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The American Journal of Medicine (2007) 120, 713-719

CLINICAL RESEARCH STUDY

Fixed-Dose Combinations Improve Medication Compliance: A Meta-Analysis


Sripal Bangalore, MD, MHA, Gayathri Kamalakkannan, MD, MPH, Sanobar Parkar, MD, MPH, Franz H. Messerli, MD, FACC
Department of Medicine, Division of Cardiology, St. Lukes-Roosevelt Hospital and Columbia University, New York, NY. ABSTRACT BACKGROUND: Compliance with treatment is a sine qua non for successful treatment of chronic conditions like hypertension. Fixed-dose combinations are designed to simplify the medication regimen and potentially improve compliance. However the data on comparison of xed-dose combination with free-drug regimen to improve patients medication compliance is limited. METHODS: We conducted a MEDLINE search of studies using the words xed-dose combinations, compliance and/or adherence. The inclusion criteria were studies which involved xed-dose combination versus free-drug components of the regimen given separately. Only studies which reported patients compliance were included. RESULTS: Of the 68 studies on xed-dose combinations, only 9 studies fullled the inclusion criteria. Two studies were in patients with tuberculosis, 4 in the hypertensive population, 1 in patients with human immunodeciency virus (HIV) disease and 2 in the diabetic population. A total of 11,925 patients on xed-dose combination were compared against 8317 patients on free-drug component regimen. Fixed-dose combination resulted in a 26% decrease in the risk of non-compliance compared with free-drug component regimen (pooled relative risk [RR] 0.74; 95% condence interval [CI], 0.69-0.80; P .0001). There was no evidence of heterogeneity in this analysis ( 2 14.49, df 8; P .07). A subgroup analysis of the 4 studies on hypertension showed that xed-dose combination (pooled RR 0.76; 95% CI, 0.71-0.81; P .0001) decreased the risk of medication non-compliance by 24% compared with free-drug combination regimen. CONCLUSIONS: Fixed-dose combination decreases the risk of medication non-compliance and should be considered in patients with chronic conditions like hypertension for improving medication compliance which can translate into better clinical outcomes. 2007 Elsevier Inc. All rights reserved. KEYWORDS: Combination; Compliance; Fixed-dose; Free drug; Hypertension

Cardiovascular disease is the leading cause of morbidity and mortality among both sexes and all races in the US.1 In patients with coronary artery disease, many of the cardiovascular risk factors (eg, hypertension, diabetes, hyperlipidemia) co-exist, and their effect on cardiovascular mortality and morbidity is shown to be more than just additive.2,3 Clinical trials have emphasized that treatment of risk factors can reduce the risk of
This work was presented in part at the 21st Annual Scientic Session of the American Society of Hypertension, New York, NY. Requests for reprints should be addressed to Franz H. Messerli, MD, Hypertension Program, Division of Cardiology, Columbia University College of Physicians and Surgeons, St. Lukes-Roosevelt Hospital Center, 1000 Tenth Avenue, Suite 3B-30, New York, NY 10025. E-mail address: fmesserl@chpnet.org.

future cardiovascular events by as much as 50% in patients at high risk for coronary artery disease.4,5 This also would mean that patients with coronary artery disease frequently have a range of concomitant medical conditions that require pharmacological therapy, and polypharmacy is common in this population.6,7 In chronic cardiovascular conditions like hypertension, hyperlipidemia and diabetes, a majority of patients are on 2 or more medications for optimal treatment.8 A number of studies have shown that treatment with a single antihypertensive agent will reduce blood pressure below 140/90 mm Hg in 50% of individuals, regardless of the class of antihypertensive medications used.9-11 Evidence now suggests that the majority of hypertensives will require combinations of antihy-

