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Showing posts with label Dr Thomas Dayspring. Show all posts
Showing posts with label Dr Thomas Dayspring. Show all posts

Tuesday, September 3, 2013

So is niacin a dead drug? Dayspring

Commentary on Niacin’s Effect on Lp(a) in AIM HIGH


Here are my thoughts as a clinical lipidologist (By: Thomas Dayspring, MD, FACP, FNLA, NCMP)

We must get apoB (LDL-P) to goal in all at-risk patients. Lifestyle therapies and statins are the mainstay of therapy. However residual risk is high if apoB (LDL) remains elevated despite at-goal LDL-C, non-HDL-C), any level of HDL-C or if Lp(a) mass is elevated.

So I would have no hesitancy in adding niacin to high and very high risk patients who have not achieved apoB (LDL-P) goals with whatever therapies they are using or using niacin as a monotherapy in those intolerant of other apoB lowering meds.

Data from HPS THRIVE 2 (discussed in a recent commentary) suggested statin plus ezetimibe was better at event reduction than statin plus niacin [9]. In view of that and the very significant side effects reported in HPS THRIVE 2 [bleeding (GI, intracranial, other) in the niacin group: 326 (2.5%) to 238 (1.9%) and infection 1031(8%) to 853 (6.6%)] [3] makes niacin a tertiary or quaternary add-on drug (some may prefer the bile acid sequestrant colesevelam as an apoB lowering medication).
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Read the complete article here.

Thursday, August 29, 2013

Niacin’s Effect on Lp(a) in AIM HIGH - Dayspring

Commentary on Niacin’s Effect on Lp(a) in AIM HIGH
    
In 2013 we have already published two commentaries on niacin (Commentary on Niacin vs Ezetimibe as add on to Statin) and (Examination of the Recently Announced Preliminary Results of the HPS2-THRIVE Study), specifically extended release available as Niaspan, a seemingly potent lipid- and lipoprotein-modulating drug that dates back to the 1960’s. Initially it was used to reduce elevated cholesterol levels but eventually it was found to also raise HDL-C which for a variety of reasons was assumed to be very desirable (thought being that if low HDL-C is a strong CV risk factor, then raising it must be beneficial).  Also of interest was niacin’s ability to significantly reduce lipoprotein (a) mass [Lp(a)]. Indeed, a group entitled European Atherosclerosis Society Consensus Panel issued a statement strongly advising niacin be used for CV benefits in patients with elevated Lp(a) [1]. Interestingly that panel noted there was virtually no clinical trial support for this recommendation other than the fact that niacin does indeed reduce Lp(a) mass. Most lipidologists agreed with the belief that even if reducing Lp(a) does not matter, niacin would at least reduce apolipoprotein B (apoB) which is seemingly always desirable. NCEP ATP-III simply advocated achieving LDL-C goals in persons with risk related to Lp(a) issues. 
 
niacinandlpacommentary
 
 
 
Recent trials [The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM HIGH) and large Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events  (HPS THRIVE 2)] have not shown additional event reduction in well-treated patients with stable CHD related to adding niacin to a statin or statin/ezetimibe regimen [2,3]. To say the results of those studies were a shock to the lipidology community is an understatement. AIM HIGH (all of the patients had low HDL-C at baseline) was published first and for those who believed niacin’s benefit was related to raising HDL-C, the results were a punch to the jaw. Despite a substantial (25%) HDL-C increase (remember the old well accepted but never proven caveat that for every 1% rise in HDL-C there is a 3% event reduction) there was no CV outcome improvement. The usual side effects associated with niacin were present including a questionable nonsignificant rise in ischemic stroke. Then along came the still not published HPS THRIVE 2 (baseline HDL-C was not an enrollment criteria) where again the addition of niacin to a statin or statin/ezetimibe regimen provided no additional outcome benefit. Common to both AIM HIGH and HPS THRIVE 2 was the fact that the lifestyle with statin or statin/ezetimibe had normalized LDL-C, non-HDL-C and apoB. Thus niacin was being added to patients who were at those goals (keeping in mind that there is no NCEP ATP-III goal for HDL-C). Should we really have expected niacin, whose primary mechanism of action is to lower apoB (or its lipid surrogates) to do anything to CV events in persons with normal apoB?  The answer is yes if raising HDL-C or lowering Lp(a) mass is critical to event reduction (well accepted concepts that have never ever been proven in any type of trial). Well we may have those answers now and at this point one has to reasonably conclude the evidence is strong that in patients on LDL-receptor inducing drugs (statins or statin + ezetimibe) raising HDL-C (note – niacin also raises apoA-I, but not apoA-II or total HDL-P) [4] or reducing Lp(a) mass with niacin provides no benefit in folks who are at apoB (LDL-C, non-HDL-C) goal.
 
