Cardiac resynchronization therapy in Romania – results from the European Society of Cardiology CRT Survey II

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Ioana Sus1, Radu Vatasescu2, Calin Siliste3, Alexandru Deutsch4, Dragos Cozma5, Radu Ciudin6, Sorin Micu7, Horia Rosianu8, Cristian Statescu9, Gabriel Gusetu10, Kenneth Dickstein11, Camilla Normand11,12, Cecilia Linde13, Dan Dobreanu1


1 Institute for Cardiovascular Disease and Transplant, Tirgu Mures, Romania
2 Clinical Hospital Floreasca, Bucharest, Romania
3 University Clinical Hospital, Bucharest, Romania
4 Colentina Clinical Hospital, Bucharest, Romania
5 Heart Institute, Timisoara, Romania
6 „Prof. Dr. C.C. Iliescu” Institute for Cardiovascular Diseases, Bucharest, Romania
7 ICCO Clinics, Brasov, Romania
8 Heart Institute, Cluj-Napoca, Romania
9 Heart Institute, Iasi, Romania
10 Clinical Hospital of Rehabilitation, Cluj Napoca, Romania
11 Division of Cardiology, Stavanger University Hospital, Stavanger, Norway
12 Institute of Internal Medicine, University of Bergen, Norway
13 Heart and Vascular Theme, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden


Abstract: Objectives – The European Cardiac Resynchronization Therapy Survey II is the second CRT survey of the Heart Failure Association and European Heart Rhythm Association designed to observe implantation and follow-up practices across European countries. These data allow, for the fi rst time, a valuable insight on CRT implantation strategies for Romanian patients. Methods – A total of 214 patients undergoing CRT-P/CRT-D implantations in 7 Romanian implantation centers were included in the survey. A one-time online case report form including data on implantation indication and procedure was completed for each implantation attempt. Results – Romanian patients were younger than the other European pati-ents (p<0.001), had more severe symptoms of heart failure, lower ejection fraction and wider QRS complexes. More than half of the patients had non-ischemic cardiomyopathy. Most of the patients were in sinus rhythm, with a median intrinsic QRS duration of 163±24 ms. Echocardiography was the imaging method most often used and the median left ventricular ejection fraction was 24.9±8%. In comparison with other European countries, CRT-D devices and multipolar ventricular leads were more rarely implanted (p<0.001). Conclusions – In Romania indications regarding CRT implantation follow the most recent ESC guidelines, but the ratio of CRT-D devices in Romania is lower than in the other European countries and patients with more severe heart failure receive CRT. CRT should be considered earlier in heart failure patients in order to improve outcome.Keywords: heart failure, cardiac resynchronization therapy.

Rezumat: Obiective – European Cardiac Resynchronization Therapy Survey II este al doilea sondaj privind terapia de re-sincronizare cardiacă (CRT) al Heart Failure Association şi al European Heart Rhythm Association, realizat cu scopul de a evalua practicile de implant şi urmărire a pacienţilor în ţările europene. Aceste date permit, pentru prima dată, o imagine în detaliu asupra strategiilor de implant CRT la pacienţii din România. Metode – În studiu au fost incluşi 214 pacienţi cărora li s-a implantat un CRT-P/CRT-D în 7 centre de implant din România. Pentru fiecare tentativă de implant s-a completat online un formular incluzând date despre indicaţie şi procedură. Rezultate – Pacienţii cu CRT din România au fost mai tineri decât restul pacienţilor din Europa (p<0,001), au avut simptome de insuficienţă cardiacă mai severe, fracţie de ejecţie mai scăzută şi o durată mai crescută a complexului QRS. Mai mult de jumătate dintre pacienţi au avut cardiomiopatie non-ischemică. Ma-joritatea pacienţilor au fost în ritm sinusal şi au avut o durată medie a complexului QRS de 163±24 ms. Metoda imagistică cel mai frecvent folosită a fost ecocardiografia, iar fracţia de ejecţie medie a ventriculului stâng a fost 24,9±8%. În comparaţie cu celelalte ţări europene, în România au fost implantate mai puţine dispozitive de tip CRT-D şi sonde ventriculare multipolare (p<0,001). Concluzie – În România indicaţiile privind terapia de resincronizare cardiacă urmează recomandările celor mai recente ghiduri ale ESC, dar proporţia dispozitivelor de tip CRT-D în România este mai mică decât în celelalte ţări Europene şi pacienţi cu insuficienţă cardiacă mai severă benefi ciază de CRT. CRT ar trebui să fie luată în considerare mai precoce la pacienţii cu insuficienţă cardiacă pentru ameliorarea răspunsului. Cuvinte cheie: insuficienţă cardiacă, terapie de resincronizare cardiacă.

