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Transcript for Recorded Teleconference about the AIM-HIGH Trial

May 26, 2011

11:00 a.m. ET

 

(Diane Striar):

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?

(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)?

(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)?

(Jeff Probstfield):

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.

(Susan Shurin):

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.

(Operator):

And at this time, I would like to remind everybody, in order to ask a question, please press star one on your telephone keypad.  Your first question comes from the line of (Rob Stein).  Your line is now open.

(Rob Stein):

Oh, Hi.  Yes, thank you very much for taking my questions.  I was wondering if you could just talk a little bit about if you're disappointed with these results and also what they say – what you think they say about the HDL hypothesis?

(Susan Shurin):

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.

(William Boden):

(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. 

(Operator):

And your next question comes from the line of (Lauran Neergard) from Associated Press.  Your line is now open.

(Lauran Neergard):

Hi, thank you.  I was wondering if you could talk a little bit about why it might be that you can raise the HDL and not have the downstream good affect that you want.  Are we starting perhaps with patients who've already had too much damage for the HDL to be of use?  And what does this mean for patients outside clinical trials who are using Niacin.

(Susan Shurin):

I'm going to ask (Dr. Probstfield) to address that question.

(Jeff Probstfield):

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.

(William Boden):

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.

(Operator):

Your next question comes from the line of (Ron Winslow) from Wall street Journal.  Your line is now open.

(Ron Winslow):

Hi, thank you for taking the question.  Have you looked at, when you had about 15 percent of patients that were taking Ezetimibe in this trial, was that – did that, do you know, affect any of the results?

(Jeff Probstfield):

We haven't analyzed the data sufficiently to make comment about that at this point.

(Operator):

And your next question comes from the line of (Scott Hensley) from (NPR).  Your line is now open.

(Scott Hensley):

My questions were asked already.  Thank you very much.

(Operator):

Your next question comes from the line of (Matthew Herper) from (Forbes).  Your line is now open.

(Matthew Herper):

Hey, so my fundamental question here, I guess, is can you talk at all a bit about, I guess, the (inaudible) asked to say how much efficacy do you rule out?  I mean how much do – how much do we know that this is not effective in this population?  And can you say anything about the underlying risk of CV Disease in this population?  Was it – was – is it possible that the – that because of the – the really effect of LDL lowering therapy, there just wasn't enough risk for the Niacin to have an effect?

(William Boden):

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.

(Matthew Herper):

I guess the other part; can you say anything about what the overall rate of – of events in the trial was?

(Ruth McBride):

Dr. Shurin, this is (Ruth McBride).  Do you want me to answer that question?

(Male):

Yes, please.

(Susan Shurin):

Yes, would you please?

(Ruth McBride):

Yes.  Hi, this is (Ruth McBride) from the Coordinating Center.  The overall rate of the primary end point that was described is five point (inaudible) year in the placebo group and 5.8 (inaudible) year in the Niacin.

(Matthew Herper):

What was in the – what was in the placebo?

(Ruth McBride):

Five point six (inaudible) per year the annualized rate. 

(Matthew Herper):

And how much of the different – how much does the difference in strokes become if we annualize it?  Is that the difference we're seeing there or?

(Ruth McBride?):

No, I would have to say not.  I think..

(Matthew Herper):

OK.  OK.  So it was actually slightly higher in the Niacin group?

(Ruth McBride):

Very slightly.

(Matthew Herper):

Very slightly.  Right.  But – OK.

(Susan Shurin):

This is Dr. Shurin.  So do ...

(Matthew Herper):

(Ruth), could you spell your name?

(Ruth Shurin):

OH.

(Matthew Herper):

No, not Dr. Shurin. 

(Ruth McBride):

It's (Ruth McBride). 

(Matthew Herper):

Thank you.

(Susan Shurin):

It's Dr. Shurin.  (Inaudible) data suggested there were more strokes in the Niacin group but the overall frequency was less than 1 percent and it's not been found in the previous studies.  So the stroke obviously is one component of the cardiovascular end point. 

(Matthew Herper):

Right.

(Female):

... (inaudible)

(Matthew Herper):

I was just – I couldn't – I couldn't annualize it in my head so I was wondering if the 0.2 per year could have been the – could have been the stroke rate but that was ...

