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READ
THE JOURNAL
ARTICLE ON NIACIN WITH CAUTION
JK has included this study not reliable because it reveals what
big PhARMA is doing to limit the use of Niacin, which is an off-patent
competition of the statins. JK has
uncovered a pattern of attacking off-patent
drugs when doing so improves the sales of block buster classes of drugs. A pattern of new studies designed to show the
existing therapy inferior to the new patented therapy. In this website are sections which set the record
straight in 3 off-patent drugs: a)
aspirin which competes with Warfarin and Plavix, b) estrogen which competes
with bisphonates for osteoporosis; c) Niacin which competes with Statins. Both
aspirin & estrogen also greatly lower the risk for Alzheimer’s. Thus they
reduce the sales of acetylcholinesterase inhibitors (Tacrine, Rivastigmine,
Galantamine
and Donepezil)
and the other (memantine) is an NMDA receptor antagonist, and other drugs
used to suppress various behavior issues.
Aspirin and to a lesser extent estrogen (estradiol) lower the risk of
cancer. (It should be noted that the
bisphonates and drugs used to treat Alzheimer’s are minimally effective at
best, and that statins which lover LDL have not been consistently shown to
prolong life or reduce MI. All these
minimal-at-best results are obtained by marketing departments of Big PhARMA and
published in journal articles that lack proper peer review; viz., the raw data on
which the articles are based upon is not submitted for peer review, and average
positive bias runs 32% according to one study which obtained the raw for
comparison).
Judging from the author’s connection to pharmaceutical
industry is very likely another hatchet job on the non-prescription drug. Among signs are the fact that MI &
strokes are reduced by Niacin by 26% & 24%, yet this was considered insignificant.
Also indicative of the hatchet job is the
use of the flushing form of niacin and a high dosage (1500-3000 mgs). Standard literature recommends a treatment
likely to have very poor compliance. JK
needs to research the use of non-flush forms of niacin and lower doses. JK
would have to go to early studies, before big PhARMA was pushing statins.
As with aspirin and estrogen, it is not the earlier studies
that are flawed, so JK hopes to find the same for niacin.
The New England Journal of Medicine http://www.nejm.org/doi/full/10.1056/NEJMe1112346?query=OF
Niacin
at 56 Years of Age — Time for an Early Retirement?
Editorial: Robert P. Giugliano,
M.D., S.M. November 15, 2011 (10.1056/NEJMe1112346)
A reduction in serum cholesterol with niacin therapy in humans was first
described in 1955, when Altschul and colleagues reported, in a letter to the
editor, the findings in 11 healthy medical students and 57 patients.1
Subsequent clinical studies showed multiple favorable effects of niacin therapy
on lipid particles, including decreases in levels of low-density lipoprotein
(LDL) cholesterol, triglycerides, small dense LDL cholesterol, very-low-density
lipoprotein, lipoprotein(a), and apolipoprotein Β and increases in levels of
high-density lipoprotein (HDL) cholesterol and selective lipoprotein A-1
particles.2
The mechanism of action of niacin is complex, involves several biochemical
pathways, and is still not well defined.3
The current indications for niacin — reducing the risk of reinfarction,
favorably altering lipid levels, and slowing the progression of atherosclerosis
— are derived from three lines of evidence: the
Coronary Drug Project (CDP),4
studies of combination therapy consisting of niacin and a second lipid-lowering
agent, and evaluation of surrogate markers.
From 1966 through 1969, the CDP enrolled 8341 men, 40 to 64 years of age,
with a prior myocardial infarction to one of five lipid-modifying therapies.
