UPLIFTing News for COPD

COPD (Chronic Obstructive Pulmonary Disease also known as chronic bronchitis and/or emphysema) has certainly been in the news lately. I have recently blogged about both good news and bad news for COPD. Now, the New England Journal of Medicine has recently released the UPLIFT study ahead of press, a third study which in combination with the TORCH study I believe helps but everything into perspective.


There are currently a few types of medications used to treat COPD. Bronchodilators do what they sound like they would, open up the airways. There are two types: anit-cholinergics and beta agonists that work by different mechanisms. Each type has a short acting version lasting a few hours and taken several times a day and a long acting version lasting 12 hours and taken twice a day. In the US, the short acting bronchodilator (SABA) used is albuterol and common long acting bronchodilators (LABA) are salmeterol (Serevent) and formoterol (Foradil). The short acting anticholinergic used is ipratriopum and te long acting anti-cholinergic is tiotropium (TIO) sold as Spiriva. Another common bronchodilator is a combination of ipratropium and albuterol sold as Combivent (there is not yet a combination of the long acting bronchodilators). In addition, inhaled corticosteroids (ICS) have been used to treat COPD, usually in combination with a LABA, such as Advair and more recently Symbicort.

With all of these medications, which one should be used and when? According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (jointly sponsored by the NIH and the World Health Organization), in addition to smoking cessation and other preventative measures such as flu shots, patients are initially to use SABA or ipratropium, and when lung function becomes decreased to add LABA and/or TIO, and reserve adding an ICS for when lung function is worse that 50% of what it should be, especially if there are frequent exacerbations.

So what do the new studies show?

As mentioned previously, the first study published in the Annals of Internal Medicine studied a VA population and found that patients taking ipratropium had significantly higher death rate of about 11%. This was the headline in the media, but the study also found a 20% lower risk of death for patients on ICS and an 8% lower risk of death for patients on LABA.

The second study was a meta-analysis published in JAMA that analysed date from 14,783 patients with COPD and found that patients taking either ipratropium or TIO (or both) had a 58% increase in cardiovascular death, heart attack or stroke when compared to patients taking other meds (Advair, albuterol or placebo). As I mentioned in this post meta-analysis need to be interpreted with caution, using the Avandia meta-analysis as an example, since the more scientifically rigorous long-term, large randomized controlled trials have not showed similar results.

This leads to the recent UPLIFT trial, which was a long-term, large randomized controlled trial (4 years, almost 6000 patients) looking at TIO and its ability do decrease that rate of lung function decline which normally accompanies COPD. The trial showed no difference in this outcome between patients taking TIO and placebo. However, there were fewer exacerbations and improved quality of life. Additionally, there was about 10% relatively fewer deaths, though this result did not reach statistical significance. Thus, though anti-cholinergic medicines may cause some harm, it appears that this is likely mainly for the short acting ipratropium and not for the long acting tiotropium.

Also important to understanding the implications of the results of these three studies, one has to consider the TORCH trial This was also another long term (3 year) large (over 6000 patients) in patients with COPD taking either ICS, LABA or both (Advair) that found a significant reduction in exacerbations and almost (like UPLIFT) decreased death. In addition, a recent analysis of this study showed what UPLIFT (and any other medication for COPD for that matter) could not: preventing the decline in lung function seen with COPD. One downside of TORCH was an increase in pneumonia in patients taking ICS (alone or in combination).

What to do now?

According to the GOLD guidelines, "the effects of oral and inhaled glucocorticosteroids in COPD are much less dramatic than in asthma" and "regular treatment with inhaled glucocorticosteroids does not modify the longterm decline of FEV1 in patients with COPD." The first statement does not seem very evidence based, especially in light of recent data and the later statement is now incorrect.

It is time to update COPD guidelines in light of the new data. Short acting bronchodilators should likely be used with caution given the risk of death, and inhaled corticosteroids (used in combination with a long acting beta agonist) should likely be given a more prominent role given robust exacerbation reduction, disease modifying properties and potential mortality benefit. The UPLIFT study is reassuring for patients using Spiriva.

JAMA study on News Media Misses the Bigger Problem

It is not surprising that there is limited media coverage of a JAMA article which criticizes the media for their coverage of medical studies. Specifically, of studies published in the major medical journals (New England Journal of Medicine, JAMA, Lancet, Annals of Internal Medicine, and Archives of Internal Medicine), that were covered in the media, 42%; did not report that the research had received company funding and of the studies on drugs with both a generic and brand name, 67% of the media reports mentioned the drug by brand name at least half of the time.