BACKGROUND
Cardiac resynchronization therapy (CRT) is an impor-tant therapeutic option for patients with symptoma-tic heart failure, a wide QRS complex, left ventricular ejection fraction below 35% receiving optimal medical treatment1. The 2013 European Society of Cardiology (ESC) guideline for Pacing and Cardiac Resynchroniza-tion Therapy2 and 2016 ESC Acute and Chronic Heart Failure guideline1 provide a class I recommendation for CRT and the technology is continuously evolving improving the outcome in patients receiving CRT. However, there are important differences regarding implantation choices among the European countries3. The European Cardiac Resynchronization Therapy Sur-vey II is the second CRT survey from the Heart Fai-lure Association and European Heart Rhythm Association of European Society of Cardiology designed to observe implantation and follow-up practices across European countries.3 The first CRT survey in 2009 revealed a high percentage of off-label implantations, 19% of the patients had a QRS complex duration below 130 ms and 22% were in NYHA functional class I and II4. Since the publication of CRT Survey I, guidelines have been updated and indications which were considered off-la-bel are now class I indications due to results in recent trials such as Resynchronization reVErses Remodeling in Systolic left vEntricular dysfunction trial (REVERSE)5, Mul-ticenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT)6 and Resynchronization-Defi brilation for Ambulatory Heart Fa-ilure Trial (RAFT)7.
For Romania, this is the first data collection and analysis regarding CRT implantation practice. These data provide a valuable insight on CRT implantation strategies for Romanian patients.

METHODS
Study design
The European Cardiac Resynchronization Therapy Survey is an international snapshot survey initiated by Heart Failure Association and European Heart Rhythm Associ-ation, including patients from 42 ESC countries un-dergoing CRT implantation3. CRT implanting centers from the 47 ESC countries detailed in EHRA White Book 2013 were invited to participate in the survey.

Study population
Consecutive patients undergoing de novo CRT-P/ CRT-D implantations or upgrade from permanent implantable cardiac defibrillator or pacemaker were included between October 2015 and December 2016. A one-time online case report form was completed for each implantation attempt, regardless of the pro-cedural success. Collected data included information about demographics, heart failure etiology, past me-dical history and major comorbidities, pre-implanta-tion electrocardiography, clinical indication for CRT, details regarding the implantation procedure compri-sing LV lead position, peri-procedural complications, device programming, treatment and follow-up plan at discharge. No informed consent was obtained for the survey as the eCRT was completely anonymized. The study protocol was approved by the Romanian Society of Cardiology and local ethics committees.

Statistical analysis
Data analysis was performed by Institut fur Herzin-farktforschung in Ludwigshafen, Germany, appointed by the organizing associations. Data is presented as percentages and numbers or mean and standard de-viation, as appropriate. For comparison, Chi-squared or Mann-Whitney-Wilcoxon tests were used accor-dingly.

RESULTS
The registry included a total of 11.088 patients from 288 implantation centers in 42 countries. In Romania, 7 implantation centers responded to the survey and 214 patients were included, constituting 1.93% of the survey population. In Romania these 214 patients con-stituted 57% of all CRT implantations performed in the time period of the Survey, making the data very representative for national CRT implantation patterns. These patients underwent 216 implantation attempts with 212 successful attempts (99.1%).
Romanian implantation centers were similar to the other European centers regarding the number of de-dicated electrophysiological labs (1.3±0.5 vs. 1.3±0.9, p=0.77), electrophysiologists (2±1 vs. 3±2, p=0.59) and heart failure specialists (1±2 vs. 1±2, p=0.38). The reported number of CRT implantations per year was smaller in Romanian implantation centers compared with the total cohort. (38±24 vs. 73±61, p=0.09), but statistically significant only for CRT-D devices (20±16 vs. 50±46, p=0.02).

