Download Cardiac Resynchronisation Therapy in Patients with NYHA Class I-II

Cardiac Resynchronisation Therapy in Patients with
NYHA Class I-II
C. LINDE
Background
Chronic heart failure (HF) due to systolic dysfunction is a major health
problem, and there is an increasing prevalence as a result of better survival
after acute myocardial infarction, improved diagnostic methods, and aging
of the population. In the USA, there are approximately five million HF
patients in a total population of nearly 294 million [1], while in Europe there
are 10 million in a total of 666 million people. Asymptomatic left ventricular
dysfunction (ALVD) is estimated to have a similar prevalence [2, 3]. The
prognosis of HF is poor if the underlying cause cannot be treated. Recent
advances in drug treatment, particular those that modify neurohormones,
have been shown to reduce HF-related morbidity and mortality [4–6].
Overt HF symptoms generally follow ALVD, which is linked to increased
morbidity and mortality [5–7]. In the Framingham trial, a mortality rate of
40% over a 5-year follow-up was found in patients with a marginally reduced
left ventricular ejection fraction (LVEF) (< 50%) [6]. In the SOLVD prevention study, the development of HF was studied in patients with ALVD
defined by a LVEF of < 35%. Over 8.3 months, 30% in the placebo group,
compared to 21% in the enalapril group, developed overt HF. If electrical
dyssynchrony accompanies left ventricular (LV) dysfunction, the prognosis
is worse [8–10]. Health-care expenditures on HF typically account for 1–2%
of total health budgets, of which hospitalisations account for 60–70% of costs
[11–13]. Thus, in addition to optimal HF medication, interventions that
would halt disease progression and thereby reduce hospitalisation will
reduce health-care expenditure in these patients.
Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
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Cardiac resynchronisation therapy (CRT) has recently emerged as new
and additional form of treatment for patients with chronic HF and evidence
of ventricular dyssynchrony. The clinical efficacy of CRT is now established
in patients with moderate to severe (NYHA class III–IV) HF [14, 15]. Reverse
ventricular remodelling has consistently been demonstrated with CRT
[16–18]. It reflects prevention of disease progression and is possibly associated with better outcome. Recent data [19] suggest that reverse LV remodelling by CRT can also be observed in less symptomatic HF patients (NYHA
class II) patients. The purpose of this chapter is to elucidate the rationale for
CRT in patients with ALVD with prior HF symptoms or with mild systolic
HF (NYHA class II) and to discuss ongoing studies in these patients.
The Effects of CRT in Patients with Classical Indications for CRT
In studies including 3- to 6-months of follow-up, CRT, either alone or combined with an implantable cardioverter-defibrillator (ICD), has been shown
to improve symptoms, exercise tolerance, and quality of life [14, 15, 20] and
to reverse LV remodelling [16–18] in patients with moderate to severe HF
and wide QRS. Two studies have focused on morbidity and mortality with
longer follow-up periods in similar patients. One of these demonstrated
reduced HF-related deaths and hospitalisations by CRT whereas reduced
overall mortality was only demonstrated in combination with ICD therapy
[21]. Recently, however, total mortality and HF-related hospitalisations were
found to be reduced by CRT compared to control treatment in the CARE-HF
trial [22]. Thus, there is a clear evidence for improvements in total and HFrelated mortality by CRT per se, which justifies the choice of a CRT device
without a defibrillator in many HF patients, especially in the elderly.
Present Knowledge Regarding the Effects of CRT in NYHA II Patients
Whether CRT has similar benefits in patients with less severe HF remains
controversial [23]. One recent study focused on patients with NYHA class-II
HF and a classical indication for an ICD [19]. This was a relatively small, randomised, double-blind, parallel-controlled 6-month study on optimal medical therapy of HF patients. All of the patients had NYHA class-II symptoms,
an LVEF ≤ 35%, and a left ventricular end-diastolic diameter (LVEDD) ≥ 55
mm. In this study, 101 patients were randomised to CRT OFF and 85 to CRT
ON. Based on the clinical composite endpoint developed by Packer [24] to
assess HF patients, significant improvement of CRT compared to control
treatment was shown (Fig. 1).
