Transcript for Recorded Teleconference about the AIM-HIGH Trial

Good morning.  This is (Diane Striar), Chief of the Public Affairs Branch in the National Heart, Lung and Blood Institute's Office of Communications.  Thank you for participating in today's briefing. 

We'll start this morning with a statement from Dr. Susan Shurin, Acting Director of the National Heart, Lung and Blood Institute.  Following Dr. Shurin's remarks, the two co-investigators of the AIM-HIGH Trial will make statements.  AIM-HIGH stands for atherothrombosis Intervention and Metabolic Syndrome with Low HDL High triglyceride. 

After the speaker's remarks, we will field questions.  If you have not received the press release on AIM-HIGH, it is now online at www.nhlbi.nih.gov.  Dr. Susan Shurin?

Good morning.  Today we are announcing the early stopping of the AIM-HIGH Trial, which has met its objectives.  This major clinical trial studied whether adding high dose extended release Niacin under the brand name Niaspan, to statin treatment in individuals with cardiovascular disease would reduce their risk of major cardiovascular events such as heart attacks and strokes. 

Medical therapies for cardiovascular disease have made tremendous progress.  However, there is still a burden of cardiovascular disease among people whose LDL or bad cholesterol is in the desirable range particularly among those who’s HDL or good cholesterol and triglycerides remain in undesirable ranges.

The participants in the AIM-HIGH study met these criteria.  The NHLBI supported this study to test whether raising HDL and lowering triglycerides would reduce the risk of cardiovascular events among patients with this profile. 

This study has ended 18 months early because we answered the primary questions.  While high dose Niacin raised participant's HDL cholesterol and lowered triglycerides, it did not affect the overall rate of cardiovascular events.

There was also an unexplained higher incidents of ischemic stroke in the high dose Niacin group compared to the group on statins alone.  It remains unclear whether this trend arose by chance but this trend contributed to the institute's decision to stop the trial early in the context of lack of efficacy. 

The overall frequency of stroke was less than 1 percent and previous studies do not suggest that stroke is a potential complication of Niacin. 

The FDA is aware of the findings and plan and is recommending no change in labeling or practice pending full analysis of the data.  The FDA's statement on AIM-HIGH is now posted on its Web site and we will be linking to it, as well.

Over the years, scientists have sought ways to reduce the incidents of cardiovascular events that remain in patients whose LDL cholesterol has been effectively lowered but who still have low HDL cholesterol and high triglycerides. 

Higher HDL cholesterol is known to be associated with a lower cardiovascular risk but it has not been clear whether treatments to raise HDL cholesterol in those with low levels would affect that risk.  This was the scientific justification for AIM-HIGH, which is a well designed study. 

Although no clinical benefit was found, the study contributes to our understanding of cholesterol and cardiovascular disease and promises to guide future research efforts.

Cardiovascular disease remains a crucial public health issue.  The NHLBI continues to pursue ways to reduce risk and develop new therapies. 

Now that the study has been stopped and participants have been informed, we will begin the important task of analyzing the data in detail.  In depth analysis will be presented at a National Scientific meeting and publications will be presented in late 2011.

Today you will learn the details of AIM-HIGHs results that lead to the decision to stop the trial, as well as insights into the strategy of raising HDL levels to reduce cardiovascular risks. 

Our first speaker today will be (Dr. William Boden), Professor of Medicine and Preventive Medicine at the University of Buffalo's School of Medicine and Public Health and Co-Principal Investigator of the AIM-HIGH study. 

(Dr. William Boden) will discuss the background, rationale, and design of AIM-HIGH.  Then (Dr. Jeffery Probstfield), Professor of Medicine and Epidemiology at the University of Washington in Seattle and AIM-HIGHs Co-Principal Investigator will discuss the results. 

(Ms. Ruth McBride), the Co-Director of the Studies Data Coordinating Center of Axio Research Center in Seattle is available to answer questions.  (Dr. William Boden)?

