Update: What are the new ESC guidelines on device therapy in heart failure?




Panos E. VARDAS, MD, PhD
Professor of Cardiology
President Elect of the ESC
Department of Cardiology
Heraklion University Hospital
Heraklion (Crete)
GREECE

What are the new ESC guidelines on device therapy in heart failure?


by P. E. Vardas , Greece



New data derived from recent clinical trials necessitate the update of the previous 2008 European Society of Cardiology (ESC) Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure and the 2007 ESC Guidelines for Cardiac Pacing and Resynchronization Therapy. The 2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure was developed by a Task Force of 10 European experts in heart failure and cardiac resynchronization therapy, with the special contribution of the Heart Failure Association (HFA) and the European Heart Rhythm Association (EHRA). The new Guidelines represent a comprehensive document, which concerns not only cardiologists, but all physicians interested in the field. There are a number of important main features that distinguish this Guidelines document from its predecessors. This article briefly highlights the main messages derived from the new 2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure. The new Guidelines set new standards of clinical excellence and their implementation is expected to have a major impact in clinical practice in reducing the complications of heart failure.

Medicographia. 2011;33:451-456 (see French abstract on page 456)



New data derived from recent clinical trials necessitate the update of the previous 2008 European Society of Cardiology (ESC) Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure (HF)1 and the 2007 ESC Guidelines for Cardiac Pacing and Resynchronization Therapy.2 The 2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure was developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association (EHRA). The new Guidelines represent a comprehensive document, which concerns not only cardiologists, but all physicians interested in the field. There are a number of important main features that distinguish this Guidelines document from its predecessors.

In contrast to previous guidelines, this focused update considers the characteristics of the patients included in the trials and contains several examples. In MADITCRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy), only 15% of the patients were classified as New York Heart Association [NYHA] class I, although the protocol permitted inclusion of patients in both NYHA I and II functional class and the favorable effect on the primary endpoint was limited to patients with a QRS width ≥150 ms, although the inclusion criteria permitted randomization of patients with a QRS width ≥130 m.

This article briefly highlights the changes from the prior guidelines and the main messages derived from the new 2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure.

Synopsis of the previous guidelines for cardiac resynchronization therapy

The previous ESC/EHRA 2007 Guidelines for Cardiac Pacing and Cardiac Resynchronization Therapy recommended the use of cardiac resynchronization therapy by pacemakers (CRT-P) or implantable cardioverter defibrillator (ICD) devices (CRT-D) in HF patients, who remain symptomatic in New York Heart Association (NYHA) classes III-IV, despite optimal medical therapy, with:
_ Left ventricular ejection fraction (LVEF) ≤35 %.
_ Left ventricular (LV) dilatation.
_ QRS complex ≥120 ms.
_ Normal sinus rhythm.

That was a Class I, Level of evidence A recommendation for CRT-P to reduce morbidity and mortality, and CRT-D was an acceptable option for patients who had a survival expectancy of >1 year.

Table I summarizes the class and the level of evidence of the recommendations for CRT for specific issues mentioned in the previous 2007 pacing guidelines.

Table I
Table I. CRT for specific issues mentioned in the previous 2007
pacing guidelines.

Abbreviations: CRT, cardiac resynchronization therapy; HF, heart failure; ICD,
implantable cardioverter defibrillator.

In order to keep these guidelines up to date, the new guidelines modify the recommendations and levels of evidence according to the most recent clinical trial evidence as follows.

New guidelines for CRT-P/CRT-D in patients with heart failure in NYHA class III/IV

A large number of randomized multicenter trials with crossover or parallel treatment design3-9 using CRT pacemakers (CRT-P) or CRT-ICD devices (CRT-D) have evaluated the long-term clinical effects of CRT. The usual study enrollment criteria were: NYHA functional class III or IV despite optimal pharmacological treatment, LVEF ≤35%, sinus rhythm, LV dilatation, and QRS duration ≥120/≥130 ms. Meta-analyses also suggested10-13 that the most efficacious option in patients with HF and low LVEF would be a CRT-D. The aforementioned randomized clinical trials confirmed a significant alleviation of symptoms and increase in exercise capacity conferred by CRT.

