Table 2 Methods of measuring adherence and persistence, and their validity indicators (n = 77)

Ali M, 2023 [24]

ATV, SIM, PRA, FLU

Adherence: PRR (MPR)

Optimal adherence: MPR ≥ 1.0

Adequate adherence: MPR > 0.8 and < 1.0

Sub-optimal adherence: MPR < 0.8

No

–

–

Allonen J, 2012 [25]

All types

Adherence: PRR (days counted from discharge date to purchase date)

Adherent:

- Early: within 7 days

- Delayed: between 7 and 120 days

- Late: after 120 days

Non-adherent: did not purchase medication

No

–

–

Persistence: PRR (days counted from discharge date to purchase date)

Non-users: no purchase or only one purchase; first purchase > 180 days after prescription

Irregular users: first purchase ≥ 30 days after discharge or multiple purchases with > 180-day gap

Regular users: multiple purchases, first within 30 days of discharge, no long gaps

Alsabbagh W, 2017 [26]

All types

Adherence: PRR (PDC)

Optimum: PDC ≥ 80%

No

–

–

Al-Khadra S, 2014 [31]

All types

Persistence: self-reported (direct questioning via phone or home visits)

Discontinuity if the treatment was interrupted for ≥ 90 days

No

–

–

Bell KJ, 2011 [32]

PRA

Adherence: self-reported (direct questioning)

Adherent: taking any pills

Non-adherent: stopped taking them

No

–

–

Blackburn DF, 2005 [33]

All types

Adherence: PRR (supply frequency of medication)

Adherent: supply frequency > 80%

Non-adherent: supply frequency ≤ 60%

No

–

–

Booth JN, 2017 [34]

All types

Persistence: PRR (PDC)

High persistence: PDC ≥ 80% (182 days post-discharge)

Discontinuation: ≥ 60 days without statin supply after initial dose

No

–

–

Brogaard HV, 2012 [35]

All types

Adherence: PRR (MPR)

Adherent: MPR ≥ 80%

No

–

–

Brown R, 2021 [36]

All types

Adherence: PRR (MPR)

Adherent: MPR ≥ 80%, or ≥ 50% for patients with low tolerance taking it every other day

No

–

–

Carey IM, 2012 [37]

ATV, CER, FLU, PRA, ROS, SIM

Adherence: PRR (PDC)

Adherent: MPR ≥ 80% (over 1 year)

No

–

–

Chan V, 2008 [38]

All types

Adherence: PRR (MPR)

Optimal adherence: MPR ≥ 80%

No

–

–

Chen PS, 2016 [39]

All types

Adherence: PRR (MPR)

Adherence:

- Good: MPR > 80%

- Intermittent: MPR 40–80%

- Poor: MPR < 40%

No

–

–

Chen ST, 2019 [40]

All types

Adherence: PRR (PDC and MPR)

Adherence:

- Good: PDC ≥ 0.8

- Suboptimal: PDC < 0.8

No

–

–

Persistence: PRR (time to non-renewal of medication)

Discontinuity: no renew the prescription for 90 days

Chi MD, 2014 [41]

All types

Adherence: PRR (MPR)

Good adherence: MPR > 80%

No

–

–

Choudhy NK, 2011 [42]

All types

Adherence: PRR (MPR)

Adherent: MPR ≥ 80%

Non-adherent: do not pick up prescribed medication

No

–

–

Chow CK, 2022 [43]

All types

Adherence: self-reported (direct questioning)

Adherent: take ≥ 80% of prescribed doses (maintain at 6 and 12 months)

No

–

–

Chung PW, 2018 [44]

All types

Adherence: self-reported (MMAS-8)

- High: score = 8 points

- Moderate: score = 6–7 points

- Low: score < 6 points

Yes, by previous authors for hypertensive patients (results retracted) [23]

Sensitivity = 93%

Specificity = 53%

Internal consistency (Cronbach’s alpha) = 0.83

Coberley C, 2008 [45]

All types

Adherence: PRR (supply frequency)

