Trials on Timing of Cardiovascular Medication Administration

Abstract

The incidence of certain disease events such as myocardial infarction, stroke, aortic rupture, and sudden cardiac death is affected by the time of day. It is thus theorized that synchronization of medication timing with circadian rhythmicity (or at the minimum, clock time) may improve treatment efficacy and/or reduce the risk of serious adverse events. We launched the C³ (Cardiovascular Circadian Chronotherapy) trial concept to efficiently conduct randomized, controlled, clinical outcome trials of the timing of medication administration. This concept takes advantage of the Danish nationwide administrative health registries for participant identification and collection of baseline and follow-up data as well as the mandatory governmental electronic letter system. Although many of these interventions may only provide small effect sizes, any positive effects from simple changes in the timing of drug administration could potentially lead to large, worldwide prognostic improvements.

Central Illustration

Introduction to circadian rhythms and chronotherapy

Most circadian cycles in physiology are determined by intrinsic biological clocks.^1,2 The hypothalamic suprachiasmatic nucleus contains the pacemaker neurons that drive sleep-wake rhythms.³ This central pacemaker clock synchronizes rhythmic activity of molecular clocks in the rest of the body, including the heart and vasculature, termed peripheral clocks. Circadian disruption may occur because of artificial light, light exposure at the wrong time of day, shift work, irregular sleep and eating schedules, and jet travel, which contributes to negative health outcomes.^1,2 The incidence of certain disease events such as myocardial infarction, stroke, aortic rupture, and sudden cardiac death is also affected by the time of day, suggesting a contribution by circadian rhythms.4, 5, 6, 7 Underlying cardiovascular physiologic processes that display a variation over the course of the day include, but are not limited to, platelet activity, coagulation, vascular tone, endothelial function, and electrical conduction.8, 9, 10, 11

It is theorized that synchronization of medication timing with internal circadian rhythmicity (or at the minimum, clock time) may improve treatment efficacy and/or reduce the risk of serious adverse events.^1,2 This concept is called chronotherapy and is already used for chemotherapeutic agents targeting various types of cancers.¹² The absorption, distribution, metabolism, and excretion of medications may all be affected by circadian rhythms. Drug targets themselves may also peak at different times of the day.^1,2 Interestingly, most best-selling drugs and World Health Organization essential medicines, several of which have short half-lives, directly target the products of rhythmic genes.¹³ However, despite promising evidence from preclinical and observational studies, randomized controlled trials are needed to properly define the clinical value of chronotherapy in the cardiovascular setting. Any clinical benefit from a minor, costless, low-risk intervention such as the change in administration time could carry substantial implications.

Major clinical trials of the timing of antihypertensive medication administration

The most prominent example of chronotherapy in the field of cardiovascular medicine relates to antihypertensive medications. Blood pressure typically follows a diurnal rhythm, with lower values at sleep during the night (ie, dipping), followed by a surge in the morning. Persons whose blood pressure does not exhibit this normal diurnal variation have an increased risk of adverse outcomes.^14,15 The morning blood pressure surge also predicts cardiovascular events.¹⁶ Finally, asleep blood pressure has been suggested as the most important blood pressure derived risk factor for incident cardiovascular events, and lowering of asleep blood pressure is associated with significant reductions in cardiovascular morbidity and mortality.17, 18, 19

Fueled by a substantial body of observational evidence, the prospective, randomized, open-label, blinded endpoint (PROBE) Hygia Chronotherapy trial of antihypertensive medication administration at bedtime vs on awakening was conducted in 19,084 patients with hypertension.²⁰ Specifically, study participants were randomized to ingest the entire daily dose of their prescribed blood pressure lowering medications at bedtime or on awakening. After a median follow-up of 6.3 years, office and asleep ambulatory blood pressures were lower in the group of patients allocated to the bedtime regimen. Bedtime antihypertensive administration led to a significantly lower risk of the primary outcome, defined as a composite of myocardial infarction, coronary revascularization, heart failure, ischemic stroke, hemorrhagic stroke, or cardiovascular death (adjusted HR: 0.55; 95% CI: 0.50-0.61; P < 0.001), without causing an increase in the risk of adverse effects (bedtime regimen: 6.0% vs awakening regimen: 6.7%; P = 0.061). Rates of poor adherence at any visit were similar (bedtime regime: 2.9% vs awakening regimen: 2.8%).

