Carlo simulations at willingness-to-pay threshold of 50 000 USD/QALYs. Continuation of DAPT appears to be cost-effective in ACS patients who were event-free for 12-month DAPT after DES. The cost-effectiveness of DAPT for 30 months was highly subject to the OR of nonfatal stroke and OR of death with DAPT continuation.

CYP2C19 LOF and GOF-Guided Antiplatelet Therapy in Patients with Acute Coronary Syndrome: A Cost-Effectiveness Analysis.

PURPOSE: This study aimed to examine the cost-effectiveness of CYP2C19 loss-of-function and gain-of-function allele guided (LOF/GOF-guided) antiplatelet therapy in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS: A life-long decision-analytic model was designed to simulate outcomes of three strategies: universal clopidogrel (75 mg daily), universal alternative P2Y12 inhibitor (prasugrel 10 mg daily or ticagrelor 90 mg twice daily), and LOF/GOF-guided therapy (LOF/GOF allele carriers receiving alternative P2Y12 inhibitor, wild-type patients receiving clopidogrel). Model outcomes included clinical event rates, quality-adjusted life-years (QALYs) gained and direct medical costs from perspective of US healthcare provider. RESULTS: Base-case analysis found nonfatal myocardial infarction (5.62%) and stent thrombosis (1.2%) to be the lowest in universal alternative P2Y12 inhibitor arm, whereas nonfatal stroke (0.72%), cardiovascular death (2.42%), and major bleeding (2.73%) were lowest in LOF/GOF-guided group. LOF/GOF-guided arm gained the highest QALYs (7.5301 QALYs) at lowest life-long cost (USD 76,450). One-way sensitivity analysis showed base-case results were subject to the hazard ratio of cardiovascular death in carriers versus non-carriers of LOF allele and hazard ratio of cardiovascular death in non-carriers of LOF allele versus general patients. In probabilistic sensitivity analysis of 10,000 Monte Carlo simulations, LOF/GOF-guided therapy, universal alternative P2Y12 inhibitor, and universal clopidogrel were the preferred strategy (willingness-to-pay threshold = 50,000 USD/QALY) in 99.07%, 0.04%, and 0.89% of time, respectively. CONCLUSIONS: Using both CYP2C19 GOF and LOF alleles to select antiplatelet therapy appears to be the preferred antiplatelet strategy over universal clopidogrel and universal alternative P2Y12 inhibitor therapy for ACS patients with PCI.

Conversations in cardiology: bridging antiplatelet therapy before surgery.

Bridging for antiplatelet therapy remains a subject of debate with data favoring GP blockers but at a risk of bleeding. This Conversation in Cardiology addresses a key and often asked question about use of alternatives to P2Y12 agents in patients requiring surgery within 6 months after drug eluting stent implantation.

[Is long-term use of clopidogrel cost-effective in high-risk atherothrombotic patients?]. / L'utilisation prolongée du clopidogrel est-elle rentable chez les patients athérothrombotiques a haut risque?

The objective of the analysis is to estimate the long-term costs and effects of clopidogrel versus aspirin in the secondary prevention of ischemic events in patients with a history of more than one atherothrombotic event in Belgium. The following high-risk subpopulations within the CAPRIE trial were analysed: patients with a history of myocardial infarction (MI) or ischemic stroke (IS) prior to the event qualifying for enrolment and patients with prior multiple vascular territory involvement. A Markov model that combined clinical, epidemiological and cost data was used. The base case scenario was based on a treatment duration of 5 years reflecting the long-term use of clopidogrel. A lifelong time horizon was taken, by applying life expectancy data based on the Saskatchewan database. Belgian cost estimates were derived from publicly available sources and literature. Long-term clopidogrel treatment compared to aspirin in patients with a history of MI or IS prior to the event qualifying for enrolment is associated with an incremental cost-effectiveness ratio (ICER) ranging between 2.730 Euro per life year gained (LYG) for the first year of treatment and 8.000 Euro/LYG for a treatment duration of 5 years. In patients with prior multiple vascular territory involvement the ICER of clopidogrel compared to aspirin lays between 3.110 Euro and 5.750 Euro/LYG for the respective treatment durations. Use of clopidogrel for the prevention of subsequent cardiovascular events in patients with a history of more than one ischemic event is associated with favourable ICERs, independently of the presumed treatment duration. Sensitivity analyses varying life expectancy, efficacy of clopidogrel, costs of events and cost of adverse events and discount rates demonstrated the robustness of the results.

Clopidogrel versus aspirin in patients with atherothrombosis: CAPRIE-based calculation of cost-effectiveness for Germany.

