Impact of Fixed Dose Combination Treatment on Adherence, Blood Pressure Control, Clinical Outcomes and Cost of Treatment
Systematic Review of Randomized Controlled Clinical Trials and Cohort Studies
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Abstract
Background: Initial combination therapy, preferentially fixed-dose combination (FDC) therapy is recommended by most of the clinical guidelines for the management of hypertension in adults. However, there is inadequate evidence on the impact of FDC on Blood pressure control, clinical outcomes, and cost of treatment. Therefore, this review was conducted to synthesize evidence impact of FDC treatment strategies on adherence, blood pressure control, clinical outcomes, and cost of treatment. Methods: We systematically searched articles written in the English language from January 2000 to January 2020 from the following databases: PubMed/Medline, Embase, and Google scholar. Results: Controlled trials were conducted among 17,465 adult hypertensive patients and retrospective cohort studies were conducted among 1,587,737 adult hypertensive patients. FDC strategy Improved treatment adherence and reduced adverse effects. However, the effect of FDC on blood pressure control, clinical outcomes, overall mortality, major adverse cardiac event-free survival, and overall cost of treatment were variable ranging from small changes to insignificant differences. Conclusion: Fixed-dose combination therapy improved treatment adherence and reduced side effects. However, the role of FDC on treatment outcomes like blood pressure reduction, CVD risk factor reduction, reduction in hospitalization rate, and the overall mortality rate was inconclusive. More strong multi-center trials involving patients with good adherence are required to see the actual effect of FDCs on the treatment outcomes of hypertension patients. In addition, ensuring medicine availability and conducting economic evaluations from different perspectives are required to recommend FDC as a first-line treatment option for the treatment of hypertension in adults.DiPette DJ, Skeete J, Ridley E, Campbell NR, Lopez-Jaramillo P, Kishore SP, et al. Fixed-dose combination pharmacologic therapy to improve hypertension control worldwide: Clinical perspective and policy implications. Journal of clinical hypertension (Greenwich, Conn). 2019;21(1):4.
Organization. WH. Prevention of Cardiovascular Disease: Guidelines for assessment and management of cardiovascular risk2007.
World Health Organization. It’s time to walk the talk: WHO independent high-level commission on noncommunicable diseases final report. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. 2019.
health Wh. HEARTS: Technical package for cardiovascular disease management in primary health care. Geneva: World Health Organization. 2016.
Gabb GM, Mangoni AA, Anderson CS, Cowley D, Dowden JS, Golledge J, et al. Guideline for the diagnosis and management of hypertension in adults—2016. Medical Journal of Australia. 2016;205(2):85-9.
Leung AA, Daskalopoulou SS, Dasgupta K, McBrien K, Butalia S, Zarnke KB, et al. Hypertension Canada's 2017 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults. Canadian Journal of Cardiology. 2017;33(5):557-76.
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 Practice guidelines for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. Blood pressure. 2018;27(6):314-40.
Elijovich F, Laffer C. A role for single-pill triple therapy in hypertension. Therapeutic advances in cardiovascular disease. 2009;3(3):231-40.
Kjeldsen SE, Messerli FH, Chiang C-E, Meredith PA, Liu L. Are fixed-dose combination antihypertensives suitable as first-line therapy? Current medical research and opinion. 2012;28(10):1685-97.
Bramlage P, Schmidt S, Sims H. Fixed-dose vs free-dose combinations for the management of hypertension—An analysis of 81 958 patients. Journal of Clinical Hypertension. 2018;20(4):705-15.
Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension (Dallas, Tex : 1979). 2010;55(2):399-407.
Chobanian A, Bakris G, Black H, Cushman W, Green L, Izzo Jr J, et al. Joint National Committee on Prevention DE, Treatment of High Blood Pressure. National Heart L, Blood I, National High Blood Pressure Education Program Coordinating C. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure Hypertension. 2003;42(6):1206-52.
