Helping to explain the results of “Galantamine Cuts Mortality”*…

Galantamine Slashes
Heart Attacks and Death

The possible mechanisms may surprise you

By Will Block

A new study has found that subjects taking the highest recommended doses of cholinesterase inhibitors (ChEIs)—including donepezil (at 10 mg/day), rivastigmine (at 6 mg/day), and galantamine (at 24 mg/day)—had significantly lower levels of myocardial infarction (MI, aka heart attack) or significantly reduced risk of death from any cause.1 The research was conducted at Karolinska University Hospital, Stockholm, Sweden where over 7000 subjects (mean age 79 years) from the Swedish Dementia Registry with the diagnoses of Alzheimer’s dementia or Alzheimer’s mixed dementia since 2007 were followed for a mean period of 503 days.

In the study, those who used ChEI, compared to those who did not, experienced:

  • 38% lower risk of heart attack
  • 26% lower risk of death from stroke and other cardiovascular diseases
  • 36% lower risk of death from any cause

Absolute Reductions in Risk

“If you translate these reductions in risk into absolute figures, it means that for every 100,000 people with Alzheimer's disease, there would be 180 fewer heart attacks—295 as opposed to 475—and 1,125 fewer deaths from all causes—2,000 versus 3,125—every year among those taking ChEIs compared to those not using them,” said study lead author Professor Peter Nordström, of Umea University in Sweden.2

The risk reduction was similar in subcohorts of subjects, independent of age, gender and cognitive function, presence of cardiovascular disease, and diagnosis of Alzheimer’s dementia or Alzheimer’s mixed dementia. Moreover, this risk reduction was also similar in case–control cohorts that were matched based on all potential confounders. Confounders are factors that can alter results. According to the researchers, “The risk of both MI and death decreased with an increasing dose of ChEI.” More was shown to be better.

A Blog Comments on Galantamine’s Mortality Reduction

Unfortunately, the research that ceded the aforementioned Life Enhancement article, “Galantamine Cuts Mortality” has not yet been published. However, we have more on that topic from Prof. Dr. med. Gerhard Gründer’s blog:3


* See this article in the April 2013 issue of Life Enhancement.


Today I want to once again report from the 51st Congress of the American College of Neuropsychopharmacology (ACNP), 2nd–6th December 2012 in Hollywood, Florida, even though the Congress has already ended. The study was presented as a poster, but I believe it could have been also presented in the “Highlights” session, in which unfortunately the preclinical work dominated.


The risk reduction was similar in
subcohorts of subjects, independent
of age, gender and cognitive function,
presence of cardiovascular disease,
and diagnosis of Alzheimer’s dementia
or Alzheimer’s mixed dementia.


At least in Germany, acetylcholinesterase inhibitors still have the reputation of being of dubious benefit in patients with dementia of the Alzheimer’s type. It is widely believed that their effect is limited and is in no way proportionate to the adverse effects and costs.

But Prof. Gründer begs to differ. He relates that the study leader, Klaus Hager from the Center for Medicine in Old Age in the Diakonie Hospital Henriettenstiftung in Hannover, Germany,4 reported the results of a large multicenter double-blind placebo-controlled study in patients with mild to moderate Alzheimer’s dementia, who were treated with galantamine or placebo. This study, exceeding the usual treatment duration of six months, went on for two years (Prof. Gründer gave this an “!”). Also noteworthy, in his opinion, was the size of the study in which 2225 patients were screened and 2051 were randomized. Of these, more than 1000 patients in each group received the study drug.

Two-Thirds of the Patients Were Female

The Mini Mental State Examination (MMSE) score was 19.0 points at baseline in both groups (the mean age was 73 years in both groups and about two-thirds of the patients were female). The patients were treated with 16–24 mg galantamine daily. The primary efficacy endpoint was the change in MMSE score from baseline until month 24, a secondary efficacy endpoint was the change in the daily activities—as measured by the Disability Assessment in Dementia (DAD) scale from baseline to months 12 and 24. The primary safety endpoint was mortality.