The important issue of morbidity and mortality was examined by two important studies, CARE-HF (CArdiac REsynchronization– Heart Failure [study]) and COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure).8-9

_ In COMPANION, CRT-D was associated with a significant decrease in all-cause mortality (relative risk reduction: 36%; P=0.003), while the 24% relative risk reduction in mortality associated with CRT-P was nearly statistically significant (P=0.059).
_ In CARE-HF, CRT-P produced a 36% relative reduction in the risk of death (P<0.002) after a mean follow-up time of 29 months. In the CARE-HF extension study, a relative risk reduction of 40% (P<0.0001) was observed, mainly due to a marked reduction in HF-related deaths.14 Moreover, a consistent finding in the randomized trials has been an absolute re- duction in LV end-diastolic diameter and an increase in LVEF following CRT.15,16 In the CARE-HF study, the mean reduction in LV end-systolic volume was 18% at 3 months and 26% after 18 months of CRT. Similarly, the mean LVEF increase was 3.7% at 3 months increasing to 6.9% at 18 months.9

These findings provided strong evidence of a sustained and progressive reverse remodeling effect conferred by CRT. The effect was significantly greater in patients with nonischemic than in those with ischemic heart disease. Regarding QRS morphology (left bundle-branch block, LBBB vs right bundlebranch block, RBBB), a baseline typical LBBB pattern predicted a favorable outcome defined as freedom from death or major cardiovascular event in the CARE-HF study.16

As a consequence of the results of the aforementioned studies, the new guidelines recommend the use of CRT-P/CRT-D to reduce morbidity and mortality (Class I, level of evidence A) in patients with NYHA function class III/IV, LVEF≤35%, QRS≥120 ms, sinus rhythm, and optimal medical therapy.3-17 It is also stated that reasonable expectation of survival with good functional status for >1 year is required for CRT-D and that patients with a secondary prevention indication for an ICD should receive a CRT-D.

Regarding class IV patients, it is clearly stated that they should be ambulatory: no admissions for HF during the last month and a reasonable expectation of survival >6 months. Comparing the new recommendations with the previous ones, the reader will discover that LV dilatation is no longer required in the recommendation, class IV patients should be ambulatory, and a reasonable expectation of survival with good functional status for >1 year is required for CRT-D implantation. It is also specified that the level of evidence is similar for CRT-P and CRT-and strongest for patients with typical LBBB.

New guidelines for CRT-D in patients with heart failure in NYHA class I/II

As already mentioned, CRT was not recommended in the 2007 guidelines, in patients with mild HF or asymptomatic LV systolic dysfunction (Class III, Level of evidence C).

The clinical impact of CRT in mildly symptomatic or asymptomatic patients with a depressed LVEF and a wide QRS complex has been evaluated in three trials:

_ MIRACLE ICD II7 (Multicenter, InSync™RAndomized CLinical Evaluation Implantable Cardioverter Defibrillator II) was a small pioneer trial that enrolled 186 candidates for ICD, who presented with NYHA function class II and sinus rhythm, and whose LVEF was ≤35%, QRS duration ≥130 ms, and LV enddiastolic diameter ≥55 mm. All patients received a CRT-D, and CRT was randomly activated in 85 patients. Despite the development of significant reverse LV remodeling, their exercise capacity was not increased.

_ MADIT-CRT18 enrolled 1820 patients in NYHA function classes I (15%) of ischemic etiology or II (84%) of any etiology and sinus rhythm, whose LVEF was ≤30% and QRS duration ≥130 ms. Using a 2:3 randomization scheme, 731 patients were assigned to receive an ICD and 1089 received a CRT-D. The primary end point was a composite of death from any cause and nonfatal HF-related adverse events. During a mean follow up of 2.4 years, the relative risk of sustaining a primary end point was reduced by 34% in the CRT-Dtreated group, a benefit attributable primarily to a 41% decrease in HF-related adverse events. However, there was no significant difference in mortality between the CRT-D- and ICD-only arms.