Thank you, Dr. Shurin and good morning.  By way of background, while Coronary Heart Disease survival has increased appreciably since the late 1960s, the condition remains the leading cause of death and disability among both men and women in the Western world. 

Currently over 18 million Americans have been diagnosed with Coronary Heart Disease a common condition that causes hardening of the arteries or atherosclerosis and can lead to heart attack, stroke or death. 

The prevalence of heart disease and stroke along with the death rates from these conditions remains unacceptably high despite significant advances in both drugs and medical treatment techniques over the past four decades.

Elevated low density lipoprotein cholesterol, known as LDL or bad cholesterol has long been known as a major predictor of Coronary Heart Disease risk. 

Current National Cholesterol Education Program or NCEP guidelines, recommend aggressive LDL cholesterol reductions typically with statins to less than 100 mg per (dactyl) litre in high risk individuals.

For those who are deemed to be very high risk, the target is even lower to below 70 mg per deciliter.  Despite these guidelines, treating and more importantly, achieving these recommended LDL targets has been a challenge outside of the clinical research setting.

Early observational studies have demonstrated that elevated levels of LDL cholesterol are not the only predictor of increased Coronary Heart Disease events.  Low levels of High Density Lipoprotein Cholesterol known as HDL or good cholesterol are also recognized as a major predictor of Coronary Heart Disease risk.  The lower one's HDL cholesterol, the higher the risk of developing Coronary Heart Disease. 

Multiple small but rigorously conducted clinical trials have shown that raising HDL reduces coronary atherosclerotic plaque and further suggests that there may also be a favorable affect on reducing cardiovascular events.

In contrast to the well defined treatment targets for LDL previously sited, NCEP has not yet established such treatment targets for increasing HDL cholesterol. 

Importantly, there is a growing number of patients for whom statins alone may not be the best therapeutic option.  This group includes a large number of patients with low HDL cholesterol levels but normal LPL cholesterol who may comprise 50 percent or more of all Coronary Heart Disease patients. 

Statin therapy, while very effective clinically for lowering LPL cholesterol in cardiovascular risk, unfortunately raising HDL cholesterol only a small amount, between 5-10 percent.  This modest effective statins on HDL cholesterol has therefore, rekindled interest in the use of Niacin alone or in combination with other drugs for patients with mixed blood lipid abnormalities. 

Niacin in high doses is the most effective known drug for raising HDL levels.  Niacin also moderately reduces triglycerides another fat in the blood,   Lipoprotein A, an LPL-like particle and in higher does, LPL cholesterol.

Niacin is an essential nutrient and is known as Vitamin B3.  To raise HDL cholesterol, one must take Niacin doses that are about 100 times the recommended daily allowance.  Despite these multiple potential benefits, however, Niacin's clinical use has been limited, as some patients do not tolerate the drug well at high doses. 

A common adverse reaction is skin flushing and itching particularly when older immediate release formulations of Niacin are used. 

The AIM-HIGH study was designed to evaluate the affect of high dose extended release Niacin in people who have had cardiovascular disease events related to diseased artery walls and whose LPL cholesterol is well controlled.  There were strong reasons for using Niacin in these patients. 

As I mentioned, earlier studies have shown a strong relationship between low HDL cholesterol and increased cardiovascular risk even in patients on statin therapy. 

High dose Niacin is the most effective available treatment for raising HDL cholesterol.  Secondly, Niacin has a beneficial affect on specific blood lipids found in people with metabolic syndrome, a cluster of risk factors for heart disease.  This benefit includes a further reduction in LPL cholesterol levels on top of that seen with statin treatment.

Thirdly, Niacin may promote a health affect on the inner lining of blood vessels and the inflammation associated with plague build up in the arteries.  Previous studies have shown that high dose Niacin may reduce obstructive plague in coronary artery narrowing's.

Finally, Niacin has been used in high doses for more than 50 years, so its side effects are well known.

AIM-HIGH is a double blind randomized placebo controlled clinical trial designed to determine if high dose extended release Niacin added to a statin would decrease the rate of cardiovascular events compared to a statin alone.