In AIM HIGH baseline apoB and apoA-I levels were low and baseline Lp(a) was elevated at 33.8 nmol/L [using Caucasian adult data from Framingham as a comparator, Lp(a) averaged 20 nmol/L]. Nearly 30% of AIM HIGH patients had severe Lp(a) elevations > 100 nmol/L compared to 20% of Framingham cohort. The addition of niacin to statin or statin + ezetimibe raised HDL-C by 25%, apoA-I by 7% and reduced LDL-C by 12%, TG by 30% and apoB by 13%. [5]
 
Lp(a) as expected was significantly associated with CV events despite the fact that LDL-C was at goal and thus elevated Lp(a) is associated with residual risk. A one standard deviation of Lp(a) was associated with a 21% increase in CV risk. There was a 21% overall reduction [but with a 20%, 39% and incredible 64% decreases in patients at the 50th, 75th and 90th percentile cut points] in Lp(a) in the niacin group compared to 6% in placebo group. So the higher the Lp(a) level, the more dramatic was niacin’s ability to lower it.  Here is the shocker: there was no difference in event rate between those on or not on niacin (remember all were statin or statin + ezetimibe) DESPITE GREATER DECREASES in Lp(a) for those using niacin. Even in those in the highest Lp(a) quartile (> 125 nmol/L) there was no reduction in events when niacin was added.
 
So where do we stand with niacin? There is no level one evidence anywhere supporting the use of niacin to reduce clinical events: The Coronary Drug Project (CDP) is often quoted as proof of niacin’s efficacy but few realize that niacin monotherapy (high dose of immediate release preparation) had no impact on the primary endpoint of the study (mortality): thus the benefit of reducing non-fatal myocardial infarction (a secondary endpoint) makes this benefit hypothesis generating [6].Of course there is the famous 15 year follow up of CDP which encompassed 6 years of the trial where niacin was used and then a subsequent 9 year period off niacin. Mortality was significantly reduced in that post hoc analysis (data derived not from examination or in person review but questionnaires sent to participants): this is the weakest data imaginable [7]. So this supposedly late benefit of niacin is in fact analysis of post hoc follow data up from a trial where niacin failed to reduce the primary endpoint. If niacin was a new drug, it would have no prayer of gaining FDA approval based on the CDP. Several subsequent trials using angiographic or CIMT endpoints showed niacin monotherapy or combination with bile acid sequestrants or statins showed imaging benefit. One small (~500 patients) open-label outcome trial (Stockholm Ischemic Heart Disease Secondary Prevention Trial), combining clofibrate and IR niacin did reduce clinical events with statistical significance [8].
 
In my opinion niacin became a major lipid drug because of its ability to raise HDL-C and to lower Lp(a) and not for what is likely its real mechanism of action, namely lowering LDL-C and apoB and LDL-P. After extended-release niacin (Niaspan) hit the market, it was also heavily promoted because of its ability to increase both HDL and LDL size. KOS made a fortune by promulgating those messages as it seemingly made so much sense. Of course over time, we have learned that influencing LDL or HDL particle size or raising HDL-C and apoA-I has no effect on outcomes. Looking at lipid/lipoprotein risk factors in 2013 the outcome evidence only supports lowering apoB (LDL-P) or perhaps raising total HDL-P. At this time unfortunately, there is no support for reducing Lp(a) with niacin: admittedly the Lp(a) data from the much larger HPS THRIVE 2 study of 25,000 patients is pending.  
 
