PSA: To Screen or Not to Screen

There has been much confusion/concern/media attention since the recent announcement (see the NY Times article US Panel Says No to Prostate Screening for Healthy Men) that PSA tesing was no longer recommended by the US Preventative Services Task Force. (Here's the full version of their draft recommendation.) There are many responses out there (Tara Parker Pope's Answering Questions about the PSA test is a good one), but I believe there is still more to say on the issue.

Before answering the question regarding whether we should follow the USPSTF's new recommendation, please consider...

1. The USPSTF is the same group that says

-Women shouldn't get mammograms before 50

- Recommends against teaching self-breast examination

-States that screening for testicular cancer is harmful

-Only recommends screening for diabetes in patients with high blood pressure

-Recommends against screening for depression for most primary care doctors

(I am not stating that I necessarily disagree with these recommendations.  However, it is important to understand where USPSTF is coming from when considering their PSA recommendation). 

2. Prostate cancer is still a leading cancer killer for men in the US. 

From NY Times:

One in six men in the United States will eventually be found to have prostate cancer, making it the second most common form of cancer in men after skin cancer. An estimated 32,050 men died of prostate cancer last year and 217,730 men received the diagnosis. 

The new recommendations come from findings of two large studies.  One in the US that showed no benefit in saving lives, and one in Europe that showed only some benefit.  The US study have some major limitations, including that many of the men in the placebo/no-screening group actually got screened, so I will focus on the European study.

The European Randomized Study of Screening for Prostate Cancer looked at close to 200,000 men between 50-74 for about 9 years. Not surprisingly they found almost double the rate of prostate cancer in the screened group compared to the non-screened group (8.2% vs. 4.8%).  More importantly, they reduced the rate of death by about 20%. Unfortunately, most of the men treated for prostate cancer did not benefit.  They found that for every 1410 screened, there were 48 additional cases of prostate cancer found, that if treated would only prevent one death from prostate cancer. In other words, if you are treated for prostate cancer, there's only about 1/50 chance it will save your life. Now, if the treatment were without side effects, then besides costs, there would be no reason not to screen.  (My friend Dr. Stewart Segal in his post PSA Confusion suggests covert rationing is one motivation behind the USPSTF's recommendation).  The problem is that there are side effects with treatment, and not inconsequential ones. There is about a 20-30% chance of impotence, incontinence or both. 

However, there seems to be two things not discussed in any of the reports:

1. Though the writers of the guideline seem to give value/risk of the harms of treatment, they do not address the potential benefits of the piece of mind from a negative screen.  In the European study, over 90% of men had a negative screening over the course of almost a decade.  In other words, the vast majority of men screened had the piece of mind knowing that probably didn't have to worry about prostate cancer. (There is also additional evidence that men 65 and older with a very low PSA  will likely never get prostate cancer, and screening should be stopped). 

 

2. Just because you are diagnosed with prostate cancer, doesn't mean you need to treat it.  Given the complications as a result of prostate cancer treatment, and the fact that prostate cancer tends to progress slowly, especially after the first year, watchful waiting is a reasonable approach. If in fact, if the cancer remains stable, treatment can be deferred potentially indefinitely.  However, without the diagnosis, watchful waiting can not occur. 

Bottom Line:  There is no right answer for everyone.  Patients, in consultation with their doctor, need to make a decision that's right for them.  If you are a healthy person, with no cancer risks, worry about side effects and complications of medical treatment,  and realize that there's a 98% chance that screening for prostate cancer will not save your life, you should not get a PSA test or prostate exam.  However, if you are someone that is very fearful of cancer, would have substantial piece of mind if you were one of the 90% of men that tested negative, and if you did get diagnosed with prostate cancer are willing risk treatment knowing there is only a 1/50 chance it will save your life, but about a 20-30% chance you will get side effects from treatment, then you should get tested. 

