Month: September 2018

Irbesartan slows aortic root dilatation in Marfan syndrome

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MUNICH — Irbesartan in standard doses is linked to a significant decrease in the rate of aortic dilatation in patients with Marfan syndrome, according to data from the AIMS study presented at the European Society of Cardiology Congress.

In the AIMS trial, Michael Mullen, MBBS, MD, FRCP, from St. Bartholomew’s Hospital in London, and colleagues randomly assigned patients aged 6 to 40 years with Marfan syndrome at 22 centers in the United Kingdom to irbesartan or placebo. The researchers aimed to recruit 490 patients but only enrolled 192 patients.

After an initial run-in period during which all patients received irbesartan 75 mg, 104 patients were up-titrated to targets of 300 mg for patients weighing more than 50 kg and 150 mg for patients weighing less than 50 kg or placebo. Treatment with beta-blockers was not mandated but was encouraged because it is standard treatment, Mullen said.

Patients were followed for up to 5 years and underwent yearly echocardiograms, for which a core lab was used. The primary endpoint was annual change in aortic root diameter and secondary endpoints included annual change in z score and clinical events and requirement for surgery, including aortic dissection.

At baseline, there was a reasonable spread across various age groups, with approximately half of patients younger than 18 years and a good balance between male and female patients. Fifty-seven percent were also taking beta-blockers.

The overall study population was normotensive, and aortic root diameter was similar for the placebo (35.3 mm) and irbesartan groups (34.8 mm). The aortic z score was approximately 3 in both groups, “meaning that, compared with other trials, these patients were fairly early in pathogenesis of their disease,” Mullen said.

Key findings

The rate of aortic dilatation was slower in patients taking irbesartan vs. placebo, with a mean annual rate of change in aortic root diameter of 0.53 mm in the treatment group vs. 0.74 mm in the placebo group (difference, –0.22 mm; 95% CI, –0.41 to –0.02). Significant differences in the change in aortic root diameter were apparent at 1 year and continued out to 5 years, according to Mullen.

In terms of safety, irbesartan was well-tolerated, with four patients in both the placebo and irbesartan groups failing to tolerate medication. There was also no difference in the rate of adverse events between groups. Four patients in both groups underwent cardiac surgery, but the study was again not powered to detect differences in clinical outcomes, according to Mullen. No deaths occurred during the study.

Aortic z score, which adjusted the aortic diameter for patients’ body surface area and particularly any changes in body surface area, appeared to be fairly stable in the irbesartan group (annual rate of change, 0.05; 95% CI, –0.2 to 0.11) when compared with the placebo group (annual rate of change, 0.15; 95% CI, 0.08-0.22). The difference of –0.1 (95% CI, –0.19 to –0.01) was statistically significant, Mullen noted.

The researchers also evaluated the effect of treatment on BP, as irbesartan is a well-recognized antihypertensive treatment, he said. Results showed a significant reduction in systolic BP in patients taking irbesartan vs. placebo (–0.42 mm Hg vs. 1.27; mean difference, –1.69 mm Hg), which was maintained out to 5 years.

There was no difference in treatment effect of irbesartan in patients taking beta-blockers vs. those who were not, suggesting that there was no interaction or synergy between the two drugs. The annual rate of change in aortic diameter between study groups was also not significantly different when analyzed according to aortic z score. Additionally, no statistically significant difference was noted based on patient age, although the effect size appeared to be numerically larger in younger patients.

However, Mullen noted that the study was significantly underpowered to analyze subgroups and suggested interpreting the results with caution.

Interpretations, implications

The results of this study, according to Mullen, suggest that irbesartan may have potential benefits for patients with Marfan syndrome.

“The current treatment strategy is based around beta-blockade, based on small trials conducted many years ago, and monitoring aortic dimensions with timely surgical intervention. However, some patients will still experience aortic dissection prior to presentation or before reaching those thresholds for surgical intervention,” Mullen said. “If translated into clinical practice, long-term irbesartan treatment may impact favorably on clinical outcomes in patients with Marfan syndrome.”

During a discussion of the results, Artur Evangelista Masip, MD, PhD, from Hospital Universitari Vall d’Hebron in Barcelona, Spain, highlighted several issues that may affect these findings, including the study’s sample size.

Evangelista Masip also noted that the inclusion of children and adults in the same series complicates the ability to perform an accurate analysis of this study as well as other trials. The measurement of changes in aortic diameter in systole may also be affected by the reduction in systolic BP.

“It would be interesting to know their results measuring at end-diastole,” he said.

Additionally, Evangelista Masip said the difference in the rate of change in aortic root diameter between the irbesartan and placebo groups occurred mainly during the first year and was similar thereafter.

“This is an important study and I agree that long-term irbesartan treatment may impact favorably in the evolution of patients with Marfan syndrome,” he said. “However, we have to clarify some of the previous doubts and elucidate in future studies if the reduction or aortic enlargement is secondary to biological effect or related to the decrease of BP.” – by Melissa Foster


Mullen M. Hot Line Session 5. Presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.

Disclosures: Mullen and Evangelista Masip report no relevant financial disclosures.

