How to truly value implantable cardioverter-defibrillators technology: up-front cost or daily cost?

BACKGROUND: We calculated the daily cost of implantable cardioverter-defibrillators (ICDs) based on their actual longevity to prove whether the up-front cost is a reliable parameter for the ICD purchasing-process. METHODS. Longevity of single chamber (SC), double chamber (DC), and biventricular (BiV) ICDs from Medtronic (MDT), Guidant (GDT), and St. Jude Medical (SJM) was measured in all the patients implanted in years 2000, 2001, 2002 who reached device replacement within December 31, 2009. The cost of each ICD (device + lead/s) was normalized for its own longevity. Data are expressed as median (25th-75th percentile). RESULTS: A total of 123/153 patients completed the study, 70 percent being alive 8 years after implantation. MDT devices had a superior longevity compared with GDT and SJM (p < .001). Fifty-eight percent of replaced ICDs had a service life at least 1 year shorter than the manufacturers' prediction. Longer-lasting devices had a significantly lower daily cost: €4.8 (4.6-5.7) versus €6.8 (6.2-9.2) and €6.9 (6.2-7.6) for SC (p < .001); €6.9 (6.8-7.7) versus €12.6 (11.8-13.3) and €13.4 (10.3-16.1) for DC; €8.5 (8.3-10.3) versus €15.4 (15.1-15.8) and €14.6 (14.1-14.9) for BiV (p < .005). CONCLUSIONS: The true cost of ICD treatment is strictly dependent on device longevity, whereas device up-front cost is unreliable. This aspect should be valued in the technology purchasing process, and could set the basis for an outcome-based reimbursement system. Our observations may be the benchmark respectively for ICD longevity and daily ICD cost in future comparisons. Independent observations in the real-life scenario are needed to properly value newer technologic improvements.

Longevity of implantable cardioverter-defibrillators: implications for clinical practice and health care systems.

AIMS: Comparative studies on the longevity of implantable cardioverter-defibrillators (ICDs) among different manufacturers have never been reported. Longevity of ICD devices implanted from 1 January 2000 to 31 December 2002 was prospectively investigated according to their type and manufacturer. METHODS AND RESULTS: Longevity of single-chamber (SC), double-chamber (DC), and biventricular (CRT-D) ICDs from Medtronic (MDT), Guidant (GDT), and St Jude Medical (SJM) was measured in all the patients who required device replacement. The observation follow-up ended on 31 December 2007; patients who died prematurely or were transplanted before battery exhaustion were excluded from the analysis. Factors associated with longevity (number of delivered shocks, pacing activity) were researched. One hundred and fifty-three patients received an ICD in the abovementioned period. Six underwent heart transplantation, and 23 died before device replacement; 80 had an SC device, 59 had DC device, and 14 had CRT-D device. Longevity of MDT was superior to GDT and SJM, replacement rates being, respectively, 42%, 95.3%, and 97.2%. Only MDT manufacturers and SC type were associated with greater ICD longevity. Longevity had an impact on the cost/month of treatment of replaced ICDs. CONCLUSION: Battery longevity is significantly different among manufacturers. ICD cost is strictly dependent on device longevity, whereas device up-front cost is of limited clinical meaning. Appropriate assessment of cost-effectiveness should be based on ICD longevity in the real-life scenario.

Stress induces altered CRE/CREB pathway activity and BDNF expression in the hippocampus of glucocorticoid receptor-impaired mice.