Crestor approved for primary prevention

Today the FDA announced that Crestor (rosuvastatin) is now indicated for primary prevention of cardiovascular disease. I blogged about this a few weeks ago in my post Crestor: Get Ready to Ask Your Doctor for the CRP Test. Which reviewed the advisory board's recommendation to give Crestor this extra indication. Today the FDA made it official.

Specifically, Crestor is now indicated for

" the primary prevention of cardiovascular disease to reduce the risk of stroke, heart attack, and the risk of arterial revascularization procedures (including coronary artery bypass graft, or bypass grafting of a peripheral artery or carotid artery, or angioplasty or stent placement) in individuals who have no clinically evident heart disease but are at an increased risk of heart disease due to the combined effect of the following risk factors:

• Age (> 50 years in men; > 60 years in women), and
• An elevated high-sensitivity C-reactive protein level (> 2 mg/L), and
• Presence of at least one additional cardiovascular risk factor (e.g., high blood pressure, low HDL-C, smoking, or a family history of premature heart disease). "

There are several reasons why this is interesting:

1. It won't be long before Astra Zeneca, the makers of Crestor, advertise this new indication to patients on TV ads. They will likely ask patients to ask their doctor for CRP tests. Not everyone agrees with the use of the CRP test. The US Preventative Health Task Force (same folks that said mammograms under 50 may not be a good idea), also said that there was not enough evidence to test for and treat an elevated CRP. The Jupiter study led to Crestor getting this indication was a large, well done randomized trial and strong enough evidence for the FDA. However, some (like the US task force) don't think one study is enough.

2. Lipitor goes generic within a year. Lipitor is the number one selling drug in the country. A generic version of Lipitor could thus save millions. However, Lipitor does not have the indication for primary prevention of heart disease for patients with relatively normal cholesterol. I have previously blogged about what is meant by "an indication." Essentially, this means that the drug companies can only market to patients and doctors what the FDA says that they can do. Any other claims are considered "off-label" even if there is strong evidence that the medication does indeed work. My favorite example was back when Zyrtec (Pfizer) was a prescription drug and their marketing campaign focused on Zyrtec treating both indoor and outdoor allergies. The reality is that all allergens produce symptoms from histamines, and all antihistamines work the same way. However, none of Zyrtec's competitors (Allegra, Claritin) could make this claim since they did not have the indication. Thus, Pfizer made it sound like Zyrtec might be better than the others, when in fact, there wasn't really a difference.

However, Crestor's indication takes a more substantial meaning with generic Lipitor on the way. Lipitor has not been shown to do what Crestor did and probably never will, since Pfizer chose not to spend the money on this kind of study with Lipitor's patent fading. Unlike the Zyrtec/Allegra comparison, there may be a difference. Only the very potent, high dose statins have shown to substantially reduce CRP and potentially reverse cardiovascular disease. It is likely that Lipitor at an 80mg dose would do the same thing as Crestor 20mg, but could also have more side effects. Once Lipitor goes generic, the insurance companies are going to make it virtually impossible for patients to get Crestor. Yet, for primary prevention (as well as other more agressive lipid lowering goals), Crestor may be exactly what patients need.

3. The cholesterol guidelines that most physicians accept are the Adult Treatment Panel (ATP) III from the NIH's National Heart, Lung and Blood Institute. These guidelines are about a decade old. The most recent update was back in 2004 in response to several important studies. The next version should be up for public comment in just a few weeks, and done by the summer. The FDA's decision today should force the committee (though they would've probably done this anyway) to address the CRP question. It should be very interesting as well to see if they limit treating CRP with Crestor, or generalize this to other statins.

The Pap Smear: A Symbol for Our Health Care System's Problems

Today the Wall Street Journal and other sources reported on a study from The Annals of Internal Medicine that showed that most US doctors don't know the guidelines of how often women should get a pap smear. More importantly, doctors were doing a lot of pap smears on women who didn't need them. In all the talk about health care reform, reducing costs by eliminating unnecessary testing has been mentioned multiple times. Thus, if we can figure out how to get rid of all of these unneeded pap smears, maybe we can find the cure for our health system's woes.

