ABSTRACT
Objectives
Hypertension is a leading cause of death and disease burden followed by dyslipidemia. Their asymptomatic nature leads to low adherence and persistence to treatments. A systematic literature review (SLR) investigated the impact of single-pill-combinations (SPC) compared to free-equivalent combination (FEC) on adherence, persistence, clinical outcomes, healthcare resource utilization (HCRU), and patient-reported outcomes, in patients with hypertension, dyslipidemia, or both.
Methods
MEDLINE, MEDLINE-IN-PROCESS, Embase, and Cochrane were searched from inception until 11 May 2021, for studies comparing SPC against FEC in patients with hypertension and/or dyslipidemia. Patient characteristics, study design, therapies, measures of adherence or persistence, clinical outcomes, and follow-up were extracted.
Results
Among 52 studies identified in the SLR, 27 (n = 346,030 patients) were included in the meta-analysis. SPCs were associated with significantly improved adherence compared with FEC, as assessed through medication-possession-ratio ≥80% (odds ratio (OR) 0.42, p < 0.01) and proportion of days covered ≥80% (OR 0.45, p < 0.01). SPC also improved persistence (OR 0.44, p < 0.01) and systolic blood pressure (SBP) reduction (mean difference −1.50, p < 0.01) compared with the FEC.
Conclusions
SPC use resulted in significantly improved adherence, persistence, and SBP levels compared with FEC in patients with hypertension. The findings support SPC use in reducing the burden of hypertension and dyslipidemia.
Plain Language Summary
High blood pressure is a leading cause of death and disease burden followed by high lipid levels in the blood. Due to the silent nature of the diseases, patients can fall short of optimal medical treatment adherence and persistence, leading to poor outcomes and disease complications. Simplification of the treatment regimen can be achieved using SPC therapies. The study was conducted to look for published studies that compared the use of SPC with FEC in patients with high blood pressure, high lipid levels in the blood, or both. The researchers were able to find 52 already published studies, of which, 27 studies reported adherence, persistence, and SBP reduction which were included in the data analysis. Researchers found SPCs to be associated with much greater improved adherence and persistence and a higher reduction in SBP when compared with FEC in high blood pressure patients. These findings support SPC use in reducing the burden of high blood pressure and high lipid levels in the blood.
1. Introduction
Hypertension is one of the most prevalent cardiovascular diseases (CVD) with an age-standardized prevalence in adults aged 30–79 years of 35.4%, affecting over 1.13 billion individuals globally [Citation1,Citation2]. Similarly, dyslipidemia is also associated with a high prevalence, with an overall prevalence of 28.6% for elevated plasma low-density lipoprotein cholesterol levels and 37.4% for low levels of high-density lipoprotein cholesterol [Citation3]. Both diseases have been reported to be co-prevalent in patients, sometimes in combination with underlying additional cardiovascular risk factors such as diabetes, leading to higher morbidity and mortality [Citation4]. Hypertension and dyslipidemia are referred to as the ‘silent killer’ due to their asymptomatic nature [Citation5]. Untreated patients with hypertension or dyslipidemia are at an increased risk of developing other cardiovascular diseases, myocardial infarctions, and strokes [Citation6,Citation7].
Optimal hypertension control is considered among the most effective public health and population health-care strategies in reducing years of life lost and disability-adjusted life years [Citation8]. Evidence shows that concomitant treatment of hypertension or dyslipidemia with nonpharmacological approaches and/or antihypertensive drugs and statins produce a significant reduction in the risk of developing CVD complications [Citation9]. However, less than 50% of the patients with hypertension and/or dyslipidemia continue their treatments as prescribed beyond the first 6 months [Citation10]. Patients with hypertension and/or dyslipidemia rarely feel symptoms until the advanced stages of the disease, which leads to non-adherence to medications [Citation11]. Medication adherence, a term used interchangeably with compliance, refers to the act of conforming to the recommendations made by the provider concerning the timing, dosage, and frequency of the medication regimen. However, medication persistence denotes conforming to a recommendation of continuing treatment for the prescribed duration of treatment [Citation12].
Different factors have been reported to contribute to low adherence to prescribed medications such as ineffective communication between patient and caregiver, the complexity of treatment regimens, costs of medications, and the pill burden [Citation13]. Patients with hypertension and/or dyslipidemia often require a complex combination therapy to achieve blood pressure (BP) and lipid-level goals [Citation14–16].
Single-pill combination (SPC) aims to improve adherence by decreasing the number of pills patients take. Several studies suggested that SPCs, when compared with their free-equivalent combination (FEC), are associated with a significant improvement in adherence, persistence, and clinical outcomes in patients with hypertension and/or dyslipidemia [Citation17–19]. When compared with FEC, the SPC offers numerous potential advantages, which can include reducing the pill burden, improving medication tolerability, lowering drug costs, and improving patient adherence to medication [Citation15,Citation20]. SPC, therefore, have the potential to optimize BP and lipid levels in patients with hypertension and/or dyslipidemia, respectively.
