domingo, 14 de noviembre de 2010

Preventing Heart Failure and Improving Survival


Preventing Heart Failure and Improving Survival

Arthur J. Moss, M.D.
November 14, 2010 (10.1056/NEJMe1011742)
Article
References
The cause of death from heart disease is either heart failure or a malignant cardiac arrhythmia, with the latter mostly a result of ventricular fibrillation. In acquired cardiac disorders, these two terminal processes are related to an abnormal myocardial substrate that is characterized either by chronic scarring and fibrosis from ischemic or nonischemic cardiomyopathy or by myocardial ischemia or infarction secondary to acute occlusive coronary artery disease. Chronic myocardial disease is frequently associated with dysfunctional cardiac remodeling with progressive enlargement and dilatation of the left ventricular chambers and a concomitant reduction in the left ventricular ejection fraction.
Favorable reverse cardiac remodeling with improvement in the structure and function of the heart was demonstrated in a 1992 clinical trial involving patients who had had a myocardial infarction and been treated with the angiotensin-converting–enzyme inhibitor captopril.1 Improvement was also subsequently shown with other drugs. During the past decade, several clinical trials have documented beneficial reverse-remodeling effects with cardiac-resynchronization therapy (CRT) in patients with advanced heart failure. Recently, two studies have shown that heart failure can be delayed or temporarily prevented with the use of CRT in at-risk patients with cardiac disease who are relatively asymptomatic.2,3
Patients with electrical conduction delay manifested by a wide QRS complex on electrocardiography, particularly those with left bundle-branch block, have a dyssynchronous left ventricular contraction pattern on echocardiography. Even in patients without heart disease, a conduction disturbance in the left bundle branch can reduce the performance of the heart to some degree. In patients with underlying myocardial disease, this conduction disturbance can make a bad situation worse and over time can exacerbate the dysfunctional cardiac remodeling process and contribute to the development of heart failure. CRT involves pacing of the left ventricle with the use of a pacemaker electrode positioned within one of the epicardial coronary veins. In patients with a wide QRS complex, pacing of the left ventricle can reverse cardiac remodeling with improvement in cardiac size and function.4
In this issue of the Journal, Tang et al.5 provide further documentation of the beneficial effects of CRT in patients with mild-to-moderate heart failure in the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) (ClinicalTrials.gov number, NCT00251251). A total of 1798 patients with New York Heart Association class II or III heart failure, a QRS duration of 120 msec or more, and a left ventricular ejection fraction of 30% or less were randomly assigned to receive either an implantable cardioverter–defibrillator (ICD) or an ICD plus CRT; both groups also received optimal medical therapy. On average, all patients were followed for more than 3 years.
In the ICD–CRT group, there was a 25% relative reduction in the primary end point of death from any cause or hospitalization for heart failure, whichever came first, beginning shortly after randomization, with similar reductions in the individual components of the primary end point. The primary outcome occurred in 33.2% of patients in the ICD–CRT group, as compared with 40.3% of those in the ICD group, an absolute difference of 7.1 percentage points. It is interesting that improved survival did not become evident until about 2 years after the initiation of therapy in the ICD–CRT group, which suggests that the reduction in heart-failure events preceded the diminution in mortality. Despite the positive findings, it should be appreciated that device- or implant-related complications and device-related hospitalizations during follow-up were twice as frequent in the ICD–CRT group as in the ICD group.
The study by Tang et al. confirms results from an earlier trial, the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT, NCT00180271),3 which showed that CRT had an increased benefit in patients with a QRS duration of 150 msec or more and in those with left bundle-branch block, as well as better efficacy in women than in men. During the past 2 years, the consistency of the results of these two major randomized CRT trials, along with those of a third trial, the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial (NCT00271154),2 provides convincing evidence of the therapeutic prowess of CRT in appropriately selected patients with ischemic or nonischemic cardiomyopathy. In this regard, the Food and Drug Administration approved an expanded indication for ICD–CRT on September 16, 2010, on the basis of the results of the MADIT-CRT trial.6
Echocardiographic studies have provided important insights into some of the substrate mechanisms by which CRT contributes its favorable effects.4,7 In patients with substantial myocardial disease and abnormal myocardial activation with an increased QRS duration, especially left bundle-branch block, dysfunctional cardiac remodeling progresses over time, resulting in an increased left ventricular volume and a decreased ejection fraction. Central to this disorder is dyssynchronous cardiac contraction and increased myocardial strain. In such patients, left ventricular epicardial pacing creates a more synchronous contraction with partial restoration of the left ventricular systolic wringing and twisting motion that is an essential part of normal cardiac contractility.8 This improvement in contractile efficiency with CRT is associated with a reduction in myocardial energy cost and oxygen consumption, another favorable benefit from this therapy.9
Substudies emanating from the three major randomized CRT trials may answer several relevant clinical questions associated with this relatively new technology. Does CRT prevent or reduce recurrent heart failure? Does CRT inhibit ventricular tachycardia and ventricular fibrillation? Since there are many subdivisions of the coronary veins, does the branch of the coronary vein in which the left ventricular pacing lead is located influence the efficacy of CRT? These secondary studies should clarify the added benefits that can be achieved with CRT.
In the past decade, we have come a long way with combined pharmacologic and device therapies that reduce the probability of heart failure and death in at-risk patients with cardiac disease. In response to a question raised in an editorial on this topic in the Journal just a year ago,10 we can say that recent findings documenting the use of CRT in preventing heart failure in minimally symptomatic patients are indeed breathtaking.
This article (10.1056/NEJMe1011742) was published on November 14, 2010, at NEJM.org.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

SOURCE INFORMATION

From the Cardiology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
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