How Doctors Die by Ken Murray a FP at USC.  

It is largely anecdotal, but is a really an interesting perspective on how at least some physicians choose to forgo futile end-of-life treatments because they know the limits of modern medicine first hand.

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Octogenerian’s Letter to Santa

I want to weigh in briefly on all the headline news on the review in the online Archives of Internal Medicine about the increased incidence of type 2 diabetes in older women taking statins.  In this analysis of the data from the Women’s Health Initiative an increase of about 50% in the incidence of new cases of diabetes was found in women taking a statin when compared to women not taking a statin.  At first glance this sounds terrible.  Giving people at high risk of cardiovascular disease a drug that increases their risk of developing diabetes when the leading cause of death in diabetic patients is cardiovascular disease may seem odd.

For me this is really a call to reason.  I hear jokes about putting statins in the water supply as if they are a magic medication that patients really need a reason not to take.  The bulk of the evidence is clear that statins are indeed a terrific class of medications. In patients with cardiovascular disease, and in patients at high risk of cardiovascular disease, statins have proven to reduce rates of death and cardiac events like heart attack and stroke in study after study.  Still, even drugs with all the positive outcome data of the statins is not without risk.  The potential for statin side effects especially myalgia are well-known. Now we can probably add an increased risk of developing diabetes to the long-term statin risks.

I suspect that when the dust settles on this issue we are going to continue to encourage the use of statins for patients with elevated LDL cholesterol when their whole profile of risks (looking at other factors like smoking, blood pressure and diabetes in addition to just their LDL cholesterol) puts them at high risk.  I also suspect that we will become more circumspect about advising statins for patients with moderately high cholesterol and few other risks.

It looks like our water supplies are safe from added statins for the time being.  We can probably add an increased risk of type 2 diabetes to the list of statin side effects.

See also:  Simvastatin vs. Lipitor and Any Advantages or is Livalo Just One More Statin?

Click on this Image to Go to the Million Hearts Site Now!

• A= Aspirin for those people at high risk. This generally means adults with high blood pressure, diabetes, any type of vascular disease like peripheral vascular disease, coronary disease, carotid disease etc, smokers, people with high cholesterol or high blood pressure, and those with a strong family history of heart attack or stroke.
• B= Blood Pressure Control: Sounds obvious, but less than half of Americans with high blood pressure have it adequately controlled. Don’t settle for suboptimal blood pressure control. Work with your doctor to do what it takes to gain control. Also focus on the non-medication things you can do like salt restriction, weight loss and more exercise.
• C= Cholesterol management: Goals vary for different people, but ask your physician what your goal cholesterol should be, and if needed use medication plus diet to get to that goal.
• S= Smoking Cessation: If you smoke quitting is probably the number one thing you can do to reduce your chances of a heart attack or stroke. People always correlate smoking with cancer and lung disease, but the leading way smoking kills is from cardiovascular diseases like heart attacks and stroke. Do whatever it takes to find a way to quit.
So this year give the most precious gift of all, yourself through improved health and longer life, to your loved ones.

Add Some Red to Black Friday and I’ll give some Green to the American Cancer Society

Millions of Americans shop for Christmas gift bargains on Black Friday every year.  I encourage you to give a gift on Black Friday that costs you nothing more that a little time, and which can help you feel you have truly given life and hope during this holiday season.

My readers will know that I’m a big proponent of regular blood donations.  Kay, my wife has ovarian cancer and has been a recipient of donated blood when her blood counts get low from chemotherapy.  Cancer patients are among the highest users of donated blood products from red blood cells to platelets.  I’m donating regularly to be sure our family puts more blood into the blood banking system than we take out. I want you to join with me on the Friday after Thanksgiving this year by paying a visit to your local blood donation center.  There are even potential blood donation health benefits.

I’m putting out a challenge to readers, your friends and anyone else you can contact.  Black Friday is a day when many of us are out and about shopping and getting ready for the holidays.  The holiday season is also a time when blood donations tend to fall behind need.  Here is the challenge:

I’ll donate $1. (up to $1000) for every comment to this post or tweet me @DoctorPullen telling me that you have or intend to go to your local blood donation center on Black Friday and donate blood. $1. may sound like chump change, but I want to get 1000+ people who would otherwise not donate blood to do so this Friday.  We are in a world of easy communication, and I bet everyone who reads this knows 10 people who are in a position to get to their blood donation center this black Friday and donate.  Just do it!

Take a break from shopping, get off your feet, and relax while you give one special holiday gift.  Use the twitter or facebook links to send this off to your friends, tell your coworkers, shout from the roof tops, whatever but let’s make this Black Friday blood red with our generosity.

My daughter, son and I plan to go to the local Cascade Regional Blood Bank center in Puyallup Friday. I checked and they are open 7:30 AM – 5:00PM.  I’ll try to keep a counter going on the site to let you all know how we are doing.

They Turned Me Away Today

Egg on my face.  I went today to donate, but was turned away because I went to Belize on vacation a couple of months age, an area with malaria exposure potential.  I’m now ineligible for a year, joining a majority of the rest of Americans.  If you are among the 37% who are eligible donors get to your blood donation center and give.  Keep our blood supply safe and plentiful.  Happy Thanksgiving.

