Sunday, January 13, 2008

Is Your Aspirin Resisting You?

Like most of you I take aspirin daily, 325mg. Even traditional cardiologists recommend aspirin for heart disease sufferers. Aspirin works by interfering with the generation of thromboxane A2 (TXA2) which is needed for platelet aggregation (clotting). The COX-1 enzyme acts on arachidonic acid (AA) to produce endoperoxides that in turn produce TXA2 . Aspirin interferes with the generation of TXA2 by irreversably acetylating the platelet COX-1 enzyme thereby blocking its access to AA. Because platelets are anucleate, they cannot generate additional COX-1. In the absence of TXA2, platelet aggregation does not occur. Got all that?!

Most practitioners prescribe anywhere from 81mg to 325mg. Studies such as CURE suggest 81mg is optimal. The ISIS-2 study puts the dose at 162mg (for recent heart attack sufferers) and, frankly, since aspirin is so cheap, many (like me) simply make the leap to "more must be better." Ahh, but there are downsides to higher dose aspirin, among them bleeding and stomach problems (me again). But there is another dosing consideration, aspirin resistance, a reduced response to aspirin that one study suggests affects 27% of the general population.

Once again, like many of you, I am also a Track Your Plaque convert (see my early posts and disclaimers). As a numbers geek it appeals to me to have hard data to track and make intelligent decisions about controlling my heart disease. So the question those like me have is, "Is there any way to determine if I am aspirin resistant and if so, how resistant am I and how much aspirin do I need to take?" The biggest problem is that there is currently NO clinically valid definition or measurement of "aspirin resistance". However, here is the latest on available tests to provide some answers.

The PFA-100 is US Food and Drug Administration (FDA)-approved to detect platelet dysfunction, von Willebrand disease, and aspirin-induced platelet inhibition. The instrument measures collagen-induced platelet plug formation as time in seconds to occlude an aperture. Its sensitivity as a screen for platelet dysfunction is approximately 95%.

The VerifyNow Aspirin Assay is FDA-approved for detection of aspirin-dependent platelet aggregation. Its sensitivity as a screen for aspirin-induced platelet dysfunction is approximately 91%.

PlateletWorks is FDA-approved to detect platelet dysfunction due to inhibition secondary to diet, aspirin, and/or other drugs. PlateletWorks has limitations. There is a very short time allowed -- 10 minutes -- between sample collection and assay. Also, there may be unacceptably high false-positive rate because of interference by dietary substances such as chocolate and red wine.

AspirinWorks is FDA-approved to provide a quantitative measurement of aspirin-induced inhibition of TXA2 generation from a urine sample. Results are ranged in quartiles with different quartiles represent differing degrees of risk for heart attack. A patient whose results are in the first quartile has a relative risk 1 (average). A patient whose results are in the second quartile has a 1.3 times greater risk of heart attack than a patient in the first quartile. A patient whose results are in the third quartile has a 1.5 times greater risk, and a patient in the fourth quartile has twice the risk. As with many lipid tests, there are still problems to work out in comparing results based on different assay methods.

The bottom-line is there is no perfect way to determine to what degree you are aspirin resistant but the technology is improving. However, if you are looking for some way to put a hard number on where you stand there are several interesting tests available. For now, I simply take the high-end of the dose range until my tummy starts to hurt then take a break or reduce my dose.

Regards,


HeartHawk

12 comments:

g said...

Hey HH,
(I apologize -- your phrase is Track, Jack, Smack... I keep screwin that up)

Do you have upset stomach often? I'm not a physician but did you consider having an endoscopy or evaluation for H. pylori (a bacterium that can colonize and inflame the stomach/duodenum lining)? I'm really into this because I teach the heartburn/ulcer lectures at a pharmacy school (doctoral candidates).

I think that there is some great evidence now that high dose fish oil can help ameliorate colon/stomach issues by sealing up and improving the junctions of the colon/stomach lining. Fish oil also has great anti-inflammatory properties. In the brain, in fact, it increases ACh (acetylcholine) which improves mood, reduces stress, and makes people feel more calm (like yoga and exercise). If you take high dose fish oil it make take 2-4 wks to start noticing improvement; don't give up. if you have a fishy burp/gas, store the oil in the freezer to stabilize (it will still work). GOOD LUCK, g

Food Chem Toxicol. 1995 Jul;33(7):553-8. Links
Effect of acute administration of fish oil (omega-3 marine triglyceride) on gastric ulceration and secretion induced by various ulcerogenic and necrotizing agents in rats.
The fish oil commercially known as Marine-25 (omega-3 marine triglyceride) is an eicosapentaenoic acid (EPA)-rich oil. It was investigated for its ability to inhibit gastric secretion and to protect the gastric mucosa against the injuries caused by pyloric ligation, non-steroidal anti-inflammatory drugs (NSAIDs--aspirin and indomethacin), reserpine, hypothermic restraint stress and necrotizing agents [0.6 M HCl 0.2 M NaOH or 80% (v/v) aqueous ethanol]. The results showed that the fish oil, at a dose of 5 or 10 ml/kg body weight, provided significant protection in the various experimental models used. It produced a significant inhibition of gastric mucosal damage induced by pyloric ligation, NSAIDs, reserpine or hypothermic restraint ulcers. Fish oil also exerted a significant inhibitory action on gastric mucosal lesions produced by various necrotizing agents. Our findings show that fish oil rich in eicosapentaenoic acid possesses both antisecretory and antiulcerogenic effects. PMID: 7628790

