Table A2.
Summary of the original articles (n = 67) regarding aim, study setting, follow-up period, population, type of adherence outcome measures, and results.
| Author, Reference, Year of Publication, Study Country, Study Design | Study Aim, Study Setting and Follow-Up Period | Study Population | Outcome Measures | Main Results (Concerning Adherence) |
|---|---|---|---|---|
| CVD (n = 11) | ||||
| Castellano et al. [35], 2014, Argentina, Paraguay, Italy and Spain Phase 1: observational, prospective, cross-sectional study Phase 2: randomized, controlled clinical trial |
Phase 1: to identify factors interfering with adherence to CV medications for secondary prevention after an acute myocardial infarction. Phase 2: to test the impact of a polypill on adherence, blood pressure, low-density lipoprotein cholesterol, safety and tolerability. Phase 1: 64 outpatient clinics in Argentina, Brazil, Paraguay, Italy and Spain Phase 2: 63 clinics in Argentina, Paraguay, Italy and Spain Follow-up period: 9 months |
Phase 2: 695 infarct patients ≥40 years of age with a history of acute myocardial infarction within the last 2 years (350 on FDC therapy and 345 on conventional multipill treatment). | Adherence was measured via Morisky Medication Adherence Scale and pill count. | Polypills showed a significantly higher adherence in comparison with multiple pills (50.8% vs. 41%, p = 0.019). |
| Lafeber et al. [59], 2014, the Netherlands Randomized controlled trial |
To compare the morning and evening administration of a cardiovascular polypill and to assess the effect of the polypill on patients’ clinical outcomes, adherence, and preference compared to the separately administered identically dosed drugs University Medical Center Utrecht Follow-up period: 18 weeks |
78 patients with established atherosclerotic CVD and an indication for the use of cardiovascular medication (during the three treatment periods of 6 weeks, each was receiving every type of therapy regimen (polypill in the morning, polypill in the evening, and mutlipill therapy with individual drugs), but in different sequences). | Adherence was measured via microelectronic monitoring device and Morisky Medication Adherence Scale. | According to digital adherence monitoring, adherence was 5.2% (95% CIs: 1.4%–9.1%) higher when using the polypill in the morning and 5.3% (95% CIs: 1.4%–9.1%) higher when using the polypill in the evening compared to multipill therapy. Morisky scale recognized non-adherence in 4 (5%) participants when using the polypill in the morning, in 6 (8%) participants when using the polypill in the evening, and in 10 (13%) participants when using the individual agents (p = 0.22). |
| Patel et al. [45], 2014, Australia Randomized controlled trial |
To determine if polypills improve adherence in high risk CVD patients 33 Australian health centers Follow-up period: 18 months |
623 patients ≥18 years of age with high CVD risk (311 allocated to polypill treatment and 312 to conventional treatment). | Adherence was measured via self-reporting. | Patients on the polypill therapy reported an adherence rate of 70.1% at study end, while people on usual care reported a 46.9% adherence (p < 0.001). |
| Selak et al. [48], 2014, New Zealand Randomized controlled trial |
To investigate the impact of FDCT on the adherence rate and risk factor control in patients with high cardiovascular risk 54 general practices all over New Zealand Follow-up period: 12 months |
513 patients aged 18–79 years at high risk of CVD (256 allocated to FDC and 257 to usual care). | Adherence was measured via self-reporting. | Adherence in patients receiving FDCT was higher compared to the two-pill treatment (81% vs. 46%, p < 0.001). |
| Thom et al. [52], 2013, UK, India, Ireland, the Netherlands Randomized, open-label, blinded-end-point clinical trial |
To assess the impact of a polypill in comparison to usual care on adherence patterns, systolic blood pressure and low-density lipoprotein cholesterol Patient data obtained via databases, hospitals and general practices in India, England, Ireland, and the Netherlands Follow-up period: 12 months |
2004 patients ≥18 years of age with high cardiovascular risk, defined as either established CVD, or an estimated 5-year CVD risk of 15% or greater (1002 allocated to FDC group and 1002 to usual care) | Adherence was measured via self-reporting. | The FDCT group had significantly improved adherence compared to the usual care group (88% vs. 65%, p < 0.001). |
| Schaffer et al. [61], 2017, Australia Retrospective cohort study |
To compare adherence in patients initiating amlodipine/atorvastatin therapy as an FDC or free combination and to identify subgroups benefiting most from FDCs Data retrieved via Australian Pharmaceutical Benefits Scheme Follow-up period: 24 months |
9430 patients, who started their therapy with study drugs either as an FDC or in free combination (3996 on FDC and 5434 on free combination therapy). | Adherence was measured via PDC. | Patients initiating on an FDC were more likely to have near-perfect adherence compared to those with the free combination, if they were previously statin adherent irrespective of amlodipine dose (amlodipine 5 mg: OR = 1.61, 95% CIs: 1.38–1.87; amlodipine 10 mg: OR = 2.39, 95% CIs: 1.63–3.51), or if they were previously statin nonadherent and initiated on the FDC with 5-mg amlodipine (OR = 1.87, 95% CIs: 1.50–2.32). However, statin-naïve initiating on FDCT with 10-mg amlodipine were less likely to have near-perfect adherence (OR = 0.60, 95% CIs: 0.41–0.88) and more likely to have early nonadherence (OR = 1.73, 95% CIs: 1.17–2.55) compared with the free combination. |
| Bartlett et al. [58], 2016, Australia Retrospective cohort study |
To compare adherence and persistence in patients who add ezetimibe to statin therapy as a separate pill combination or FDC Data retrieved via Australian Pharmaceutical Benefits Scheme Follow-up period: 6 months |