0002-9343/$ -see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.08.033

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pertensive medications to achieve optimal blood pressure that reported medication compliance/adherence or persiscontrol.9,12-14 A survey conducted by the National Council tence when using xed-dose combination vs free-drug on Patient Information and Education showed that one third combinations were selected. Only 9 studies met the above of patients receive at least 2 prescriptions and 10% of criteria. Among the studies, 4 were in the hypertensive patients receive 4 or more prescriptions after a visit to a population, 2 in the diabetic population, 1 in the cohort of primary care physician.15 population with human immunoPoor adherence to medication deciency virus (HIV) infection, regimen contributes to the pracand 2 studies in the cohort of CLINICAL SIGNIFICANCE tice-outcome gap, in which clinipatients with tuberculosis.22-27 cal guidelines are implemented The Novartis Data Center (NDC) Evidence now suggests that the majority but expected benets are not realdataset was from a personal of hypertensives will require combinations ized.16 Noncompliance to medicacommunication from Novartis of antihypertensive drugs to achieve optitions was by far the leading cause (November 2005). mal blood pressure control. of acute decompensated heart failure, implicated in 42% of hospital Poor adherence to medication regimens Data Extraction admissions.17 The National Councontributes to the practice-outcome We based our analysis on the sumcil on Patient Information and Edmary statistics reported in the litgap, in which clinical guidelines are imucation has estimated that the erature. Data extraction was done plemented but expected benets are not compliance rate ranges to just separately for the xed-dose comrealized. over 30% for chronic conditions bination cohort and the free-drug Fixed-dose combinations provide us with like diabetes and heart failure.15 cohort. We extracted the deniBecause polypharmacy and a strong armamentarium in chronic distions used for medication complicomplexity of treatment regimen ease management. The risk of non-comance in each study. For the sake of are known to be 2 of the determisimplicity, compliance for this pliance to medication regimen is renants of poor medication complimeta-analysis was considered as duced by 24%-26% with xed-dose ance, efforts have been made to either adherence or persistence to combinations. simplify the drug regimen. Intervenmedication regimen. We extracted Fixed-dose combination should be considtions aimed at simplifying the drug the mean age of the population, regimen for patients (eg, daily dosered in patients with chronic conditions, length of follow-up, and the difing as opposed to twice daily doslike hypertension, for improving medicaference in the efcacies between ing18) have been shown to improve the 2 modalities of treatment, if tion compliance, which can translate into patients compliance in studies.18,19 available. better clinical outcomes. The efcacy and safety of xeddose combinations is well estabStatistical Analysis lished.20 Some studies have shown Statistical analysis was done using that xed-dose combinations may be more effective than constandard software (Stata 9.0, Stata Corporation, College Stacomitant administration of individual components.21 Howtion, Tex) using the METAN program.28 The mean difference ever, the data on the efcacy of xed-dose combinations to in the compliance outcomes between the 2 groups was calcuimprove patients compliance to drug regimen are not well lated for each study. The pooled effect for each grouping of dened. trials was derived from the point estimate for each separate

SUBJECTS AND METHODS Selection of Studies


We conducted a MEDLINE search of studies using the terms: xed-dose combinations, compliance, adherence, or persistence. We limited our search to studies in human subjects and English language in peer-reviewed journals from 1966 to November 2005. We checked the reference lists of reviewed articles and original studies identied by the electronic search to nd other potentially eligible studies. We then looked for studies in which xed-dose combination medications were compared against the freedrug combination medications (example: 1 pill of enalapril hydrochlorothiazide vs enalapril and hydrochlorothiazide given as 2 separate pills). Only studies

trial weighted by the inverse of the variance (1/SE2). Heterogeneity was assessed visually using funnel plots and Q ( 2) statistics using the Mantel-Haenzel test.29 If trials were homogeneous (P .05), a xed-effects model was used to calculate pooled effect sizes. Otherwise, a random-effect model of DerSimonian and Laird30 was applied to calculate overall differences. A subgroup analysis was performed for studies in hypertensive cohort. Publication bias was estimated using the rank correlation test of Begg and the weighted regression test of Egger.