Effect of fish oil on offensive and defensive factors in gastric ulceration in rats. Prostaglandins Leukot Essent Fatty Acids. 2006 Feb;74(2):109-16. PMID: 16352428

Effect of polyunsaturated fatty acids on dexamethasone-induced gastric mucosal damage.
Prostaglandins Leukot Essent Fatty Acids. 2000 Feb;62(2):85-96.
PMID: 10780873 (dexameth is like STRESS)

Aliment Pharmacol Ther. 2001 Jun;15(6):851-5. PMID: 11380323
Ukr Biokhim Zh. 2003 Jan-Feb;75(1):72-7. PMID: 14574741
Eur J Pharmacol. 2007 Jun 1;563(1-3):216-23. Epub 2007 Feb 8.
PMID: 17374531

HeartHawk said...

Dear G:

In answer to your questions I have done it all. The scope (from both ends) showed only mild and diffused gastritis. Later on I did test positive for H. Pylori (after an Emergency Room admission) and took the "Pylera" course of antibiotics. So far so good since then but I have also stopped taking Niaspan in favor of fenofibrate as it seems to have a stronger effect on my Lipoprotein(a). My lipids are still pretty good because I also take Crestor and Zetia (but don't get me started on muscle aches). Of course, I choke down fish oil as well!

Regards,

HH

g said...

Hi HH,

YYYEESS, I GAG twice a day on my fish oil too... (but I guess that's better then choking on tablespoonfuls of oil!)

My experience is that the gastritis may take 4-8wks to improve after H. pylori eradication. you're on an acid blocker right? For symptom control and optimal healing, we often use Famotidine in the AM and bedtime, and Omeprazole twice daily (noon and dinner) (take 'em 30min prior to meals)

Are you on a high dose of fish oil (like 3000 mg DHA+EPA or more)? It may not hurt... AND fish oil actually lowers Lp(a) if you take a high enough dose; did you know? The only side effects of fish oil are better skin, mood, less Alzheimers and reduction of sudden MI death. Some cardiology (and neuropsych) experts believe we have a O3-fatty acid deficiency. I would agree. where do we generate electricity in the body? if you had to choose betw a modem or high speed for your internet, which would you choose? Well, your heart and brain want high speed TOO! In nature, the longest strongest 'cables' for voltage conduction are omega-3 fatty acids. and if our organs don't have adequate conductivity, the signals and messages get 'dropped'. (it's like vit D3 deficiency -- we lived 40 Million yrs in broad daylight and eating loads of fish... and now we're all deficient in both). just something to ponder...

Sorry about the Niacin... it does wreak havoc on the stomach lining for some people... (and may cause gout too).

Do you really like Crestor? I get worried about the kidney effects as you probably know :)

I didn't know Fenofibrate lowers Lp(a) (though it makes perfect sense) - wow, that's great!

hope you feel better soon!! g

HeartHawk said...

Dear G:

I take 4000mg daily of fish oil. I like the Crestor because I can get away with 5mg daily since I get muscle aches (also take 200mg CoQ10). Regarding the fibrate I don't have much data other than my blood work. Once before I took Tricor while I went off Niaspan and noticed my Lp(a) dropped 30nmol/l. Could have just been a normal variation but it did not go up after I stopped Niaspan nor did my other lipids go haywire. So far my ALT/AST are OK with only a slight elevation in the AST.

Regards,

HH

Diane J Standiford said...

Hi, I am starting a 100 Chronic Illness Blogs list for my blog site, may I add your blog?
email me stellarlife@yahoo.com

http://dj-astellarlife.blogspot.com/

Diane J Standiford said...

I'm upping my fish oil, goes down fine; and I take lots of aspirin, as does my mother and 101yr old aunt, never any stomach isues---genes. I was afraid to increase the fish oil, but since you seem ok...I SHALL FIND NEMO!

g said...

Hi,

Did you know that tetracycline (like Doxy) is also an MMP9 inhibitor? Pylera has tetracycline in it. Doxy and Tetracycline are in the same drug class.

