New Findings Reshape Watchful Waiting for Asymptomatic Severe Mitral Regurgitation

For patients with severe primary mitral regurgitation (MR), left ventricular global longitudinal strain (LV-GLS) is a robust and significant predictor of long-term outcome that goes beyond the utility of established prognostic measures. Moreover, LV-GLS yields its prognostic value well before LV ejection fraction and LV dimensions meet guideline-defined thresholds for intervention. So finds a large, long-term observational study of Cleveland Clinic patients with asymptomatic severe primary MR recently published in Journal of the American College of Cardiology (JACC).

The study also found that exercise stress testing — i.e., percentage of predicted metabolic equivalents (METs) — offered additive prognostic information and that mitral valve surgery benefited outcomes in this population, particularly among patients with impaired LV-GLS, defined as –21.7 percent or worse.

These findings “challenge the current definitions of the watchful waiting strategy” around surgery for asymptomatic severe primary MR, notes an accompanying JACC editorial.

Seeking insights for an understudied population

The study included 737 consecutive asymptomatic patients with severe (≥ 3+) primary myxomatous MR evaluated at Cleveland Clinic from 2000 through 2011. All underwent resting and treadmill exercise echocardiography and had normal LV dimensions and preserved LV ejection fractions (≥ 60 percent). The primary objective was to determine whether resting LV-GLS (sample image shown below) and exercise testing yield incremental prognostic utility in this population.

Example of a resting left ventricular global longitudinal strain echo obtained for the study.

“In symptomatic patients and those with atrial fibrillation or overt LV dysfunction, decisions around timing of mitral valve surgery are already clear,” explains primary author Milind Desai, MD, a Cleveland Clinic cardiologist and and professor of medicine at Cleveland Clinic Lerner College of Medicine. “We focused on asymptomatic patients with preserved ejection fraction because this is the population in whom additional information may have the most utility in defining long-term risk, in view of conflicting data to date.”

Outcome determinants — new and established

Two-thirds of the study’s patients underwent subsequent mitral valve surgery, which was performed after a median of three months following initial evaluation. Over the study’s mean follow-up of 8.3 years, 9 percent of patients died. Multivariable analysis found the following factors to be associated with a significant increase in mortality risk:

• Higher Society of Thoracic Surgeons (STS) score (hazard ratio [HR] = 1.14 [95% CI, 1.04-1.25] for each percentage increase in STS score)
• Abnormal LV-GLS (HR = 1.60 [95% CI, 1.47-1.73] for each unit worsening)
• Higher baseline right ventricular (RV) systolic pressure (HR = 1.35 [95% CI, 1.10-2.32] for each 10-mm Hg increase)
• Lower exercise capacity (HR = 1.13 [95% CI, 1.04-1.22] for each 10 percent decrease in predicted METs)

The researchers then assessed reclassification of mortality risk by adding selected variables to a model for long-term mortality consisting of STS score, resting RV systolic pressure, LV end-systolic dimension and mitral effective regurgitant orifice. They found that adding predicted METs increased the model’s C-statistic from 0.61 to 0.69 and that adding LV-GLS increased it further, to 0.78 (both increases were statistically significant at P < .01).

Additional statistical analysis showed the risk of death to increase progressively as resting LV-GLS worsened below the population median of –21.7 percent.

Mitral valve surgery was associated with improved survival (HR = 0.82 [95% CI, 0.70-0.96]), and the benefit of surgery was especially pronounced among patients with an LV-GLS below –21.7 percent.

Toward better-informed watchful waiting

“We found that worsening baseline LV-GLS and reduced exercise capacity were independently associated with risk of death and provided additive — rather than duplicative — prognostic utility to previously known predictors,” says Dr. Desai. “These factors also sequentially improved risk classification in these patients, independent of known predictors.”

He notes that the study is distinguished from prior inquiries into this question by its unprecedented sample size and follow-up duration, its use of the hard end point of mortality, and its assessment of the sequentially incremental impact of LV-GLS and exercise capacity. Nevertheless, the study’s observational nature dictates validation in a prospective trial, he adds.

The accompanying JACC editorial argues that such a confirmatory trial should be multicenter in nature, given that the current data come from “a highly experienced valve center with extremely low operative morbidity and mortality.”

The editorialists — two Belgian cardiologists — nonetheless see these data as heralding what they dub “Watchful Waiting 2.0,” in which LV-GLS measurements are incorporated into the clinical management of this challenging subgroup of patients to “help bridge the controversy between ‘early referral’ and ‘current watchful waiting’ strategies, thus paving the way toward better patient care.”