Whelton PK, Carey RM, Aronow WS, Casey DE, Jr., Collins KJ, Himmelfarb CD, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: Executive summary: A report of the American college of cardiology/American Heart Association task force on clinical practice guidelines. Hypertension. 2018;71(6):1269-324.
Authors/Task Force M, Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. [Miscellaneous Article]: Journal of Hypertension October 2018;36(10):1953-2041; 2018.
Basile J, Neutel J. Overcoming clinical inertia to achieve blood pressure goals: the role of fixed-dose combination therapy. Therapeutic advances in cardiovascular disease. 2010;4(2):119-27.
Tung YC, Huang YC, Wu LS, Chang CJ, Chu PH. Medication compliance and clinical outcomes of fixed‐dose combinations vs free combinations of an angiotensin II receptor blocker and a calcium channel blocker in hypertension treatment. The Journal of Clinical Hypertension. 2017;19(10):983-9.
Jaffe MG, Lee GA, Young JD, Sidney S, Go AS. Improved blood pressure control associated with a large-scale hypertension program. Jama. 2013;310(7):699-705.
Williams B, Shaw A, Durrant R, Crinson I, Pagliari C, De Lusignan S. Patient perspectives on multiple medications versus combined pills: a qualitative study. Qjm. 2005;98(12):885-93.
Patel A, Group AC. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. The Lancet. 2007;370(9590):829-40.
Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A, et al. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. Journal of hypertension. 2005;23(12):2157-72.
Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. New England Journal of Medicine. 2008;359(23):2417-28.
Einhorn P, Davis B, Massie B, Cushman W, Piller L, Simpson L, et al. ALLHAT Collaborative Research Group: The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Heart Failure Validation Study—Diagnosis and prognosis. American heart journal. 2007;153(1):42-53.
Organization WH. World Health Organization model list of essential medicines: 21st list 2019. World Health Organization; 2019.
González-Gómez S, Meléndez-Gomez MA, López-Jaramillo P. Fixed dose combination therapy to improve hypertension treatment and control in Latin America. Arch Cardiol Mex. 2017:30046-0.
Patel P, Ordunez P, DiPette D, Escobar MC, Hassell T, Wyss F, et al. Improved blood pressure control to reduce cardiovascular disease morbidity and mortality: the standardized hypertension treatment and prevention project. The Journal of Clinical Hypertension. 2016;18(12):1284-94.
Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev.[Internet]. 2015; 4: 1.
Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. Jama. 2007;298(2):194-206.
Verhagen AP, de Vet HC, de Bie RA, Kessels AG, Boers M, Bouter LM, et al. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. Journal of clinical epidemiology. 1998;51(12):1235-41.
Berger VW, Alperson SY. A general framework for the evaluation of clinical trial quality. Reviews on recent clinical trials. 2009;4(2):79-88.
Wright B, Barry M, Hughes E, Trepel D, Ali S, Allgar V, et al. Clinical effectiveness and cost-effectiveness of parenting interventions for children with severe attachment problems: a systematic review and meta-analysis. 2015.
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed). 2011;343:d5928.
Guyatt G, Busse J. Tool to assess risk of bias in cohort studies. Hamilton, ON: In Book Tool to Assess Risk of Bias in Cohort Studies. 2011.
Matsumura K, Arima H, Tominaga M, Ohtsubo T, Sasaguri T, Fujii K, et al. Does a combination pill of antihypertensive drugs improve medication adherence in Japanese?-a randomized controlled trial. Circulation Journal. 2012;76(6):1415-22.
Selak V, Elley CR, Bullen C, Crengle S, Wadham A, Rafter N, et al. Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care. BMJ (Clinical research ed). 2014;348:g3318.
Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. Jama. 2013;310(9):918-29.
Webster R, Salam A, de Silva HA, Selak V, Stepien S, Rajapakse S, et al. Fixed Low-Dose Triple Combination Antihypertensive Medication vs Usual Care for Blood Pressure Control in Patients With Mild to Moderate Hypertension in Sri Lanka: A Randomized Clinical Trial. Jama. 2018;320(6):566-79.