So is niacin a dead drug? Here are my thoughts as a clinical lipidologist: We must get apoB (LDL-P) to goal in all at-risk patients. Lifestyle therapies and statins are the mainstay of therapy. However residual risk is high if apoB (LDL) remains elevated despite at-goal LDL-C, non-HDL-C), any level of HDL-C or if Lp(a) mass is elevated. So I would have no hesitancy in adding niacin to high and very high risk patients who have not achieved apoB (LDL-P) goals with whatever therapies they are using or using niacin as a monotherapy in those intolerant of other apoB lowering meds. Data from HPS THRIVE 2 (discussed in a recent commentary [ADD LINK]) suggested statin plus ezetimibe was better at event reduction than statin plus niacin [9]. In view of that and the very significant side effects reported in HPS THRIVE 2 [bleeding (GI, intracranial, other) in the niacin group: 326 (2.5%) to 238 (1.9%) and infection 1031(8%) to 853 (6.6%)] [3] makes niacin a tertiary or quaternary add-on drug (some may prefer the bile acid sequestrant colesevelam as an apoB lowering medication).
 
What about our patients with elevated Lp(a) mass or Lp(a)-P? The only therapy that has so far shown an inkling of success is LDL apheresis. For now we should all try to lower apoB (LDL-P as aggressively as possible and that often requires multiple combination therapies. What about future drugs: just published is the  data the PCSK9 monoclonal antibody AMG 145 reduces Lp(a) by 32% in patients on statins [10]. There is also promising data that the remaining CETP inhibitors also reduce Lp(a) but the reality is that until such reductions by these drugs are linked to outcome benefit they are of hypothetical interest. Hopefully in the future there will also be development of an apoprotein (a) antisense oligonucleotide inhibitor. 

 
References:
[2] The AIM-HIGH Investigators Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med 2011;365:2255-67.
[3] Presentation by Jane Armitage on behalf of the HPS2 THRIVE group to the National Lipid Association Annual Scientific sessions, Las Vegas NV June 2013.
[6] Coronary Drug project group. Clofibrate and Niacin in Coronary Heart Disease. JAMA 1975;231:360-381.
[7] Fifteen Year Mortality in Coronary Drug Project Patients: Long Term Benefit with Niacin. JACC 1986;8:1245-55.
[8] Reduction of Mortality in the Stockholm Ischaemic Heart Disease Secondary prevention Study by Combined Treatment with Clofibrate and Nicotinic Acid. Acta Med Scand 1988;223:405-418.[9] Masana, A. Cabré, N. Plana. HPS2-THRIVE results: Bad for niacin/laropiprant, good for ezetimibe? Atherosclerosis 2013;229:449-450.
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Read the complete article here.

Monday, August 12, 2013

Another view on unnecessary heart surgery. - Dr. Walt

President Bush’s unnecessary heart surgery

Former president George W. Bush, widely regarded as a model of physical fitness, received a coronary artery stent last week. Few facts are known about the case, but what is known suggests to me, and many others, that the procedure may have been both unnecessary and potentially harmful – not only for Mr. Bush, but for society, in general, and Medicare, in particular.First, some very important background: Before he underwent his annual physical, Mr. Bush reportedly had no symptoms. Quite the opposite: His exercise tolerance was astonishing for his age, 67. Just before his physical exam, he rode a mountain bike more than 30 miles in the heat on a bike ride for veterans injured in the wars in Iraq and Afghanistan. I would count that as one intense cardiac stress test. By all reports, Mr. Bush was completely asymptomatic. But then, he went for one of those fancy (and very expensive) executive physicals. It was then that things began to unwind.Here’s an explanation of what happend that was published in the Washington Post. It is written by Vinay Prasad, MD, who is chief fellow of medical oncology at the National Cancer Institute and the National Institutes of Health, and Adam Cifu, MD, who is a professor of medicine at the University of Chicago.

