Trough-to-peak ratios and elimination half-lives of antihypertensive drugs: implications for 24-hour blood pressure control in primary care

Abstract

Objective

To compile and critically summarize published trough-to-peak (TP) ratios and elimination half-lives of antihypertensive drugs, providing a structured reference for research and clinical interpretation of 24-h blood pressure (BP) control.

Design

Systematic review.

Data sources

MEDLINE and the Cochrane Central Register of Controlled Trials were searched up to June 2024.

Selection of studies

Clinical trials reporting TP ratios and pharmacokinetic studies reporting elimination half-life values of antihypertensive drugs were eligible.

Data extraction

TP ratio and elimination half-life values were extracted. Studies were classified according to Oxford levels of evidence for descriptive purposes. Randomized clinical trials reporting TP ratios were assessed for risk of bias using the Cochrane Risk of Bias tool (RoB 2).

Results

A total of 228 publications were included, providing data on 83 antihypertensive drugs across nine pharmacological classes. TP ratios were available for 69 drugs and elimination half-life values for 77 drugs. Substantial variability in TP ratios and elimination half-life values was observed across pharmacological classes and individual agents.

Conclusions

This systematic review compiles and organizes available TP ratio and elimination half-life data for most antihypertensive drugs. The resulting reference framework may support future research and facilitate the interpretation of 24-h BP control and antihypertensive treatment selection in clinical practice.

Resumen

Objetivo

Compilar y resumir críticamente los cocientes valle-pico (trough-to-peak, TP) y las semividas de eliminación publicados para los fármacos antihipertensivos, proporcionando una referencia estructurada para la investigación y la interpretación clínica del control de la presión arterial (PA) durante 24 horas.

Diseño

Revisión sistemática.

Fuentes de datos

Se realizaron búsquedas en MEDLINE y en el Registro Central de Ensayos Controlados de Cochrane hasta junio de 2024.

Selección de estudios

Se incluyeron ensayos clínicos que informaban cocientes TP y estudios farmacocinéticos que notificaban valores de semivida de eliminación de fármacos antihipertensivos.

Extracción de datos

Se extrajeron los valores de cociente TP y de semivida de eliminación. Los estudios se clasificaron según los niveles de evidencia de Oxford con fines descriptivos. El riesgo de sesgo de los ensayos clínicos aleatorizados que informaban cocientes TP se evaluó mediante la herramienta Cochrane Risk of Bias (RoB 2).

Resultados

Se incluyeron 228 publicaciones, que aportaron datos de 83 fármacos antihipertensivos pertenecientes a nueve clases farmacológicas. Se identificaron cocientes TP para 69 fármacos y valores de semivida de eliminación para 77. Se observó una variabilidad considerable en los cocientes TP y en las semividas de eliminación entre las distintas clases farmacológicas y entre fármacos individuales.

Conclusiones

Esta revisión sistemática compila y organiza los datos disponibles sobre cociente TP y semivida de eliminación de la mayoría de los fármacos antihipertensivos. El marco de referencia resultante puede apoyar futuras investigaciones y facilitar la interpretación del control de la PA durante 24 horas y la selección del tratamiento antihipertensivo en la práctica clínica.

Introduction

Hypertension is one of the most prevalent chronic conditions managed in primary care and remains a leading contributor to cardiovascular morbidity and mortality worldwide.^1,2 Despite the availability of effective antihypertensive therapies, blood pressure (BP) control rates in routine clinical practice are suboptimal, with fewer than half of treated patients achieving recommended targets.^3,4 This situation represents a major challenge for primary care professionals, who are responsible for the long-term management and follow-up of most patients with hypertension.

