Cover Page The handle

Cover Page

The handle http://hdl.handle.net/1887/61173 holds various files of this Leiden University dissertation.

Author: Höke U.

Title: Pacing in heart failure: focus on risk stratification and patient selection for cardiac resynchronization therapy

Issue Date: 2018-04-10

Part 2

Cardiac Resynchronization Therapy in

Subpopulations Under-Represented in

Randomized Clinical Heart Failure Trials

Chapter 3

Cardiac Resynchronization Therapy in Populations Under-Represented in Randomized Controlled Trials

Ulaş Höke MD*^,†, Nina Ajmone Marsan MD PhD* Jeroen J. Bax MD PhD*, Victoria Delgado MD PhD*

*Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands. ^†Interuniversity Cardiology Institute of The Netherlands, Utrecht, The Netherlands.

Heart. 2015 Feb;101(3):230-9

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left ventricular (LV) function of patients with heart failure symptoms have been dem- onstrated in several randomised controlled trials (RCTs).^1-8 The data from those trials form the basis of current recommendations for CRT use.^9-12 However, several sub- populations, such as elderly patients, diabetics, and patients with atrial fibrillation (AF), non-left bundle branch block QRS morphology or congenital heart disease, are underrepresented in randomised clinical trials, and the effects of CRT remain unclear. For example, the mean age of patients included in the majority of RCTs was

<75 years, whereas in the European CRT survey 31% of patients were older than 75 years.¹³ Similarly, AF was an exclusion criterion in many RCTs, while 31% of patients included in the Medicare Implantable Cardioverter-Defibrillator Registry had AF.¹⁴ Table 1 summarises the frequency of specific subpopulations included in RCTs and recent registries.^1-7,13,14 The present article provides an overview of the effects of CRT in subpopulations underrepresented in RCTs and underscores the unmet needs for evidence based treatment in these subpopulations.

NYHA FUNCTIONAL CLASS I

After the demonstrated improved outcomes of patients with New York Heart As- sociation (NYHA) functional class III–IV heart failure symptoms treated with CRT, the concept of halting the progression of heart failure in mildly symptomatic patients was the hypothesis of the MIRACLE implantable cardioverter defibrillator (ICD) II, REVERSE, MADIT-CRT, and RAFT trials.^5-7,15 A meta-analysis pooling data from six randomised trials that included 4572 mildly symptomatic heart failure patients dem- onstrated that CRT reduced the risk of all-cause mortality (relative risk 0.83, 95% CI 0.72 to 0.96).¹⁶ However, among the studies that included predominantly patients with NYHA functional class I–II heart failure symptoms, the percentage of patients in NYHA I ranged between 15–18%.^5,6 Subgroup analyses of these trials demonstrated that the prognostic benefit associated with CRT was only observed in patients with NYHA functional class II (figure 1).^5,6 The Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial, which randomised 107 NHYA functional class I and 503 NYHA functional class II heart failure patients to CRT-ON and CRT-OFF, demonstrated that patients allocated to the CRT-ON group showed a significant reduction in LV end-systolic volume at follow-up, and this reduction was similar in patients in NYHA functional class I and II.⁵ However, the European cohort of the REVERSE trial that included 262 patients showed that only patients with NYHA functional class II heart failure symptoms benefited clinically from CRT.¹⁷ Similarly, the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchro-

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Table 1. Overview of the proportion of specific subgroups in real world registries and in the large randomized controlled CRT trials. Medicare ICD registry14European CRT survey13MIRACLE1COMPANION3CARE-HF4RETHINQ2EchoCRT8MADIT- CRT6REVERSE5RAFT7 No. patiets24,1692,4384531,5208131728091,8206101,798 NYHA class I (%)1.42excludedexcludedexcludedexcludedexcluded1518excluded Non-LBBB (%)336NA296excludedexcluded303921 QRS 120-149 ms (%)4530NA21 (120-147 ms)35 (120-159 ms)27 (120-130 ms)

15 (120-130 ms)

35 (130-149 ms)

49 (120-151 ms)49 (120-149 ms) Atrial fibrillation (%)31.523excludedexcludedexcludedexcludedexcludedexcludedexcluded13 RV pacing (%)NA19excludedexcludedexcludedexcludedexcludedexcludedexcluded7.5 Elderly, age (years)75±670 (62-76)64±1167±116558-605864-6562-6366±9 Diabetes (%)35.730NA41251NA40302234 Renal dysfunction (eGFR<60 ml/ min/1.73m²) (%)