If Mr. Bush had visited a general internist (or family physician) practicing sound, evidence-based care, he would not have had cardiac testing. Instead, the doctor would have had conducted age-appropriate cancer screening. For the former president, this would include only colon cancer screening. It no longer would include even prostate-specific antigen testing for cancer. The doctor would have screened for cholesterol, checked for hypertension and made sure the patient was up to date on age-appropriate vaccinations, including those for pneumococcal pneumonia and shingles. Presumably Mr. Bush got these things, and he got the cardiac test as well.
What value does a stress test add for an otherwise healthy 67-year-old?No study has shown that this examination improves outcomes. The trials that have been done for so-called routine stress testing examined higher-risk patients. They found that performing stress tests on people at high risk of cardiovascular disease may detect blockages but does not improve symptoms or survival. Routine stress testing does, however, increase the use of procedures such as coronary stenting.

Unfortunately, Mr. Bush, like many VIPs, may be paying the price of these in-depth investigations. His stress test revealed an abnormality, prompting another test: a CT angiogram. This study showed a blockage, which was stented open during an invasive procedure. It is worth noting that at least two large randomized trials show that stenting these sorts of lesions does not improve survival. Because Mr. Bush had no symptoms, it is impossible that he felt better after these procedures.

Instead, George W. Bush will have to take two blood thinners, aspirin and Plavix, for at least a month and probably a year. (The amount of time a blood thinner is needed depends on the type of stent placed). While he takes these medications, he will have a higher risk of bleeding complications with no real benefit.

Although this may seem like an issue important only to the former president, consider the following: Although the price of excessive screening of so-called VIPs is usually paid for privately, follow-up tests, only “necessary” because of the initial unnecessary screening test, are usually paid for by Medicare, further stressing our health-care system. The media coverage of interventions like Mr. Bush’s also leads patients to pressure their own doctors for unwarranted and excessive care.
My good friend (and internationally-recognized lipidologist [expert in cholesterol and other blood fats]), Thomas Dayspring, MD, has written a more detailed editorial, “Commentary regarding the angioplasty and stent of President George W. Bush,” for medical professionals. I encourage my health professional readers to read Tom’s commentary in detail. Here’s a small excerpt:
George W. Bush underwent stent placement because during a routine physical a stress test (which is rarely indicated in an asymptomatic person) revealed an abnormality that led to a CT-angiogram test (which is rarely indicated in an asymptomatic person) that led to a coronary angiogram test (which is rarely indicated in an asymptomatic person) that as usual led to a stent (which is rarely indicated in an asymptomatic person).

Why was an angiogram done on an asymptomatic person?

There is a bit of a history here – all public knowledge. During his second year in office during a yearly physical at Bethesda his physician did a routine coronary calcium level which was 4 (trivial). Even though his LDL-C was fine (~100 mg/dL superb by 2001 standards), they started him on a statin and as one would suspect, a low fat diet. It is well known what a super exercise routine Mr. Bush pursues (then and now): secret service men cannot keep up with him on jogs or bike rides.

Now we find out that he suddenly needed a stent?