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Actual Causes of Death in the U.S.: Not What You’d Think

Leading Preventable Cause of Death in America

An argument can be made that knowing when not to do screening for a disease or condition is as important as knowing when to do screening.  The USPSTF makes recommendations to physicians and patients about what screening preventative services should be done in asymptomatic patients, and which should not be done routinely. The USPSTF is an evidence based decision making body. They carefully review the evidence and make recommendations for or against screening based solely on the available evidence which helps keep emotional and arbitrary recommendations from becoming the mandate. The recommendations are separated into 5 grades:

• A Recommendation: The USPSTF recommends the service. There is high certainty that the net benefit is substantial.
• B Recommendation: The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.
• C Recommendation: The USPSTF recommends against routinely providing the service. There may be considerations that support providing the service in an individual patient. There is at least moderate certainty that the net benefit is small.
• D Recommendation: The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.
• I Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

I thought it was timely to list a few of the screening services that the USPSTF recommends against, or finds insufficient evidence to make a recommendation for or against. This list is not intended to be comprehensive. See the USPSTF site for a complete list of their screening recommendations.
Cancer Screening Recommendations:

• The USPSTF recommends against routine testicular cancer screening in adolescent and adult males. D recommendation.
• The USPSTF recommends against routine ovarian cancer screening. D recommendation.
• The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using a whole-body skin examination by a primary care clinician or patient skin self-examination for the early detection of cutaneous melanoma, basal cell cancer, or squamous cell skin cancer in the adult general population. I recommendation.
• The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of prostate cancer screening in men younger than age 75 years. I Recommendation.
• The USPSTF recommends against screening for prostate cancer in men age 75 years or older.  Grade: D Recommendation.
• The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for bladder cancer in asymptomatic adults.  Grade: I Statement.

Heart and Vascular Disease Recommendations:

• The U.S. Preventive Services Task Force (USPSTF) recommends against screening for asymptomatic carotid artery stenosis (CAS) in the general adult population.  Grade: D Recommendation.
• The U.S. Preventive Services Task Force (USPSTF) recommends against routine screening with resting electrocardiography (ECG), exercise treadmill test (ETT), or electron-beam computerized tomography (EBCT) scanning for coronary calcium for either the presence of severe coronary artery stenosis (CAS) or the prediction of coronary heart disease (CHD) events in adults at low risk for CHD events.  Grade: D Recommendation.
• The USPSTF found insufficient evidence to recommend for or against routine screening with ECG, ETT, or EBCT scanning for coronary calcium for either the presence of severe CAS or the prediction of CHD events in adults at increased risk for CHD events.  Grade: I Statement

Other Recommendations:

• The U.S. Preventive Services Task Force (USPSTF) found insufficient evidence to recommend for or against screening adults for glaucoma. I recommendation.
• The USPSTF recommends against screening adults for chronic obstructive pulmonary disease (COPD) using spirometry. D Recommendation

These recommendations are for screening in asymptomatic persons. They are not recommendations against testing for a disease in the presence or symptoms or other factors where making a diagnosis may alter management decisions.
At first glance these recommendations  may seem disappointing. Intuitively it seems like early diagnosis of cancer, glaucoma, coronary disease or chronic lung disease should lead to better outcomes. Unfortuntely the data does not lead to those conclusions. In some cases like prostate cancer screening the early diagnosis may lead to more morbidity and problems from testing and treatment than benefits of the earlier diagnosis provide. In other situations like screening for coronary disease screening the high incidence of false positive tests and the low prevalence of disease make screening impractical. In still other situations like COPD making the diagnosis does not lead to effective interventions that alter the course of the disease.
I am grateful that the USPSTF puts out these recommendations, and am hopeful that they will become more active again after political pressure of late seems to have slowed the pace of their production to a point where new recommendations are needed in important areas like PSA screening.

by Charles Boren

The ancient Greeks used running as a form of training and competition. It was a way to test personal fortitude and improve physical health. Many of the health benefits of running were known even in those ancient times. In modern times, many start running for the same reasons. They run to improve their physical endurance, lose weight and build muscle. While these common health benefits of running influence many to start running, runners are surprised to learn just how extensive the health benefits are. Running improves the quality of sleep, fights off depression and anxiety, and improves joint health and stability.

Sleep disorders affect a surprising percent of the population today. There is good news to those who suffer from them. Running can actually improve the decrease the symptoms of sleep disorders and improve the quality of sleep. It also appears to help people sleep more efficiently. That is, the amount of time spent actually sleeping while in bed increases. Running helps people fall asleep more quickly, toss-and-turn less through the night, and wake up more rested than those who do not run.

The runner’s high is a well-documented phenomenon, and major benefit, of running. This is a unique feeling often reported during long, strenuous amounts of exercise. The feeling can range from relaxed and peaceful to intensely euphoric. It is produced when endorphins flood the brain as part of a stress response to running. These endorphins are the natural drugs of the body. They reduce pain and are responsible for the happy and content feelings similar to many those produced by narcotics. While many runners experience this phenomenon, many do not realize the long-term positive effect that is has. Over time, the regular doses of endorphins to the brain can combat both anxiety and depression. In fact, many studies have shown that following a regular running program markedly reduces the symptoms of these disorders.

A common misconception is that the high-impact nature of running negatively affects the joints in the body. The truth is that running may actually improve joint health and stability. (1) This is done in a number of ways. First, running helps keep excess weight off. Just a ten-pound increase in body weight can cause a 45-pound increase in stress on the knees (2).  Second, running causes cartilage to expand and contract with the natural movements created while running. This forces nutrients and oxygen into the cartilage cells. Without this, the cells will slowly die from oxygen depletion and starvation. Third, running strengthens the tendons and ligaments that support and stabilize joints. This prevents injury in the long-term. Overall, running greatly improves joints and prevents the onset of arthritis.

Building muscle, losing weight, and strengthening the heart are the health benefits that motivate people to start running. However, it is the unspoken benefits that keep them running. As a whole, runners have better sleep, improved mental states, and healthier joints. Many runners feel that they are taking responsibility for their health by running. They physically feel better, less stressed and they have peace of mind. This is a reward all in itself.

Bio: Charles spends much of his free time running. On the side he also runs an automotive company, where he purchases vehicles.