RESULTS Characteristics of Trials


The characteristic of the studies evaluated are elaborated in Table 1. Among the 9 studies on chronic disease evaluated,

Bangalore et al
Table 1 Trial Geiter et al, 1987

Fixed-Dose Combination and Adherence

715

Characteristics of Studies Design


24

Condition Treated Tuberculosis Tuberculosis HIV Hypertension

Compliance Outcomes Composite adherence measure based on urine testing, pill counting, and self-reporting at 8 weeks and 6 months Compliance dened as not lost to follow up or changed treatment Self-reported missed doses using patient medication adherence questionnaire Dened as medication possession ratio- sum of total days supply across prescriptions divided by total number of days from the rst prescription ll date to the rst day of the last prescription ll date. Dened as persistent if patients renewed their prescription within 3 times the number of days supplied by the previous prescription. Persistence was dened as the % of patients taking the same drug in the rst year compared with the second year of treatment Sum of days supply or medication obtained by the patient during the follow-up period divide by the total number of days in the designated follow-up period

Randomization Randomization Randomization Retrospective

Su and Perng, 200226 Eron et al, 200023 Taylor and Shoheiber, 200327

Dezii, 200022

Retrospective

Hypertension

NDC data set Melikian et al, 200225

Retrospective

Hypertension

Retrospective

Diabetes

2 were in the cohort of patients with tuberculosis, 1 study in patients with HIV, 4 studies in the hypertensive cohort, and 2 studies in the diabetic cohort. The study by Dezii et al 22 involved 2 subgroups, one using a xed-dose combination of lisinopril and hydrochlorothiazide, and the other using a xed-dose combination of enalapril and hydrochlorothiazide. The study by Melikian et al25 involved 2 subgroups with data on compliance. Three of the studies were randomized controlled trials,23,24,26 whereas the rest were retrospective database analyses of pharmacy claims.18,22,27

Compliance Outcomes: Denition


The denitions used for measurement of compliance outcomes are in Table 1. There was marked heterogeneity in the compliance measures among the studies evaluated. Some studies used composite compliance measures including pill counting, whereas others used compliance questionnaires.23,24 Some studies used medication possession ratio and persistence as the measure of compliance.22,27

Patient Characteristics
A total of 20,242 patients followed for 13.1 8.6 months were evaluated in the 9 studies published (Table 2). This included 11,925 patients on xed-dose combination and 8317 patients on free-drug combination regimens. The age of the patients ranged from 40 to 68 years, and in a few studies the majority of the patient population studied was men.23,24,26 In other studies, there was an equal distribution of men and women (Table 3).

decrease in the risk of non-compliance compared with freedrug component regimen (non-compliance rate: 35% vs 38%; P .0001). There was no evidence of heterogeneity in this analysis (Figure 1). There was no publication bias based on either the rank correlation method (Beggs test) or the weighted regression method (Egger test, P .43). The compliance outcomes based on a subgroup analysis of studies in the hypertensive cohort are shown in Figure 2. In the hypertensive cohort, similar to the overall cohort, xed-dose combination regimens reduced the risk of noncompliance by 24% compared with free-drug combination regimens (non-compliance rate: 35.7% vs 37.9%; P .0001). There was no publication bias based on either the rank correlation method (Beggs test) or the weighted regression method (Figure 2). The compliance outcomes based on an analysis of the 3 randomized studies is shown in Figure 3. Fixed-dose combination regimens reduced the risk of non-compliance by 17% (trend) compared with free-drug combination regimens (Figure 3). However, the 3 randomized studies accounted for only 1029 of the 20,242 patients evaluated. In the analysis on the 6 retrospective studies, xed-dose combination regimens reduced the risk of non-compliance by 27% compared with free-drug combination regimens (non-compliance rate: 35.4% vs 39.5%; P .0001) (Figure 4).

Efcacy Outcomes
Among the 9 studies evaluated, only 3 studies had efcacy outcomes (Table 3).23,24,26 Based on these 3 studies, it can be concluded that xed-dose combination regimens were equally efcacious or, in some cases, more efcacious than the free-drug combination regimens.