9391 patients, who initiated ezetimibe as separate pill or ezetimibe in FDC (3651 on multipill therapy and 5740 on FDC therapy). | Adherence was measured via MPR. | Adherence was similar in both groups; mean MPRs: multipill therapy = 0.99 (95% CIs: 0.98–1.01) and FDC = 0.97 (95% CIs: 0.95–0.99). |
| Kamat et al. [63], 2011, USA Retrospective cohort study |
To compare adherence between single- and multipill therapies with lipid-modifying drugs Data retrieved via HealthCore Integrated Research Database Follow-up period: 36 months |
42,460 patients ≥18 years of age newly initiating FDC dyslipidemia therapy (38,847 patients) or equivalent multipill therapy (3613 patients). | Adherence was measured via MPR. | The mean PDC was 0.76 (±0.26) and 0.70 (±0.27) in the first 3 months of treatment, 0.54 (±0.40) and 0.45 (±0.40) in the second 3 months of treatment, and 0.50 (±0.41) and 0.41 (±0.43) for the remaining 30 months for FDC and multipill groups, respectively. Average PDC was significantly higher in the SPC group (0.56 ± 0.34) than in the LDC group (0.47 ± 0.33), p < 0.0001. |
| Balu et al. [62], 2009, USA Retrospective cohort study |
To compare adherence between patients treated with the FDC multipill combination therapy, to assess the relationship between optimal adherence and CVD-associated total healthcare resource utilization and healthcare cost Data retrieved via HealthCore Integrated Research Database Follow-up period: 12 months |
8988 patients ≥18 years of age newly initiating FDC (niacin extended-release (NER) and lovastatin (NERL); 6638 patients) or multipill combination therapies (NER and simvastatin (NER/S); 1687 patients, or lovastatin (NER/L); 663 patients) between index dates. | Adherence was assessed via MPR. | NER/S and NER/L patients were 31.3% (95% CIs: 22.9%–39.5%) and 39.1% (95% CIs: 26.7%–49.4%) less likely to be adherent than NERL patients (p < 0.01). |
| LaFleur et al. [60], 2006, USA Retrospective cohort study |
To compare patient adherence between different pill regimen of lipid-lowering drugs Patient data retrieved from RxAmerica database Follow-up period: mean ca. 12 months |
1672 patients who started the therapy with any of the study drugs in the selection years (among them, 224 in the ERNL (= polypill) group and 347 in the ERN-S (= combination therapy) group. | Adherence was measured via MPR. | Adherence rates for ERNL (= polypill) and ERN-S (two pills) groups were significantly different: 72.5% vs. 75.8% (p = 0.033). |
| Taylor and Shoheiber [49], 2003, USA Retrospective cohort study |
To check if adherence is better for a single-pill regimen vs. a multiple-pill regimen. Patient data retrieved from a managed care organization that provides benefits for members enrolled in various health plans Follow-up period: 12 months |
5732 patients aged 18–64 years with a diagnosis code for HT and who were treated with one of the two study regimens and filled at least two prescriptions for their regimen on two different dates during the study period (2754 receiving FDC and 2978 receiving multipill therapy). | Adherence was measured via MPR. | The overall adherence rate in the polypill group (80.8%) was significantly higher than in the multipill group (73.8%), p < 0.001. |
| Hypertension (n = 31) | ||||
| Matsumara et al. [75], 2012, Japan Randomized controlled trial |
To investigate if medication adherence in hypertensive patients would improve with SPC 29 hospitals or clinics in Japan Follow-up period: 6 months |
207 hypertensive patients ≥20 years of age (103 allocated to FDC therapy and 104 to multipill therapy). | Adherence was measured via residual pill count. | No significant differences were found in adherence rate between SPC and multiple-pill groups (p = 0.89). |
| Bramlage et al. [66], 2014, Austria, Belgium, Germany, the Netherlands, and Switzerland Prospective, non-interventional multicenter study |
To get information on safety, tolerability and efficacy of the FDC of olmesartan/amlodipine/hydrochlorothiazide in daily practice and to check the impact of polypills on adherence in patients with HT Primary care practice in five European countries (Austria, Belgium, Germany, the Netherlands, and Switzerland) Follow-up period: 6 months |
14,979 patients ≥18 years of age with essential HT and new treatment with an FDC. | Adherence was measured via a Morisky Medication Adherence Scale. | Mean adherence raised from 6.0% to 6.9% when switching from multipill to FDCT (p < 0.001). |
| Kumagai et al. [73], 2012, Japan Prospective, multicenter, observational study |
To investigate the impact of FDC treatment on adherence, blood pressure and healthcare costs Several clinics and hospitals in Japan Follow-up period: 3 months |
196 patients with hypertension treated with free-drug combinations of ARB and amlodipine; free-drug combinations were replaced with the same dose of the FDC. | Adherence was measured via self-reported pill-count. | Adherence was significantly improved after switching from free combination to FDC therapy (p < 0.01). |
| Ah et al. [64], 2019, Korea Retrospective cohort study |
To compare adherence and persistence between single-pill and free equivalent combination and between two single-pill combinations as initial treatment hypertensive patients who also received prepackaged medications from the pharmacy Data retrieved via Korean national claims database Follow-up period: 12 months |
40,350 patients ≥18 years of age with ICD-10 code of hypertension and started on combination regimen consisting of an ARB and either a thiazide diuretic or CCB (20,175 on multipill therapy and 20,175 on single-pill therapy). | Adherence was measured via MPR. | The single-pill cohort had 30% higher medication adherence (OR 1.31, 95% CIs: 1.25–1.37) than the free pill cohort (p < 0.05). |
| Bramlage et al. [67], 2018, Germany Retrospective cohort study |
