A nursing-driven approach towards reducing hypertension: a focus on evening dosing and circadian rhythm
Submitted by Michael Schaier, MSN, BS, RN-BC, PCCN
Large epidemiological studies reveal that 1 in 3 American adults live with hypertension (HTN) and that at least 61.7% are in the geriatric population. The morbidities secondary to this medical condition are significant as are the expenditures, which run $131 billion annually. As the prevalence of HTN increases, newer approaches are necessary to address this medical condition. Traditionally, uncontrolled blood pressure (BP) has been treated by increasing the current medication dose or adding a new medication with morning dosing times to increase compliance. However, not only does this approach increase the risk of polypharmacy, it also fails to address additional considerations of the body’s circadian rhythm. There are increasing data supporting evening administration as a means of achieving better BP control through re-establishing normal sleeping dipping patterns, thereby preventing the development of comorbidities. Additionally, this dosing change has been shown to prevent the morning surge, a precursor to negative cardiovascular (CV) events, including heart attack and stroke. When the costs are high both fiscally and medically, simple and cost-free interventions should be the first-line treatments.
The American Heart Association (AHA) reports that approximately 1 in 3 American adults (36.9%) live with HTN. Not only is this number expected to rise due to increasing developments in diagnosis, but people are living longer with this condition (Kirkland, Heincelman, Bishu, Schumann, Schreiner, Axon, ... & Moran, 2018). This is a significant healthcare issue when considering that HTN is a precursor to numerous medical conditions, such as heart failure, kidney failure, blindness, heart attack, stroke, and possibly dementia (Rouch, Cestac, Hanon, Cool, Helmer, Bouhanick, ... & Andrieu, 2015; Unger, Borghi, Charchar, Khan, Poulter, Prabhakaran ,... & Schutte, 2020). The Agency for Healthcare Research and Quality (AHRQ) in their Medical Expenditure Panel Survey (MEPS) revealed that of hypertensive adults, 61.7% are in the geriatric population, and this number is likely even higher considering this study excluded the institutionalized population, which includes nursing homes (Davis, 2013). The AHA, expanding on the economic burden data reported by the MEPS, revealed that expenditures relating to HTN are greater than that of other medical conditions, with HTN expenditures averaging $131 billion per year (Kirkland, Heincelman, Bishu, Schumann, Schreiner, Axon, ... & Moran, 2018). The significant morbidities and mortalities secondary to HTN make it a priority health condition, with efforts from the World Health Organization (2021) aimed at reducing its prevalence by 33% by 2030.
To address this worldwide healthcare issue, researchers have studied BP patterns and medication timing to develop new strategies to reverse this upward trend. This research, has revealed accumulating data supporting the evening administration of antihypertensives to better control BP and to decrease negative CV events, such as heart attack and stroke (Roush, Fapohunda, & Kostis, 2014). These data are supported by chronotherapy, an area of medicine that considers the effects of a medication with respect to circadian rhythm. Current practice is to prescribe antihypertensives at a time of day that will best ensure medication adherence, which is typically in the morning. However, there is also the obligation to treat patients according to the best evidence. The purpose of this article is to address one specific area of medical and medication management from the perspective of the growing science of chronotherapy.
The chronotherapy of hypertension
The body has a natural internal clock, known as circadian rhythm, which affects the physiological function of bodily processes over a 24-hour period. This clock is initially affected by the sun which governs sleep/wake cycles, leading to a consistent day/night pattern observed in any given organism, including plants, bees, birds, and chipmunks. While this observation was first noted in 1729, it was not for another 230 years that the term “circadian rhythm” was officially coined. The rhythm is a response to a feedback loop initiated by the sun, which governs wake/sleep cycles, leading to a consistent day/night pattern (Kuhlman, Craig, & Duffy, 2018). Beyond lifestyle and behavior, such patterns have been identified down to the molecular level, affecting gene patterns and expression. In a large study on gene expression in mice, researchers found that 43% of protein-coding genes exhibit circadian rhythms with respect to transcription. Similarly, many noncoding RNAs, which aid in gene expression, were found to exhibit a circadian pattern. These findings are significant when considering that oscillating genes, or genes governed by a circadian pattern, were found to peak just prior to dusk and dawn (Zhang, Lahens, Ballance, Hughes, & Hogenesch, 2014).