Cardiac Resynchronisation Therapy in Patients with NYHA Class I-II
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Fig. 1. The clinical composite endpoint in the treatment and control groups at 6
months in the Miracle ICD II trial. From [19], with permission
Reverse Remodelling
Although patients with pathological LV remodelling experience progressive
worsening of HF, slowing or reversing of remodelling has only recently been
recognised as a goal of treatment [25]. Reverse remodelling by inhibitors of
angiotensin converting enzyme (ACEIs), in particular β-blockers [26, 27],
has been linked to reduced morbidity and mortality in all classes of systolic
HF. Furthermore, these observations have been substantiated by large trials
[28–30]. A consistent finding in the CRT trials designed with 3- to 6-months
follow-up is an 8–15% reduction in LVEDD and an increase in LVEF of 4–6%
[15–17, 23, 31], expressed in units of absolute value. In the CONTAK-CD
trial, significant reverse remodelling could also be demonstrated in the subgroup of NYHA class I–II patients after 6 months of CRT, even though benefits were less pronounced than in the much larger group of NYHA III–IV
patients [23]. In the MIRACLE ICD II study, significant reverse remodelling
by CRT was seen in NYHA class-II patients (Fig. 2) [19]. These preliminary
observations suggest that CRT might favourably impact outcomes in patients
with less severe symptoms of HF, LV systolic dysfunction, and ventricular
dyssynchrony.
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Fig. 2. The change in left ventricular (LV) volumes and LV ejection fraction after 6
months of either cardiac resynchronisation therapy or no pacing
Ongoing and Future Trials To Assess the Effects of CRT in NYHA Class I–II
Patients
To test the hypothesis that CRT might favourably impact outcomes in
patients with less severe symptoms of HF, LV systolic dysfunction, and ventricular dyssynchrony, the REsynchronization [reVErses Remodeling in
Systolic left vEntricular dysfunction (REVERSE)] study has been initiated.
This study aims at assessing the safety and efficacy of CRT in addition to
optimal medical therapy in patients with ALVD (NYHA I ACC/AHA stage C)
or mild HF (NYHA II) [32].
The REVERSE study is a prospective, multi-centre, randomised, doubleblind, parallel-controlled clinical trial designed to establish whether CRT
combined with optimal medical treatment can attenuate HF disease progression over at least 12 months compared to optimal medical treatment alone,
in patients with mild HF. Inclusion criteria are: NYHA I ACC/AHA stage C or
II HF, QRS duration ≥ 120 ms, LV ejection fraction ≤ 40%, LVEDD ≥ 55
mm, and an optimised pharmacological regimen [33].
After successful implantation of an atrio-biventricular device (CRT pacemaker or CRT defibrillator, according to the patients’ needs) approximately
500 patients from 100 centres in the USA, Canada, and Europe will be ran-
Cardiac Resynchronisation Therapy in Patients with NYHA Class I-II
515
domised to CRT versus no CRT, and followed for at least 12 months (24
months in Europe). The primary endpoint is the HF clinical composite
response, and LV end-systolic volume index is the first-order secondary endpoint. Enrolment started in September 2004 and is expected to be completed
in 2006.
The MADIT CRT aims at investigating whether prophylactic CRT inhibits
or slows symptomatic HF. Patients with previous myocardial infarction and
NYHA I–II, or patients with non-ischaemic cardiomyopathy in NYHA II will
be randomised to either the CRT or control group if they have an EF < 30%,
sinus rhythm, and QRS> 130 ms. The primary endpoint is time to mortality
(considering all causes) or HF event. This study will include 1820 subjects
with an estimated follow-up time of 24 months.
Conclusions
Cardiac resynchronisation therapy improves HF symptoms and reduces HFrelated hospitalisations and total mortality in patients with moderate to
severe HF and ventricular dyssynchrony. In smaller studies, CRT has also
been shown be beneficial in patients with less symptomatic HF. The effects
of CRT on HF outcomes is therefore currently being studied in patients with
NYHA II heart failure or ALVD.
References
1.
2.
3.
4.
5.
6.
7.
8.
Anonymous (2003) Heart disease and stroke statistics - 2004 update. American
Heart Association. In: http://www.americanheart.org/downloadable/heart/
1079736729696HDSStats2004UpdateREV3–19–04.pdf
Mosterd A, Hoes AW, de Bruyne MC et al (1999) Prevalence of heart failure and left
ventricular dysfunction in the general population; The Rotterdam Study. Eur Heart
J 20:447–455
McDonagh TA, Robb SD, Murdoch DR et al (1998) Biochemical detection of leftventricular systolic dysfunction. Lancet 351:9–13
Konstam MA, Kronenberg MW, Rousseau MF et al (1993) Effects of the angiotensin
converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. SOLVD
(Studies of Left Ventricular Dysfunction) Investigators. Circulation 88:2277–2283
The SOLVD Investigators (1992) Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327:685–691
Wang TJ, Evans JC, Benjamin EJ et al (2003) Natural history of asymptomatic left
ventricular systolic dysfunction in the community. Circulation 108:977–982
Levy D, Kenchaiah S, Larson MG et al (2002) Long-term trends in the incidence of
and survival with heart failure. N Engl J Med 347:1397–1402
Venkateshawar K, Gottipaty K, Krelis P (1999) The resting electrocardiogram pro-
516
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
C. Linde
vides a sensitive and inexpensive marker of prognosis in patients with chronic
congestive heart failure. J Am Coll Cardiol 33:145A (abs)
Baldasseroni S, Opasich C, Gorini M et al (2002) Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients
with congestive heart failure: a report from the Italian network on congestive heart
failure. Am Heart J 143:398–405
Silvet H, Amit J, Padmanabhan S (1999) Increased QRS-duration reduces survival
in patients with left ventricular dysfunction: results form a cohort of 2263 patients.