Baser O, Andrews L, Wang L, Xie L. Comparison of real-world adherence, healthcare resource utilization and costs for newly initiated valsartan/amlodipine single-pill combination versus angiotensin receptor blocker/calcium channel blocker free-combination therapy. Journal of medical economics. 2011;14(5):576-83.
Tung YC, Huang YC, Wu LS, Chang CJ, Chu PH. Medication compliance and clinical outcomes of fixed-dose combinations vs free combinations of an angiotensin II receptor blocker and a calcium channel blocker in hypertension treatment. Journal of Clinical Hypertension. 2017;19(10):983-9.
Tung YC, Lin YS, Wu LS, Chang CJ, Chu PH. Clinical outcomes and healthcare costs in hypertensive patients treated with a fixed-dose combination of amlodipine/valsartan. Journal of Clinical Hypertension. 2015;17(1):51-8.
Xie L, Frech-Tamas F, Marrett E, Baser O. A medication adherence and persistence comparison of hypertensive patients treated with single-, double- and triple-pill combination therapy. Current medical research and opinion. 2014;30(12):2415-22.
Yang W, Chang J, Kahler KH, Fellers T, Orloff J, Wu EQ, et al. Evaluation of compliance and health care utilization in patients treated with single pill vs. free combination antihypertensives. Current medical research and opinion. 2010;26(9):2065-76.
Munoz D, Uzoije P, Reynolds C, Miller R, Walkley D, Pappalardo S, et al. Polypill for Cardiovascular Disease Prevention in an Underserved Population. The New England journal of medicine. 2019;381(12):1114-23.
Ram C. Fixed-dose triple-combination treatments in the management of hypertension. Manag Care. 2013;22(12):45-55.
Verma AA, Khuu W, Tadrous M, Gomes T, Mamdani MM. Fixed-dose combination antihypertensive medications, adherence, and clinical outcomes: A population-based retrospective cohort study. PLoS medicine. 2018;15(6):e1002584.
Degli Esposti L, Perrone V, Veronesi C, Gambera M, Nati G, Perone F, et al. Modifications in drug adherence after switch to fixed-dose combination of perindopril/amlodipine in clinical practice. Results of a large-scale Italian experience. The amlodipine-perindopril in real settings (AMPERES) study. Current medical research and opinion. 2018;34(9):1571-7.
Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-Dose Combinations Improve Medication Compliance: A Meta-Analysis. The American journal of medicine. 2007;120(8):713-9.
Vrijens B, Antoniou S, Burnier M, de la Sierra A, Volpe M. Current situation of medication adherence in hypertension. Frontiers in pharmacology. 2017;8:100.
Sica DA. Rationale for Fixed-Dose Combinations in the Treatment of Hypertension. Drugs. 2002;62(3):443-62.
Malekzadeh F, Marshall T, Pourshams A, Gharravi M, Aslani A, Nateghi A, et al. A pilot double‐blind randomised placebo‐controlled trial of the effects of fixed‐dose combination therapy (‘polypill’) on cardiovascular risk factors. International journal of clinical practice. 2010;64(9):1220-7.
Lacourcière Y. A New Fixed-Dose Combination for Added Blood Pressure Control: Telmisartan Plus Hydrochlorothiazide. Journal of International Medical Research. 2002;30(4):366-79.
Liew D, Park H-J, Ko S-K. Results of a Markov model analysis to assess the cost-effectiveness of a single tablet of fixed-dose amlodipine and atorvastatin for the primary prevention of cardiovascular disease in Korea. Clinical therapeutics. 2009;31(10):2189-203.
Wan X, Ma P, Zhang X. A promising choice in hypertension treatment: Fixed-dose combinations. Asian Journal of Pharmaceutical Sciences. 2014;9(1):1-7.
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| Issue | Vol 8 No 3 (2022) | |
| Section | Review Article(s) | |
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| Fixed Dose Combination Hypertension Blood Pressure Control Clinical Outcomes Adherence Systematic Review | ||
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