Included in this data pool of evidence is the circadian rhythm of BP. In the discussion of BP, a few key terms need to be well understood, namely: dipper, non-dipper, and morning surge. Normally, the heart rate and BP decrease during sleeptime as the body enters a resting state with lower metabolic demands. This lowering, or dipping, also relieves the heart and blood vessels from their usual workload, preventing stress to the respective tissues. In non-dippers, BP does not decrease significantly and as a result the heart and blood vessels do not get to rest. This puts these individuals at a greater risk for cardiac overload, congestive heart failure, and negative CV events. Traditionally, non-dippers is the term used to refer to those hypertensive individuals whose BP does not lower significantly during sleep. More recently, non-dipping patterns have also been identified in the pulse rate, where the heart rate does not lower significantly during sleep (Oba, Kabutoya, Hoshide, Eguchi, & Kario, 2017; Fagard, Thijs, Staessen, Clement, De Buyzere, & De Bacquer, 2009). While these findings are significant, and the effects of non-dipping pulse rate must also be noted, for the purposes of this article, non-dippers will refer only to non-dipping BP patterns.
Morning surge refers to a sudden increase in BP as the body transitions from the sleeping to the wakeful state. As the body ages and develops stiffness of the peripheral and central arteries, the ability to respond effectively to a rise in BP becomes more challenging. In a healthy individual, baroreceptors detect an increased BP and signal the body to counteract by lowering the BP; the degree of baroreceptor’s sensitivity to respond is referred to as baroreflex sensitivity (BRS). However, as the body ages, particularly in those with hypertension, there is a decrease in the sympathetic BRS response. This prevents optimal response time to a sudden increase in BP, an event that occurs every day within the first 2 hours of waking, resulting in what is called the morning surge (Okada, Galbreath, Shibata, Jarvis, Bivens., Vongpatanasin, ... & Fu, 2013). Notably, medications taken once a day are at their lowest level of concentration just prior to their next dose. Additionally, once a medication is ingested, it takes time for it to be absorbed. Therefore, a patient who takes an anti-hypertensive in the morning is at a greater risk for a negative CV event when considering the risk of the morning surge.
Consistent with these findings, non-dippers have also been shown to have a significantly higher high-density lipoprotein level than dippers, which correlates with an increased platelet activation and inflammatory response. These latter findings could explain the higher risk for atherosclerosis in non-dippers compared with dippers, and therefore a greater risk for negative CV events (Kaya, Yarlioglues, Gunebakmaz, Gunturk, Inanc, Dogan, ... & Topsakal, 2010). Another study revealed that in people aged 50 years and over, decreased daytime urinary sodium excretion was correlated with a non-dipping pattern. While the significance of these findings could be attributed to aging alone, due to a decrease in renal function, the pattern nonetheless suggests a circadian pattern (Del Giorno, Troiani, Gabutti, Stefanelli, Puggelli, & Gabutti, 2020).
With increasing evidence on the role of circadian rhythm in numerous physiological processes, scientists have expanded their research to investigate the possibility of targeting medication dosing time to match the body’s internal clock. In a review of the United States’ 100 top-selling drugs, 56 were found to be directly involved in the cycle of a circadian rhythm via an interaction with the product of a circadian gene. Similar findings were found in the World Health Organization’s list of essential medicines with 119 medications targeting a circadian gene. Based on the above data, these researchers concluded that there could be great benefit in aligning medication dosing times with the body’s circadian rhythm. This would be of particular benefit when considering that many major diseases are governed by oscillating genes which, as discussed, exhibit a circadian pattern (Zhang, Lahens, Ballance, Hughes, & Hogenesch, 2014).
Timing a medication based on circadian rhythm is not new to medicine. The administration of short-acting lipid-lowering drugs in the evening instead of in the morning is already considered best practice due to observed advantages in efficacy, as synthesis of cholesterol peaks in the evening (Awad, Sahebkar, Penson, Mikhailidis, Toth, Jones, … & Banach, 2017). Now, recent studies in mice reveal a circadian pattern in atherosclerotic activity. The data show increased myeloid cell recruitment to atherosclerotic regions as the body transitions to a resting state, but their adhesion does not peak until many hours later when the body then transitions back to an active state. This finding supports the chrono-pharmacological treatment with anti-lipid agents (Winter, Silvestre-Roig, Ortega-Gomez, Lemnitzer, Poelman, Schumski, ... & Soehnlein, 2018). Such patterns facilitate future research in determining optimal drug choice and timing with respect to the identified circadian rhythm.
