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.

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).

Efficacy and safety of rivaroxaban plus aspirin in women and men with chronic coronary or peripheral artery disease.

AIMS: The COMPASS trial demonstrated that the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced major adverse cardiovascular events (MACE) in patients with chronic coronary artery disease or peripheral artery disease by 24% during a mean follow-up of 23 months. We explored whether this effect varies by sex. METHODS AND RESULTS: The effects were examined in women and men using log-rank tests and Kaplan-Meier curve. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were obtained from stratified Cox proportional hazards models to explore subgroup effects including subgroup of women and men according to baseline modified REACH risk score. Of 27 395 patients randomized, 18 278 were allocated to receive rivaroxaban plus aspirin (n = 9152) or aspirin alone (n = 9126), and of these, 22.1% were women. Women compared with men had similar incidence rates for MACE and major bleeding but borderline lower rates for myocardial infarction (1.7% vs. 2.2%, P = 0.05). The effect of combination therapy compared with aspirin in women and men was consistent for MACE (women: 3.8% vs. 5.2%, HR 0.72, 95% CI 0.54-0.97; men: 4.2% vs. 5.5%, HR 0.76, 95% CI 0.66-0.89; P interaction 0.75) and major bleeding (women: 3.1% vs. 1.4%, HR 2.22, 95% CI 1.42-3.46; men: 3.2% vs. 2.0%, HR 1.60, 95% CI 1.29-1.97; P interaction 0.19). There was no significant interaction between randomized treatment and baseline modified REACH score above or below the median for MACE or major bleeding. CONCLUSION: In patients with stable coronary artery disease or peripheral artery disease, the combination of rivaroxaban (2.5 mg twice daily) and aspirin compared with aspirin alone appears to produce consistent benefits in women and men, independent of baseline cardiovascular risk.

The role of randomized cluster crossover trials for comparative effectiveness testing in anesthesia: design of the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial.

Increasingly, clinicians and researchers recognize that studies of interventions need to evaluate not only their therapeutic efficacy (i.e., the effect on an outcome in ideal, controlled settings) but also their real-world effectiveness in broad, unselected patient groups. Effectiveness trials inform clinical practice by comparing variations in therapeutic approaches that fall within the standard of care. In this article, we discuss the need for studies of comparative effectiveness in anesthesia and the limitations of individual patient randomized-controlled trials in determining comparative effectiveness. We introduce the concept of randomized cluster crossover trials as a means of answering questions of comparative effectiveness in anesthesia, using the design of the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial (Clinicaltrials.gov identifier NCT03053869).

Effect of apixaban on brain infarction and microbleeds: AVERROES-MRI assessment study.

BACKGROUND: Clinical and subclinical (covert) stroke is a cause of cognitive loss and functional impairment. In the AVERROES trial, we performed serial brain magnetic resonance imaging (MRI) scans in a subgroup to explore the effect of apixaban, compared with aspirin, on clinical and covert brain infarction and on microbleeds in patients with atrial fibrillation. METHODS: We performed brain MRI (T1, T2, fluid-attenuated inversion recovery, and T2* gradient echo sequences) in 1,180 at baseline and in 931 participants at follow-up. Mean interval from baseline to follow-up MRI scans was 1.0 year. The primary outcome was a composite of clinical ischemic stroke and covert embolic pattern infarction (defined as infarction >1.5 cm, cortical-based infarction, or new multiterritory infarction). Secondary outcomes included new MRI-detected brain infarcts and microbleeds and change in white matter hyperintensities. RESULTS: Baseline MRI scans revealed brain infarct(s) in 26.2% and microbleed(s) in 10.5%. The rate of the primary outcomes was 2.0% in the apixaban group and 3.3% in the aspirin group (hazard ratio [HR] 0.55; 0.27-1.14) from baseline to follow-up MRI scan (mean duration of follow-up: 1 year). In those who completed baseline and follow-up MRI scans, the rate of new infarction detected on MRI was 2.5% in the apixaban group and 2.2% in the aspirin group (HR 1.09; 0.47-2.52), but new infarcts were smaller in the apixaban group (P = .03). There was no difference in proportion with new microbleeds on follow-up MRI (HR 0.92; 0.53-1.60) between treatment groups. CONCLUSIONS: Apixaban treatment was associated with a nonsignificant trend toward reduction in the composite of clinical ischemic stroke and covert embolic-pattern infarction and did not increase the number of microbleeds in patients with atrial fibrillation compared with aspirin.