Previous systematic reviews have shown that a lower adherence to cardiovascular medications including statins and antihypertensive medications can lead to an increased risk of cardiovascular events and all-cause mortality [Citation21,Citation22]. A meta-analysis of 1,356,188 hypertensive patients from 18 studies reported a lower adherence to medications which led to a significantly increased risk of stroke and mortality [Citation23].
In this study, we conducted a systematic literature review to investigate the impact of SPC compared with FEC on adherence, persistence, clinical outcomes, healthcare resource utilization (HCRU), and patient-reported outcomes (PROs) measures, in patients with hypertension, dyslipidemia, or both hypertension and dyslipidemia. The scope was further refined to conduct a meta-analysis focusing only on patients with hypertension with or without dyslipidemia and assessing the impact of SPCs on adherence, persistence, and reduction in systolic blood pressure (SBP) compared with FECs.
2. Methods
A systematic literature review (SLR) was performed to identify studies for a meta-analysis. The protocol of the review is registered with PROSPERO (CRD42022381799). This review was conducted in accordance with the PRISMA [Citation24] and MOOSE guidelines [Citation25]. The objective of the SLR was to understand the impact of SPC compared with FEC on adherence, persistence, cardiovascular (CV) outcomes, HCRU, and PRO in patients with hypertension alone, dyslipidemia alone, or both conditions. After the SLR, a feasibility assessment was conducted for a meta-analysis with a narrower scope than the SLR. The objective of the meta-analysis is to evaluate the impact of SPC compared with FEC on adherence, persistence, and reduction in SBP for patients with hypertension with or without dyslipidemia.
2.1. Systematic literature review
2.1.1. Search strategy
The searches were performed on MEDLINE, MEDLINE In-Process, EMBASE, and Cochrane Central Register of Controlled Trials databases from inception to 11 May 2021. The searches included a combination of keywords for SPC, antihypertensive medications, and lipid-lowering medications. The complete search strategies are available in Appendix 1: Search strategy. In addition to electronic databases, the relevant conference proceedings (International Cardiology and Heart Failure, British Cardiovascular Society, American College of Cardiology, and International Society for Pharmacoeconomics and Outcomes Research (ISPOR)), Google Scholar, and ClinicalTrials.gov were searched for relevant abstracts and studies. Bibliographies of literature reviews and meta-analyses were cross-checked to identify any potential additional studies. Hand searches were restricted to the last 3 years (2019–2021). No restrictions on language or geography were applied.
2.1.2. Study selection
Following the deduplication of search results, screening (titles and abstracts of all citations, then full texts of relevant studies) was performed by two independent reviewers with conflicts resolved by a third reviewer. After a full-text review, a list of the excluded studies was created with the reason for exclusion.
Studies were included if they fulfilled the PICOS framework (Population, Intervention, Comparator, Outcome, and Study type) as outlined in .
Table 1. PICOS framework.
2.1.3. Data extraction
Data from the included studies were extracted into a predefined data extraction grid by two independent reviewers, followed by a quality check of 20% of the studies by a third reviewer. Cases of conflicts between the two reviewers were resolved through consensus discussion, and if consensus could not be reached, the decision of a third reviewer was considered. The data extracted included publication details, patient characteristics, study design, drug therapy groups, measures of adherence or persistence, clinical outcomes, and length of follow-up.
2.2. Quality assessment
The quality assessment of randomized-controlled trials (RCTs) was performed using the revised Cochrane Risk of Bias tool version 2 (ROB-2) [Citation26]. The quality assessment of real-world evidence (RWE) studies was carried out by applying the Good Research for Comparative Effectiveness (GRACE) checklist for each study [Citation27]. To reduce bias, studies were excluded if no cohort adjustment was performed on the results of interest. The results of the quality assessment are shown in the Data Supplementary file.
2.3. Data analysis and synthesis
Direct pairwise meta-analyses were performed using R software (The R Foundation for Statistical Computing Platform) version 4.1.2 (released on NaN Invalid Date) and the meta package. The following studies were pooled: 1) studies evaluating the same drug class and 2) studies evaluating the same treatments. Cochran’s Q test and I2 statistic were used to assess statistical heterogeneity in the treatment effect estimates. Pooled estimates were produced using standard frequentist meta-analysis methods, and both fixed and random effects models were fitted. Due to the high level of heterogeneity as illustrated through I2, only estimates from random effects models (REM) are reported. The inverse variance-weighted method was used to analyze continuous outcomes, whereas the methods for dichotomous outcomes were model-dependent; the Mantel–Haenszel method was used for the fixed-effect model, and DerSimonian and Laird for the REM.
For meta-analyses of dichotomous outcomes (adherence and persistence), the outputs include the odds ratio and the associated 95% confidence interval. For meta-analyses of continuous outcomes (changes in BP), the outputs include the mean difference (MD) and the associated 95% confidence interval. The results are presented in forest plots.