NANA38 (excluded eGFR<30)

2318NA13332950 Congenital heart disease (%)NANANANANANANANANANA Abbreviations: CARE-HF = Cardiac Resynchronization-Heart Failure; COMPANION = Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure; MADIT-CRT = Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy; MIRACLE = Multicenter InSync Randomized Clini- cal Evaluation; No = number; NA = not available; Non-LBBB = non-left bundle branch block; NYHA = New York Heart Association; RAFT = Resynchronization- Defibrillation for Ambulatory Heart Failure Trial; RV = right ventricular

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nisation Therapy (MADIT-CRT) trial which randomised 1820 patients with mild heart failure symptoms (18% in NYHA functional class I) to CRT-D (defi brillator) or ICD showed that CRT-D improved the outcomes of patients with NYHA functional class II heart failure symptoms.⁶ The low number of patients with NYHA functional class I heart failure symptoms enrolled in those trials precludes strong recommendations for the use of CRT in this subpopulation. Future studies designed specifi cally to an- swer the question whether CRT is benefi cial in NYHA functional class I heart failure patients may change current recommendations.^9,10

QRS DURATION AND MORPHOLOGY

Various meta-analyses and sub-analyses of RCTs evaluating the impact of QRS dura- tion and morphology on CRT effects have demonstrated that CRT reduced all-cause mortality and heart failure hospitalisations in patients with wide QRS (>140– 150ms) and left bundle branch block (LBBB) morphology.^18-21 A recent trial including 809 heart failure patients with narrow QRS (<130 ms) and LV dyssynchrony (based on echocardiographic techniques), who were randomised to CRT-D or ICD, provided further evidence on the futile effects of CRT on LV function and long term outcome Figure 1. Forest plot of study-specifi c and hazard ratio/odds ratio and 95% confi dence interval for the endpoint study (risk of death or heart failure in the MADIT-CRT trial and risk of heart failure clinical composite response in the REVERSE trial). Adapted with permission from Moss et al.⁶ and Linde et al.⁵ Abbreviations: CI: confi dence interval; CRT: cardiac resynchronization therapy; ICD: implantable car- dioverter defi brillator; No: number; NYHA: New York Heart Association.

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in this group of patients.⁸ Therefore, current guidelines have included class I rec- ommendation for CRT in patients with LBBB and QRS duration >120 ms (level of evidence A for QRS duration >150 ms, level of evidence B for QRS between 120–150 ms), whereas CRT is not recommended in patients with QRS duration <120 ms.^9,10

While for heart failure patients with narrow QRS the current evidence may be robust enough for not recommending CRT, for patients with wide QRS (specially 120–140 ms) and non-LBBB morphology the evidence is limited. Specifically, the percentage of patients included in RCTs with non-LBBB QRS morphology ranged between 6–39% (approximately 1200 patients). This relatively low number of patients may have underpowered the sub-analyses comparing the effects of CRT between patients with LBBB versus non-LBBB morphology. In addition, recent meta-analysis¹⁸ with access to individual patient data of five randomised CRT trials (in contrast to previous meta-analyses using aggregate data from trials¹⁹) has shown that QRS duration predicted the magnitude of the CRT effect on all-cause mortality and heart failure hospitalisations. In particular, a QRS duration >140 ms indicated a high probability of benefit from CRT. In contrast, QRS morphology did not provide incremental information on the clinical benefit.¹⁸ The different LV activation pat- terns described in heart failure patients with right bundle branch block (RBBB) and patients with LBBB may explain the differences in CRT efficacy.^22,23 In patients with RBBB, the right ventricle (RV) shows the most dyssynchronous activation while the LV shows minimal dyssynchrony (figure 2).^22,23 In contrast, heart failure patients with LBBB show a pronounced LV dyssynchrony with the septum contracting earlier than the lateral free wall. As a consequence, the LV activation time is longer in patients with LBBB than in patients with RBBB, which may influence the effects of CRT. The results of the meta-analysis by Cleland et al¹⁸ suggest that a wide QRS may supersede the effects of QRS morphology on CRT response and, beyond a certain QRS duration (>140 ms), QRS morphology may no longer influence the CRT outcomes. However, large RCTs including patients with non-LBBB QRS morphologies may provide further evidence in this subpopulation.