The subsequently reported results from the TIME (Treatment in Morning versus Evening) study did not support the encouraging findings from Hygia.²¹ Like Hygia, TIME was designed as a PROBE trial. A total of 21,104 patients with hypertension were randomized to take all their antihypertensive medications in either the morning or in the evening. At median 5.2 years, the primary composite outcome of vascular death or hospitalization for nonfatal myocardial infarction or nonfatal stroke was similar in the evening group as compared with the morning group (HR: 0.95; 95% CI: 0.83-1.10; P = 0.53). More individuals in the evening group withdrew from follow-up (5.0% vs 3.0%). Fewer participants in the evening dosing group reported adverse events during the study than did participants in the morning dosing group (69.2% vs 70.5%; P = 0.041). At study end, nonadherence was reported among 19.8% patients in the evening dosing group and 7.1% in the morning dosing group.

In addition to the dissimilar results as well as the general controversies surrounding the Hygia Chronotherapy trial,²² there were key methodological differences between the 2 trials.^23,24 Although both were focused on individuals from the primary care setting, Hygia used conventional in-person visits for patient enrollment, whereas the TIME investigators screened U.K. National Health Service practice lists and messaged potentially suitable participants, inviting them to register on the study website. Hygia was conducted within a network of 40 primary care centers. All participants were required to attend in-person clinic visits at least once every year. During these visits, data on blood pressure, adherence, clinical outcomes, and adverse events were collected. Clinical outcomes data were also gathered from the electronic medical records. The recruitment process lasted ∼10 years. The TIME trial was decentralized. Screening, consent, randomization, and follow-up were performed through an online study portal and by email. Participants were invited to complete online follow up questionnaires on adherence, outcomes, and adverse events at regular intervals. Event data were also obtained from various registries. Recruitment took ∼6.5 years. In summary, uncertainty remains regarding the optimal timing of antihypertensive medications.^25,26

Other selected cardiovascular examples of interest

Aspirin

The existence of a circadian periodicity in the onset of myocardial infarction was suggested decades ago. A prominent example used data from the Multicenter Investigation of Limitation of Infarct Size database.⁴ Among 2,999 patients with a myocardial infarction, the peak frequency in pain onset occurred from 6 AM to noon. In a subgroup of 703 patients in whom the time of the first elevation in plasma creatine kinase–myocardial band concentration could be used, there was also a clear increase in the onset of myocardial infarction in the morning hours (peak at 9 AM) compared with the evening hours (trough at 11 PM). The same group of investigators subsequently examined platelet activity over 24 hours in healthy men and observed an increase in platelet aggregation from 6 AM to 9 AM.⁸ Adding to this, some pilot studies have suggested potential benefits of taking aspirin at bedtime rather than in the morning. For example, one group of investigators reported significant reductions in both systolic and diastolic blood pressure among patients with untreated hypertension or prehypertension randomized to low-dose aspirin (100 mg daily) at bedtime compared with aspirin in the morning or no aspirin, possibly due to effects on the renin–angiotensin–aldosterone system and on nitric oxide production.27, 28, 29 These findings were also supported by a recent meta-analysis of randomized controlled trials.³⁰ Other investigators have suggested a reduction in morning platelet reactivity with bedtime aspirin (100 mg daily) intake,^31,32 but the overall quality of evidence has been too poor to draw firm conclusions,³³ and large, randomized controlled trials with clinical outcomes are warranted.³⁴

Statins

The activity of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase, peaks at night, possibly because this reflects a fasting state.³⁵ This has led to the traditional practice of prescribing statins, at least those with a short half-life, in the evening. For example, 2 clinical trials of evening vs morning administration of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase with a short elimination half-life, found significantly lower concentrations of total and low-density lipoprotein cholesterol among those who took their medication in the evening.^36,37 However, both trials were small, and the drug doses were lower than what is generally recommended in the contemporary setting. The data are even less clear for agents with long half-lives such as atorvastatin.³⁸ One small randomized trial suggested potential clinical benefits of atorvastatin administration in the evening after dinner compared with in the morning after breakfast in patients scheduled for elective percutaneous coronary intervention, but the study was not powered for clinical outcomes.³⁹ Other studies did not report differences in lipid concentrations with atorvastatin administration in the evening vs in the morning.^40,41 Further complicating matters, concentrations of atorvastatin are typically lower following evening compared with morning administration.⁴² A meta-analysis found significantly greater, albeit rather modest, reductions in low-density lipoprotein cholesterol levels among individuals who took their statin in the evening, irrespectively of drug half-life.⁴³ Of the 11 studies included, 9 were randomized controlled trials and 3 involved either atorvastatin or rosuvastatin.