3. Results
3.1. SLR study flow
A total of 11,058 records were screened by title and abstract after deduplication. Following the title and abstract screening, 10,879 articles were excluded, and further 144 articles were excluded after full-text review, identifying a total of 35 studies from electronic databases. The reasons for exclusion on full-text review include population not of interest (n = 6), intervention/comparator not of interest (n = 113), outcomes not of interest (n = 14), study type not of interest (n = 7), and duplicate records (n = 4). After the identification of 17 articles from hand searching, a total of 52 studies were finally included in the SLR as shown in .
Figure 1. PRISMA flow diagram.
3.2. Feasibility assessment
The scope of the SLR is further refined for the meta-analysis to meet the inclusion criteria of the PICOS framework of the meta-analysis. During the feasibility assessment, eight RCTs that did not report data for outcomes of interest or patients with hypertension were excluded. A total of nine RWE studies were excluded that did not meet the inclusion criteria for the meta-analysis, seven did not report outcomes of interest and two included only patients with dyslipidemia. However, in addition to the PICOS criteria, the quality of RWE studies were further assessed using the GRACE checklist. Finally, RWE studies were also assessed for cohort adjustment between the two treatment arms, and whether the same database was used in more than two studies, due to the high heterogeneity among the studies. Based on these criteria, zero RWE studies were excluded based on the quality assessment criteria, five studies for no cohort adjustment between the treatment arms, and two studies for including patients from the same database. After a feasibility assessment, a total of 27 studies from 28 publications including 19 RWE [Citation28–46] and 8 RCTs [Citation47–55] were finally included. The full list of included studies along with the study characteristics are reported in Appendix 2: Study characteristics
The final list of included studies in the meta-analyses consisted of both RCT and RWE studies. Only adherence, persistence, and SBP outcomes were assessed as feasible for meta-analysis. Insufficient evidence was identified for studies reporting dyslipidemia outcomes. For adherence and persistence outcomes, only RWE studies reporting the outcomes met the inclusion criteria, while for reduction in SBP, both RCTs and RWE studies met the inclusion criteria. For SBP reduction, both study types were included in the analysis, to look at all the evidence. However, given the potential bias introduced by the different types of study designs, sensitivity analyses per study design were also conducted for SBP.
3.3. Meta-analyses
All studies included in the meta-analyses focused on patients with hypertension or a combination of hypertension and dyslipidemia. Meta-analyses were conducted for adherence (14 studies), persistence (10 studies), and reduction in SBP levels (12 studies). Four comparisons were conducted to estimate the effect of SPC on adherence to medications: two continuous outcomes; mean medication possession ratio (MPR) and mean proportion of days covered (PDC), and two dichotomous outcomes; proportion of patients with MPR ≥ 80% and PDC ≥ 80%.
3.3.1. Medication adherence
3.3.1.1. Adherence defined through mean MPR
Seven RWE studies assessed adherence at 12 months through mean MPR. Statistical heterogeneity was detected when considering all studies and when focusing on studies comparing the same treatments (I2 = 99%). The MD [95% CI] was −0.14 [−0.21; −0.07] as shown in , indicating a significantly higher adherence in patients treated with SPC compared with FEC of the same drug class. In a subgroup analysis with only two studies comparing the same treatments, the results go in the same direction as the main analysis; however, due to the limited number of studies the results were not significant (MD = −0.17 [−0.39; 0.04]).
Figure 2. Effect of SPCs versus FECs on adherence defined through a) mean MPR and b) proportion of patients with MPR > 80%.
A sensitivity analysis was conducted to limit the potential heterogeneity in the outcome definition of adherence, as two studies included in the base case analysis used compliance as a proxy for adherence [Citation34,Citation46]. After removing the two studies, the direction of effects was similar with MD [95% CI] remaining significantly in favor of SPC: −0.12 [−0.22; −0.02]. The two studies removed compared the same drug class; therefore, the findings obtained when focusing on the same treatment comparison remain unchanged.
3.3.1.2. Good adherence defined through MPR ≥ 80%
Only three studies (all RWE studies) reported data for MPR ≥ 80%, and all assessed adherence at 12 months. The pooled OR [95% CI] was 0.42 [0.27; 0.65] as shown in (with substantial heterogeneity, I2≥96%), indicating a significant benefit in terms of adherence in favor of SPC versus FEC. When focusing on studies comparing the same treatments, OR [95% CI] remained significant (0.35 [0.25; 0.49]).
3.3.1.3. Adherence defined through the mean PDC
Six RWE studies assessed the mean PDC in patients with hypertension or with both hypertension and dyslipidemia. However, adherence was assessed at different time points (6 to more than 12 months). The MD [95% CI] was −0.17 [−0.24; −0.09] as shown in (I2 = 99%) for studies comparing the same drug class, indicating a statistically significant higher mean adherence in patients treated with SPC compared with FEC. In the analysis restricted to studies assessing the same treatments, the MD [95% CI] remained significantly in favor of SPC: −0.19 [−0.34; −0.04]); I2 = 99%.