(Female):

There was a total of about 500 events.

(Matthew Herper):

OK.  Thank you.

(Operator):

And your next question comes from the line of (Daniel Denoon) from Web MD.  Your line is now open.

(Daniel Denoon):

Thanks for taking my question.  I've heard a lot of talk about not all HDL being the same.  That some forms of HDL may be more beneficial than others.  Was there a – a study of any HDL subtype in the study?  And can you talk in general about the effect that Niacin might have on different subtypes of HDL?  Thank you.

(Susan Shurin):

I'm going to ask (Dr. Probstfield) to respond to that.

(Jeff Probstfield):

Well, it's correct that Niacin has different effects on different subgroups of the HDL.  We have a very extensive sub study within the trial, which remains under analysis.  So at some point in the future we can give you much more detail about this.  But currently, that’s still under analysis.

(Daniel Denoon):

Is there a feeling that Niacin tends to raise a particular helpful form of HDL or that there would be more to be desired about that form of HDL?

(Jeff Probstfield):

The general answer to that – it is thought to raise the more beneficial sub groups of HDL.  But what it – what actually happened in this trial we still don't have evidence about.

(William Boden):

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.

(Male):

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?

(Susan Shurin):

So we don't see that the study results here would recommend any general change in approach to the use of Niacin.  The FDA concurs with that, at least so far.  We would strongly recommend that any individual who is taking Niacin, have that conversation with their physicians.  But there's nothing in here that would be compelling.

(Male):

Yes.  So for high risk primary prevention, these results in no way bear on that issue or question.

(Daniel Denoon):

Thank you. 

(Operator):

Your next question comes from the line of (Leslie Wade) from CNN.  Your line is now open.

(Leslie Wade):

Yes, good morning.  You've pretty much basically answered this question with that last line but what – what do we tell patients out there in general who have heart disease?

(William Boden):

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.

(Leslie Wade):

Super.  Thank you.

(Jeff Probstfield):

This is (Dr. Probstfield) if I could add to that.  I think the FDA statement that was issued also helps us and at the present time, they're not prepared to change any of the labeling or indications regarding the medication.  And that this will be further explored as we get into the data set in more detail.

(Leslie Wade):

Thank you.

(Operator):

And your next question comes from the line of (Larry Husten) from Cardio Exchange.  Your line is now open.

(Larry Husten):

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.

(Female):

I'm going to ask ...

(Male):

Yes, Larry.

(Larry Husten):

I'm sorry.

(Susan Shurin):

I'm going to ask (Ruth McBride) to address that please.

(Ruth McBride):

I'm sorry.  Could you repeat the question?

(Larry Husten):

Yes, so the first part is, how did your actual event rate compare to what your expectations were going into the trial? 

(Ruth McBride):

The actual event rate was actually 1 percent per year less than what we projected when we designed the trial and did the (inaudible) in sample size.  We expected a 6.5 percent per year rate in the control arm. 

(Larry Husten):

And then the other part was, can you tell us about the individual components of the primary end point?  And I'm just sort of guessing that most of the events were in the re-vascularization component. 

(Ruth McBride):

Most of the events were actually non-fatal MIs.  There were quite a few – you're right.  Most of them were hospitalization for ACS and followed closely by non-fatal MI.  Very small number of strokes, as was stated before and about 40 deaths.  There were also 140 re-vascularization. 

(Larry Husten):

Is- is it possible to get the numbers or percentages for the different components and the different arms?

(Ruth McBride):

Dr. Susan Shurin, do you want me to just give that over the phone or do you want to provide that separately?  How would you like to handle that?

(Male):

So (Ruth), just before we move on from that.  I think we should make the final point about the power discussion that even with all the considerations that (Ruth) just described to you, the power was still well powered. 

(Larry Husten):

OK.

(Male):

You know, (Larry), with respect to the question about the individual end points, remember, we're still accruing events and so whatever numbers we would give you on the telephone today will almost certainly not be the final numbers when the database is cleaned up and locked. 

(Larry Husten):

Cool.

(Male):

So I – I just don't think it would be well advised to be using numbers that are sort of preliminary ones at this stage.

(Female):

Yes, I ...

