Análise de custo-efectividade da terapêutica de ressincronização cardíaca : avaliação da selecção baseada na dessincronia mecânica

RESUMO - A Terapêutica de Ressincronização Cardíaca (TRC) apresenta benefícios significativos na classe funcional, função ventricular, hospitalização e mortalidade. É uma técnica com custos elevados e, com os actuais métodos de selecção de doentes, a taxa de não-respondedores ronda os 30%. Objectivo: Compreender se a inclusão da dessincronia mecânica (DM) na selecção de doentes para TRC contribui para a sua relação custo-efectividade, na perspectiva do Serviço Nacional de Saúde português. Metodologia: Estudo prospectivo baseado em coortes histórias de 12 meses de dois grupos submetidos a TRC com desfibrilhador, o grupo de intervenção com doentes seleccionados com inclusão da DM (n=133) e o de controlo com selecção baseada exclusivamente nas recomendações internacionais (n=71). Reuniram-se dados clínicos e de custos nos 12 meses subsequentes à implantação, para cálculo do rácio custo-efectividade incremental (RCEI). Resultados: O grupo de intervenção apresentou uma sobrevivência de 91% e o de controlo de 93%, aos 12 meses (p=0,335). O grupo de intervenção apresentou 60 re-internamentos e o de controlo 46 re-internamentos por qualquer causa aos 12 meses (p=0,032), com RCEI=6.886,09€/re-internamento evitado. O grupo de intervenção apresentou 19 re-internamentos e o de controlo apresentou 31 re-internamentos por Insuficiência Cardíaca (IC) descompensada aos 12 meses (p<0,001), com RCEI=2.686,26€/re-internamento por IC descompensada evitado. Relativamente à melhoria da classe funcional e da fracção de ejecção não foi possível estabelecer associações com custos (p>0,05). Conclusão: É seguro afirmar que recomendar a selecção com inclusão da DM, nos hospitais com capacidade instalada, é um passo positivo na redução de custos com re-internamentos de doentes com TRC.

One-year cardiac morphological and functional evolution following permanent pacemaker implantation in right ventricular septal position in chagasic patients

INTRODUCTION: The septal position is an alternative site for cardiac pacing (CP) that is potentially less harmful to cardiac function. METHODS: Patients with Chagas disease without heart failure submitted to permanent pacemaker (PP) implantation at the Clinics Hospital of the Triângulo Mineiro Federal University (UFTM), were selected from February 2009 to February 2010. The parameters analyzed were ventricular remodeling, the degree of electromechanical dyssynchrony (DEM), exercise time and VO2 max during exercise testing (ET) and functional class (NYHA). Echocardiography was performed 24 to 48h following implantation and after one year follow-up. The patients were submitted to ET one month postprocedure and at the end of one year. RESULTS: Thirty patients were included. Patient mean age was 59±13 years-old. Indication for PP implantation was complete atrioventricular (AV) block in 22 (73.3%) patients and 2nd degree AV block in the other eight (26.7%). All patients were in NYHA I and no changes occurred in the ET parameters. No variations were detected in echocardiographic remodeling measurements. Intraventricular dyssynchrony was observed in 46.6% of cases and interventricular dyssynchrony in 33.3% of patients after one year. CONCLUSIONS: The findings of this work suggest that there is not significant morphological and functional cardiac change following pacemaker implantation in septal position in chagasic patients with normal left ventricular function after one year follow-up. Thus, patients may remain asymptomatic, presenting maintenance of functional capacity and no left ventricular remodeling.

Clinical and echocardiographic predictors of mortality in chagasic cardiomyopathy - systematic review

Diagnosis, prognosis and evaluation of death risk in Chagas cardiomyopathy still constitute a challenge due to the diversity of manifestations, which determine the importance of using echocardiography, tissue Doppler and biomarkers. To evaluate, within a systematic review, clinical and echocardiographic profiles of patients with chronic chagasic cardiomyopathy, which may be related to worse prognosis and major mortality risk. To perform the systematic review, we used Medline (via PubMed), LILACS and SciELO databases to identify 82 articles published from 1991 to 2012, with the following descriptors: echocardiography, mortality and Chagas disease. We selected 31 original articles, involving diagnostic and prognostic methods. The importance of Chagas disease has increased due to its emergence in Europe and United States, but most evidence came from Brazil. Among the predictors of worse prognosis and higher mortality risk are morphological and functional alterations in the left and right ventricles, evaluated by conventional echocardiography and tissue Doppler, as well as the increase in brain natriuretic peptide and troponin I concentrations. Recently, the evaluations of dyssynchrony, dysautonomia, as well as strain, strain rate and myocardial twisting were added to the diagnostic arsenal for the early differentiation of Chagas cardiomyopathy. Developments in imaging and biochemical diagnostic procedures have enabled more detailed cardiac evaluations, which demonstrate the early involvement of both ventricles, allowing a more accurate assessment of the mortality risk in Chagas disease.