ATRIAL FIBRILLATION

The prevalence of AF increases along with the severity of heart failure²⁴: of 4228 NYHA functional class I heart failure patients enrolled in the Studies of LV Dysfunc- tion (SOLVD) Prevention trial,²⁵ 4.2% had AF, whereas in the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial,²⁶ which included 256 patients with NYHA functional class IV heart failure symptoms, the prevalence of AF was almost 50%. However, heart failure patients with AF have been excluded from

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or underrepresented in most CRT trials (table 1). Patients with AF seem to benefit from CRT to a lesser extent than patients in sinus rhythm. Pooled data from 7495 CRT patients (25.5% of them in AF) demonstrated that the non-response rate to CRT was significantly higher among patients with AF compared with patients with sinus rhythm (34.5% vs 26.7%, p=0.001).²⁷ Several reasons may explain this reduced response to CRT. First, compared with patients in sinus rhythm, patients with AF who receive a CRT device are usually older and have more associated comorbidities that may have an effect on symptoms, LV function, and prognosis. In addition, loss of biventricu- lar capture due to pseudo-fusion or fusion beats preclude adequate biventricular pacing delivery reducing the response to CRT (figure 3).²⁸ A recent study showed that biventricular pacing ≥98% ensures successful CRT.²⁹ Therefore, if adequate control rate and biventricular pacing cannot be achieved with medical treatment, atrioventricular (AV) node ablation may be considered. However, RCTs comparing Figure 2. Left ventricular dyssynchrony assessed with left ventricular activation time (LVAT) measured with electrode mapping along the atrioventricular ring through the coronary sinus (CS). The surface electrocardiographic recordings and intracardiac electrograms of heart failure patients with normal QRS duration (<120 ms) and configuration (NQRSHF), with right bundle branch block morphology (RBBBHF) and with left bundle branch block morphology (LBBBHF) are shown on top panels. The his- tograms of the LVAT for each group of patients are shown in bottom panels. The LVAT was longer in LBBBHF patients compared with patients in groups NQRSHF and RBBBHF indicated larger LV dyssynchro- ny. ds: distal; px: proximal; RVA: right ventricular apex Adapted with permission from Varma et al.²³

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the efficacy of CRT in patients with AF and rate control with medical treatment versus AV node ablation are lacking. Current evidence leads to a class IIa recommendation for CRT in NYHA functional class III ambulatory IV heart failure patients with QRS duration ≥120 ms and LV ejection fraction (LVEF) ≤35%.^9,10 There is no evidence of the efficacy of CRT in NYHA functional class II heart failure patients with AF.

Figure 3. Atrial fibrillation and cardiac resynchronisation therapy (CRT). Among patients with <98%

CRT pacing, atrial tachycardia/atrial fibrillation (AT/AF) are the most frequent reason for loss of CRT (30%), followed by premature ventricular contractions (PVC) (17%) and ventricular sensing episodes (VSE) (9%. Reproduced with permission from Cheng A et al.²⁸

On the other hand, in patients with AF and uncontrolled ventricular response who may be candidates for AV node ablation, and in whom an RV pacemaker may have a deleterious impact on LV function, CRT has been demonstrated to reduce heart failure hospitalisations and induce LV reverse remodelling.³⁰ A recent meta-analysis including 686 AF patients with reduced LVEF undergoing AV node ablation for rate control and receiving a CRT device (n=413) or RV pacing (n=273) showed that CRT was associated with lower mortality (risk ratio 0.75, p=0.3) and fewer heart failure hospitalisations (risk ratio 0.38, p=0.02).³⁰ Despite this modest evidence (small RCTs and heterogeneous populations), CRT should be considered in patients with AF, uncontrolled heart rate, and reduced LVEF who are candidates for AV node ablation (class IIa recommendation).^9,10

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NYHA functional class II–IV heart failure, comparing rate control versus AV node ablation, will provide further evidence.

RV PACING

RV pacing has been associated with increased risk of heart failure hospitalisation and all-cause mortality, particularly in patients with pre-existent LV dysfunction, myocardial infarction, and AF.^31,32 In addition, these risks increase with the cumulative percentage of RV pacing, duration of paced QRS complex (ventricular dyssynchrony induction) and pacing mode (single vs dual chamber pacing—AV dyssynchrony induction).³³ Ap- proximately 6% of heart failure patients are pacemaker dependent and may benefit from CRT.³⁴ However, the percentage of patients with indications for antibradycardia pacing who may benefit from a de novo CRT implantation remains unknown.

