A Cost-Utility Analysis of the Syncope: Pacing or Recording in The Later Years (SPRITELY) Trial.

Background: The Syncope: Pacing or Recording in the Later Years (SPRITELY) trial reported that a strategy of empiric permanent pacing in patients with syncope and bifascicular block reduces major adverse events more effectively than acting on the results of an implantable cardiac monitor (ICM). Our objective was to determine the cost-effectiveness of using the ICM, compared with a pacemaker (PM), in the management of older adults (age > 50 years) with bifascicular block and syncope enrolled in the SPRITELY trial. Methods: SPRITELY was a pragmatic, open-label randomized controlled trial with a median follow-up of 33 months. The primary outcome of this analysis is the cost per additional quality-adjusted life-year (QALY). Resource utilization and utility data were collected prospectively, and outcomes at 2 years were compared between the 2 arms. A decision analytic model simulated a 3-year time horizon. Results: The mean cost incurred by participants randomized to the PM arm was $9918, compared to $15,416 (both in Canadian dollars) for participants randomized to the ICM arm. The ICM strategy resulted in 0.167 QALYs fewer than the PM strategy. Cost and QALY outcomes are sensitive to the proportion of participants randomized to the ICM arm who subsequently required PM insertion. In 40,000 iterations of probabilistic sensitivity analysis, the PM strategy resulted in cost-savings in 99.7% of iterations, compared with the ICM strategy. Conclusions: The PM strategy was dominant-that is, less costly and estimated to result in a greater number of QALYs. For patients with unexplained syncope, bifascicular block, and age > 50 years, a PM is more likely to be cost-effective than an ICM.

Contexte: L'essai SPRITELY ( S yncope: P acing or R ecording i n t h e L ater Y ears) a été mené auprès de patients ayant subi une syncope et un bloc bifasciculaire. Elle a montré qu'une méthode de stimulation électrique permanente et empirique du cœur permet de réduire les événements indésirables majeurs plus efficacement qu'une méthode reposant sur les résultats d'un moniteur cardiaque implantable. Notre objectif était de déterminer le rapport coût-efficacité de l'utilisation du moniteur cardiaque implantable par rapport à un stimulateur cardiaque dans la prise en charge de personnes âgées de plus de 50 ans présentant un bloc bifasciculaire et une syncope, inscrits à l'essai SPRITELY. Méthodologie: SPRITELY était un essai contrôlé ouvert et pragmatique à répartition aléatoire, dont le suivi médian était de 33 mois. Le paramètre d'évaluation principal de cette analyse était le coût supplémentaire par année de vie ajustée en fonction de la qualité (AVAQ). Les données sur l'utilisation des ressources et l'utilité ont été recueillies de manière prospective, et les résultats à deux ans ont été comparés entre les deux groupes. Un modèle décisionnel analytique a été utilisé pour simuler un horizon temporel de trois ans. Résultats: Le coût moyen pour les participants répartis aléatoirement dans le groupe utilisant un stimulateur cardiaque était de 9 918 $ CAN comparativement à 15 416 $ CAN pour ceux utilisant un moniteur cardiaque implantable. La stratégie du moniteur cardiaque implantable s'est traduite par une réduction de 0,167 du nombre d'AVAQ par rapport à la stratégie reposant sur le stimulateur cardiaque. Les résultats relatifs aux coûts et aux AVAQ sont sensibles à la proportion de participants répartis aléatoirement dans le groupe du moniteur cardiaque implantable qui ont par la suite dû recevoir un stimulateur cardiaque. Sur 40 000 itérations de l'analyse de sensibilité probabiliste, la stratégie du stimulateur cardiaque a occasionné des économies dans 99,7 % des itérations comparativement à la stratégie du moniteur cardiaque implantable. Conclusions: La stratégie du stimulateur cardiaque était dominante, autrement dit moins coûteuse et, selon les estimations, entraînerait un plus grand nombre d'AVAQ. Pour les patients de plus de 50 ans présentant une syncope idiopathique et un bloc bifasciculaire, un stimulateur cardiaque est plus susceptible d'être moins coûteux qu'un moniteur cardiaque implantable.