_ The REVERSE trial19 (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) enrolled 610 NYHA class II patients and class I patients with previous HF symptoms, with QRS ≥120 ms, EF <40%, and LV end-diastolic diameter ≥55 mm. They underwent implantation of a CRT-D or CRT-P, according to the investigators’ recommendations, though, ultimately, only 15% of patients received a CRT-P. Patients were randomly assigned to CRT activated (ON) versus CRT not activated (OFF). The primary end point was the HF clinical composite response that scored patients as improved, unchanged, or worsened over a relatively short follow-up of 12 months. The study did not meet the primary end point: 16% of patients worsened in the CRT-ON compared with 21% in the CRT-OFF (P=0.10) group. However, patients assigned to CRT-ON experienced a greater improvement in LV end-systolic volume index and other measures of LV remodeling. European investigators of this trial followed 262 of the patients up to 24 months and the primary end point of worsening was found to be significantly lower in the CRT-ON group than in the CRT -OFF group (19% vs 34%, respectively; P=0.01).20 Time to first HF hospital stay or death in the European cohort was also significantly delayed by CRT.

We should also mention that in prespecified subgroup analyses of data collected in MADIT-CRT18 and REVERSE,21 patients with a wide QRS duration ≥150 ms, as well as female patients, had significantly more benefit from CRT-D than male patients with QRS <150 ms. Further analyses revealed that patients with LBBB derived a significant benefit from CRT-D, whereas patients with a wide QRS complex and RBBB or indeterminate ventricular conduction disturbances (regardless of QRS duration) did not demonstrate reduction in primary events. MADIT-CRT18 and REVERSE19,20 enrolled a small proportion of asymptomatic patients (15% and 18%, respectively). As a result there is no convincing evidence that CRT is indicated in patients presenting with no or transient, mild symptoms and the recommendations in the new guidelines are restricted to patients in NYHA II class. Specifically, CRT preferentially by CRT-D is recommended to reduce morbidity or to prevent dis ease progression (Class I, Level of evidence A) in patients with NYHA function class II, LVEF≤35%, QRS≥150 ms, sinus rhythm, and optimal medical therapy.11,18-20

To conclude, improvement is primarily seen in patients with QRS≥150 ms and typical LBBB, survival advantage is not established, and in MADIT-CRT the extent of reverse remodeling was concordant with, and predictive of, improvement in clinical outcomes.

A few months after the publication of the ESC Guidelines, a new important study was published, RAFT (Resynchronization/ defibrillation for Ambulatory heart Failure Trial). RAFT enrolled 1798 NYHA class II or III HF patients with an EF <30% and an intrinsic QRS ≥120 ms or a paced QRS ≥200 ms, and randomized them 1:1 to an ICD alone or an ICD plus CRT (CRT-D).22

It should be mentioned that only 20% of patients had NYHA class III HF at study entry. After amean follow-up of 40months, the risk of occurrence of the primary end point (hospitalization for HF or death) was significantly reduced by 25%, from 40.3% in the ICD-only group to 33.2% in the CRT-D group (P<0.001).Moreover,mortality was also reduced by 25%(hazard ratio, 0.75; P=0.003), from 26.1% in the ICD-only patients to 20.8% in the CRT-D patients. Specifically, in NYHA class II patients, RAFT showed a significant 29% reduction in mortality (P=0.006), whereas in NYHA class III patients the reduction in mortality was nonsignificant (21%, P=0.14).

When comparing 2-year mortality rates in patient treated with CRT devices, RAFT showed about 20% 2-year mortality in the CRT-D arm, which is comparable with about 18% 2-year mortality in CARE-HF, the trial enrolling class III and IV patients, and comparable with a 25% 2-year mortality observed in the CRT-D arm of the COMPANION trial, which also enrolled class III and IV patients.

These rates are much higher than the 6% 2-year mortality observed in MADIT-CRT patients randomized to CRT-D therapy. RAFT seems to be more similar to CARE-HF or COMPANION than to MADIT-CRT, which probably explains the differences between trials regarding the magnitude of the effect of CRT-D on HF events and differences in the effect on mortality. Longterm follow-up of MADIT-CRT patients will possibly allow us to determine whether in these mild HF patients, CRT-D also reduces mortality, which would be expected after about a 40% reduction the risk of HF events.

New guidelines for CRT-P/CRT-D in patients with heart failure and permanent atrial fibrillation

The majority of randomized CRT studies to date have been almost exclusively restricted to patients in sinus rhythm, although approximately 1/5 of patients receiving CRT in Europe have permanent atrial fibrillation (AF).