To assess the effect of FDCs on persistence, adherence, and medication costs, to acquire data regarding the differences in patient characteristics and comedications between patients prescribed an FDC and those prescribed a free-dose combination, and to assess motivations behind prescription of one or another of the combination therapy types Data retrieved via IMS® Disease Analyzer, which contains medical records provided by 2500 physician practices in Germany Follow-up period: 12 months |
81,958 hypertensive patients who filled at least one prescription for one of two drugs combinations, either as a single-pill FDC or as a two-pill free-dose combination (10,938 on ramipril/amlodipine FDCT, 60,525 on ramipril/amlodipine free dose therapy, 1413 on candesartan/amlodipine FDCT, 9082 on candesartan/amlodipine free dose therapy). | Adherence was assessed via MPR. | The mean MPR was higher for patients prescribed FDC compared to those taking a free-dose combination (ramipril/amlodipine: 0.72 vs. 0.58, p < 0.001; candesartan/amlodipine: 0.92 vs. 0.79, p < 0.001). |
| Degli Esposti et al. [69], 2018, Italy Retrospective cohort study |
To assess the changes in treatment adherence in patients who switched from single-pill or two-pill therapy to FDCT Data retrieved via administrative databases involving three local health units in three Italian regions Follow-up period: 24 months |
24,020 patients ≥18 years of age receiving at least one prescription of selected antihypertensive drugs in selection period (1093 with two-pill treatment, 302 switched to FDCT, 791 did not; 22,927 with MT, 3295 switched to FDCT, 19,632 did not). | Adherence was measured via PDC. | Adherence rose significantly among the subjects who switched to FDC from two-pill therapy (+13%, p < 0.001), while it was almost unchanged or slightly decreased among the subjects who did not (−4%, p < 0.001). |
| Ho et al. [71], 2018, Taiwan Retrospective cohort study |
To compare the clinical outcomes of FDC vs. free combinations of renin–angiotensin system inhibitor and thiazide diuretic in hypertension management Data retrieved via National Health Insurance Research Database of Taiwan Follow-up period: at least 12 months |
17,568 patients newly diagnosed with hypertension aged ≥18 years who were prescribed with FDC (13,176 patients) or free combination (4,392 patients) of renin–angiotensin system inhibitors and thiazide diuretic. | Adherence was measured via PDC. | FDC was associated with better adherence (PDC 58.01% vs. 46.96%; p < 0.001) than free combination therapy. |
| Tilea et al. [77], 2018, Romania Retrospective cross-sectional study |
To assess the level of adherence to antihypertensive treatment and analyze how FDCT affects it Family medicine practice in Tirgu Mures, Romania Follow-up period: 48 months |
525 patients ≥18 years of age, newly diagnosed with HT, who started with therapy that continued for at least 3 consecutive months (90 on FDCT in the beginning, 173 in the end). | Adherence was measured via prescription records review. | Interventions based on FDC during all 4 years of study showed significantly higher adherence compared to interventions with single active ingredients (p = 0.001). |
| Verma et al. [79], 2018, Germany Retrospective cohort study |
To compare clinical outcomes and patient adherence with FDC therapy and multipill therapy Data retrieved via Ontario Drug Benefit database Follow-up period: 5 years |
13,350 patients ≥66 years of age who were new users of antihypertensive therapy (6675 on multipill therapy and 6675 on FDCT). | Adherence was measured via the time to the first instance of discontinuation and PDC. | The median time to the first discontinuation of therapy as well as the PDC was higher in FDC group (191 days, 70%) than in multipill group (150 days, 42%; p < 0.01). |
| Lauffenburger et al. [74], 2017, USA Retrospective cohort study |
To investigate patterns of antihypertensive therapy initiation and compare adherence and persistence between patients initiating FDC and single-pill therapies Data retrieved via a large national health insurer Follow-up period: 12 months |
484,493 patients ≥18 years of age, who initiated an oral antihypertensive medication therapy (78,958 on FDC, 383,269 on single-pill therapy, 22,266 on multipill therapy). | Adherence was measured via PDC. | Patients with FDC therapy were 13% more likely to be adherent than patients on single-pill therapy (RR: 1.13; 95% CIs: 1.11–1.14; p < 0.05). |
| Tung et al. [53], 2017, Taiwan Retrospective cohort study |
To compare the clinical outcomes of FDCs and free combinations of ARB and CCB in management of HT Data retrieved via National Health Insurance Research Database of Taiwan Follow-up period: 2.1 years (mean) |
5680 hypertensive patients ≥18 years of age, who were prescribed an ARB and a dihydropyridine CCB (1136 on FDC therapy and 4544 on free combination therapy). | Adherence was measured via PDC. | Adherence was higher among patients receiving an FDC compared with the free combination group (PDC ≥80%: 64.97% vs. 56.88%; PDC from 50% to 80%: 22.55% vs. 24.16%; PDC <50%: 12.48% vs. 18.95% (p < 0.001)). |
| Levi et al. [42], 2016, Italy Retrospective cohort study |
To compare adherence to FDCT and LDCT in primary care Data retrieved via HS IMS Health LPD, an Italian general practice database Follow-up period: 6 months |
6612 hypertensive patients ≥18 years of age, who were treated with olmesartan/amlodipine as an extemporaneous combination or FDC (2090 on extemporaneous combination and 4522 on FDCs). | Adherence was measured via PDC. | 55.1% of the patients treated with FDC were found to be highly adherent (PDC >80%), whereas, among patients treated with the extemporaneous combination, only 15.9% were highly adherent (p < 0.001). |
| Sonawane et al. [76], 2016, USA Retrospective cohort study |
To compare the adherence of alternative treatment modification strategies and characterize the factors associated with adherence after such modifications Data retrieved via BlueCross BlueShield of Texas commercial claims data Follow-up period: 12 months |