Galantamine Superiority

After the two years, 339 patients treated with galantamine and 322 of the placebo-treated patients completed the study with two-thirds of the patients receiving the maximum dose of 24 mg galantamine, while only 3.4% received less than the targeted 16 mg. In those patients treated with galantamine, the MMSE score decreased by only 1.4 points, while the placebo group decreased by 2.1 points. This difference was highly significant. Also, with regard to the change in the DAD score, galantamine was significantly superior to placebo. After two years: placebo had a 10.8 point decrease, but galantamine had an 8.2 point decrease.

To Prof. Gründer, new in this study was the analysis of safety data with 56 deaths occurring (5.5%) in the placebo group and 33 deaths (3.2%) in the galantamine group. This difference was statistically significant demonstrating that mortality was reduced to almost half. Furthermore, the rate of adverse events in those treated with galantamine was only slightly higher than in the placebo group (54.0% vs. 48.6%). Serious adverse reactions were similarly frequent in those taking or not taking galantamine.

Prof. Gründer ends his blog posting with the notice that the Hager et al AChEI study is unique, showing for the first time that galantamine benefits cognitive performance and activities of daily living, while at the same time reducing the mortality from the disease. But what is the mechanism?

The Global Dilemma of Cardiovascular Disease

Worldwide, cardiovascular disease (CVD) is the leading cause of death. According to the World Health Organization, in 2008 12.6% of all deaths around the globe were caused by ischemic heart disease.5 The estimated global cost of CVD was $863 billion in 2010, and this cost is expected to rise by 22% in the next 20 years due to population aging.6 While CVD risk factors—including hypertension, hyperlipidemia, smoking, and diabetes—are well known and effective or somewhat effective drugs are available, the risk of cardiovascular death is about 5 times greater in individuals when at least two of these risk factors are present by 55 years of age, as compared to those with no risk factor.7 Consequently, any new drug or nutrient finding that reveals a new use is highly valuable, especially when it comes to reducing both heart attacks and death.

ChEI Study Details

Returning to the new research,1 the study cohort consisted of 7073 men and women with a mean age of 78.9 (range 41–99) years at baseline. Of these, 5159 (72.9%) received ChEIs at least once. The mean interval between the first and last time ChEI was given was 495 (range 0–2008) days. Compared with the rest of the cohort, these subjects were younger and female, had higher MMSE scores, and lived at home alone with no home care. In addition, fewer of these subjects had a history of CVD than those who had never been prescribed ChEIs.


The Hager et al AChEI study is
unique, showing for the
first time that galantamine
benefits cognitive performance and
activities of daily living, while
reducing the mortality from
dementia diseases.


In those prescribed ChEI at least once, 74 subjects suffered an MI and 427 subjects died during a mean follow-up period of 571 (range 0–2009) days. In the rest of the cohort (n = 1914), 42 subjects suffered an MI and 329 subjects died during a mean follow-up period of 392 (range 2–1333) days.

Confounders examined (and adjusted for) included the influences of age, gender, mixed dementia, MMSE score, living conditions, history of CVD and use of antidepressants, antihypertensive drugs, antidiabetics, and neuroleptics.

After adjustment for all confounders, subjects who used ChEIs had a 34% lower risk for MI or death during the follow-up than those who did not. Protective factors with respect to MI or death in these analyses included younger age, female gender, higher MMSE score, living at home without home care, absence of CVD and stroke, and no antihypertensive medication at baseline.

ChEI doses were categorized as low, moderate, or high. Using subjects who had never been prescribed ChEIs as the reference and adjusting for all confounders, the researchers found that the risk of the composite outcome of MI or death decreased with increasing ChEI dose, and those receiving the highest ChEI doses (donepezil 10 mg, rivastigmine 6 mg or more, galantamine 24 mg) had the lowest risk compared with the reference. The highest dose of ChEI was also associated with the highest risk reduction for MI and death, when evaluated separately, or MI in a cohort with previous CVD.