Tabex was reported in the prestigious New England Journal of Medicine to be more effective than placebo for help in quitting smoking.  Sounds great until you read the actual numbers.  Tabex was shown in a single fairly small study including only 740 patients that was conducted in Poland to have a 1 year success rate of 8.4% as compared to a 2.4% success rate with placebo.  Admittedly this sounds like it is helpful in a small percentage of patients, but at best only about 1 in 12 patients using Tabex will be successful in quitting smoking.

Still having an inexpensive and over the counter product patients can use to try to get help in quitting smoking is exciting.  Studies show that most smokers would like to quit smoking.  Smoking rates have decreased significantly in the United States over the last couple of decades, but many patients in my practice just cannot seem to quit smoking.  Chantix has been quite helpful for many patients, but significant Chantix side effects including cardiovascular concerns, vivid dreams, depression and even suicidality have been deterents to Chantix use. The high price of Chantix is also a major deterrent to widespread use.  Bupropion, originally marketed as Zyban for smoking cessation, is sometimes helpful, but far from a panacea.

Tabex, chemical name cytosine, is structurally similar to nicotine, and functions as a nicotinic acetylcholine receptor agonist.  It is an extract of the seeds of Golden Rain acacia (Cytisus laborinum) and Chantix is actually a derivative of cytosine and has been approved for smoking cessation in the U.S. since 2006.  Tabex has b een used in Europe for nearly 40 years for smoking cessation and has been produced by a Bulgarian company Sopharma AD.

In the NEJM study Tabex was used on a 25 day tapering schedule, taking 6 tablets daily for the first 3 days, five tablets on days 4-12, and then tapering more quickly by taking 4 days on 4/day, 4 days on 3/day, until stopping on day 25 after 2 days of two tablets daily.  At this dose toxicity seemed minimal, although the authors admit the study was too small to find uncommon adverse effects of Tabex.   Cytisine has been documented to have serious side effects at much higher doses, so users should not take more than this regimen used in the NEJM study.

Tabex appears to be inexpensive, on E-bay I found vendors selling #100 1.5 mg tablets for $13.35 USD.  This would amount to enough pills for a person to take the recommended 25 day regimen and have just a few pills left over.  This compares to Chantix which costs about $179/ month at Drugstore.com.

This small NEJM study implies that this inexpensive, seemingly fairly safe drug, available without a prescription, is marginally effective for helping smokers quit the habit.  I think it may be worth a try for smokers who have been unable to quit using nicotine replacement systems, cannot tolerate, cannot afford or have reasons not to use Chantix, and are motivated to quit.  The long term adverse health effects of continuing to smoke seem to far outweigh the risks of essentially all of the smoking cessation aides for patients without specific contraindications to their use.

In European use for over 40 years there does not seem to have been much in the way of serious problems with Tabex use, and I anticipate the use of Tabex to increase significantly in the U.S since the NEJM article has given more validity to its use.

There is really little to no evidence that the other SSRI drugs like citalopram or sertraline help patients to quit smoking.

The abstract of the NEJM article is available here.

Tagline:  But Not By Much, and at a High Cost.

July 20, 2011 AstraZenica received FDA approval for their new antiplatelet agent Brilinta (ticagrelor) for use in acute coronary syndrome.  Brilinta joins an increasingly crowded market of antiplatelet agents that includes the longstanding leader in the class Plavix and Effient, which came to market July 10, 2009.  Effient has not become terribly popular, likely due to its higher rate of bleeding complications including life threatening bleeding and an increased incidence of stroke in patients with previous stroke.  These risks seem to have held sway over the modestly reduce rate of restenosis of coronary artery stents seen in Effient vs. Plavix patients when used post coronar artery stent placement.

The primary selling point of Brilinta is that in the PLATO clinical trial the mortality rate in patients with acute coronary syndrome was stastically significantly lower in patient using Brilinta (9.8%) vs. Plavix (11.7%) P<0.001.  Patients on Brilinta had lower death rates from heart attack and stroke, but had higher rates of non-fatal bleeding complications. The reversible mechanism of action of Brilinta has its drawbacks though, requiring twice daily dosing vs. daily dosing with Plavix.

The primary issue with Brilinta is whether this statistically significant reduction in death rates in acute coronary syndrome is practically significant, and whether the potential drawbacks of twice daily dosing and the non-compliance issues this may engender will erode those benefits when used for longer periods of time.  When the Plavix patent expires soon and generic clopidogrel becomes available the benefits of Brilinta and its current high cost of $7.24/day will need to be enough to make that cost difference palatable.  Plavix has been an effective, well tolerated and extremely popular drug. It is the third highest gross sales drug in the US  (2009 data) and is anticipated to be available as an inexpensive generic in about May 2012.

These are some of the pros and cons that patients and physicians will need to consider when making a decision between Plavix and Brilinta

Brilinta, like Plavix and Effient works as a platelet aggregation inhibitor, but acts with a slightly different mechanism of action, binding at a site different from the ADP receptor it blocks.  It is a reversible receptor inhibitor, and Brilinta, unlike Plavix does not require hepatic activation which may be a potential advantage in some patients. The importance of the hepatic metabolism issue in overall efficacy is unclear, and this may be just a theoretic issue of little clinical significance.

Brilinta currently has a black box warning similar to that with Plavix warning against use in patients with active bleeding, a history of intracranial hemorrhage, and tha bleeding should be suspected in any patient with hypotension who has had a recent procedure like CABG, coronary angiography or any other surgery.  Unlike Plavix the black box warning also includes an increased risk of cardiovascular events if Brilinta is discontinued, making the twice daily dosing and compliance an even larger concern.  The black box warning also noted the reduced effectiveness of Brilinta if aspirin at doses higher than 100 mg daily are used.  This could easily be done inadvertently in patients taking OTC aspirin products.  If you do not personally have a history with Aspirin usage, consider this resource about aspirin side effects.