Efficacy of Hospital at Home in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

BACKGROUND: Heart failure (HF) is the commonest cause of hospitalization in older adults. Compared to routine hospitalization (RH), hospital at home (HaH)--substitutive hospital-level care in the patient's home--improves outcomes and reduces costs in patients with general medical conditions. The efficacy of HaH in HF is unknown. METHODS AND RESULTS: We searched MEDLINE, Embase, CINAHL, and CENTRAL, for publications from January 1990 to October 2014. We included prospective studies comparing substitutive models of hospitalization to RH in HF. At least 2 reviewers independently selected studies, abstracted data, and assessed quality. We meta-analyzed results from 3 RCTs (n = 203) and narratively synthesized results from 3 observational studies (n = 329). Study quality was modest. In RCTs, HaH increased time to first readmission (mean difference (MD) 14.13 days [95% CI 10.36 to 17.91]), and improved health-related quality of life (HrQOL) at both, 6 months (standardized MD (SMD) -0.31 [-0.45 to -0.18]) and 12 months (SMD -0.17 [-0.31 to -0.02]). In RCTs, HaH demonstrated a trend to decreased readmissions (risk ratio (RR) 0.68 [0.42 to 1.09]), and had no effect on all-cause mortality (RR 0.94 [0.67 to 1.32]). HaH decreased costs of index hospitalization in all RCTs. HaH reduced readmissions and emergency department visits per patient in all 3 observational studies. CONCLUSIONS: In the context of a limited number of modest-quality studies, HaH appears to increase time to readmission, reduce index costs, and improve HrQOL among patients requiring hospital-level care for HF. Larger RCTs are necessary to assess the effect of HaH on readmissions, mortality, and long-term costs.

Patient outcomes using the European label for dabigatran. A post-hoc analysis from the RE-LY database.

In the RE-LY trial dabigatran 150 mg twice daily (D150) showed significantly fewer strokes, and 110 mg (D110) significantly fewer major bleeding events (MBE) compared to well-controlled warfarin in patients with atrial fibrillation (AF). The European (EU) label currently recommends the use of D150 in AF patients who are aged < 80 years without an increased risk for bleeding (e.g. HAS-BLED score <3) and not on concomitant verapamil. In other patients, D110 is recommended. In this post-hoc analysis of the RE-LY dataset, we simulated how dabigatran (n=6,004) would compare to well-controlled warfarin (n=6,022) used according to the EU label. "EU label simulated dabigatran treatment" was associated with significant reductions in stroke and systemic embolism (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.60-0.91), haemorrhagic stroke (HR 0.22; 95%CI 0.11-0.44), death (HR 0.86; 95%CI 0.75-0.98), and vascular death (HR 0.80; 95%CI 0.68-0.95) compared to warfarin. Dabigatran was also associated with less major bleeding (HR 0.85; 95%CI 0.73-0.98), life-threatening bleeding (HR 0.72; 95%CI 0.58-0.91), intracranial haemorrhage (HR 0.28; 95%CI 0.17-0.45), and "any bleeds" (HR 0.86; 95%CI 0.81-0.92), but not gastrointestinal major bleeding (HR 1.23; 95%CI 0.96-1.59). The net clinical benefit was significantly better for dabigatran compared to warfarin. In conclusion, this post-hoc simulation of dabigatran usage based on RE-LY trial dataset indicates that "EU label simulated dabigatran treatment" may be associated with superior efficacy and safety compared to warfarin, and are in support of the EU label and the 2012 European Society of Cardiology AF guideline recommendations. Thus, adherence to European label/guideline use results in a clinically relevant benefit for dabigatran over warfarin, for both efficacy and safety.

Cost-effectiveness of dronedarone in patients with atrial fibrillation in the ATHENA trial.

BACKGROUND: The ATHENA trial randomized 4628 patients with atrial fibrillation (AF) or atrial flutter, aged ≥ 70 years with risk factors or ≥ 75 years without risk factors, to receive 400 mg dronedarone twice daily or placebo in addition to standard therapy. Our objective was to evaluate the cost-effectiveness of dronedarone from a Canadian health care perspective based on resource utilization and cardiovascular hospitalization or death in ATHENA. METHODS: Data on medical resource utilization (cardiovascular hospitalizations, hospitalization because of treatment-related adverse events, outpatient examinations and procedures, study drug and concomitant medications) were aggregated for all randomized patients during the entire trial period (mean 21 months). Effectiveness was measured using the total number of avoided cardiovascular hospitalizations and deaths from any cause, and projected survival and quality-adjusted survival using life tables adjusted for AF mortality and data on determinants of utility in AF. We used standard unit costs from Canada (2008), discounting costs and effects at 5% per year. RESULTS: Patients receiving dronedarone incurred a mean total cost (undiscounted) of CAD $7402 during the trial period, compared with CAD $6708 for patients receiving placebo. The cost of dronedarone was partly offset by savings for cardiovascular hospitalizations and concomitant medications. On average, patients taking dronedarone experienced 0.18 fewer events (cardiovascular hospitalizations or death). The cost per event avoided was CAD $3807, the cost per life-year gained was CAD $5204, and the cost per quality-adjusted life-years was CAD $7560. CONCLUSIONS: Compared with generally accepted thresholds, our results indicate that treatment with dronedarone as in ATHENA is cost-effective.