No Reduction in MIs or Death for Memantine

In a third set of analyses, the association between memantine, a selective NMDA-receptor antagonist, and the different outcomes was analyzed. After adjustment for all confounders, the use of memantine (n = 1747) was not associated with the composite outcome of MI or death, death, or MI when analyzed separately.

Even in the earliest analysis, the associations between ChEI use and the composite outcome of MI or death remained significant for subgroups according to different gender, age, CVD at baseline, use of hypertensive drugs, mixed dementia, Alzheimer’s dementia, and cognitive function. These associations were also similar in the subgroups for the outcome of death and MI when analyzed separately. Secondly, when ChEI use was analyzed in the matched case–control cohort it was was associated with a decreased risk for the composite outcome of MI or death, death, and MI. Finally, exclusion of all subjects that died within 90 days only slightly attenuated the associations between ChEI use and the composite outcome of MI or death, MI, or death in the total cohort after adjustment for all confounder.


ChEI treatment is not typically
considered in AD subjects with CVD.


Thirty-Five Percent Reduced Risk of MI or Death

In the current observational study, ChEI use was associated with 35% reduced risk of MI or death in a cohort of subjects with diagnosed AD. It is significant to note that this risk reduction was similar in subcohorts of subjects according to different age, gender and cognitive function, presence of CVD or not, and diagnosis of Alzheimer’s dementia or Alzheimer’s mixed dementia. This risk reduction was also similar in case-control cohorts that were matched based on all potential confounders.

Increased Dose Yields Greatest Reduced Risk

The risk of both MI and death decreased with higher doses of ChEI. To the researchers’ knowledge, no previous clinical study has connected the use of ChEIs to a reduced risk of CVD in general or MI in particular (perhaps the Hager et al study will show this). Nor has the incidence of MIs been reported in any high-quality randomized controlled trials with durations of at least 5 months investigating the effects of ChEIs in subjects with AD. This is probably owing to small numbers of participants and relatively short follow-up periods.

Of interest, the survival curve for MI or death in the present study seems to show that the treatment effects associated with ChEIs may appear in the early stages following onset use. This effect could be related to the possibility that ChEI treatment is not typically considered in AD subjects with CVD. Thus, adjustment for previous CVD examined a subcohort of subjects with known CVD at baseline. The risk reduction associated with ChEI use was similar in both cohorts, although the estimated treatment effects only reached statistical significance for the highest ChEI doses in the subcohort with previous CVD.


Critically ill patients are
not typically prescribed ChEIs at
the time of diagnosis.


Given that CVD is the major cause of death in Sweden and worldwide, the researchers also tested the hypothesis that ChEI use was related to a reduced risk of death in subjects with AD. Given that ChEI use was associated with a reduced risk of MI and death of 35%, these results should be carefully interpreted, given the risk that critically ill patients are not typically prescribed ChEIs at the time of diagnosis. Remember that the exclusion of subjects that died within 3 months only slightly attenuated the treatment effect results with respect to death.

The Possible Mechanisms

Regarding MIs, the treatment effect with respect to death increased with higher ChEI doses. The researchers could only speculate about the mechanisms of action underlying the cardiovascular effects found. Atherosclerosis, which underlies most MIs, is considered to be an inflammatory disease. Within atherosclerotic plaque, immune cells produce cytokines that decrease the stability of the plaque, increasing the risk of plaque rupture, and a subsequent MI. Therefore, the anti-inflammatory properties of ChEIs due to reduced acetylcholine breakdown is of interest. Treatment with ChEIs has been shown to reduce peripheral cytokine production in experimental studies and in humans.


The anti-inflammatory properties of
ChEIs due to reduced acetylcholine
breakdown is of interest and
may reduce MIs.