There was no significant difference between the men who were treated with
niacin (1119 subjects) and those who received placebo (2789 subjects) in the
primary end point of the rate of death from any cause
(24.4% and 25.4%, respectively) over
a minimum follow-up period of 5 years. However, the rates of myocardial
infarction and of cerebrovascular events were significantly reduced with niacin
— by 26% and 24%, respectively. It is worth
noting, however, that 40 or more years ago, many therapies that have since been
proved to reduce mortality or morbidity after myocardial infarction either were
not routinely administered (e.g., aspirin and beta-blockers) or were not yet
available (e.g., statins, inhibitors of the renin–angiotensin–aldosterone
system, P2Y12 inhibitors, and implantable
defibrillators). The second line of evidence, derived from studies of combined
therapy consisting of niacin and a second lipid-lowering drug, do not inform us
about the benefit of adding niacin alone to background therapy; for example, in
the HDL-Atherosclerosis Treatment Study (ClinicalTrials.gov number,
NCT00000553), was it simvastatin, simvastatin plus niacin, or niacin alone that
was responsible for the observed clinical benefit?5
Finally, studies using surrogate markers (e.g., carotid intima–media thickness)
remain
controversial,6 since they have shown inconsistent
results, even when proven lipid-modifying therapies that clearly reduce
clinical end points have been evaluated by these means.7,8
Thus, a critical appraisal of the prior studies of niacin reveals three shaky
pillars supporting its clinical efficacy and identifies a need for large,
modern trials of clinical end points. The first of these is reported in this
issue of the Journal.9
The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High
Triglycerides: Impact on Global Health Outcomes trial (AIM-HIGH, NCT00120289)9
was designed with 85% power to show a 25% reduction in the primary end point (a
composite of the first event of death from coronary heart disease, nonfatal
myocardial infarction, ischemic stroke, hospitalization for an acute coronary
syndrome, or symptom-driven coronary or cerebral revascularization), with the
addition of 1500 to 2000 mg of niacin per day in patients 45 years of age or
older with established cardiovascular disease and an atherogenic dyslipidemia.
The trial was cast as a test of the HDL-raising effects of niacin, but as shown
in the causal diagram10
in Figure
1Figure 1 Causal Diagram of the Relationships among Niacin, Major
Lipid Levels, and Clinical Outcomes., any clinical benefit observed with
niacin would be difficult to attribute solely to the effect on HDL. The
strengths of the trial design include the efforts made to maintain the
double-blinding (blinding of lipid values other than LDL and administration of
very low doses of niacin in the placebo group), the well-controlled LDL
cholesterol level achieved (a median of <70 mg per deciliter [1.81 mmol per
liter]), the event-driven design, and the low rates of loss to follow-up (0.7%)
and withdrawal of consent (0.8%). Despite achievement of the expected favorable changes in the
levels of HDL cholesterol (an increase of 25%), LDL cholesterol (a decrease of
12%), and triglycerides (a decrease of 29%) with niacin, the clinical results
were chillingly null; niacin did not reduce the incidence of the primary
composite end point, nor did it show any clinical benefit overall or in a major
subgroup. The trial was stopped early by the independent data and safety
monitoring board because the boundary for futility had been crossed, and an
unexpected higher number of ischemic strokes was observed in patients assigned
to niacin.
What are the potential explanations for these findings? It is important to
understand that although the event rate was lower than initially projected, it
would be incorrect to conclude that the study was designed with insufficient
power, since by definition, an event-driven trial is adequately powered for the
number of events and the treatment effect specified. Rather, the assumption of
a 25% treatment effect appears to have been too generous given the modest
absolute difference between the treatment groups in the HDL cholesterol levels
achieved (a difference of 4 to 5 mg per deciliter [0.10 to 0.13 mmol per
liter]), the low LDL cholesterol levels achieved owing to potent background
lipid therapy (with approximately 75% of the patients in the placebo group
receiving simvastatin at doses ≥40 mg, and approximately 20% receiving
combination therapy consisting of ezetimibe plus simvastatin), and a 25% rate
of premature discontinuation in the niacin group. Although the numeric excess
in ischemic strokes (which, after inclusion of three upgraded events identified
during a post hoc re-review of investigator-reported transient ischemic
attacks, yielded a borderline significant result) is of concern, there are
several reasons, internal and external to the study, that raise doubts
regarding a causal relationship. No prior study or meta-analysis with niacin
had observed a similar imbalance in ischemic stroke (in fact, the rate of total
stroke was reduced by approximately 20% in the CDP), and no plausible biologic
mechanism has been advanced. Furthermore, eight patients (all in the niacin
group) had a stroke 2 months or more after discontinuation of the drug.