As mentioned, there is limited coverage of this study in the mainstream media, as well as little chatter on this in the blogsphere. Though most of the focus will be on the lack of reporting of industry funding, there are bigger issues here. I am not too bothered by the findings of the study because 1) most studies involving therapeutic agents are funded by the industry and 2) the public knows the medications by the brand name and not the generic. The real issues are regarding media coverage of medicine in general.

Dr. Kevin Pho of the blog KevinMD correctly points out that

Part of the problem is that some reporters cross-cover medical stories, and are
not specifically trained in the nuances that are unique to health reporting.

In addition, the shear volume of articles is worth mentioning as well. In the study, they looked at articles published over 4 years in the aforementioned journals regarding an industry sponsored drug study. Of the 358 studies they found, 117 were reported in the media using 306 unique reports. This means that over the course of 4 years, there was an article reported about every other week and mentioned three unique times. And this is only for the findings in the 5 biggest impact journals. This doesn't include articles coming out of specialty journals, which also get a lot of press (such as the recent study about Hep B and Pancreatic cancer reported in the NY Times and published in the Journal of Clinical Oncology). This doesn't include reports from agencies like the CDC (such as the report on Superbugs in the WSJ today). This doesn't include announcements from the FDA, which I have mentioned have increased in recent days. This doesn't include non-pharmaceutical reports (such as ABC News' piece on holistic ways to treat the common cold) and it doesn't include medical "buzz" reports such as CNN's reporting of celebrity Jenny McCarthy's crusade against vaccines because the may cause Autism (CDC says that they don't Jenny).

The public is inundated on a daily basis with medical information that is not always reported accurately, that often takes a negative spin (because scary things sell papers and thus advertising dollars), that leave the public and patients confused, and in many cases lead patients to distrust any product and even their own doctors. (My post on a Men's Health article regarding 8 drugs doctors would never take being a perfect example).

One of my main purposes for starting this blog was to help my patients and friends (as well as others) sort through the media mess. However, I am finding it is an uphill battle.

Bad news for COPD: Why this meta-analysis should be believed (and the Avandia one should not)

OK, I may have jumped the gun a few days ago when I posted about the good news for COPD. I was reacting to the negative media reports about a study which did show that certain inhalers were bad, but seemed to forget to mention that other inhalers were life-saving! Well, this is still true; however, the bad news did just get a little worse.

The study released in today's JAMA which gave more evidence of concerns with certain COPD inhalers was picked up by a few media outlets such as USA Today and ABC News. However, it is surprising* that it hasn't created the media firestorm cause by the Avandia meta-analysis given that COPD is the 4th leading cause of death (diabetes is 6th), over 11 million US adults have COPD, and Advair (a drug used for COPD) is one of the top selling drugs in the US and world (Avandia is only #23).

What did the study show?
The study was systematic review (looked carefully to find all appropriate studies) and meta-analysis of data from 17 clinical trials studying 14,783 patients with Chronic Obstructive Pulmonary Disease (COPD, sometimes called emphysema). The study found that patients taking anticholinergic inhalers -ipratropium (Atrovent) or tiotropium (Spiriva) had a 58% increase in cardiovascular death, heart attack or stroke when compared to patients taking other meds (Advair, albuterol or placebo). Unfortunately, the data looks bad for both the older drug (ipratropium) and the newer Spiriva, when analyzed separately.

Why should I believe this study and not the Avandia one?
I have blogged multiple time about Avandia , and have criticized Dr. Nissen's meta-analysis several times. So why believe this meta-analysis and not Dr. Nissen's?

Methodology
In order to determine whether a rare event is true or not, you need a study with a lot of patients. Sometimes that data is not available or doing the study is impractical. The next best thing is a meta-analysis, which combines similarly designed studies with similar patients looking at similar things, and statistically "squishes" the data together to find a true (statistically significant) finding, that could not have been found from the individual studies alone.
The authors of this study first performed a systemic review of the literature to find all published studies that were appropriate for analysis, whereas Dr. Nissen only used the GSK (makers of Avandia) studies that were published on their web site. The studies used for this meta-analysis were similarly designed, the patients were very similar (most had the same lung function) and looked at the same outcome (lung function); where some of the patients in Dr. Nissen's study didn't even have diabetes and the studies were designed to look at different things (safety, sugar control, etc.). The authors looked at the data in a variety of ways (long term vs. short term studies, taking out the one big study out of the 17, looking at different agents) and found very similar findings. Dr. Nissen, on the other hand, never explains why the rate of heart attacks in his study was LOWER in the Avandia group, but the meta-analysis showed a 43% increase in heart attack. (Another author re-analyzed Nissen's results using different methods and found no difference in heart attacks with Avandia).