J Am Coll Cardiol 33:145A (abs)
McMurray J, McDonagh T, Morrison CE et al (1993) Trends in hospitalization for
heart failure in Scotland 1980–1990. Eur Heart J 14:1158–1162
Berry C, Murdoch DR, McMurray JJ (2001) Economics of chronic heart failure. Eur
J Heart Fail 3:283–291
Ryden-Bergsten T, Andersson F (1999) The health care costs of heart failure in
Sweden. J Intern Med 246:275–284
Cazeau S, Leclercq C, Lavergne T et al (2001) Effects of multisite biventricular
pacing in patients with heart failure and intraventricular conduction delay. N Engl
J Med 344:873–880
Abraham WT, Fisher WG, Smith AL et al (2002) Cardiac resynchronization in chronic heart failure. N Engl J Med 346:1845–1853
Stellbrink C, Breithardt OA, Franke A et al (2001) Impact of cardiac resynchronization therapy using hemodynamically optimised pacing on left ventricular remodeling in patients with congestive heart failure and ventricular conduction disturbances. J Am Coll Cardiol 38:1957–1965
Linde C, Leclercq C, Rex S et al (2002) Long-term benefits of biventricular pacing
in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 40:111–118
St John Sutton MG, Plappert T, Abraham WT et al (2003) Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure.
Circulation 107:1985–1990
Abraham WT, Young JB, Smith AL et al (2004) Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure:
the MIRACLE ICD Trial. Circulation 110:2864–2868
Young JB, Abraham WT, Smith AL et al (2003) Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure:
the MIRACLE ICD Trial. JAMA 289:2685–2694
Bristow MR, Saxon LA, Boehmer J et al (2004) Cardiac resynchronization therapy
with or without an implantable defibrillator in advanced chronic heart failure. N
Engl J Med 350:2140–2150
Cleland JGF, Daubert JC, Erdmann E et al (2001) on behalf of the CARE-HF
Steering Committee and Investigators. The CARE-HF study (Cardiac
Resynchronisation in Heart Failure study) rationale, design and end-points. Eur
Heart Failure 3:481–489
Higgins SL, Hummel JD, Niazi IK et al (2003) Cardiac resynchronization therapy
for the treatment of heart failure in patients with intraventricular conduction delay
and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 42:1454–1459.
Packer M (2001) Proposal for a new clinical end point to evaluate the efficacy of
drugs and devices in the treatment of chronic heart failure. J Card Fail 7:176–182
Cohn JN, Ferrari R, Sharpe N (2000) Cardiac remodeling – concepts and clinical
implications: a consensus paper from an international forum on cardiac remode-
Cardiac Resynchronisation Therapy in Patients with NYHA Class I-II
26.
27.
28.
29.
30.
31.
32.
33.
517
ling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol
35:569–582
Bristow MR, Gilbert EM, Abraham WT et al (1996) Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic
heart failure. MOCHA Investigators. Circulation 94:2807–2816
Kawai K, Takaoka H, Hata K et al (1999) Prevalence, predictors, and prognosis of
reversal of maladaptive remodeling with intensive medical therapy in idiopathic
dilated cardiomyopathy. Am J Cardiol 84:671–676
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II)(1999): a randomised trial.
Lancet 353:9–13
Packer M, Coats AJ, Fowler MB et al (2001) Effect of carvedilol on survival in severe
chronic heart failure. N Engl J Med 344:1651–1658
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL (1999)
Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet
353:2001–2007
Lau CP, Yu CM, Chau E et al (2000) Reversal of left ventricular remodeling by synchronous biventricular pacing in heart failure. Pacing Clin Electrophysiol
23:1722–1725.
Hunt SA, Baker DW, Chin MH et al (2002) ACC/AHA guidelines for the evaluation
and management of chronic heart failure in the adult: executive summary. J Heart
Lung Transplant 21:189–203
Linde C, Gold M, Abraham WT, Daubert JC (2005) for the REVERSE study group.
Rationale and design of a randomised controlled clinical study to assess if cardiac
resynchronisation therapy can slow disease progression in mild to moderate heart
failure – The Resynchronisation reVerses Remodelling in aSymptomatic left
vEntricular dysfunction (REVERSE) study. Am Heart J (in press)