Finally, the specter of a spurious association between a therapy and a
low-frequency unexpected event in a moderate-sized trial, when multiple end
points are evaluated without statistical adjustment for multiplicity of
testing, is not new to the lipid field.11
Nonetheless, the disappointing results of AIM-HIGH do not provide support
for the use of niacin as an add-on therapy to statins in patients with
preexisting stable cardiovascular disease who have well-controlled LDL
cholesterol levels. Given the lack of efficacy shown in this trial, the
frequent occurrence of flushing with niacin therapy that some patients find
intolerable, and the unresolved question of an increased risk of ischemic
stroke, one can hardly justify the continued expenditure of nearly $800 million
per year in the United States for branded extended-release niacin.12
However, before holding a final retirement party for niacin, it would appear to
be more prudent to assign it to occasional part-time work, such as in
statin-intolerant patients (see the Perspective article by Maningat and Breslow13),
while we await the results from the much larger Heart Protection Study 2:
Treatment of HDL to Reduce the Incidence of Vascular Events trial (HPS2-THRIVE;
NCT00461630),14
which is targeted to be completed in 2013. Regardless of whether niacin is
ultimately retired or not, one should not abandon the HDL-raising hypothesis
altogether. Several ongoing studies15,16
with other promising drugs that raise HDL cholesterol levels substantially (by
as much as 150%) by means of different mechanisms, and that in some cases can
lower LDL cholesterol levels by as much as 40%, are well under way.
1. Altschul R, Hoffer A, Stephen JD. Inf luence of nicotinic
acid on serum cholesterol in man. Arch Biochem Biophys 1955;54: 558-9.
2. Kamanna VS, Kashyap ML. Mechanism of action of niacin on
lipoprotein metabolism. Curr Atheroscler Rep 2000;2:36-46.
3. Hochholzer W, Berg DD, Giugliano RP. The facts behind
niacin. Ther Adv Cardiovasc Dis 2011;5:227-40.
4.
Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-81.
5. Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and
niacin, antioxidant vitamins, or the combination for the prevention of coronary
disease. N Engl J Med 2001;345:1583-92.
6. Polak JF, Pencina MJ, Pencina KM, O’Donnell CJ, Wolf PA,
D’Agostino RB. Carotid-wall intima–media thickness and
cardiovascular events. N Engl J Med 2011;365:213-21.
7. Carotid Atorvastatin Study in Hyperlipidemic
Post-Menopausal Women. a Randomised Evaluation of Atorvastatin versus Placebo
(CASHMERE) (NCT#00163163). Pfizer PhRMA Web synopsis protocol A2581051. Final
report. October 29, 2007
(http://www.clinicalstudyresults.org/documents/companystudy_2902_0.pdf ).
8. Smilde TJ, van Wissen S, Wollersheim H, Trip MD,
Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid
lowering on atherosclerosis progression in familial hypercholesterolaemia
(ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577-81.
9. The AIM-HIGH Investigators. Niacin in patients with low
HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011.
DOI: 10.1056/NEJMoa1107579.
10. Greenland S, Pearl J, Robins JM. Causal diagrams for
epidemiologic research. Epidemiology 1999;10:37-48.
11. Peto R, Emberson J, Landray M, et al. Analyses of cancer
data from three ezetimibe trials. N Engl J Med 2008;359:1357-66.
12. DrugPatentWatch. Niaspan patent expiration dates, annual
sales, and drug therapeutic class (http://www.drugpatentwatch.com).
13. Maningat P, Breslow JL. Needed: pragmatic clinical
trials for statin-intolerant patients. N Engl J Med 2011. DOI:
10.1056/NEJMp1112023.
14. Heart Protection Study 2: treatment of HDL to reduce the
incidence of vascular events. (NCT #00461630). HPS2 THRIVE home page (http://www.hps2-thrive.org).
15. Cannon CP, Shah S, Dansky HM, et al. Safety of
anacetrapib in patients with or at high risk for coronary heart disease.
N Engl J Med 2010;363:2406-15.
16. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale
and design of the dal-OUTCOMES trial: efficacy and safety of
dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009;158(6):896.e3-901.e3.
Copyright
© 2011
Combination of Statin and extended, high
dose, niacin has no benefit. Better to
take Niacin alone.