The C³ trial concept

We launched the C³ (Cardiovascular Circadian Chronotherapy) trial concept to conduct randomized, controlled, clinical outcome trials of the timing of medication administration. Our setting allows for such studies to be run at a lower cost and more efficiently than previously seen. The 3 main reasons for this are as follows: 1) the Danish Research Ethics Committees and the Danish Medicines Agency do not consider allocation to different ingestion times of already administered medications as interventional drug trials and typically waives applications related to such interventions; 2) the administrative health registries span nationwide and can be used for both identification of trial participants and collection of baseline and follow-up data; and 3) the mandatory governmental electronic letter system (Central Illustration). Our experiences from the NUDGE (Nationwide Utilization of Danish Government Electronic Letter System) and DANFLU (High-Dose Quadrivalent Influenza Vaccine vs Standard-Dose Quadrivalent Influenza Vaccine) programs further helped shape the C³ trial concept.^44,45

Central Illustration.

Central Components of the C³ Trial Concept

C³ = Cardiovascular Circadian Chronotherapy.

Denmark uses a universal welfare model built on the principle that all citizens have equal rights to social security. This includes equal access to health care, whether general practitioners, hospitals, or specialty care, irrespectively of social and financial background. Most health care services except dental care are tax-funded and public and are thus provided without copayment, whereas the contribution from the private health care sector is minimal.^46,47 All acute medical care is provided by the public health care sector. All procedures and diagnoses registered in both the public and private sector are captured in the administrative health registries. These registries contain data on all encounters within the public health system, including inpatient contacts, outpatient contacts, emergency room visits, primary care visits, prescription fills, and procedures.^48,49 Unambiguous individual participant-level linkage is enabled by a Civil Personal Registry (CPR) number, which is a unique social security number, assigned to all legal Danish residents at birth or immigration.⁵⁰ The CPR number is consistent across administrative registries that hold data related to demographics, occupation, health care, and social services.

Within the C³ trial concept, the registries are used for the following: 1) identification of eligible trial participants; 2) collection of baseline data; and 3) collection of follow-up data. Various combinations of variables extracted from the Danish Civil Registration System,⁵¹ the Danish Registry of Causes of Death,⁵² the Danish National Patient Registry,^49,53 the Danish National Prescription Registry,⁴⁸ and the Registry of Laboratory Results for Research are used for these purposes.⁵⁴ Given the universal coverage of these registries, the reach with respect to both participant identification and subsequent follow-up is nationwide. The Danish National Patient Registry uses diagnostic codes based on the International Classification of Diseases-10th Edition system and surgical and procedural codes based on the Nordic Medico-Statistical Committee classification. The Danish National Prescription Registry uses the Anatomical Therapeutic Chemical classification. Finally, the Registry of Laboratory Results for Research uses Nomenclature, Properties, and Units codes for recording the type of biomarker.

The diagnostic coding in the Danish National Patient Registry is usually performed by the treating physician. There is no personal financial incentive in relation to this process; however, the budgeting of each hospital and department may in part depend on the accuracy of such coding.⁴⁷ In general, many diagnoses coded in the Danish National Patient Registry, particularly those related to the cardiovascular field, carry very high positive predictive values.⁴⁹

Finally, in 2014, the government made it mandatory for all legal residents ≥15 years of age to use a digital mailbox for communicating with public authorities. This governmental electronic letter system, Digital Post/eBoks, was rolled out to deliver official governmental communications to residents and works similar to a conventional e-mail system, but can also be used for research purposes, for instance, recruitment into clinical trials and delivery of surveys.⁵⁵ The system uses the CPR number for delivery which again facilities linkage between data obtained from the registries and delivery of interventions.