Upgrading single or dual chamber pacemakers to CRT devices represents almost one third of CRT implantations.¹³ Several small RCTs have demonstrated improve- ment in symptoms and LV systolic function, with reduction in heart failure hospitali- sations in patients undergoing CRT upgrade (table 2).^35-44 However, upgrading to CRT is associated with an 18.7% complication rate, and therefore the decision should be individualised.⁴⁵ Theoretically, a de novo CRT implantation in patients with conven- tional indications for antibradycardia pacing who may develop heart failure would overcome the associated complications of a CRT upgrade. The Biventricular versus RV Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK-HF) trial pro- vides the most evidence on the efficacy of CRT in preventing heart failure among patients with indications for pacemaker with AV block who have NYHA functional class I–III heart failure symptoms and LVEF ≤50%.⁴⁶ Patients assigned to the CRT arm had a significantly lower incidence of the primary endpoint (time to all-cause mor- tality, heart failure hospitalisation, and LV dilatation) compared with patients who received standard RV pacing (hazard ratio 0.74, CI 0.60 to 0.90) (figure 4).⁴⁶

Current guidelines recommend upgrading to CRT from pacemaker or ICD in patients with LVEF <35% who remain in NYHA functional class III– ambulatory IV de- spite optimal medical treatment, and suggest considering a de novo CRT in patients with reduced LVEF and expected high RV pacing percentage (>40%) to reduce the risk of heart failure worsening.^9,10 Identification of patients with indications for anti- bradycardia pacing who may benefit from an upgrade remains challenging. In addi- tion, potential complications associated with implantation of complex biventricular systems and upgrading to CRT, the associated costs of the biventricular devices,

56 57

Chapter 3

Table 2. Cardiac resynchronization therapy in patients with indications for antibradycardia pacing: focus on de novo CRT and upgrade pacing devices. Study No. PatientsBaseline characteristicsOutcomes NYHALVEF (%)Ischemic heart disease (%)

QRS duration (ms) CRT versus RV pacing (cross-over design)

Delnoy et al.734078% III33.3±9.632177±31Compared with RV pacing, CRT improved QoL score by 27%, LVEF by 40% and induced significant reductions in LVEDV and MR van Geldorp et al.743678% I-II36±1036195±26Compared with RV pacing, CRT significantly improved NYHA functional class and was associated with higher response rates in terms of LV reverse remodelling (53%) and LVEF improvement (56%) Leclercq et al.75443.2±0.425±952206±26Compared with RV pacing, CRT improved NYHA, 6-minute walked distance and QoL score by 18%, 29% and 19%, respectively. No significant changes in LV volumes or LVEF

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Chapter 3

Upgrade to CRTBaker et al.3660100% III-IV21±856NAUpgrading to CRT was associated with significant improvements in NYHA, QoL score and LVEF Laurenzi et al.3738100% III-IV27±645179±19Upgrading to CRT was associated with significant improvements in NYHA, QoL score and LVEF Vatankulu et al.382696% III-IV39±1148176±23Upgrading to CRT was associated with significant improvements in NYHA and LVEF and reductions in LV volumes and dyssynchrony Leon et al.3920100% III-IV21.5±6.955213±40Upgrading to CRT was associated with improvements in NYHA and QoL by 29% and 33%, respectively. LVEF increased by 44% and LV end-diastolic and end-systolic diameters reduced by 8.5% and 6.5%, respectively Witte et al.40323.3±0.120±250207±5Upgrading to CRT induced significant improvements in heart failure symptoms, LVEF and LV dyssynchrony Foley et al.41583.4±0.623.1±10.772163±32Upgrading to CRT induced significant improvements in heart failure symptoms, LVEF and LV volumes comparable to those observed in the novo CRT implantation Fröhlich et al.357072% III-IV24 (18-30)51184 (163- 205)Upgrading to CRT induced significant improvements in heart failure symptoms, LVEF and LV volumes comparable to those observed in the novo CRT implantation Nazeri et al.4221NA31.2±3.8excluded159±27Upgrading to CRT was associated with improvement in symptoms in 76% of patients, significant improvements in LVEF and LV dimensions and reductions in BNP levels Marai et al.43253.2±0.523±992203±32Upgrading to CRT induced significant improvements in heart failure symptoms, LVEF and LV volumes comparable to those observed in the novo CRT implantation Paparella et al.443981% III-IV23±741186±22Upgrading to CRT induced significant improvements in heart failure symptoms, LVEF and LV volumes comparable to those observed in the novo CRT implantation The present table included studies with >20 patients receiving an upgrade to CRT.