(Larry Husten):

So it is fair to say that most of the events were re-vascularization and hospitalization for ACS?

(Female):

I think that would be a fair statement but it – but there were substantial numbers of events in Coronary Heart Disease, deaths and non-fatal MI. 

(Larry Husten):

Thank you.

(Female):

Let me just go a little bit further in the power analysis.  This – this study is, as (Dr. Probstfield) said, was well powered for the hypothesis that we set out to examine.  And although the overall event rate was lower than what we expected, we still felt that the conclusions that we reached with this early stopping were conclusive.

(Larry Husten):

Perfect, thank you.

(Female):

OK.

(Operator):

Your next question comes from the line of (Chris Kaser) from (MedPage) Today.  Your line is now open.

(Chris Kaser):

Hi, thank you for taking my question.  Actually I have two.  The first one is, you mentioned an increase in HDL of 20 percent.  Is that a target that you're satisfied with or would you – would like to see a higher HDL level?

(Jeff Probstfield):

We were expecting something of the order of 20-25 percent.  I gave you the approximate figure of 20, I believe, it was actually about 22 percent but the important point is it is well within the range of what we had predicted and it was well within the range of what we had used for the power calculations.

(William Boden):

In addition to that, there was also the expected or anticipated reduction in triglycerides that we observed, as well.  So clearly, the use of Niaspan had exactly the therapeutic effect we would have expected or predicted on the lipid profile, recognizing again, that we still haven't done a deep dive into some of the other lipoprotein analysis as yet.

(Chris Kaser):

Thank you.  And my second question is, this is yet another failure, if you will, on whether the raising of HDL can – can prevent CV events.  Do you think it's probably time to stand back and – and say that this approach doesn't work?

(William Boden):

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.

(Chris Kaser):

Thank you.

(Operator):

And your next question comes from the line of (Kerry Walkter) from Internal Medicine News.  Your line is now open.

(Kerry Walkter):

Hi.  Thanks for taking my question.  What was the specific predefined trigger for stopping the study that you reached and how was that decided upon as a – a predefined sounding point?

(Susan Shurin):

I'm going to ask (Ruth McBride) to address that one.

(Ruth McBride):

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. 

(Kerry Walkter):

OK.  Great.  Thanks.

(Ruth McBride):

You're welcome. 

(Operator):

And again, if you would like to ask a question, please press star one on your telephone keypad.  Your follow up question comes from the line of (Matthew Herper) from (Forbes).  Your line is now open.

(Matthew Herper):

Hey, (Bill).  I – I wanted to just ask again, I mean, why doesn't this result given that we – that we have so little outcomes data on Niacin, why doesn't this impact the – the use of the drug in higher risk patients?  Given that this is the only study we've got, I mean, why – why believe that as you move from low risk to the high risk that you're going to see a benefit that seems to have been really completely absent here?

(William Boden):

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.

(Matthew Herper):

OK. 

(Operator):

Your next question comes from the line of (Judy Silverman) from NBC News.  Your line is now open.

(Judy Silverman):

Hi.  How – thank you for taking my question.  How commonly prescribed is Niacin in this group of patients  – patients with – with heart disease but with well controlled LDL and low HDL?

(Female):

That's a good question.  I'm not sure I know the answer to it.

(William Boden):

We don't – we don't really know what the actual – I mean I'm certain that there are millions of patients that are taking Niaspan for many, perhaps different indications.  So, you know, we can't, you know, give you precise statistics in terms of medication usage at this point.

(Judy Silverman):

But is this considered, you know, good standard medical practice to put these types of patients on Niacin?

(Jeff Probstfield):

Yes.  Absolutely. 

(Susan Shurin):

Absolutely.

(William Bowden):

Yes.

(Judy Silverman):

So at least for this patient population you're saying that recommendation should change?

(Female):

Well, what we're not demonstrating is a benefit of – we're not at all convinced that there's (inaudible).

(William Boden):

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. 

(Judy Silverman):

Right.  But let's say you did have a patient who after a few months, you know, did establish low LDL levels.  Would you take them off Niacin at that point even if they didn't have a high enough HDL?

(William Boden):

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.

(Judy Silverman):

Right.