Compliance Outcome
The compliance outcomes based on the 9 studies are shown in Figure 1. Fixed-dose combinations resulted in a 26%

716
Table 2 Trial Geiter et al, 1987
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Characteristics of Studies Intervention n (Intervention) Comparison Same medications separately n (Comparison) Follow-up 532 6 months

Su and Perng, 200226 Eron et al, 200023 Taylor and Shoheiber, 200327 Dezii, 200022 Dezii, 200022 NDC dataset, 2003 Melikian et al, 200225 Melikian et al, 200225

169 Ritafer (FDC of isoniazide, rifampicin, pyrazinamide) for 2 months followed by Rinah (FDC of isoniazide, rifampicin) for 4 months 57 Ritafer ethambutol for 2 months followed by Rinah for 4 months Combivir (Lamivudine 150 110 mg/Zidovudine 300 mg) bid Protease Inhibitor FDC of Amlodipine/Benazepril 2754

Same medications separately

48

2 years

FDC of Lisinopril/HCTZ FDC of Enalapril/HCTZ FDC of ARB/Diuretic FDC of glyburide/metformin FDC of glyburide/metformin

1644 969 6058 105 59

Lamivudine 150 mg bid 113 Zidovudine 200 mg tid Protease inhibitor Dihydropyridine CCB and 2978 an ACEI given separately Lisinopril and diuretic 624 given separately Enalapril and diuretic 705 given separately ARB and diuretics given 1443 separately Glyburide and metformin 1815 given separately Glyburide and metformin 59 given separately
calcium channel blockers; FDC

4 months

2 years

1 year 1 year 2 year 6 months 6 months


xed-dose combi-

ACEI angiotensin converting enzyme inhibitors; ARB nation; HCTZ hydrochlorothiazide.

angiotensin receptor blockers; CCB

DISCUSSION
This study evaluated the role of xed-dose combination regimens to improve medication compliance in patients with chronic illness. The results of this study show that xed-dose combination regimens reduce the risk of noncompliance by 24%-26% compared to free-drug combination regimens. In the subgroup of patients with hypertension, xed-dose combination regimens reduced the risk of medication non-compliance by 24% compared to free-drug combination regimens.

Polypharmacy in Chronic Disease Management


Table 4 lists some of the common chronic conditions and the recommended long-term treatment. As is obvious from the table, chronic disease management requires the use of multiple medications. In conditions like hypertension, hyperlipidemia, and diabetes, a majority of patients are on 2 or more medications for optimal treatment.8 The National Health and Nutrition Examination Survey of 1988-1991 (NHANES III) found that the blood pressure control rate in the United States is 27%-29%.31 Corresponding data from other countries have shown even lower control rates than those in the United States.32 These low blood pressure control rates have been in part attributed to poor medication compliance by patients. A number of studies have shown that treatment with a single antihypertensive agent will reduce the blood pressure below 140/90 mm Hg

in only 50%-60% of individuals, regardless of the class of antihypertensive medications used.9-11 Evidence now suggests that the majority of hypertensives will require combinations of antihypertensive medications to achieve optimal blood pressure control.9,12-14 In fact, the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) recognizes that most people with hypertension will require 2 or more antihypertensive medications to achieve a blood pressure goal and recommends using combination therapy as the initial line of management in patients with a blood pressure 20/10 mm Hg above goal or systolic blood pressure 160 mm Hg.33 The Joint National Committee recognizes polypharmarcy as one of the barriers to achieve blood pressure goals and considers medication noncompliance as one of the causes of resistant hypertension.33 The Joint National Committee also recommends using combination medication to reduce prescription cost. In patients with diabetes, intensive glycemic control is important in reducing micro- and macrovascular complications. However, many patients with type 2 diabetes are unable to achieve or maintain the American Diabetes Associations recommended glycosylated hemoglobin (HbA1C) goal of 7.0.34 In the United Kingdom Prospective Diabetes Study (UKPDS), patients receiving a combination of sulfonylurea and metformin achieved better glycemic control than those receiving sulfonylurea alone.35 In

