Many hands make better trials: cutting cardiovascular risk in chronic kidney disease
The kidneys are a vital part of the body’s internal ‘plumbing’. Not only do they filter waste products out of the blood and produce urine, but they play an essential role in maintaining blood pressure and keeping the correct balance of chemicals in the body.
Unfortunately, they can gradually fail over time – usually as a result of diseases or inherited gene faults affecting the kidneys themselves, or from other conditions such as diabetes – leading to chronic kidney disease. There is no cure, and treatment can mean life-long medication, dialysis or a kidney transplant.
In addition, chronic kidney disease also increases the risk of cardiovascular disease. By building an international research network and running the world’s largest ever clinical trial in kidney disease, Professor Colin Baigent and his team at the NDPH are working out how to make a difference.
A personal connection
Baigent’s research career started back in the 1990s with a chance meeting with Professor Sir Richard Peto, co-director of the NDPH Clinical Trial Service unit (CTSU), who persuaded him to abandon his stressful medical training in favour of research. When he first came to the NDPH, Baigent began work on a combined analysis of clinical trials of clot-busting drugs and aspirin for cardiovascular disease. But while studying for a Master’s degree at the London School of Hygiene and Tropical Medicine and waiting for a second kidney transplant (he is affected by a rare hereditary form of kidney disease), Baigent realised something important.
“I had noticed a report showing that people with chronic kidney disease were at a hugely increased risk of cardiovascular disease, so when I was recovering from my transplant I wrote up a thesis on this topic,” he says. “If you're an epidemiologist, anything big like that makes you take notice. And as I was affected by kidney disease it seemed like an interesting thing to explore.”
Baigent came back to Oxford with an idea for a clinical trial. Around this time, researchers at the NDPH were getting very interested in the potential of statin drugs for reducing the risk of cardiovascular disease by cutting the ‘bad’ cholesterol in the bloodstream (read more). So he set up a series of pilot studies in preparation for a major clinical trial to test whether lowering cholesterol with drugs could make a difference and reduce the risk of cardiovascular disease in these patients. However, there was a problem.
Research by NDPH scientists had already shown that it’s the absolute levels of cholesterol reduction that matter when it comes to cutting heart disease risk rather than the percentage reduction. But people with chronic kidney disease tend to have quite low cholesterol levels, so giving them high enough doses of statins to achieve a big enough cholesterol reduction to have a measurable effect was likely to cause dangerous side effects.
Luckily, a new drug called ezetimibe had been developed, which blocked the absorption of cholesterol from the gut into the bloodstream. Baigent and his team figured that using a combination of two drugs that reduce cholesterol in different ways – a statin plus ezetimibe – would achieve the big drop he was looking for, without the risk of unacceptable side effects.
The SHARP trial
Working with Professor Martin Landray at the NDPH, Baigent set up the Study of Heart and Renal Protection, known as the SHARP trial. Starting in 2003, they recruited more than 9,000 patients over three years, randomised to take either the combination of simvastatin and ezetimibe or a placebo (dummy) drug. The scale of the trial – the largest ever run in kidney disease – meant that he had to work with kidney specialists in 380 hospitals arounds the world, building an impressive and unprecedented research network.
Even then, the problems weren’t over. “There were some very big challenges, because the problem is that having kidney disease isn't nice,” Baigent explains. “People have to take lots of tablets anyway, and they’re not necessarily convinced that the tablets they’re being given for the trial are doing them any good. So, not unreasonably, they have a low threshold for stopping the treatment and dropping out of the trial, which affects our statistical power.” Even so, more than 6,000 recruits made it through to the end of the study period, which turned out to be sufficient to get a clear answer.
Then there was another blow. Whilst SHARP was in progress, another trial with ezetimibe suggested that the drug might increase the risk of cancer. Straight away, he and his team obtained permission to look at the data on cancer in SHARP and other ongoing trials. Reassuringly, there was no increased risk of cancer in the patients taking ezetimibe compared to the placebo pills. “That's what running trials is like,” he sighs. “It's one crisis after another, but you need to try and understand what the drug is doing. But in 2011 we finally got there. It's hard to convey the excitement of finishing a trial like that!”
Publishing their results in 2011 in the prestigious journal The Lancet, Baigent and his team found that taking the combination of simvastatin and ezetimibe cut the risk of heart attacks, strokes and operations to open blocked arteries by about one quarter in people with chronic kidney disease. Importantly, they found no evidence of possible side effects such as muscle or liver problems, or of increased cancer risk.
The researchers are continuing to follow up patients on the trial, checking for long term benefits and any late-emerging side effects. They are also investigating whether the kind of information routinely collected by doctors about patients on the study is as reliable as the more detailed information currently gathered by clinical researchers, which could save a lot of time and effort in the future.
Thanks to the results of SHARP, it’s now standard practice to give statins to people with chronic kidney disease. However, the combination ezetimibe isn’t routinely used. This is because the medical regulators in the UK don’t usually accept combinations of drugs without evidence that each one of them works individually in a particular group of patients. There’s already sufficient evidence from various studies of statins, but none of ezetimibe on its own. But the whole point of the SHARP trial was to test the combination, so as to use lower, safer doses of each drug without the risk of side effects.
However, there’s yet another twist in the story. Research into cardiovascular problems in people with chronic kidney disease has moved on since the 1990s, and it now appears that cholesterol is probably only a minor player for this group of patients. “It turns out that their cardiovascular disease is more related to structural problems with the heart than with furring up of coronary arteries with cholesterol,” explains Baigent.
“There are abnormalities in the heart muscle, stiffness of the arteries and problems related to blood pressure. We’re learning now that the kidney is more important than anyone has realised in terms of contributing to the risk of heart failure. The real challenge now is how to prevent heart failure in chronic kidney disease, and how to prevent progression, and we’ve got ideas for clinical trials that might be able to do that.”
Although it may seem like Baigent’s work has been slow and painstaking, he’s still excited about the insights that he and his team have generated through their trials and subsequent analyses. “This is a very long game and you have to have a certain mindset,” he says. “What makes me tick is getting data like this and working with statisticians to understand what’s going on in there and why drugs are behaving as they are. That’s what motivates me – I just love the data!”
- The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Baigent et al (2011) The Lancet volume 377, 2181–2192
- Find out more about the SHARP trial http://www.sharpinfo.org/
- Listen to Professor Baigent talk about the results of the SHARP trial in this podcast from the University of Oxford https://www.ndm.ox.ac.uk/colin-baigent-lowering-cholesterol-in-chronic-kidney-disease