NIH stops clinical trial on
combination cholesterol treatment
http://www.fiercepharma.com/press_releases/nih-stops-clinical-trial-combination-cholesterol-treatment?utm_medium=nl&utm_source=internal Posted May 26, 2011
IH stops clinical trial on
combination cholesterol treatment
Lack of efficacy in reducing
cardiovascular events prompts decision
The National Heart, Lung, and Blood Institute (NHLBI) of the National
Institutes of Health has stopped a clinical trial studying a blood lipid
treatment 18 months earlier than planned. The trial found that adding high
dose, extended-release niacin to statin treatment in people with heart and
vascular disease, did not reduce the risk of cardiovascular events, including
heart attacks and stroke.
Participants were selected for
AIM-HIGH because they were at risk for cardiovascular events despite
well-controlled low-density lipoprotein (LDL or bad cholesterol). Their increased risk was due to a history
of cardiovascular disease and a combination of low high-density lipoprotein
(HDL or good cholesterol) and high triglycerides, another form of fat in the
blood. Low HDL and elevated triglycerides are associated with an increased risk
of cardiovascular events. While lowering LDL decreases the risk of
cardiovascular events, it has not been shown that raising HDL similarly reduces
the risk of cardiovascular events.
During the study's 32 months of
follow-up, participants who took high dose, extended-release niacin and statin
treatment had increased HDL cholesterol and lowered triglyceride levels
compared to participants who took a statin alone. However,
the combination treatment did not reduce fatal or non-fatal heart attacks,
strokes, hospitalizations for acute coronary syndrome, or revascularization
procedures to improve blood flow in the arteries of the heart and brain.
"Seeking new and improved ways
to manage cholesterol levels is vital in the battle against cardiovascular
disease," said Susan B. Shurin, M.D., acting director of the NHLBI.
""This study sought to confirm earlier and smaller studies. Although
we did not see the expected clinical benefit, we have answered an important
scientific question about treatment for cardiovascular disease. We thank the
research volunteers whose participation is key in advancing our knowledge in
this critical public health area, and the dedicated investigators who conducted
the study."
The AIM-HIGH trial, which stands for
Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High
Triglycerides: Impact on Global Health, enrolled 3,414 participants in the
United States and Canada with a history of cardiovascular disease who were
taking a statin drug to keep their LDL cholesterol low. Study participants also
had low HDL cholesterol and high triglycerides, which meant that they were at
significant risk of experiencing future cardiovascular events. Niacin, also
known as Vitamin B3, has long been known to raise HDL and lower triglycerides. Eligible participants
were randomly assigned to either high
dose, extended-release niacin (Niaspan) in gradually increasing doses up to
2,000 mg per day (1,718 people) or a placebo treatment (1,696 people).
All participants were prescribed simvastatin (Zocor), and 515 participants were
given a second LDL cholesterol-lowering drug, ezetimibe (Zetia), in order to
maintain LDL cholesterol levels at the target range between 40-80 mg/dL.
The NHLBI funded the AIM-HIGH study
with additional support from Abbott Laboratories, a pharmaceutical company
based in Abbott Park, Ill. Abbott also provided Niaspan and Merck
Pharmaceuticals, based in Whitehouse Station, N.J., provided Zocor. All drugs
used in the study were approved for marketing in the United States and Canada
and have been on the market for many years.
Researchers began recruiting
participants in early 2006. The study was scheduled to finish in 2012. The
average age of the participants was 64 years. Pre-existing medical conditions
included coronary artery disease (92 percent); metabolic syndrome, which is a
cluster of risk factors for heart disease (81 percent); high blood pressure (71
percent); and diabetes (34 percent). More than half of participants reported
having a heart attack prior to entering the study.
The rationale for the AIM-HIGH study
was based in part on a large number of observational studies that consistently
showed that low HDL cholesterol increases the risk of cardiovascular events in
men and women, independent of high LDL cholesterol. In addition, previous small
clinical studies showed that relatively high residual cardiovascular risk
exists among patients with cardiovascular disease, low HDL cholesterol, and
high triglycerides despite intensive management of LDL cholesterol.
