Effectiveness, utilisation and cost associated with implantable loop recorders versus external monitors after ischaemic or cryptogenic stroke.

OBJECTIVE: Implantable loop recorders (ILRs) are increasingly used for long-term rhythm monitoring after ischaemic and cryptogenic stroke, with the goal of detecting atrial fibrillation (AF) and subsequent initiation of oral anticoagulation to reduce risk of adverse clinical outcomes. There is a need to determine the effectiveness of different rhythm monitoring strategies in this context. METHODS: We conducted a retrospective cohort analysis of individuals with commercial and Medicare Advantage insurance in Optum Labs Data Warehouse who had incident ischaemic or cryptogenic stroke and no prior cardiovascular implantable electronic device from 1 January 2016 to 30 June 2021. Patients were stratified by rhythm monitoring strategy: ILR, long-term continuous external cardiac monitor (>48 hours to 30 days) or Holter monitor (≤48 hours). The primary outcome was risk-adjusted all-cause mortality at 12 months. Secondary outcomes included new diagnosis of AF and oral anticoagulation, bleeding, and costs. RESULTS: Among 48 901 patients with ischaemic or cryptogenic stroke, 9235 received an ILR, 29 103 long-term continuous external monitor and 10 563 Holter monitor only. Mean age was 69.9 (SD 11.9) years and 53.5% were female. During the 12-month follow-up period, patients who received ILRs compared with those who received long-term continuous external monitors had a higher odds of new diagnosis of AF and oral anticoagulant initiation (adjusted OR 2.27, 95% CI 2.09 to 2.48). Compared with patients who received long-term continuous external monitors, those who received ILRs had similar 12-month mortality (HR 1.00; 95% CI 0.89 to 1.12), with approximately $13 000 higher costs at baseline (including monitor cost) and $2500 higher costs during 12-month follow-up. CONCLUSIONS: In this large real-world study of patients with ischaemic or cryptogenic stroke, ILR placement resulted in more diagnosis of AF and initiation of oral anticoagulation, but no difference in mortality compared with long-term continuous external monitors.

Timing of Anticoagulation after Stroke in Patients with Non-Valvular Atrial Fibrillation Assessment of Provider Practices.

BACKGROUND: Optimal timing of oral anticoagulation (TOAC) in acute ischemic stroke (AIS) in patients with atrial fibrillation (AF) is unknown. The risk of recurrent ischemic events when treatment is delayed is often weighed against that of hemorrhagic transformation (HT) when anticoagulation is started in the subacute phase, especially in moderate to large infarctions. Despite substantial evidence for the benefit of oral anticoagulation (OAC) in reducing stroke recurrence, current nationally recognized practice guidelines do not provide clear recommendations on the TOAC after AF-related AIS. MATERIALS AND METHODS: We surveyed neurologists on therapeutic approaches to timing of anticoagulation after stroke in patients with AF (without moderate or severe mitral stenosis or a mechanical heart valve) using an online questionnaire. Several ischemic and hemorrhagic stroke scenarios with various stroke sizes, locations, and high-risk thrombotic complications were presented, and survey respondents were asked to provide post-stroke timeframe for TOAC. Practice background, specialty and years of experience of respondents were recorded. RESULTS: Majority of participants favored early initiation of OAC in small infarcts. In moderate to larger infarct burden, or when ischemia was complicated by HT, there was an overall trend to delay any initiation of OAC, irrespective of specialty or years of experience. The overt presence of an additional cardiac embolic source such as cardiac thrombus led decisions for early anticoagulation. CONCLUSION: Although general practice trends were captured, optimal TOAC following AIS in AF remains unknown. Further research is warranted to determine optimal timing and anticoagulant selection.

Anticonvulsant Primary and Secondary Prophylaxis for Acute Ischemic Stroke Patients: A Decision Analysis.

