It will recruit 20,000 patients with vascular disease from the UK, China and Scandinavia to investigate whether combining niacin with a new drug (MK-0524A) that minimises niacin's side-effects (chiefly facial flushing) can drive down still further the risk of serious heart attacks and strokes among people already taking treatment to lower their bad "LDL" cholesterol levels effectively.
It is being co-ordinated at Oxford University by the Clinical Trial Service Unit (CTSU), the research unit famous for running huge international studies, including the ground-breaking Heart Protection Study (HPS) which showed that a third of all heart attacks and strokes can be safely avoided in people at risk of vascular disease by using statins to lower LDL cholesterol.
The new study – called HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) – will be funded through a £42million grant to Oxford University by the pharmaceutical company Merck & Co., Inc. (Whitehouse Station, NJ, USA), developers of the combined HDL raising tablet. However, the CTSU has designed the study and will be responsible for coordinating it and analysing its results, independently of the funders.
Large-scale randomised studies have shown that lowering LDL cholesterol by about 1mmol/l for four to five years cuts the risks of heart attacks and strokes by about a quarter, and recent studies suggest that more intensive LDL-lowering can produce extra benefits. Even so, the risk among patients who already have vascular disease remains high, but there is limited scope for lowering LDL cholesterol much more.
So, the Oxford research team are taking a different approach by testing a combination tablet that can enable people to tolerate long-term use of an effective HDL cholesterol-raising treatment.
Dr Jane Armitage of the CTSU, one of the principal investigators, explained: "It has long been known that higher levels of good HDL cholesterol are correlated with lower risks of heart disease. Unfortunately, there is little evidence to date that raising HDL cholesterol with drugs is beneficial. Most studies have used fibrates, which raise HDL only modestly and results have been mixed.
"We have known for a long time that niacin is a very effective HDL raising agent. It increases HDL cholesterol by between a fifth and a quarter, as well as decreasing dangerous fatty substances in the blood called triglycerides by between a fifth and a third. But, the only large randomised study of niacin was conducted long before the introduction of statins, and patients find it difficult to take niacin long-term because it produces an uncomfortable side-effect of flushing. This flushing is caused by niacin dilating blood vessels in the skin through stimulating the release of a substance called prostaglandin D2.
"What Merck has done is to combine their own extended-release niacin with a specific blocker of prostaglandin D2 to make MK-0524A. Early studies with daily doses of this new combination in a few thousand people have shown that it substantially increases HDL cholesterol levels and is well tolerated with much lower frequency and intensity of flushing."
HPS2-THRIVE will recruit men and women aged between 50 and 80 with a history of heart attack, stroke or peripheral arterial disease. Up to 7,000 of these people will also have diabetes. Oxford's CTSU will be the central co-ordinating centre, with three regional co-ordinating centres in the UK, China and Scandinavia. About 7,500 people will be recruited in the UK, 7,500 in China and 5,000 from Denmark, Norway, Finland and Sweden.
Potentially eligible patients who agree to take part will first have their LDL cholesterol treatment optimised with statin-based therapy. They will then be randomly allocated to receive the new combination HDL-raising tablets (MK-0524A) or matching placebo (dummy) daily for at least four years. Participants will have checks at three and six months, and six monthly thereafter during the study.
The primary objective of the study is to see whether fewer participants given the combination HDL-raising tablet (MK-0524A) have heart attacks, strokes or revascularisation procedures than do those in the placebo arm. The researchers will also be looking at long-term safety of the combination tablet.
"This study of HDL-raising treatment is extremely important, and a natural follow-up to our Heart Protection Study of LDL-lowering therapy" said Dr Armitage "As with HPS, it will involve 20,000 participants at elevated risk of vascular disease so, like HPS, it will be able to give us really reliable results. Vascular disease is a major killer in the developed world and, increasingly, in the developing world. In addition to encouraging preventive lifestyle measures, we need to find even better preventive treatments. This new treatment should produce an average increase in HDL cholesterol of around 20%, which might realistically translate into a reduction of about one fifth in the risk of suffering a heart attack or stroke, or of being killed by vascular disease."
Cholesterol is a type of fat, called a lipid, present in blood and in cell membranes. Low density lipoprotein (LDL) cholesterol is often called "bad" cholesterol because it is taken up by the artery walls, leading to the narrowing of the vessels which causes heart attacks and strokes. On the other hand, high density (HDL) cholesterol is call "good" cholesterol because it removes cholesterol from the circulation, thus protecting against vascular disease. The average total blood cholesterol level for adults in developed countries is about 5.5 mmol/l, which typically reflects LDL cholesterol levels of about 3.5 to 4.0 mmol/l and HDL cholesterol levels of about 1.0 mmol/l. The balance between the levels of LDL and HDL cholesterol is vital.
Materials provided by Clinical Trial Service Unit, Oxford University. Note: Content may be edited for style and length.
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