Registry Suggests Risk Estimate, Best Treatment in Long QT

Debra L. Beck

April 10, 2018

A new registry study aims to help physicians share personalized and quantitative information on the risk for life-threatening arrhythmic events associated with long-QT syndrome (LQTS).    

Also, for the first time, the investigators, led by Silvia G. Priori, MD, PhD, University of Pavia, Italy, firmly establish the superiority of nadolol over other β-blockers for risk reduction in LQTS.

Independent of long-GT genotype, the estimated risk for life-threatening arrhythmic events (LAEs), including sudden cardiac death, aborted cardiac arrest, and hemodynamically nontolerated polymorphic ventricular tachycardia, increased by 15% for every 10-ms increment of corrected QT (QTc) duration in this study.

In an intergenotype comparison, the risk in patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration compared with patients with LQT1.

"Now when I'm asked how I would risk stratify a patient with, say, LQT1 and a QT interval of 600 milliseconds compared to one with LQT2 and a QT interval of 500 milliseconds, I have an answer that goes beyond the previous assumption that LQT1 had a more favorable outcome than LQT2," Priori told | Medscape Cardiology.

"And I can use the tables we've produced from our data to show how for every 10-millisecond increment of QT duration, depending on the patient's genotype, we can estimate the 5-year risk of having a hard arrhythmic event."

Priori suggested their findings are particularly helpful in explaining risk to newly diagnosed patients and for emphasizing the need for treatment adherence to patients and families.

"With these data, we can partner with our patients and communicate better with them the importance of compliance, or in a pediatric patient who needs an implantable cardioverter-defibrillator, why we are suggesting such a difficult intervention," she said.

"We also can finally explain clearly why, for example, one brother needs a defibrillator and the other can get by with just taking a β-blocker, even though they have the same genetic mutation," she added.

Their report was published online April 9 in the Journal of the American College of Cardiology.

"Based on the size and length of follow-up, these data give confidence to previous statements that have been made," said Andrew A. Grace, MB, PhD, University of Cambridge, United Kingdom, and coauthor of an accompanying editorial, in an interview.

Priori and colleagues also developed a visualization of the 5-year risk for LAEs by genotype and QTc interval before and after therapy with nadolol.

"With nadolol we can reduce the risk by approximately 60%," she said, adding that only nadolol was found to significantly reduce arrhythmic risk in all three genotypes compared with no therapy (hazard ratio [HR], 0.38; P = .03).

Neither propranolol (HR, 0.74; P = .47) nor the selective β-blockers (HR, 0.79; P = .56) significantly reduced LAE risk at follow-up.

Fifteen Years Waiting for More Data

This analysis is a follow-up of an earlier study published in 2003 in the New England Journal of Medicine, in which Priori and colleagues showed that arrhythmic risk is modulated by QTc as well as by the locus of the causative mutation. In that study, only 647 patients with LQTS were available for evaluation.

The new study includes data on 1710 individuals with LQTS from 812 families who were followed for a median of 7.1 years. All were carriers of a single mutation in one of the major LQTS genes: KCNQ1 (LQT1 locus), KCNH2 (LQT2 locus), or SCN5A (LQT3 locus).

"Until now we were making these decisions without really having any data, and it was very difficult to explain why we made the decisions as we did," said Priori.

Of course, she added, they would be happy to see their data confirmed, but she realizes that "it may take a while" before another similarly large study is completed.

US and European guidelines risk stratify patients according to evidence that patients with LQT2 and LQT3 have a greater risk for events than do LQT1 patients and that individuals with QTc duration greater than 500 ms are at higher risk than patients with shorter QTc durations. Priori and colleagues sought to develop a more refined approach to risk stratification.

"We waited 15 years to analyze the numbers again because I wanted to make sure we had a large enough sample to clearly establish a new baseline," she said.

Nadolol Is First Choice

For Grace, the real importance of these new data is that they settle the lingering question of which β-blocker is best for mitigating arrhythmic risk in LQTS. The findings aren't surprising and are consistent with research he's conducted on the effects of β1 and β2 blockade in animal models.

"There are patients, particularly in the United States, who are on, say, atenolol or another cardioselective β-blocker, and I believe they are being served poorly," Grace said in an interview.

In their editorial, Grace and coauthor Gareth DK Matthews, MD, BChir, PhD, University of Cambridge, United Kingdom, call for a "moratorium" on the use of selective β1-adrenoceptor antagonists in patients with LQTS.

"In addition, we now have this distinction between nadolol and propranolol, which is also extremely important so that we can give the people at the greatest risk the proper treatment."

In agreement with Grace, Priori suggests that use of cardioselective β-blockers should be avoided.

Propranolol would be a reasonable second choice for patients who cannot tolerate nadolol or who do not have access to it, but it has a tendency for more side effects, said Priori.

"Especially in the pediatric population, it is associated with central nervous system side effects, like nightmares, but propranolol is still a better option as compared to the selective β-blockers."

"Definitely after these data, I would expect physicians to be much more reluctant to give patients one of the selective β-blockers and stop there, especially if they have a long QT and are in the highest-risk groups," said Priori.

"What concerns me is that a lot of physicians are using the more contemporary β-blockers, those usually adopted for patients with heart failure, but there is really zero experience on how these drugs work in the long-QT syndromes," Priori said.

 "Also, nadolol is not available in many countries…so now with such strong data, I hope physicians in these countries will be able to make the point to their governments that their patients needed access to nadolol."

Priori heads active research groups in both Italy and Spain, is professor of cardiology at the University of Pavia and the scientific director at the Hospital ICS Maugeri, in Pavia, Italy, and is the director of the Laboratory of Molecular Cardiology at the Centro de Investigaciones Cardiovasculares Carlos III, in Madrid, Spain. For over two decades her groups have studied inherited arrhythmias and investigated the molecular basis of cardiac excitability.

This work was funded by the Italian Ministry of Health and ICS Maugeri intramural funding scheme. Priori and Grace have disclosed no relevant financial relationships. Two coauthors reported relevant relationships with Health in Code SL, a genetic testing company that contributed genetic analysis to the study: Ortiz has received personal fees, and Monserrat is a shareholder.

J Am Coll Cardiol. 2018;71:1663-1671, 1672-1675. Abstract, Editorial

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