An unexpected issue with Brilinta is a much higher incidence of dyspnea (13%) vs Plavix (7%).

In summary I expect Brilinta to be a niche product used in uncommon circumstances once clopidogrel becomes available as an inexpensive generic.

All of the drugs released so far work as direct inhibitors at one point or another in the coagulation cascade, unlike warfarin which as a vitamin K antagonist works by reducing the production of key clotting factors.  Apixaban and Xarelto are factor Xa (X as the Roman numeral for 10, and “a” for activated) inhibitors, and Pradaxa is a direct thrombin inhibitor.  They are immediately active in their functional roles after being absorbed from the gut, and so the speed of action of these drugs is much faster than the speed of action of warfarin.  This is likely to play a key role in looking at the overall cost of use of these drugs.  Warfarin use requires several days to take effect, and the necessary dose is highly variable.  From significant personal experience I can say that when quick anticoagulation is needed as in DVT management there are two major drawbacks to warfarin use.  First it is necessary to treat patients with heparin initially in order to get prompt anticoagulation.  Secondly it is very common to take a week or more to achieve therapeutic levels of anticoagulation. Often the initial dose chosen is either too high or too low. The prothrombin time, or more commonly the INR, is used to measure the degree of anticoagulation with warfarin.  Dosing of warfarin can be anywhere from <1 mg daily to 15 mg daily, and is difficult to predict.  It is not uncommon to have patients significantly over anti-coagulated a week after starting warfarin requiring that the dose be reduced, only to then to reduce the dose and a few days later find that they are now significantly under anti-coagulated.  This yo-yo effect necessitates frequent INR monitoring and visits to have INR testing.  Essentially all of the new drugs work within one to two days, and are twice a day dosed because of relatively short half-lives.  Although twice daily dosing may seem a drawback due to patient compliance issues (vs. once daily warfarin dosing),  I see it a potential benefit because its corollary is that the drug will be out of the system quickly so that any bleeding complications will likely be short lived when they do occur.

Warfarin can be reversed with vitamin K or fresh frozen plasma, but the use of vitamin K takes at least a couple of days, and use of fresh frozen plasma exposes patients to human blood product risks.  I see the faster onset and faster loss of efficacy of apixaban and Pradaxa as significant benefits.

This combined with superiority in three major measures of efficacy and safety for apixaban make it likely that when this drug is approved for use in the U.S. that it will become a very popular new drug.  Pradaxa is already gaining traction among cardiologists in stroke prevention in atrial fibrillation patients, but I suspect that unless Pradaxa can show superiority rather than its current “non-inferiority” claims to warfarin that apixaban may quickly gain favor among physicians and patients. Another drug rivaroxiban is already on the market in Europe and has shown non-inferiority to warfarin in stroke prevention, superiority in bleeding risk, but did not improve overall survival in comparison to warfarin.

Apixaban is in phase three clinical trials and is expected to receive FDA approval by the end of 2011. Some market analysts anticipate that apixaban may end up the overall winner in the competition for the leading position among the new anticoagulant drugs. I suspect that they are correct because to this point only apixaban can claim significant superior efficacy and safety in comparison to warfarin.  I expect warfarin use to be significantly impacted because in addition to the increased efficacy and increased safety, its use eliminates the need for INR monitoring. The real question is going to be whether the first-to-market advantage of Pradaxa is enough to hold off apixaban, and whether insurance companies perceive there is an overall cost benefit to paying for the new drugs.

Another issue is that Pradaxa is only approved for use in non-valvular atrial fibrillation for stroke prevention, and Xarelto is only approved at this time for post-operative DVT prevention in total joint replacement patients. It is likely that apixaban will only get an indication for stroke prevention in non-valvular atrial fibrillation.  I expect wider indication approvals to be forthcoming for this class of drugs as there is little reason to expect that they will not also work for therapy of DVT and DVT prophylaxis in hypercoagulable states.  Stay tuned to see if apixaban gains the popularity that some predict it is destined to have.

So what are the benefits of resistance exercise?  Actually they are multiple, some obvious and others less obvious.

• Resistance Exercise Builds Strength:  This is one of the obvious benefits, but some aspects may not be appreciated. One aspect that some may not fully appreciate is that this benefit does not go away with age.  One study of the elderly (average age 87) showed that an 8 week program of resistance training 3x/ week increased strength by over 100%, increased walking speed by 12%, and reduced the incidence of falls.  With the sedentary life style many jobs enforce, and the lack of outdoors physical work by many of us, resistance training can make a huge difference in the way we feel, in our functional capacity to do tasks without hurting ourselves, and in our overall functional capacity.
• Resistance Training Builds Bone Strength:  Bones are a living tissue, constantly remodeling based on the stress loads placed upon them.  Resistance training while bearing weight can lead to increased bone strength and help prevent the fractures of osteoporosis as we age.
• Resistance Training Helps Lower Mild Hypertension:  Aerobic exercise is the backbone of maintaining cardiovascular health, but resistance training also helps reduce blood pressure to at least some degree.
• Resistance Training can Increase Metabolic Rate:  Aerobic exercise is again the mainstay of weight control and maintenance, but there is considerable evidence that resistance training when combined with aerobic training leads to higher metabolic rate and more weight loss than aerobic training alone.
• Improved Self Image:  This is just my opinion and experience, but I believe that maintaining strength, physical capability and muscle mass is has a positive effect on self-image.  I know I feel better about myself when I feel strong and fit.  Resistance exercises are a key to this for me.

