Prevalence for indications and outcome of cardiac resynchronisation therapy in specific patient groups

Background. The cardiac resynchronisation therapy (CRT) is well established. Several randomised clinical trials have proven its efficacy and framed the population that benefits the most from its utilisation. The presence of symptomatic heart failure (HF), in particular HF with reduced ejection fraction (HFrEF) and a certain grade of intraventricular conduction delay identified at the ECG as a prolonged Q, R, and S waves (QRS) duration or right ventricular paced rhythm indicates a possible benefit provided by the CRT. Despite these well-known results, everyday clinical experience and observational studies show how, in real-world practice, there is a substantial delay and lack of CRT use.

Aims. The common aim of the project was to understand, describe and identify the underuse of CRT to help construct a foundation for improvement and further study the implementation of CRT.

In particular, the first study focused on describing the state of the art of CRT utilisation in different populations and countries, comparing information from various data sources.

The second study also looked at the implementation of CRT from the perspective of a more defined but unselected population.

The third study wanted to examine the impact of a device implant on patients' quality of life.

The final study aimed to describe the subpopulation with HF and a high percentage of right ventricular pacing (RVP) who also have proved to benefit from CRT implants.

Materials. The first study consisted of a cross-sectional analysis of three data sources: the European Society of Cardiology (ESC) HF-Long Term Registry (ESC-HF-LT), the Swedish Heart Failure Registry (SwedeHF) and the second European Society of Cardiology survey on CRT (ESC- CRT Survey II).

The other three studies used data from the National implantable cardioverter defibrillator (ICD) and Pacemaker (PM) registry.

Study II combined it, thanks to the national personal registration number that every Swedish subject has, with the National Patient Registry and the Cause of Death Registry together with the regional electrocardiogram (ECG) database (MUSE).

Study IV used data from the ICD and PM Registry, the National Patient Registry and the Cause of Death Registry linked with the Longitudinal integrated database for health insurance and labour market studies (LISA) from the Statistic of Sweden and The National Prescribed Drug Registry.

Study I. "What determines who gets Cardiac Resynchronization Therapy in Europe? A comparison between ESC-HF-LT registry, SwedeHF registry and ESC-CRT Survey II" Three large data sources were compared at the patient level (the ESC-CRT survey II, 11,088 patients; the ESC-HF-LT registry, 1,031 patients; and the SwedeHF registry, 5,008 patients). All patients in the ESC-CRT survey II were implanted. In ESC-HF-LT, 36% had a CRT indication, of which 47% had CRT. In SwedeHF, the corresponding percentages were 30% and 25%. The median age of patients with CRT or CRT indication was comparable for the ESC-CRT survey II and ESC-HF-LT registry (70 years and 68 years, respectively) and lower compared to the SwedeHF registry (76 years). The ESC-CRT survey II and ESC-HF-LT registry are representative of a more specialised healthcare system compared to the broader enrolment pool of the SwedeHF registry (University hospitals 63%, 80%, 30% respectively, CRT implanting centres 100%, 86%, 46% respectively).

In the ESC-HF-LT registry, the predictors of CRT were atrial fibrillation (AF), prior HF hospitalisation, and New York Heart Association (NYHA) class. In the SwedeHF registry, besides the previously mentioned factor, with the exception of prior HF hospitalisation, age, previous myocardial infarction, non-smoking, enrolment at a university hospital and follow-up at HF centre/Hospital were associated with CRT use. In SwedeHF, above median income and higher education level were also independently associated with the use of CRT.

Study II. "Prognosis of CRT-treated and CRT-untreated unselected population with LBBB in Stockholm County"

We collected 5,359 patients with a first ECG with QRS > 150ms and left bundle branch block (LBBB) morphology in the Stockholm region. The median age was 76 years, 36% were female. At the time of index ECG, 41% had a previous history of HF and 27% developed HF. Among 1053 patients with a class I indication for CRT, only 60% received the CRT with a median delay of 137 days and it was associated with a lower risk of death (hazard ratio (HR): 0.45 95% 95% confidence intervals (CI): 0.36-0.57), cardiovascular death (CVD) (HR: 0.47 95% CI: 0.35-0.63) and HF hospitalisation (HR: 0.56 95% CI: 0.48-0.66). The age of over 75 years and the diagnosis of dementia and chronic obstructive pulmonary disease were predictors of CRT non-use, while having a pacing/defibrillator device independently predicted CRT use.