Our target population was patients with well controlled LPL cholesterol levels, namely in a range between 40-80 mg/deciliter. 

The cardiovascular events that we sought to reduce include death from Coronary Heart Disease, non-fatal heart attack and stroke due to blockage of arteries leading to the brain.  We also hoped to reduce the number of hospitalizations for Acute Coronary Syndrome or the need for surgical re-vascularization of the coronary or cerebral blood vessels because of worsening symptoms. 

As already noted, participants had to have both a documented history of established Cardiovascular Disease and an abnormal lipid profile consisting of low HDL cholesterol and high triglycerides in order to be enrolled in the study.

After signing consent forms, eligible patients were given both a statin and extended release Niacin beginning at 500 mg/day.  We increased the dosage of Niacin to 2000 mg/day over 4-8 weeks to verify whether patients could tolerate high dose treatment. 

Those who could take at least 1500 mg/day of Niacin without significant side effects, were then randomly assigned to extended release Niacin or a placebo containing a tiny dose, that is 50 mg of immediate release Niacin to induce flushing.  This small amount of Niacin in the placebo ensured that the study staff, as well as the participants, could not tell who was taking the treatment or placebo.  

All participants had their dose of simvastatin adjusted during the first six months after being assigned to the treatment group to reach a target LPL, that is to say, between 40-80 mg/deciliter. 

Another LPL lowering drug, Azimuth, could be added when required if simvastatin treatment was ineffective in lowering the LPL cholesterol to the desired goal. 

Study patients were to be followed in clinic and by phone to a common end date, expected to be late 2012.  All participants were treated in accordance with existing clinical practice guidelines using standard secondary prevention therapies, such as Aspirin, Beta blockers, ACE Inhibitors, or Angiotensin and Reception blockers as needed.  

A group of independent investigators proposed AIM-HIGH, which was funded by the NHLBI based on the trial's high scientific priority score assigned by an independent Review Committee.  The grant to support it is a cooperative agreement with the NHLBI.

Laboratories, originally Coast Pharmaceuticals, supported the trial by providing high dose extended release Niacin in a significant unrestricted research grant to the investigators.  Merck provided the simvastatin used in the trial.

The NHLBI appointed a Data and Safety Monitoring Board or DSMB, an independent panel of experts to oversee the scientific conduct of the trial and to ensure patient's safety.  Panel members were experts in the field of lipid treatment, preventive cardiology, clinical trials, biostatistics and medical ethics.

The DSMB met up to twice a year or more often as needed, to review all aspects of the trial.  DSMB members regularly communicated with the AIM-HIGHs Executive Leadership and NHLBI Project Officers on matters of study performance and safety.  They carefully reviewed all reported adverse events or side effects, as well as trial in points to which the Trial Leadership and NHLBI Project staff were blinded.

Now my colleague and Co-Principal Investigator, (Dr. Jeff Probstfield) will provide the important details of the trial data and the study's results as reviewed by the DSMB.  (Jeff)?

Thank you, (Bill).  As (Dr. Boden) mentioned, the AIM-HIGH DSMB met regularly to go over the trial data.  By the time of the group’s recent meeting on April 25th, AIM-HIGH had already achieved the enrollment goal for the study.  There was an excellent level of adherence to the study medication and participants had achieved the intended targets of higher HDL cholesterol, lower triglycerides and similar levels of LDL cholesterol. 

However, at that April 25th meeting, after a thorough review of all the data, the DSMB recommended stopping the study and after careful review, the NHLBI accepted that recommendation and stopped AIM-HIGH. 

The trial was stopped because the data showed that there was less than a 1 in 10,000 chance that the trial would ever show the expected benefit planned in the protocol on the primary outcome measure.  That is, a reduction in the combined rates of Coronary Heart Disease deaths non-fatal heart attacks, stroke due to blockage of arteries leading to the brain, hospitalization for Acute Coronary Syndrome or symptom driven Coronary or Cerebral re-vascularization surgeries. 