Figure 3. Effect of SPCs versus FECs on adherence defined through a) mean PDC and b) the proportion of patients with MPR > 80%.
A sensitivity analysis was conducted to assess the potential impact of observed heterogeneity in terms of the time point of assessment. When focusing on the two studies [Citation35,Citation40] that assessed adherence at 12 months, findings were similar with MD [95% CI] still significantly in favor of SPC: −0.11[−0.15; −0.07].
3.3.1.4. Good adherence defined through PDC ≥ 80%
Seven RWE studies defined good adherence as PDC ≥ 80% in patients with hypertension or a combination of hypertension and dyslipidemia. However, adherence was assessed at different time points (6 to more than 12 months). The pooled OR was 0.45 [0.35; 0.59] when considering the same class comparison as shown in (I2 = 98%), indicating a statistically significant benefit for patients treated with SPC compared with FEC. When considering only studies comparing the same treatments, the result remained significant (OR = 0.46 [0.30; 0.71], I2 = 94%). To assess the potential impact of heterogeneity due to differences in time points, analyses restricted to the four studies [Citation35,Citation40,Citation43,Citation45] that assessed adherence at 12 months were conducted. Similar results were obtained with pooled ORs still significantly in favor of SPC: 0.52 [0.39; 0.68] when comparing the same drug class and 0.53 [0.36; 0.77] when focusing on the same treatment comparison.
3.3.2. Medication persistence
A total of 10 RWE studies assessed persistence with a follow-up time of 12 months. Persistence was defined by study authors in six RWE studies only. Three studies defined persistence as any gap in SPC components greater than 30 days. Other definitions reported in single studies include patients who did not discontinue therapy at either 180 or 365 days, succeeding in renewing a prescription within three times the number of days supplied by each prescription or having filled relevant prescriptions at least once every 6 months. The pooled OR was 0.44 [0.34; 0.57] when comparing the same drug class as shown in (I2 = 99%), indicating a statistically significant benefit in terms of persistence when patients are treated with SPC compared with FEC. When focusing on studies comparing the same treatments, the results remained significant (OR = 0.42 [0.32; 0.53]); I2 = 96%.
Figure 4. Effect of SPCs versus FECs on persistence.
3.3.3. Decrease in SBP
Eleven studies, including both RCTs (n = 8 studies) and RWE studies (n = 3 studies), assessed changes in SBP. The follow-up durations differed between studies (1–12 months). Statistical heterogeneity was detected when considering all the studies (I2 = 77%), as well as when focusing on studies comparing the same treatments (I2 = 80%). The pooled MD was −1.50 mmHg [−2.78; −0.23] as shown in (I2 = 77%) when considering all studies, indicating a statistically significant greater reduction in SBP for patients treated with SPC compared with FEC. When considering only studies comparing the same treatments, the results were non-significant (MD = −1.30 [−2.95; 0.36]), potentially due to a low number of studies. Results from RCT studies only showed a significant decrease in SBP in favor of patients treated with SPCs. When considering only RWE studies comparing the same treatments and drug classes, the results were non-significant (MD = −0.63 [−1.63; 0.37]); however, due to the high heterogeneity the results should be interpreted with caution.
Figure 5. Effect of SPCs versus FECs on change in blood pressure readings.
4. Discussion
This meta-analysis investigated the impact of SPC in patients with hypertension with or without dyslipidemia compared with their FEC on adherence, persistence, and BP outcomes. Results from the meta-analysis of 27 studies showed that patients treated with SPC had significantly improved adherence, persistence, and SBP reduction compared with patients treated with FEC. The findings of this meta-analysis support the use of SPC to improve hypertension management, as recommended by the European Society of Cardiology and the European Society of Hypertension (ESC/ESH) 2018 guidelines [Citation15].
Evidence from published reviews and original searches further confirms our review findings. Results from previous reviews have shown that SPC therapy leads to better adherence and persistence compared with free equivalents [Citation17,Citation19]. A previous review by Parati et al. [Citation17] assessed adherence levels in adults with hypertension treated with any SPC versus FEC. The meta-analysis was not restricted to having the same treatments or the same drug classes in both treatment arms (i.e. any study comparing an SPC with an FEC was included). Evidence from 44 studies in their review showed that SPC therapy improved adherence when compared with FEC therapy, potentially leading to better BP control in patients with hypertension. Results from a meta-analysis of nine RWE studies further confirm our review findings [Citation56]. This review describes a significant improvement in adherence and persistence of hypertension treatment regimen with SPC compared to FEC products for hypertension. Similar findings were described in a meta-analysis of 12 RWE studies, which also detected statistically significant improvements in adherence and persistence, and lower health-care costs for SPC compared with FEC [Citation57]. An observational retrospective analysis from a sample of local health units (LHU) covering around 11% of the Italian population demonstrated that in a subset of 158 patients, the proportion of adherent patients was significantly higher with perindopril/indapamide/amlodipine single-pill combination (75.3%) than with perindopril/indapamide plus amlodipine combinations (44.3%) (P < 0.05) [Citation58]. A microsimulation model based on the 2017 Institute for Health Metrics and Evaluation (IHME) Global Burden of Disease, Risk Factors, and Injuries (GBD) study [Citation59] for five countries including Italy, Russia, China, South Korea, and Mexico was reported by Borghi et al. [Citation60]. Over a 10 years horizon, the model showed SPC therapy was projected to improve adherence and health outcomes including blood pressure control compared with current treatment practices (CTP), single drug with dosage titration, then sequential addition of other agents (start low and go slow, SLGS), and free choice combination with multiple pills (FCC) in all five countries.