Supporting Evidence
As I mentioned in my previous post, this study comes out just after another study was released that analyzed thousands of patients from the VA that showed increased deaths (11%) for patients taking ipratropium. The "good news" lost in the media was that they also found a 20% lower risk of death for patients on inhaled steroids and an 8% lower risk of death for patients on long acting β-agonists. In contrast, multiple large randomized controlled trials (as above, the most accurate way to find a true answer) show no increased rates of heart attacks with Avandia.

Biologic Plausibility
The findings have to make some sense from a biologic basis to believe them. Though the authors of this study point out that the mechanisms of how anticholinergic drugs like Atrovent and Spiriva would cause cardiovascular death, heart attacks and strokes are unknown; these medications do affect things like heart rate and rhythm. In contrast, there is really no good explanation why Avandia would cause a heart attack (though it may worsen heart failure which is not the same thing), and in fact some studies of another medication in the same class suggest that these types of diabetes medicines might actually PREVENT heart attacks.


Bottom Line: Current guidelines recommend inhaled bronchodilators as first line therapy for COPD. Given that ipratropium (Atrovent) and tiotropium (Spiriva) have been implicated in cardiac events and death, this may not be such a great idea. Interestingly, combination with an inhaled steroid is recommended only as second line. Much of the evidence from these recommendations comes from the fact that inhaled steroids (ICS) didn't improve lung function as well as the other bronchodilators. However, we have known for some time that ICS improve quality of life and reduce symptoms, and we now (very recently) know that an inhaled steroid combined with a long acting beta agonist (LABA) not only reduces COPD exacerbations, but also prevents decline in lung function and seems to prevent death. Not sure what the pulmonary experts are going to do with this new information, but it seems like ICS/LABA combination for COPD is probably the best way to go for now. If you are taking ipratoprium (Atrovent) there are likely better alternatives given it's short onset of action. If you are taking Spiriva, don't stop! Discuss this with your doctor. There is also great risk for poorly controlled COPD, and several studies that show Spiriva reduces exacerbations. The UPLIFT study is currently underway, and may have reasurring data about Spiriva. If you are diagnosed with COPD and your doctor recommends an inhaler, consider Advair or Symbicort (which is approved in the US for asthma, but like Advair, works well in COPD).

*I am not really surprised. The FDA had their own Avandia meta-analysis data and were waiting for results of the larger trials to make an overall decision. Dr. Nissen and the NEJM intentionally "scooped" the FDA and purposefully used the information to create a media frenzy which now ultimately seems not to be an issue and may have harmed some patients, since many stopped Avandia without informing their physicians.

Good News for COPD

A recent study in the Annals of Internal Medicine linked an older drug used for COPD (ipratropium) to deaths in patients with COPD (chronic obstructive pulmonary disease or emphysema). ABC News reported Older Emphysema Drug Linked to Heart Deaths, which initially sounds like bad news, but actually the study's findings (which barely got any press) were actually very good news. The study looked at data from the U.S. Veterans Health Administration health care system and compared patients respiratory medicines for patients who had died to patients who were living. They did find that death rate was significantly higher (11%) for patients taking ipratropium, and older, short acting inhaler for COPD. However, they also found a 20% lower risk of death for patients on inhaled steroids and an 8% lower risk of death for patients on long acting β-agonists. This data is consistent with recent prospective studies looking at combination of long acting β-agonists and inhaled steroids which found that they reduced exacerbations and may have decreased death. A recent analysis of this study showed that this combination also prevented the decline in lung function seen with COPD. This is now the only report of a medication that has been able to show this, as the only other method to prevent decline in lung function is smoking cessation. There was also another comparison of long acting β-agonists and inhaled steroids (Advair) vs. tiotropium (Spiriva) which found no difference in exacerbations, but a lower rate of death in the Advair group.

