Oral Xa inhibitors

Managing patients on warfarin therapy is an art.  There is a fine balance between achieving a supratherapeutic and subtherapeutic INR.  In addition to blindly making changes based on the INR reading, the practitioner must also take into account any changes in the patient's diet, missed doses, and any new medications among other considerations.  So far so Goude, right?

As previously covered in my entry on dabigatran, there is a demand for new oral anticoagulants that require less management and have less drug interactions than warfarin.  Dabigatran is a direct thrombin inhibitor, but there have also been a number of oral direct Xa inhibitors in development.

So where did the direct Xa inhibitors come from?  From heparin, which accelerates the inactivation of thrombin, Xa, and IXa.  Then came the low weight molecular heparins (enoxaparin, dalteparin, and tinzaparin).  The LWMHs are more selective for Xa, although they do have some anti-thrombin activity.  There is more grace with fondaparinux, which is a direct Xa inhibitor.  It is not reversible with protamine and it is specific for Xa inhibition.

Currently there are two Xa inhibitors in phase III trials in the U.S.: rivaroxaban and apixaban.

Rivaroxaban has already been approved in some European countries, but still has not been FDA approved.  For the criticism for the slow FDA approval process, I have only one thing to say: thalidomide.

Two of the major trials for rivaroxaban were the EINSTEIN and ROCKET-AF trials.  The EINSTEIN trial compared rivaroxaban to warfarin bridged by enoxaparin in the treatment of venous thromboembolism (VTE) and found that rivaroxaban prevented more events with no increased risk of bleed.  The ROCKET-AF compared rivaroxaban to warfarin for the prevention of VTE in patients with atrial fibrillation.  This trial has met the primary outcome, where rivaroxaban is non-inferior to warfarin, but superiority analyses have yet to be done.

A new multi-center RCT, AVERROES, was just published online in the New England Journal of Medicine comparing apixaban 5 mg BID to aspirin 81-324 mg in patients with atrial fibrillation that were unable to take warfarin.  Patients were followed for a year and the primary outcome was stroke or systemic embolism.

The trial was beautifully done and showed that apixaban reduced the risk of stroke or embolism in only a years time with no statistically significant increase in bleeding. 

On further inspection of the trial, I saw that 65% of patients taking aspirin were only taking 81 mg and about 26% were taking 162 mg.  I am more impressed that there was no associated increased risk of bleed compared to aspirin, rather than apixaban is more efficacious in stroke prevention than baby aspirin.

ARISTOTLE is an ongoing non-inferiority trial comparing apixaban to warfarin in patients with atrial fibrillation.  The results to this trial may offer more insight into apixaban than the AVERROES trial.

The ADVANCE trial(s) with apixaban were more impressive.  In this trial, apixaban was compared to enoxaparin for prophylaxis of VTE after a hip replacement.  Apixaban showed an absolute risk reduction of 2.5% with no increased risk of bleed.

Even if or when these drugs become FDA approved, it will take a lot more than FDA approval to replace warfarin.  Undoubtably the market is large; warfarin is difficult to manage, in some patients especially more than others.

Dabigatran, for example, still has a long way to go before it comes close to replacing warfarin.  Problems with dabigatran in clinical practice include high rates of dyspepsia, 30 day expiration, and high variability in absorption between patients.  Rivaroxaban has been shown to have a more predictable absorption between patients but it will be interesting to see what kinds of challenges for the medication may arise when/if it becomes available on the market.

One of the greatest questions with the new oral anticoagulants- dabigatran, rivaroxaban, and apixaban- is if they are more cost-effective than warfarin.  Are the costs of these medications off set by the decreased monitoring associated with them?

This is an exciting time for anticoagulation.  Unfortunately for now, we will just have to wait and see what happens.

This entry is also in reference to Jean-Paul Goude, whose work I have always admired, after being lucky enough to randomly buy his work "So far so Goude" at Club Monacco for $10... and it was worth every penny.