Background and Purpose: We examined the impact of 3 anticonvulsant prophylaxis strategies on quality-adjusted life-years (QALYs) among patients with an incident acute ischemic stroke. Methods: We created a decision tree to evaluate 3 strategies: (1) long-term primary prophylaxis; (2) short-term secondary prophylaxis after an early seizure with lifetime prophylaxis if persistent or late seizures (LSs) developed; and (3) long-term secondary prophylaxis if either early, late, or persistent seizures developed. The outcome was quality-adjusted life expectancy (QALY). We created 4 base cases to simulate common clinical scenarios: (1) female patient aged 40 years with a 2% or 11% lifetime risk of an LS and a 33% lifetime risk of an adverse drug reaction (ADR); (2) male patient aged 65 years with a 6% or 29% LS risk and 60% ADR risk; (3) male patient aged 50 years with an 18% or 65% LS risk and 33% ADR risk; and (4) female patient aged 80 years with a 29% or 83% LS risk and 80% ADR risk. In sensitivity analyses, we altered the parameters and assumptions. Results: Across all 4 base cases, primary prophylaxis yielded the fewest QALYs when compared with secondary prophylaxis. For example, under scenario 1, strategies 2 and 3 resulted in 7.17 QALYs each, but strategy 1 yielded only 6.91 QALYs. Under scenario 4, strategies 2 and 3 yielded 2.85 QALYs compared with 1.40 QALYs for strategy 1. Under scenarios in which patients had higher ADR risks, strategy 2 led to the most QALYs. Conclusions: Short-term therapy with continued anticonvulsant prophylaxis only after postischemic stroke seizures arise dominates lifetime primary prophylaxis in all scenarios examined. Our findings reinforce the necessity of close follow-up and discontinuation of anticonvulsant seizure prophylaxis started during acute ischemic stroke hospitalization.

Cost-Effectiveness Analysis of Percutaneous Patent Foramen Ovale Closure Preventing Secondary Ischemic Stroke in Japan.

OBJECTIVES: Patent foramen ovale is a hemodynamically insignificant interatrial communication that may cause ischemic stroke. Percutaneous patent foramen ovale closure reduces the risk for recurrent ischemic stroke in patients with a history of cryptogenic ischemic stroke. This study evaluated the cost-effectiveness of patent foramen ovale closure against medical therapy in patients after their first cryptogenic ischemic stroke in Japan. MATERIALS AND METHODS: The cost-effectiveness of patent foramen ovale closure compared with medical therapy was evaluated using the Markov model. The target patients started with patent foramen ovale closure or medical therapy for preventing secondary ischemic stroke under a stable state. Quality-adjusted life year was used as the outcome of effectiveness, and the analysis was conducted with a discount rate of 2% applied to both cost and effectiveness. The results of a multicenter open-label randomized controlled trial (RESPECT trial) evaluating patent foramen ovale closure using the Amplatzer™ PFO Occluder were used as clinical evidence. Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio. It was evaluated as cost-effective if it was lower than 5 million JPY/ quality-adjusted life year. RESULTS: Patent foramen ovale closure was dominant over medical therapy by 2.53 quality-adjusted life years and an estimated cost reduction of 2,353,926 JPY. The probability of patent foramen ovale closure being dominant was 82.9%. CONCLUSIONS: Patent foramen ovale closure was dominant over medical therapy for preventing secondary ischemic stroke in patients with cryptogenic ischemic stroke.

Burden of oral anticoagulation in embolic stroke of undetermined source without atrial fibrillation.