Adherence: having at least one pharmacy claim during each 12 months

No

–

–

Colantonio LD, 2017 [46]

ATV, ROS

Adherence: PRR (PDC)

- High adherence: PDC ≥ 80%

- Low adherence: PDC < 80%

No

–

–

Persistence: PRR (time to non-renewal of medication)

Discontinuity: no renew the prescription for or supply of statins in the last 60 days of the 6-month period

Cooke CE, 2006 [47]

ATV, FLU, LOV, PRA, ROS, SIM

Adherence: PRR (MPR)

- Good: MPR ≥ 0.8

- Poor: MPR 0.5 ≤ MPR < 0.8

- Very poor: MPR < 0.5

No

–

–

Persistence: PRR (time between prescription and supply dates)

Persistence: time between prescription and supply ≤ 30 days

Di Martino M, 2016 [48]

All types

Adherence: PRR (MPR)

Adherence: MPR ≥ 0.75

No

–

–

Fanaroff AC, 2020 [49]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80% (1 year)

No adherence: PDC < 80%

No

–

–

Persistence: PRR (PDC)

Persistence: supply without a break ≥ 30 days

No persistence: break in supply > 30 days or never picked up

Fang R, 2015 [50]

All types

Adherence: self-reported (MMAS-4)

- Good: MMAS = 0

- Fair: MMAS = 1–2

- Poor: MMAS = 3–4

Yes, by previous authors for hypertensive patients [105]

Sensitivity: 0.81

Specificity: 0.44

Cronbach’s alpha: 0.61

Faridi KF, 2016 [51]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80% at 90 days and 1 year

No

–

–

Griffiths B, 2014 [52]

All types

Adherence: self-reported (direct questioning via phone)

Adherence: continued use at 6–9 months after discharge

No

–

–

Ho PM, 2014 [53]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80% (1 year)

No adherence: PDC < 80%

No

–

–

Hoang C, 2011 [54]

All types

Persistence: self-reported (direct questioning via phone)

Discontinuity: if they discontinued at 6–12 months after discharge

No

–

–

Hudson M, 2006 [55]

All types

Persistence: PRR (MPR)

Persistence: MPR ≥ 80% during the first year

No

–

–

Persistence: PRR (continuity of prescription)

Persistence: active prescription at the end of follow-up (60 days)

Huynh T, 2018 [56]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80%

No

–

–

Jia X, 2019 [57]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80%

No adherence: PDC < 80%

No

–

–

Adherence: self-reported (24-h recall)

Adherence: reported taking all medications in the last 24 h

Adherence: PRR (CHCS)

Adherence: refills matched prescribed days, always within 90 days

Kirsch F, 2020 [58]

All types

Adherence: PRR (PDC)

Not reported

No

–

–

Kocas C, 2013 [59]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80% (1 year)

No adherence: PDC < 80%

No

–

–

Korol S, 2022 [60]

All types

Persistence: PRR (supply frequency)

Persistence: regular use without discontinuation at 6, 12, and 24 months

No

–

–

Kristiansen O, 2021 [61]

ATV

Adherence: self-reported (MMAS-8)

Low adherence: score < 6

No

–

–

Adherence: self-reported (Gehi’s adherence question)

Reduced adherence: if they answer any of these options: “most of the time” (75%), “about half the time” (50%), or “less than half of the time” (< 50%)

No

–

Adherence: self-reported (7-day recall)

Adherence: < 6/7 days

No

–

Adherence: direct method (TDM: HPLC–MS/MS)

Partial adherence: ATV + metabolites < 0.10 nM/mg (≥ 2 consecutive skipped doses)

Non-adherence: 2-OH atorvastatin acid < 0.014 nmol/L (> 3 consecutive missed doses)

Analytical method validated by the same authors [62]

All ATV and metabolite analyses met the acceptance criteria for analytical runs in the EMA Guideline on Validation of Bioanalytical Methods

Sensitivity = 100%

Specificity = 92%

Khunti K, 2018 [62]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80%

No

–

–

Kulik A, 2011 [63]