All of this combined makes medical sense. First, ipratropium is a short acting bronchodilator. When used alone, it is supposed to be taken 4 times a day but is often taken as needed. Thus, it makes sense that patients with lung disease might do poorly on this. Having long acting medicines on board likely improves control of the lung disease thereby preventing death. Secondly, COPD has a component of inflammation, so using anti-inflammatory medications has benefit. Not only are exacerbations lower, but this seems to prevent death. Taken together this suggests that patients with COPD should be on a combination of a long acting bronchodilator to control their symptoms and an inhaled steroid to prevent exacerbations, prevent decline in lung function and reduce their chance of dying.

Factors Associated with Medical Students' Career Choice Regarding Internal Medicine: Pay is Not Really One of Them!

I am very pleased that our work on Factors Associated with Medical Students' Career Choice Regarding Internal Medicine was just published in JAMA. This was a survey of 1,177 medical students who were just about to graduate from our institution and 10 other US medical schools. We were interested in the factors affecting career choice, both for those choosing internal medicine (IM) and those who chose to do something else. About 23% percent chose IM careers, but only 2% of students (24/1177) stated they were choosing general internal medicine. This means that most of those choosing IM had decided already to go into subspecialties such as gastroeterology and oncology. We found that three factors influenced career choice in internal medicine: educational experience, nature of patient care and lifestyle. For those students choosing IM, these factors pushed them toward IM. For those not choosing IM, these factors generally pushed them away from IM.



There are a few things that may not be obvious from what was in the paper or what will be reported in the media.



This is a crisis!

The survey did not ask specifically about primary care. Of the 2% of students stating they were interested in general IM, many of them could (and will likely) do hospital medicine which is becoming a popular choice for generalist IM physicians. Also, only 4.9% of students selected family medicine, which it the other group that practices general, outpatient primary care. Therefore, not including pediatrics or OB, only about 6% of graduating medical students want to go into general primary care. To me this is clearly a crisis. If almost all of our future physicians don't want to go into primary care, who is going to take care of our aging population with multiple medical problems?



Changing the curriculum is unlikely the answer

As a medical educator, I am happy in the sense that most students (78%) were satisfied with their IM experience during medical school and felt they had adequate exposure to what an internist does. However, I am frustrated that few students (20%) felt that their education experience made a career in IM more appealing. In other words, they feel that they have seen and learned alot, and appreciate the teaching on their IM rotations, but say "no thank you" when it comes to IM as a career choice. In the past, educators have suggested that adding more outpatient experiences might help enhance student interest in IM, but the study showed that for students who trained in an outpatient IM setting, about 1/3 said this made an IM career more attractive, but about 1/3 also said it made an IM career less attractive.





Paying primary docs more is not the (only) answer

One factor that did not significantly influence career decision was reimbursement, and this was irrespective of student debt (an average of over $100,000). According to the survey, compared with other specialties that they were considering, students saw IM as requiring a greater breadth of knowledge, but requiring more paper work and having a lower income potential; paperwork being the biggest detractor from an IM career. This should not be a big surprise, since student are knowledgeable about the problems of the health care system and generally don't go into medical school to get that big pay check. Most do initially go into medicine for altruistic reasons.



Lifestyle was clearly an important factor, and this generation of students values a balance of work and personal/family life. However, outpatient primary care is about at close to 9 to 5 as you can get (I certainly couldn't wake up as early as my surgical colleagues). In addition, many primary care docs no longer do inpatient medicine, so going to the hospital in the middle of the night no longer necessarily applies. In addition, though shift work allows for more time off, it also causes more time on.



We are currently analyzing some of the open response questions, and hope to have this out soon. However, my impression regarding lifestyle has more to do with the nature of practice and patient care (which was the other influencing factor). Though we primary care physicians work closer to "normal people" hours, we end up bringing a lot of work home, much of it paper work. Students see primary care physicians trying to see complex patients in short time slots, filling out endless paper work (not just notes in the chart, but referral forms, prior authorizations, medical billing, etc.) and spending a lot of time doing extra "busy" work such a phone calls back to patients about results or to an insurance company to approve a drug (which students quickly realize in uncompensated care). This is not why they went to medical school. They went to medical school to take care of patients and spend time with them, not to rush them through a visit and help them through a bureaucratic system. The fact that primary care pays less than the other specialties is very likely the icing on the cake of why students are not choosing primary care.