Evidence-Based Practice of evening dosing of anti-hypertensives
A 2011 Cochrane review recognizes the potential of evening dosing in improving BP control, but does not offer any conclusions regarding a reduction in negative CV events (Zhao, Xu, Wan, & Wang, 2011). Since then, many more studies have been published which reinforce the strength of the data. In a study of people receiving 3+ anti-hypertensives, including a diuretic, who also experienced refractory arterial hypertension and a non-dipping pattern, the participants were instructed to switch all BP meds, except the diuretic, to the evening. At the end of the 6-week follow-up, there was a notably observed decrease in BP as well as a restoration of a dipping pattern in 15% of the participants (Almirall, Comas, Martínez-Ocaña, Roca, & Arnau, 2012). Another study focusing on the calcium-channel blocker barnidipine revealed improved evening BP in non-dippers and also restored evening dipping (Crippa, Zabzuni, Cassi, & Bravi, 2016). In addition to improved BP control and a reduction in negative CV events, this dosing time change has been shown to reduce albuminuria and improve overall renal function (Hermida, Ayala, Mojón, & Fernández, 2011a; Wang, Ye, Liu, Zhou, Lv, Cheng, ... & Liu, 2017).
As for safety, several studies have shown the efficacy and safety of evening dosing for all classes of antihypertensives; one of the more well-known studies is the MAPEC study (Hermida, Ayala, Mojón, & Fernández, 2010). Furthermore, the data show that evening administration is safe in patients with numerous comorbidities, including type 2 diabetes (Hermida, Ayala, Mojón, & Fernández, 2011b), chronic kidney disease (Hermida, Ayala, Mojón, & Fernández, 2011a; Wang, Ye, Liu, Zhou, Lv, Cheng, ... & Liu, 2017), obesity, obstructive sleep apnea (Crippa, Zabzuni, Cassi, & Bravi, 2016), and previous CV events (Hermida, Crespo, Domínguez-Sardiña, Otero, Moyá, Ríos, ... & Salgado, 2019). With regard to exact timing, one study postulates that dosing 2 to 4 hours before bedtime offers the best results, as additional factors such as optimal absorption time must also be considered (Huangfu, Duan, Xiang, & Gao, 2015).
Nonetheless, despite increasing data supporting this dosing time transition, there is still hesitancy in officially making the change. The American Diabetes Association (ADA, 2020) appreciates the potential benefits of evening dosing, but states a need for further data support. Similarly, the AHA has yet to give their support and only states that once-daily dosing is better than multiple times daily for improved compliance (Unger, Borghi, Charchar, Khan, Poulter, Prabhakaran, ... & Schutte, 2020). From the various sources, it appears that the main factor preventing stronger support for evening dosing is the need for more data.
Perhaps the needed data are found in a recent study which followed 19,084 participants over a minimum of 5 years. The HYGIA study, headed by Dr. Ramon Hermida, author of many similar studies, including the MAPEC study, supports the above-stated benefits of evening dosing and concludes that 1 or more BP medications should be administered in the evening (Hermida, Crespo, Domínguez-Sardiña, Otero, Ríos, ... & Salgado, 2019). The authors of that study conclude that evening dosing both lowers evening BP and maintains daytime BP. The only noted negative effect was sleep-time hypotension in 0.3% of participants. Limitations of the study include its exclusion of certain high-risk individuals, such as those with heart failure, as well as hospitalized patients. Also, study participants were limited to Caucasian Spanish men and women who have a routine sleeping pattern. Last, while the participants in this study took all medications at night, many people may prefer diuretics in the daytime to prevent nocturia, or frequent urination at night.
Application to care
While optimal dosing time is within the jurisdiction of the prescriber and pharmacist, nurses play a significant role in implementing this strategically-timed dosing. Nurses, in addition to keen assessments, contribute through an intimate knowledge of their patients, learning of the barriers and facilitators towards compliance. Nurses can further contribute through a knowledge of the latest evidence and advocate for best practice.