Well do not clogged pipes; I mean arteries – need plumbers to fix them? And is it not dietary fat and cholesterol that clogs the arteries?
Earlier in the year Dr. Dayspring posted a commentary in which he answered his own questions. In the editorial, “Coronary Artery Disease as Clogged Pipes A Misconceptual Model,” Dr. Dayspring writes that his commentary, “… was provoked by a perspective authored by Michael Rothberg of the Cleveland Clinic which was published in Circulation Cardiovascular Quality Outcomes (2013;6:129-132) entitled ‘Coronary Artery Disease as Clogged Pipes: A Misconceptual Model‘.” Dr. Dayspring writes, “It is a brilliant piece and needs to be read by all health professionals, including Mr. Bush’s physicians.” Here are some of the many highlights verbatim from that perspective:
  1. Although the image of coronary arteries as kitchen pipes clogged with fat is simple, familiar, and evocative, it is also wrong.
  2. The clogged pipe analogy implies cholesterol plaques in the arterial walls slowly encroach on the lumen, causing silent ischemia first, then angina, and eventually infarction. Diagnosis begins with physiologic stress testing, looking for supply–demand mismatch, and progresses to angiography to find blockages. Treatments based on this theory include both coronary bypass and angioplasty, the latter often explained to patients as a Roto-Rooter.
  3. Results of such revascularization procedures are visually striking and, in stable disease, may lead to the erroneous conclusion that the plumbing problem has been fixed and the risk of myocardial infarction ameliorated.
  4. Although high-grade stenoses can cause chronic angina, most cardiac events occur at lesions that appeared mild on previous angiography —- Before rupture, these plaques often do not limit flow and may be invisible to angiography and stress tests. They are therefore not amenable to percutaneous coronary intervention (PCI).
  5. Local interventions can only relieve symptoms; they cannot prevent future myocardial infarctions. Indeed, at least 12 randomized trials conducted between 1987 and 2007 and involving >5 000 patients have found no reduction in myocardial infarction attributable to angioplasty in any of its forms. Despite this overwhelming evidence, the plumbing model, complete with blockages that can be fixed, continues to be used to explain stable coronary disease to patients, who understandably assume that PCI will prevent heart attacks. Cardiologists also cling to the belief that for patients with stable coronary disease, an open artery is beneficial, and the approach to stable coronary artery disease continues to be a search for ischemia. Not surprisingly, a substantial minority of cardiologists also believe that elective angioplasty and stenting can prevent heart attacks.
  6. The plumbing model—in which dietary fat or cholesterol is slowly deposited in arterial walls, leading to blockages—also perpetuates misconceptions about fat consumption. Although atheromatous plaques contain lipids, they are not composed of fat directly from the diet.
  7. Recommended limiting total dietary fat to 30% of calories and saturated fat to 10% on the basis of the caloric density of fat and the association of saturated fat with coronary heart disease across countries. The interpretation of this evidence was selective. — low-fat diets became synonymous with heart-healthy diets and gave birth to a generation of low-fat, high-sugar substitutes. — More recent observational studies do not support the use of low-fat diets. Subsequent studies have also found no link between saturated fat and heart disease
  8. In these diets, fat is simply replaced by sugar. More recently, the AHA recommended that people limit their intake now appears to contribute to obesity, hypertension, and subsequently coronary heart disease. However, patients and many doctors have not gotten this message. The AHA’s heart-healthy label still appears on a number of low-fat, high-sugar foods, including fruit juices and sugary cereals. —- patients continue to believe that dietary fat, especially the saturated fat found in cheese and bacon, is the cause of heart disease.
  9. The 2011 American College of Cardiology Foundation/AHA/Society for Cardiovascular Angiography and Interventions guideline for PCI — “evaluation of 61 trials of PCI conducted over several decades shows that despite improvements in PCI technology and pharmacotherapy, PCI has not been demonstrated to reduce the risk of death or [myocardial infarction] in patients without recent [acute coronary syndrome] — clinicians and investigators, working from an outdated conceptual model, have mistakenly focused on improving the technology for keeping open flow-limiting lesions, believing that better stents would eventually yield a mortality benefit in stable disease. The inflammatory disease model makes clear that such attempts are doomed to fail because vulnerable plaques cannot be identified or stented before rupture.
  10. Clearly, the current consent process in regard to PCI for stable angina is deeply flawed because most patients do not correctly understand the benefits of the procedure they are about to undergo, and many do not have angina.
  11. It is difficult to admit that in the past we got it wrong and performed what now appear to have been unnecessary procedures.
Dr. Dayspring adds:
Has anyone watched the expert doctors on many TV channels commentating on Mr. Bush?
Many seem to be unaware of the concepts outlined above. A physician expert on NBC in Manhattan commented in clueless fashion that Mr. Bush’s only prayer – and that of the asymptomatic American public looking to avoid a fatal heart attack – is to restrict dietary fat ever lower. Is she aware of the recently published in the New England Journal of Medicine (the LOOK AHEAD trial) where a low fat diet/exercise regimen caused weight loss in obese T2DM (type 2 Diabetes Mellitus) patients but the trial was stopped for futility because there was no reduction in clinical CV events? Is she aware of the complete absence of clinical trials showing any benefit from a low-fat diet on any hard CV endpoint? Is she not aware that dietary cholesterol plays almost no role in atherosclerosis – that the problem is endogenously produced cholesterol?