The results of the study are not surprising to me, as I have seen this in clinical practice. The more I thought about why this is occurring, the more I thought about the pap smear as a symbol of our health care system's problems. So why so many pap smears?

1. Pap smears have saved lives. Cervical cancer used to be a major killer of US women. Now it is rare to hear about a women who has died of cervical cancer. Not true in third world countries when screening is not possible. The fact that we have virtually gotten rid of a cancer with early detection is truly amazing. But the danger here is that it has set up the paradigm that this is true for all diseases and cancers. Recently, breast cancer and prostate cancer screening have come under fire for not really saving any lives. However, even with the data, patients and advocacy groups will not likely take a screen only if proven life saving approach. Breast self-examination has absolutely no data to support this practice, and in young women who are likely to find non-cancerous bumps, may actually be harmful. Yet, this practice is routinely recommended for many young women.

2. Women (and many men) want/expect a yearly physical, and most women believe that a pap smear is part of this. Similar to other types of cancer screenings, there is very little evidence that a routine check up is beneficial. This is not to say that you shouldn't visit your doctor regularly. However, many of the things doctors do during a physical have limited to no value. There are some things that have tremendous value, such as checking blood pressure and weight, and talking about diet, exercise, smoking cessation, etc. However, having the doctor check your whole body every year when your feeling just fine is unlikely to be helpful. Yet, the American public expect a full exam every year. After all, their health care premiums are quite high, so they might as well get checked out. This extends to the pap smear. It saves lives (as above), is part of my regular check up, and I am paying a lot of money for this; so therefore I expect my yearly pap.

3. Physicians have little disincentive to refuse to do a pap smear. The pap smear only takes a few minutes. Trying to take the time to explain #1 and #2 above makes little sense for the primary care physician who is not paid by time spent counselling a patient, but by how many patients she can see. In other words, talking a patient out of an unneeded test actually costs the primary care doc money, because that time could be used for seeing another patient. More importantly, if the physician refuses the pap smear, and the patient goes elsewhere to get the pap smear and is found to have cervical cancer; the physician could get sued placing her entire career in jeopardy!

If pap smears save lives, patients expect/demand them, talking a patient out of an unnecessary pap smear only costs me money and not doing the pap could get me sued, why wouldn't I do a pap smear on every women that wanted one?

4. The pap smear rep reminded me to get the test. The drug companies are not really the problem any more. Every day you read about a drug company laying off employees. This is because most drugs are or will soon go generic and there is little in the pipeline. This is not the case for devices and testing. Big labs have reps that come to physician's offices to discuss the latest fancy new test. Like the drug reps, they bring lunch too. The difference: medical devices and testing though FDA approved are not nearly has heavily regulated as the drug companies when it comes to selling to physicians. Drug reps by law are restricted to saying only what is in their label to physicians. It works a little bit differently for the lab and device reps. As newer tests and devices become available, watch for more of a focus on selling these products. Don't be surprised to see direct to consumer advertisements asking patients to ask their doctors about such and such a test.

5. The experts don't agree. It is very hard to keep up with evidence based guidelines in primary care. It's even harder when there are multiple guidelines, and harder still when they don't agree. For prostate cancer, the American Cancer Society and the American Urological Society say that doctors should test for prostate cancer. The US Preventative Health Task Force guidelines say that we shouldn't. Initially, some of the groups recommended more frequent pap smears, but recently decreased the interval due to evidence that less frequent screening was better. However, with all multiple guidelines that often differ, it is not surprising that so few primary care physicians actually knew what all the experts actually did agree upon. Another issue is that reasons behind differing guidelines have to do primary with politics and money. The Urologists want primary care docs to test for prostate cancer because they make money when the test comes back positive. The government doesn't want you to test for prostate cancer, because testing leads to more testing and treatment which costs them (you the taxpayer) more money.