The DSMB of well designed trial such as AIM-HIGH, established boundaries at the beginning of the study to guide their recommendations as the independent group reviews the data.  These boundaries improved guidance in the situation that the trial is showing unexpected early benefit or a lack of benefit.

In AIM-HIGH, the pre-established mark for showing a lack of efficacy was reached before the planned end of the trial.  This trend for lack of efficacy was present over time.

Since the NHLBIs decision to stop the trial, we have notified all participants and investigators and we are notifying all of the primary care physicians of the participants.

The DSMB also observed that while a total number of strokes among study participants was low, there was an imbalance in the occurrence of strokes, which reached a level of statistical significance. 

In AIM-HIGH, there were 40 participants who had strokes due to blockage of arteries to the brain, known as ischemic stroke.  Twenty-eight of those occurred in this Niaspan group. 

We are performing further analysis to explore this unexpected finding.  No similar finding has been observed in previous with any form or dose of Niacin therapy given for any length of time.  And as (Dr. Boden) said, until AIM-HIGH, previous studies had shown a consistent reduction in stroke associated with Niacin use. 

I would also like to note that 1/3 of the strokes in the Niacin group occurred long after Niaspan was stopped by those participants in this study. 

There were no signs of significant adverse side effects in the study beyond the expected increase in flushing and skin irritations frequently associated with Niacin.  Participants had a modest amount of flushing.

I want to re-emphasize that statin therapy has proven benefits from previous studies.  As (Dr. William Boden) described earlier, all participants in AIM-HIGH were treated with statin therapy.  Statins are a well established therapy for the treatment of fatty deposit related Cardiovascular Disease and they have been shown in other studies to reduce all of the main cardiovascular events that we measured in AIM-HIGH. 

Further, as (Dr. William Boden) said, the National Cholesterol Education Program has published guidelines on the use of statins and target LDL values for this patient population.  AIM-HIGH offers no reason to change the recommended use of statins alone or in combination with Ezetimibe for lowering LDL cholesterol. 

It is important to know that the high dose extended release Niacin used in AIM-HIGH produced the predicted effect on all lipids measured.  As expected, Niaspan raised HDL cholesterol levels approximately 20 percent.  This is consistent with previous studies of a similar dose of Niacin. 

Niaspan also lowered triglycerides by approximately 25 percent, again, in keeping with other studies of comfortable doses of Niacin.  The total in LDL cholesterol levels were lowered primarily by statin therapy. 

Because of our ability to adjust both the statin dose and add Azimuth for additional cholesterol lowering if desired, reduction of LDL and total cholesterol was roughly comparable in the two treatment groups and only a small portion of this effect could be attributed to Niaspan. 

We accepted the DSMBs recommendation that the NHLBI and Investigators continued to follow the participants in AIM-HIGH for another 12-18 months to determine whether we can learn anything additional regarding the imbalance in ischemic stroke observed between the two treatment groups.

We have presented today the preliminary results of the AIM-HIGH trial, which lead to the DSMBs recommendation and NHLBIs decision to stop the trial before its expected conclusion.  We have answered the question this study set out to answer and found that while high dose Niacin raised the participants HDL cholesterol levels, it did not affect the rate of their cardiovascular events. 

We don't know if the same outcome would have occurred in a different population or with a different drug.  We are now exploring our data to determine if there are answers that explain the findings including the observed imbalance in ischemic stroke. 

As Dr. Shurin said, a full report will be delivered at a major future scientific meeting and a complete – and complete findings will be published in a peer reviewed journal.

We will continue to follow the participants to monitor their health through phone calls and clinic visits. 

We extend our thanks to all of the 3414 participants.  Finally, if you are a patient who takes cholesterol lowering or other lipid altering drugs and you have questions after learning of the early stopping of this study, please contact your physician before making any changes to your drug therapy for your blood fat disorder.

Thank you, (Dr. Probstfield) and (Dr. Boden) for providing the details and results of this study.  In summary, we have stopped the AIM-HIGH trial because we answered an important scientific question.

Although high dose Niacin effectively raised the participants HDL cholesterol, it did not affect the overall rate of cardiovascular events.