However, efforts to find HDL-raising
treatments that actually reduce this residual risk have thus far proved
disappointing. Fenofibrate, an HDL-raising drug, failed
to reduce the rate of cardiovascular events in patients with diabetes in the
Action to Control Cardiovascular Risk in Diabetes (ACCORD trial) despite
favorable effects on HDL and triglycerides. Another HDL-raising drug,
torcetrapib, actually increased the rate of cardiovascular events in the
Investigation of Lipid Level Management to Understand its Impact in
Atherosclerotic Events (ILLUMINATE) trial despite lowering LDL and
triglycerides and raising HDL levels, as intended.
Earlier studies of niacin had shown more favorable
results. Unlike AIM-HIGH, the earlier studies were not designed specifically to
evaluate the impact of raising HDL on the risk of cardiovascular events while
maintaining excellent LDL control. Several other trials testing this
hypothesis, including a large international trial of high dose,
extended-release niacin, are still ongoing.
As is customary in clinical trials,
the NHLBI established an independent data and safety monitoring board (DSMB) to
monitor trial progress and participant safety. At a regularly scheduled meeting
on April 25, 2011, the study's DSMB concluded that high dose, extended-release
niacin offered no benefits beyond statin therapy alone in reducing
cardiovascular-related complications in this trial. The rate of clinical events
was the same in both treatment groups, and there was no evidence that this
would change by continuing the trial. For this reason, the DSMB recommended
that the NHLBI end the study.
The DSMB also noted a small and unexplained increase in ischemic stroke rates
in the high dose, extended-release niacin group. This contributed to the NHLBI
acting director's decision to stop the trial before its planned conclusion.
During the 32-month follow-up period, there were 28 strokes (1.6 percent)
reported during the trial among participants taking high dose, extended-release
niacin versus 12 strokes (0.7 percent) reported in the control group. Nine of
the 28 strokes in the niacin group occurred in participants who had
discontinued the drug at least two months and up to four years before their
stroke. Previous studies do not suggest that stroke is a potential complication
of niacin, and it remains unclear whether this trend in AIM-HIGH arose by
chance, was related to niacin administration or some other issue.
All AIM-HIGH study participants have
been informed of the results and will be scheduled for clinic visits within the
next 2.5 months. Participants will be followed for an additional 12 to 18
months.
"Patients who were not in the
AIM-HIGH trial should not stop taking high dose, extended-release niacin
without talking to their doctor first," said Shurin.
"The lack of effect on
cardiovascular events is unexpected and a striking contrast to the results of
previous trials and observational studies," said Jeffrey Probstfield,
M.D., AIM-HIGH co-principal investigator and professor of medicine and
epidemiology at the University of Washington, Seattle. "The AIM-HIGH
findings do not support the trial's hypothesis that, in the population studied,
adding extended-release niacin to simvastatin in participants with
well-controlled LDL cholesterol can provide additional clinical benefit."
"The results from AIM-HIGH
should not be extrapolated to apply to potentially higher-risk patients such as
those with acute heart attack or acute coronary syndromes, or in patients whose
LDL cholesterol is not as well-controlled as those in AIM-HIGH," said
William E. Boden, M.D., AIM-HIGH co-principal investigator and professor of
medicine and preventive medicine at the University at Buffalo, N.Y.
The niacin tested in the study is a
proprietary formulation used in doses of 500-2,000 milligrams (mg),
manufactured by Abbott Laboratories and approved and regulated by the U.S. Food
and Drug Administration. Low doses of niacin, typically 20 to 100 mg, can be
found in multivitamin formulations available without a prescription. The FDA
regulates the use of high doses of niacin (over 500 mg), which is approved by
prescription for helping treat low HDL cholesterol and/or high triglycerides.
At prescription-level doses, some people experience flushing. The
extended-release formulation of niacin tested in AIM-HIGH was intended to help
reduce the likelihood of flushing.
An estimated 1 in 7 Americans has
high blood cholesterol. It is a major risk factor for cardiovascular disease,
which kills 800,000 Americans a year. Cholesterol can build up in the walls of
arteries and cause them to narrow, a condition known as atherosclerosis.