OBJECTIVES: To model the 2-year cost-effectiveness of secondary prevention with clopidogrel versus aspirin (acetylsalicylic acid) (ASS) in German patients with myocardial infarction (MI), ischaemic stroke (IS) or diagnosed with peripheral arterial disease (PAD), based on CAPRIE trial data and from the perspective of German third party payers (TPP). METHODS: An existing Markov model was adapted to Germany by using German cost data. The model was extended by using different datasets for cardiovascular event survival times (Framingham vs. Saskatchewan health databases) and in two separate scenarios. RESULTS: The treatment with clopidogrel leads to a reduction of 13.19 vascular events per 1000 patients, of which 2.21 are vascular deaths. The overall incremental costs for the 2-year management of atherothrombotic patients with clopidogrel instead of ASS are calculated to be about euro1 241 440 per 1000 patients. The number of life-years saved (LYS) has been calculated as the difference in the number of life-years lost due to vascular death or events with ASS versus clopidogrel: it is 86.35 LYS when analysis is based on Framingham data and 66.07 LYS with Saskatchewan-based survival data. The incremental costs per LYS are euro14 380 and euro18 790, respectively. Cost-effectiveness is sensitive to changes in survival data, discounting and daily costs of clopidogrel, but stable against substantial (+/- 25%) changes in all other cost data. CONCLUSION: The findings for Germany are in line with published results for Belgium (euro13 390 per LYS) and also with results for Italy (euro17 500 per LYS), both based on Saskatchewan data, and with a French analysis based on Framingham data (euro15 907 per LYS). Even if no officially accepted cost-effectiveness threshold exists for Germany at present, incremental cost-effectiveness results of less than euro20 000 per LYS for the treatment with clopidogrel can be assumed to be acceptable for German third party payers.

Cost-effectiveness analysis of enoxaparin versus unfractionated heparin in the secondary prevention of acute coronary syndrome.

BACKGROUND: The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) and Thrombolysis in Myocardial Infarction (TIMI) 11B studies revealed that enoxaparin reduced the incidence of death, myocardial reinfarction and recurrent angina in patients with acute coronary syndrome (ACS) compared with unfractionated heparin (UFH). OBJECTIVE: To perform a pharmacoeconomic analysis to evaluate the cost effectiveness of treatment with enoxaparin compared with UFH in Spanish patients with ACS. DESIGN AND SETTING: Retrospective cost-effectiveness analysis using data and costs from Spanish sources, conducted from the perspective of the National Health System. PATIENTS, INTERVENTIONS AND OUTCOMES MEASURES: The study was based on the results of the ESSENCE and TIMI 11B clinical trials, which included more than 7,000 patients with ACS treated with enoxaparin or UFH. The main variables studied were the success rate, expressed as patients with no complications (reinfarction, unstable angina or death), and the decrease in the utilisation of healthcare resources (revascularisation procedures and hospitalisation). RESULTS: The base-case results of the analysis showed superior efficacy and lower total treatment and follow-up costs with enoxaparin compared with UFH. The total savings in direct health costs per patient with enoxaparin ranged between 448 and 659 euros (time horizons of 1 month and 1 year, respectively) [2001 values]. The sensitivity analysis results confirmed the advantage of enoxaparin in all cases, except in one scenario: when simultaneously using all the minimum values of the confidence interval for absolute risk reduction (ARR) in the utilisation of health resources. CONCLUSIONS: This study suggests that enoxaparin is a more effective and less expensive treatment option than UFH in secondary prevention of patients with ACS in Spain, confirming the results obtained in other pharmacoeconomic analyses performed in the UK, USA, France and Canada.

Cost-effectiveness of gamma radiation for treatment of in-stent restenosis: results from the Gamma-1 trial.

BACKGROUND: Recently, several randomized trials have demonstrated that intracoronary brachytherapy can reduce the rates of both angiographic and clinical restenosis in patients undergoing percutaneous coronary intervention (PCI) for in-stent restenosis. Whether this practice is cost-effective is unknown. METHODS AND RESULTS: Between December 1997 and July 1998, 252 patients with in-stent restenosis were randomized to receive brachytherapy or placebo after successful PCI as part of the Gamma-1 trial. We collected detailed resource utilization and cost data for each patient's initial hospitalization and for 1 year after randomization. Compared with conventional treatment, intracoronary brachytherapy increased procedure duration, physician services, and equipment costs. As a result, initial costs were increased by nearly $4100 per patient ($15 724 versus $11 675, P<0.001). Over the 1-year follow-up period, brachytherapy reduced the need for repeat revascularization by 21% and reduced the need for bypass surgery by 44%. Although follow-up medical care costs were $2200/patient lower with brachytherapy, total costs remained higher at 1 year ($28 543 versus $26 737, P=0.46). In a sensitivity analysis that incorporated recent technical modifications and the use of prolonged antiplatelet therapy to prevent late thrombotic occlusion, follow-up cost savings increased to $3600/patient, and 1-year costs were slightly lower with brachytherapy ($26 352 versus $26 729, P=0.87). Subgroup analysis demonstrated significant cost savings in patients with diabetes and patients who did not undergo repeat stenting. CONCLUSIONS: As performed in the Gamma-1 trial, coronary brachytherapy for in-stent restenosis improved clinical outcomes but increased 1-year costs compared with standard therapy. If late thrombosis can be eliminated, however, this technology has the potential to reduce overall medical care costs.