References:

Bauersachs R et al.  Oral rivaroxaban for symptomatic venous thromboembolism.  The New England Journal of Medicine 2010; 363:2499-2510.

O'Riordan M.  Off orbit? ROCKET-AF: rivaroxaban non-inferior to warfarin, but superiority analyses at odds.  The Heart 2010; available at http://www.theheart.org/article/1148785.do.  Accessed 02/23/2011.

Lassen MR et al.  Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.  New England Journal of Medicine 2010; 363(26):2487-2498.

Connolly SJ et al. Apixaban in patients with atrial fibrillation.  The New England Journal of Medicine; published online 02/10/2011.  Accessed 02/21/2011.

Images by Jean-Paul Goude

People in Gallup like...

These six weeks have been a whirlwind.  I now have, not only a job for next year, I have my dream job.  I showed up in New Mexico exactly five weeks ago and bought a car on my second day here.  I knew what I wanted and planned accordingly.  In the week leading up to the residency selection, I thought,

My god, Vishnu Shiva and Brahma.  What am I doing?  I bought a car.  I jumped through hoops to register it in New Mexico.  What am I going to do if I don't get this?

But I got it.  I'm moving back to Gallup in July.

People are people no matter where you go.  I've lived in the bay area, Boston, and soon Gallup, New Mexico.  Despite the differences in geography, not only are we all human, we are all American.  But there are some interesting differences of interests between places.

For example, people in Boston like cranberries, rotaries, shell-fish (including lobster), the Red Sox, saying "wicked", and mis-prounouncing words in general.

So far, I've noticed that people in New Mexico are all about keeping their headlights on at all hours, looking at rocks, talking about rocks, biking, potlucks, large belt buckles, and anything silver and turquoise.  There is also much more of a "do it yourself" attitude out here.  I'm not sure if that is only representative of pharmacists in New Mexico, but my coworkers all like to brew their own beer, grow their own vegetables and hops, sew, and one of the pharmacists even mentioned wanting to start making his own soap.

I told him not to go all fight club on me.

I have a lot to learn about the history here.  I ask my 65 year old roommate a lot of questions.  I'm not really sure what he does.  He seems to maybe do something with park maintenance and was a pilot for a long time.  Maybe he still is one.  He was also telling me about some of the Navajo customs through his eyes.

We talked about medicine men.  He told me that he had found a religious set up of children's shoes, toys, feathers and rocks over the hill above the school that was meant to put a hex on the kids at the Rehoboth school.

He says,

You know, they're white when its better to be white and they're Indian when that works out better for them.  They come off with all this crap about caring for the land but I tell you what Marie.  You go to the res and see what they're doing with their land.  And all the crap about land ownership... jeez.  It makes me laugh.  They certainly believe it now.

Disheartening.

Gallup is on the eastern border to the Navajo Nation.  The largest reservation in the United States.  I can't say that cultures collide because the Navajo are mostly westernized today.  But if you dig a little, you most likely will be able to find some animosity on both sides.  Had history been different, the Navajo would probably have assimilated into western culture on their own.  The difference is that they were forced to.

My roommate told me that Navajo comes from the word for "horse thief".  Long ago the nation had called themselves Dine.  The people.  According to wikipedia, "Navajo" comes from "tewa navahu" or "fields adjoining a ravine".  Whatever the meaning of the word, the tribe recognizes themselves as "Navajo" today.

The Navajo also believe that if a person has something that they are not using, it is ok to take it to make use of it.  They also believe that if no one sees you take it, it is not stealing.  There are no words for "sin" and "forgiveness".

The Navajo language is not progressive.  New words are not made for new concepts of things; rather other words are used to describe the concept or item.  When I hear many Navajo translating for their grandmothers, I also hear English words mixed in.  Which isn't surprising.