However, since the publication of the previous guidelines on CRT, several studies in addition to a meta-analysis have been published.23-25 The majority of patients in this meta-analysis had undergone atrioventricular (AV) nodal ablation. A large, prospective, observational registry26 showed that, during longterm follow-up, hybrid therapy combining CRT with AV ablation (resulting in 100% effective biventricular stimulation) conferred improvements in LV function and exercise capacity comparable to those achieved in patients with sinus rhythm. In the same cohort,27 the authors provided evidence that patients with HF and AF treated with CRT received the same survival benefit as that achieved in patients with sinus rhythm only when AV ablation was performed shortly after CRT implantation.

Summarizing the existing data, there is consensus that essentially complete ventricular capture is mandatory in order to maximize clinical benefit and improve the prognosis of patients with permanent AF. Thus, AV nodal ablation may be required to assure adequate pacing. The evidence is strongest for patients with an LBBB pattern, and there are not sufficient data for mortality recommendation.

The new guidelines for CRT in patients with HF and permanent atrial fibrillation (AF) recommend that CRT-P/CRT-D should be considered to reduce morbidity in patients with NYHA function class III/IV, LVEF≤35%, QRS≥130 ms and pacemaker dependency induced by AV nodal ablation (Class IIa, level of evidence B).

CRT-P/CRT-D should be also considered to reduce morbidity in patients with NYHA function class III/IV, LVEF≤35%, QRS≥130 ms and slow ventricular rate and frequent pacing defined as ≥95% pacemaker dependency (Class IIa, Level of evidence C).

New guidelines for CRT-P/CRT-D in patients with heart failure and a conventional pacemaker indication

Taking into consideration the fact that prospective randomized controlled studies specifically addressing the issue of CRT in patients with a narrow QRS complex are currently lacking and there are only several retrospective observational series or small prospective trials demonstrating a clinical benefit, the level of recommendations is B or C.

Specifically, in patients with HF and a concomitant class I pacemaker indication, CRT-P/CRT-D is recommended to reduce morbidity in patients with NYHA function class III/IV, LVEF&le35% and QRS ≥120 mms (Class I, Level of evidence B).28-35

It is also stated that CRT-P/CRT-D should be considered to reduce morbidity in patients with NYHA function class III/IV, LVEF≤35%and QRS<120 ms (Class IIa, Level of evidence C). Concerning patients with NYHA function class II, CRT-P/ CRT-D is recommended to reduce morbidity in patients with LVEF≤35%and QRS<120ms (Class IIb, Level of evidence C).

New guidelines for LV assist device as destination therapy for patients with severe HF ineligible for cardiac transplantation

Patients with end-stage HF have a poor quality of life, a very high mortality rate, and are potential candidates for implantation of a LV assist device. Although cardiac transplantation is associated with high 1- and 10-year survival rates, organ supply is limited. The technical improvements and proven success of implantable LV assist devices have made it a reasonable treatment option in these patients, either as a bridge to cardiac transplantation or as destination therapy. Patient selection for an LV assist device is crucial. Patient population mainly consists of patients on inotropic (and/or mechanical) support prior to LV assist device implantation.

Patients with severe renal, pulmonary, or hepatic dysfunction as well as patients with active infection or cardiogenic shock should not be considered as candidates. Data from the National Institutes of Health (NIH) supported INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support) indicate that approximately 10% of patients in clinical practice receive an LV assist device as destination therapy.36 The available evidence suggests that a continuous flow device is superior to a pulsatile flow device.37 However, no controlled data is available as bridge to cardiac transplantation.

The new guidelines for LV assist device in patients with severe HF ineligible for transplant state that LV assist devicesmay be considered as destination treatment to reduce mortality in patients with NYHA function class III/IV, LVEF≤25% and peak VO2<14 mL/kg/min. (Class IIb, Level of evidence B).36-40

Conclusion

The new ESC Guidelines set new standards of clinical excellence and their implementation is expected to have a major impact in clinical practice in reducing the complications of HF. The ESC has as a strategic priority: not only the production of high-quality guidelines, but also their correct implementation. The national societies have shown interest and understanding with regard to the need for implementation. What is needed is systematic and organized collaboration between national societies and the ESC and an assessment of the results on an annual basis. _

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Keywords: cardiac resynchronization therapy; guidelines; heart failure; left ventricular assist device; left ventricular ejection fraction