Demographics and history
Romanian patients were younger than the other Euro-pean patients (65.2±11.1 vs 68.6±10.8 years, p<0.001), with the majority below the age of 65 years of age (43.9%). A smaller proportion of patients were above 75 years of age compared to all other countries (21.0% vs. 32.2%) (Table 1). Although male gender was more prevalent over-all, a higher percentage of female patients were implanted in Romania than in the other European countries (32.2% vs. 24.1%, p=0.006).
The etiology of heart failure was in more than half of the patients non-ischemic (63.6%). Regarding major comorbidities, patients undergoing CRT implantation in Romania had lower prevalence of previous myocar-dial infarction, prior revascularization, hypertension or atrial fibrillation, but more frequently had valvular heart disease.
Among the 214 patients, 48 (22.4%) had a previous device implantation, most often a permanent pacema-ker (32 patients, 66.7%). A signifi cantly lower number of Romanian patients had a previous ICD implanted in comparison with all other countries (16.7% vs. 31.9%, p=0.02).

Pre-implant evaluation
Before CRT implantation, Romanian patients had more severe symptoms according to NYHA functio-nal class than other European patients (Figure 1). The majority of them were in NYHA functional class III (57.5%) and IV (17%), and more Romanian patients had been hospitalized for heart failure during the past year (65.9% vs. 46.1%, p<0.001) as a sign of worse heart failure condition in Romanian patients. They also had more commonly mitral regurgitation which was also of greater severity in Romanian patients.
Most of the Romanian patients were in sinus rhythm, 78.4%, and a smaller proportion; 17.4% were in atrial fibrillation at time of implantation (Table 2). The median heart rate was 72±13 bpm. The median PR interval was 179±52 ms, and intrinsic QRS durati-on was 163±24 ms. Left bundle branch block morpho-logy was dominant (83.1%), followed by right bundle branch block (5.6%), and 2.8% of the patients had a normal QRS morphology. Twenty-four (11.3%) of the Romanian patients were pacemaker dependent, with a median paced QRS duration of 165±23 ms. Fewer patients with narrow QRS complex (<120 ms) underwent CRT implantation in Romania compared with other countries (3.6% vs. 7.5%) (Table 2), and 6.2% of Romanian patients compared to 12.9% in all other countries had a QRS complex duration below 130 ms which suggests better guidelines adherence in Romania. Echocardiography was the imaging method most frequently used for evaluating left ventricular function (97.2% of the patients), followed by cardiac magnetic resonance (4.2%). Romanian patients had larger left ventricular end diastolic diameters and smaller ejecti-on fractions. Moderate and severe mitral regurgitation were present more often in Romania in 37.7% and 22.5% of patients, respectively reflecting the more se-vere HF disease state of Romanian patients (Table 2).
Amongst indications for CRT (bearing in mind that more than one could be given in the CRF) heart failure with wide QRS complex was considered the indication for CRT in 72.3% of patients, in contrast with 59.7% in other countries. This was followed by evidence of mechanical dyssynchrony in 40.4% of Romanian pati-ents and left ventricle dysfunction combined with an indication for ICD in 48.2% of the patients implanted in the other centers (Figure 2).

Figure 1. Pre-implantation New York Heart Association class in Romanian and European patients. Data available for 214 and 10643 patients, respectively.

CRT-implantation procedure
The 214 patients underwent a number of 216 CRT implantation attempts, with a success rate of 98.6%, si-milar to the European cohort. The three unsuccessful attempts were all due to failure to place the LV lead. The 212 successful implantations resulted in an almost equal number of CRT-P (50.5%) and CRT-D (49.5%) devices, in contrast with the other countries where CRT-D devices were more frequently used (70.2%, p<0.001).
In Romania, 97.6% of implantations were performed by electrophysiologists (in contrast with the other countries, 76.6%) and the remaining ones by cardiac surgeons, whereas in Europe 12.6% of devices were implanted by invasive cardiologists and 5.1% by heart failure specialists. A significantly higher number of pro-cedures were performed in catheterization laborato-ries (40.1%), followed by device implantation labora-tories (29.2%) and dedicated electrophysiology labo-ratories (29.2%) in Romania. In contrast, in Europe the majority of devices were implanted either in device implantation (33.6%) or dedicated electrophysiology laboratories (30.7%). In Romania, procedures lasted longer (113.6±37.2 min vs. 99.5±46.4 min, p<0.001), but there was no difference in fluoroscopy time, with a median of 17 min. Right ventricular lead was most often implanted first (74.4%), more frequently in a septal position in Romanian patients (64.7%), whereas in the other countries the apical position was prefer-red (61.8%).
For LV lead implantation, almost all Romanian pa-tients had a coronary venogram (95.3% vs. 91.4%, p=0.048).
Left ventricular (LV) lead was placed epicardially in 10% of the Romanian patients, similar to the glo-bal results (9.2%). Bipolar leads were most frequently used in Romanian patients (80.1% vs. 41.5%, p<0.001), with a low percentage of multipolar leads (19.4% vs. 57.8%). LV lead position was usually evaluated with biplane x-ray projections (92.6%) and optimized based on the measured electrical delay (time interval from onset of Q wave to LV EGM) in most of the Romanian patients, while in the other countries the paced QRS duration was the elected criteria for LV lead position optimization.
The incidence of periprocedural complications was almost double in Romania versus the other countries (9.3% vs. 5.5%, p=0.016), bleeding and coronary si-nus dissection being the most common complications (35% of complications each), followed by pneumotho-rax and pericardial tamponade (10% of complications each) (Table 3).

