Wednesday, May 26, 2010

Fracture Risk and Acid Blocking Medications: What Should You Do?

Yesterday, the FDA released a Drug Safety Communication warning about a possible risk of increased fractures with acid blocking medications called proton pump inhibitors or PPI's.

PPI's have been a major advance in medical science. Prior to these and ealier medications, the treatment for severe gastroesophageal reflux disease (GERD) was major surgery. PPI's are now commonly prescribed for GERD and less serious heart burn, many are generic, and some are now sold over the counter. The popular PPI's include Nexium (esomeprazole), Prilosec (omeprazole), Prevacid (lansoprazole), and Protonix (pantoprazole) which are available by prescription. Prilosec OTC and Prevacid 24HR are sold over-the-counter (OTC). Given the use and popularity of these medications, this warning may cause great concern among patients who rely on these medications.

What did the FDA find?
The FDA analyzed the data from several epidemiologic studies in thousands of patients studied for several years and in 6/7 studies found a greater risk for certain kinds of fractures when patients took PPI's. These risks seemed to be the greatest when patients were taking the medications regularly, for a long time, and at a high dose.

So is this a real problem?
Maybe. It is important to know that the gold standard of studies is the randomized clinical trial (RCT). Only RCT's can prove a cause and effect. None of the RCT's with PPI's thus far have shown and increase fracture risk with PPI's. The problem with RCT's is that they are hard to do and are usually limited in time (6 months) and have fewer patients. So a rare but serious side effect is unlikely to be picked up in an RCT. The epidemiologic studies are useful, but have limitations (which the FDA readily points out). These studies are case-control, meaning they look for people who had fractures, find similar people who didn't have fractures, and then see how common PPI use was in each group. Though the studies show that people with fractures were more likely to take PPI's than people without fractures, this doesn't mean that PPI's cause fractures. Maybe the folks who took PPI's had stomach troubles and were less likely to take things that prevent fractures like Calcium or Bisphosphates (drugs which prevent fractures but are relatively contraindicated in those patients with GERD). In addition, these studies use claims databases. This means that to get the data, doctors never examined or interviewed patients, rather the investigators looked at insurance claims for fractures, medication use, etc. For example, we don't know what the bone density scores (DEXA) were for the patients in this study. It is very possible (and even likely) that the patients in the fracture group had lower DEXA scores, and this more than the PPI use accounted for fracture. Also, if you have ever received a bill or claim notification from your insurance company, you problem know that the information they contain is not always 100% accurate. That said, the number of patients studied and the consistency of this relationship suggests that there may indeed be a cause and effect.

What should you do?
It is unlikely that short term use of PPI's substantially increase risk of fractures. So if you need an occasional Prilosec OTC (like after a big barbecue this Memorial Day weekend), this is probably fine. If you need to take PPI's, either prescription or over the counter, on a daily basis and have symptoms when you do not take them regularly, this could be a sign of more serious disease and should be investigated by a physician (regardless of a fracture risk). For those patients who have had an extensive medical work up for a stomach condition and told by a physician that taking a PPI on a daily basis for years to come is the recommended treatment, then they should discuss the risks and benefits of PPI's as it relates to fractures. This would be particularly important if you have an increased risk for fracture such as a previous fracture, family history of osteoporosis, or low bone density.

Friday, May 14, 2010

Lipitor or Crestor for LDL's above 160

I just read A systematic review and meta-analysis on the therapeutic equivalence of statins. This artilce will not make any major U.S. headlines because it is a Taiwanese study from a not very well known journal. However, the methodology is sound and makes an important point to patients who need a statin and are deciding between a generic and more expensive brand name medication.