Due to limited data availability, a meta-analysis was not conducted for HCRU and PRO. However, results from studies included in the SLR show that consistently lower HCRU and health-care costs were reported with SPC when compared with FEC [Citation28,Citation29,Citation31,Citation34,Citation35,Citation45,Citation46,Citation61–65]. Hospitalizations, emergency departments, and outpatient physician visits were the most reported HCRUs. PROs were reported in only one RCT [Citation66] for hypertensive patients, who were treated with amlodipine and lisinopril SPC or the FEC. The quality of life (QoL) was significantly improved after 14 weeks of treatment with an SPC compared with FEC (p < 0.001), as measured through the 36-item Short Form (SF-36) questionnaire.
Several limitations should be considered when interpreting the results. Firstly, there was considerable heterogeneity in terms of study characteristics such as study type, time point of assessment of outcomes, adjustment between cohorts, measurement methods, and the definitions of endpoints within RWE studies. To address this, only REM was used since it allows studies to vary as a parameter is added to illustrate this variability, while a fixed effects model assumes that all included studies are uniform on the same true effect. Secondly, the studies included in the meta-analysis were mainly from high-income countries; therefore, the observed levels of adherence in these studies might be higher than the general population globally. Due to the aforementioned limitation, the results of the analysis could not be generalized to low-income nations which have seen an increasing burden of hypertension over the past three decades [Citation67]. Finally, for SBP reduction both RCT and RWE study types were included in the analysis, to look at all the evidence, which might not be the best statistical approach; however, sensitivity analyses were conducted looking at only one study type.
5. Conclusion
This meta-analysis showed that the use of SPC resulted in higher adherence and persistence to treatment compared with FEC in patients with hypertension with or without dyslipidemia, which further led to significantly reduced SBP. These results suggest that SPC could play a role in reducing hypertension and dyslipidemia burden for patients as well as the health-care system. Further evidence would be needed to strengthen the positive link between SPC and clinical outcomes, healthcare resource use, and PRO, and to understand if those results stand in emerging markets.
Article highlights
Patients with hypertension and/or dyslipidemia rarely feel symptoms until the advanced stages of the disease, which leads to non-adherence to medications. SPC aims to improve adherence by decreasing the number of pills patients take.
This systematic review and meta-analysis included a total of 52 studies that investigated the impact of SPC in patients with hypertension with or without dyslipidemia compared with their FEC on adherence, persistence, and BP outcomes.
The searches were performed on MEDLINE, MEDLINE In-Process, EMBASE, and Cochrane Central Register of Controlled Trials databases from inception to 11 May 2021. In addition to electronic databases, the relevant conference proceedings, Google Scholar, and ClinicalTrials.gov were searched for relevant abstracts and studies.
Results from the meta-analysis of 27 studies showed that patients treated with SPC had significantly improved adherence, persistence, and SBP reduction compared with patients treated with FEC.
The findings of this meta-analysis support the use of SPC to improve hypertension management, as recommended by the European Society of Cardiology and the European Society of Hypertension 2018 guidelines.