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Table 3 Trial Geiter et al, 1987

Fixed-Dose Combination and Adherence

717

Patient Characteristics and Outcomes Age


24

Efcacy Outcome Male (%) (FDC vs Free-drug) 75

Adherence Outcomes (FDC vs Free-drug)

NA

Su and Perng, 200226

NA

89

Eron et al, 200023

39.9

8.0

85

Taylor and Shoheiber, 200327 53 Dezii, 2000 (Lisinopril)22 Dezii, 2000 (Enalapril)22 NDC dataset, 2003 Melikian et al, 200225 Melikian et al, 200225
FDC xed-dose combination.

50 NA NA NA 50.1 50.8

NA NA NA 67.5 62.5

12.5 12.8

Sputum conversion at 8 weeks: Urine testing, pill counting, self-reporting: 86.6% vs 77.7% (P .05) At 8 weeks96.5% vs 98.1% (P ns) At 6 months 88.5% vs 87.3% (P .05) Compliance Sputum conversion: At 6 months: 70.2% vs 66.7% (P .05) 2 months95% vs 88.9% (P ns) 6 months 100% vs 100% (P ns) Radiological improvement: At 2 years92.3% vs 84% (P ns) Fewer missed doses of FDC at 8 weeks Treatment failure (viral load) (P .007) and at 16 weeks (P .046). 3.6% vs 7.1%, P .26 (FDC Adherence questionnaire: Patients on FDC vs free-drug). FDC non had higher total scores at 8 weeks inferior to free-drug (P .002) and at 16 weeks (P .020) combinations NA Medication possession ratio 80.8% vs 73.8% (P .001) NA Persistence at 12 months: 68.7% vs 57.8% (P .05) NA Persistence at 12 months: 70.0% vs 57.5% (P .05) NA Persistence at 2 years: 55% vs 45% NA Adherence (medication possession ratio) at 6 months: 77% vs 54% (P .0001) NA Adherence (medication possession ratio) at 6 months: 87% vs 71% ( P .0001)

fact, the current American Diabetes Association guidelines recommend that combination therapy (eg, a biguanide and a sulfonylurea) is a secondary approach in patients for whom monotherapy fails.34 In addition, type II diabetics need other medications, for example, aspirin and statins for car-

dioprotection, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers for renal protection. Hence, polypharmacy is common in this cohort of patients as well. Polypharmacy is common in infectious disease states where resistance to the microbial agent is reduced with combination

Figure 1 Effect of xed-dose combination vs free-drug combination on the risk of non-compliance to medication regimens. Vertical solid line null effect; vertical dotted line overall effect on compliance; boxes and horizontal lines relative risk (95% CI).

Figure 2 Effect of xed-dose combination vs free-drug combination on the risk of medication non-compliance in cohort with hypertension. Vertical solid line null effect; vertical dotted line overall effect on compliance; boxes and horizontal lines relative risk (95% CI).

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Table 4 Combinations Drug Regimens for Common Medical Conditions Condition Heart failure Medications

Figure 3 Effect of xed-dose combination vs free-drug combination on the risk of medication non-compliance in the randomized controlled trials. Vertical solid line null effect; Vertical dotted line overall effect on compliance; boxes and horizontal lines relative risk (95% CI).

Diuretic Beta-Blocker ACEI/ARB Aldosterone blocker Digoxin Post myocardial Aspirin Beta-Blocker ACEI/ARB infarction Statin Post PCI Aspirin Clopidogrel Statin BetaBlocker ACEI/ARB Hypertension Combinations of at least 2 of ( Stage I) following: ACEI/ARB, CCB, Diuretics, Beta-blockers Diabetes (NonSulfonylurea Biguanide Aspirin insulin-dependent) ACEI/ARB Statins Hypercholesterolemia Statins Ezetimibe or Statins Niacin HIV 2 Nucleoside Reverse Transcriptase Inhibitor 1 Protease Inhibitor Tuberculosis INH Rifampin Pyrazinamide Ethambutol
ACEI angiotensin converting enzyme inhibitors; ARB angiotensin receptor blockers; CCB calcium channel blockers; HIV human immunodeciency virus; INH isoniazide; PCI percutaneous coronary intervention.