Left Atrial Volume Determinants in Patients with Non-Ischemic Dilated Cardiomyopathy

Background:Left atrial volume (LAV) is a predictor of prognosis in patients with heart failure.Objective:We aimed to evaluate the determinants of LAV in patients with dilated cardiomyopathy (DCM).Methods:Ninety patients with DCM and left ventricular (LV) ejection fraction ≤ 0.50 were included. LAV was measured with real-time three-dimensional echocardiography (eco3D). The variables evaluated were heart rate, systolic blood pressure, LV end-diastolic volume and end-systolic volume and ejection fraction (eco3D), mitral inflow E wave, tissue Doppler e´ wave, E/e´ ratio, intraventricular dyssynchrony, 3D dyssynchrony index and mitral regurgitation vena contracta. Pearson´s coefficient was used to identify the correlation of the LAV with the assessed variables. A multiple linear regression model was developed that included LAV as the dependent variable and the variables correlated with it as the predictive variables.Results:Mean age was 52 ± 11 years-old, LV ejection fraction: 31.5 ± 8.0% (16-50%) and LAV: 39.2±15.7 ml/m2. The variables that correlated with the LAV were LV end-diastolic volume (r = 0.38; p < 0.01), LV end-systolic volume (r = 0.43; p < 0.001), LV ejection fraction (r = -0.36; p < 0.01), E wave (r = 0.50; p < 0.01), E/e´ ratio (r = 0.51; p < 0.01) and mitral regurgitation (r = 0.53; p < 0.01). A multivariate analysis identified the E/e´ ratio (p = 0.02) and mitral regurgitation (p = 0.02) as the only independent variables associated with LAV increase.Conclusion:The LAV is independently determined by LV filling pressures (E/e´ ratio) and mitral regurgitation in DCM.

Cost-effectiveness analysis of cardiac resynchronization therapy in patients with NYHA I and NYHA II heart failure in Spain

Objectives: The aim of the study was to combine clinical results from the European Cohort of the REVERSE study and costs associated with the addition of cardiac resynchronization therapy (CRT) to optimal medical therapy (OMT) in patients with mild symptomatic (NYHA I-II) or asymptomatic left ventricular dysfunction and markers of cardiac dyssynchrony in Spain. Methods: A Markov model was developed with CRT + OMT (CRT-ON) versus OMT only (CRT-OFF) based on a retrospective cost-effectiveness analysis. Raw data was derived from literature and expert opinion, reflecting clinical and economic consequences of patient"s management in Spain. Time horizon was 10 years. Both costs (euro 2010) and effects were discounted at 3 percent per annum. Results: CRT-ON showed higher total costs than CRT-OFF; however, CRT reduced the length of hospitalization in ICU by 94 percent (0.006 versus 0.091 days) and general ward in by 34 percent (0.705 versus 1.076 days). Surviving CRT-ON patients (88.2 percent versus 77.5 percent) remained in better functional class longer, and they achieved an improvement of 0.9 life years (LYGs) and 0.77 years quality-adjusted life years (QALYs). CRT-ON proved to be cost-effective after 6 years, except for the 7th year due to battery depletion. At 10 years, the results were 18,431 per LYG and 21,500 per QALY gained. Probabilistic sensitivity analysis showed CRT-ON was cost-effective in 75.4 percent of the cases at 10 years. Conclusions: The use of CRT added to OMT represents an efficient use of resources in patients suffering from heart failure in NYHA functional classes I and II.