Outcomes
Atrioventricular (AV) and interventricular (VV) delay programming was performed in the majority of pati-ents prior to discharge, more often in Romanian patients compared with the total cohort (85.0% vs. 57.3%, p<0.001 and 67.1% vs. 56.1%, p=0.001, respectively). While 37.1% of the European patients had a device-based software optimization for AV and VV delays, in Romania this was the option for only one patient.
Post-CRT, a shortening of average 32±24 ms of the duration of QRS complex was obtained, this shorte-ning was more pronounced in the Romanian patients (all other countries 20±30ms, p<0.001) and the ave-rage QRS duration was 132±16 ms, with 48.8% of the patients having paced QRS duration between 130 and 150 ms.
All patients were discharged alive, after an average length of hospital stay of 7±5.7 days. The incidence of major adverse events during hospitalization after pro-cedure was low (5.6%), predominantly represented by arrhythmias (2.8%), followed by worsening renal func-tion (1.9%). Five patients experienced lead dislocation or displacement (2.8%), this related to the LV lead in 80% of the cases. No peri-procedural infections were reported. More than 80% of patients were discharged on guideline-recommended heart failure medication, including betablocker, angiotensin converting enzyme inhibitor and mineralocorticoid receptor antagonist (Table 1).
The follow-up strategy in Romania was very di-fferent from all other countries, as all patients were scheduled for follow-up in the implanting center, whe-reas in the other countries 8.2% were scheduled to be followed in other hospital, 10.6% in CRT/pacemaker clinics and 2.6% in heart failure management clinic (all p<0.05).

Figure 2. Indications for CRT in Romanian and European patients. HF – heart failure; LV – left ventricle; PM – pacemaker.