(Jeff Probstfield):

And if I could add, this is (Jeff Probstfield).  Just – just remember that at least at this point with the relatively preliminary elements of the data set explored, the FDA has recommended no change in the prescribing patterns for this – this agent.

(Judy Silverman):

Could you tell us how many years of follow up there was?  You know, these events occurred ...

(Jeff Probstfield):

The average length of follow up I believe, was 32 months.

(Female):

And we're planning to continue to follow these patients for at least another 18 months.

(Judy Silverman):

OK.  Thank you.

(Operator):

And your next question comes from the line of (Ron Winslow) from Wall Street Journal.  Your line is now open.

(Ron Winslow):

Sorry to keep beating on this one but is Niacin generally, I mean, you wouldn't necessarily think of Niacin used only in – in very high risk patients who are presenting with ACS, I mean this is pretty widely used as a – a prophylactic as preventive prevention for secondary events or possibly even primary prevention is it not?

(Female):

Yes, that's correct.

(Jeff Probstfield):

Yes, that's true.  That's exactly right.

(Ron Winslow):

And – and – and does it say anything about use of this in primary prevention?

(William Boden):

It doesn't say anything about the use in primary prevention.

(Ron Winslow):

OK.

(Female):

It's totally a secondary prevention study.

(Ron Winslow):

OK.  Thank you.

(Operator):

Your next question comes from the line of (Cesa Nelgoolan) from The Heart.Org.  Your line is now open.

(Cesa Nelgoolan):

Thank you.  Could you just reiterate the – the patients who would normally (inaudible) commonly be receiving this kind of extended dose of Niacin (inaudible)?

(William Boden):

Well ... right, so – so remember now, the first ...

(Cesa Nelgoolan):

You've talked about a lot different preventions

(William Boden):

We need to follow the NCEP guidelines ...

(Cesa Nelgoolan):

Yes.

(William Boden):

Which are the first and most important therapeutic intervention is to use a statin and in a very high risk patient, I try to get the patients to an LDL below 70. 

(Cesa Nelgoolan):

Yes.

(William Boden):

If having achieved that, you know, there is, you know, still evidence of – of low HDL, then this has been the kind of population in which Niacin ...

(Cesa Nelgoolan):

Yes.

(William Boden):

... has been used but this is why I believe the results of the study are important.  You know, this was one of the most, I think, important and compelling scientific questions that was not answered, which, you know, (inaudible)

(Cesa Nelgoolan):

Yes.

(William Boden):

... 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 ...

Cesa Nelgoolan):

Yes.

(William Boden):

... and, you know, to date, you know, we are still, you know, looking to see if modulating HDL by any therapeutic intervention results in improved clinical outcomes.

(Cesa Nelgoolan):

Can you just tell me a little bit about the other study that's ongoing that's mentioned in the press release?  Is that the same study population?

(Jeff Probstfield):

Yes, HPS2-THRIVE is a study that's being carried on primarily in Europe ...

(Cesa Nelgoolan):

Yes.

(Jeff Probstfield):

... 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. 

(Cesa Nelgoolan):

Yes.

(Jeff Probstfield):

So it's a different population, a different agent being used ...

(Cesa Nelgoolan):

Yes.

(Jeff Probstfield):

... I think those are the key issues.

(William Bowden):

Yes.  Just to add to this ...

(Cesa Nelgoolan):

Is there a comparable dose of Niacin?

(Jeff Probstfield):

The answer to that is yes. 

(William Bowden):

Yes.

(Cesa Nelgoolan):

OK. 

(William Boden):

But remember, AIM-HIGH by design targeted patients with a low HDL ...

(Cesa Nelgoolan):

Yes.

(William Boden):

... and in the HPS2-THRIVE, they have no preset lipid selection criteria or inclusion criteria.  So they have more of an all commerce design with any baseline HDL or LDL being ...

(Cesa Nelgoolan):

Yes.

(William Boden):

... eventually fair game for enrollment.

(Cesa Nelgoolan):

Yes.

(Jeff Probstfield):

And the last point that – that (Bill) made is probably the really key one and that is there is no intensive effort to control LDL in that study.

(Cesa Nelgoolan):

Yes.  Thank you.

(Operator):

And there are no further questions. 

(Susan Shurin):

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.

END

 

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