Midodrine for the Prevention of Vasovagal Syncope : A Randomized Clinical Trial.

BACKGROUND: Recurrent vasovagal syncope is common, responds poorly to treatment, and causes physical trauma and poor quality of life. Midodrine prevents hypotension and syncope during tilt tests in patients with vasovagal syncope. OBJECTIVE: To determine whether midodrine can prevent vasovagal syncope in usual clinical conditions. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT01456481). SETTING: 25 university hospitals in Canada, the United States, Mexico, and the United Kingdom. PATIENTS: Patients with recurrent vasovagal syncope and no serious comorbid conditions. INTERVENTION: Patients were randomly assigned 1:1 to placebo or midodrine and followed for 12 months. MEASUREMENTS: The primary outcome measure was the proportion of patients with at least 1 syncope episode during follow-up. RESULTS: The study included 133 patients who had had a median of 6 syncope episodes in the prior year (median age, 32 years; 73% female). Compared with patients receiving placebo, fewer patients receiving midodrine had at least 1 syncope episode (28 of 66 [42%] vs. 41 of 67 [61%]). The relative risk was 0.69 (95% CI, 0.49 to 0.97; P = 0.035). The absolute risk reduction was 19 percentage points (CI, 2 to 36 percentage points), and the number needed to treat to prevent 1 patient from having syncope was 5.3 (CI, 2.8 to 47.6). The time to first syncope was longer with midodrine (hazard ratio, 0.59 [CI, 0.37 to 0.96]; P = 0.035; log-rank P = 0.031). Adverse effects were similar in both groups. LIMITATION: Small study size, young and healthy patients, relatively short observation period, and high proportion of patients from 1 center. CONCLUSION: Midodrine can reduce the recurrence of syncope in healthy, younger patients with a high syncope burden. PRIMARY FUNDING SOURCE: The Canadian Institutes of Health Research.

A proof of principle study of atomoxetine for the prevention of vasovagal syncope: the Prevention of Syncope Trial VI.

AIMS: There are few effective therapies for vasovagal syncope (VVS). Pharmacological norepinephrine transporter (NET) inhibition increases sympathetic tone and decreases tilt-induced syncope in healthy subjects. Atomoxetine is a potent and highly selective NET inhibitor. We tested the hypothesis that atomoxetine prevents tilt-induced syncope. METHODS AND RESULTS: Vasovagal syncope patients were given two doses of study drug [randomized to atomoxetine 40 mg (n = 27) or matched placebo (n = 29)] 12 h apart, followed by a 60-min drug-free head-up tilt table test. Beat-to-beat heart rate (HR), blood pressure (BP), and cardiac haemodynamics were recorded using non-invasive techniques and stroke volume modelling. Patients were 35 ± 14 years (73% female) with medians of 12 lifetime and 3 prior year faints. Fewer subjects fainted with atomoxetine than with placebo [10/29 vs. 19/27; P = 0.003; risk ratio 0.49 (confidence interval 0.28-0.86)], but equal numbers of patients developed presyncope or syncope (23/29 vs. 21/27). Of patients who developed only presyncope, 87% (13/15) had received atomoxetine. Patients with syncope had lower nadir mean arterial pressure than subjects with only presyncope (39 ± 18 vs. 69 ± 18 mmHg, P < 0.0001), and this was due to lower trough HRs in subjects with syncope (67 ± 30 vs. 103 ± 32 b.p.m., P = 0.006) and insignificantly lower cardiac index (2.20 ± 1.36 vs. 2.84 ± 1.05 L/min/m2, P = 0.075). There were no significant differences in stroke volume index (32 ± 6 vs. 35 ± 5 mL/m2, P = 0.29) or systemic vascular resistance index (2156 ± 602 vs. 1790 ± 793 dynes*s/cm5*m2, P = 0.72). CONCLUSION: Norepinephrine transporter inhibition significantly decreased the risk of tilt-induced syncope in VVS subjects, mainly by blunting reflex bradycardia, thereby preventing final falls in cardiac index and BP.

ABT-888 restores sensitivity in temozolomide resistant glioma cells and xenografts.

