Original article 2011 link
AIM-HIGH: Results Raise Controversy Over Early Stopping
Sue Hughes
November 15, 2011
Highlights of article:
Final results of the AIM-HIGH trial appear to suggest that the signal of increased ischemic stroke with niacin, which was one of the reasons the study was stopped early, could have been the play of chance, with the final p value for ischemic stroke coming in at a nonsignificant 0.11.
This has provoked a backlash from researchers in the field against the National Institutes of Health (NIH) sponsors of the study who made the decision to terminate the trial.
Dr Steven Nissen (Cleveland Clinic, OH), who was not involved in AIM-HIGH but is a key player in lipid research, was particularly vocal on this issue. He commented to heartwire : "I do not agree with the decision to stop this trial. It was completely inappropriate. The NIH sponsors saw a weak signal of stroke and panicked, and when all the data have come in,
this doesn't appear to be an issue. Now we have lost the opportunity to properly answer the very important question of whether niacin adds any benefit in this population with low LDL levels."
this doesn't appear to be an issue. Now we have lost the opportunity to properly answer the very important question of whether niacin adds any benefit in this population with low LDL levels."
The AIM-HIGH trial randomized 3414 patients with established heart disease, low HDL levels,
and raised triglycerides to extended-release niacin (1500–2000 mg per day) or placebo.
and raised triglycerides to extended-release niacin (1500–2000 mg per day) or placebo.
All patients also received simvastatin plus ezetimibe if needed to maintain LDL levels
below 80 mg/dL (2.07 mmol/L).
below 80 mg/dL (2.07 mmol/L).
The trial was stopped earlier this year after a mean follow-up of three years.
The statement from the National Heart Lung and Blood Institute at the time said
the trial had been stopped because niacin was showing no additional benefits over placebo and there was also a small, unexplained increase in ischemic stroke in the niacin group.
The statement from the National Heart Lung and Blood Institute at the time said
the trial had been stopped because niacin was showing no additional benefits over placebo and there was also a small, unexplained increase in ischemic stroke in the niacin group.
Results presented today at the American Heart Association (AHA) 2011 Scientific Sessions
and published online simultaneously in the New England Journal of Medicine
show that at two years, niacin therapy had increased HDL levels from a median of 35 to 42 mg/dL,
lowered triglyceride levels from 164 to 122 mg/dL, and lowered LDL levels from 74 to 62 mg/dL.
and published online simultaneously in the New England Journal of Medicine
show that at two years, niacin therapy had increased HDL levels from a median of 35 to 42 mg/dL,
lowered triglyceride levels from 164 to 122 mg/dL, and lowered LDL levels from 74 to 62 mg/dL.
Focus on the Low LDL Level
Speculation on the reason for the lack of benefit with niacin is focusing on
the low LDL level achieved in the trial.
the low LDL level achieved in the trial.
Lead investigator Dr William Boden (University at Buffalo School of Medicine, NY)
commented to heartwire : "if you are starting off with an LDL of 70,
it may not be possible to show any incremental benefit."
He also pointed out that patients in the trial were very well-treated in terms of other medical therapy,
and many patients had been on statins for several years.
But he said these patients were not representative of the real world,
where only about 15% to 20% of patients actually get their LDL levels down to 70.
"I would urge people not to overreact to these results.
They should not be extrapolated to patients with LDLs of 100 or more,
which is much more the norm. We must not throw the baby out with the bathwater."
commented to heartwire : "if you are starting off with an LDL of 70,
it may not be possible to show any incremental benefit."
He also pointed out that patients in the trial were very well-treated in terms of other medical therapy,
and many patients had been on statins for several years.
But he said these patients were not representative of the real world,
where only about 15% to 20% of patients actually get their LDL levels down to 70.
"I would urge people not to overreact to these results.
They should not be extrapolated to patients with LDLs of 100 or more,
which is much more the norm. We must not throw the baby out with the bathwater."
But Boden and Nissen both stressed that reducing LDL to 70 with high-dose statins
is still the first priority. Nissen commented:
"I am less likely to use niacin after this trial,
but I would still use it in patients who can't get to LDL goals with statins."
is still the first priority. Nissen commented:
"I am less likely to use niacin after this trial,
but I would still use it in patients who can't get to LDL goals with statins."
" Dr. Robert Giugliano says, "before holding a final retirement party for niacin,
it would be appear to more prudent
to assign it to part-time work such as in statin-intolerant patients."
it would be appear to more prudent
to assign it to part-time work such as in statin-intolerant patients."
Stroke: "A Causal Association or the Play of Chance"?