So unless the former President was suddenly having angina-type symptoms (which has not been mentioned in any reports – and it is doubtful to me that he was as I do not see how he could be doing his intense daily exercise regimen) – there is precious little evidence that his new stent will make a damn bit of difference.

We have any number of modern trials showing aggressive medical management is just as good at reducing subsequent CV morbidity and mortality as is a “plumbing” procedure.
What Mr. Bush really needed was an intensive biomarker search to define what lipid, lipoprotein, metabolic (including insulin resistance), genetic, inflammatory, and coagulation, etc., abnormalities he has. Only then could specific nutritional and therapeutic advice be sanely offered.

If insulin resistance issues are present he needs to consult enlightened nutritionists (and cardiologists) who understand that considering the low-fat diet (and angioplasty and stents in asymptomatic individuals) to be the cure all for every case of atherosclerosis is akin to following the leech and blistering therapies of the past.
For more opinions on the inappropriateness of the workup please see this article in Heart.org.
I’ll be interested in the comments of readers.
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Read the complete article here.
Listen to Dr. William Blanchet podcast on Bush's stent here.

Friday, August 9, 2013

The angioplasty and stent of President George W. Bush - Dayspring

Commentary regarding the angioplasty and stent of President George W. Bush           
Commentary from Thomas Dayspring MD, FACP, FNLA regarding the angioplasty and stent of President George W. Bush 
gwbush
George W. Bush underwent stent placement because during a routine physical a stress test (which is rarely indicated in an asymptomatic person) revealed an abnormality that led to a CT-angiogram test (which is rarely indicated in an asymptomatic person) that led to a coronary angiogram test (which is rarely indicated in an asymptomatic person) that as usual led to a stent (which is rarely indicated in an asymptomatic person). Why was an angiogram done on an asymptomatic person? Did the test show early marked ST depression that suggested a main stem lesion? There is a bit of a history here – all public knowledge. During his second year in office during a yearly physical at Bethesda his physician did a routine coronary calcium level which was 4 (trivial). Even though his LDL-C was fine (~100 mg/dL superb by 2001 standards) they started him on a statin and as one would suspect, a low fat diet. It is well known what a super exercise routine Mr. Bush pursues (then and now): secret service men cannot keep up with him on jogs or bike rides. Now we find out that he suddenly needed a stent. Well do not clogged pipes; I mean arteries – need plumbers to fix them? And is it not dietary fat and cholesterol that clogs the arteries? For more opinions on the inappropriateness of the workup please see  http://www.theheart.org/article/1567069.do
 
Earlier in the year I posted a commentary on LecturePad.org regarding “Clogged Arteries.” (click here to review) That posting was provoked by a perspective authored by Michael Rothberg of the Cleveland Clinic which was published in Circulation Cardiovascular Quality Outcomes. (Circ Cardiovasc Qual Outcomes. 2013;6:129-132) entitled Coronary Artery Disease as Clogged Pipes A Misconceptual Model. It is a brilliant piece and needs to be read by all providers including Mr. Bush’s physicians. Here are some of the many highlights verbatim from that perspective ....
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Read the complete article here.

I also recommend The Doc's Opinion on President Bush here.

Listen to podcast by Dr. William Blanchet here.

Tuesday, March 26, 2013

Niacin references.

Niacin seems to be in the news a lot of late. Here is a reference to some sources of some info re the subject worthy of a read by any interested.

 

There also is Dr Daysprings writing on it in his lipid library on site here worth comparing.
http://heartlifetalk.com/forums/yaf_postst949_Lipid-Center--Dr-Thomas-Dayspring-Resources.aspx

===========================================Updated 3/30/2013