Étude du comportement électromécanique du ventricule gauche canin sous différents modes de stimulation

La thérapie de resynchronisation cardiaque (CRT) est un traitement qui diminue la mortalité et améliore la qualité de vie des patients atteints d’insuffisance cardiaque et présentant un dyssynchronisme de la contraction ventriculaire gauche. Malgré le succès de cette thérapie, plus de 30% des patients ne présentent pas l’amélioration désirée. Plusieurs études portant sur le synchronisme électrique ou mécanique de la contraction ont été effectuées mais peu d’entres elles se sont attardées sur le couplage électromécanique à l'échelle macroscopique. Ce projet a comme objectif d’observer le comportement électromécanique des ventricules canins en présence d’un resynchronisateur cardiaque. Un logiciel a été développé pour permettre l’analyse des informations provenant de la cartographie endocardique sans contact et de la ventriculographie isotopique tomographique chez 12 sujets canins insuffisants. Pour observer la réponse mécanique suite à l’activation électrique, nous avons premièrement recalé les surfaces issues des 2 modalités. Ensuite, nous avons défini les limites du cycle cardiaque, analysé les signaux électriques et les courbes de déplacement de la paroi endocardique. Le début de la contraction est défini par un déplacement radial de 10% vers le centre du ventricule. Les résultats démontrent que la durée d’activation du ventricule gauche et la largeur du QRS augmentent en présence d’une stimulation externe et que les délais électromécaniques sont indépendants dans les modes de stimulation étudiés (sinusal, LVbasal, RVapex ou BIV) avec une moyenne de 84,56±7,19 ms. Finalement, nous avons noté que la stimulation basolatérale procure une fonction cardiaque optimale malgré une durée prolongée du QRS.

New Equation for Prediction of Reverse Remodeling after Cardiac Resynchronization Therapy

Objectives: To integrate data from two-dimensional echocardiography (2D ECHO), three-dimensional echocardiography (3D ECHO), and tissue Doppler imaging (TDI) for prediction of left ventricular (LV) reverse remodeling (LVRR) after cardiac resynchronization therapy (CRT). It was also compared the evaluation of cardiac dyssynchrony by TDI and 3D ECHO. Methods: Twenty-four consecutive patients with heart failure, sinus rhythm, QRS = 120 msec, functional class III or IV and LV ejection fraction (LVEF) = 0.35 underwent CRT. 2D ECHO, 3D ECHO with systolic dyssynchrony index (SDI) analysis, and TDI were performed before, 3 and 6 months after CRT. Cardiac dyssynchrony analyses by TDI and SDI were compared with the Pearson's correlation test. Before CRT, a univariate analysis of baseline characteristics was performed for the construction of a logistic regression model to identify the best predictors of LVRR. Results: After 3 months of CRT, there was a moderate correlation between TDI and SDI (r = 0.52). At other time points, there was no strong correlation. Nine of twenty-four (38%) patients presented with LVRR 6 months after CRT. After logistic regression analysis, SDI (SDI > 11%) was the only independent factor in the prediction of LVRR 6 months of CRT (sensitivity = 0.89 and specificity = 0.73). After construction of receiver operator characteristic (ROC) curves, an equation was established to predict LVRR: LVRR =-0.4LVDD (mm) + 0.5LVEF (%) + 1.1SDI (%), with responders presenting values >0 (sensitivity = 0.67 and specificity = 0.87). Conclusions: In this study, there was no strong correlation between TDI and SDI. An equation is proposed for the prediction of LVRR after CRT. Although larger trials are needed to validate these findings, this equation may be useful to candidates for CRT. (Echocardiography 2012;29:678-687)

Global and Regional Ventricular Repolarization Study by Body Surface Potential Mapping in Patients with Left Bundle-Branch Block and Heart Failure Undergoing Cardiac Resynchronization Therapy

Background: The controversial effects promoted by cardiac resynchronization therapy (CRT) on the ventricular repolarization (VR) have motivated VR evaluation by body surface potential mapping (BSPM) in CRT patients. Methods: Fifty-two CRT patients, mean age 58.8 +/- 12.3 years, 31 male, LVEF 27.5 +/- 9.2, NYHA III-IV heart failure with QRS181.5 +/- 14.2 ms, underwent 87-lead BSPM in sinus rhythm (BASELINE) and biventricular pacing (BIV). Measurements of mean and corrected QT intervals and dispersion, mean and corrected T peak end intervals and their dispersion, and JT intervals characterized global and regional (RV, Intermediate, and LV regions) ventricular repolarization response. Results: Global QTm (P < 0.001) and QTcm (P < 0.05) were decreased in BIV; QTm was similar across regions in both modes (P = ns); QTcm values were lower in RV/LV than in Intermediate region in BASELINE and BIV (P < 0.001); only RV/Septum showed a significant difference (P < 0.01) in the BIV mode. QTD values both of BASELINE (P < 0.01) and BIV (P < 0.001) were greater in the Intermediate than in the LV region. CRT effect significantly reduced global/regional QTm and QTcm values. QTD was globally decreased in RV/LV (Intermediate: P = ns). BIV mode significantly reduced global T peak end mean and corrected intervals and their dispersion. JT values were not significant. Conclusions: Ventricular repolarization parameters QTm, QTcm, and QTD global/regional values, as assessed by BSPM, were reduced in patients under CRT with severe HF and LBBB. Greater recovery impairment in the Intermediate region was detected by the smaller variation of its dispersion.

