Low-Flow, Low-Gradient Patients More Likely to Die, Less Likely to Undergo AVR

Patients with so-called paradoxical low-flow, low-gradient severe symptomatic aortic stenosis (AS) present diagnostic and therapeutic challenges for clinicians, but a new meta-analysis suggests aortic valve replacement (AVR) offers a survival benefit when undertaken. Even so, these patients are nearly 70% less likely than those with higher transvalvular gradients to be referred for treatment. 

The findings are being published in the December 15, 2015, issue of the Journal of the American College of Cardiology.

Philippe Pibarot, DVM, PhD, of Québec Heart and Lung Institute (Québec, Canada), and colleagues examined data from 18 studies published between 2005 and 2015 that looked at overall mortality or outcomes after AVR (surgical or transcatheter) vs conservative management in patients with low-gradient, severe AS and those with high-gradient or moderate AS.

All 7,459 patients had preserved LVEF. They were classified as:

• Low gradient (< 40 mm Hg with aortic valve area < 1.0 cm² and/or indexed aortic valve area < 0.6 cm²/m²)  
• Low-flow, low-gradient (stroke volume index < 35 mL/m² and gradient < 40 mm Hg with aortic valve area < 1.0 cm² and/or indexed aortic valve area < 0.6 cm²/m²)  
• Normal-flow, low-gradient (stroke volume index > 35 mL/m² and gradient < 40 mm Hg with aortic valve area < 1.0 cm² and/or indexed aortic valve area < 0.6 cm²/m²)  
• High gradient (≥ 40 mm Hg)  
• Moderate AS (< 40 mm Hg with aortic valve area >1.0 cm² and/or indexed aortic valve area > 0.6 cm²/m²) 

All studies were retrospective, nonrandomized, and unmatched, with the exception of the echocardiography substudy of the PARTNER trial.

High Mortality, Low Referral

Patients with low-flow, low-gradient AS had higher overall mortality than those with moderate AS; normal-flow, low-gradient AS; or high-gradient AS.

In the studies that looked at treatment outcomes, low-flow, low-gradient patients had a 56% reduction in mortality with AVR vs conservative management. A similar reduction was seen in normal-flow, low-gradient patients (HR 0.48; 95% CI 0.28-0.83). However, the greatest overall benefit of AVR was seen in high-gradient patients (HR 0.25; 95% CI 0.19-0.35).

Importantly, the studies also showed that low-flow, low-gradient patients were much less likely than those with high-gradient AS to be referred for AVR (OR 0.32; 95% CI 0.21-0.49).

Pibarot and colleagues say the presence of low transvalvular gradients “may result in underestimation of the stenosis severity and thus in underuse of AVR in patients with paradoxical [low-flow, flow-gradient] AS. This may have contributed to the increased risk of mortality observed in this subset,” they write.  

Overestimation of Survival Benefit?

This may not be the full explanation, however. In an editorial accompanying the study, William A. Zoghbi, MD, of Houston Methodist DeBakey Heart and Vascular Center (Houston, TX), observes that low-flow, low-gradient severe AS with preserved LVEF “is a clinical condition that is frequently accompanied by comorbidities that inherently have an impact on prognosis and may explain, at least in part, the worse outcome observed.”

While acknowledging that AVR confers better survival compared with conservative therapy in low-gradient patients with both low and normal flow, Zoghbi questions whether the benefit may have been overestimated, since the populations “were not matched or randomized, leaving the medically treated cohorts with more comorbidities and higher overall risk for the same severity of AS.”

According to Zoghbi, the meta-analysis’ findings are consistent with the ACC/AHA guidelines, which give a class IIa indication for AVR to treat symptomatic low-flow, low-gradient patients.

However, the included studies that enrolled patients with moderate stenosis “raise a concern of patient selection: 59% had symptoms similar to or higher than those with [severe] AS, and 35% of them underwent AVR,” Zoghbi writes. “This is an unusually high prevalence of symptoms and AVR in moderate AS and should not be extrapolated to the AS population at large, because moderate AS has been shown to have an intermediate prognosis.” Furthermore, Zoghbi says, 2 studies that compared AVR with medical therapy in moderate AS found no advantage of valve replacement.

All of these things pose challenges to clinicians, Zobhbi adds. Therefore, in patients with low-gradient severe AS with preserved LVEF, and particularly in low-flow conditions, it is “of paramount importance” to ascertain the severity of AS and “the echocardiographer needs to ensure that the data on quantitated flow and derived valve area are internally consistent with low flow through the AS,” he writes.

“If inconsistencies occur and cannot be resolved, they should be communicated to the clinician and additional testing suggested for further evaluation of AS severity, such as dobutamine echocardiography, cardiac magnetic resonance, computed tomography, or invasive hemodynamics, as deemed appropriate—another facet of the heart team approach to cardiac care in valvular heart disease,” Zoghbi concludes.

Sources: 
1. Dayan V, Vignolo G, Magne J, et al. Outcome and impact of aortic valve replacement in patients with preserved LVEF and low-gradient aortic stenosis. J Am Coll Cardiol. 2015;66:2594-2603.
2. Zoghbi WA. Low-gradient severe aortic stenosis with preserved ventricular function: trust but verify [editorial]. J Am Coll Cardiol. 2015;66:2604-2606. 

Disclosures:

• Dayan and Zoghbi report no relevant conflicts of interest. 

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