The unexplained risk of stroke in this group that took extended release Niacin, also contributed to the decision to stop the decision before its planned conclusion.

Studies such as these are extremely important to determine whether promising therapies have real world benefit to patients. 

The results of this study build upon our body of knowledge and as we analyze the data further, will help guide future research and provide important evidence for the FDA in making labeling decisions.

Before we take questions, I would like to acknowledge the outstanding work of the Principal Investigators and Staff of the AIM-HIGH trial at 90 clinical sites, as well as the NHLBI Project Office Staff including Doctors (Patrice Devine Nickons), (Jerome Flag) and (Sonye). 

Thanks to the DSMB for thoughtful oversight and monitoring.  All of these individuals have shown great dedication and commitment to this important research effort. 

My thanks also goes to (Abbott) Pharmaceuticals for substantial support and drug as we seek an independent investigation of the HDL hypothesis.  In addition, we are most grateful to Merck Pharmaceuticals for providing the statins used in this trial.

Most of all, I want to extend the Institute's deepest appreciation to the 3,414 study participants and the Investigators in the US and Canada.  Without them, this trial would not have been possible and their efforts have helped us advance our knowledge in the important public health areas.

Now we will be pleased to take your questions.  Please identify yourself and your organization.

Well, you have to keep in mind that nearly half of clinical practice currently as a recommendations from the American College of Cardiology and the American Heart Association are not evidenced-based. 

And so the reason for doing the trial was recognizing that although this is – this is – this is now a common practice that the evidence did not seem to be as solid as we thought it should be.

Our general approach is that we undertake studies to ask – answer important clinical and scientific questions and this study has been quite successful from that standpoint. 

Your point – your question about the HDL hypothesis, I think is one of the most important ones that we're facing.  LDL has proven to be a very effective target for therapy.  If you have a low LDL, you have a lower risk of Cardiovascular Disease.  And if you have high HDL and we lower it, we can lower your risk of Cardiovascular Disease. 

The same has not proven to be true for HDL.  If you have a high HDL, you have a lower risk of Cardiovascular Disease.  But approaches that raise HDL have not actually been shown to lower cardiovascular risk. 

So this sends us a bit back to the drawing board in terms of trying to figure out how to approach these hypothesis.  Either the approach to raise HDL was not – not effective or HDL is just not a good target for therapy in – in the setting of other lipid lowering agents.

(Rob), this is (Bill Boden).  Thank you for your question.  You asked whether were we disappointed about the results.  You know, certainly there was abundant epidemiologic data and data from observational studies in small clinical trials to really support the use of Niacin as used in this trial with combination with simvastatin. 

As Dr. Shurin mentioned, you know, there's an enormous unmet need of increased residual risks even among patients who take statins.  And I think one of the challenges that we as Physicians and Cardiologists face is to try to address that unmet need therapeutically. 

So – so certainly the – the intent of using extended release Niacin in this population was with the hope that we would be able to demonstrate incremental benefits when used in combination with a statins among those patients with low HDL cholesterol. 

But bear in mind also, that the on-treatment LDL in this group was 71 at baseline, which really indicates how incredibly well-treated these patients were by the investigators. 

So my first comment would be, we have to focus specifically on the fact that we had a very special population in this study.  The only thing that we can say about alteration of HDL is in relationship to the population we addressed in this study.

There may be other populations which will respond differently and I think (Bill's) earlier point about the fact that this group had such a low LDL, may very well be the important issue here.

And I would add only to what (Dr. Probstfield) said.  The reason that we – and Dr. Shurin mentioned this in her remarks as well.  The reason we undertake clinical trials such as AIM-HIGH, is – is to really clarify whether we can document clinical benefit. 

We know that many drugs for many conditions may improve laboratory parameters or surrogate outcomes.  But really what physicians want to know is, you know, at the end of the day, does treatment X or treatment Y result in more favorable survival or better clinical outcomes and that was really the intent of what we tried to show here.

