Stroke Re

Editorial
# The Lancet, Vol 368, page 2034

One of the most promising new approaches in cardiovascular medicine hit the buffers on Dec 2 when Pfizer announced the stopping of its phase III clinical trial development of torcetrapib. Only days previously, the company had announced its hope to have the drug licensed next year in the USA. Torcetrapib was the lead compound in a new class of inhibitors of cholesterol ester transfer protein (CETP). Inhibition of this enzyme increases concentrations of HDL-cholesterol. The hope was that the combination of a statin (to reduce simultaneously concentrations of LDL-cholesterol) with a CETP inhibitor would further decrease the risk of atherothrombotic´cardiovascular events. Observational studies and randomised trials (with a fibrate or nicotinic acid) have shown that HDL-cholesterol concentrations are inversely associated with cardiovascular risk.

The company’s announcement followed routine scrutiny by the data and safety monitoring board for the ILLUMINATE study. This trial was a large international randomised study of torcetrapib plus atorvastatin versus atorvastatin alone in 15 000 patients with or at risk of coronary heart disease. There had been 82 deaths in the torcetrapib plus atorvastatin group, compared with 51 deaths in the group taking atorvastatin.

Why the Pfizer combination caused excess deaths is not known. A hint comes from a recent study of torcetrapib with atorvastatin, in which systolic blood pressure was slightly higher in the patients taking the combination than in those taking the single agent. Another view is that somehow HDL-cholesterol becomes dysfunctional after CETP inhibition.

The big question is whether the excess deaths observed in ILLUMINATE indicate a class eff ect for CETP inhibitors. Two other companies are studying CETP inhibitors in clinical trials, but data are not yet available. It would be intriguing to know whether and how patients in these studies are being informed about the demise of torcetrapib.

www.thelancet.com Vol 368 December 9, 2006

Saturday, 3 June 2006, 23:07 GMT 00:07 UK

A pill could increase the levels of "good" cholesterol

A major international trial has been set up to see whether a treatment to increase so-called "good" cholesterol can prevent heart attacks and strokes.

"Good" cholesterol - high density lipoproteins (HDL) - cuts heart disease risk removing fat from the circulation.

The treatment, designed to increase levels of HDL, will be given alongside drugs to reduce "bad" cholesterol, which can raise the risk of disease.

A team at Oxford University is leading the trial involving 20,000 volunteers.

To be eligible for the trial patients must be aged between 50 and 80 with a history of heart attack, stroke or peripheral artery disease.

Around 7,500 men and women will be recruited from the UK with people from China and Scandinavia making up the rest of the participants.

The main ingredient in the trial drug is niacin, which has been found to increase levels of HDL by between a fifth and a quarter as well as decreasing dangerous fatty substances called triglycerides.

"The trial will be in people at risk of future heart problems despite the fact that their LDL cholesterol has been lowered" Dr Jane Armitage, Trial leader

But patients have found it difficult to take niacin long-term because it produces an uncomfortable side-effect of flushing.

To combat this effect, niacin has been combined with another drug, which blocks the release of prostaglandin D2 - the substance which produces the flushing effect.

The team at the Clinical Trials Unit at Oxford previously carried out the landmark Heart Protection Study which showed a third of all heart attacks and strokes could be avoided in people at risk of vascular disease by using statins to lower "bad" cholesterol or low density lipoproteins (LDL).

Large-scale trials have shown that lowering LDL for four to five years cuts the risk of heart attacks and stroke by a quarter.

But the risk among patients who already have vascular disease remains high even with the use of statins and there is limited scope for reducing LDL much more so researchers are starting to look at ways of also increasing HDL.

'The next step'

Dr Jane Armitage who is leading the trial said: "The difficulty has been that there haven't been good quality drugs that raise HDL very much.

"The trial will be in people at risk of future heart problems despite the fact that their LDL cholesterol has been lowered.

"If it's shown to work the epidemiology suggests it will be possible for people at lower risk of heart problems to benefit," she said.

Professor Gilbert Thompson, a lipidology expert at Imperial College said treatments which raise HDL were the "next step" in cholesterol research.

