Journal Article | Cardio-Metabolic

July 30, 2021

Verma, A., et al



Hypertension is the most common condition seen in the primary care setting. This usually leads to myocardial infarction, stroke, renal failure, and death if not detected and treated early and appropriately. It is one of the most common cause of death and disability in the world.


Hypertension can be classified as primary or secondary. Ninety-five percent of adults with hypertension have primary hypertension and five percent have secondary hypertension.


The cause of primary hypertension is unknown. Excess intake of salt, obesity, and sedentary lifestyle are environmental factors associated with primary hypertension. Genetically related factors include inappropriately high activity of the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system. Another factor linked with primary hypertension is stiffening of the aorta with increasing age. Causes of secondary hypertension are chronic kidney disease, renal artery stenosis, excessive aldosterone secretion, pheochromocytoma and sleep apnea.


Pre-hypertension is defined as systolic blood pressure between 120 mmHg and 139 mmHg or diastolic pressures between 80 and 89 mmHg. Stage 1 hypertension include those with systolic blood pressure of 140 to 159 mmHg or diastolic blood pressure of 90 to 99 mmHg. Stage 2 hypertension include those with systolic blood pressure of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg.


James, P., et al in 2013 published an evidence-based guideline for the management of high blood pressure on adults.  This was based on the report from the panel members appointed to the Eight Joint National Committee (JNC 8). There was a strong evidence in treating hypertensive persons aged 60 years or older to a blood pressure goal of less than 150/90 mmHg.

The panel also recommended a blood pressure goal of less than 140/90 mmHg for those below 60 years old with no diabetes or chronic kidney disease. For hypertensive adults with diabetes and chronic kidney disease with or without diabetes, the blood pressure goal of less than 140/90 mmHg was also recommended.


The World Health Organization (WHO) reported that medication adherence among patients with chronic diseases averages only fifty percent in developed countries. This was recognized as a significant public health issue and global burden. Poor health outcomes and increased healthcare costs can result from medication non-adherence. Several studies have compared the effect of fixed-dose combination therapy and multipill combination therapy in the treatment of hypertension.


The fixed-dose combination therapy has been showed to improve medication adherence and clinical outcomes since patients are more likely to adhere to single-pill rather than multipill treatment regimens.The study of Mazza, A., et al in 2017 evaluated the efficacy of fixed-drug combination (FDC) versus free-combination therapy in lowering office and 24-hour blood pressure values.


Ninety-two patients with uncontrolled essential hypertension (systolic blood pressure of 140 mmHg or diastolic blood pressure of 90 mmHg) previously treated with a renin–angiotensin–aldosterone system (RAAS) inhibitor plus hydrochlorothiazide were switched to once-daily FDC therapy with perindopril/indapamide/amlodipine. Office blood pressure and 24-hour ambulatory blood pressure monitoring were evaluated at baseline and after 1 and 4 months. Significant reductions in blood pressure were found in the FDC group relative to reductions seen with free-combination therapy after the first month of follow-up. Target blood pressure values were reached by more recipients of FDC than free-combination therapy at the fourth month of follow-up.


A meta-analysis performed by Gupta, A., et al in 2010 was done to assess compliance, blood pressure control and safety associated with fixed-drug combination (FDC) anti-hypertensive medications in comparison with their free-drug components. Compared with free-drug combinations, the use of FDCs was associated with a significant improvement in compliance with therapy. The results also showed a 20% decrease in adverse effects associated with the use of an FDC as compared with the free-drug combination.


                   A cohort study was done by Lauffenburger, J., et al in 2016. The study showed that among the 484,493 patients who were initiated with anti-hypertensive medications, 78,958 patients had fixed-dose combinations while 383,269 were initiated with a single therapy, and 22,266 were given multipill combinations.


                   Patients who were initiated on fixed-dose combinations were thirteen percent more likely to be adherent than those who were started on a single anti-hypertensive therapy. Refill rates were also slightly higher among fixed-dose combination initiators.


The study of Verma, A., et al in 2018 was a population-based retrospective cohort study which aimed to determine the adherence and clinical outcome of fixed-dose combination antihypertensive medications.




Medication non-adherence can lead to several problems which are potentially costly and dangerous. Adherence to medication is therefore a crucial part of patient care for reaching clinical goals. This study discussed the significant benefits of using fixed-dose combination antihypertensive therapy versus multipill antihypertensive therapy among individuals with hypertension.




The retrospective cohort study aims to examine the association between initiating fixed-dose combination versus multipill antihypertensive therapy and cardiovascular events or death in a real-world setting. The primary outcome is a composite of death or hospitalization for acute myocardial infarction, heart failure, or stroke.