Well, clearly in analyzing the data for the trial primary end point, there was – there was certainly no benefit for the five component end point.  And that, as was mentioned by Doctors (Shurin) and (Probstfield), led to the DSMB recommendation to stop the study early.

You know, clearly, you know, we have not had an opportunity to really delve into the study findings more than what we've already just reported this morning.  And we certainly hope that there'll be other opportunities to do so. 

Again, what about the risk profile of this group?  We excluded by design, patients who had Acute Coronary Syndrome or Acute Myocardial Infarction within the preceding four weeks.  Or we excluded, and I should so, we excluded patient who were destined to undergo Angioplasty or Stinting within the preceding four weeks.

And so what we, I think, included in the trial here in terms of the study population were largely a group of patients with stable Ischemic Heart Disease or prior Cerebral Vascular Disease and Peripheral Arterial Disease, that is to say, established Vascular Disease who met certain features of risk that we deemed to be an appropriate candidate for the use of these two (inaudible) therapeutic interventions.

And so I think clearly we enrolled the group of patients who perhaps were not the very highest risk population and that clearly is why we can't generalize these findings, as (Dr. Jeffery Probstfield) said, to patients that we didn't study in the AIM-HIGH trial.

Yes.  Let me add to this.  This is (Bill Boden) again.  I think, as everybody knows, many prior studies have shown that Niacin exerts very favorable effects on LDL particle size and composition. 

And as (Dr. Probstfield) mentioned, we'll be able to do a very careful and thorough quantitative analysis of the effect of the two treatment strategies not only on HDL subtypes but on LDL particle size and composition in numbers so that we'll be able to answer some of these important questions in the months to come.

And if I might just extend that just one last question.  The – there a lot of patients who are much earlier in the disease process of CVD than the patients in the study. 

Many of them are taking Niacin prophylactically for the very reasons to prevent heart disease.  Is there any information or any advice you have of the patients who are taking moderate doses of Niacin prophylactically?

Well, I think what we tell them is what the NCEP recommendations have been for well over the last decade.  The most important determinant of dyslipidemic risk is elevated LDL and the most important therapeutic imperative is to get the LDL down with statins. 

I think the study results from AIM-HIGH clearly underscore the importance of LDL reduction and as I mentioned, the fact that these patients were so incredibly well treated, I think just amplifies and underscores that the results that we encountered showed that in such very well treated patients, with respects to their LDL cholesterol, we could not in that sub-population demonstrate incremental benefit of HDL raising.

That doesn't mean that there isn't a group of patients out there that might benefit from HDL raisin.  It's just that we don't have evidence from trials to guide us.

Hi.  Thank you for taking my question.  It's a two parter, actually.  Can you tell me how your actual event rate compared with what your initial expectations were?  In other words, was the residual risk about what you expected and what was your power to actually detect the change? 

And then, is there any way you could tell us a little bit more about the actual event rates for the individual components of the primary (implant)?  I'm kind of guessing most of the events were for the re-vascularization component.  So anything more you could say.

No.  You know, I think there will be a temptation to view this study with its result as a quote unquote negative trial.  I think we really kind of need to remember that the purpose of undertaking clinical research trials is to seek scientific clarity, you know, where there is often therapeutic uncertainty or ambiguity. 

So I think, you know, viewed from that perspective, I think, AIM-HIGH tells us, and we answered a very important question.  That is to say, you know, in the setting of an optimally treated LDL with low levels as we had in this trial and in patients who with – within that context also had low HDLs and high triglycerides where we felt there was increased residual risk, we could not in this setting demonstrate incremental benefit of Niaspan on top of statin therapy versus placebo.

That doesn't say that we wouldn't potentially see benefits of HDL raising in populations that we didn't study.  For example, only 6 percent of the patients in AIM-HIGH were statin (inaudible) at the time of trial entry.  So many patients, you know, in the world, so to speak, have far higher LDL levels at baseline than we encountered in this trial.

So it's – it's difficult therefore, to generalize or speculate about whether, you know, HDL raising therapies are completely ineffective.  What we can say is that in the study population that we tested, we couldn’t demonstrate benefit.