5998 hypertensive patients aged ≥18 years who received treatment modifications (1395 on free-pill strategies and 1207 on FDC therapy). | Adherence was measured via PDC. | Adherence for FPC and FDC strategies was 0.67 ± 0.25 and 0.69 ± 0.29, respectively, which was not statistically significant (p < 0.05). |
| Hsu et al. [5], 2015, Taiwan Retrospective cohort study |
To compare adherence and persistence in hypertensive patients on FDCT and LDCT among newly diagnosed hypertensive patients Patient data obtained from the National Health Insurance Research Database (NHIRD) Follow-up period: 24 months |
7348 newly diagnosed HT patients ≥20 years of age (5725 on FDC therapy and 1623 on free combination therapy). | Adherence was measured via MPR. | Adherence was higher for patients on FDCT than patients on free dosing: 66.6% vs. 63.9% after six months; 52.6% vs. 46.7% after one year; 42.1% vs. 32.5% after two years (all p < 0.001). |
| Machnicki et al. [82], 2015, USA Retrospective cohort study |
To assess whether amlodipine/valsartan/hydrochlorothiazide SPC is associated with improved adherence, persistence, and reduced healthcare utilization and costs compared to the FCT Data retrieved using the Truven MarketScan Commercial and Medicare Supplemental Database Follow-up period: 12 months |
14,594 hypertensive patients ≥18 years of age (10,800 in single-pill group, 3794 in free combination group). | Adherence was measured via PDC and MPR. | Patients on SPC exhibited higher adherence according to MPR (85.7% vs. 77.0%) and mean PDC (73.8% vs. 60.6%), all p < 0.0001. |
| Degli Esposti et al. [70], 2014, Italy Retrospective cohort study |
To investigate the reasons for prescribing polypills and the influence of polypills on adherence in hypertensive patients. Three Italian local health units (patient data retrieved via the Medications Prescription Database) Follow-up period: 6 months |
21,008 hypertensive patients ≥18 years of age with a 6-month history of receiving free combination treatment (2395 patients) or polypill treatment (18,613 patients). | Adherence was measured via PDC. | An increased percentage of patients who switched to FDCT were adherent: +24% when coming from a two-pill regime and +42% when coming from single-pill regime (p < 0.001). |
| Tung et al. [78], 2014, Taiwan Retrospective cohort study |
To compare the clinical outcomes, healthcare costs, persistence, and adherence of HT treatment with an FDC of amlodipine/valsartan and free-drug combinations of ARB and CCB Data retrieved via the National Health Insurance Research Database (NHIRD) of Taiwan Follow-up period: 15 months |
16,505 patients ≥18 years of age with the diagnosis of HT (13,204 in FDC group FDC, 3301 in combination therapy group). | Adherence was measured via PDC. | The FDC group had a significantly higher PDC than the combination therapy group (80.35% vs. 72.57%, p < 0.001). |
| Wang et al. [80], 2014, Taiwan Retrospective cohort study |
To assess the effect of single-pill formulations on adherence in hypertensive patients Patient data retrieved from the Taiwanese National Health Insurance database Follow-up period: 12 months |
896 patients who switched from free pill combination therapy to FDC therapy of the same compound. | Adherence was measured via MPR. | In patients with low or intermediate preindex adherence (n = 729), switching to SPCs resulted in improved MPR (36% difference; 95% CIs: 33%–39%; p < 0.001). However, patients with high preindex adherence (n = 167) switching to SPCs resulted in a lower MPR (−13% difference; 95% CIs: −17% to −9%; p < 0.001). |
| Xie et al. [81], 2014, USA Retrospective cohort study |
To assess what the impact of the pill burden is on adherence in hypertensive patients Data retrieved via health care claims from the MarketScan Commercial and Medicare Supplemental database Follow-up period: 12 months |
17,465 hypertensive patients ≥18 years of age, who were prescribed three antihypertensive agents in the form of single-, double- or triple-pill regimens (8516 in single-pill group, 7842 in double-pill group, 1107 in triple-pill group). | Adherence was measured via PDC. | Patients in the double-pill cohort and triple-pill cohort were 55% and 74%, respectively, less likely to be adherent than patients receiving only one pill (p < 0.001). |
| Panjabi et al. [83], 2013, USA Retrospective cohort study |
To assess the impact of fixed- versus loose-dose triple-combination therapy on adherence, clinical, and economic outcomes in patients with hypertension Data retrieved from a large US health plan associated with OptumInsight Follow-up period: at least 12 months |
16,290 patients initiating triple therapy with an ARB, ACEi, or BB plus amlodipine and hydrochlorothiazide (10,696 on two-pill therapy (FDC + a second pill) and 5594 on a three separate pills therapy). | Adherence was assessed via PDC. | Mean PDC was greater in patients receiving two-pill therapy (ARB cohort: three-pill = 0.41, two-pill = 0.53; ACEi cohort: three-pill = 0.43, two-pill = 0.50; BB cohort: three-pill = 0.42, two-pill = 0.55; p < 0.001). |
| Baser et al. [65], 2011, USA Retrospective cohort study |
To compare adherence of valsartan/amlodipine SPC to ARB/CCB multiple-pill free combination Data retrieved via US commercial healthcare insurance claims Follow-up period: 12 months |
12,628 hypertensive patients ≥18 years of age (3259 in single-pill group, 9369 in free combination group). | Adherence was measured via PDC. | Patients on SPC were 1.38 times more adherent to their therapy than multiple pill users (95% CIs: 1.24–1.53). |
| Hussein et al. [72], 2010, USA Retrospective cohort study |
To compare the adherence between polypill and two-pill regimen of the same drugs (statin + CCB) Patient data obtained from the Health Plan Claims (US) database Follow-up period: 6 months |