6. Doctor's don't follow guidelines anyway. Even if there was one clear and definitive guideline for docs to follow, they probably wouldn't. There are likely multiple reasons. Our current Continuing Medical Education system (CME) that is supposed to keep docs up to date is horrible and funded by commercial interest. The stimulus package already gave some money for comparative effectiveness research and there will likely be more money for this in any health care reform bill that passes. However, if docs don't know the results of what is best or what actually works, then the data is not all that useful. It is unlikely that a drug company is going to fund a CME program that shows their drug is not useful. So who is going to fund the dissemination of comparative effectiveness findings? There is also no real incentive to follow guidelines. Again, docs get paid for how many patients they see, not by how beneficial their advice was to patients or whether they gave guideline appropriate care.

Since pap smears don't cost a substantial amount of money, it is unlikely that getting rid of all these unnecessary pap smears is going to put a dent in health care spending. However, the underlying reasons behind the many unneeded pap smears is a symbol of what what's right and wrong about our health care system. We should give this study's findings, and more importantly the reasons behind these findings, a critical look.

Sick About Singulair

The New York Times' business section recently reported that despite a second-quarter earnings fall, hurt by lower sales of its cholesterol drugs (specifically Vytorin, see my posts on why you should no longer use this product), Merck actually beat profit forecasts due to good sales of its asthma drug Singulair. Singulair's quarterly sales jumped 16 percent to $1.3 billion. That's a lot of money! Indeed, based on pharmacy data (via drugtopics.com, thanks again Mr. Medsaver for this great resource), Singualir was the 4th most commonly prescribed drug in 2008 at a close to 26 million prescriptions! Moreover, a recent report from the WSJ Health Blog states that Merk is looking to put Singualir over the counter.



I have no ill will towards Merk. It is an American company that has come up with some products that I find beneficial for patients including Fosamax (which is now generic) and Januvia, and they are the makers of two important vaccines: Gardisil and Zostavax. However, I am concerned about high sales of the asthma drug Singulair, because national guidelines state it should not be used as a first line therapy for asthma.



Facts about asthma



According to the American Lung association, in 2007, it was estimated that 22.9 million Americans currently have asthma. Of these, 12.3 million Americans (3.8 million children under 18) had an asthma attack. In 2005, there were 3,884 deaths attributed to asthma. During 2006, 444,000 hospitalizations and close to 1.7 million emergency room visits were attributed to asthma.



In 2007, the NIH released updated guidelines about asthma. Regarding treatment, the guidelines suggest that all asthmatics with persistent asthma (symptoms or rescue medication use more than twice a week) be initiated on inhaled corticosteroids (ICS). ICS's are considered first line treatment for all asthmatics, from babies to children to adults and to the elderly. The reason is based on solid evidence that these agents work the best in improving lung function and decreasing symptoms. Singulair is listed as an alternative agent. Singulair is an anti-leukotriene. Leukotrienes, like histamines, are substances released in an allergic response that cause the airways to tighten up. Thus, Singulair works in the same way that antihistamines work: by treating the symptoms. ICS's work by blocking inflammation which is what causes the release of leukotrienes in the first place. Singulair is not anti-inflammatory, ICS's are. Singulair treats the symptoms, whereas ICS's treat the problem. This is why study after study proves that ICS's are superior to Singulair, and why guidelines place ICS's as first line treatment and Singulair as alternative.





Does Singulair work?
Of course Singulair works. In order for a drug to be approved by the FDA, the drug company has to show that its product is efficacious. The problem is that it has to show that it is efficacious compared to placebo. Thus, Singulair works better than a sugar pill. However, compared to any other asthma medication, it is not as good. Even when added on to an ICS, it is not as good as other add ons, such as long acting beta agonists (LABA's).