BACKGROUND: Temozolomide (TMZ) is active against glioblastomas (GBM) in which the O6-methylguanine-DNA methyltransferase (MGMT) gene is silenced. However, even in responsive cases, its beneficial effect is undermined by the emergence of drug resistance. Here, we tested whether inhibition of poly (ADP-ribose) polymerase-1 and -2 (PARP) enhanced the effectiveness of TMZ. METHODS: Using patient derived brain tumor initiating cells (BTICs) and orthotopic xenografts as models of newly diagnosed and recurrent high-grade glioma, we assessed the effects of TMZ, ABT-888, and the combination of TMZ and ABT-888 on the viability of BTICs and survival of tumor-bearing mice. We also studied DNA damage repair, checkpoint protein phosphorylation, and DNA replication in mismatch repair (MMR) deficient cells treated with TMZ and TMZ plus ABT-888. RESULTS: Cells and xenografts derived from newly diagnosed MGMT methylated high-grade gliomas were sensitive to TMZ while those derived from unmethylated and recurrent gliomas were typically resistant. ABT-888 had no effect on the viability of BTICs or tumor bearing mice, but co-treatment with TMZ restored sensitivity in resistant cells and xenografts from newly diagnosed unmethylated gliomas and recurrent gliomas with MSH6 mutations. In contrast, the addition of ABT-888 to TMZ had little sensitizing effect on cells and xenografts derived from newly diagnosed methylated gliomas. In a model of acquired TMZ resistance mediated by loss of MMR gene MSH6, re-sensitization to TMZ by ABT-888 was accompanied by persistent DNA strand breaks, re-engagement of checkpoint kinase signaling, and interruption of DNA synthesis. CONCLUSION: In laboratory models, the addition of ABT-888 to TMZ overcame resistance to TMZ.

Targeted nitric oxide delivery preferentially induces glioma cell chemosensitivity via altered p53 and O(6) -methylguanine-DNA methyltransferase activity.

Glioblastoma multiforme is the most common malignant central nervous system tumor, and also among the most difficult to treat due to a lack of response to chemotherapeutics. New methods of countering the mechanisms that confer chemoresistance to malignant gliomas could lead to significant advances in the quest to identify novel drug combinations or targeted drug delivery systems for cancer therapy. In this study, we investigate the use of a targeted nitric oxide (NO) donor as a pretreatment to sensitize glioma cells to chemotherapy. The protein chlorotoxin (CTX) has been shown to preferentially target glioma cells, and we have developed CTX-NO, a glioma-specific, NO-donating CTX derivative. Pretreatment of cells with CTX-NO followed by 48-h exposure to either carmustine (BCNU) or temozolomide (TMZ), both common chemotherapeutics used in glioma treatment, resulted in increased efficacy of both therapeutics. After CTX-NO exposure, both T98G and U-87MG human malignant glioma cells show increased sensitivity to BCNU and TMZ. Further investigation revealed that the consequences of this combination therapy was a reduction in active levels of the cytoprotective enzyme MGMT and altered p53 activity, both of which are essential in DNA repair and tumor cell resistance to chemotherapy. The combination of CTX-NO and chemotherapeutics also led to decreased cell invasion. These studies indicate that this targeted NO donor could be an invaluable tool in the development of novel approaches to treat cancer.

Targeted diazeniumdiolates: localized nitric oxide release from glioma-specific peptides and proteins.

Nitric oxide (NO) is a small yet important biological messenger, which at sufficient concentrations has been shown to induce apoptosis as well as increase radiosensitization in tumor cells. However, the short half-life of NO gas itself has limited its utility as a therapeutic agent. The objective of this study was the development of targeted NO donors and we illustrate their utility as a potential therapeutic for treatment of glioblastoma multiforme, the most common and aggressive malignant primary brain tumor in adults. We have synthesized two diazeniumdiolate NO donors by reacting NO gas with glioma-specific targeting sequences, VTWTPQAWFQWVGGGSKKKKK (VTW) and chlorotoxin (CTX), and achieved repeatable NO release from both donors. FITC-labeled biomolecules, when incubated with glioma and control cells preferentially bound to the glioma cells and showed only minimal binding to the control cells. Additionally, tumor cell viability was significantly decreased when cells were incubated with the NO donors whereas control cell viability was not affected.