A Migraine Is NOT Just A Headache!

I think this is a very interesting time to examine this topic since we seem to be subjected to an ever increasing number of “combination” medications for various cardiovascular ailments. Typically this is limited to a drug class, like hypertension or dyslipidemia, but lately it has expanded, with a good example being amlodipine and atorvastatin for Pfizer’s “Caduet”. The most nefarious example of this, of course, is the dreaded “polypill“.

Besides testing my ability to remember “brand” drug names, there are two major motivators driving the expanded NDA applications and approval for these medications. First, this is basically low-hanging fruit for the pharmaceutical industry. They typically take a drug with which they own the patent and combine it with a generic that is dirt cheap in order to give them an additional drug in their portfolio. A good example is combining valsartan with amlodipine, a combination which is a great contemporary BP regimen, into “ExForge” which brings to mind tales of King Arthur and the Sword in the Stone. Pure coincidence, of course. Amlodipine’s patent, by the way, has long went the way of the dodo and can be found at very low prescription drug prices.

The second reason is a perception by prescribers that by combining two medications into one (even if they are both once a day), we will reduce “pill count” for patients and therefore improve compliance. Compliance, you see, is a large problem in the health care industry, but particularly with cardiology where medications often are preventative and don’t result in a perceived symptom relief. Statins for cholesterol are a great example of this. I did a little bit of research into the argument that combination pills improve compliance and, alongside my own perceptions of compliance habits, have a few thoughts for you. Three studies which are a good cross-section of this literature:

The first, from Dezil, examined a PBM database and compared compliance (measured by refill records) by examining patients taking lisinopril or enalapril and hydrochlorothiazide prescriptions separately versus patients taking a combination lisinopril/HCTZ or enalapril/HCTZ. I won’t bother to go into why this is extraordinarily flawed study, but suffice to say you are probably comparing apples and oranges here and that there are probably significant differences between these populations which are not accounted for in the statistical analysis. Regardless, patients taking the combination pill were more compliant (as determined by refill adherence) by 18.8% and 21.7% (absolute). We’ll call this one a win for the combination pills.

The second study, conducted at some worthless institution known as the University of Michigan, examined claims data and found that patients taking a combination of metformin and glyburide compared to the prescriptions separately were more adherent (again examining refill history) by 13% (absolute). See above comments about apples and oranges.

Finally, the last study is one that I believe everyone should read since they do a great job in more comprehensively breaking down this literature with more room than I have. Shalansky and Levy conducted a survey regarding adherence and number of prescription medications in 367 patients with cardiovascular disease and found….. that patients with more “pills” were less adherent? Nay. That it didn’t make a difference? NAY. They actually found that patients taking fewer prescriptions were LESS likely to be compliant. Not only that, but fewer prescriptions was an independent predictor of compliance (OR = 0.85 per medication,
95% CI 0.74 to 0.94; p = 0.01).

My point with this post is that this literature is a mixed bag with few high quality studies demonstrating an improvement in compliance with combination pills. My own perception is that patients will or won’t be compliant and that the combination pills are a mess to deal with in the health care system since it leads to medication reconciliation issues as well as frequent non-recognition of the drugs as separate components (leading to hidden adverse effects). So left with this knowledge that combination pills are of questionable benefit, patients and, more accurately, the insurance companies, are paying a premium for a convenience. You may have noticed a lot of chatter about health care expenditures recently and I’m going to go out on a limb and say that I think you’ll start seeing a lot of reimbursement push back against combination therapies combining a cheap generic with an expensive brand drug. I do not disagree with this action.

Dezii CM.A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care. 2000 Sep;9(9 Suppl):2-6.
Pan F, Chernew ME, Fendrick MA. Impact of Fixed-Dose Combination Drugs on Adherence to Prescription Medications. J Gen Intern Med. 2008 May;23(5):611-4.
Shalansky SJ, Levy AR. Effect of number of medications on cardiovascular therapy adherence. Ann Pharmacother. 2002 Oct;36(10):1532-9.