Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.965776

Vol. 30, No. 12, 2014, 2423–2424

Article ST-0353/965776 All rights reserved: reproduction in whole or part not permitted

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Editorial The case for single pill combinations

Rainer Du¨sing


Hypertoniezentrum Bonn, Germany Address for correspondence: Prof. Dr. Rainer Du¨sing, Hypertoniezentrum Bonn, Schwerpunktpraxis Kardiologie, Angiologie, Pra¨vention, Rehabilitation, Am Burgweiher 52–54, 53123 Bonn (Duisdorf), Germany. Tel.: +49 228 9621000; Fax: +49 228 96210033; [email protected] Accepted: 10 September 2014; published online: 29 September 2014 Citation: Curr Med Res Opin 2014; 30:2423–4

Keywords: Adherence – Antihypertensive – Fixed-dose combination – Pill burden

! 2014 Informa UK Ltd

Although the need for combination therapy of hypertension was obvious from the early intervention trials, administration of such therapy as fixed-dose or single-pill combinations has only reached general acceptance in recent years. The main reason for this change of mind documented in the recommendation of using single-pill combinations in almost every recent hypertension guideline is our increasing knowledge about non-adherence to drug therapy. In the multifactorial origin of non-adherence, the complexity of therapy, especially in elderly patients with comorbidities and polypharmacy, has been identified as a major factor involved. So an important rule in hypertension treatment, and maybe in drug therapy in general, is to keep things as simple as possible.

As a young resident at a German University hospital in the early 1970s, I would not have dared to prescribe a fixed-dose combination (FDC) drug for any one of my hypertensive patients. Although the need for combination therapy of hypertension was already documented in the early intervention studies, the Veterans Administration Trials in 1967 and 1970, administering the necessary combination therapy in a single pill was far from being generally accepted. In the following years, a growing popularity of FDCs with up to four antihypertensive agents could be noted amongst family doctors in Germany. They were impressed by the antihypertensive efficacy of FDCs containing (di)hydralazine, b-blocker and a thiazide diuretic (and in some instances even the potassium sparing triamterene). In contrast, academic medicine continued to mostly reject these modern therapeutic options. One major objection at the time was that the flexibility to change the doses of the individual agents is abolished in a fixed-dose combination. Today, however, many FDCs available for the treatment of hypertension come in a variety of doses offering either 12.5 or 25 mg of hydrochlorothiazide, 5 or 10 mg of amlodipine and either low to moderate or high doses of ACE inhibitors or angiotensin receptor blockers. This is also the reason why the term ‘fixed-dose’ combination has largely been replaced by ‘single-pill’ combination (SPC). Another argument may still be valid today. When SPCs of thiazide diuretics and potassium sparing diuretics were commonly used, many doctors did not realize that the prescribed diuretic actually contained either triamterene or amiloride both of which have definite limitations e.g. in patients with renal impairment. Therefore, SPCs, at least those with a trade name and thus not listing the contained agents in their label, may lower physicians’ awareness of what drugs are actually being used in a given patient. A final point is that the industry is using fixed-dose combinations to extend patent protection, which has run out on the individual components. Thus, using SPCs may be more expensive than prescribing two or three generic drugs separately. The critical stance towards SPCs has markedly regressed over the past few decades due to our increasing knowledge about the extent, the clinical The case for single pill combinations Du¨sing


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Current Medical Research & Opinion Volume 30, Number 12

December 2014

importance and the economic consequences of non-adherence to drug therapy1,2. Among the multiple factors involved, the complexity of the prescribed therapy has been identified as a major factor for non-adherence3. Several studies have shown that the number of dosing time points per day4 and especially the number of daily tablets, the so-called pill burden5,6, have a marked impact on adherence with the prescribed therapy. So an important rule in any medical therapy is to keep things as simple as possible with the smallest conceivable pill burden. In this issue of CMRO, Xie and colleagues add further support to this concept7. In their retrospective analysis of data from a huge healthcare database, 417,000 patients with triple antihypertensive therapy containing an angiotensin receptor blocker (olmesartan or valsartan), amlodipine and hydrochlorothiazide were identified. Combinations with these three agents were prescribed either as three separate pills, as two pills with one containing two of these antihypertensives, or as a single pill combination of all three agents. Their data demonstrate that a greater pill burden is directly and significantly associated with decreased adherence and persistence in a real practice setting7. This aspect of therapy may be further highlighted by recent data pointing to the magnitude of polypharmacy especially in the elderly population. A recent analysis of medical insurance data in Germany demonstrated that in a sample of 263,056 patients who received medical therapy, more than one third (35.6%) were prescribed five or more drugs. In patients 65 years of age, that figure was up to two thirds of all treated patients (61.3%)8. As a consequence of all this more recent knowledge, things have changed completely 40 years after my early days as a resident in the hypertension clinic. As a senior doctor now, weighing the pros and cons of SPCs, I would not accept a young doctor prescribing dual or triple antihypertensive therapy as two or three separate pills, except


The case for single pill combinations Du¨sing

for initial up-titration of therapy or other well argued reasons.

Transparency Declaration of funding This editorial was not funded. Declaration of financial/other relationships R.D. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article. R.D received honoraria for giving lectures on the topic of compliance and single pill combinations for Novartis, UCB and Berlin Chemie.

References 1. Metry J-M, Meyer UA. Drug Regimen Compliance. Issues in Clinical Trials and Patient Management. Chichester, UK: Wiley & Sons Ltd; 1999 2. American Heart Association. Medication Adherence – Taking Your Meds as Directed. 2013. Available at: More/ConsumerHealthCare/Medication-Adherence-Taking-Your-Meds-asDirected_UCM_453329_Article.jsp. Last accessed 5 July 2014 3. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med 2005;165:1147-52 4. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23: 1296-310 5. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 2007;120:713-19 6. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension 2010;55:399-407 7. Xie L, Frech-Tamas F, Marret E, Baser O. A medication adherence and persistence comparison of hypertensive patients treated with single-, doubleand triple-pill combination therapy. Curr Med Res Opin 2014;30(12):2415-22 8. hkk Gesundheitsreport 2012: Polypharmazie. Eine Analyse mit hkkRoutinedaten von Dr. Bernard Braun (BIAG). Available at: http:// Last accessed 5 July 2014 ! 2014 Informa UK Ltd

The case for single pill combinations.

Although the need for combination therapy of hypertension was obvious from the early intervention trials, administration of such therapy as fixed-dose...
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