Parameters and algorithms to evaluate cardiac mechanics by conductance catheter

This work is structured as follows: In Section 1 we discuss the clinical problem of heart failure. In particular, we present the phenomenon known as ventricular mechanical dyssynchrony: its impact on cardiac function, the therapy for its treatment and the methods for its quantification. Specifically, we describe the conductance catheter and its use for the measurement of dyssynchrony. At the end of the Section 1, we propose a new set of indexes to quantify the dyssynchrony that are studied and validated thereafter. In Section 2 we describe the studies carried out in this work: we report the experimental protocols, we present and discuss the results obtained. Finally, we report the overall conclusions drawn from this work and we try to envisage future works and possible clinical applications of our results. Ancillary studies that were carried out during this work mainly to investigate several aspects of cardiac resynchronization therapy (CRT) are mentioned in Appendix. -------- Ventricular mechanical dyssynchrony plays a regulating role already in normal physiology but is especially important in pathological conditions, such as hypertrophy, ischemia, infarction, or heart failure (Chapter 1,2.). Several prospective randomized controlled trials supported the clinical efficacy and safety of cardiac resynchronization therapy (CRT) in patients with moderate or severe heart failure and ventricular dyssynchrony. CRT resynchronizes ventricular contraction by simultaneous pacing of both left and right ventricle (biventricular pacing) (Chapter 1.). Currently, the conductance catheter method has been used extensively to assess global systolic and diastolic ventricular function and, more recently, the ability of this instrument to pick-up multiple segmental volume signals has been used to quantify mechanical ventricular dyssynchrony. Specifically, novel indexes based on volume signals acquired with the conductance catheter were introduced to quantify dyssynchrony (Chapter 3,4.). Present work was aimed to describe the characteristics of the conductancevolume signals, to investigate the performance of the indexes of ventricular dyssynchrony described in literature and to introduce and validate improved dyssynchrony indexes. Morevoer, using the conductance catheter method and the new indexes, the clinical problem of the ventricular pacing site optimization was addressed and the measurement protocol to adopt for hemodynamic tests on cardiac pacing was investigated. In accordance to the aims of the work, in addition to the classical time-domain parameters, a new set of indexes has been extracted, based on coherent averaging procedure and on spectral and cross-spectral analysis (Chapter 4.). Our analyses were carried out on patients with indications for electrophysiologic study or device implantation (Chapter 5.). For the first time, besides patients with heart failure, indexes of mechanical dyssynchrony based on conductance catheter were extracted and studied in a population of patients with preserved ventricular function, providing information on the normal range of such a kind of values. By performing a frequency domain analysis and by applying an optimized coherent averaging procedure (Chapter 6.a.), we were able to describe some characteristics of the conductance-volume signals (Chapter 6.b.). We unmasked the presence of considerable beat-to-beat variations in dyssynchrony that seemed more frequent in patients with ventricular dysfunction and to play a role in discriminating patients. These non-recurrent mechanical ventricular non-uniformities are probably the expression of the substantial beat-to-beat hemodynamic variations, often associated with heart failure and due to cardiopulmonary interaction and conduction disturbances. We investigated how the coherent averaging procedure may affect or refine the conductance based indexes; in addition, we proposed and tested a new set of indexes which quantify the non-periodic components of the volume signals. Using the new set of indexes we studied the acute effects of the CRT and the right ventricular pacing, in patients with heart failure and patients with preserved ventricular function. In the overall population we observed a correlation between the hemodynamic changes induced by the pacing and the indexes of dyssynchrony, and this may have practical implications for hemodynamic-guided device implantation. The optimal ventricular pacing site for patients with conventional indications for pacing remains controversial. The majority of them do not meet current clinical indications for CRT pacing. Thus, we carried out an analysis to compare the impact of several ventricular pacing sites on global and regional ventricular function and dyssynchrony (Chapter 6.c.). We observed that right ventricular pacing worsens cardiac function in patients with and without ventricular dysfunction unless the pacing site is optimized. CRT preserves left ventricular function in patients with normal ejection fraction and improves function in patients with poor ejection fraction despite no clinical indication for CRT. Moreover, the analysis of the results obtained using new indexes of regional dyssynchrony, suggests that pacing site may influence overall global ventricular function depending on its relative effects on regional function and synchrony. Another clinical problem that has been investigated in this work is the optimal right ventricular lead location for CRT (Chapter 6.d.). Similarly to the previous analysis, using novel parameters describing local synchrony and efficiency, we tested the hypothesis and we demonstrated that biventricular pacing with alternative right ventricular pacing sites produces acute improvement of ventricular systolic function and improves mechanical synchrony when compared to standard right ventricular pacing. Although no specific right ventricular location was shown to be superior during CRT, the right ventricular pacing site that produced the optimal acute hemodynamic response varied between patients. Acute hemodynamic effects of cardiac pacing are conventionally evaluated after stabilization episodes. The applied duration of stabilization periods in most cardiac pacing studies varied considerably. With an ad hoc protocol (Chapter 6.e.) and indexes of mechanical dyssynchrony derived by conductance catheter we demonstrated that the usage of stabilization periods during evaluation of cardiac pacing may mask early changes in systolic and diastolic intra-ventricular dyssynchrony. In fact, at the onset of ventricular pacing, the main dyssynchrony and ventricular performance changes occur within a 10s time span, initiated by the changes in ventricular mechanical dyssynchrony induced by aberrant conduction and followed by a partial or even complete recovery. It was already demonstrated in normal animals that ventricular mechanical dyssynchrony may act as a physiologic modulator of cardiac performance together with heart rate, contractile state, preload and afterload. The present observation, which shows the compensatory mechanism of mechanical dyssynchrony, suggests that ventricular dyssynchrony may be regarded as an intrinsic cardiac property, with baseline dyssynchrony at increased level in heart failure patients. To make available an independent system for cardiac output estimation, in order to confirm the results obtained with conductance volume method, we developed and validated a novel technique to apply the Modelflow method (a method that derives an aortic flow waveform from arterial pressure by simulation of a non-linear three-element aortic input impedance model, Wesseling et al. 1993) to the left ventricular pressure signal, instead of the arterial pressure used in the classical approach (Chapter 7.). The results confirmed that in patients without valve abnormalities, undergoing conductance catheter evaluations, the continuous monitoring of cardiac output using the intra-ventricular pressure signal is reliable. Thus, cardiac output can be monitored quantitatively and continuously with a simple and low-cost method. During this work, additional studies were carried out to investigate several areas of uncertainty of CRT. The results of these studies are briefly presented in Appendix: the long-term survival in patients treated with CRT in clinical practice, the effects of CRT in patients with mild symptoms of heart failure and in very old patients, the limited thoracotomy as a second choice alternative to transvenous implant for CRT delivery, the evolution and prognostic significance of diastolic filling pattern in CRT, the selection of candidates to CRT with echocardiographic criteria and the prediction of response to the therapy.