The Navajo seem to have a good sense of humor about language.  My other roommate (a 29 year old male working at the Christian school) said that the direct translation of the word for "cell phone" is something like, "that thing that makes you walk up the hill".  Cell phone service is poor on the reservation.

What a culture emphasizes becomes apparent once you begin to learn the language.  I think learning some Swahili helped me to gain a better understanding of the cultures in East Africa.

At the present, I know two words in Navajo and I pronounce them poorly.  I have my work cut out for me.

Fatty Liver Disease

I'm building better relationships with my coworkers, but right now its getting them to hang out with me on the weekends that is the trick.  I'm spending another Friday night inside and all this sitting around is making me think a lot about non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease, or NAFLD, is such a bizarre concept.  The disease is not fully understood and it tends to be highly under-diagnosed.  In the absence of viral hepatitis, alcohol and iron overload, high levels of triglycerides cause a build up of fatty deposits within the liver eventually leading to liver dysfunction.  A more specific, scientific definition would be macrovesicular hepatosteatosis occurring in the absence of alcohol consumption.  The estimated prevalence of the disease is anywhere from 15-33%.

NAFLD can lead to NASH can lead to cirrhosis of the liver.  The prevalence of NASH is between 5.7-17%.  NASH, or non-alcoholic steatohepatitis, is scarring and inflammation of the liver occurring secondary to large amounts of fat deposits in the liver.

As America gets bigger, so do obesity related complications and there have been increasingly more studies investigating the effects of obesity.  In more recent years, adipocytes (fat cells) have been more and more established as having endocrine functions, if not considered endocrine organs in and of themselves.  The cytokines and inflammatory mediators released from adipocytes are hypothesized to lead to NASH.  Adipocytes release leptin (causing fibrinogenesis), resistin (resulting in insulin resistance), angiotensin (vasoconstriction), TNF-alpha (death to hepatocytes and mitochondrial dysfunction), and decreased levels of adiponectin, which may be protective against insulin resistance.  Overgrowth of bacteria in the small intestines has also been implicated in the pathophysiology of NASH, but more research is needed.

Over 80% of patients with NAFLD meet the minimum criteria for metabolic syndrome and about 98% of NAFLD patients have insulin resistance.  In fact, NAFLD is becoming more established as the hepatic component of metabolic syndrome.

Metabolic syndrome is a disease state recognized by multiple organizations, but the definition may vary.  ATP III defines it as a patient meeting three of the five following criteria:  insulin resistance, elevated triglycerides, low HDL, hypertension, and/or a high waist circumference.  If you are really interested in diagnosing metabolic syndrome, feel free to reference the Grundy article at the end of this entry.  Waist circumference is used in place of BMI because visceral obesity is a better marker for obesity related complications and risk of NAFLD.  The metabolic syndrome diagnosis is a little bit edgy because each of the components need to be treated separately.  I like the concept because it gives recognition to obesity as a disease that affects many facets of the body but the diagnosis does not change how the patient would be treated.

Ok so let's get back to the liver.

Patients present with elevated aminotransferases not explained by the usual suspects.  They will often suffer from right upper quadrant discomfort, fatigue and malaise.  The physician may note hepatomegaly (enlarged liver), jaundice (caused by elevated bilirubin) and portal hypertension (caused when an inflamed and scarred liver impedes the flow of blood through the liver).

For the physician to make a diagnosis, he or she must first establish two things: that fatty liver disease is present and that it is unrelated to alcohol consumption.  The gold standard to establish the presence of fatty liver is a biopsy.  Realistically, biopsies are generally not the best option.  They are usually expensive and invasive.  They can potentially put the patient at risk of other complications.  A biopsy would only be performed if the results would change the course of treatment.  Otherwise, MRI, CT scan, and sonography can be used to show the presence of fatty liver.