Current clinical characteristics and economic impact of subacute stent thrombosis.

Subacute stent thrombosis (SAT), while uncommon, continues to produce serious clinical consequences, including major myocardial infarction (MI) in 60 70% of cases, and short-term mortality rates of 20% or higher. A number of procedural and patient factors have been shown to predict the occurrence of SAT, including longer stent length, smaller minimum luminal diameter, persistent dissection, multivessel intervention, and possibly acute coronary syndrome (ACS) presentation. Despite substantial knowledge about the clinical and technical aspects of SAT, the economic impact of these events has not been previously reported. Methods. We retrospectively reviewed 26 cases of SAT that occurred at our institution from 1998-2000. Baseline clinical and procedural data, as well as clinical outcomes for the initial hospital admissions required to treat SAT, were obtained by record review. Direct health care costs for these admissions were calculated based on hospital billing data and measured resource utilization for catheterization laboratory procedures. Results. Most cases of SAT occurred in high-risk circumstances, including ACSs, multi-stent interventions, and treatment of 3.0 mm or smaller vessels. Most patients suffered significant MIs and were treated with repeat percutaneous coronary intervention. The median time to SAT was 3.5 days, with 58% of events occurring on an outpatient basis. Median total hospital costs were $11,100 per patient, with more than half of the costs generated by the catheterization laboratory and pharmacy. Conclusions. Despite its low overall frequency, the clinical and economic costs of SAT are substantial. Specific strategies at preventing its occurrence are warranted, particularly in high-risk situations.

Economic assessment of rheolytic thrombectomy versus intracoronary urokinase for treatment of extensive intracoronary thrombus: Results from a randomized clinical trial.

BACKGROUND: Despite advances in mechanical and pharmacologic therapy, thrombus-containing lesions are at high risk for adverse events and remain a challenging subset for percutaneous coronary revascularization. Recently, rheolytic thrombectomy with the AngioJet device has been shown to safely remove intracoronary thrombus, but the overall cost-effectiveness of this technique is unknown. METHODS: We determined in-hospital and 1-year follow-up costs for 349 patients with overt intracoronary thrombus who were randomly assigned to treatment with intracoronary urokinase (6- to 30-hour infusion followed by definitive revascularization; n = 169) or immediate thrombectomy with the AngioJet device (n = 180) as part of the Vein Graft AngioJet Study (VeGAS) 2 trial. Catheterization laboratory costs were based on measured resource utilization and 1998 unit costs, whereas all other costs were estimated from hospital charges and cost center-specific cost-to-charge ratios. RESULTS: Compared with urokinase, rheolytic thrombectomy reduced the incidence of periprocedural myocardial infarction (12.8% vs 30.3%, P <.001) and major hemorrhagic complications (2.8% vs 11.2%, P <.001) and shortened length of stay by nearly 1 day (4.2 vs 4.9 days; P =.02). As a result, AngioJet treatment reduced procedural costs, hospital room/nursing costs, and ancillary costs with resulting hospital cost savings of approximately $3500 per patient during the initial hospitalization ($15,311 vs $18,841, P <.001). These cost savings were maintained at 1 year of follow-up ($24,389 vs $29,109, P <.001). CONCLUSIONS: Compared with standard treatment with intracoronary urokinase, rheolytic thrombectomy both improves clinical outcomes and reduces overall medical care costs for patients with extensive intracoronary thrombus.

A cost-effectiveness model for coronary thrombolysis/reperfusion therapy.

A model was designed to examine the relations between incremental costs and benefits of coronary thrombolysis/reperfusion therapy. The model allows for the study of intravenous and intracoronary streptokinase, intravenous tissue plasminogen activator and primary angioplasty. Three strategies for the management of reocclusion are also compared. It was found that each of the following four variables can be responsible for a 2- to 15-fold variation in the costs per additional survivor: 1) the quantity of jeopardized myocardium, 2) the duration of coronary occlusion before the onset of therapy, 3) the time required from the onset of therapy until reperfusion is achieved, and 4) the reocclusion management strategy. Therapeutic strategies involving intravenous administration of thrombolytic agents were found to be consistently more cost effective than were strategies involving intracoronary administration of thrombolytic agents and primary angioplasty. In patients with a large or moderate-sized infarct, proper selection of intravenous protocols and reocclusion management strategies leads to costs of $7,000 to $100,000/additional survivor, costs that are similar to those of many generally accepted medical practices. Substantially higher costs per additional survivor are incurred with the routine use of thrombolytic therapy in patients with a small infarct or the routine use of coronary artery bypass surgery to reduce the risk of reocclusion after successful thrombolytic therapy. Decisions regarding which patients should receive thrombolysis/reperfusion therapy depend on society's willingness to pay for its incremental benefits.