Modification of outcomes with aspirin or apixaban in relation to CHADS(2) and CHA(2)DS(2)-VASc scores in patients with atrial fibrillation: a secondary analysis of the AVERROES study.

BACKGROUND: The impact of apixaban versus aspirin on ischemic stroke and major bleeding in relation to the CHADS(2) and CHA(2)DS(2)-VASc stroke risk scores in atrial fibrillation has not been investigated. METHODS AND RESULTS: In this secondary analysis of the AVERROES trial, our principal objective was to assess the effect of treatment with aspirin or apixaban on ischemic stroke and major bleeding, in relation to the CHADS(2)/CHA(2)DS(2)-VASc scores. We found no significant heterogeneity for treatment efficacy on ischemic stroke for apixaban when subdivided by stroke risk strata, based on CHADS(2)/CHA(2)DS(2)-VASc. Effects were consistent irrespective of baseline risk, and thus, absolute benefits were greatest in the high-risk groups. There was also no significant heterogeneity for apixaban versus aspirin with regard to major bleeding, when subdivided by CHADS(2)/CHA(2)DS(2)-VASc scores. In multivariable analysis, significant predictors of stroke on aspirin were age ≥75 years, prior stroke or transient ischemic attack, estimated glomerular filtration rate <60 mL/min, and nonparoxysmal atrial fibrillation. Proportions of the study cohort classified as low/moderate/high risk using the CHADS(2) and CHA(2)DS(2)-VASc scores were 0.3%/71.7%/28.1% and <0.1%/10.5%/89.5%, respectively. CONCLUSIONS: In an atrial fibrillation population, apixaban was superior to aspirin for stroke prevention, with similar rates of major bleeding, in the presence of one or more stroke risk factors, with consistency of the treatment effect by CHADS(2)/CHA(2)DS(2)-VASc scores.

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.

Canadian Registry of ICD Implant Testing procedures (CREDIT): current practice, risks, and costs of intraoperative defibrillation testing.

BACKGROUND: There is uncertainty about the proper role of defibrillation testing (DT) at the time of implantable cardioverter defibrillator (ICD) insertion. METHODS: A prospective registry was conducted at 13 sites in Canada between January 2006 and October 2007. OBJECTIVES: To document the details of DT, the reasons for not conducting DT, and the costs and complications associated with DT. RESULTS: DT was conducted at implantation in 230 of 361 patients (64%). DT was more likely to be conducted for new implants compared with impulse generator replacements (71% vs 32%, P = 0.0001), but was similar for primary and secondary prevention indications (64% vs 63%, P = NS). Among patients not having DT, the reason(s) given were: considered unnecessary (44%); considered unsafe, mainly due to persistent atrial fibrillation (37%); lack of an anesthetist (20%); and, patient or physician preference (6%). When performed, DT consisted of a single successful shock > or = 10J below maximum device output in 65% of cases. A 10J safety-margin was met by 97% of patients, requiring system modification in 2.3%. Major perioperative complications occurred in 4.4% of patients having DT versus 6.6% of patients not having DT (P = NS). ICD insertion was $844 more expensive for patients having DT (P = 0.16), largely due to increased costs ($28,017 vs $24,545) among patients having impulse generator replacement (P = 0.02). CONCLUSIONS: DT was not performed in a third of ICD implants, usually due to a perceived lack of need or relative contraindication.

Assessment of resynchronization therapy on functional status and quality of life in patients requiring an implantable defibrillator.