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and the shorter life of CRT devices needs to be considered when deciding between conventional RV pacing and a de novo CRT device implantation.

Figure 4. De novo cardiac resynchronisation therapy (CRT) in patients with conventional indications for antibradycardia pacing and left ventricular ejection fraction ≤50%. The BLOCK-HF trial showed a significantly lower cumulative event-free rate for the primary endpoint in patients undergoing right ventricular pacing compared with patients treated with a CRT. Reproduced with permission from Cur- tis et al.⁴⁶

ELDERLY PATIENTS

Elderly patients form a group consistently underrepresented in randomised clinical trials of heart failure therapy.⁴⁷ Although the prevalence of heart failure increases with age, the evidence shows that patients >70 years of age are a minority (if not explicitly excluded) in RCTs (table 1). The associated comorbidities such as severe renal dysfunction (frequently an exclusion criterion) or cognitive disease that preclude obtaining consent, result in low recruitment of elderly patients in the tri- als. However, similar to several registries, in the European CRT survey one third of patients treated with CRT were older than 75 years.^13,14 The salutary effects of CRT on clinical symptoms and LV function have also been described in elderly patients.^48-50 Verbrugge et al⁴⁸ demonstrated that the improvement in NYHA functional class and reduction in LV volumes at 6 months after CRT was comparable among groups of patients younger than 70 years, aged between 70 and 79 years, and 80 years and older. Despite a significantly higher annualised mortality rate among octogenarians

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failure hospitalisation was similar across the age groups.⁴⁸ These findings are con- sistent with sub-analyses of the Multicenter InSync Randomised Clinical Evaluation (MIRACLE) and MIRACLE-ICD trials.⁵⁰ Therefore, age should not be considered as an exclusion criterion for CRT implantation.

Another highly debated issue is the type of device to implant: CRT with defibril- lator capabilities (CRT-D) versus CRT-pacemaker (CRT-P). The majority of the series have shown that the proportion of CRT-P is higher among elderly patients compared with patients younger than 80 years (21.1% vs 8%, p<0.001).48,51,52,71-73 However, the number of patients in each age group comparing survival benefit between CRT-P and CRT-D is rather small.^48,51 A recent meta-analysis including 8307 patients showed that, compared with medical treatment, CRT-D reduced the number of deaths by 30%, but compared with ICD or CRT-P, CRT-D was not associated with better sur- vival.⁵³ The meta-analysis included data from RCTs where the elderly patients were underrepresented. Therefore, these conclusions may not be generalisable to elderly cohorts.

Furthermore, the rate of implantation related complications has been reported to be higher among elderly patients compared with younger cohorts (5.2% in pa- tients older than 85 years vs 5.0% and 4.4% in patients aged 80–85 and 19–79 years, respectively).⁵² Associated comorbidities, particularly cerebrovascular accidents, renal dysfunction and chronic pulmonary disease, were strongly associated with an increased procedural complications rate. The number of complications was not related to the type of device (CRT-P vs CRT-D); however, CRT-D was associated with increased length of stay and hospitalisation costs.⁵²

The current evidence emphasises the need for careful selection of elderly patients who may be CRT candidates, taking into consideration associated comorbidities and patient expectations in terms of survival benefit or symptomatic improvement. Ad- ditional RCTs specifically designed to establish the appropriateness of the type of device selected (CRT-P vs CRT-D) would provide further evidence.

