Chicago, IL - Prolongation of the QRS interval, an electrocardiographic marker for ventricular dyssynchrony, is present in more than a third of low-LVEF patients hospitalized for acute heart failure and independently predicts all-cause mortality and cardiovascular morbidity after discharge, suggests a post hoc analysis of almost 3000 patients in a major international clinical trial [1].

The long-QRS-associated risk was elevated even among patients in whom it developed anew during the hospitalization and despite judicious background medical therapy that included beta blockers and ACE inhibitors or angiotensin receptor blockers, report Dr Norman C Wang (University of Pittsburgh, PA) and associates in the June 11, 2008 issue of the Journal of the American Medical Association.

Their findings are based on a retrospective look at data from the previously published Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), conducted at more than 300 centers in Europe and North and South America [2,3]. The trial had randomized 4133 patients with chronic systolic heart failure treated in the hospital for an acute exacerbation with either 30 mg/day of the oral vasopressin antagonist tolvaptan (Samska, Otsuka Pharmaceuticals) or placebo on top of standard IV therapy.

A prolonged QRS interval, defined as QRS >120 ms, was identified at baseline in about 44% of the patients eligible for the post hoc analysis, which excluded those with implanted pacemakers or defibrillators.

To senior author Dr Mihai Gheorghiade (Feinberg School of Medicine, Chicago, IL), the analysis goes beyond simply identifying a marker for risk stratification after a heart-failure hospitalization. It shows that an easily assessed ECG feature in a population already at high risk for mortality and cardiovascular events identifies a group with an even worse prognosis, who might potentially respond to an established heart-failure therapy, he observed for heartwire.

Dyssynchrony as characterized by a QRS duration exceeding 120 ms is a prerequisite for cardiac resynchronization therapy (CRT) in patients with chronic systolic NYHA class 3-4 heart failure not responding to evidence-based drug therapy.

Even though 44% of patients in the analysis had QRS-defined dyssynchrony, CRT was very rarely recommended after discharge, Gheorghiade observed. "That points out how behind we are." Potentially, he said, the EVEREST analysis shows that CRT should be considered in a huge proportion of patients who don't have devices and are discharged after an exacerbation of chronic systolic heart failure and "gives us great hope that [CRT] can make a major difference in outcomes."

Gheorghiade cautioned that the analysis doesn't actually show that treating dyssynchrony in EVEREST-like patients improves outcomes and that it doesn't necessarily apply to all patients hospitalized with systolic heart failure; it excluded, for example, the very elderly and patients with multiple comorbidities and other conditions that would have raised their risk status.

In the study's primary analyses, as previously reported by heartwire, oral treatment with tolvaptan in addition to standard therapy appeared safe and was associated with modest but significant improvements in dyspnea, fluid volume, edema, and, among those initially with hyponatremia, serum sodium levels. Over a mean follow-up of about 10 months, tolvaptan had no apparent effect on either all-cause mortality or a composite of cardiovascular death or HF hospitalization, both primary end points. Nor were differences seen in cardiovascular mortality, cardiovascular death or hospitalization, or worsening heart failure.

In the post hoc analysis, QRS prolongation was associated with a nonsignificant 30% increase in adjusted risk of mortality and a significant 40% increase in adjusted risk of CV death or hospitalization over three months. Both end points were significantly increased for patients with a long QRS duration in the long-term analysis.

The most common cause of death, regardless of QRS duration, was progressive heart failure (35.8% and 38.0% of deaths among patients in the short- and long-QRS groups, respectively). About 30% of patients in both groups died of sudden cardiac death.

According to Gheorghiade, the EVEREST trial is the first of its kind in which the causes of death throughout the follow-up were independently adjudicated. "This is the first time we know how they die."

Tolvaptan is scheduled for a June 25 review by the Cardiovascular and Renal Drugs advisory committee of the FDA, which will decide whether the drug should be indicated for hypervolemic and euvolemic hyponatremia; not on the agenda that day is Otsuka's concurrent filing for the drug's approval in acute decompensated heart failure.