35,430 patients ≥18 years of age with a pharmacy claim for single-pill amlodipine/atorvastatin or claims for both a CCB and a statin within any 30-day window in a selection year (patients were categorized into 4 cohorts according to use of CCB and/or statin therapies before the index date and within each cohort based on receiving FDC or multipill therapy). | Adherence was measured via PDC. | Adherence rates were overall higher for polypill groups and varied depending on patients’ previous treatment experiences. The differences in adherence range from no significant difference (OR = 1.00) in naïve patients to significantly higher adherence (OR = 2.81, p < 0.001) in the experienced cohort. |
| Yang et al. [55], 2010, USA Retrospective cohort study |
To compare compliance, persistence, health care resource utilization and costs among hypertensive patients on FDCT and LDCT Data retrieved via Thomson Reuters MarketScan Commercial and Medicare Supplemental Databases Follow-up period: 6 months |
579,851 patients ≥18 years of age initiating on either of the selected FDC therapies (382,476 patients) or the equivalent free-pill therapies (197,375 patients). | Adherence was measured via MPR. | Patients receiving FDCT showed significantly higher MPR than patients on free-pill therapies (72.8% vs. 61.3%; 95% CI: 11.4%, 11.7%; p < 0.05). |
| Zeng et al. [56], 2010, USA Retrospective cohort study |
To assess adherence to ARB/CCB FDC therapy compared with free-pill combination Data retrieved via MedImpact Healthcare Systems database Follow-up period: 12 months |
4525 hypertensive patients ≥18 years of age initiating on either of selected FDC (2213 patients) or free-pill therapies (2312 patients). | Adherence was measured via PDC. | Patients in the FDC group were significantly more likely to adherent (OR = 1.90, p < 0.001) compared to patients on free combination therapy. |
| Chapman et al. [68], 2009, USA Retrospective cohort study |
To compare the rate of adherence between patients on one polypill and patients with the same drugs in separate pills Data retrieved using PharMetrics Patient-Centric Database Follow-up period: 6 months |
4556 hypertensive patients ≥18 years of age prescribed amlodipine who switched to amlodipine/atorvastatin FDC (1139 patients) or added a statin to their amlodipine regimen (3417 patients). | Adherence was measured via PDC. | After 180 days, the follow-up showed that patients on the polypill had a greater improvement in adherence in comparison to multiple pill cohort: 50.8% vs. 44.3% (p < 0.001). |
| Hess et al. [41], 2009, USA Retrospective cohort study |
To evaluate medication compliance, persistence and hypertension-related expenditures among patients that switched from FDC to free-combination therapy Data obtained from the Thomson Medstat MarketScan database Follow-up period: 12 months |
14,449 patients (7224 switching to free combination therapy and 7225 controls continuing their FDC therapy) were enrolled. | Adherence was measured via MPR. | Adherence among the patients continuing on FDC therapy was 22.1% higher (p < 0.001) compared to the patients who switched to free combination therapy. |
| Brixner et al. [33], 2008, USA Retrospective cohort study |
To compare the adherence, persistence and medication costs between single- and multipill drugs Data retrieved via IHCIS National Managed Care Benchmark Database Follow-up period: 12 months |
8711 hypertensive patients ≥18 years of age, who were prescribed study drugs in combination and had at least 110 days of recorded data during which no other antihypertensive medications were prescribed before the start of therapy (8510 in FDC group, 561 in multipill group). |
Adherence was measured via MPR. | Adherence in patients receiving FDCT was higher compared to the multipill treatment: adherence rates were 64.2% for FDCT and 57.6% for LDCT (p < 0.001). |
| Dickson and Plauschinat [39], 2008, USA Retrospective cohort study |
To investigate the difference between FDCs and separate drugs in adherence and total costs Patient data retrieved from South Carolina Medicaid database Follow-up period: 12 months |
5704 patients aged 65–100 years who received at least two prescriptions for study drugs in one of the selection years (2336 in FDC group and 3368 in free combination group). | Adherence was measured via MPR. | Adherence was significantly higher in patients receiving FDCT than patients receiving free-dose therapy: 63.4% vs. 49.0% (p < 0.0001). |
| Dickson and Plauschinat [38], 2008, USA Retrospective cohort study |
To assess adherence with antihypertensive therapy among African American and White Medicaid patients receiving FDC or free combination therapy Patient data retrieved from the South Carolina Medicaid database Follow-up period: 12 months |
4076 patients aged 18–100 years who received at least two prescriptions for study drugs in one of the selection years (3363 in the FDC group and 713 in the free combination group). |
Adherence was measured via PDC. | Adherence was significantly higher in patients on FDCT compared to LDCT: 58.6% vs. 48.1% (p < 0.05). |
| Patel et al. [46], 2008, USA Retrospective cohort study |
To investigate if the adherence in hypertensive patients is better with an FDC than with multiple pills Patient data retrieved from MedImpact Healthcare Systems Follow-up period: 6 months |
4703 patients ≥18 years of age who started a CCB or statin treatment simultaneously or within 30 days (5 cohorts, only one (n = 795) receiving polypill therapy). | Adherence was measured via PDC. | After 180 days, the adherence rates of the polypill group were 9%–17% higher than those of other groups (p < 0.001) After one year, 63.9% of FDCT patients were adherent, while only 33.1%–43.6% were adherent in the group with the separate pills (p < 0.001). |
| Gerbino and Shoheiber [40], 2007, Italy Retrospective cohort study |
