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A collaborative study led by researchers at Oxford Population Health has found that combination drug therapy with Angiotensin Receptor Blockers (ARBs) and beta-blockers may delay the need for surgery to correct aortic enlargement in people with Marfan syndrome. The results were published today in The Lancet and presented at the European Society of Cardiology Congress.

There are over one million people worldwide estimated to be living with Marfan syndrome, which causes enlargement of the body’s main artery, the aorta, usually caused by a mutation in the Fibrillin-1 gene. This increases the risk of tears or rupture between the layers of the aortic wall (aortic dissection) by over 100 times compared to the general population. Aortic dissection usually requires immediate surgery and commonly results in premature death or disability, sometimes in early adulthood. Preventative surgery to replace the aortic root may be recommended for people with Marfan syndrome, when aortic dissection is imminent, but surgery carries an additional risk of death or disability, and recovery can take months.

People with Marfan syndrome are often prescribed beta-blockers or, more recently, ARBs, to try to slow down the rate of aortic enlargement and delay the need for aortic surgery, but the separate and combined effects of these treatments were uncertain. The Marfan Treatment Trialists’ (MTT) Collaboration conducted an analysis of the results of seven randomised trials involving 1,442 participants with no prior aortic surgery to assess the effects on the rate of change in aortic root size, adjusted for age, sex, and body surface area of: 1) ARBs versus control; 2) ARBs versus beta-blocker; 3) indirectly, beta-blocker versus control.

Lead author, Dr Alex Pitcher, Consultant Cardiologist at Oxford University Hospitals said ‘We found that ARBs and beta-blockers have similar, substantial and independent effects on reducing the rate of enlargement of the aortic root which, if maintained over a period of several years, would be expected to delay the need for surgery. The findings suggest that combining the two therapies may benefit those patients with Marfan syndrome who are able to tolerate both treatments.’

The researchers first analysed four trials involving 676 participants which compared the effects of an ARB compared to a placebo or open control. During a median follow up of three years, the researchers found that ARBs had approximately halved the rate of change in the participants’ aortic root size compared to control participants. The effects were particularly great in those with a proven pathogenic mutation in the Fibrillin-1 gene at baseline, and were independent of any benefits of beta-blockers.

The researchers then analysed three further trials involving 766 participants and assessed the effects of ARBs compared to those of beta-blockers. During a median follow up of three years, the annual change in the aortic root size was similar in the two groups.

Results from the two analyses were also used to indirectly evaluate the effects of beta-blockers on the rate of change in aorta size and found that beta-blockers approximately halved the annual rate of change.

The researchers concluded that ARBs and beta-blockers were each effective at slowing the rate of aortic root enlargement in these trials, but that combination therapy of an ARB plus a beta-blocker may reduce the rate of change by at least half and potentially by more over a three year period or longer. Reducing the rate of change in the size of the aortic root would therefore be expected to delay surgery.

Professor Colin Baigent, Director of the Medical Research Council Population Health Research Unit at the University of Oxford, and senior author of the paper said ‘Aortic enlargement and its complications are the major causes of premature death or disability in people with Marfan syndrome. This new evidence about the potential benefits of angiotensin receptor blockers and of beta-blockers could provide doctors and patients with additional options to help to slow aortic growth and delay surgery to prevent its complications.’

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, said:

'This news should be hugely reassuring to people with Marfan syndrome. By slowing the growth of their aortas, this simple combination of two cheaply available medications offers hope that those with the condition will be able to live more of their lives free from the threat of needing risky surgery or experiencing a potentially deadly aortic tear.'

Case study

Growing up, Shona Cobb, 25, from St Albans knew she would need surgery to replace part of her aorta one day. ‘My cardiologist was always very open with me about that, but we didn’t think I’d actually need the operation until my late 20s or early 30s,’ she said. ‘But, on New Year’s Day 2021 I just had a feeling that I was about to be told I needed surgery soon.’ 

Shona has Marfan syndrome, an inherited condition which affects her connective tissue. She said: ‘I ended up having surgery to replace my aortic root in June 2021 when I was 23. Due to the COVID-19 pandemic I’d had to wait six months, much longer than usual for someone in my position. I’d always known I had a ticking time bomb in my chest, but that feeling doubled as soon as I was told I needed surgery. I’d seen other family members with Marfan syndrome pass away after having aortic dissections, and I was very aware of being in this strange place of waiting while knowing my aorta was at risk.

‘I never imagined I’d have major heart surgery by my mid-20s. I was no stranger to operations growing up as I’d already had several to manage the secondary conditions I’d developed. But nothing could have prepared me for going through and recovering from major heart surgery, especially so young. 

‘These results are amazing news for people with Marfan syndrome. Being able to delay my surgery to an age where I had more life experience would have meant I was in a better place to handle everything that came with it.

‘I know we’re not at the stage where doctors can completely remove the need for surgery, so to be told that taking a couple of tablets a day could delay this is an opportunity I would grab with both hands.’