Current and planned trials

Ongoing and planned trials from the C³ trial concept are shown in Table 1. All trials will include adult individuals (age ≥18 years) on long-term treatment with a relevant medication. Only persons taking the particular medication once daily will be considered. An individual patient level randomization scheme will be employed.

Table 1.

Ongoing and Planned Trials From the C³ Trial Group

Trial Name	Clinicaltrials.gov	Medication	Primary Outcome
Ongoing Trials
ASPIRIN-C3	NCT05932472	Aspirin	Death from cardiovascular causes, myocardial infarction, coronary revascularization, stroke, or transient ischemic attack
STATIN-C3	NCT06856772	Any statin	Death from cardiovascular causes, myocardial infarction, coronary revascularization, stroke, or transient ischemic attack
Planned trials
ANGIOTENSIN-C3	Pending	Angiotensin converting enzyme inhibitor or angiotensin II receptor blocker	Death from cardiovascular causes, myocardial infarction, coronary revascularization, heart failure, stroke, or transient ischemic attack
BLOCK-C3	Pending	Beta blocker	Death from cardiovascular causes, myocardial infarction, coronary revascularization, heart failure, stroke, or transient ischemic attack
CCB-C3	Pending	Calcium channel blocker	Death from cardiovascular causes, myocardial infarction, coronary revascularization, heart failure, stroke, or transient ischemic attack
CLOPIDOGREL-C3	Pending	Clopidogrel	Death from cardiovascular causes, myocardial infarction, coronary revascularization, stroke, or transient ischemic attack
RIVAROXABAN-C3	Pending	Rivaroxaban	Death from cardiovascular causes, myocardial infarction, coronary revascularization, stroke, transient ischemic attack, or systemic embolism

C³ = Cardiovascular Circadian Chronotherapy; CCB = calcium channel blocker.

Design considerations, challenges, and limitations

Sample size calculation will be based on prior studies, with an emphasis on randomized, controlled trials whenever possible. In case only studies of biomarkers, including blood pressure, are available, we will estimate the treatment effect based on known correlations between these biomarkers and clinical outcomes. Nevertheless, the anticipated relative risk reduction will not be set below 10% since this marks the lower limit of what is considered a moderate effect size,⁵⁶ and because it would not be feasible to carry out trials powered for smaller effect sizes, even though our intervention carries no cost and very low risk. The nationwide reach of the registries and the governmental electronic letter system enable recruitment of virtually all participants who are willing, but potentially short follow-up times will be balanced against lag-time to benefit of medications, for instance, statins.

One of the major challenges is adherence to both the medication itself and to the time of ingestion. Prior studies have suggested poorer adherence with evening compared with morning administration of medication.^57,58 A similar observation was made in the TIME trial.²¹ The study investigators noted that this could have been due to the fact that most participants were taking their medication in the morning before randomization. Although we will circulate digital reminders and collect longitudinal information throughout the duration of each trial, even small degrees of nonadherence can lead to considerable dilutions of the treatment effects.⁵⁹ Nevertheless, we have not taken this into account in ASPIRIN-C³ and STATIN-C³ because of the already small anticipated relative risk reduction (10%) used for sample size calculation in these trials.

In line with the pragmatic nature of the C³ concept, the trials will be performed as open-label studies. The risk of bias related to the reporting of nonserious adverse events, reasons for treatment discontinuation, and patient-reported outcomes is higher in open-label trials.⁶⁰ However, the PROBE design also offers many advantages, including increased feasibility, reduced costs, greater similarity to regular clinical practice, and possibly better compliance. In addition, hard outcomes like myocardial infarction, stroke, and death are less likely to be affected by knowledge of the treatment to which a participant is allocated.⁶¹ Because the study investigators are not involved in the daily clinical management of the participants, they have no influence on the decision to admit and evaluate for specific medical conditions.