If you believe in the benefits of resistance exercise how should you go about setting up a program?  First be real with yourself.  Set goals that you believe are possible, sustainable and affordable.  You can go to a gym, buy free weights or machines for home, or simply do exercises using your own body weight like pushups, pull-ups, and squats.  Rubber band type resistance equipment is inexpensive and very effective.  Secondly aim for 3 days a week for resistance exercise.  Taking a day between training sessions gives the muscles exercised time to recover and grow.  Third learn from Milo of Croton in that progressive overload is the principle behind steadily increasing strength. You don’t need a calf to carry every day until it has grown.  Just start with exercises where 8-15 repetitions lead to fatigue.  Once this is easy, slightly increase the resistance.  Keep increasing the resistance as the exercise becomes easy.  Last if a certain exercise leads to persistent pain, change something rather that thinking you can work through the pain.  Often some minor change may avoid an overuse injury.

Add resistance training to your regular exercise to reap the full benefits of exercise.  Enjoy.

Xarelto has been used in Canada and Europe for about 3 years so it is not expected that huge unexpected aftermarket risks will show up.  The original studies compared Xarelto to a fairly low dose of low molecular weight heparin The studies generally show that Xarelto is more effective at preventing DVT than the low dose enoxaparin (Lovenox).  In the U.S. the FDA approved dose for DVT prophylaxis is 30 mg twice daily of enoxaparin twice daily, not the 40 mg once daily used in the comparison trials.  It is not unexpected that Xarelto leads to less DVTs and more bleeding than the low dose enoxaparin. I would like to see a study comparing warfarin use with Xarelto in prophylaxis of DVT post lower extremity total joint replacement. If I were having my hip replaced tomorrow I’d pass on Xarelto given what I can see from the current studies.  I’ll keep an eye on future studies and clinical experience as my opinion may change with more studies and broad clinical experience.

Potentially more exciting is the very recent August 10, 2011 study in the NEJM where a very large cohort of patients with atrial fibrillation was treated with either Xarelto 20 mg daily or variably dosed warfarin.  The results were very promising; with clear cut non-inferiority of Xarelto when compared to warfarin, and a fair probability that Xarelto is superior at preventing stroke.  For the statisticians among readers the p-value for non-inferiority was <0.001 and the p-value for superiority was 0.12.  The 95% range of confidence is 0.74-1.03.  Total bleeding risk was equal at about 14-15% annual risk of bleeding annually in both treatment arms, and the risk of serious intracranial bleeding or death from bleeding significantly lower with Xarelto.  This sounds promising and when FDA approved for prevention of stroke in a-fib, which seems very probable, Xaralto is going to give Pradaxa a run for its money in the non-valvular a-fib market.  Xarelto promises to have similar benefits as Pradaxa in that it requires no anti-coagulation monitoring.  This is a big deal for a-fib patients where the duration of treatment is often many years.  The long-term hassle of constant blood monitoring of a condition where treatment is likely to go on indefinitely is significant.  The issue of monitoring coagulation status for just 10-35 days post operatively is much less onerous.  I anticipate a much higher level of excitement for xarelto for atrial fibrillation than for post operative DVT prophylaxis.  (Since this post was published Xarelto has recieved FDA approval for stroke prevention in atrial fibrillation at a dose of 20 mg once daily.  Even more exciting was a study presented at a large cardiology meeting showed in a large clinical trial that low dose Xarelto at 2.5 mg twice daily reduced death by 30% in the year post an acute coronary event like a heart attack.  This could change the standard care from just anti-platelet therapy to anti-platelet therapy plus low dose Xarelto if it holds up to careful review.  The risk of bleeding in this study was only modestly higher and overall death reduction was significant. )

It appears that there may be more drug interaction issues with Xarelto than with Pradaxa.  Xarelto is extensively metabolized through the CYP 3A4 pathway, whereas Pradaxa has far less extensive hepatic metabolism and so less likelihood of patients being on drugs with the likelihood of interactions.  That alone may make Pradaxa easier to use in this group of patients who are often subject to polypharmacy.

Of further note there are multiple other novel anticoagulant drugs that are likely to be brought to market in the next year or two, and it is likely that each will find a niche.

Update:  Today, 9-8-2011, the FDA advisatory committede voted  to recommend to the FDA against approval of Xarelto for use in stroke prevention in patients with atrial fibrillation. It looks like Xarelto is not likely soon to be added to Pradaxa as FDA approved new directly acting drugs for use in A-fib for stroke prevention.  Apixaban is likely to get FDA approval soon.

Since its release Multaq has been in the news frequently as the FDA time after time has released warnings about its use.  Not phased the manufacturer pushed ahead with the PALLAS trial.  This study was undertaken to see if Multaq would reduce the incidence of major cardiovascular events like stroke, arterial embolization, MI, or cardiovascular death in patients with permanent a-fib.  To date no anti-arrhythmic drugs have been shown to improve outcomes in this high-risk group of patients, and there were hints from the initial ATHENA trial of Multaq that it might improve outcomes.  The PALLAS trial appears to have turned out to be a disaster for Sanofi-aventis when instead of improving outcomes in patients with permanent a-fib it appeared to double the rate of the very cardiovascular events Multaq was hoping to prevent.  This led to the premature halt of the trial and the FDA warning of last month.

Multaq has had a really rough first 2 years with a seemingly never-ending litany of FDA warnings about its use.  In early 2010 the FDA warned about the possibility of an increased risk of congestive heart failure (CHF) in patients on Multaq.  On Feb 22, 2010 the FDA changed the warning label of Multaq to note that some patients had worsening of CHF on the drug.  In the second quarter of 2010 the FDA warned about a possible link of Multaq with Torsades de pointes, a potentially lethal and very difficult to treat cardiac arrhythmia.  In the third quarter of 2010 it became apparent that Multaq could interact with warfarin, an anticoagulant used in most a-fib patients to prevent strokes, leading to an increase in the anticoagulation effect and risk of hemorrhage.  Near the end of 2010 cases of severe liver damage due to Multaq began to surface, and on Feb 11, 2011 the FDA warned that Multaq should be stopped if there is a suspicion of liver damage.