The study did a systematic review of all the studies which compared the different statins. They found that at comparable doses, statins are therapeutically equivalent in reducing LDL (or bad cholesterol). This would suggest that if statins are essentially equal, provided you use the right dose, then you should always go with a generic. However, the other thing they found was that "the only two statins that could reduce LDL-C more than 40% were rosuvastatin and atorvastatin at a daily dose of 20 mg or higher." In other words, those patients who need cholesterol lowering drugs and have to get their cholesterol down by less than 40% should be OK with generic, but those who need to get their LDL cholesterol by more than 40% should use either Crestor (rosuvastatin) or Lipitor (atorvastain). Though new guidelines should be out by the end of the year, current guidelines suggest that patients with increased risk for heart attack and stroke (all diabetics, mulitple risk factors,etc.), who are generally the patients we use statins in, need their LDL's under 100. This means that if you are at increased risk for heart attack and stroke, and your LDL is 160 or above, you should not take the generic (even if it is cheaper), but take the more expensive branded cholesterol medicines.
Fortunately, as I mentioned in a recent post Are Drug Reps and Free Samples Bad For Patients? It Depends, both companies offer coupons to offset the additional out of pocket costs, so you should not pay much more for Crestor or Lipitor than what you would pay for a generic medication.

Monday, May 3, 2010

Are Drug Reps and Free Samples Bad For Patients? It Depends

One of my favorite blogs, KevinMD, featured a post by Internist and fellow blogger Dr. Leslie Ramirez (founder of Leslie’s List, which helps the uninsured and underinsured find more affordable medications and health care services) on the true cost of free drug samples. Her point was that "free" drug samples may cost a patient in the long run if they are followed up with an expensive prescription that the patient can't afford. I posted a response on Kevin's site (more below) stating the issue was a little more complex, as Dr. Ramirez' example applied specifically to a patient who was paying out of pocket for medications, which is not usually the case. However, this post received numerous responses about the value/evils of both drug reps and the samples they provide. Below is an edited/expanded version of my replies.

The Benefit and Harm of Reps and Samples
Do drug reps/free samples…
-influence doctors? Absolutely.
-increase prescribing of non-generic meds? Absolutely.
-contribute to health care dollars spent on meds? Absolutely.
-harm or are bad for patients? It depends.

It is true that whenever a generic medication has equal safety and efficacy as a branded medication, the patient and public benefit when a generic is used. However, just because there are generic medications available, does not always mean that generics are the best choice for patients.

A good example is type 2 diabetes. The RECORD (see For the RECORD, Avandia does not cause heart attacks) study looked at cardiovascular safety of the much maligned drug Avandia. (RECORD showed it not to increase risk of CV death or hospitalization-something the media continues to ignore). The study took patients on a generic diabetes medication (either metformin or sulfonylurea) and randomized them to either an expensive, branded diabetes medicine (Avandia) or the other generic. Patients in the Avandia group who still had uncontrolled diabetes on Avandia + one generic could add the other generic. Patients in the other group who were uncontrolled on both generics had to go to insulin.

In addition to showing no difference in cardiovascular safety (primary endpoint), the patients in the Avandia group had better diabetes control, less weight gain, better cholesterol profiles, less hypoglycemia and less insulin use. In other words, though it certainly costs more money, (in this study) it was better to add Avandia then sticking with only generics. This should not be surprising since we know that the older diabetes drugs fail after a few years, and that TZD's like Avandia (seen now in ADOPT, RECORD, and BARI 2D) sustain glycemic control.

There are a few other examples where generic products exist, but branded products may be better. Branded statins (Crestor, Lipitor) are likely better then generics for patients with high cardiovascular risk who need to get their LDL (bad) cholesterol down more than 40%. In hypertension, losartan is the first generic angiotensin receptor blocker (ARB). Though there are several ACE inhibitors that are good once a day generics (lisinopril), up to 10% of patients will get a cough and need to be switched to an ARB. Now we finally have a generic ARB, except this one is not nearly as good as the other 4 branded products on the market. Because insurance companies will likely make it very difficult (higher co-pays and prior authorizations) to get one of the branded ARB's, patients will likely need to get a cough on an ACE and then fail losartan, before they are allowed to use the newer, better ARBs (and will still have a very high co-pay).

In addition, there are many medications that have no generics. All the respiratory medications (Advair, Symbicort, Spiriva, etc.) essentially have no generic equivalent. Having a drug rep provide samples of these meds will (as stated above) certainly increase prescriptions and therefore increase healthcare spending. However, asthma kills about 11 patients a day, COPD is the 4th leading cause of death, and both conditions are substantially under treated. Writing more prescriptions of these medications, and thus the reps that provide them, should therfore be a good thing. Even if the medicines are costly, their increased use will prevent exacerbations, hospitalizations, and even death (which have their own costs).