therapy. Compliance to medication is of paramount importance as noncompliance can lead to resistance to the drug, endangering not only the patient but the community at large. In patients with established coronary artery disease, many of the cardiovascular risk factors coexist, resulting in clustering of risk factors, and polypharmacy is therefore common in this subgroup as well.2,3

Polypharmacy, Fixed-Dose Combination, and Compliance


Polypharmacy and complexity of treatment regimen are known to be 2 of the determinants of poor medication compliance. Poor compliance to medication regimen contributes to the practice-outcome gap, in which clinical guidelines are implemented but expected benets are not realized.16 The National Council on Patient Information and Education has

estimated that the compliance rate ranges to just over 30% for chronic conditions like diabetes and heart failure.15 Fixed-dose combinations have the potential to improve compliance by reducing the pill burden (polypharmacy). In this study we have shown that xed-dose combinations reduce the risk of medication non-compliance by 24%-26%. The efcacy and safety of xed-dose combination is well established.20 In this study, although not all studies had efcacy measures, in the studies that did report them, xed-dose combinations were more efcacious or at least noninferior to free-drug combination regimens. This is in concordance with studies that have shown that xed-dose combinations may be more effective than concomitant administration of individual components.21 Wald and Law proposed a polypill that included a statin with 3 antihypertensive medications (a thiazide, a beta-blocker, and an angiotensin-converting enzyme inhibitor) with folic acid and aspirin.36 They proposed that if this polypill was taken by all people over the age of 55 years and those with preexisting coronary artery disease, it would result in 88% lower risk of ischemic heart disease and 80% decreased risk of stroke.36 Whether this magic bullet is indeed practical is a matter of debate. However, this highlights the importance of xed-drug combinations that can improve adherence and thereby the clinical outcomes of patients.

Limitations
Figure 4 Effect of xed-dose combination vs free-drug combination on the risk of medication non-compliance in the retrospective studies. Vertical solid line null effect; vertical dotted line overall effect on compliance; boxes and horizontal lines relative risk (95% CI).

Like any other meta-analysis, the data included in the studies were not sufcient enough to control for potential confounding variables, like the number of medications, other comorbidities, age, socioeconomic strata, and education level. The denition for compliance was not uniform in the