In daily practice, treatment decisions are frequently based on office BP measurements, drug class preferences and tolerability considerations. However, isolated clinic measurements do not adequately reflect BP behaviour over the 24-h period. Ambulatory blood pressure monitoring (ABPM) provides a more accurate assessment of average BP levels, circadian BP patterns and short-term BP variability, all of which have been shown to be independently associated with cardiovascular risk and target organ damage. Increasing evidence supports the use of ABPM in primary care to improve diagnostic accuracy, guide treatment adjustments and reduce cardiovascular events.^5–7

Beyond mean BP values, BP variability over 24 h has emerged as a relevant prognostic factor. Excessive BP fluctuations are associated with a higher risk of cardiovascular complications.⁵ Consequently, antihypertensive drugs with sustained and homogeneous effects throughout the dosing interval are generally preferred in primary care, particularly when once-daily regimens are prescribed to improve adherence. Nevertheless, the real duration of action of antihypertensive drugs may differ substantially between agents, even within the same pharmacological class.⁸

Several indices have been proposed to evaluate the consistency of BP control throughout the dosing interval, including the trough-to-peak (TP) ratio, the smoothness index (SI) and the treatment-on-variability index (TOVI).^9–11 Among these, the TP ratio is the most widely reported in clinical trials and regulatory documents. It reflects the proportion of BP reduction maintained at the end of the dosing interval relative to the maximum effect achieved. According to regulatory criteria, a TP ratio of at least 50% is generally required to support once daily dosing¹² (Table 1).

Table 1.

Indices for assessing the consistency of blood pressure (BP) control throughout the dosage interval.

Index	Explanation	Comments
TP (Trough to peak ratio)	Relation between the decrease in BP at the end of the dosing interval (trough) and the maximum decrease achieved after administering the drug (peak).	The closer to 100%, the more uniform the 24 h coverage. A drug must have a TP ≥ 50% to be considered as a single daily dosage.
SI (smoothness index)	Ratio between the mean of the hourly BP differences over 24 h and the standard deviation of the mean of these hourly differences.	Degree of BP reduction during the whole 24 h period (less variability than TP).
TOVI (treatment on variability index)	Relation between the mean 24 h BP reduction due to treatment and a measure of the short-term variability of BP under the same treatment (24 h weighted standard deviation).	Few studies performed.
Half-life	Time required to eliminate 50% of the plasma concentration achieved by one dose of medicine.	It sets the intervals between doses.

Another key parameter influencing dosing decisions is the elimination half-life of antihypertensive drugs, a pharmacokinetic parameter that reflects the time required for plasma drug concentration to decrease by 50%.¹² In primary care, awareness of drug half-life is essential to avoid end-of-dose BP loss, early morning BP surges, and unnecessary dose escalation or drug switching. In addition, elimination half-life remains a useful comparative descriptor of drug persistence and is frequently reported in the literature.¹³Table 1 shows a summary table with the different assessment indices.

Although TP ratios and elimination half-life values have been reported for many antihypertensive drugs, this information is scattered across clinical trials, pharmacokinetic studies and regulatory documents. To date, these parameters have not been systematically compiled within a single framework, making comparisons across drug classes difficult.

The objective is a systematic review aimed at compiling and critically summarizing published TP ratios and elimination half-lives of antihypertensive drugs, to provide a structured reference for research and clinical interpretation of 24-h BP control.

Methods

This study is a systematic review conducted to compile and critically summarize published TP ratios and elimination half-life values of antihypertensive drugs.

The review was designed according to the PICO framework and conducted following PRISMA recommendations for systematic reviews.

Registration and reporting standards. This systematic review was not registered in PROSPERO data base. Given the descriptive and non-comparative nature of the review, which focused on compiling pharmacodynamic and pharmacokinetic parameters rather than estimating treatment effects or comparing interventions. Although this review could have been registered in PROSPERO, it was not prospectively registered, which should be considered a limitation. The study selection process followed PRISMA guidance and is presented using a PRISMA flow diagram (Fig. 1).

Figure 1.

PRISMA flow diagram of study selection. The study selection process followed PRISMA recommendations. A total of 1985 records were identified through database searching (MEDLINE and Cochrane Collaboration Library). After removal of duplicates, 1294 records were screened, and 761 full-text articles were assessed for eligibility. Of these, 533 full-text articles were excluded because they did not report TP ratio and/or elimination half-life values or because BP was not assessed using office measurement or ABPM. The final qualitative synthesis included 228 studies corresponding to 83 unique antihypertensive drugs. Abbreviations: TP, trough-to-peak ratio; BP, blood pressure; ABPM, ambulatory blood pressure monitoring.

Data sources and search strategy. A systematic literature search was performed in the MEDLINE database (via PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL). No restriction was applied to the earliest publication date. The search included all eligible articles published up to June 2024.