Declaration of interest
J B Brière is an employee at Servier. P Le Nouveau, P Kodjamanova, M Kochoedo, O Irfan, and P Atanasov are employees at Amaris Consulting, which received funding from Servier for the study. Z M Khan is a paid consultant for Servier. A P Kengne received an honorarium for his support in contributing to the study protocol, and interpretation of results.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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References
- World Health Organization. Hypertension fact sheet [Internet]. 2019. https://www.who.int/news-room/fact-sheets/detail/hypertension
- Pan American Health Organization (PAHO). Hypertension [Internet]. 2019. https://www.paho.org/en/enlace/hypertension
- Pirillo A, Casula M, Olmastroni E, et al. Global epidemiology of dyslipidaemias. Nat Rev Cardiol. 2021;18(10):689–700. doi: 10.1038/s41569-021-00541-4
- Williams B, Masi S, Wolf J, et al. Facing the challenge of lowering blood pressure and cholesterol in the same patient: report of a symposium at the European Society of hypertension. Cardiol Ther. 2020;9(1):19–34. doi: 10.1007/s40119-019-00159-1
- World Heart Federation. Hypertension [Internet]. https://world-heart-federation.org/what-we-do/hypertension/#:~:text=Hypertension%20is%20the%20leading%20preventable,10%20million%20people%20every%20year
- Fuchs FD, Whelton PK. High blood pressure and cardiovascular disease. Hypertension. 2020;75(2):285–292. doi: 10.1161/HYPERTENSIONAHA.119.14240
- Chou R, Dana T, Blazina I, et al. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2016;316(19):2008–2024. doi: 10.1001/jama.2015.15629
- Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020;16(4):223–237. doi: 10.1038/s41581-019-0244-2
- Schwalm J-D, McKee M, Huffman MD, et al. Resource effective strategies to prevent and treat cardiovascular disease. Circulation. 2016;133(8):742–755. doi: 10.1161/CIRCULATIONAHA.115.008721
- Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165(10):1147–1152. doi: 10.1001/archinte.165.10.1147
- Sanz G, Fuster V. Polypills for cardiovascular prevention: a step forward? Nat Rev Cardiol. 2013;10(12):683–684. doi: 10.1038/nrcardio.2013.157
- Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11(1):44–47. doi: 10.1111/j.1524-4733.2007.00213.x
- Zidan A, Awaisu A, El-Hajj MS, et al. Medication-related burden among patients with chronic disease conditions: perspectives of patients attending non-communicable disease clinics in a primary healthcare setting in Qatar. Pharmacy. 2018;6(3):85. doi: 10.3390/pharmacy6030085
- Zodda D, Giammona R, Schifilliti S. Treatment strategy for dyslipidemia in cardiovascular disease prevention: focus on old and New drugs. Pharmacy. 2018;6(1):10. doi: 10.3390/pharmacy6010010
- Williams B, Mancia G, Spiering W, et al. ESC/ESH guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of hypertension (ESH). Eur Heart J. 2018;39(33):3021–3104. doi: 10.1093/eurheartj/ehy339
- Mancia G, Kreutz R, Brunström M, et al. 2023 ESH guidelines for the management of arterial hypertension the task force for the management of arterial hypertension of the European Society of hypertension: endorsed by the International Society of hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023;41(12):1874–2071. doi: 10.1097/HJH.0000000000003480
- Parati G, Kjeldsen S, Coca A, et al. Adherence to single-pill versus free-equivalent combination therapy in hypertension: a systematic review and meta-analysis. Hypertension. 2021;77(2):692–705. doi: 10.1161/HYPERTENSIONAHA.120.15781
- Sarzani R, Laureti G, Gezzi A, et al. Single-pill fixed-dose drug combinations to reduce blood pressure: the right pill for the right patient. Ther Adv Chronic Dis. 2022;13:20406223221102754. doi: 10.1177/20406223221102754
- Tsioufis K, Kreutz R, Sykara G, et al. Impact of single-pill combination therapy on adherence, blood pressure control, and clinical outcomes: a rapid evidence assessment of recent literature. J Hypertens. 2020;38(6):1016. doi: 10.1097/HJH.0000000000002381
- Iellamo F, Werdan K, Narkiewicz K, et al. Practical applications for single pill combinations in the cardiovascular continuum. Card Fail Rev. 2017;3(1):40. doi: 10.15420/cfr.2017:5:1
- Chowdhury R, Khan H, Heydon E, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J. 2013;34(38):2940–2948. doi: 10.1093/eurheartj/eht295
- De Vera MA, Bhole V, Burns LC, et al. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol. 2014;78(4):684–698. doi: 10.1111/bcp.12339
- Xu T, Yu X, Ou S, et al. Adherence to antihypertensive medications and stroke risk: a dose‐response meta‐analysis. J Am Heart Assoc. 2017;6(7):e006371. doi: 10.1161/JAHA.117.006371
- Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10(1):1–11. doi: 10.1186/s13643-021-01626-4
- Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283(15):2008–2012. doi: 10.1001/jama.283.15.2008
- Sterne JA, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi: 10.1136/bmj.l4898
- Dreyer NA, Bryant A, Velentgas P. The GRACE checklist: a validated assessment tool for high quality observational studies of comparative effectiveness. J Manag Care Spec Pharm. 2016;22(10):1107–1113. doi: 10.18553/jmcp.2016.22.10.1107
- Bramlage P, Schmidt S, Sims H. Fixed‐dose vs free‐dose combinations for the management of hypertension—an analysis of 81 958 patients. J Clin Hypertens. 2018;20(4):705–715. doi: 10.1111/jch.13240
- Brixner DI, Jackson I, Kenneth C, et al. Assessment of adherence, persistence, and costs among valsartan and hydrochlorothiazide retrospective cohorts in free-and fixed-dose combinations. Curr Med Res Opin. 2008;24:2597–2607. doi: 10.1185/03007990802319364
- Gerbino PP, Shoheiber O. Adherence patterns among patients treated with fixed-dose combination versus separate antihypertensive agents. Am J Health Syst Pharm. 2007;64(12):1279–1283. doi: 10.2146/ajhp060434
- Taylor AA, Shoheiber O. Adherence to antihypertensive therapy with fixed‐dose amlodipine besylate/benazepril HCl versus comparable component‐based therapy. Congest Heart Fail. 2003;9(6):324–332. doi: 10.1111/j.1527-5299.2003.03269.x
- Choi JM, Lee S-H, Jang YJ, et al. Medication adherence and clinical outcome of fixed-dose combination vs. Free combination of angiotensin receptor Blocker and statin. Circ J. 2021;85(5):CJ–20. doi: 10.1253/circj.CJ-20-0966
- Dezii C. A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care Langhorne Pa. 2000;9:2–6.