Now in a blow that I suspect may lead to the demise of Multaq  the FDA has told patients on Multaq that they should contact their physicians to see if they should stop Multaq.  The warning specifically tells patients not to stop Multaq without consulting their physician, but it appears that with the information we now have that the use of Multaq in patients with persistent atrial fibrillation is contraindicated.  The FDA is telling physicians that they should not prescribe Multaq for patients with persistent a-fib and that the PALLAS data, which is preliminary at this point, is being analyzed to see how to apply this new information to therapy of patients with paroxysmal a-fib and flutter.

MULTAQ is a drug whose primary indication is the potential benefit of reducing hospitalization rates in patients with atrial fibrillation by maintaining a sinus rhythm. the concern of potential risks of hepatic failure, worsening of CHF, drug interactions with warfarin and now higher risk of death, stroke and heart failure hospitalization in patients with permanent atrial fibrillation make it seem less than prudent to start almost any patients on Multaq.  The primary question remaining is whether patients currently on Multaq who are maintaining a regular sinus rhythm without any or many episodes of intermittent a-fib should continue the medication or be taken off Multaq.  My guess is that Multaq will fall into the category of drugs rarely used very quickly if Aventis-sanofi decides to keep the drug on the market at all.  As recommended by the FDA if you are taking Multaq you should contact your physician to see if you are better off continuing to take Multaq, or if you are better off to discontinue the medication.  Don’t stop on your own.

Kelly posts the Weight watchers WW pts+ information on each of her recipes, and the PB2 Thai Chicken recipe looks great and has just  +1 WWpts+ for the sauce.  I don’t think you can smell traditional peanut butter without a higher score.  (actually a 2 tbsp. helping of traditional peanut butter has 5 WWpts+ and a 2 tbsp. serving of PB2 has 1 WWPts+)  I’m not in weight watchers but do try to watch my weight so I’m jazzed.  PB2 is essentially peanut butter powder that can be reconstituted with water for use. I read the nutritional information about PB2 and it appears that PB2 has most of the protein goodness or peanut butter without the high fat calories.  Here is a brief comparison of nutritional info for a 2 tablespoon serving of Adams No Stir peanut butter and PB2:

The first thing I noted on this nutritional information is that PB2 appears to be a lower calorie food that does not try to make up for the fat by adding sugar and salt.   The whole question comes down whether you think PB2 tastes good enough to substitute for regular peanut butter as a snack or sandwich with jelly.   I think it is clearly going to be a great substitute in recipes.  Either way for a peanut butter lover like me the thought of avoiding the extra calories of peanut butter and still getting the PB taste I love makes using PB2 a solid option.  If your are as excited as I am consider checking out the

Bell Plantation Store and maybe try some yourself.

So far I’ve found great recipe sources.  Great examples of these are on daily homemade and include:

PB2 Chocolate Chip Cookie Bar

There are hundreds of recipes for use of PB2 in cooking on the Bell Plantation site.  I found 38 entrees, 47 side dishes, 67 deserts, 10 beverages, 10 no-bake recipes and others under the category of “healthy.”  I suspect all of the recipes will fall under at least “healthier” than real peanut butter when used for cooking.

Warfarin has been the choice of most physicians and patients for prevention of stroke in patients with atrial fibrillation because it works well.  The annual risk of stroke in patients with atrial fibrillation is 4.5% without warfarin anticoagulation, and 1.4% with warfarin treatment.  This risk varies a great deal from individual to individual depending on associated risk factors like coexisting hypertension, diabetes, congestive heart failure, prior TIA or stroke and age over 75.  A scoring algorithm called the CHADS2 score is often used to better assess an individual’s risk.   For most patients the absolute reduction in risk of stroke is high enough that most physicians have encouraged most of their atrial fibrillation patients to take warfarin.  Warfarin therapy is no small undertaking though and has very significant bleeding risks. Several major problems are involved with use of warfarin as an anticoagulant:

• A patient has to wait several days for the anticoagulation effects of warfarin to take effect.  During this time the patient needs to be tested frequently, sometimes daily, to assess whether the prescribed dose of warfarin is just right.
• It often takes one to several weeks to get the dose just right.  Then after the INR is just right they will still need monthly blood tests to assure they remain adequately but not overly anticoagulated.  If this sounds like a big hassle and expense you are very perceptive.  It is.
• Many drugs interfere with warfarin metabolism and so drug interactions are notoriously difficult to manage in patients on warfarin.
• Because Warfarin is a vitamin K antagonist dietary variation in vitamin K content can have a significant effect on the anticoagulation effect of warfarin.
• The therapeutic window for warfarin dosage is quite narrow, meaning the difference in dose between not enough and too much can be quite small.  It is very difficult to predict what dose an individual patient will need.

Pradaxa is approved by the FDA for treatment of atrial fibrillation at a single fixed dose for most patients.  It is dosed at 150 mg twice daily, and is effective within hours of taking the first dose.  It works at least as well as warfarin to prevent stroke in patients with non-valvular atrial fibrillation, and overall the Pradaxa side effects profile is generally lower than with warfarin.  In addition Pradaxa has far fewer drug interactions than warfarin which is notoriously affected by both diet changes and innumerable other medications.  Bleeding risks with Pradaxa seem to be about the same overall as with warfarin.  There may be a minimally lower risk of major cerebral hemorrhage and a higher risk of gastrointestinal bleeding with Pradaxa vs. warfarin.