For each antihypertensive drug, searches were conducted using the drug's generic name combined with the following terms: “trough-to-peak”, “half-life”, “hypertension”, “blood pressure” and “efficacy”. In MEDLINE, the filters human, randomized clinical trials and English language were applied. In CENTRAL, searches were limited to clinical trials. Although randomized clinical trial filters were applied to identify TP ratio data, additional pharmacokinetic and regulatory studies were included to obtain elimination half-life values.

In addition, the reference lists of all selected articles were manually reviewed to identify relevant studies that may not have been captured through the systematic database search.

Inclusion criteria:

• -

  Clinical trials assessing antihypertensive efficacy using ABPM and reporting trough-to-peak ratio values.

• -

  Pharmacokinetic studies, clinical trials or regulatory sources reporting elimination half-life values of antihypertensive drugs.

• -

  Studies conducted in human subjects.

• -

  Articles published in English.

As elimination half-life is a pharmacokinetic parameter, values were extracted from pharmacokinetic studies or regulatory documents when not available from randomized clinical trials.

Exclusion criteria:

• -

  Blood pressure was not assessed using ABPM or office BP measurement.

• -

  TP ratio and/or elimination half-life values were not reported.

• -

  Duplicate publications reporting identical data.

Study selection process. Titles and abstracts retrieved from the database searches were screened to identify potentially eligible studies. Full-text articles were subsequently reviewed to confirm eligibility according to the predefined inclusion and exclusion criteria.

When more than one study reported TP ratio or elimination half-life values for the same antihypertensive drug, all eligible articles were assessed. If reported values were concordant, the most frequently reported value was selected. In cases of discordant results, a qualitative assessment was performed considering consistency across studies, study design, completeness of ABPM reporting and risk of bias in randomized clinical trials. The value most consistently supported in the literature was retained; when only two discordant studies were available, the most recent publication was selected.

Quality assessment and level of evidence. Assessment of study quality and risk of bias

Levels of evidence were initially classified according to the Oxford Centre for Evidence-Based Medicine criteria for descriptive purposes. Given the descriptive objective of this review, aimed at compiling pharmacokinetic and pharmacodynamic parameters rather than estimating treatment effects, a formal risk-of-bias assessment using tools such as ROBINS-I or Newcastle–Ottawa Scale was not systematically applied to all included studies.

A formal assessment of risk of bias using the Cochrane Risk of Bias tool (RoB 2) was performed only for randomized clinical trials reporting trough-to-peak ratio values, as this tool is specifically designed for randomized studies and because these studies provided the most structured and comparable data.

Pharmacokinetic studies and regulatory sources reporting elimination half-life values were not assessed using RoB 2 because this instrument is not applicable to non-comparative pharmacokinetic designs. Instead, consistency across multiple sources was used as a pragmatic criterion for data selection.

Data extraction and synthesis. For each included study, data were extracted on antihypertensive drug name, pharmacological class, TP ratio (when available) and elimination half-life value.

Given the heterogeneity in study design, patient populations, ABPM protocols and outcome reporting, a quantitative meta-analysis was not performed. Results were synthesized qualitatively by compiling and organizing TP ratio and elimination half-life values according to pharmacological class and individual agents.

Reporting. The final qualitative synthesis included 228 studies, providing TP ratio data for 69 antihypertensive drugs and elimination half-life data for 77 drugs, covering a total of 83 unique antihypertensive agents across nine pharmacological classes.

Results

Results were summarized by compiling available TP ratio and elimination half-life values and organizing them according to pharmacological class.

A total of 83 antihypertensive agents which were classified into 9 different pharmacological groups of antihypertensive drugs: angiotensin-converting enzyme (ACE) inhibitors, centrally acting antiadrenergic agents, alpha1-blockers, other alpha-blockers, beta-blockers, calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs), direct renin inhibitors and diuretics. Of the 83 drugs, the TP ratio was obtained in 69 and the half-life in 77 (Table 2, 2 continued).

Table 2.

List of antihypertensive drug list according to TP ratio and half-life.