To check differences in adherence patterns between an antihypertensive polypill and the drugs taken separately Data retrieved via a pharmacy claims database of a managed care organization in the USA Follow-up period: 12 months |
6206 hypertensive patients, who received at least two prescriptions for FDC or double-pill therapy (2839 in FDC group, 3367 in double-pill group). | Adherence was measured via MPR. | Adherence rates were significantly higher in the FDCT group in comparison to the double-pill group: 87.9% vs. 69.2% (p < 0.0001). |
| Diabetes (n = 10) | ||||
| Rombopoulus et al. [85], 2015, Greece Prospective cohort study |
To evaluate the differences in the adherence in DMII patients on FDC and free-dose therapy of the selected drugs Multiple centers in Greece Follow-up period: 24 weeks |
659 diabetic patients aged >18 years with inadequate glycemic control with metformin monotherapy (366 on FDC and 293 on free-dose therapy). | Adherence was measured via a questionnaire. | In FDC group, 98.9% of patients were compliant, compared to 84.6% in free-dose group (p < 0.005). The odds ratio for FDC vs. free-dose group was 18.9 (95% CIs: 6.2–57.7; p < 0.001). |
| Lokhandwala et al. [86], 2015, USA Retrospective cohort study |
To compare persistence, adherence and economic outcomes between diabetic patients using FDC and LDC products Data retrieved via MarketScan Commercial and Medicare Supplemental Databases Follow-up period: 12 months |
23,361 patients ≥18 years of age with DMII and one additional oral anti-diabetic prescription of the same regimen (FDC/LDC) as the index prescription; 12,590 on FDCT and 10,771 on LDCT. | Adherence was measured via MPR. | FDC patients had significantly higher rate of adherence than patients on LDCT (OR = 1.28; 95% CIs: 1.20–1.36; p < 0.001). |
| Vittorino Gaddi et al. [84], 2013, Italy Retrospective cohort study |
To evaluate antidiabetic drug adherence between MT, LDCT, and FDCT Patient data obtained via the ARNO database Follow-up period: 12 months |
169,375 diabetes patients with at least one oral antidiabetic prescription claim (91,816 in MT group, 31,674 in FDCT group and 19,573 in LDCT group; 15.5% were excluded due to therapy switch in the follow-up period). | Adherence was measured via MPR. | Adherence rates were higher in the FDCT group (68.5%) than in LDCT group (60.3%) (p < 0.05). |
| Barner [31], 2011, USA Retrospective cohort study |
To compare the adherence and costs between MT, LDCT, and FDCT in the treatment of DMII Data retrieved via Texas Medicaid prescription claims database Follow-up period: at least 12 months |
270 patients aged 18–65 years prescribed FDCT with pioglitazone and metformin in post index period and the analogous LDCT or MT in pre index period. | Adherence was measured via MPR. | There was a significant increase in adherence of 8.9% (76.0% to 82.8%) when switching from LDCT to FDCT (p = 0.0081). |
| Thayer et al. [51], 2010, USA Retrospective cohort study |
To assess changes in adherence and HbA1c in diabetes patients on different drug regimes Data obtained via two large databases (not specified) Follow-up period: at least 6 months |
16,490 patients ≥18 years of age with 1 or more prescription fills for rosiglitazone, a sulfonylurea, or rosiglitazone/glimepiride FDCT during the identification period (patients were grouped according to baseline and follow-up period treatment plan; 2518 switched from mono to dual therapy, 543 from MT to FDCT, 13,145 remained on dual, 284 from dual to FDCT). | Adherence was measured via MPR. | Switching from dual therapy to FDC therapy showed a statistically significant increase in adherence rate (p < 0.001). |
| Cheong et al. [36], 2008, USA Retrospective cohort study |
To check the influence of multiple drug regimens (FDCT/dual therapy) on patient adherence Patient data retrieved via the Texas Medicaid prescription claims database Follow-up period: 12 months |
22,512 patients aged 22–89 years, who were prescribed an oral antidiabetic FDCT or the analogous dual therapy during the identification period (7750 FDCT users and 14,762 dual therapy users). | Adherence was measured via MPR. | Patients on FDCT had a higher MPR than dual therapy users: 78.6% vs. 77.2% (p < 0.001). Patients who switched from dual therapy to FDCT saw an increase in MPR of 12.4%, whereas people who continued dual therapy only saw a rise of 5.1% (p < 0.001). |
| Pan et al. [44], 2008, USA Retrospective cohort study |
To compare the patient adherence between single-pill (FDCT) and two-pill regimen Patient data retrieved via the Medstat MarketScan database Follow-up period: 6 months |
9170 patients ≥18 years of age prescribed metformin or sulfonylurea or both before July 2000 and both metformin and sulfonylurea concurrently (either separately or FDC) after August 2000 (2275 FDC users and 6895 non-FDC users). | Adherence was measured via MPR. | The adherence to the FDCT in comparison to the two-pill regimen was 12.8% higher (p = NA). |
| Vanderpoel et al. [54], 2005, USA Retrospective cohort study |
To observe the changes in adherence rates in patients switching from mono- or dual therapy to a FDCT Data retrieved via pharmacy claims database Follow-up period: 6 months |
16,928 patients ≥18 years of age with at least one pharmacy claim for rosiglitazone or metformin during the identification period (patients were grouped according to treatment change from preindex to postindex period; 14,291 remained on mono therapy, 1230 on dual therapy, 931 switched from mono to dual, 349 from mono to FDCT, 127 from dual to FDCT). | Adherence was measured via MPR. | A significant improvement has been observed for patients switching from dual therapy to FDCT (3.5% vs. −1.3%, p < 0.005). |
| Blonde et al. [32], 2003, USA Retrospective cohort study |
To check the impact of single-pill drugs on HbA1c values and adherence rates in DMII patients Patient data retrieved via Medco Health Solutions and Quest Diagnostics Follow-up period: 6 months |