ATV, FLU, LOV, PRA, ROS, SIM

Adherence: PRR (PDC)

Fully adherence: PDC > 80%

No

–

–

Lee JK, 2007 [64]

All types

Adherence: pill count method

Adherence: taking 85–100% of expected pills

No

–

–

Adherence: self-reported (24-h recall)

Adherence: self-reported full medication intake in the last 24 h

Adherence: PRR (CHCS)

Adherence: refills aligned with prescribed days within 90 days

Liao YB, 2023 [65]

All types

Adherence: PRR (MPR)

No adherence: MPR < 0.8

No

–

–

Librero J, 2016 [66]

All types

Adherence: PRR (MPR)

Adherence: PDC ≥ 0.8

No

–

–

Lip GYH, 2023 [67]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 0.8

No adherence: PDC < 0.8

No

–

–

Maddison R, 2021 [68]

All types

Adherence: PRR (MPR)

Adherence: MPR ≥ 80%

No adherence: MPR < 80%

No

–

–

Adherence: self-reported (MMAS-8)

- High: score = 0

- Medium: score = 1–2

- Low: score = 3–6

Yes, by previous authors for hypertensive patients (results retracted) [23]

Sensitivity = 93%

Specificity = 53%

Internal consistency (Cronbach’s alpha) = 0.83

McGinnis BD, 2009 [69]

PRA, LOV, ATV, SIM, ROS, FLU

Adherence: PRR (PDC)

- Adherence: PDC > 80%

- Partial adherence: PDC = 20 to ≤ 80%

- Non-adherence: PDC < 20%

No

–

–

Mechtouff L, 2018 [70]

All types

Adherence: PRR (CMA)

Adherence: CMA ≥ 0.8

No

–

–

Persistence: PRR (supply frequency)

Persistence: if they purchase at least one prescribed treatment during the studied year

Navar AM, 2019 [71]

SIM

Persistence: self-reported (direct questioning)

Discontinuation: permanent stop of medication

- Early: < 30 days

- Intermediate: 30 days to 1 year

- Late: > 1 year

No

–

–

Padilla López A, 2021 [72]

All types

Adherence: PRR (PDC)

Adherence: PDC > 80%

No

–

–

Park LG, 2014 [73]

All types

Adherence: electronic monitoring device (MEMS: % of doses)

Adherence: quantitative measurement was used but threshold not reported

Adherence: yes, by previous authors in patients with hypertension [106]

Sensitivity = 76%

Specificity = 83%

Correlation coefficient = 0.20

Adherence: self-reported (SEAMS)

Good adherence: high scores

Adherence: yes, by previous authors [107]

Adherence: test–retest reliability:correlation = 0.57

Adherence: internal consistency (Cronbach’s alpha) = 0.89

Adherence: self-reported (MMAS-8)

Adherence: quantitative measurement was used but threshold not reported

Adherence: yes, by previous authors for hypertensive patients (results retracted) [23]

Adherence: sensitivity = 93%

Specificity = 53%

Adherence: internal consistency (Cronbach’s alpha) = 0.83

Phan DQ, 2019 [74]

All types

Adherence: PRR (PDC)

- High: PDC ≥ 80%

- Partial: PDC ≥ 40 to < 80%

- Low: PDC < 40%

No

–

–

Pietrzykowski L, 2020 [75]

ATV, SIM, ROS

Adherence: PRR (days on treatment and days of interruption)

Not reported

No

–

–

Persistence: PRR (days of interruption)

- Short-term discontinuation: less than 30 days

- Long-term discontinuation: 30 days or more

- Permanent discontinuation: when the patient stops taking the medication permanently

Qvist I, 2020 [76]

SIM, ATV

Adherence: PRR (PDC)

- Good: PDC ≥ 80%

No

–

–

Rasmussen JN, 2007 [77]

All types

Adherence: PRR (PDC)

- High: PDC ≥ 80%

- Intermediate: PDC 40–79%

- Low: PDC < 40% (1 year)