OBJECTIVE: Prevention of recurrent stroke in patients with embolic stroke of undetermined source (ESUS) is challenging. The advent of safer anticoagulation in the form of direct oral anticoagulants (DOACs) has prompted exploration of prophylactic anticoagulation for all ESUS patients, rather than anticoagulating just those with documented atrial fibrillation (AF). However, recent trials have failed to demonstrate a clinical benefit, while observing increased bleeding. We modeled the economic impact of anticoagulating ESUS patients without documented AF across multiple geographies. METHODS: CRYSTAL-AF trial data were used to assess ischaemic stroke event rates in ESUS patients confirmed AF-free after long-term monitoring. Anticipated bleeding event rates (including both minor and major bleeds) with aspirin, dabigatran 150 mg, and rivaroxaban 20 mg were sourced from published meta-analyses, whilst a 30% ischaemic stroke reduction for both DOACs was assumed. Cost data for clinical events and pharmaceuticals were collected from the local payer perspective. RESULTS: Compared with aspirin, dabigatran and rivaroxaban resulted in 17.9 and 29.9 additional bleeding events per 100 patients over a patient's lifetime, respectively. Despite incorporating into our model the proposed 30% reduction in ischaemic stroke risk, both DOACs were cost-additive over patient lifetime, as the costs of bleeding events and pharmaceuticals outweighed cost savings associated with the reduction in ischaemic strokes. DOACs added £5953-£7018 per patient (UK), €6683-€7368 (Netherlands), €4933-€9378 (Spain), AUD$5353-6539 (Australia) and $26,768-$32,259 (US) of payer cost depending on the agent prescribed. Additionally, in the U.S. patient pharmacy co-payments ranged from $2468-$12,844 depending on agent and patient plan. In all settings, cost-savings could not be demonstrated even when the modelling assumed 100% protection from recurrent ischaemic strokes, due to the very low underlying risk of recurrent ischaemic stroke in this population (1.27 per 100 patient-years). CONCLUSIONS: Anticoagulation of non-AF patients may cause excess bleeds and add substantial costs for uncertain benefits, suggesting a personalised approach to anticoagulation in ESUS patients.

Effect of Intensive Versus Standard Blood Pressure Control on Stroke Subtypes.

[Figure: see text].

CKD Progression in Medicare Beneficiaries With Nonvalvular Atrial Fibrillation Treated With Apixaban Versus Warfarin.

RATIONALE & OBJECTIVE: Comparing kidney disease progression among patients treated with direct oral anticoagulants (DOACs) versus warfarin has not been well studied. We hypothesized that apixaban would be associated with lower risks of progression of chronic kidney disease (CKD) and progression to incident kidney failure than warfarin in patients with atrial fibrillation (AF). STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Medicare recipients with stage 3, 4, or 5 CKD and incident AF who received a new prescription for apixaban or warfarin from 2013 through 2017. EXPOSURE: Apixaban or warfarin. OUTCOMES: Progression to incident kidney failure or, separately, to a more advanced stage of CKD. ANALYTICAL APPROACH: Marginal structural cause-specific proportional hazards models with inverse probability weighting to estimate marginal hazard ratios (HRs) for each outcome. HRs compared apixaban to warfarin in intention-to-treat and censored-at-drug-switch analyses. RESULTS: 12,816 individuals met inclusion criteria (50.3% received apixaban; 49.7% received warfarin). After weighting, the mean age of the cohort was 80 ± 7 years, 51% were women, and 88% were White. Approximately 84% had stage 3, 15% had stage 4, and 1% had stage 5 CKD. In the intention-to-treat analysis, apixaban, relative to warfarin, was associated with an HR of developing incident kidney failure of 0.98 (95% confidence interval [CI], 0.79-1.22) and of CKD stage progression of 0.90 (95% CI, 0.82-0.99). Corresponding HRs for censored-at-drug-switch analyses were 0.81 (95% CI, 0.56-1.17) and 0.81 (95% CI, 0.70-0.92). Results were similar for a series of subgroup and sensitivity analyses. LIMITATIONS: CKD was defined based on diagnosis codes from claims; findings may not be generalizable to non-Medicare CKD populations. CONCLUSIONS: Apixaban, compared with warfarin, was associated with lower risk of CKD stage progression, but not with incident kidney failure.

Synthesis of systematic reviews of percutaneous device closure of patent foramen ovale (PFO) for prevention of recurrent cryptogenic stroke: Redundant publications and methodological deficiencies.