There is also the issue of direct cost to the patient (out of pocket costs) and the convenience factor. The FDA just approved a combination pill of Nexium and Naprosyn for rheumatoid arthritis. Many patients with rheumatoid arthritis need to take NSAIDs like naproxen on a regular basis. One of the side effects is stomach ulcers. Acid blocking proton pump inhibitors (PPI's) like Nexium can prevent these ulcers and guidelines recommend the use of PPI's with chronic NSAID therapy. The newly approved, branded pill will be an expensive, once a day pill that will treat the arthritis and protect the stomach. However, Prilosec (another PPI) and Naprosyn, are both over the counter. Why not just take two over the counter pills a day instead of an expensive branded pill? CVS brand naproxen would cost about 10 cents for two 22omg pills (prescription dose is 500mg), and one Prilosec 20mg OTC (not as strong as Nexium, but should do) is about 70 cents a day. Thus, a patient needing NSAIDs and stomach protection would need to take 3 pills at 80 cents/day, or $24/month. However, it is very likely that the drug company will provide coupons for patients that guarantee them that their co-pay is no more than $25/month. I would think that most patients would prefer the better, once a day pill than the 3 pills a day for about the same price. (There is also a potential safety benefit as combining the pills ensures the stomach is protected when taking an NSAID).

As already alluded to, the issue becomes further complicated when insurance coverage, samples and coupons create complex equations where decision making becomes a challenge. One example would be high cholesterol. Let’s say your bad cholesterol or LDL is 160 and your doctor tells you it needs to be under 100 based on your risk for heart attack and stroke. Simivastatin is generic and has been proven effective, but you will likely need the highest dose of 80mg to get to your goal (the higher the dose, the greater the likelihood of side effects). Generic simvastatin (no samples) costs you $10 month at your local CVS. There is also Lipitor, a branded drug that will get you to goal at a 20mg dose, but at a price of $25 per month. However, I can give you a four week sample of Lipitor to try (to make sure there are not side effects, etc.) and a coupon that will lower your monthly cost to $15. This will last for a year (at which point Lipitor should be generic). Using the branded product with samples and coupons, the additional out of pocket cost to the patient is only $50/year or an extra $4/month, but they get to try the med first, and received a drug that worked better, with fewer side effects. Which is better for the patient? (Before you say that $50/year is a lot for a poor person, keep in mind that very poor patients are on Medicaid and won't pay any difference for the medications, and people who do not have prescription coverage might have problems being able to afford either, as generic simvastatin 80mg is $33/month).

To be fair, there are PLENTY of examples where branded drugs are promoted heavily by the industry using drug reps and samples, where an equally safe and effective medications are available generically. Dr. Ramirez' post regarding generic citalopram and Lexapro is a great example. In addition, the argument can be made that drug companies should be putting their resources coming up with useful new agents, rather than re-packaging older medicines into one pill (like Naprosyn and Nexium).

The point is that the issue of the samples, drug reps and the industry is a complex one. The drug industry is one of the most profitable industries in the US. Their use of expensive, direct to consumer advertising may seem inappropriate to some, when so many in our country can not afford medications. Past excesses of lavish gifts to physicians (no longer allowed) and more recent settlements of off label promotions (see Pharma Should Not Settle Off-Label Promotional Suits) has certainly eroded trust in the industry from the public, patients and many physicians.

However, drugs save lives. Even in recent years, we have seen the remarkable difference prescriptions medications have made (HIV, cancer, heart attacks). Also, the majority of prescriptions being used today are now generic, and were made possible because they were once sold under a brand name. As stated above, generics are not always the best choice for patients, and while drug company promotional efforts will undoubtedly increase sales of expensive drugs, this is not necessarily a bad thing if patients' lives are improved. Finally, the way medications are covered and paid for create a sometime perverse set of circumstances where samples and coupons for expensive medicines may actually be in the patient's best interest even if similar medications are available generically or over the counter. Many (especially in the media) want to paint the influence of the pharmaceutical industry as black and white. However, this issue remains very, very grey.