Yes.  Thank you.  At the beginning of the trial we designed an interim analysis plan, which had asymmetric boundaries for benefit and lack of benefit.  And those boundaries, especially the ones for lack of benefit were conservative in that we did not want to stop the trial if there was any chance that we could show a benefit by the end of the study.

We did cross that lack of benefit boundary and as, I believe, (Dr. Probstfield) mentioned, at the time that we crossed that boundary, there was less than 1 in a 10,000 chance that we would have been able to show a benefit for Niaspan by the end of the study. 

I guess I can answer that question in a bit of an – an analogy to PCI.  Why does PCI work in Acute Coronary Syndromes and (ST) elevations in my patient but seemingly not in stable ischemic heart disease?

So I think, maybe, the insight here, (Matt) is – is that the population studied here was a group with stable ischemic heart disease with a different pathobiology than we might encounter in patients with Acute Coronary Syndrome or Acute MI where there's a plaque rupture and a higher risk. 

So we didn't study those patients and therefore, I don't think that you can necessarily say that this drug wouldn't benefit those patients because we haven't studied them yet. 

I personally think that this is a very high risk target population where there's very significant increase residual risk. 

I think another thing that we've been, you know, thinking about over the last couple of weeks is we've, you know, mulled these (inaudible) over, you know, is that maybe these patients were so well treated that their – that their (inaudible) lipid cores were depleted by intensive aggressive statin treatment, you know, such that in that setting, we made the vulnerable plaques less vulnerable to rupture and we know that that's what drives late events. 

So again, I think, AIM-HIGH is constant ant with many other studies over the last decade, which shows that robust aggressive multifaceted medical therapy, you know, has a major affect on leveling the playing field and reducing the (inaudible). 

Remember, these patients didn't just take simvastatin and Niaspan or placebo, they also received Beta blockers, Aspirin, in many instances, (inaudible), Ace Inhibitors, ARBs, and so, I think in the aggregate, you know, we maybe converted this group through our, you know, efforts at intensive treatment, we may have modified the risk sufficiently that we couldn’t demonstrate incremental benefits.

Yes.  You know, and remember, you know, what if you had a patient that came into the hospital with Acute Coronary Syndrome and an LDL of 140 and an HDL of 25 as an example? 

I personally think that is a very high risk patient and as a clinician, you know, my instincts are to double down on all the medications available to me to reduce that risk in whatever way I can to reduce events.

Now the results today I don't apply to that kind of a patient because that's not largely kinds of patients that we studied in this trial. 

Well, remember, you know, again, if it was a patient population like we've studied, again, it wouldn't apply to Acute Coronary Syndrome patients or MI patients. 

But if we had a patient group, let's say, with Chronic Angina, who started out with a high LDL and you got it down to the 60s or 70s as we did in this study, you know, again, the results of this trial would suggest that there is no benefit for continuing Niacin in that group of patients and that's all we can say.

... which is in the setting of a very well optimally controlled LDL cholesterol, could we demonstrate that there was added clinical benefit from using Niaspan to raise HDL in this group?  And we answered that question in the population studied.

But as I said, also, there are many patients with – with – with very abnormal lipid profiles who, I believe, you know, would be appropriate candidates for use of combination dyslipidemic therapy.  And certainly there's a good deal of active investigation looking at other forms of HDL raising therapies ...

... and in China.  It has 25,000 patients in it.  They are using a different agent, which was developed by Merck Company, which is focused on – the agent is a focus on minimizing flush. 

The population is a bit – quite a bit different than the one we're looking – that we looked at because it contains the – the whole panorama of HDL levels and – and it's – it's different in a number of other respects. 

OK.  Thank you very much for participating in today's press briefing and audio playback of this briefing will be available within two hours of the end of this call.  If you call 1-800-642-1687 or outside of the United States and Canada call 706-645-9291.  The conference ID for both numbers is 68182914. 

A recording of this briefing will also be posted on the NHLBI Web site where you will find additional information and you can find that at www.nhlbi.nih.gov.

So thank you all very much for your time and attention.