Critical assessments of systemic reviews and meta-analyses have found them to often be redundant, lacking in novel perspectives, of poor methodological quality, and written by authors with potential conflicts of interest. We sought to investigate these issues as they relate to systemic reviews and meta-analyses of percutaneous patent foramen ovale closure for the prevention of recurrent cryptogenic stroke.

Assessment of Trends in Statin Therapy for Secondary Prevention of Atherosclerotic Cardiovascular Disease in US Adults From 2007 to 2016.

Importance: Atherosclerotic cardiovascular disease (ASCVD) is highly prevalent in the US, with studies indicating substantial rates of nonadherence to and undertreatment with statin therapy. The 2013 American College of Cardiology/American Heart Association guideline recommended high-intensity statins for all patients age 75 years and younger with documented ASCVD in whom such therapy is tolerated, but there is limited evidence documenting population trends of statin use, adherence, and outcomes in the periods before and after the update to the guideline. Objective: To assess trends in the use, adherence, cost, and outcomes of statin therapy for secondary prevention in patients with different types of ASCVD between 2007 and 2016. Design, Setting, and Participants: This retrospective cohort study used data from the OptumLab Data Warehouse database containing privately insured and Medicare Advantage enrollees with demographic characteristics similar to the national US population. Participants were adult patients (age ≥21 years) who had their first ASCVD event between January 1, 2007, and December 31, 2016. Data were characterized as belonging to 3 groups: (1) cardiovascular heart disease (CHD); (2) ischemic stroke or transient ischemic attack (TIA); and (3) peripheral artery disease (PAD). Data were analyzed from July 1 to August 1, 2018. Exposures: Calendar year of the initial ASCVD event. Main Outcomes and Measures: Trends in the statin use (within 30 days of discharge from hospitalization), adherence (proportion of days covered ≥80% within the first year), cost, major adverse cardiac events (1-year cumulative risk), and statin intolerance (within the first year). Results: Of the 284 954 patients with a new ASCVD event, 128 422 (45.1%) were women; the median age was 63 years (interquartile range [IQR], 54-72 years); 207 781 (72.9%) were White. The use of statins increased from 50.3% in 2007 to 59.9% in 2016, the use of high-intensity statins increased from 25.0% to 49.2%, and the adherence increased from 58.7% to 70.5% (P < .001 for all trends). Patients with CHD were more likely to receive statins and high-intensity statins and adhere to medications than patients with ischemic stroke, TIA, or PAD despite similar observed treatment benefit. In 2016, 80.9% of patients with CHD used a statin vs 65.8% of patients with ischemic stroke or TIA and 37.5% of patients with PAD. Out-of-pocket cost per 30-day decreased from a median of $20 (interquartile range, $7.6-$31.9) in 2007 to $2 (interquartile range, $1.6-$10.0) in 2016 (P < .001) with the increasing use of generic statins (42.0% in 2007 vs 94.9% in 2016; P < .001). Major adverse cardiac events decreased from 8.9% in 2007 to 6.5% in 2016 (P < .001) whereas statin intolerance increased from 4.0% to 5.1% (P < .001). Conclusions and Relevance: There have been modest improvements in the use, adherence, and cardiovascular outcomes over the past decade for statin therapy in patients with ASCVD, but a substantial and persistent treatment gap exists between patients with and without CHD, between men and women.

The role of device closure of patent foramen ovale in patients with cryptogenic stroke.

One of the most frequent causes of cardiac embolism in cryptogenic stroke is a paradoxical embolus, which originate from systemic venous source though an unidentified patent foramen ovale (PFO). PFO is a common finding in the general population with a prevalence of 25% to 30%. Transcatheter PFO device closure is known to be feasible and safety treatment for such patients. In recent years, several randomized controlled trials (RCTs) have been conducted to address the superiority of PFO closure over medical therapy alone in the prevention of stroke recurrence in patients with PFO. In contrast to findings from early 3 RCTs, recent 4 RCTs could successfully show the benefits of PFO device closure compared with medical therapy, with less peri- and postprocedural complication. Based on these data, PFO device closure is recommended to carefully select cryptogenic stroke patients aged from 18 to 65 years, with a high probability of a causal role of the PFO in stroke events. However, it is still uncertain whether PFO closure is superior to oral anticoagulants therapy in these patients. Therefore, further prospective randomized trials are needed to address the efficacy of PFO device closure to oral anticoagulants therapy.