"It seems a perfectly reasonable approach but it won't necessarily give you a straight answer about HDL because niacin also lowers triglyceride. But it will be a good trial.

Dr Anthony Wierzbicki, Chair of Heart UK Scientific Medical and Research Committee, said looking for ways of raising HDL in addition to lowering LDL was the next logical step.

"There are a number of trials looking at this that are either under way or starting soon all following the protocol of adding HDL-raising agents to baseline statin therapy in a variety of patient populations."

A group of drugs called CETP inhibitors have also been shown to increase levels of "good" cholesterol and are currently in clinical trials.

Source: BBC
http://news.bbc.co.uk/1/hi/health/5029616.stm

Linda Brookes, MSc

Presenter: Peter H. Jones, MD (Baylor College of Medicine, Houston, Texas)

The results of the COMParative Effects on Lipid Levels of Niaspan and statins versus other lipid therapies (COMPELL) trial showed that in patients at high risk for cardiovascular events, low-density lipoprotein (LDL)-cholesterol levels can be lowered to goal and high-density lipoprotein (HDL)-cholesterol levels raised without the need for high doses of statin medications, the investigators believe. In the COMPELL study, low-dose combination therapy with extended-release niacin (Niaspan; Kos Pharmaceuticals, Cranbury, New Jersey) and either atorvastatin or rosuvastatin reduced LDL cholesterol, apolipoprotein (apo) B, and non-HDL cholesterol comparably to reductions with moderate-to-high doses of rosuvastatin monotherapy or ezetimibe-simvastatin fixed-dose combination tablet over 12 weeks.^[1] In addition, the niacin plus statin combinations had greater benefits for HDL cholesterol, HDL2, triglycerides, and lipoprotein(a) [Lp(a)] than either of the other 2 regimens.

Treatment

The objective of COMPELL, a phase 4, open-label, parallel-group efficacy trial sponsored by Kos, was to compare the effect of a statin plus niacin or ezetimibe vs a statin alone. The treatments used were niacin in combination with atorvastatin or rosuvastatin, ezetimibe-simvastatin fixed-dose combination, and rosuvastatin monotherapy. Treatment was given over 12 weeks and included low-to-moderate doses of atorvastatin or rosuvastatin vs moderate-to-high doses of rosuvastatin or ezetimibe-simvastatin. Doses were increased at 4 and/or 8 weeks (Table 1), and lipids were measured at baseline, week 8, and week 12 visits, with safety evaluations done at each 4-weekly visit.

Table 1. Dose Regimens (mg/day) at Randomization

Weeks	Niacin + Atorvastatin	Niacin + Rosuvastatin	Ezetimibe- Simvastatin	Rosuvastatin
1-4	500/20	500/10	10/20	10
5-8	1000/20	1000/10	10/20	20
9-12	2000/40	1000/20	10/40	40

A total of 292 patients were enrolled at 32 US centers, with an average age of 58 years, 29% aged ≥ 65 years, about 50% women, 84% white, and mean body mass index 29 kg/m². Mean baseline lipid values were LDL 5.1 mmol/L (197 mg/dL), HDL 1.3 mmol/L (50 mg/dL), and triglycerides 1.9 mmol/L (171 mg/dL). After washout, screening, and qualification, patients were randomized to:

• Atorvastatin plus niacin (n = 60);
  
  
• Rosuvastatin plus niacin (n = 65);
  
  
• Ezetimibe-simvastatin (n = 72); or
  
  
• Rosuvastatin monotherapy (n = 73).

Results

No difference was seen between treatment groups in percentage of LDL-cholesterol lowering from baseline to 8 weeks or 12 weeks, the primary endpoint of the study (Table 2). Greater effects with the statin plus niacin combinations were seen on HDL cholesterol and triglycerides at 12 weeks compared with ezetimibe-simvastatin or rosuvastatin monotherapy.