"As we continue to search for
new approaches to treating cholesterol problems, it is important to remember
the value of existing treatments. The key to treating high cholesterol so
patients can reduce their risk of cardiovascular disease is to lower the level
of LDL cholesterol, through well-established drug treatments such as statins
and lifestyle changes," said Patrice Desvigne-Nickens, M.D., NHLBI project
officer for the AIM-HIGH trial.
The AIM-HIGH investigators will now
focus on completing data collection and analysis. The preliminary outcomes of
the study are expected to be reported at scientific meetings in the fall of
2011.
Find more information about this
clinical trial (NCT00120289) at www.clinicaltrials.gov.
To arrange an interview with an
NHLBI spokesperson, please contact the NHLBI Communications Office at (301)
496-4236 or nhlbi_news@nhlbi.nih.gov. To arrange an interview with Jeffrey
Probstfield, M.D., contact University of Washington School of Medicine, Office
of Communications at 206-616-6730. To arrange an interview with William E.
Boden, M.D., contact Ellen Goldbaum-Kolin in the Public Relations Department at
716-645-4605, or Dr. Boden at 716-859-1784.
Part of the National Institutes of
Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts,
and supports research related to the causes, prevention, diagnosis, and
treatment of heart, blood vessel, lung, and blood diseases; and sleep
disorders. The Institute also administers national health education campaigns
on women and heart disease, healthy weight for children, and other topics.
NHLBI press releases and other materials are available online at
www.nhlbi.nih.gov.
About the National Institutes of
Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes
and Centers and is a component of the U.S. Department of Health and Human
Services. NIH is the primary federal agency conducting and supporting basic,
clinical, and translational medical research, and is investigating the causes,
treatments, and cures for both common and rare diseases. For more information
about NIH and its programs, visit www.nih.gov.
Those who have a financial interest in the outcome manipulate the results, Major study finds that all 37 journal articles positive effects over stated; the average was 32%. Statins cause erectile
dysfunction, cognitive imparement, and cancer.
Lipitor (2011) lifetime sales $131
billion, tops all drugs. Plavix at
$60 billion is second.
STATINS CANCER Link
52% short term
LA Times, Health section, July 21, 2008 -- excerpts
Vytorin, the
combination drug (simvastatin (better known by its commercial name Zocor) and ezetimibe--known as Zetia) prescribed to lower
cholesterol, sustained another blow today, when the author of a major clinical trial announced that the medication had failed
to drive down hospitalization and death due to heart failure in patients with narrowing of the aortic valve. In the process,
researchers in Norway detected a significant blip in cancers in the 1,800 subjects they followed
Today's findings
suggested something more ominous: the incidence of cancer -- and of dying of cancer -- was significantly higher in the patients
taking Vytorin. Altogether, 67 patients on placebo developed cancer during the trial.
Among subjects on Vytorin, 102 developed cancers of various kinds.* This
is the second adverse press—the first being in March 08, when the ENHANCE trial found that Vytorin fared no better than
a placebo at reducing plaque buildup on the walls of patients' arteries.* *
Comments
by jk
Simvastatin (Zocor) is off patent. Thus in a scramble for profits a combination drug (on patent) was introduced. Direct to consumer market cost $155 in 07—mainly TV ads.
*
The pressing issue is that since the development of Statins, the very
first animal studies in the 60s it has been known that Statins increase the incidents of cancer. However, nearly all studies done thereafter have not included cancer.
*
Several studies have failed to find a reduction in the build of plaque, even thought the statins including Zocor, reduce
LDL and cholesterol. Few studies include the
principle reason for taking a statin, namely a reduction in the death rate. Claims
for such reduction probably entail a failure to control the contravening variable, aspirin usage. Given a pile of evidence, including the very mechanism of plaque formation, which involves inflammation
process, I must conclude that the use of statins is highly suspect. Given the
harm done including cognitive impairment, weakness, and cancer, if my skepticism is born out, the harm done by statins as
a course of treatment will far surpass that of VIOXX which killed over 200,000 people world wide by accelerating atherosclerosis.
EXTENDED RELEASE NIACIN IS A SAFER, AND A MORE EFFECTIVE WAY TO LOWER
MI RISK!
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