Race/Ethnicity and Sex-Related Differences in Direct Oral Anticoagulant Initiation in Newly Diagnosed Atrial Fibrillation: A Retrospective Study of Medicare Data.

BACKGROUND: Atrial fibrillation (AF) is the most common heart rhythm disorder and is associated with a 5-fold increased risk of ischemic stroke. Racial/ethnic minorities and women with AF have higher rates of stroke compared to white individuals and men respectively. Oral anticoagulation reduces the risk of stroke, yet prior research has described racial/ethnic and sex-based variation in its use. We sought to examine the initiation of any oral anticoagulant (warfarin or direct-acting oral anticoagulants, DOACs) by race/ethnicity and sex in patients with incident, non-valvular AF. Further in those who initiated any anticoagulant, we examined DOAC vs. warfarin initiation by race/ethnicity and sex. METHODS: We used claims data from a 5% sample of Medicare beneficiaries to identify patients with incident AF from 2012 to 2014, excluding those without continuous Medicare enrollment. We used logistic regression to assess the association between race/ethnicity (white, black, Hispanic), sex, and oral anticoagulant initiation (any, warfarin vs. DOAC), adjusting for sociodemographics, medical comorbidities, stroke and bleeding risk. RESULTS: The cohort of 42,952 patients with AF included 17,935 women, 3282 blacks, and 1958 Hispanics. Overall OAC initiation was low (49.2% whites, 48.1% blacks, 47.5% Hispanics, 48.1% men, and 51.5% women). After adjusting, blacks (odds ratio (OR) 0.84; 95% CI, 0.78-0.91) were less likely than whites to initiate any oral anticoagulant with no difference observed between Hispanics and whites (OR 0.92; 95% CI, 0.83-1.01). Women were less likely than men to initiate any oral anticoagulant, OR 0.59 (95% CI 0.55-0.64). Among initiators of oral anticoagulation, DOAC use was low (35.8% whites, 29.3% blacks, 40.0% Hispanics, 41.6% men, and 42.4% women). After adjusting, blacks were less likely to initiate DOACs than whites, OR 0.75 (95% CI 0.66-0.85); the odds of DOAC initiation did not differ between Hispanic and white patients or between men and women. CONCLUSION: In a national cohort of Medicare beneficiaries with newly-diagnosed AF, overall oral anticoagulant initiation was lower in blacks and women, with no difference observed by Hispanic ethnicity. Among oral anticoagulant initiators, blacks were less likely to initiate novel DOACs, with no differences identified by Hispanic ethnicity or sex. Identifying modifiable causes of treatment disparities is needed to improve quality of care for all patients with AF.

Effectiveness and Safety of Restarting Oral Anticoagulation in Patients with Atrial Fibrillation after an Intracranial Hemorrhage: Analysis of Medicare Part D Claims Data from 2010-2016.