Table 2. Percentage of Changes in LDL Cholesterol, HDL Cholesterol, and Triglycerides at Week 12

Regimen	LDL Cholesterol	HDL Cholesterol	Triglycerides
Niacin + atorvastatin	-56	+22	-47
Niacin + rosuvastatin	-51	+24	-40
Ezetimibe-simvastatin	-57	+10*	-33*
Rosuvastatin	-53	+7*	-25*

HDL = high-density lipoprotein; LDL = low-density lipoprotein

*P < .05 vs atorvastatin + niacin

At 8 weeks, low-dose niacin plus either atorvastatin (20 mg) or rosuvastatin (10 mg) had already lowered LDL cholesterol by about 50%, Dr. Jones noted. The statin plus niacin combinations lowered apo B, non-HDL, and total/HDL cholesterol comparably to ezetimibe-simvastatin or rosuvastatin (Table 3).

Table 3. Percentage of Changes in apo B, Non-HDL Cholesterol, and Total Cholesterol/HDL Cholesterol at Week 12

Regimen	Apo B	Non-HDL Cholesterol	Total Cholesterol/ HDL Cholesterol
Niacin + atorvastatin	-49	-55	-50
Niacin + rosuvastatin	-46	-49	-48
Ezetimibe-simvastatin	-45	-54	-47
Rosuvastatin	-42	-50	-43

Apo = apolipoprotein; HDL = high-density lipoprotein

*P < .05 vs atorvastatin + niacin

A trend toward an increase in Lp(a) was seen with ezetimibe-simvastatin and rosuvastatin monotherapy, whereas both statin-niacin combinations showed a significant reduction in Lp(a) compared with the 2 non-niacin therapy groups. The statin plus niacin combinations showed no difference vs the other treatment groups in effects on small HDL particles (HDL3), but large HDL particles (HDL2) were significantly increased by the statin-niacin combinations.

Table 4. Percentage of Changes in Lp(a), HDL2, and HDL3 at Week 12

Regimen	Lp(a)	HDL2	HDL3
Niacin + atorvastatin	-14	+93	+5
Niacin + rosuvastatin	-5	+102	+10
Ezetimibe-simvastatin	+7*	+41*	+6
Rosuvastatin	+18*	+31*	+5

HDL2 = large high-density lipoprotein particles; HDL3 = small high-density lipoprotein particles; Lp(a) = lipoprotein(a)

*P < .05 vs atorvastatin + niacin

Safety and Tolerability

All drug regimens were generally well tolerated, with similar rates of adverse events (55% to 67%) and serious adverse events (3% to 4%) on all treatment arms. Approximately 90% of patients on ezetimibe-simvastatin or rosuvastatin completed the trial vs approximately 75% to 80% of patients on statin plus niacin combinations. Most discontinuations in patients on the niacin-containing regimens were due to flushing or other cutaneous reactions. These may have been related to a low rate (60%) of aspirin use in the study, Dr. Jones suggested.

No drug-related myopathy (myalgia plus elevated creatine kinase > 10 x upper limit of normal [ULN]) was observed, and no patient had asymptomatic creatine kinase elevation > 5 or > 10 x ULN. One patient receiving rosuvastatin had a reversible liver enzyme elevation > 3 x ULN on 2 successive measurements. Small increases in fasting glucose (+3 to +5 mg/dL) were observed with the nicotinic acid-statin combinations, but at 12 weeks there was no change in hemoglobin A1c levels. A slight increase in uric acid (approximately 0.1 mg/dL) occurred in patients on the statin plus niacin treatments compared with no change or a decrease (0.4-0.5 mg/dL) in other groups.

Implications

"The bottom line of the COMPELL study is that we can lower LDL cholesterol substantially, by 50% to 55%, with statins, but what we cannot do with statins is increase HDL-cholesterol and lower triglycerides," Dr. Jones commented later. "In patients who need substantial triglyceride lowering and HDL increases, the COMPELL study shows that you can double or triple your increase in HDL cholesterol, and you can improve your triglyceride lowering by at least 50% by adding niacin to statin therapy," he said. "So for patients who need more than LDL-cholesterol lowering, for raising HDL cholesterol and lowering triglycerides, niacin extended-release is a safe and very effective drug in combination for clinicians to consider."