Although non-alcoholic and alcoholic fatty liver disease may visually appear very similar, there are some major differences in presentation.  Aminotransferases are rarely highly elevated in the non-alcoholic disease; they are generally below 250 IU/L.  Additionally, the AST/ALT ratio in alcoholic liver disease is classically above 2.  In NAFLD, the ratio is less than 1.  Studies with NAFLD patients have excluded those with liver disease that could potentially be due to alcohol by excluding patients that consume greater than 2 drinks daily or greater than 4 drinks weekly.

The most common cause of mortality in patients with NAFLD is cardiovascular disease.  Patients with NASH are twice as likely to die of cardiovascular causes as the general population and NAFLD is being established as a CV risk factor independent of diabetes, hypertension, and hyperlipidemia.  A recent study published in the New England Journal of Medicine in 2010 provides a wonderful overview of cardiovascular considerations in patients with NAFLD.

Liver dysfunction is also a common complication of NAFLD, guessing that doesn't take rocket science.  About 15-25% of patients with NASH will progress to cirrhosis. The 10 year mortality for patients with cirrhosis secondary to NASH is about 30-40%.

www.nataliedee.com

The only treatment that has shown major benefit is weight loss.  Patients need to decrease fructose, carbohydrates, and saturated fats in their diets.  Moderate to high intensity excercise should also be emphasized for 30 minutes 3-5 times per week.  There have also been studies investigating sibutramine and orlistat in NAFLD.  Sibutramine caused a decrease in LFTs, but it is no longer on the market due to an increase in CV events.  As cardiovascular mortality is the greatest risk associated with NAFLD, the potential decrease in LFTs hardly seems worth the risk.  Orlistat did not show benefit in the trials that I investigated.  So patients, you are on your own.

www.toothpastefordinner.com

Patients also need to take care to avoid other medications or external factors that could further damage their liver.  Alcohol in any portion size is not recommended for patients with NAFLD, even though the disease was not caused by alcohol initially.

Vitamin E has been investigated in some trials.  Its anti-oxidant properties have been hypothesized to be beneficial in preventing further disease progression.  A daily dose of the RDA of vitamin E has very little risk of harm so could be recommended.  It is possible that other anti-oxidants, like vitamin C, may also be beneficial.

I previously mentioned that 98% of patients with NAFLD are also insulin resistant.  The pathophysiology of NAFLD has been closely linked to that of insulin resistance, therefore it was hypothesized that insulin sensitizing medications would also improve liver function.

Metformin.  The gold standard of care in type II diabetes unless you have an elevated serum creatine or don't like diarrhea.  The only available biguanide.  Early studies with smaller sample sizes showed benefit but later meta-analyses showed that there was no improvement in liver function tests with the use of metformin.  As type II diabetes is a common co-morbidity in this patient population, it still may be beneficial to many of the patients, but as a anti-hyperglycemic, not as a medication that would decrease liver damage.

Thiazolidinediones.  After six years of pharmacy school I am proud to say that I can actually pronounce the name of this medication class.  Through lies and bullshit of the pharmaceutical companies, the FDA has voted to keep GlaxoSmith Kline's rosiglitazone, Avandia, on the market.  Rosiglitazone did show benefit in reduction of LFTs in NAFLD along with pioglitazone, Actos.  However, rosiglitazone is associated with an increased risk of myocardial infarctions (heart attacks) and strokes.  I would never in a million years recommend rosiglitazone for any patient and it is insulting to patients and providers that the FDA allows it to stay on the market.

Pioglitazone came out with early mortality benefit data but it causes edema that can exacerbate heart failure and there has also been an increased risk of myocardial infarction associated with it.  I could say a lot more about the thiazolidinediones, cardiovascular disease and NAFLD, but I will conclude by saying that I would consider use of pioglitazone in patient with NAFLD.

The only thing left to do for patients with NAFLD is to monitor and treat other risk factors for cardiovascular disease.