- Dickson M, Plauschinat CA. Compliance with antihypertensive therapy in the elderly. Am J Cardiovasc Drugs. 2008;8(1):45–50. doi: 10.2165/00129784-200808010-00006
- Machnicki G, Ong S, Chen W, et al. Comparison of amlodipine/valsartan/hydrochlorothiazide single pill combination and free combination: adherence, persistence, healthcare utilization and costs. Curr Med Res Opin. 2015;31(12):2287–2296. doi: 10.1185/03007995.2015.1098598
- Levi M, Pasqua A, Cricelli I, et al. Patient adherence to olmesartan/amlodipine combinations: fixed versus extemporaneous combinations. J Manag Care Spec Pharm. 2016;22(3):255–262. doi: 10.18553/jmcp.2016.22.3.255
- Zeng F, Patel B, Andrews L, et al. Adherence and persistence of single-pill ARB/CCB combination therapy compared to multiple-pill ARB/CCB regimens. Curr Med Res Opin. 2010;26(12):2877–2887. doi: 10.1185/03007995.2010.534129
- Ho C-T, Tung Y, Chou S, et al. Clinical outcomes in hypertensive patients treated with a single‐pill fixed‐dose combination of renin‐angiotensin system inhibitor and thiazide diuretic. J Clin Hypertens. 2018;20(12):1731–1738. doi: 10.1111/jch.13413
- Simons LA, Chung E, Ortiz M. Long-term persistence with single-pill, fixed-dose combination therapy versus two pills of amlodipine and perindopril for hypertension: Australian experience. Curr Med Res Opin. 2017;33(10):1783–1787. doi: 10.1080/03007995.2017.1367275
- Saito I, Kushiro T, Matsushita Y, et al. Medication-taking behavior in hypertensive patients with a single-tablet, fixed-dose combination in Japan. Clin Exp Hypertens. 2016;38(2):131–136. doi: 10.3109/10641963.2015.1047949
- Erdoğan D, İ̇çli A, Aksoy F, et al. The effect of fixed-dose combination of valsartan and amlodipine on nighttime blood pressure in patients with non-dipper hypertension. Turk Kardiyol Dern Ars. 2016;44:404–413. doi: 10.5543/tkda.2015.98250
- Min J, Min K, Kim H-J, et al. MPS 02-07 ADHERENCE to SINGLE-PILL and TWO-PILL ANGIOTENSIN II RECEPTOR BLOCKERS/STATIN REGIMENS and THEIR EFFICACY in LOWERING BLOOD PRESSURE and LIPID TARGETS in KOREAN PATIENTS. J Hypertens. 2016;34(Supplement 1):e82. doi: 10.1097/01.hjh.0000500070.98851.c6
- Patel BV, Leslie RS, Thiebaud P, et al. Adherence with single-pill amlodipine/atorvastatin vs a two-pill regimen. Vasc Health Risk Manag. 2008;4:673.
- Simons LA, Ortiz M, Calcino G. Persistence with a single pill versus two pills of amlodipine and atorvastatin: the Australian experience, 2006–2010. Med J Aust. 2011;195(3):134–137. doi: 10.5694/j.1326-5377.2011.tb03240.x
- Hussein MA, Chapman RH, Benner JS, et al. Does a single-pill antihypertensive/Lipid-lowering regimen improve adherence in US managed care enrollees? Am J Cardiovasc Drugs. 2010;10(3):193–202. doi: 10.2165/11530680-000000000-00000
- Hess G, Hill J, Lau H, et al. Medication utilization patterns and hypertension-related expenditures among patients who were switched from fixed-dose to free-combination antihypertensive therapy. Pharm Ther. 2008;33:652.
- Sung J, Ahn K, Cho B, et al. Adherence to triple component antihypertensive regimen is higher in single-pill combination than two-pill regimen: data from a randomized controlled trial using medication event monitoring system. Eur Heart J. 2019;40(Supplement_1):747–747. doi: 10.1093/eurheartj/ehz748.0069
- Nedogoda SV, Stojanov VJ. Single-pill combination of perindopril/indapamide/amlodipine in patients with uncontrolled hypertension: a randomized controlled trial. Cardiol Ther. 2017;6(1):91–104. doi: 10.1007/s40119-017-0085-7
- Nedogoda S, Stojanov V. PP.07.21: EFFICACY and SAFETY of PERINDOPRIL/INDAPAMIDE/AMLODIPINE (P/I/A) SINGLE PILL versus FREE COMBINATION (P/I + A) at the SAME DOSE in PATIENTS with UNCONTROLLED ESSENTIAL HYPERTENSION. J Hypertens. 2015;33(Supplement 1):e195. doi: 10.1097/01.hjh.0000467934.09921.a4
- Tasić N, Balević M, Tasić D, et al. Efficacy and tolerability of a fixed combination of perindopril/amlodipine/indapamide in patients with essential hypertension: pilot study. Serbian J Exp Clin Res. 2016;17(1):21–26. doi: 10.1515/sjecr-2016-0016
- Visco V, Finelli R, Pascale AV, et al. Larger blood pressure reduction by fixed-dose compared to free dose combination therapy of ace inhibitor and calcium antagonist in hypertensive patients. Transl Med UniSa. 2017;16:17.