Drug	TP index	Half-life
ACE inhibitors
Benazepril 20–80 mg	0.4^14	10–11 h^21
Captopril 25–100 mg	0.25^15,20	<2 h^20
Cilazapril 2.5 and 5 mg	0.51^14	10 h (SR 40–50 h)^22
Delapril 30 mg	0.70^15,16	1.5 h^23
Enalapril 5, 10 and 20 mg	0.40–0.64^14	11 h^24
Fosinopril 20 mg	0.64^14,17	12 h^25
Imidapril 2.5 mg–20 mg	0.63–0.84^17	12 h^26
Lisinopril 10–80 mg	0.30–0.70^15,17	12 h^27
Perindopril 2–16 mg	0.35^18	3–7 h (SR 30–120 h)^28
Quinapril 10–80 mg	0.30–0.40^15,17	2 h (SR 25 h)^29
Ramipril 5 and 10 mg	0.52–0.59^19	13–17 h^30
Trandolapril 1 and 2 mg^a	0.84^18	6 h (SR 16–24 h)^30
Centrally acting antiadrenergic agents
Clonidine	<0.5^31	7.4–11.4 h^32
Methyldopa	0.42^33	1.28 h^34
Moxonidine	0.7^35	2.5 h^36
Alpha1-blockers
Doxazosin	0.52–0.60^37	18–20 h^37
Prazosin	0.57^38	2.5 h^38
Terazosin	>0.5^39	12 h^40
Beta-blockers
Acebutolol	0.71^41,45	2.1–4.3 h^41
Atenolol	0.46–1.0^44	6–9 h^23
Betaxolol	0.72^42	NA
Bisoprolol	0.58^43	9–12 h^23
Carvedilol	0.85^43	6–10 h^23
Carvedilol CR 20, 40 and 80 mg	0.64–0.73^44	6–7 h^44
Celiprolol	NA	4–5 h^23
Esmolol^b	NA	0.15 h^23
Labetalol	0.63^44	4 h^23
Metoprolol	0.44^45	3–7 h^23
Nadolol	NA	10–24 h^23
Nevibolol	0.91^43,46	11–20 h^23
Oxprenolol	NA	NA
Propranolol	1.07^44	2–5 h^23
Sotalol	NA	10–12 h^47
Other alpha-blockers
Phenoxybenzamine	NA	<24 h^48
Phentolamine	NA	5–7 h^49
Metyrosine	NA	3.4–3.7 h^50
Tolazoline^c	NA	3–10 h^51
Urapidil	NA	3 h^52

Drug	TP index	Half-life
Calcium channel blockers
Amlodipine 5	0.56^54/0.7 (0.5–1)^53	30–50 h^8
Barnidipine	0.53–0.63^83	20 h^82
Clevidipine^d	NA	NA
Diltiazem SR 180-240-360	0.66 (0.2–0.8)^53–55	8–11 h^81
Felodipine 5	0.49^53	11–16 h^81
Felodipine 10	0.5^53	11–16 h^81
Lacidipine	0.4–1.0^82	13–19 h^82
Lercanidipine 10–20	0.8^56	8–10 h^82
Manidipine 10–20	0.67 (0.62–0.79)^57,58	20 h^82
Nicardipine	NA	8 h^81
Nifedipine GITS 30	0.9^59	2 h^81
Nifedipine GITS 60	1.0^59	7 h^81
Nimodipine	NA	9 h^82
Nisoldipine	0.74^82	7–12 h^81
Nitrendipine	0.47 (0.1–0.8)^53	8 h^82
Verapamil SR 180–240	0.58–1.0^53,60	Verapamil 4–6 h^81Verapamil SR 4.5–12 h^81
Angiotensin receptor blockers
Candesartan 8 mg	1.0^61	9 h^84
Candesartan 16 mg	0.87–0.88^61	9 h^84
Eprosartan 400 mg	0.67^62	5 h^84
Eprosartan 800 mg	0.67^62	5 h^84
Eprosartan 1200 mg	1.0^63	5 h^84
Irbesartan 75 mg	0.36^64	11–15 h^84
Irbesartan 150 mg	0.66–0.74^64,65	11–15 h^84
Irbesartan 300 mg	0.71^66	11–15 h^84
Irbesartan 300 mg/HCTZ 25 mg	0.84–0.92^67	NA
Losartan 50 mg	0.64–0.69^61,68	6–9 h^84
Losartan 100 mg	0.61^65,69	6–9 h^84
Losartan 50 mg/HCTZ 12.5 mg	0.70–0.90^70	6–9 h^84
Losartan 100 mg/HCTZ 25 mg	0.86–0.88^71	6–9 h^84
Olmesartan 20 mg	0.50–0.52^72	14–16 h^84
Olmesartan 40 mg	0.44–0.59^74	14–16 h^88
Olmesartan 80 mg	0.60–0.64^73	14–16 h^84
Olmesartan 20 mg/amlodipine 5 mg	0.72–0.80^75	NA
Olmesartan 40 mg/amlodipine 5 mg	0.71–0.78^75	NA
Telmisartan 40 mg	0.61–0.85^76	24 h^84
Telmisartan 80 mg	0.70^76	24 h^84
Valsartan 80 mg	0.48–0.55^77	6 h^84
Valsartan 160 mg	0.59–0.60^72	6 h^84
Valsartan 80 mg/HCTZ 12.5 mg	0.51–0.61^65,72	6 h^84
Direct renin inhibitors
Aliskiren 150 mg	0.64^78	34–41 h^78
Aliskiren 300 mg	0.79^78	34–41 h^78
Diuretics
Hydrochlorothiazide	0.74^67,70,71	6–14 h^85
Indapamide 1.5 mg SR	0.89^79	11 h^86
Indapamide 2.5 mg IR	0.98^80	11 h^86
Chlortalidone	NA	29–55 h^87