The use of statins in this patient population has been somewhat controversial.  Most statins pass through the liver and can potentially cause increases in LFTs.  However, the beneficial modification of the lipid profile and decreased inflammation in the blood vessels has been hypothesized to be beneficial to liver disease caused by NAFL.  Although studies have not shown an improvement in liver function, they have shown that statins are safe and efficacious in reduction of LDL in these patients.  I would still recommend pravastatin or rosuvastatin which are more renal than other statins.

Angiotensin is implicated in the pathophysiology of NAFLD and NASH.  ACE inhibitors and angiotensin receptor blockers may be able to play a role in this disease state other than just causing blood pressure reduction.  I looked at a few small studies using losartan in patients with NAFLD.  Although the trials showed benefit, the sample sizes were very small and more trials are needed to prove a benefit.  I also would probably first consider an ACE inhibitor, for cost reasons only, even though no trials to my knowledge have been conducted in this patient population.

I really enjoyed reading about NAFLD and NASH, but unfortunately, the best advise a practitioner can give to the patient is to lose weight through diet and exercise and to decrease their other risk factors for cardiovascular disease.

References:

Ramesh S et al.  Evaluation and management of non-alcoholic steatohepatitis.  Journal of Hepatology 2005; 42:S2-S12.

American Gastroenterological Association medical position statement: nonalcoholic fatty liver disease.  Gastroenterology 2002; 123:1702-1704.

McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis.  Journal of Clinical Gastroenterology 2006; 40:S17-S29.

Grundy SM et al.  Diagnosis and management of metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.  Circulation 2005; 112:2735-2752.

Targher G et al.  Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.  New England Journal of Medicine 2010; 363(14):1341-1350.

Promrat K et al.  Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.  Hepatology 2010; 51:121-129.

Sabuncu T et al.  The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis.  Romanian Journal of Gastroenterology 2003; 12(3):189-192.

Harrison SA.  Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial.  Hepatology 2009; 49:80-86.

Rakoski MO et al.  Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis.  Alimentary Pharmacology and Therapeutics 2010; 32:1211-1221.

Schernthaner G et al.  Cardiovascular risk and thiazolidinediones- what do meta-analyses really tell us? Diabetes, Obesity and Metabolism 2010;12:1023-1035.

Ratziu V et al.  Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues.  Hepatology 2010; 52(6):2206-2215.

Shields WW et al.  The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial.  Therapeutic Advances in Gastroenterology 2009; 2(3):157-163.

Yokohama S et al.  Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatits.  Hepatology 2004; 40(5):1222-1225.

Yeah Yeah New Mexico.

Its a mad house.  This modern life.


Its a mad house.  My faithless bride.


Art Star.

My god Karen O is just the best.  I recently went through another blog that had written praise about her saying she was great because her wardrobe, stage presence, and that she didn’t care about being beautiful.  I have disagree with the last statement.  It's not that she cares or doesn’t care about being beautiful.  She just is.  She knows she’s  awesome and grooves to her own tune.  I love Karen.

I drove through the Hopi/Navajo reservation to Tuba City today.  Vast open spaces.  Beautiful.  So all my interviews are done.  All I need is a job.

I was flipping through radio stations and found a native religious chanting station.  Probably Hopi.  Maybe Navajo.  Awesome.  

Even the concept of the reservation is strange.  I was talking with some of the physicians at lunch yesterday about culture and socio-economic problems of our patients.  Many of the problems mirrored the troubles of the Maasai.  There’s no work on the reservation, but people are encouraged to stay there because they get money from the government.  Unemployment is 65%.  Unheard of.

I also heard at Ft. Defiance that only 20% go away to college (ok this isn’t terrible I thought) but then only 5% of Native Americans (or just Navajo? not sure) will actually graduate.  I asked why.  My potential preceptor replied that it was geography.  For people that have lived their life only on the reservation, whose entire religion revolves around living between 4 mountain peaks, how are they able to finish college?  It is culture shock.

Was it the cure?