Right ventricular systolic function and cardiac resynchronization therapy

AIMS: The effect of cardiac resynchronization therapy (CRT) on right ventricular ejection fraction (RVEF) has not been well studied. Furthermore, it is unclear whether baseline RVEF influences response to CRT. To evaluate the acute and chronic effects of CRT on right ventricular systolic function, and to investigate whether baseline RVEF impacts response to CRT. METHODS AND RESULTS: Forty-four patients with a standard indication for CRT underwent radionuclide angiography at baseline and after at least 6 months' follow-up for measuring RVEF, right ventricular synchrony (using phase analysis), and left ventricular ejection fraction (LVEF). In addition, NYHA functional class and 6-min walking distance (6MWD) were evaluated. There were no significant acute changes in RVEF with CRT. After a mean follow-up of 9 +/- 5 months, RVEF was slightly improved (by 1.9 +/- 5.0% in absolute terms, P = 0.016), and to a lesser extent than LVEF (5.1 +/- 9.0%, P = 0.009 compared with RVEF). Right ventricular dyssynchrony was significantly improved at follow-up (P = 0.016). Patients with a baseline RVEF < or = 0.35 (n = 19) were less likely to improve in NYHA class (P = 0.016), and also tended to improve less in 6MWD and LVEF (P < 0.06). CONCLUSION: Cardiac resynchronization therapy has no acute effect on RVEF, and only slightly improves RVEF at follow-up. Patients with reduced RVEF at baseline were less likely to respond to CRT, indicating that right ventricular systolic dysfunction may play a role in patient selection.