Ref. TP: trough-to-peak; ACE: angiotensin-converting enzyme; SR: sustained release; NA: no available.

TP ratio values are expressed as trough-to-peak ratios.

Superscript numbers indicate bibliographic references corresponding to the reported values.

nn-nn: Ranges indicate variability across different studies.

a

Trandolapril onset of action at 120 min, duration 48 h, dose no. 1.

b

Exclusive and restricted to hospital use, intravenous (vials): short half-life (9 min) according to MEDIMECUM 2023.

c

Indication in paediatrics.

Ref. TP: Trough-to-peak; NA: No available; HCTZ: Hydrochlorothiazide.

TP ratio values are expressed as trough-to-peak ratios.

Superscript numbers indicate bibliographic references corresponding to the reported values.

nn-nn: Ranges indicate variability across different studies.

d

Exclusive and restricted to hospital use, intravenous (vials): ultra-short half-life (1 min) according to MEDIMECUM 2023.

Overall, randomized clinical trials reporting TP ratios showed predominantly low to moderate risk of bias across RoB 2 domains. The most frequent methodological limitations were incomplete reporting of ABPM procedures and limited detail on allocation concealment. High risk of bias was uncommon among the included trials.

Discussion

An important finding of this review is the heterogeneous availability of TP ratio and elimination half-life data across antihypertensive drug classes. While TP ratios were frequently reported for ARBs and calcium channel blockers, data were scarce or absent for several beta-blockers and alpha-blockers. In contrast, elimination half-life information was more consistently available, although often derived from pharmacokinetic studies rather than clinical trials. From a primary care perspective, this information is particularly relevant, as it allows clinicians to better understand the real duration and consistency of BP-lowering effects beyond nominal dosing recommendations.

In routine primary care, inadequate BP control is often attributed to poor adherence or insufficient drug intensity. However, loss of antihypertensive effect at the end of the dosing interval may also play an important role, especially in patients treated with once-daily regimens. Drugs with low TP ratios or short half-lives may provide satisfactory office BP readings while failing to maintain adequate nocturnal or early morning BP control, situations that are associated with increased cardiovascular risk.

Current clinical guidelines increasingly recommend initiating anti-hypertensive treatment with combination therapy. Evidence from studies such as the TALENT trial suggests that combination therapy not only improves BP reduction but may also enhance the homogeneity of BP control over 24 h, as reflected by higher TP ratios and smoothness indices.⁸⁸ From a primary care standpoint, selecting drug combinations with complementary pharmacokinetic properties and mechanisms of action may help achieve more stable BP control with fewer adjustments.