No

–

–

Rana JS, 2021 [78]

All types

Adherence: PRR (CMG: % time without adequate supply)

- Good: CMG ≤ 20%

- Inadequate: CMG > 20%

No

–

–

Reddy A, 2016 [79]

All types

Adherence: PRR (MPR)

Poor adherence: MPR < 80%

No

–

–

Adherence: self-reported (MMAS-4)

- High: score = 0

- Medium: score = 1–2

- Low: score = 3–4

Adherence: yes, by previous authors for hypertensive patients [105]

Adherence: sensitivity = 0.81

Specificity = 0.44

Adherence: Cronbach’s alpha = 0.61

Adherence: electronic monitoring device (GlowCap®)

Adherence: number of days opening the jar over a period of time. No exact threshold specified

No

–

–

Rodríguez F, 2019 [80]

FLU, LOV, SIM, PIT, PRA, ATV, ROS

Adherence: PRR (MPR)

Adherence: MPR ≥ 80%

No

–

–

Schiele F, 2021 [81]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80% (1 year)

No

–

–

Schwalm JD, 2020 [82]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80%

No

–

–

Persistence: PRR (days between supply dates)

Persistence: no ≥ 30-day gap in supply during follow-up (1 year)

Shalev V, 2014 [83]

SIM, PRA, LOV, FLU, ATV, CER, ROS, PIT

Persistence: PRR (PDC)

- Low: PDC ≤ 33%

- Moderate: PDC = 34–79%

- High: PDC ≥ 80%

No

–

–

Shau WY, 2019 [84]

All types

Adherence: PRR (PDC)

Good adherence: PDC ≥ 0.8

No adherence: PDC < 0.8

No

–

–

Persistence: PRR (continuity of prescription)

- No persistence: discontinuity > 90 days

- Intermittent use: resumption of statin prescription after non-persistent status

- Recent suspension < 90 days

- Consistent use: continuous administration or statins

Simonyi G, 2014 [85]

ATV

ROS

SIM

Adherence: self-perceived adherence by physicians

Not reported

No

–

–

Adherence: PRR (supply frequency)

Adherence: ≥ 8 prescriptions/year

Persistence: PRR (supply frequency)

- High: regular supply frequency

- Low: low supply frequency

Sjölander M, 2016 [86]

All types

Adherence: PRR (PDC)

Adherence: PDC > 80%

No

–

–

Soldati S, 2021 [87]

All types

Adherence: PRR (MPR)

Adherence: MPR ≥ 0.75 (6 months)

No

–

–

Souza Groia Veloso R, 2021 [88]

All types

Adherence: self-reported (MAT)

Adherence: score = 5–6

Non-adherent: score = 1–4

Yes, by authors for another drug and field; internal consistency analyzed for statin-adapted MAT [108]

–

MAT adapted to statins: Cronbach’s alpha = 0.66

Adherence: self-reported (VAS)

- Adherent patient: VAS score ≥ 80%

- Non-adherent patient: VAS score < 80%

No

–

–

Adherence: self-reported (7-day recall)

- Non-adherent: statin use ≤ 5 days

- Adherent: use of statin 6 or 7 days

No

–

–

Stuart B, 2013 [89]

All types

Adherence: PRR (PDC)

Good adherence: PDC ≥ 80%

No

–

–

Thompson D, 2021 [90]

ATV or other

Adherence: self-reported (7-day recall)

Not reported

No

–

–

Adherence: direct method, TDM (HPLC–MS/MS in urine sample analysis)

Adherence: detection of drug in urine (detection limit between 1 and 200 ng/mL)

Yes, by previous authors [109]

Sensitivity > 90%

–

Vethe NT, 2019 [91]

ATV

Adherence: direct method, TDM (LC–MS/MS)

Non-adherent: ≥ 3 days without medication. The threshold of adherence was not reported

Validated by the authors per EMA and FDA guidelines

Mean accuracy: 92 to 110%

Coefficients of variation (CV): ≤ 8.1%

–

Vethe NT, 2022 [92]