DISCUSSION
The European Cardiac Resynchronization Therapy Survey was designed to evaluate actual practices regarding CRT across European countries, to identify variations in patient selection, procedural options and CRT out-come in a real-life population3. In Romania, the num-ber of implanted CRT units increased four-fold, from a total of 99 to 421, between 2008 and 20168,9. The increase may not only be due to extension of implan-tation indications to patients in NYHA functional class in the 2013 ESC Guidelines for Pacing and CRT2 and ESC HFA Guidelines on Acute and Chronic Heart Failure1, but also to the technology which has become more widely available and more affordable. This is very good but the proportion of patients in NYHA II could most probably still increase and NYHA IV decrease in view of the long-term disease modifying effects of CRT le-ading to decreased mortality and HF related hospitalisations and the less efficacy of CRT for NYHA IV patients.
Even if the ratio of CRT-D devices increased in the last 8 years from one third to almost a half of the im-planted CRT devices in Romania, these numbers are still lower than in the other European countries whe-re CRT-Ds are implanted in more than 70% of cases. This might be partly explained by the fact that only 36.4% of the patients had ischemic cardiomyopathy in the Romanian cohort. Both dilated cardiomyopathy and ischemic heart disease patients with heart failure and with left ventricular ejection fraction below 35% despite 3 months of optimal medical treatment have a class I indication for ICD implantation in primary prevention1 and CRT is indicated when ICD implan-tation is planned2. Even if half of the patients in this European cohort were implanted a CRT device due to heart failure with indication for ICD, this indication only accounted for 28.6% of implantations in the Ro-manian group. There is a reasonable amount of data on the benefi t of ICD implantation in patients with is-chemic cardiomyopathy, but there is still controversy regarding whether CRT-D implantation has benefi ts compared with CRT-P in patients with non-ischemic dilated cardiomyopathy. The DANISH trial showed a decrease in sudden cardiac death incidence in CRT-D patients, but no over-all survival benefit over CRT-P10 except in a subgroup of patients below 70 years of age. Recent data has confirmed more favourable outcomes in ischemic cardiomyopathy patients implanted with a CRT-D versus CRT-P, but no survival benefi t of CRT-D over CRT-P was observed in patients with non-is-chemic dilated cardiomyopathy, with only 0.4% excess sudden cardiac death in CRT-P patients11.
Financial limitations also limit physician’s options, probably contributing to CRT-P choice over CRT-D in some cases. This might be an important issue, espe-cially given the fact that Romanian patients were yo-unger but with more severe heart failure, more heart failure-related hospitalizations, larger ventricles, lower ejection fractions and wider QRS complexes. Besides device choice, economic factors limiting patients’ ac-cess to radiofrequency ablation for atrial fibrillation or premature ventricular complexes also relevant cost-driving interventions influence, in the end, the medi-cal treatment. This could be one of the reasons why Romanian patients receive more often amiodarone. Another important difference in medical treatment observed in this survey was a more frequent use of MRA in Romania. As 84% of Romanian patients had an LVEF of less than 40%, with an indication for MRA, the percentage of patients treated with MRA was higher than the one reported in QUALIFY survey12, where 69% percent of patients were on MRA, mirroring the more advanced heart failure in Romanian cohort and an increased guideline adhesion most probably given the fact that Romanian implant centres are university hospitals.
Besides differences in device options, choice of im-planted leads were also slightly different. Bipolar left ventricular leads were chosen in 80.1% of Romanian patients, while 57.8% of the other European patients received multipolar leads. The choice of the LV lead did not affect the QRS narrowing which was similar to the European total cohort. Moreover, it remains to be shown if multipolar leads are linked to better outcome.
Several procedural differences between Romanian and other European physicians are worth emphasizing. First, LV lead position was optimized based on EGM by Romanian physicians and on surface ECG in other European centres. Second, AV and VV delay program-ming were performed in Romanian patients before discharge significantly more often than in other Eu-ropean patients. Further data on outcome would be interesting on this matter.
One of the interesting fi nding of this survey was that, even if Predictors of Response to CRT (PROSPECT)13 and Echocardiography Guided Cardiac Resynchronization The-rapy (EchoCRT)14 trials did not show any benefit of assessing mechanical dyssynchrony by echocardiogra-phy for CRT indication on top of conventional crite-ria, echocardiography was highly used in the Romani-an group. Moreover, the ECHO-CRT study failed to show the value of mechanical dyssynchrony criteria for CRT response in patients with narrow QRS. In this study CRT in such patients was actually linked to worse survival. Despite of this scientific evidence mecha-nical dyssynchrony was amongst indications for CRT in 40.4% of Romanian patients, whereas this was taken into account for only 11.0% of implantations in the other European countries. One reason for difference may be the financial limitations in Romania which may have imposed a stricter patient selection than in other countries and echocardiographic criteria could contri-bute to this selection. Concerning imaging techniques in these patients, similar to other countries, cardiac MRI was rarely used in this heart failure cohort.
As expected, the patients had fairly wide QRS com-plexes, most frequently with left bundle branch block and the majority was in sinus rhythm. The small num-ber of patients with atrial fibrillation in the Romanian group may also be due to financial limitations. Due to the class IIa indication for CRT in patients with per-manent atrial fibrillation1,2, physicians may choose to direct resources towards patients with class I indica-tions.
In comparison with the first CRT survey, a low number of off-label CRT implantations were observed in the Romanian group, with a small proportion of pa-tients with narrow QRS complex, with left ventricular ejection fraction above 35% and no patient in NYHA functional classI.
The complications incidence was higher in Roma-nian cohort. Several factors could contribute to this. First, as many implant centres from Romania were in-cluded in this survey, this reflects the fact that some centres are still on the learning curve. Second, 32% of patients were anticoagulated, and the higher incidence of bleeding complications arises from a still common practice of anticoagulation bridging. The results from the CRT Survey II may initiate a discussion and action plan on how to bring down the complication rates.

STUDY LIMITATIONS
This survey has several limitations. No standardized method was used for assessing left ventricular ejec-tion fraction, which has an important impact on CRT decision. Also, there is no available data whether a de-fibrillator was indicated as primary or secondary pre-vention of sudden cardiac death. Further data would be needed in order to understand the actual CRT-D patient profile in different European countries.

CONCLUSIONS
Romanian heart failure patients are more symptomatic and have worse outcome features, such as a lower left ventricular ejection and wide QRS complexes. Indi-cations regarding CRT implantation follow the most recent ESC guidelines, but the ratio of CRT-D devices in Romania is lower than in the other European coun-tries. More data is needed in order to understand the underlying causes for our findings.

Conflict of interest: None declared.

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