Verma, A., et al in 2018 conducted a population-based, propensity score-matched, retrospective cohort study. This was conducted among residents of Ontario, Canada aged 66 years or older who initiated combination antihypertensive therapy between April 1, 2004 and December 31, 2014.


Individuals newly initiated with one angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II-receptor blocker (ARB) plus one thiazide diuretic were included in the study. New users were defined as receiving no prescription for any antihypertensive medication in the year prior to study enrollment.


Those excluded in the study were individuals initiating multipill combination therapy on separate days, individuals with any hospitalization for stroke, transient ischemic attack (TIA), heart failure, or myocardial infarction in the year prior to study enrollment, individuals with any emergency department visit for stroke or TIA in the year prior to study enrollment, and individuals who were prescribed any antihypertensive medications in addition to the initial combination therapy on the day of study enrollment.


High-dimensional propensity score matching was used to compare individuals receiving fixed-dose combination (FDC) versus multipill therapy. Prescription drug claims, diagnosis codes, and procedure codes from all hospitalizations and emergency department visits, insurance claims and diagnosis codes for physician services were used to develop the high-dimensional propensity scoring.


After propensity score matching, 13,350 individuals (6,675 in each group) were identified. The individuals included in the study were new users of combination antihypertensive therapy with an ACEI or ARB plus a thiazide diuretic. All baseline characteristics except medication class at index were balanced between the two groups. The median age at index was 71 years old. In both groups, 42.7% of individuals received low-dose medication, 43.0% received intermediate-dose, and 14.3% received high-dose. FDC users were more likely to receive an ARB (65.1% versus 23.3% in multipill group) than an ACEI and more likely to receive hydrochlorothiazide (88.2% versus 82.9% in multipill group) than other thiazides.


The study conducted two analyses: on-treatment and intention-to-treat analysis. The on-treatment analysis included patients until discontinuation of medication. Therefore, outcomes were assessed only during active treatment, which removed the effect of adherence. The intention-to-treat analysis, on the other hand, included individuals irrespective of disruptions in treatment. This quantified the difference in drug adherence between groups and assessed its impact on clinical outcomes.


Outcomes in the on-treatment analysis were similar among adults who were actively receiving treatment. However, outcomes of the intention-to-treat analysis showed significant differences between groups with respect to adherence, with 70% of total days covered during follow-up in the FDC group compared with 42% in the multipill group. This observation states that improved medication adherence associated with FDC use confers significant clinical benefits.


This study implies that FDC formulations are associated with better medication adherence and clinical outcomes. Using FDC therefore is beneficial in controlling hypertension and reducing the global burden of morbidity and mortality associated with the disease.




The clinical outcomes in the on-treatment analysis showed no significant difference between the use of fixed-dose combination and multipill antihypertensive therapy. In the intention-to-treat group on the other hand, fixed-dose combination antihypertensive therapy showed a significantly lower rate of death or hospitalization for heart attack, heart failure, or stroke than multipill antihypertensive therapy. These differences were related to better medication adherence of fixed-dose combination antihypertensive therapy compared to multipill antihypertensive therapy.




1. Gupta, A., et al. Compliance, Safety, and Effectiveness of Fixed-Dose Combinations of Antihypertensive Agents: A Meta-analysis. Hypertension. 2010.

2. Mazza, A., et al. Fixed-dose Triple Combination of Antihypertensive Drugs Improves Blood Pressure Control: From Clinical Trials to Clinical Practice. Advances in Therapy. 2017.

3. Lauffenburger, J., et al. Effect of Combination Therapy on Adherence Among US Patients Initiating Therapy for Hypertension: a Cohort Study. Journal of General Internal Medicine. 2016.

4. James, P., et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). Journal of American Medical Association. 2013.

5. Weber, M., et al. Clinical Practice Guidelines for the Management of Hypertension in the Community A Statement by the American Society of Hypertension and the International Society of Hypertension. Journal of Clinical Hypertension. 2014.

6. Buess, D., et al. Fixed-dose Combinations of Antihypertensive Drugs May Not Improve Blood Pressure Control Compared to Free Drug Combinations- Findings from the Swiss Hypertension Cohort Study. Journal of Hypertension. 2016.

7. Angeli, F., et al. Fixed-dose Combination Therapy in Hypertension. High Blood Pressure and Cardiovascular Prevention. 2012.

8. Lam, W., et al. Medication Adherence Measures: An Overview. BioMed Research International. 2015.

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