SIM

Adherence: direct method, TDM (HPLC–MS/MS)

- Reduced adherence: dose omission (t48h, t72h, t96h)

- Cutoff levels: simvastatin acid ≥ 1.0 × 10⁻² nmol·L⁻¹·mg⁻¹; total components ≥ 2.0 × 10⁻² nmol·L⁻¹

- Detection: 100% for 2 missed doses, 60% for 1 missed dose

Yes, by the same authors. Plasma concentration normalized per dose after 2 missed doses vs. adherent dosing [92]

Sensitivity = 100%

Specificity = 100%

–

Virani SS, 2014 [93]

ATV, FLU, LOV, PRA, ROS, SIM, PIT

Adherence: PRR (PDC)

Adherence: PDC ≥ 80%

Non-adherence: PDC < 80%

No

–

–

Vitturi BK, 2021 [94]

All types

Adherence: self-reported (MMAS-8)

- Poor: score < 6 points

- Intermediate: score = 6 or < 8 points

Yes, by previous authors for hypertensive patients (results retracted) [23]

Sensitivity = 93%

Specificity = 53%

Internal consistency (Cronbach’s alpha) = 0.83

Volpp KG, 2017 [95]

All types

Adherence: PRR (PDC for 1 year)

Quantitative, but adherence threshold not defined

No

–

–

Wake M, 2019 [96]

PRA, SIM, FLU, ATV, ROS, PIT

Adherence: PRR (PDC)

Adherence: PDC ≥ 80%

No

–

–

Persistence: PRR (time between prescription and supply dates)

Persistence: no gap > 1.5 × the median treatment duration

Wawruch M, 2017 [97]

All types

Persistence: PRR (continuity of prescription)

Persistence: continuous treatment without interruption

Non-persistence: ≥ 6 months without a prescription after the last covered day

No

–

–

Wei L, 2002 [98]

All types

Adherence: PRR (PDC)

- Non-adherent: no statin prescription

- Good adherence: PDC > 80%

- Maximum adherence: compliance > 100% (excess medication pickup)

No

–

–

Xie G, 2017 [99]

All types

Adherence: PRR (supply frequency)

- Good adherence: continuous statin use without tapering for 6 months post-discharge

- Poor adherence: interruption or dosage reduction within 6 months post-discharge

No

–

–

Xie G, 2022 [100]

ATR

SIM

ROS

PRA FLU

Persistence: standardized questionnaire (phone interview and personal visits)

Persistence: use at statins at either the 6- or 12-month follow-up

No

–

–

Yaglioglu H, 2022 [101]

ATV, ROS

Adherence: direct method, TDM (HPLC–MS/MS)

Non-adherence threshold: -ATV < 4.88 ng/mL, -ROS < 3.95 ng/mL (LLOQ)

Yes, by the same authors. Follow the recommendations of the FDA guidance [101]

LLOQ:

ATV: 4.88 ng/mL

ROS: 3.95 ng/mL

Accuracy (intra-day and inter-day CV%):

ATV: 1.7–5.9%

ROS: 1.7–5.9%

Accuracy (% recovery):

-ATV: 93.8–110.4%

-ROS: 93.8–110.4%

Matrix effect (%):

-ATV: − 7.63 to − 2.83%

-ROS: − 8.84 to 3.65%

–

Yan LL, 2021 [102]

All types

Adherence: self-reported (MMAS-4)

Perfect adherence: score = 0

Yes, by previous authors for hypertensive patients [105]

Sensitivity: 0.81

Specificity: 0.44

Cronbach’s alpha: 0.61

Yao X, 2020 [103]

ATV

ROS

SIM

Adherence: PRR (PDC)

Adherence: PDC ≥ 80% within the first year

No

–

–

Yu G, 2018 [104]

All types

Adherence: PRR (PDC)

Adherence: PDC ≥ 80%

Non-adherence: PDC < 80%

No

–

–