- Asplund J, Danielson M, Ohman P. Patients compliance in hypertension‐the importance of number of tablets. Br J Clin Pharmacol. 1984;17(5):547–552. doi: 10.1111/j.1365-2125.1984.tb02388.x
- Graham R. Treating mild-to-moderate hypertension: a comparison of lisinopril-hydrochlorothiazide fixed combination with captopril and hydrochlorothiazide free combination. J Hum Hypertens. 1991;5:59–60.
- Marazzi G, Pelliccia F, Campolongo G, et al. Greater cardiovascular risk reduction with once-daily fixed combination of three antihypertensive agents and statin versus free-drug combination: the ALL-IN-ONE trial. Int J Cardiol. 2016;222:885–887. doi: 10.1016/j.ijcard.2016.07.163
- Mazza A, Lenti S, Schiavon L, et al. Fixed-dose triple combination of antihypertensive drugs improves blood pressure control: from clinical trials to clinical practice. Adv Ther. 2017;34(4):975–985. doi: 10.1007/s12325-017-0511-1
- Du L, Cheng Z, Zhang Y, et al. The impact of fixed‐dose combination versus free‐equivalent combination therapies on adherence for hypertension: a meta‐analysis. J Clin Hypertens. 2018;20(5):902–907. doi: 10.1111/jch.13272
- Sherrill B, Halpern M, Khan S, et al. Single‐pill vs free‐equivalent combination therapies for hypertension: a meta‐analysis of health care costs and adherence. J Clin Hypertens. 2011;13(12):898–909. doi: 10.1111/j.1751-7176.2011.00550.x
- Borghi C, Jayagopal PB, Konradi A, et al. Adherence to triple single-pill combination of perindopril/indapamide/amlodipine: findings from real-world analysis in Italy. Adv Ther. 2023;40(4):1765–1772. doi: 10.1007/s12325-023-02451-y
- Stanaway JD, Afshin A, Gakidou E, et al. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global burden of disease study 2017. Lancet. 2018;392:1923–1994.
- Borghi C, Wang J, Rodionov AV, et al. Projecting the long-term benefits of single pill combination therapy for patients with hypertension in five countries. Int J Cardiol Cardiovasc Risk Prev. 2021;10:200102. doi: 10.1016/j.ijcrp.2021.200102
- Kumagai N, Onishi K, Hoshino K, et al. Improving drug adherence using fixed combinations caused beneficial treatment outcomes and decreased health-care costs in patients with hypertension. Clin Exp Hypertens. 2013 [2012 Oct 18] ed;35(5):355–360. doi: 10.3109/10641963.2012.732644
- Stankus V, Campbell HB, RC N, et al. Reducing costs and improving hypertension management. Can J Clin Pharmacol. 2009Winter;16(1):e151–5. Epub 2009 Feb 4. PMID: 19193969.
- Tung YC, Lin YS, Wu LS, et al. Clinical outcomes and healthcare costs in hypertensive patients treated with a fixed-dose combination of amlodipine/valsartan. J Clin Hypertens Greenwich. 2015 [2014 Dec 6] ed; 17(1):51–58. doi: 10.1111/jch.12449
- Breitscheidel L, Ehlken B, Kostev K, et al. Real-life treatment patterns, compliance, persistence, and medication costs in patients with hypertension in Germany. J Med Econ. 2012 [2011 Nov 1] ed; 15(1):155–165. doi: 10.3111/13696998.2011.635229
- Kamat SA, Bullano MF, Chang C-L, et al. Adherence to single-pill combination versus multiple-pill combination lipid-modifying therapy among patients with mixed dyslipidemia in a managed care population. Curr Med Res Opin. 2011;27(5):961–968. doi: 10.1185/03007995.2011.562494
- Gridina S, Povetkin S. Comparative assessment of effects of free and fixed combinations of hypotensive drugs on quality of life of patients with arterial hypertension of high and very high risk. Kardiologiia. 2016;56:25–29. doi: 10.18565/cardio.2016.3.25-29
- Schutte AE, Srinivasapura Venkateshmurthy N, Mohan S, et al. Hypertension in low-and middle-income countries. Circ Res. 2021;128(7):808–826. doi: 10.1161/CIRCRESAHA.120.318729