He continued:

Niacin is the best HDL-cholesterol raising drug right now. Fenofibrate is good, but not as good as niacin, and the statins have only a modest effect. The cholesteryl ester transfer protein (CETP) inhibitors will come along in the next couple of years, and they can raise HDL more than any of these other drugs, but we do not have any real data to back up the benefits of raising HDL by that method. We at least have some clinical trial evidence that niacin is a safe and effective medication. We have the results of the HDL Atherosclerosis Treatment Study (HATS) trial^[2]; we have data on angiographic regression using niacin; and we have data on niacin from the Coronary Drug Project,^[3,4] so we know that niacin has benefits. So until the data about CETP inhibition come out, we think niacin, especially niacin extended-release, is the best for raising HDL cholesterol. Eventually the 2 ways of raising HDL cholesterol will have to be compared, but that will not happen for several years, and in the meantime we have the AIM HIGH and the HPS-THRIVE studies.

Ongoing Trials of Statin Plus Niacin

The AIM HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-cholesterol/High Triglyceride and Impact on Global Health Outcomes) and HPS-THRIVE (Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events) phase 3 trials are each investigating whether treating multiple lipid abnormalities with a statin plus niacin combination is more effective in reducing coronary heart disease (CHD) risk than statin therapy alone in patients with established cardiovascular disease.

AIM-HIGH, a US-Canadian multicenter, randomized, double-blind, parallel-group, controlled clinical trial, is comparing extended-release niacin plus simvastatin with simvastatin alone over a median follow-up of 4 years at comparable levels of on-treatment LDL cholesterol in patients with atherogenic dyslipidemia, ie, low HDL cholesterol (≤ 40 mg/dL) and high triglycerides (≥ 150 mg/dL). The study will enroll an estimated 3300 men and women aged > 45 years old. The primary composite clinical endpoint is CHD death, nonfatal myocardial infarction (MI), ischemic stroke, or hospitalization for high-risk acute coronary syndrome with objective evidence of ischemia (troponin-positive or ST-segment deviation). A secondary endpoint is the composite of CHD death, nonfatal MI, or ischemic stroke. Follow-up will extend through 2010. AIM HIGH is sponsored by the National Heart, Lung, and Blood Institute with additional support from Kos Pharmaceuticals.

HPS2-THRIVE is studying a new combination tablet containing extended-release niacin plus a specific blocker of prostaglandin D2 to prevent the flushing associated with niacin. HPS2-THRIVE will recruit 20,000 men and women aged between 50 and 80 years who have a history of MI, stroke, or peripheral arterial disease, one third of whom will also have diabetes. Patients will first have their LDL-cholesterol treatment optimized with statin-based therapy, and then they will be randomly allocated to receive the new combination HDL-raising tablets or matching placebo daily for ≥ 4 years. Centers in the United Kingdom, China, and Scandinavia are participating in the study, which is being coordinated at Oxford University, Oxford, United Kingdom, under a grant from Merck & Co., Inc. (Whitehouse Station, New Jersey), developer of the combined HDL-cholesterol raising tablet, MK-0524A. MK-0524A is also being studied in a combination tablet with simvastatin.

References

1. McKenney JM, Jones PH, Bays HE, et al. Comparative lipid effects of combination therapy with a statin and extended-release niacin versus statin plus ezetimibe versus a statin alone. Atherosclerosis. 2006;7(suppl):174. Abstract Tu-W27:4.
2. Brown G, Zha X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592. Abstract
3. Coronary Drug Project report on clofibrate and niacin. Atherosclerosis. 1978;30:239-240. Abstract
4. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255. Abstract

Source: MedScape
http://www.medscape.com/viewarticle/541811

Related Links:
Systematic review of dietary intervention trials to lower blood total cholesterol in free-living subjects

31 May 2006

A major international study to test whether a new combination treatment that increases good “HDL” cholesterol prevents heart attacks and strokes will start to recruit patients later this year, it was announced today (Wednesday 31 May).

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.”

(ends)

Note: 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.

Further information:

Margaret Willson Tel: +44(0)1536 772181. Mobile: +44(0)7973 853347.

Email: m.willson@mwcommunications.org.uk

Source: Oxford Clinical Trial Service Unit (CTSU)
http://www.ctsu.ox.ac.uk/pressreleases/2006-05-31/hps2-thrive-press-release

Related Links:
Merck Co.
MedScape