The TP ratio has been the subject of debate due to its inherent variability and reliance on two time points within the dosing interval.^88–92 Nevertheless, it remains the most extensively studied and reported index, particularly in contrast to the SI and TOVI, for which data are more limited and less easily generalizable.⁸⁸ The TP ratio is useful for evaluating the persistence and homogeneity of antihypertensive effects throughout the dosing interval and may contribute to improved 24-h BP control. The trough-to-peak ratio has also been discussed in regulatory contexts for the evaluation of antihypertensive drug duration throughout the dosing interval.⁹³ For primary care clinicians, the TP ratio offers a pragmatic and accessible indicator of whether a drug is likely to maintain BP control throughout the day.

Several studies have shown that TP ratio and SI provide largely overlapping information regarding the duration of antihypertensive effect, with no consistent evidence demonstrating the superiority of one index over the other.^94–97 In this context, the greater availability of TP ratio data supports its practical usefulness in everyday clinical decision-making.

From an applied perspective, the information summarized in this review may assist primary care professionals in specific clinical scenarios, such as patients with uncontrolled morning BP, nocturnal hypertension or non-dipping BP patterns identified by ABPM. In these cases, choosing antihypertensive agents with higher TP ratios and longer half-lives may reduce BP variability and improve overall control without increasing pill burden. In primary care, this information may support treatment selection in patients with uncontrolled morning blood pressure or inadequate 24-h BP control despite apparently normal office measurements.

Limitations. This review has several limitations that should be acknowledged, particularly from a primary care perspective.

• -

  TP ratio data were not available for all antihypertensive agents, including some alpha-blockers, selected beta-blockers, certain calcium channel blockers and chlorthalidone. Although some of these drugs are less frequently used as first-line therapy in primary care, the absence of data limits direct comparison across all therapeutic options.

• -

  The studies included showed heterogeneity in ABPM protocols, dosing schedules and patient populations, which may influence the reported TP ratios and half-life values. In addition, most trials were conducted in selected populations and under controlled conditions, which may not fully reflect real-world primary care settings.

• -

  Limited information was available on fixed-dose combinations, which are increasingly recommended in primary care guidelines. Consequently, extrapolation of TP ratio and half-life data from individual components should be interpreted with caution.

• -

  Although a formal risk-of-bias assessment was performed for randomized trials, a standardized assessment was not applied to all included studies, particularly pharmacokinetic and non-randomized designs, which may limit the methodological comparability of the evidence. Furthermore, many studies were conducted before current ABPM reporting standards were established, and details regarding ABPM methodology and operator training were often insufficient.

Finally, this review was not prospectively registered in PROSPERO, which should be considered a limitation. In addition, many included studies were sponsored by pharmaceutical companies, potentially introducing reporting bias. Despite these limitations, the rigorous selection of high-level evidence studies strengthens the overall validity of the compiled data.

Implications for primary care practice

The findings of this review have relevant implications for primary care practice. Knowledge of TP ratios and elimination half-lives may assist clinicians in interpreting ABPM results, particularly in patients with uncontrolled morning BP, nocturnal hypertension, or increased BP variability. In these situations, selecting antihypertensive agents with longer duration of action and higher TP ratios may improve 24-h BP control without increasing treatment complexity.

Furthermore, integrating pharmacokinetic and pharmacodynamic considerations into routine clinical decision-making may facilitate more appropriate dose adjustments, reduce therapeutic inertia, and optimize individualized long-term BP control in the primary care setting.

Key points

• -

  This review summarizes published trough-to-peak ratios and elimination half-lives of antihypertensive drugs.

• -

  Availability of trough-to-peak ratio data varies markedly across antihypertensive drug classes, while elimination half-life information is more consistently reported.

• -

  Most trough-to-peak ratio estimates are based on ambulatory blood pressure monitoring studies, although relevant evidence gaps persist.

• -

  The compiled data may assist primary care clinicians in interpreting 24-h blood pressure control and selecting antihypertensive therapies with sustained effects.

Ethical considerations

The variables recorded come from clinical trials that do not contain any personal data. For this reason, the approval of an ethics committee was not considered necessary.

Funding

This research has not received specific aid from public sector agencies, commercial sector or non-profit entities.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.