Another potential limitation relates to the use of administrative registries. The Danish registries are known for very high quality data,⁴⁹ but the reliance on administrative, routinely collected data may introduce misclassification bias, for instance, due to coding errors or because only filled prescriptions are recorded. It is critical to ensure that the population of interest can be easily identified based on simple and reproducible eligibility criteria, and it may also be advantageous to use widely encompassing endpoints like hospitalization for cardiovascular causes, hospitalization for any cause, and death from any cause as the validity of more specific diagnoses is often lower. Nevertheless, in a decentralized, randomized trial setting with prespecified, registry-based endpoint definitions and no direct contact with study participants, misclassification should not differ between the study groups. Moreover, the use of a clinical endpoint adjudication committee increases the costs and logistic challenges of clinical trials, and recent evidence suggests that registry-based or investigator-reported outcomes provide similar treatment effect estimates as compared with outcomes assessed by adjudication committees.62, 63, 64, 65 Finally, no systematic laboratory testing will be carried out, but the frequency and concentrations of routinely measured laboratory tests should be similar in the study groups.

The Danish registries are not able to catch data after emigration, but emigration rates from Denmark are generally low. In NUDGE-FLU, <0.1% emigrated during an 8.5-month follow-up period.⁶⁶ The date of emigration is also recorded, allowing for censoring at the time of emigration. In other words, almost complete follow-up is ensured.

According to the European Commission, Denmark is highly digitalized, and Danes have a very high level of digital literacy,⁶⁷ underscoring the utility of a national, governmental electronic letter system. Still, a significant proportion, particularly among older individuals, are exempt from this system and instead receive official correspondence as physical letters. Overall coverage is ∼95%, and in the NUDGE-FLU trial of individuals ≥65 years of age, ∼17% had exemptions, with those exempt characterized by an older age and a higher prevalence of comorbidities.⁶⁶ Additionally, in trials that require individual participant consent like those planned by the C³ Group, healthier persons than those representing the overall eligible population would agree to participate. This was also seen in the DANFLU-1 trial and may limit generalizability to particularly vulnerable populations.⁴⁵ Nevertheless, access to the registries enable comparisons between invited and included persons and thus quantification of the magnitude of selection bias.

Future perspectives

The trial concept introduced here allows us to efficiently test the effects of administration time of a wide array of commonly prescribed cardiovascular medications and can also readily be applied to other medical specialties. As an example, the C³ trial group is collaborating with pulmonologists on the Comparing Morning and Evening Dosing of Inhaled Long-Acting Muscarinic Antagonists for the Prevention of Hospitalization Requiring Acute Exacerbations of Chronic Obstructive Pulmonary Disease or Death From All Causes trial.⁶⁸ In the future, this setup could also be used to examine other features of medication administration. This may include testing the frequency of administration, for instance, once daily vs twice daily, and whether to take medications without or with food, among others. Although many of these interventions may only provide small effect sizes, any positive effects from simple changes in the mode of drug administration could potentially lead to large, worldwide prognostic improvements.

Funding support and author disclosures

Dr Pareek is on the advisory board for AstraZeneca, Janssen-Cilag, and Novo Nordisk; has received grant support from Danish Cardiovascular Academy funded by the Novo Nordisk Foundation and the Danish Heart Foundation (grant number: CPD5Y-2022004-HF), and the Danish Heart Foundation (2024-12587); has received speaker honorarium from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen-Cilag, and Novo Nordisk. Dr Bhatt is on the advisory board for Angiowave, Antlia Bioscience, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Stasys, and Tourmaline Bio; is on the Board of Directors of American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); is a consultant for Altimmune, Broadview Ventures, Corcept Therapeutics, GlaxoSmithKline, Hims, SERB, SFJ, Summa Therapeutics, and Youngene; is on the Data Monitoring Committees of Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News and ACC.org; is Chair of the ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; is on the AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); is on: Clinical Cardiology (Deputy Editor); has a patent for Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon [neither I nor Brigham and Women's Hospital receive any income from this patent]); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); and is a Site Co-Investigator for Cleerly. Dr Olsen has received grant support from the Novo Nordisk Foundation and the Danish Heart Foundation; has received speaker honorarium from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Teva. Dr Biering-Sørensen has received research grants from Bayer, Novartis, Pfizer, Sanofi Pasteur, GSK, Novo Nordisk, AstraZeneca, Boston Scientific, and GE Healthcare; has received consulting fees from Novo Nordisk, IQVIA, Parexel, Amgen, CSL Seqirus, GSK, and Sanofi Pasteur; and has received lecture, fees from AstraZeneca, Bayer, Novartis, Sanofi Pasteur, GE Healthcare, and GSK. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.