I had heart burn/chest pain once with Doxy (I took it for acne -- it didn't work)... make sure you don't lie down afterwards for 2-4hrs! They're drugs which may burn a hole through mucus membranes and tissues.

http://www.ncbi.nlm.nih.gov/pubmed/18221118?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Mol Cell Biochem. 2004 Sep;264(1-2):183-91. Links
Expression of matrix metalloproteinase activity in idiopathic dilated cardiomyopathy: a marker of cardiac dilatation.
BACKGROUND: Idiopathic dilated cardiomyopathy (DCM), ventricular systolic dysfunction and chamber dilatation are accompanied by architectural remodeling, wall thinning and cardiac myocyte slippage. Recent work has demonstrated an association between collagen degradation and an increased expression of matrix metalloproteinases (MMPs). Accordingly, we have sought to correlate (a) collagen degradation with MMP elevations and, (b) assay the neutralizing potential of a known inhibitor of MMP, tetracycline on MMPs in DCM. METHODS: Assessment of LV volume and shape by 2-D echocardiography was performed. Light microscopic assessment of histopathology in picrosirius red stained biopsy samples of 11 DCM patients and six post-transplant patients was performed. Zymographic estimation of MMP activity and influence of tetracycline on MMP activity was assessed. RESULTS: Small amount of interstitial collagen was noted in the control group, whereas in the DCM hearts, chamber dilatation was associated with areas of scanty myocyte necrosis, islands of excess collagen, and focal areas of absent or scanty collagen with intact myocytes. In cardiomyopathic tissue, collagenase activity was markedly elevated at 63% compared with 8% in post-transplant tissue. Tetracycline at a concentration of 285+/-10 microM (IC50) inhibited collagenase activity by 50% in cardiomyopathic tissue. CONCLUSIONS: Areas of focal interstitial collagen accumulation were accompanied by collagen fiber lysis and increased collagenase activity in dilated cardiomyopathy. This enhanced collagenolytic activity found in endomyocardial biopsy tissue was inhibited by tetracycline. The non-antibiotic property of tetracycline may be of potential value in the prevention of ventricular dilatation in idiopathic dilated cardiomyopathy.
PMID: 15544047

-g

HeartHawk said...

Dear g:

Yup, doxy is in the tetracycline family. A funny characteristic of using Doxycycline is that the anti-MMP effect is durable meaning it lasts well after you stop taking doxy. I have talked to Dr. Davis about it and neither of us is certain as to why, it's just what the studies show.

Regards,

HH

g said...

HH,

Are the effects on Lp(a) durable as well, I wonder. There is a link betw Lp(a) and MMP. MMP-12 seems to cleave apo(a). You seem to be figuring out what scientists aren't even aware of. Somehow they are linked... (b/c Both Lp(a) and MMPs seem involved in vascular remodeling in chronically inflamed subpops like T2DMs)

You and Dr. Davis remind me of another dynamic duo... but you guys are fightin evil MMP-marauders, on the edge of science! See you later Robin, g

http://www.jbc.org/cgi/content/full/274/15/10019

Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in diabetic and healthy subjects.Diabetes Metab. 2007 Apr;33(2):129-34. Epub 2007 Feb 22. PMID: 17320450

HeartHawk said...

g:

TO THE BATCAVE! Interesting find on MMP and Lp(a)!

Thanks,

HH

g said...

Yes!! you guys are my SUPER HEROES! :) *ha haa*

g said...

Dude,
This is about your stomach... again...
In Atkins Advantage, they advise L-glutamine (LGN) supplement for stomach intolerances (and controlling hunger/carb-cravings). Glutamine has a role in wound healing (probably ulcers I believe,??) and improving nutritonal status. Here's a link about this protein's immunemodulating benefits (LGN is an amino acid, like L-arginine). The dose advised orally was 500-1000mg an hour prior to meals. It's found in food (beef, chicken, beans, dairy) but hard to get in sufficient quantities for therapeutic benefits (like L-arg).
-g

Curr Opin Anaesthesiol. 2006 Apr;19(2):132-9. Nutrients with immune-modulating effects: what role should they play in the intensive care unit?Ali S, Roberts PR.

PURPOSE OF REVIEW: This review will summarize recent clinical and experimental data on the use of immune-modulating nutrients in critical illness. It will present the concept of these nutrients as pharmacologic agents or 'nutraceuticals' administered in addition to protein, calorie, vitamin, and trace element sources. RECENT FINDINGS: Studies have defined the physiologic roles of arginine in critical illness, such as its role as a precursor for the production of nitric oxide. Investigations have determined that, in critical illness, glutamine levels decrease and severe glutamine deficiency is associated with increased mortality. Experimental studies have revealed that glutamine attenuates proinflammatory cytokine responses, improves gut barrier and immune cell functions, increases the ability to mount a stress response, and decreases mortality. Clinical trials and meta-analyses of studies testing immune-modulating nutritional formulations have reported numerous benefits but also some conflicting results. Dose and route of administration are key factors that influence the benefit, or lack thereof, of these nutraceuticals. SUMMARY: Cumulative studies of enteral immune-modulating nutritional formulations report benefits in surgical critically ill patients such as burn, trauma, or gastrointestinal surgery populations. Conflicting data in patients with sepsis warrant concern and further evaluation; in particular, controversy seems to stem around the use of arginine. Glutamine is beneficial when given in high doses or via the parenteral route (>0.20-0.30 g/kg per day or >or=30 g/day). Providing both omega-3 and omega-6 polyunsaturated fatty acids is important in immune modulation. The best doses and combinations of immune-modulating components remain unclear.
PMID: 16552219

 
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