Study III. "Health-related quality of life in a large cohort of patients with cardiac implantable electronic devices - a registry-based study" In 2019, 1,479 patients implanted with a cardiac implantable electronic device completed the EuroQol Group Association five-dimension questionnaire (EQ-5D) before and after one year of the implant. Of those, 80% received a PM, 10% an ICD, 5% a cardiac resynchronization therapy pacemaker (CRT-P) and 6% a cardiac resynchronization therapy defibrillator (CRT-D). The median age was 77 years, with a prevalence of females ranging from 38% in the PM group to 17% in the ICD group. The EuroQoL visual analogue scale (EQ-VAS) and the EQ-5D index significantly increased in patients with PM and CRT-P (EQ-VAS +2.8, standard deviations (SD) 23 and +5.8, SD 24.9; EQ-5D index +0.019, SD 0.114 and +0.051, SD 0.125) while only the EQ-5D index increased in patients with ICD (+0.002, SD 0.104). After adjusting for age, sex and health-related quality of life (HRQoL) at baseline, the presence of a defibrillator was associated with lower EQ-VAS (-3.4, 95% CI -6.7; - 0.1 and -4.8, 95% CI -8.8; - 0.7) and EQ-5D index (-0.018, 95% CI -0.035; - 0.0003 and -0.025 95% CI -0.046; - 0.004) at follow-up compared to PM.

Study IV. "Management and clinical outcomes in patients with heart failure and a high percentage of right ventricular pacing. A nationwide registry-based study".

Out of 220,752 patients with HF from 2011 to 2021, 5,558 (2,5%) had a high burden of RVP (inferred from the presence of III° AV-block at pacemaker implantation) with a higher prevalence of males (63% vs 54%), hypertension (70% vs 65%), chronic kidney disease (20% vs 16%), ischemic aetiology (53% vs 43%). The exposed to a high percentage of RVP had a higher risk of CVD and HF hospitalisation (HR 1.08 95% CI 1.03-1.13 and HR 1.25 95% CI 1.19-1.30). Only a minority of those exposed were upgraded to CRT. High Age and hypertension were independently associated with a lower probability of upgrading to CRT therapy, while male sex and high-level education were associated with a higher probability of upgrade.

Conclusions. This thesis and its component studies suggest that: 1. There is a large heterogeneity in CRT utilisation based on population characteristics, data sources and clinical or socio- economical factors. 2. Despite strong evidence of CRT efficacy, its underutilisation is alarming, and further study and actions to improve patient management should be undertaken. 3. Patients' perspectives should be considered in therapeutic decisions. 4. Outcomes of specific populations, such as those with HF and a high percentage of RVP, are poor and further need the implementation of beneficial therapies like CRT.

List of scientific papers

I. Gatti, Paolo, Cecilia Linde, Lina Benson, Tonje Thorvaldsen, Camilla Normand, Gianluigi Savarese, Ulf Dahlström, Aldo P. Maggioni, Kenneth Dickstein, och Lars H. Lund. "What Determines Who Gets Cardiac Resynchronization Therapy in Europe? A Comparison between ESC-HF-LT Registry, SwedeHF Registry, and ESC- CRT Survey Il". European Heart Journal. Quality of Care & Clinical Outcomes 9, nr 8 (22 december 2023): 741-48. https://doi.org/10.1093/ehjqcco/qcad024

II. Gatti, Paolo, Stefan Lind, Ingibjörg Kristjánsdóttir, Ava Azari, Gianluigi Savarese, Matteo Anselmino, Cecilia Linde, och Fredrik Gadler. "Prognosis of CRT-Treated and CRT-Untreated Unselected Population with LBBB in Stockholm County". Europace: European Arrhythmias, Pacing, and Cardiac Electrophysiology: Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology 25, nr 7 (04 Juli 2023): euad192. https://doi.org/10.1093/europace/euad192

III. Gatti, Paolo, Carolin Nymark, Fredrik Gadler. "Health-related quality of life in a large cohort of patients with cardiac implantable electronic devices - A registry-based study". PLOS ONE 19(12): e0314978. https://doi.org/10.1371/journal.pone.0314978

IV. Gatti, Paolo, Lina Benson, Gianluigi Savarese, Matteo Anselmino, Cecilia Linde, Lars H. Lund, Fredrik Gadler. "Management and clinical outcomes in patients with heart failure and a high percentage of right ventricular pacing. - A nationwide registry- based study". [Manuscript]