Hope not.

The physicians were also talking about differences in the Navajo between generations.  The older generation still has a stronger work ethic.  They wake up early to take care of the land, take care of the cattle.  The physicians opinion was that the younger generation tended to mooch off the elders.  

From what I have seen, it is very common for the grandparents to take care of their grandchildren.  There is a lot of teen pregnancy.  I can’t say right now if this has always been the case and is cultural, or if there has been a rise in teen pregnancy in the past 20-30 years.  Yesterday I counseled a girl who had come in with a toddler on her antibiotic.  She was born in 1992.  She was 18.  I didn’t ask if the child was hers.  I wouldn’t have been surprised.

In addition to the grandchild connection, through the grapevine I heard that it wasn’t uncommon for the children/grandchildren to take grandma’s check from the government every month.  This creates problems because when grandma’s meds go missing, it is GIMC policy that we can’t replace them, but we can call a script into Walmart.  Grandma replies that she can’t afford the $4 co-pay because her kids took her money.

They probably also took her pills, a doctor replied. 

The Navajo are historically not a social bunch.  Other tribes will live together in a common area with the land surrounding them.  The Navajo space themselves out around the land.  While ties to other members of their tribe may not be as strong, they have very close ties with their family members.

I heard one of my potential preceptors remarking that it was comical to hear the technicians asking for time off because some 3rd cousin was sick.  Only immediate family members.  In America, only your nuclear family matters.  

I can imagine that along with the close family ties comes the concept of what is mine is my children’s.  At the moment, I would prefer to think that children are not maliciously stealing grandma’s check from the government, but that grandma is offering it up freely.  What is hers is also theirs.

no fame

all there is 

all there was

Before my interview, I received a tour of the facilities at Tuba.  We passed through the ICU.  I asked the most common reason of admission to the ICU.

Honestly

my future preceptor replied

The Navajo have some strange beliefs about death.  It is taboo.  They don't talk about it.  They don't want to hear about it.  If someone dies, they have to burn the entire house down and rebuild.

The most common reason for people to come into the ICU is to die.

Sometimes I feel like we are more of a nursing home than anything else.  It is much easier for them to drop grandma and grandpa off here on their death bed than to have to destroy their home and rebuild. 

I thought that this was strange.  A few other people had told me of this custom of the Navajo, but in my experience, it is generally the westerner that considers death taboo and is unable to discuss it.  I wonder where this belief came from.

Modern things don’t die just stain

Try me out, find what I’m all about

and we can make some noise not like the other boys

I've also been wondering about the water quality on the reservations.  Most of my patients say they rarely drink water.  I don't know if it is in their best interest to recommend drinking more.  The taste of the water in Gallup is questionable; I can't imagine what it is like on the reservation.

Should I tell them to boil their water?  It makes no sense to suggest buying it.  

We were also talking about drug induced nephrolithiasis on Friday over lunch.  My conclusion is that the patient in question was more likely just dehydrated.  Drugs can cause kidney stones through either decreasing excretion of calcium or purine metabolism, or if the drug itself or its metabolite are renally excreted but poorly soluble.


Triamterene, sulfonamides, and indinavir are big offenders of being renally excreted but easily crystalizing in the renal tubules.


Carbonic anhydrase inhibitors, like acetazolamide, encourage formation of calcium crystals in the kidney.  Incidence of stones is up to 10%.  Topiramate and zonisamide, anti-epileptics also under other indications, also function as carbonic anhydrase inhibitors.

And baby I'm afraid of a lot of things

But I ain't scared of loving you.

Because all I see

is what's in front of me

and that's you.






for more information on drug induced nephrolithiasis, check out...

Daudon M et al.  Drug-induced renal calculi: epidemiology, prevention and management.  Drugs 2004; 64(3):245-275.

Matlaga BR et al.  Drug-induced urinary calculi.  Reviews in Urology 2003; 5(4):227-231.