Thus, loan repayment (for students choosing primary care careers) and increased compensation for primary care is a step in the right direction and should occur. However, in order to prevent the eventual lack of US trained primary care physicians in this country, the system has to change. The nature of practice and patient care that turns students away from primary care is due to a system that does not properly compensate cognitive services while heavily reimbursing tests and procedures. I have previously written about how this has radically changed how mental health services are delivered in this country, and the same is about to happen in primary care if something is not done quickly.



Though each of the Presidential candidates have different approaches to health care reform, both leave the private insurance and government funded systems relatively intact, thus not addressing the problems of reimbursement for cognitive services and mounds of paperwork to deliver care. The medical home has been mentioned as one possible solution. If this indeed changes the nature of practice of primary care, then students may become more interested in the IM and other primary care fields. However, if the medical home becomes extra paperwork to complete to eek a few extra dollars out of the system, then we are indeed in trouble.

P.S. Thanks to Dr. Karen Hauer for her leadership on this project, as well as all the hard work by my colleauges from the Clerkship Directors in Internal Medicine.

FDA to List Drugs Being Investigated

As first reported in the Washington Post, the FDA is now going to report quarterly on drugs that they are looking into. The report which will be published online is the result of a new law requiring the agency to reveal drugs under safety review each quarter.

I am in favor of the public and physicians knowing about medications that can be potentially concerning. However, as I have mentioned previously, posting information without data to back it up has potential dangers as well. The FDA will mention the name of the drug and the nature of the "adverse events" but they will not describe the seriousness of the problem or the number of complaints received for which the investigation was initiated. The problem is that with the 24/7 news cycle, and the media waiting for the next Vioxx, once a drug gets on the list, the public's reaction will generally be that the drug is dangerous. According to the FDA:

"The appearance of a drug on this list does not mean that FDA has concluded that the drug has the listed risk, or that FDA has identified a causal relationship between the drug and the listed risk. It is on the list only because FDA has identified a potential safety issue."

However, this has not been my experience. In fact, we evaluated our practice's diabetic patients and many of them stopped Avandia without even discussing this with their physician. There are risks and benefits to every drug, and the FDA ought to be extremely vigilant in following up any complaint they deem worth investigating. However, posting these publicly may lead patients to stop taking medications that even if the adverse event turned out to be true would still be outweighed by the benefit of the medication. The public has the right to know, but the public has the right to know all of the information. In my opinion, the FDA should post all of the information or nothing at all.

Vytorin: No good reason to use, yet 80,000 prescriptions a week

The Medical Letter is an non-profit, non-industry funded publication that reviews therapeutics. They are one of the few unbiased sources about drugs, sort of like a Consumer Reports for pharmaceuticals. The Medical Letter is a paid subscription service, so you may not have access to their recent article on Ezitimibe Revisited. Ezitimibe or Zetia is the second compononent of Vytorin, which combines Zetia with a statin (simvastatin). The Medical Letter describes both the ENHANCE trial and the SEAS study, both studies which showed no benefit of Vytorin. I have blogged about Vytorin and these studies in previous posts (including Zetia In, Vytorin Out and Dear Doctor: Vytorin ), and the good folks at The Medical Letter have drawn the same conclusions I have.


"A large clinical-endpoint trial in patients with hypercholesterolemia comparing the simvastatin-ezetimibe combination with simvastatin alone is underway; results are expected in 2012. Until then, drug treatment of hypercholesterolemia should continue to aim at achieving LDL-C levels below 100 mg/dL in high-risk patients and, if possible, below 70 mg/dL for patients at very high risk. For patients who cannot achieve these goals with a safe dose of a statin alone, adding another LDL-C lowering drug such as niacin, a bile acid sequestrant or ezetimibe continues to be a reasonable option."

In other words, for patients requiring cholesterol lowering drugs, first start with a statin. If goals can not be achieved, several options including adding Zetia seem reasonable. Since other statins such as Lipitor or Crestor are more potents then simvastatin and other generics, if cholesterol goals can't be acheived with a generic, a switch to a more potent statin should be considered (or Lipitor or Crestor should be started in patients whose LDL is too high for simvastatin to acheive control). If cholesterol goals are still not acheived, then one can add Zetia. Thus, there is really no reason to ever use Vytorin. Interestingly, as of last month, according to the Wall Street Journal, "new prescriptions for Vytorin in the US have held steady at more than 80,000 a week over the last month."