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14. Waeber B. Treatment strategy to control blood pressure optimally in hypertensive patients. Blood Press. 2001;10:62-73. 15. Dezii CM. Medication noncompliance: what is the problem? Manag Care. 2000;9(9 Suppl):7-12. 16. Ziegelstein RC. Adherence to medication regimens and recommended lifestyle changes in patients with cardiovascular disease. Adv Stud Med. 2003;3:150-156. 17. Michalsen A, Konig G, Thimme W. Preventable causative factors leading to hospital admission with decompensated heart failure. Heart. 1998;80:437-441. 18. Dezii CM, Kawabata H, Tran M. Effects of once-daily and twice-daily dosing on adherence with prescribed glipizide oral therapy for type 2 diabetes. South Med J. 2002;95:68-71. 19. Breekveldt-Postma NS, Herings RM. Persistence with antihypertensives related to formulation: the case of nifedipine. Ann Pharmacother. 2005;39:237-242. 20. Blank R, LaSalle J, Reeves R, et al. Single-pill therapy in the treatment of concomitant hypertension and dyslipidemia (the amlodipine/atorvastatin gemini study). J Clin Hypertens (Greenwich). 2005;7:264273. 21. Blonde L, Wogen J, Kreilick C, Seymour AA. Greater reductions in A1C in type 2 diabetic patients new to therapy with glyburide/ metformin tablets as compared to glyburide co-administered with metformin. Diabetes Obes Metab. 2003;5:424-431. 22. Dezii CM. A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care. 2000;9(9 Suppl):2-6. 23. Eron JJ, Yetzer ES, Ruane PJ, et al. Efcacy, safety, and adherence with a twice-daily combination lamivudine/zidovudine tablet formulation, plus a protease inhibitor, in HIV infection. AIDS. 2000;14:671681. 24. Geiter LJ, OBrien RJ, Combs DL, Snider DE Jr. United States Public Health Service Tuberculosis Therapy Trial 21: preliminary results of an evaluation of a combination tablet of isoniazid, rifampin and pyrazinamide. Tubercle. 1987;68(2 Suppl):41-46. 25. Melikian C, White TJ, Vanderplas A, et al. Adherence to oral antidiabetic therapy in a managed care organization: a comparison of monotherapy, combination therapy, and xed-dose combination therapy. Clin Ther. 2002;24:460-467. 26. Su WJ, Perng RP. Fixed-dose combination chemotherapy (Rifater/ Rinah) for active pulmonary tuberculosis in Taiwan: a two-year follow-up. Int J Tuberc Lung Dis. 2002;6:1029-1032. 27. Taylor AA, Shoheiber O. Adherence to antihypertensive therapy with xed-dose amlodipine besylate/benazepril HCl versus comparable component-based therapy. Congest Heart Fail. 2003;9:324-332. 28. Bradburn MJ, Deeks JJ, Altman D. Sbe24: metan an alternative meta-analysis command. Stata Tech Bull Reprints. 1998;8:86-100. 29. Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. Stat Med. 1988;7:889-894. 30. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-188. 31. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension. 1995;25: 305-313. 32. Julius S. Worldwide trends and shortcomings in the treatment of hypertension. Am J Hypertens. 2000;13:57S-61S. 33. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289:2560-2572. 34. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2002;25:213-229. 35. UKPDS 28: a randomized trial of efcacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. U.K. Prospective Diabetes Study Group. Diabetes Care. 1998;21:87-92. 36. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419.

studies, and further studies are needed in this regard. In this study we used compliance to represent adherence or persistence. Although this is not ideal, given the heterogeneity of the denitions used in the studies and the limited number of studies available, we used this denition for simplicity. Some studies based their compliance measures on medication possession ratio, and it is difcult to verify whether these patients actually consumed their medications.

CONCLUSIONS
Fixed-dose combinations provide us with a strong armamentarium in chronic disease management. Non-compliance to medication regimens is reduced by 24%-26% with xed-dose combination regimens. Fixed-dose combinations should be considered in patients with chronic conditions, like hypertension, for improving medication compliance, which can translate into better clinical outcomes.

References
1. American Heart Association. 2004 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association; 2004. 2. Neaton JD, Blackburn H, Jacobs D, et al. Serum cholesterol level and mortality ndings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med. 1992;152:1490-1500. 3. Thomas F, Bean K, Guize L, et al. Combined effects of systolic blood pressure and serum cholesterol on cardiovascular mortality in young ( 55 years) men and women. Eur Heart J. 2002;23:528-535. 4. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393. 5. Gaede PH, Jepsen PV, Larsen JN, et al. The Steno-2 study. Intensive multifactorial intervention reduces the occurrence of cardiovascular disease in patients with type 2 diabetes. Ugeskr Laeger. 2003;165: 2658-2661. 6. Dailey G, Kim MS, Lian JF. Patient compliance and persistence with anti-hyperglycemic therapy: evaluation of a population of type 2 diabetic patients. J Int Med Res. 2002;30:71-79. 7. Veehof L, Stewart R, Haaijer-Ruskamp F, Jong BM. The development of polypharmacy. A longitudinal study. Fam Pract. 2000;17:261-267. 8. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281:2005-2012. 9. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997. 10. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993;328:914-921. 11. Philipp T, Anlauf M, Distler A, et al. Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study. HANE Trial Research Group. BMJ. 1997;315:154-159. 12. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755-1762. 13. Ruzicka M, Leenen FH. Monotherapy versus combination therapy as rst line treatment of uncomplicated arterial hypertension. Drugs. 2001;61:943-954.

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