Virginia native Darius Minor dies during college football workout

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ORONO, Maine — Orange County High School football standout Darius Minor died July 24 after he collapsed during a preseason football workout at the University of Maine, according to a university spokesperson. Minor, 18, was a first-year student at the university and was set to play defensive back on the school’s football team.

“The Athletics Department, our student-athletes and the entire campus mourn the loss of this bright and promising member of our community,” UMaine President Joan Ferrini-Mundy said. “We ask all to keep him, his family and his friends in your thoughts.”

Minor collapsed on the football field during a “supervised light workout” Tuesday at about 1:15 p.m., according to the university. The team’s training staff and first responders were not able to resuscitate him.

“Words cannot express the grief we have following this tragic loss,” UMaine head coach Joe Harasymiak said. “Our thoughts and prayers go out to Darius’ family and friends during this terrible time.”

In high school, Minor led his Orange County High School to three-consecutive post season appearances. He was named All-Central Virginia first-team wide receiver and second-team defensive back in 2017.

The Locust Grove teen was to be a political science major at the University of Maine.

Common antibiotics linked to increased risk of aortic dissection

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Exposure to fluoroquinolones—one of the most popular classes of antibiotics in the world—is associated with more than double the risk of aortic aneurysm (AA) or aortic dissection (AD), according to a study published online in the Journal of the American College of Cardiology.

Using national databases from Taiwan, researchers analyzed fluoroquinolone prescriptions among 1,213 patients hospitalized for AA or AD from 2001 to 2011. They compared exposure to the drug in the 60 days leading up to the AA/AD event to a randomly selected 60-day interval between 60 and 180 days before the event.

Lead author Chien-Chang Lee, MD, ScD, and colleagues found 1.6 percent of patients had been exposed to fluoroquinolone in the two months leading up to their event, versus only 0.6 percent in a preceding 60-day period. That translated to a 2.71-fold risk of AA/AD related to more recent fluoroquinolone use.

In addition, Lee et al. found that prolonged exposure to the antibiotics further increased risk. Those who were prescribed the drugs for between three and 14 days showed a 2.41-fold increased risk versus no prescription at all, while those prescribed fluoroquinolones for more than 14 days demonstrated a 2.83-fold risk.

“Typically, AA/AD develop slowly in patients, but our data suggest that use of fluoroquinolone can contribute in the short term to aneurysm progression or rupture that may require emergency department visits and hospitalization,” wrote Lee, with the department of emergency medicine at National Taiwan University Hospital, and coauthors.

Population-based studies support that AA and AD are rare diseases, occurring in between three and 20 people per 100,000 population each year. However, annual incidence among elderly individuals rises to as much as 130 per 100,000 people, the researchers noted.

Despite the relative rarity of the conditions, Lee et al. suggested the rising prescriptions of fluoroquinolones may be cause for concern, particularly since AA and especially AD are life-threatening without timely treatment.

The authors estimated 25.2 million U.S. outpatients were prescribed fluoroquinolones in 2012, which they calculated would result in an additional 2,591 cases of AA/AD.

“In the United States alone, fluoroquinolone prescriptions have more than tripled, from 7 million in 1995 to 22 million in 2002. With an estimated 25 million people prescribed with fluoroquinolones in the United States annually, which is expected to increase even more, it is clear that fluoroquinolones may contribute substantially to the current and future burdens of AA/AD.”

In a related editorial, Sonal Singh, MD, MPH, and Amit Nautiyal, MD, noted fluoroquinolones “have been known to cause tendon rupture mediated by their adverse effects on collagenous structures”—and the aorta is rich in type I and type III collagen.

“Although the exact biological mechanism remains unknown, several plausible mechanisms have been proposed to explain how fluoroquinolones might affect the synthesis or structural integrity of collagen in the aortic wall,” Lee and colleagues wrote. “First, fluoroquinolones have chelating properties against several metal ions (e.g., calcium, magnesium, aluminum), which are essential for type 1 collagen synthesis. Second, fluoroquinolones can decrease collagen synthesis by increasing the expression of matrix metalloproteinases, which lead to extracellular matrix degradation and medial layer degeneration.”

Based on the biological plausibility of those experimental studies—as well as the consistently increased risk found in epidemiological research—Lee et al. believe there is strong evidence to support that fluoroquinolone contributes to the incidence of AA and AD.

“Although the rare incidence of AA/AD attenuates the public health impact, the rapid increase of fluoroquinolone consumption still poses a large burden of AA/AD in the general population,” they wrote. “Clinicians are advised to consider alternative antibiotic regimens in patients with pre-existing collagen-related disorder or aortic aneurysm.”

Singh and Nautiyal agreed, saying the “cumulative strength” of multiple studies, with different designs and different patient populations, makes it unlikely an unknown confounding factor is biasing all of the studies.

“It would be prudent to entertain the possibly of aortic aneurysms/aortic dissection associated with fluoroquinolones use in patients presenting with chest pain, shortness of breath, or syncope after recent exposure to the fluoroquinolones,” they wrote. “Although one should be careful in extrapolating from mechanistic studies, judicious use of fluoroquinolones may be particularly warranted among patients with risk factors for aortic aneurysms such as increasing age, the presence of smoking, hypertension, and Marfan’s syndrome.”

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