The big issue holding back the widespread use of Pradaxa seems to be its cost.  In a recent cost effectiveness analysis in the Annals of Internal Medicine for use in patients age >65 with non-valvular heart disease, assuming a daily cost of Pradaxa at $13.60 the conclusion was that Pradaxa has incrememtally higher costs and incrementally higher added years of life.  Currently Pradaxa costs $230./ 60 doses , ie. 30 days supply or $7.66/day at Costco.com.  With this lower cost than assumed in the study it seems like Pradaxa may win in the cost effective analysis.

I believe this study takes into consideration the lower risk of cerebral hemorrhage complications that can often lead to very expensive hospitalizations and long term nursing home care with Pradaxa.  When I talk with other physicians they generally tell me that they would rather deal with GI bleeding, which is slightly more common with Pradaxa, than with intracranial bleeding which is slightly more common with warfarin.    I’ll be interested to see more post marketing cost analysis comparisons as they become available, and to see how many patients are switched from warfarin to Pradaxa, and how many new patients are started on each of these medications.

I will not be surprised if as more physicians gain experience with Pradaxa, and more cost analysis is done, that Pradaxa will become the standard of care for treatment of atrial fibrillation for stroke prevention in patients at high enough risk of stroke to warrant the risks of therapy.

While you’re here be sure to follow @DoctorPullen on Twitter and  subscribe (at the right) so you don’t miss a post  and get the between-post  random thoughts, new ideas as they happen.

Yesterday I posted a brief article about the new announcement of the FDA restrictions on the use of simvastatin 80 mg.  Some patients, especially those with diabetes or preexisting atherosclerotic vascular disease, have LDL goals that are really low.  There is some evidence that pushing LDL levels as low as 70 or lower can prevent progression or even possibly reverse this vascular disease.  For many patients in order to achieve these levels a reduction of 40-50% or more in their baseline LDL cholesterol level is needed.  In order to achieve this degree of LDL lowering one of the more potent statin regimens is often needed.

Simvastatin was the third of the currently used statins to lose its patent and become available as a generic drug.  First generic was lovastatin, generic for Mevacor.  Mevacor was the first statin medication to gain FDA approval in the U.S.  It was somewhat slow to gain widespread use as it took some time for data to become available about the benefits of statin use to lower LDL cholesterol.  By the time statin used became widespread statins with greater effect on LDL reduction became available.  Pravachol (Pravastatin) and Zocor (simvastatin) followed Mevacor to market.  Shortly after Zocor became available Lipitor came to market.  Lipitor zoomed to become the market leader based on a number of factors.  One of the factors was the greater LDL reduction available with Lipitor.  In head to head comparison of simvastatin vs. Lipitor, Simvastatin has a considerably more modest LDL reduction.  See the table below.  In addition Lipitor was featured in several high profile studies which vaulted the popularity of statins for both secondary and primary prevention of coronary artery disease.

Lipitor, a Pfizer product,  is the number one grossing drug in the world, with over $10 billion in sales in 2010.  Simvastatin reclaimed a huge portion of statin sales in 2009 when generic simvastatin became available, in part because at the top dose of 80 mg simvastatin’s LDL reduction approaches the LDL reduction possible with lower doses of Lipitor.  The news this week that the FDA is limiting the use of simvastatin 80 mg is going to make the simvastatin vs. Lipitor/atorvastatin choice lean much more toward Lipitor/atorvastatin.  On Nov 30, 2011 a generic for atorvastatin is going to become available.  Despite this I anticipate another 6 months, when multiple generic companies can market atorvastatin before generic atorvastatin prices drop to the range of the other generic statins.  The apparent lack of an abnormally high incidence of myopathy as a lipitor side effect is going to drive this change.

Still that’s only a year from now, and the simvastatin vs. Lipitor choice is now one I can realistically entertain, knowing that the price excess of Lipitor is soon to disappear.  I’ll consider changing my simvastatin 80 mg patients to Lipitor now, and generic atorvastatin when it becomes available unless they have been stable and symptom free for a long period of time.  The FDA recommends change unless a patient has tolerated simvastatin 80 mg for over a year.  This is because most cases of myopathy and rhabdomyolysis from simvastatin 80 mg happen in the first year of use.  I’ll still consider low dose simvastatin for patients who need only a more modest reduction in LDL reduction, but I expect atorvastatin to quickly become the most widely used statin after it competes in price with simvastatin.
In the long run the simvastatin vs. Lipitor choice looks like one that Lipitor, soon to be generic atorvastatin, is going to win by a runaway.  I’ll report back in a couple of years to let you know if I’m right.

As with any individual physician my “n” or number of patients treated is small enough that it is not possible from personal experience to detect issues like the increased incidence of myopathy and rhabdomyolysis noted with simvastatin 80 mg, or with lower doses used in patients on meds like amlodapine, diltiaziem, and others.

As I noted in an earlier post generic Lipitor is expected to lose its patent this year, and generic atorvastatin should be available.  This is likely to obviate the need for higher doses of simvastatin for lipid control in patients with very high cholesterol.  Since the earlier warnings I’ve been using lower dose simvastatin and avoiding simvastatin 80 mg in most patients, but this recent evidence presses the need to avoid simvastatin 80 mg even more.  For the press release by the FDA see:

FDA Drug Safety Communication:  New restrictions, contraindications, and dose limitations for Zocor (simvastatin)  to reduce the risk of muscle injury

Safety Announcement

Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary
Simvastatin Dose Limitations
Relative LDL-lowering Efficacy of Statin and Statin-based Therapies
References

This led me to investigate psyllium properties and benefits.  I was pleased to find the psyllium is different from most of the other available fiber supplements available then, or available today.  The biggest difference is that psyllium husk is a water soluble fiber that binds bile salts.  Bile salts consist in significant part of cholesterol, and by binding the bile salts it prevents the reabsorption from the gut of the cholesterol and lowers LDL cholesterol.  This technique of lowering LDL cholesterol was the mechanism of action of the primary LDL lowering drug available in the early 1980’s called cholestyramine.  The problem with cholestyramine was that it causes significant constipation.  This is often severe enough to prevent compliance with the four daily doses needed to be effective.  Metamucil on the other hand is often used to prevent or treat constipation, and helps promote regular, soft, easy bowel habits.  See the psyllium husk benefits post for lots of details on the cholesterol benefits of psyllium husk.