1421 patients aged 18–80 years who initiated single-pill or multipill therapy and had A1C measurements at baseline and within 76–194 days of initiating combination therapy (471 on multipill therapy and 950 on single-pill therapy). | Adherence was measured via MPR. | Patients were more adherent to the polypill in comparison to two-pill regimen: 84% vs. 76% (p < 0.0001). |
| Melikian et al. [43], 2002, USA Retrospective cohort study |
To investigate if adherence is different in diabetes patients with different drug regimens (FDCT, MT, combination therapy) Patient data obtained via pharmacy claims from a pharmacy benefit and medical-management company Follow-up period: 6 months |
6502 patients ≥18 years of age who had an index pharmacy claim for an oral antidiabetic and were continuously enrolled in the health plan (4545 receiving metformin MT, 1651 glyburide MT, 219 combination therapy (59 of those switched to FDCT), 87 FDCT). | Adherence was measured via MPR. | For newly diagnosed diabetics, there was no significant difference in adherence between the therapies. Patients switching from combination therapy to FDCT (pill burden reduction) showed a better adherence with FDCT: 71% vs. 87% (p < 0.001). |
| HIV (n = 14) | ||||
| Langebeek et al. [88], 2014, the Netherlands, Belgium Randomized controlled trial |
To investigate the effect of simplified regimens (1 pill/multiple pills) on adherence, life quality and treatment satisfaction 11 different sites in Belgium and the Netherlands Follow-up period: 24 months |
120 HIV patients (59 on multipill therapy and 61 on single-pill therapy). | Adherence was measured via Simplified Medication Adherence Questionnaire. | Single pill therapy resulted in better adherence than multipill therapy (p = NA). |
| Arrabal-Duran et al. [90], 2017, Spain Observational prospective study |
To data on the effectiveness of switching to an FDC regimen in HIV patients with sustained virological suppression Gregorio Marañon University Hospital, Madrid, Spain Follow-up period: 96 weeks |
57 HIV patients whose previous therapy was based on twice-daily therapy regimen and switched to the examined FDC therapy. | Adherence was measured via PDC. | The proportion of patients with adherence <90% improved from 15.5% to 10.4% (p = 0.915), when they switched to FDC therapy, but this difference is not statistically significant. |
| Chen et al. [91], 2016, USA Observational prospective study |
To study adherence barriers associated with medication regimen complexity and simplification Patients in Atlanta, Georgia Follow-up period: 6 weeks |
750 HIV patients aged ≥18 years receiving antiretroviral therapy (166 patients on FDC, 300 taking single-dose multipill regimen, 284 taking multi-dose multipill regimen). | Adherence was measured via pill count. | A higher number of patients in polypill group (76%) achieved ≥85% adherence compared to both the group taking single-dose (68%) and the group taking multi-dose multipill regimen (66%); p < 0.043. |
| Buscher et al. [34], 2012, USA Prospective cohort study |
To study the impact of antiretroviral therapy regimen on adherence in new HIV patients (FDC vs. LDC and once-daily vs. twice-daily dosing) Houston, TX Follow-up period: 18 months |
99 newly diagnosed HIV patients (34 on FDCT, 36 on once daily multipill regimen, 29 on twice daily regimen). | Adherence was measured via a 30-day VAS scale. | No significant difference in adherence was seen between the FDCT and LDCT once-daily dosed group (p = 0.34). |
| Airoldi et al. [87], 2010, Italy Prospective cohort study |
To check if there is a link between a reduction in pill burden and adherence in HIV patients 6 medical centers in Italy Follow-up period: 6 months |
212 HIV patients who switched from multipill to single-pill therapy. | Adherence was measured via VAS. | Adherence increased clinically meaningfully for 1.1% (p = 0.01). |
| Bangsberg et al. [30], 2010, USA Prospective cohort study |
To check the influence of a decreased pill burden on adherence in HIV therapy Data obtained via the REACH (The Research on Access to Care in the Homeless) cohort Follow-up period: 6 months |
118 HIV patients (47 on single-pill therapy, 57 and 14 on different multipill therapies, respectively). | Adherence was measured via unannounced pill-count. | Adherence was significantly greater for polypills than for multiple pill users (p = 0.006). |
| Santoleri et al. [92], 2018, Italy Retrospective cohort study |
To compare adherence between patients receiving single or multiple tablet regimen antiretroviral therapy Hospital Pharmacy of “Santo Spirito” Hospital of Pescara, Italy Follow-up period: 5 years |
290 patients who had withdrawn from taking antiretroviral drugs for at least 6 months in the 5-year period (66 on single pill and 227 on multipill (2, 3, 4, or 5 pills daily) therapy). | Adherence was measured via RDD/PDD ratio. | Single pill therapy group had excellent adherence value of 0.98, whereas multiple pill therapy groups had lower adherence levels of 0.92–0.96 during years 1–5 of the study. |
| Yager et al. [94], 2017, USA Retrospective cohort study |
To compare antiretroviral and non-antiretroviral adherence between single and multiple tablet regimens Data retrieved via pharmacy refill records (Upstate New York Veterans’ Healthcare Administration) Follow-up period: 1.1 years for multipill and 2.3 for single-pill therapy |
1202 HIV patients ≥18 years of age on ≥3 antiretroviral medications for ≥3 months and available pharmacy refill records (165 patients were on single-pill, 1037 on multiple tablet regimens). | Adherence was measured via MPR. | Adherence was significantly higher for single tablet regimens treatment-naïve recipients (80.8%–15.4%) compared to the multipill therapy (65.9%–21.3%), p < 0.001. |
| Sutton et al. [57], 2016, USA Retrospective cohort study |
To evaluate the impact of antiretroviral therapy as a single-tablet regimen or multiple-tablet regimen on outcomes in HIV patients Data retrieved via Veterans Health Administration electronic health record system Follow-up period: at least 60 days |