HEART FAILURE PATIENTS WITH DIABETES MELLITUS

Diabetes is a well known risk factor for the development of heart failure and an important prognostic factor among heart failure patients. Similar to the elderly cohorts, diabetic patients have ischaemic heart disease and renal dysfunction more frequently, which may reduce the benefit derived from CRT. However, data from clinical trials on the efficacy in diabetic heart failure patients are inconclusive.^54-58 As shown in table 1, diabetic patients are also underrepresented in RCTs. Sub-analyses

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of a few landmark trials have also demonstrated the survival benefit of CRT in this subpopulation.^54,56 The Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial reported lower rates of all-cause mortality together with fewer cardiovascular hospitalisations, heart failure hospitalisations or all-cause hospitalisations in patients assigned to CRT (n=484) as compared to their counter- parts (n=138).⁵⁴ Similarly, the Cardiac Resynchronisation-Heart Failure (CARE-HF) trial demonstrated significant risk reduction of all-cause mortality and heart failure hospitalisations among diabetic patients randomised to CRT (n=101) as compared to diabetic patients on optimal medical therapy only (n=106).⁵⁶ In addition, in mildly symptomatic heart failure patients, the MADIT-CRT trial demonstrated that diabetic patients have worse survival than non-diabetic patients (all-cause mortality or heart failure hospitalisation rate: 26.6% vs 18%, respectively; p<0.001).⁵⁷ However, CRT-D was associated with a 44% reduction of the risk of allcause mortality or heart failure hospitalisation, compared with a 33% risk reduction among nondiabetic patients, suggesting that diabetic patients also benefit from this device therapy. Furthermore, the MADIT-CRT sub-analysis revealed that improvement in LV dimensions and function was comparable between diabetic and non-diabetic patients. The associ- ated comorbidities in diabetic patients may have influenced long term survival and, similar to elderly patients, accurate selection of those diabetic heart failure patients who have a higher probability of benefiting from CRT-D (particularly patients with non-ischaemic heart disease and LBBB morphology) is needed.

RENAL DYSFUNCTION

Renal dysfunction is relatively common among heart failure patients. The Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE-HF) registry, which included 13 164 heart failure patients, showed that more than half of the population had stage 3 or greater chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²).⁵⁹ The prognostic implications of CKD in heart failure patients are dismal: heart failure patients with significant CKD have a threefold higher mortality risk than patients without CKD.⁶⁰ This evidence may have influenced the design of CRT RCTs, which frequently ex- cluded patients with stage 3 or greater CKD (table 1). However, the evidence—based on small subanalyses or observational registries—has shown that CRT is associated with improvement in renal function, clinical symptoms, and LV function in patients with renal dysfunction.^61-65

The MIRACLE trial showed that patients with an eGFR between 30–60 mL/

min/1.73 m² significantly improved their renal function with CRT therapy compared

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defined by ≥15% decrease in LV end-systolic volume at 6 months follow-up, a re- cent observational study showed that patients with more impaired renal function (eGFR <60mL/min/m²) had a lower response rate to CRT than patients with eGFR 60–90 mL/min/1.73 m and >90 mL/min/1.73 m² (43% vs 58% and 62%, respectively;

p<0.001) (figure 5).⁶⁴ These differences in response to CRT based on the CKD stage may influence the prognosis of heart failure patients treated with CRT. Each 10 mL/

min/1.73 m² decrease in eGFR has been associated with a hazard ratio of 1.18 (95% CI 1.09 to 1.27; p<0.001) for all-cause mortality of heart failure patients treated with CRT (figure 5).^61,64 These results were confirmed by the sub-analysis of the MADIT-CRT trial which reported that eGFR<60 mL/min/1.73 m² was associated with all-cause mortality or heart failure hospitalisation with a hazard ratio of 1.49 (95% CI 1.15 to 1.93, p=0.002).⁶⁶

The absence of strong evidence showing the beneficial effects of CRT in patients with moderate or severe CKD may have resulted in the low use of CRT. However, the IMPROVE-HF registry showed that patient characteristics and comorbidities rather than renal function were the main determinants of the low use of this guideline recommended therapy.⁵⁹

Furthermore, the choice between CRT-D and CRT-P in patients with renal dys- function remains debatable. Subanalyses of RCTs and retrospective series provide limited evidence on the efficacy of primary prevention ICD in reducing all-cause

Figure 5. Cardiac resynchronisation therapy (CRT) in patients with renal dysfunction. (A) Echocardio- graphic response to CRT for each estimated glomerular filtration rate (eGFR) subgroup of the National Kidney Foundation practice guidelines. The response rates were significantly lower among patients with an eGFR <60 mL/min/1.73 m² (43%) compared with the patients with more preserved renal func- tion (58% and 62%, respectively). (B) Cumulative survival rates for heart failure patients divided accord- ing to the eGFR: ≥90, 60–90, and <60 mL/min/1.73 m². Patients with an eGFR <60 mL/min/1.73 m² had significantly worse prognosis compared with the other groups. Adapted with permission from van Bommel et al.⁶⁴