Side-effects of ChEIs include a beneficial effect on the vagus nerve, which controls the rate at which the heart beats. Some experimental studies have suggested that ChEIs could also possess cardiovascular regulatory properties. However, there are also other, and perhaps more likely mechanisms that may contribute to the associations found in the present study. In an experimental model in rats, vagal nerve stimulation after MI resulted in improved cardiac function and survival. Also, effects on the cardiac system from ChEI use could reduce oxygen demands, improve cardiac function, and thereby reduce the risk of MI and death.

Preventing MI and Death

In summary, ChEI use was found to be associated with reduced risks of MI, stroke, and death in subjects with AD, and more strongly so with higher ChEI doses.

As Prof. Nordström explained: “If you translate these reductions in risk into absolute figures, it means that for every 100,000 people with Alzheimer’s disease, there would be 180 fewer heart attacks—295 as opposed to 475—and 1125 fewer deaths from all causes—2000 versus 3125—every year among those taking ChEIs compared to those not using them.”8

Nordström also went on to say: “As far as we know, this is the first time that the use of ChEIs has been linked to a reduced risk of heart attacks and deaths from cardiovascular disease in general or from any cause. As this is an observational study, we cannot say that ChEI use is causing the reduction in risk, only that it is associated with a reduction. However, the strengths of the associations make them very interesting from the clinical point of view, although no clinical recommendations should be made on the basis of the results from our study. It would be of great value if a meta-analysis of previous, randomized controlled trials could be performed, as this might produce answers on which clinical recommendations could be based.”

A Stronger Reason for Supplementing with Galantamine

Not everyone who takes galantamine, does so because of dementia (including Alzheimer’s). Many take it as a preventive for memory decline. So it’s a great plus to know that it can also be beneficial for cardiovascular disease: a supplement for hearts and minds.

References

  1. Nordström P, Religa D, Wimo A, Winblad B, Eriksdotter M. The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer’s disease. Eur Heart J. 2013 Jun 4. [Epub ahead of print] PubMed PMID: 23735859.
  2. Alzheimer’s Disease Drugs Linked to Reduced Risk of Heart Attacks. Science Daily. June 5, 2013 [cited 21 June 2013]. Available from: http://www.sciencedaily.com/releases/2013/06/130605090257.htm.
  3. Gründer G. Mind and Brain Blog [Internet]. Aachen: Gerhart Grunder. 2012 Dec. 13 [cited 2013 June16]. Available from: http://www.mind-and-brain-blog.de/en/377/report-from-the-51-acnp-congress-iv-galantamin-reduces-mortality-in-alzheimers-dementia/.
  4. Hager K, Baseman AS, Han JH, Sano M, Richards HM. In a 2-Year Placebo-controlled Randomized Trial, Galantamine-treated Patients had Lower Mortality Rates and Slower Decline in Cognition and Activities of Daily Living. Neuropsychopharmacology. (2012) 38, S328. doi:10.1038/npp.2012.221 www.nature.com/npp/journal/v38/n1s/full/npp2012221a.html. Updated: December 5, 2012. Accessed: June 21, 2013.
  5. WHO. The 10 leading causes of death by broad income group. June 2011 [cited 20 June 2013]. Available from: http://www.who.int/mediacentre/factsheets/fs310/en/index.html.
  6. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD,Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA,Nichol G, Orenstein D, Wilson PW, Woo YJ. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123:933–44.
  7. Berry JD, Dyer A, Cai X, Garside DB, Ning H, Thomas A, Greenland P, Van Horn L, Tracy RP, Lloyd-Jones DM. Lifetime risks of cardiovascular disease. N Engl J Med. 2012;366:321–9.
  8. Nordqvist C. Alzheimer's Medications Lower Heart Attack And Death Risk. MediLexicon. Jun 3 2013 [cited Jun 20, 2013]. [Available from: http://www.medilexicon.com/medicalnews.php?newsid=261457.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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