BACKGROUND: The effect of cardiac resynchronization therapy (CRT) on physical function and Quality of Life (QoL) in patients who require an implantable defibrillator but do not meet guideline criteria for CRT has not been studied in detail. METHODS AND RESULTS: This was a randomized study of 72 patients with high risk of sudden cardiac death, ejection fraction (EF) < or =35%, mild-to-moderate heart failure symptoms, and QRS > 120 ms. Patients received a CRT defibrillator and were randomized to CRT turned ON or OFF. Objective and subjective measures were performed at baseline and after 6 months. There was no difference in change in left ventricular end-systolic volume (ESV) by radionuclid angiogram scan, the primary endpoint, between the CRT ON group (DeltaESV =-7 +/- 52 mL), and CRT OFF group (DeltaESV =-30 +/- 47 mL). Similarly, echocardiogram measures of ESV and EF showed no difference between the two groups. In the CRT ON group, selected measures of QoL and subjective exercise tolerance but not heart failure symptoms improved significantly. Six-minute walk distance prolonged in the CRT ON group (baseline 313.6 +/- 114.4 m, 6-month 365.0 +/- 122.5 m, P = 0.01), but the difference in change in walk distance between the two groups was not significant. CONCLUSION: Further studies with larger sample size and longer follow-up will be required to allow definite conclusions regarding the potential benefit of CRT in this patient population.

Cost-effectiveness of physiologic pacing: results of the Canadian Health Economic Assessment of Physiologic Pacing.

OBJECTIVES: The purpose of this study was to determine the cost-effectiveness of physiologic pacemakers. BACKGROUND: The Canadian Trial of Physiologic Pacing (CTOPP) was a large randomized trial that evaluated the efficacy of physiologic pacing compared with ventricular pacing. CTOPP also included a prospective cost-effectiveness substudy. METHODS: Resource usage and costs were collected from a subset of 472 patients (of 1,094) who received a physiologic pacemaker and 586 (of 1,474) who received a ventricular pacemaker. Costs included initial pacemaker implantation and all health care follow-up costs over a follow-up of 5.2 years. Costs are reported in 2004 Canadian dollars (1 Canadian dollar = 0.76 US dollars), with adjustments for censoring. Incremental cost-effectiveness was estimated as the ratio of the difference (treatment-control) in mean cost to the difference in life expectancy (mean survival), with costs and effects discounted at 3% per year. RESULTS: Over a mean follow-up of 3.1 years, physiologic pacing was associated with a gain of 0.01 life-years. This benefit increases to 0.25 life-years in the subgroup of patients with an intrinsic (unpaced) heart rate < or =60 bpm. Physiologic pacing was more expensive than ventricular (16,833 Canadian dollars vs 13,857 US dollars), largely because of the increased cost of dual-chamber devices. Among all substudy patients, the incremental cost-effectiveness of physiologic pacing is 297,600 Canadian dollars per life-year gained; however, this value falls to 16,343 Canadian dollars in patients with an intrinsic heart rate >60. CONCLUSIONS: In the short term, a strategy of routine implantation of physiologic pacemakers is not cost-effective by currently accepted standards. The selective use of these devices in patients likely to be pacemaker dependent appears to be cost-effective. Further studies with longer follow-up and which consider the benefit of reducing nonfatal cardiac events would be valuable.

Double-blind, placebo-controlled, randomized trial of prophylactic metoprolol for reduction of hospital length of stay after heart surgery: the beta-Blocker Length Of Stay (BLOS) study.

BACKGROUND: Atrial fibrillation (AF) is a common complication of heart surgery. Previous studies have shown that there is an association between postoperative AF and prolongation of hospital length of stay. No previous trials have been primarily directed at demonstrating that the use of drugs that prevent AF would shorten length of stay and reduce the costs of postoperative care. METHODS: A randomized, double-blind, placebo-controlled trial of metoprolol was performed in patients immediately after nonemergent heart surgery. Metoprolol was given orally at a dose of 100 mg per day after the patient's arrival in the intensive care unit until hospital discharge or 14 days, whichever was sooner. This dose was increased to 150 mg per day after the enrollment of 411 patients. The primary outcome measure of the study was hospital length of stay from admission to intensive care unit until hospital discharge. There were 1000 patients enrolled, evenly distributed to the metoprolol and placebo groups. RESULTS: There was a 20% reduction in the risk of AF developing with metoprolol, from 39% of patients to 31% of patients (P =.01). There was no effect of treatment on hospital length of stay, which was 152 +/- 61 hours for placebo and 155 +/- 90 hours for metoprolol (P = 0.79). The cost of postoperative care in the 2 treatment groups was similar. CONCLUSION: Prophylactic metoprolol reduces the risk of AF after heart surgery. It does not reduce hospital length of stay. Although it is cost effective for the reduction of AF, it did not reduce the overall cost of care.