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mortality and sudden cardiac death in this subgroup of patients.^66,76-78 While heart failure patients with mild-to-moderate renal dysfunction showed significant reduc- tions in all-cause mortality and sudden cardiac death (32% and 66%, respectively), patients with severe renal dysfunction (GFR <35 mL/min/1.73 m²) did not experi- enced such benefit (hazard ratio 1.09 for all-cause mortality (p=0.84) and 0.95 for sudden cardiac death (p=0.95)).⁷⁶ In addition, the survival benefits were observed in patients with moderate renal dysfunction who were <80years of age, with decreas- ing age thresholds for more advanced renal dysfunction (<75 years and <65 years for severe and end-stage renal dysfunction, respectively).^66,76-78 Accordingly, current American Heart Association/American College of Cardiology/ European Society of Cardiology (AHA/ACC/ESC) guidelines recommend an individualised choice between CRT-P and CRT-D in patients with moderate to severe renal dysfunction, taking into consideration age related factors and comorbidities that may reduce life expectancy.^8,9

CONGENITAL AND PAEDIATRIC PATIENTS

Advances in surgical therapy have improved the survival of patients with congenital heart disease and contribute to the increasing prevalence of heart failure in the adult population. Heart failure is the main prognostic determinant of these patients.

Evidence of the beneficial effects of CRT on heart failure symptoms, ventricular function, and the prognosis of congenital heart disease and paediatric populations is highly anecdotal. Few registries including almost 300 patients have reported improvements in NYHA functional class and function of the systemic ventricle.^67-69 The implantation success rates ranged between 82–85%⁷⁰ (significantly lower than the 95% success rate reported in the main RCTs¹⁶). However, the complications rates ranged between 9–19% and were significantly higher compared with the complica- tions rates reported in RCTs (<10%).^16,70

This specific subpopulation poses important challenges for CRT implantation. The highly variable cardiac anatomy requires a careful and tailored implantation strategy.

An epicardial LV lead is needed in the presence of a congenital defect with right- to-left shunt or postoperative absence of transvenous access to the target chamber.

In addition, a recent registry including 187 paediatric patients with congenital com- plete AV block and structurally normal heart undergoing lifelong pacing showed that implantation of a pacing lead in the LV apex or midventricular lateral wall was associated with better LVEF after a median follow-up of 5.4 years, compared with other locations such as the RV apex or outflow tract (61% vs 54%, p=0.001) (figure 6).⁷¹ LV apex or midventricular lateral wall pacing sites were also associated with less LV

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this evidence is not sufficient to recommend the use of CRT or LV pacing in this population.^9,10 Furthermore, the variable anatomy and underlying pathophysiology is also one of the main determinants of response to CRT. Janousek et al showed that the response rate was lower among patients with dilated cardiomyopathy, whereas Cecchin et al demonstrated that patients with a single ventricle showed the higher response rates.⁶⁷ Cardiac imaging plays a pivotal role in the selection of paediatric and congenital heart disease patients for CRT and for planning individualised im- plantation strategies.

Figure 6. Optimal pacing site in paediatric patients. Approximate location of pacing site (based on biplane chest x-ray), left ventricular ejection fraction (LVEF) (panel A), and LV dyssynchrony (based on septal to posterior wall motion delay (SPWMD)) (panel B). Each pacing location site is colour coded based on LVEF and SPWMD. The LV apical and midventricular lateral wall were associated with better LVEF and less LV dyssynchrony whereas right ventricular outflow tract and lateral wall pacing sites were associated with more depressed LVEF and more dyssynchronous LV activation. Adapted with permis- sion from Janousek et al ⁷¹

CONCLUSIONS

CRT is an effective treatment for heart failure patients who meet the inclusion criteria of the main RCTs. Current estimations indicate that around 400 patients/million population/year might be candidates for CRT.^72-74 However, the number of CRT units

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implanted in 2011 were 140 units/ million population/year (data from 16 European countries).⁷² Therefore, there is still a significant margin for improvement in the treat- ment of heart failure patients. Whether older age, non-LBBB QRS morphology or the presence of associated comorbidities such as renal dysfunction or diabetes contribute to the low use of this guideline recommended therapy remains unclear.

Dedicated RCTs in these subpopulations are needed to further determine which patients may benefit from CRT.

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