15,602 patients to whom HIV medications were dispensed as single-tablet (6191 patients) or multiple-tablet (9411 patients) during the study period. | Adherence was measured via MPR. | The odds of adherence were approximately two times higher in polypill group than in multiple therapy group (OR, 2.16; 95% CIs: 1.92–2.43; p < 0.001). |
| Sutton et al. [93], 2016, USA Retrospective cohort study |
To assess the impact of pill burden in HIV patients receiving single-tablet or multi-tablet regimen on clinical outcomes Data retrieved via South Carolina Medicaid medical and pharmacy paid claims data Follow-up period: at least 60 days |
2174 patients aged ≥18 years who were receiving a complete antiretroviral single-tablet (580 patients) or multiple-tablet regimen (1594 patients) for at least 60 days | Adherence was measured via PDC. | Adherence was higher in single-pill than in multiple-pill group (80% vs. 67%, p < 0.0001). |
| Raffi et al. [47], 2015, France Retrospective cohort study |
To compare adherence and persistence in HIV adult patients receiving combination ART (cART) as a once-daily single-tablet regimen versus other administration schedules Data retrieved via French National Healthcare Insurance Database Follow-up period: mean 32.8 months |
362 patients ≥18 years of age receiving cART reimbursed in selection years (76 on single-tablet regimen, 242 taking >1 pill once daily, 248 having >1 daily intake). | Adherence was measured via pill count. | Better adherence was observed with the polypill in comparison with regimens with >1 daily intake but no difference was observed in comparison with regimens involving >1 pill once daily (mean adherence 89.6% for the polypill, 86.4% for cART with >1 pill once daily and 77.0% for cART with >1 daily intake (p < 0.0001)). |
| Tennant et al. [50], 2014, USA Retrospective cohort study |
To compare adherence and virologic outcomes in adult HIV patients on single-tablet or multiple-tablet antiretroviral therapy Patients enrolled in AIDS Drug Assistance Program at two independent clinics in South Carolina and Alabama Follow-up period: mean 22 months (multipill group) and 14 months (single-pill group) |
389 HIV patients aged ≥18 years with a documented visit to one of the two clinics and prescribed one of the two examined antiretroviral therapy regimens (165 in single-tablet and 224 on multipill therapy). | Adherence was assessed via MPR and self-reporting. | Median adherence rates were similar in both groups, regardless of the way it was assessed (based on clinic records: 91% and 93% (p < 0.14) in single-pill and multipill group, respectively; self-reporting: 100% and 99% (p < 0.05) in single-pill and multipill group, respectively). However, the proportion of adherent patients was higher in single-pill therapy group; 61.6% vs. 51.5% (p = 0.047; based on clinic records) and 92.8% vs. 85.4% (p = 0.0179; based on self-reporting). |
| Cohen et al. [37], 2013, USA Retrospective cohort study |
To compare adherence, healthcare utilization and costs in antiretroviral therapy with once-daily single-tablet regimen to the therapy with two or more pills per day Data retrieved from the MarketScan Medicaid Multi-State Database Follow-up period: at least 60 days |
7381 patients (5584 taking two or more pills per day and 1797 on a single-pill therapy) with an HIV diagnosis receiving complete antiretroviral therapy. | Adherence was measured via MPR. | Patients on single-tablet regimens were significantly more likely to reach 95% adherence (p < 0.01). |
| Legoretta et al. [89], 2005, USA Retrospective cohort study |
To investigate the influence of pill-burden on adherence in HIV-positive patients Data obtained via 2 databases, West Coast and Southeast state Medicaid Follow-up period: at least 2 months |
1427 HIV patients ≥18 years of age, who were newly started on antiretroviral therapy and had at least one prescription refill in the first 60 postindex days (1363 on polypill therapy, 64 on multipill therapy). | Adherence was measured via MPR. | Mean adherence was 85% for polypills, while it was significantly lower (75%) for multiple pills therapy (p < 0.001). |
| LUTS/BHP (n = 1) | ||||
| Drake et al. [95], 2017, the Netherlands Retrospective cohort study |
To compare treatment persistence and adherence with α-blocker plus antimuscarinic combination therapy in men with LUTS/BPH between those prescribed an FDC and those on multipill therapy Data retrieved via the Netherlands IMS LifeLink™ LRx database, which contains data from pharmacies and dispensing (general practices) in the Netherlands Follow-up period: 12 months |
1891 patients ≥45 years of age, who received combination therapy with study drugs as FDC or multipill therapy (665 on FDC therapy and 1,226 on multipill therapy). | Adherence was measured via MPR. | Adherence was similar in both groups of patients; 80.0% of the patients on FDC therapy were adherent, while the adherence among patients on α-blocker and antimuscarinic concomitant therapy was 85.8% and 75.2%, respectively (p = NA). |
FDCT, fixed-dose combination therapy; LDCT, loose-dose combination therapy; FDC, fixed-dose combination; LDC, loose-dose combination; SPC, single-pill combination; MT, monotherapy; MPR, medication possession ratio; RDD/PDD, received daily dose/prescribed daily dose; PDC, proportion of days covered; VAS, visual analog scale; ICD, international classification of diseases; CVD, cardiovascular disease; DMII, diabetes mellitus type II; HIV, human immunodeficiency virus; HT, hypertension; LUTS/BPH, lower urinary tract symptoms associated with benign prostatic hyperplasia; CCB, calcium channel blocker; ACE-I, angiotensin-converting enzyme inhibitor type I; ARB, angiotensin receptor II blocker; ART, antiretroviral therapy; CI, confidence interval; OR, odds ratio; NA, not available.