BACKGROUND: In patients with atrial fibrillation (AF) who survive an anticoagulant-related intracranial hemorrhage (ICH), the benefits of restarting oral anticoagulation (OAC) remain unclear. OBJECTIVE: In this study, we sought to determine the effectiveness and safety associated with resumption of OAC in atrial fibrillation patients who survive an ICH. METHODS: Using 2010-2016 Medicare claims data, we identified patients with non-valvular AF who experienced an OAC-related ICH and survived at least 6 weeks after the ICH (n = 1502). The primary outcomes included the composite of ischemic stroke and transient ischemic attack (TIA), thromboembolism (TE), a composite of ischemic stroke/TIA and TE, recurrent ICH, and all-cause mortality. We constructed Cox proportional hazard models to evaluate the association between post-ICH OAC resumption, which was measured in a time-dependent manner, and the risk of primary outcomes, while controlling for a comprehensive list of covariates. RESULTS: Among patients who survived an ICH, 69% reinitiated OAC within 6 weeks of the event, and among those who resumed OAC, 83% restarted warfarin. There was no significant difference in the risk of ischemic stroke/TIA (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.62-1.21), TE (HR 0.85, 95% CI 0.55-1.32), and ischemic stroke/TIA/TE (HR 0.81, 95% CI 0.61-1.07) between post-ICH OAC use and non-use. Post-ICH OAC use was associated with a lower risk of recurrent ICH (HR 0.62, 95% CI 0.41-0.95) and all-cause mortality (HR 0.48, 95% CI 0.37-0.62) compared with non-OAC use. CONCLUSIONS: In AF patients who survived an ICH, restarting OAC was not associated with a greater risk of recurrent ICH. Evidence from randomized controlled studies is needed to further clarify the clinical benefit of restarting OAC in this high-risk population. Further evaluation of which individuals benefit from restarting OAC is also needed to provide more clinical guidance.

Comparative Outcomes of Treatment Initiation With Brand vs. Generic Warfarin in Older Patients.

The anticoagulant response to warfarin, a narrow therapeutic index drug, increases with age, which may make older patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Using US Medicare claims linked to electronic medical records from two large hospitals in Boston, we designed a cohort study of ≥ 65-year-old patients. Patients were followed for a composite effectiveness outcome of ischemic stroke or venous thromboembolism, a composite safety outcome, including major hemorrhage, and a 1-year all-cause mortality outcome. After propensity score fine-stratification and weighting to account for > 90 confounders, hazard ratios comparing brand vs. generic warfarin initiators (95% confidence intervals) for the effectiveness, safety, and all-cause mortality outcomes, were 0.97 (0.65-1.46), 0.94 (0.65-1.35), and 0.84 (0.62-1.13), respectively. Results from subgroup analyses of patients with atrial fibrillation, CHADS-VASc score ≥ 3, and HAS-BLED score ≥ 3 were consistent with the primary analysis.

Cost-effectiveness of rivaroxaban versus warfarin for stroke prevention in non-valvular atrial fibrillation in the Japanese healthcare setting.

Aims: This article aimed to examine the cost-effectiveness of rivaroxaban in comparison to warfarin for stroke prevention in Japanese patients with non-valvular atrial fibrillation (NVAF), from a public healthcare payer's perspective.Materials and methods: Baseline event risks were obtained from the J-ROCKET AF trial and the treatment effect data were taken from a network meta-analysis. The other model inputs were extracted from the literature and official Japanese sources. The outcomes included the number of ischaemic strokes, myocardial infarctions, systemic embolisms and bleedings avoided, life-years, quality-adjusted life-years (QALYs), incremental costs and incremental cost-effectiveness ratio (ICER). The scenario analysis considered treatment effect data from the same network meta-analysis.Results: In comparison with warfarin, rivaroxaban was estimated to avoid 0.284 ischaemic strokes per patient, to increase the number of QALYs by 0.535 per patient and to decrease the total costs by ¥118,892 (€1,011.11) per patient (1 JPY = 0.00850638 EUR; XE.com, 7 October 2019). Consequently, rivaroxaban treatment was found to be dominant compared to warfarin. In the scenario analysis, the ICER of rivaroxaban versus warfarin was ¥2,873,499 (€24,446.42) per QALY.Limitations: The various sources of data used resulted in the heterogeneity of the cost-effectiveness analysis results. Although, rivaroxaban was cost-effective in the majority of cases.Conclusion: Rivaroxaban is cost-effective against warfarin for stroke prevention in Japanese patients with NVAF, giving the payer WTP of 5,000,000 JPY.