On the stroke issue, the AIM-HIGH investigators report in the paper
that ischemic stroke occurred as the first event in 27 niacin patients (1.6%) vs
15 placebo patients (0.9%).
that ischemic stroke occurred as the first event in 27 niacin patients (1.6%) vs
15 placebo patients (0.9%).
However, eight of the strokes in the niacin group occurred
between two months and four years after discontinuation of niacin treatment.
between two months and four years after discontinuation of niacin treatment.
"When all the patients with ischemic stroke were considered,
rather than just those in whom the stroke was the first study event,
a nonsignificant higher trend persisted in the niacin group," they say.
They add: "The overall rate of ischemic stroke was low,
and it is not clear whether the increase seen with niacin reflects a causal association
or the play of chance."
rather than just those in whom the stroke was the first study event,
a nonsignificant higher trend persisted in the niacin group," they say.
They add: "The overall rate of ischemic stroke was low,
and it is not clear whether the increase seen with niacin reflects a causal association
or the play of chance."
Boden added to heartwire : "When the NIH stopped the trial,
there was an increase in ischemic stroke of borderline significance.
I think they saw neutral outcome data, and because of a potential ethical safety issue
they decided to stop the trial.
But there was no signal of an increase in fatal stroke or of all-cause or cardiac mortality.
And now that we have all the data, the effect is far from significant,
and when we look just at strokes that occurred when the patients were actually on treatment,
we have 21 on niacin vs 18 on placebo.
The earlier numbers were clearly an aberration--just the play of chance."
there was an increase in ischemic stroke of borderline significance.
I think they saw neutral outcome data, and because of a potential ethical safety issue
they decided to stop the trial.
But there was no signal of an increase in fatal stroke or of all-cause or cardiac mortality.
And now that we have all the data, the effect is far from significant,
and when we look just at strokes that occurred when the patients were actually on treatment,
we have 21 on niacin vs 18 on placebo.
The earlier numbers were clearly an aberration--just the play of chance."
Boden said he was "disappointed that we couldn't complete the trial as designed,"
especially in view of the previous VA-HIT trial,
which was conducted before statin use became so widespread
and showed a reduced event rate with gemfibrozil (which also raises HDL),
but this didn't start to appear until 18 months into the study.
"We had planned a 4.6-year follow-up, but we only got three years,
so we are unable to know for sure the effect of niacin in this patient group."
especially in view of the previous VA-HIT trial,
which was conducted before statin use became so widespread
and showed a reduced event rate with gemfibrozil (which also raises HDL),
but this didn't start to appear until 18 months into the study.
"We had planned a 4.6-year follow-up, but we only got three years,
so we are unable to know for sure the effect of niacin in this patient group."
Quotes from M Davidson and T Dayspring from 2014 link
I first wrote about low dose, low cost triple therapy to lower non-HDLc in 2010 in my book, The Tubby Theory from Topeka
Steps:
1-Endur-acin (over the counter niacin) is a proprietary wax matrix that does not cause flushing. Take only 1,000 mg a day.
2-After a month if not at non-HDLc goal, add one half tab Zetia (now generic Ezetimibe 10 mg)
3-After another month if non-HDLc not at goal, take full pill of Zetia.
4- After another month if non-HDLc not at goal get Lipitor 10 mg (now generic atorvastatin) take one half tab a day.
5- Now on triple low dose medications, if non-HDLc not at goal increase to full tablet of Lipitor 10 mg.
These three medications at low dose have very little side effects.
The three medications together may only cost about $100 a year.
Enduracin 500 mg on internet costs $90 for 1,000 tablets. (a two year supply)
Atorvastatin 10 mg is $40 for one year supply.
Ezetimibe is a new generic and may still be a little costly, but at half a pill a day it is much cheaper than the brand Zetia.
I first wrote about low dose, low cost triple therapy to lower non-HDLc in 2010 in my book, The Tubby Theory from Topeka
1-Endur-acin (over the counter niacin) is a proprietary wax matrix that does not cause flushing. Take only 1,000 mg a day.
2-After a month if not at non-HDLc goal, add one half tab Zetia (now generic Ezetimibe 10 mg)
3-After another month if non-HDLc not at goal, take full pill of Zetia.
4- After another month if non-HDLc not at goal get Lipitor 10 mg (now generic atorvastatin) take one half tab a day.
5- Now on triple low dose medications, if non-HDLc not at goal increase to full tablet of Lipitor 10 mg.
These three medications at low dose have very little side effects.
The three medications together may only cost about $100 a year.
Enduracin 500 mg on internet costs $90 for 1,000 tablets. (a two year supply)
Atorvastatin 10 mg is $40 for one year supply.
Ezetimibe is a new generic and may still be a little costly, but at half a pill a day it is much cheaper than the brand Zetia.
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