The gene coding for the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is a stress-responsive gene. Changes in its expression may underlie some of the pathological effects of stress-related disorders like depression. Data on the stress-induced regulation of the expression of BDNF in pathological conditions are rare because often research is conducted using healthy animals. In our experiments, we used transgenic mice with glucocorticoid receptor impaired (GR-i) expression in the hypothalamus created as a tool to study the neuroendocrine changes occurring in stress-related disorders. First, under basal condition, GR-i mice displayed lower levels of BDNF exons IX and IV and decreased CRE(BDNF) binding activity with respect to wild-type (WT) mice in the hippocampus. Then, we exposed GR-i and WT mice to an acute restraint stress (ARS) to test the hypothesis that GR-i mice display: 1] different ARS induced expression of BDNF, and 2] altered activation of signaling pathways implicated in regulating BDNF gene expression in the hippocampus with respect to WT mice. Results indicate that ARS enhanced BDNF mRNA expression mainly in the CA3 hippocampal sub-region of GR-i mice in the presence of enhanced levels of pro-BDNF protein, while no effect was observed in WT mice. Moreover, ARS reduced CREB signaling and binding to the BDNF promoter in GR-i mice but enhanced signaling and binding, possibly through ERK1/2 activation, in WT mice. Thus, life-long central GR dysfunction resulted in an altered sensitivity at the transcriptional level that may underlie an impaired response to an acute psycho-physical stress. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Time-dependent effects of escitalopram on brain derived neurotrophic factor (BDNF) and neuroplasticity related targets in the central nervous system of rats.

Chronic treatment with antidepressants affects several proteins linked to neuroplasticity, particularly brain derived neurotrophic factor (BDNF): this leads eventually to their therapeutic effects. It is possible that also for putative early therapeutic onset, antidepressants may act by promoting cellular adaptations linked to neuroplasticity. Escitalopram, known to be already effective in preclinical models of depression after 7 days, allowed us to investigate whether two effective treatment regimens (7 and 21 days) may contribute to synaptic plasticity by acting on BDNF signalling. We focused our attention on two regulators of BDNF transcription, CREB and CaRF (calcium responsive factor), and on kinases, CaMKII, ERK1/2 and p38 MAPK, linked to BDNF that play a distinctive role in synaptic plasticity. We evaluated whether the effects of escitalopram on these targets may be different in brain areas involved in the depressive symptomatology (hippocampus, frontal and prefrontal cortex). Here we demonstrate that escitalopram regulates intracellular pathways linked to neuroplasticity at both the time points evaluated in an area-specific manner. While the two escitalopram-treatment regimens failed to affect gene expression in the rat frontal cortex, 7days of treatment with escitalopram activated intracellular pathways linked to BDNF and increased the levels of Pro-BDNF in the rat prefrontal cortex. Moreover, 21 days of treatment with escitalopram decreased CREB/BDNF signalling while increasing p38 levels in the rat hippocampus. Even if further experiments with different antidepressant strategies will be needed, our data suggest that escitalopram efficacy may be mediated by early and late effects on synaptic plasticity in selective brain areas.

Early neonatal inflammation affects adult pain reactivity and anxiety related traits in mice: genetic background counts.

UNLABELLED: Protracted or recurrent pain and inflammation in the early neonatal period may cause long-lasting changes in central neural function. However, more research is necessary to better characterize the long-term behavioral sequelae of such exposure in the neonatal period. OBJECTIVES: (1) to study whether timing of postnatal exposure to persistent inflammation alters responsiveness to thermal pain in the adult animal; (2) to assess whether animals experiencing early postnatal chronic inflammation display altered anxiety related behavior; (3) to study the importance of genetic background. Newborn mice (outbred strain, CD1 and F1 hybrid strain, B6C3F1) received an injection of Complete Freund's Adjuvant (CFA) or saline on either postnatal day 1 or 14 (PND1; PND14) into the left hind paw. Pain to radiant heat and anxiety were examined in 12-week-old adult animals. Adult baseline PWL was significantly decreased in CD1 mice exposed to CFA on PND 1 and 14 as compared to their saline treated counterparts. B6C3F1 mice exposed to CFA on PND14 showed markedly reduced baseline PWL compared to the PND14 saline group. Persistent inflammation experienced by B6C3F1 mice on PND1 failed to affect baseline adult thermal responsiveness. Adult mice, CD1 and B6C3F1, displayed low anxiety traits only if they had been exposed to persistent inflammation on PND1 and not on PND14. Our research suggests a role for genetic background in modulating long-term behavioral consequences of neonatal persistent inflammation: the data support the hypothesis that pain experienced very early in life differentially affects adult behavioral and emotional responsiveness in outbred (CD1) and hybrid mice (B6C3F1).