Why do physicians prescribe so much Singulair when is not what the guidelines recommend?

This is an extremely important question. Some may chalk it up to drug company marketing. However, all the ICS and ICS/LABA making companies due their job marketing their product as well. I think the main reason has to do with fear of ICS's. Corticosteroids are different than the kind of steroids athletes take. However, they are not without side effects. Earlier studies on older medications showed some growth delay in children, which is why pediatricians may be so reluctant to use ICS's. However, more recent studies showed that for the newer agents, long term use with mild to moderate doses did NOT cause growth delay. In 2002, the NIH reviewed all the literature and determined that at low to medium doses of ICS's, there are NO SIGNIFICANT SIDE EFFECTS. This is when ICS's became considered first line therapy for ALL asthmatics.

The other issue is the convenience factor of a pill vs. an inhaler. Inhaler use is clearly not as easy as taking a pill (Singulair comes chewable for children).

The thought is probably, "it's a once a day pill that might help my patient, and probably won't hurt them, so why not give it try?" The problem with this approach, is the failure to consider the risks of uncontrolled asthma. Uncontrolled asthma leads to ER visits, hospitalizations, and possible even death. Asthma is a serious disease. For patients who have persistent asthma, following the guideline recommendations of ICS's as first line agents is the right thing to do.

What about allergies?

Singulair is also indicated for allergic rhinitis or allergies. As above, like histamine, leukotrienes play a role in allergic rhinitis, and this is why Singulair is used. I have posted about Singulair and allergic rhinitis previously. Basically, there are several treatments for nasal allergies:Non-sedating antihistamines (Claritin, Zyrtec, Allegra), Leukotriene modifiers (Singulair), inhlaed nasal steroids (Flonase or fluticasone, Rhinocort, Nasacort, Veramyst) and inhaled nasal antihistamines (Astepro). Muliple studies that show that fluticasone (Flonase) is better than Singulair, better than Claritin, and several studies that show that the combination of Singulair and Claritin is not better than either agent alone. However, in one study, though the combination of Singulair and Claritin was better than either agent alone, the individual agents were no better than placebo. An excellent review by Dr. Robert Nathan showed that "leukotriene receptor antagonists (Singulair) are sometimes more effective than placebo, are no more effective than nonsedating antihistamines (Claritin) , and are less effective than intranasal corticosteroids in the treatment of allergic rhinitis." Finally, a recent guideline from World Health Organization suggests that for patients with mild, intermittent allergic rhinitis; treatment with non-sedating antihistamines and leukotriene modifiers were both acceptable forms of treatment, but patients with more chronic or bothersome symptoms, inhaled nasal steroids should be used.

Some would argue that having both allergies and asthma together would be a reason to take Singulair. There is no question that treating allergic rhinitis may help with asthma symptoms. However, the killing two birds in one stone approach simply hasn't been proven to be the case. If you have allergic rhinitis that makes your asthma worse, you should take the most effective agent, which is inhaled nasal steroids.





What if I am taking Singulair for asthma?

Singulair has been proven more effective than placebo, and in some individuals controls their asthma and allergies. However, a recent internet survey revealed that about 55% of asthmatics have uncontrolled asthma, and many of them are on regular medications. Asthma control is the key, according to the new NIH guidelines. If your asthma is well controlled on Singulair, then it is probably OK to take. However, there is a theoretical risk that by taking Singulair (treating the symptoms without treating the underlying inflammation), that though you feel well now, your lung function will be worsening over time. More importantly, if you are taking Singulair and your asthma is not well controlled, then you should definitely switch to at least an inhaled corticosteroid, or possibly an agent combining an ICS with a long acting brochodilator (LABA) such as Advair or Symbicort. There are many ways to determine asthma control, including how much rescue medications you are taking and how asthma affects your daily life. The easiest way to determine your asthma control is by taking the Asthma Control Test