Psyllium also slows the absorption of simple carbohydrates from the gut when consumed with a meal.  This has the benefit of lowering blood sugar levels after the meal, and can be helpful in patients with glucose intolerance.  It’s not really considered a treatment for diabetes, but may be slightly helpful in this regard.

Psyllium is available for consumption in multiple forms.  The most commonly used and popular form is as a powder that can be mixed with water or juice to drink.  This is an inexpensive and simple way to take psyllium.  The trick to this is to mix and drink it quickly, as it tends to form a gel if left in the liquid for more than a few seconds.  I recommend mixing in just 4 ounces of water and the drinking a large glass of water immediately afterwards to dilute the mixture in the stomach.  The usual dosing is 1-3 large heaped teaspoons daily.  This can be all in one dose, or split into 2-3 doses a day.  It’s best to gradually increase to a full dose, because if you start on a high dose initially it can cause gas and bloating.

Psyllium is also available in capsules that range from 100-500 mg in dosing.  The problem with these is that to get a useful dose you need to take so many capsules.  A heaping teaspoon has up to 4 grams (4000 mg) so to take the equivalent in capsules would be 8 of the 500 mg capsules.  This would cost a lot more and just be a lot of very large capsules to take.

Psyllium can be consumed as crackers or wafers. Metamucil makes a psyllium wafer in apple crisp and cinnamon flavors, but I cannot find good nutritional data on these to assess dosing and calorie content.  There are many online recipes for making psyllium into crackers.

Since 1989 psyllium has been an ingredient in several cereals available commercially.  These vary in the amount of psyllium and the other nutritional values.  A good review is available here.

Overall I recommend just using the less expensive and very effective psyllium powders like Metamucil, Konsyl, or multiple other brands.  I use branded sugar free orange flavored Metamucil as I find the texture of some of the slightly less expensive generics to be less palatable, but any of them should be equally good water soluble fiber sources.

PSVT, or paroxysmal supraventricular tachycardiaia, is one of the cardiac conditions where over the last few decades researchers have made tremendous progress in diagnosis, treatment, and even cure of the condition.  PSVT is a common medical condition in which sudden paroxysms or attacks of very rapid heart rate seem to arise out of nowhere.  They can be brief, just a few seconds or a minute or two, or can last hours and lead to circulatory compromise.

When everything is working normally in our heart, each heartbeat is triggered by the sinoatrial node in the right atrium.  This node starts causing heart muscle fibers in the heart to depolarize, an amazing electrical/chemical reaction that rapidly spreads to all adjacent heart muscle cells.  Special heart muscle cells called Purkinje cells, that connect to form Purkinje fibers, are able to incredible quickly transmit this depolarization from cell to cell and through the atria until they reach the atrioventricular node (AV node) where after a momentary pause, the depolarization races through bundles of Purkinje fibers in the ventricles called bundle branches out to the ventricular heart muscle.  In the perfectly formed heart there is a fibrous tissue that separates the atria and the ventricles so that the depolarization of heart muscles can only pass from the atria to the ventricles through the AV node.

In most patients with PSVT there is an aberrant group of muscle cells that goes through this connective tissue separator allowing the depolarization to get from the atria to the ventricles, or backwards, other than through the AV node.  When this is present sometimes a circular movement of the depolarization can occur, leading to a very rapid heart rate.   This very rapid heart rate, often at rates as high as 190-200 beats/ minute is called PSVT.

Some patients with PSVT have a resting EKG that shows a specific abnormality where the PR interval is very short and there is a “slur” on the QRS wave.  This specific type of PSVT is called Wolfe-Parkinson-White syndrome.

Treatment of PSVT can be with medications to slow the ability of the heart to beat, and make PSVT less rapid and so better tolerated.  The biggest breakthroughs though in PSVT management have been the ability to use cardiac catheters along with tiny instruments to map the conducting ability of the heart and find the aberrant tissue that connects the atria to the ventricles.  If this can be located the cardiologist can then destroy the aberrant fibers usually using thermal probes and so effectively cure PSVT.  In patients with frequent, prolonged, or very rapid PSVT this has revolutionized therapy, and been life-changing and at times lifesaving therapy.

Experienced cardiology electophysiologists have rates of success with PSVT ablation of 95% or higher.  It has become a standard of therapy for many patients where PSVT is not easily controlled medically.  Newer cryoablation procedures are being developed to allow treatment of the few PSVT patients who cannot have radiofrequency ablation.  The cryotherapy procedures allow treatment of aberrant pathways in areas too close to key structures like the AV node to treat with radiofrequency.

March 16, 2011, 12:01 am

Is Fitness All in the Genes?

Why do some people respond to an aerobic workout routine by becoming incredibly fit, whereas others who exercise just as hard for months end up no fitter than when they began?

That question has bedeviled countless people who’ve started exercise programs. It has also motivated a major new study of the genetics of fitness. Scientists long have known that when any given group of people faithfully follows the same aerobic workout routine, some increase their cardiorespiratory fitness substantially, while an unfortunate few seem to get no benefits at all. But what, beyond the fundamental unfairness of life, makes one person’s body receptive to exercise and another’s resistant? According to the new study, which will soon be published in The Journal of Applied Physiology, part of the answer may depend on the state of specific genes.  Read more