In primary care, there is already a push for nurses to take the lead in health maintenance. The role of the BSN-RN in this setting is preventative care, chronic disease management, medication reconciliation, case management, and post-hospitalization follow-up. These nurse-led clinics have been proven effective at lowering BP and cholesterol, decreasing hospitalizations, and lowering medical expenditures. Patients have been shown to increase their medication compliance and report greater satisfaction with their care. This may be in part due to effective nursing interventions in education, lifestyle modification, and setting practical goals. (Brown, 2017; Vanhook, Bosse, Flinter, Poghosyan, Dunphy, & Barksdale, 2018). Success of these interventions could be further enhanced through effective planning in medication compliance with evening dosing. For some, taking a BP pill with dinner can serve as a reminder; others may benefit from a reminder system on their phone, which can be set up in the clinic with the help of the nurse. In addition, there would be benefit for nurses to develop an app that would aide in reminding patients to take their medications at the prescribed times.
In the acute-care setting, there are often factors that relate to this dosing regimen. The current data focus on non-hospitalized patients, but in the inpatient setting, complex patient acuity may affect dosing strategies. Furthermore, hospitalized patients are subject to disruption at all hours of the day and night, which may affect their circadian rhythm, thereby blunting the potential benefits of this dosing plan. This further highlights the importance for nurses to cluster their care as best as possible to limit sleep interruptions. One other challenge with BP control in this setting is from patients with limited mobility. Hospitalized patients often remain in bed due to acuity or weakness. Nurses are encouraged to get patients out of bed as soon as it is deemed safe; however, even being on bedrest for 24 hours increases the risk for orthostatic hypotension. Not only will this deter ambulatory effort due to fall risk, restricting the patient to bed also prevents the added benefits of mobility to overall BP management (Khan, Kunselman, Leuenberger, Davidson Jr, Ray, Gray, ... & Sinoway, 2002). Last, the healthcare team should pay close attention to the default timings of antihypertensives as medications timed “once daily,” may be defaulted to the morning and “twice daily” may either be 9:00AM/5:00PM or 9:00AM/9:00PM depending on the coding system.
In all care settings, nurses should be mindful of patients’ BP in conjunction with prescribed medications. Special attention towards BP patterns could help in early detection of non-dipping patterns and a morning surge, permitting quicker identification and intervention. Evening dosing can be considered before increasing the dose of current medications, changing medications, or adding a new medication, which could potentially decrease polypharmacy and its associated health risks and medical expenditures.
The increasing evidence regarding the circadian rhythm of hypertension lends further support towards transitioning optimal dosing time to the evening. This change has the potential to restore normal dipping patterns, thereby delaying or eliminating development of comorbidities. There is also the possibility of reducing the number of negative CV events upon wakening due to morning surge. Outside of the concern over medication adherence, this dosing change is risk-free in most individuals. Nevertheless, medication adherence is more important than optimal dosing time; therefore, if none of the strategies or interventions prove effective at maintaining medication compliance, then morning dosing would be optimal. Finally, chronotherapy is a cost-free option towards optimizing positive outcomes.
In summary, potential benefits of this change in practice include: (1) improved BP control, (2) lowered risk of developing comorbidities, (3) decreased incidence of negative CV events, and (4) decreased expenditures. Recommendations for practice include: (1) advocating for evening dosing, (2) assessing for non-dipping and the morning surge, (3) checking with the facility’s policies regarding medication default timing. Recommendations for future research include (1) methods to improve medication adherence, such as through the incorporation of technology, and (2) exploring the impact of evening dosing on hospitalized patients.
- Almirall, J., Comas, L., Martínez-Ocaña, J. C., Roca, S., & Arnau, A. (2012). Effects of chronotherapy on blood pressure control in non-dipper patients with refractory hypertension. Nephrology Dialysis Transplantation, 27(5), 1855-1859.
- American Diabetes Association. (2020). Cardiovascular disease and risk management: Standards of medical care in diabetes—2020. Diabetes Care, 43(Supplement 1), S111-S134. doi: 10.2337/dc20-S010
- Awad, K., Sahebkar, A., Penson, P., Mikhailidis, D., Toth, P., Jones, S., … & Banach, M (2017). Effects of morning vs evening statin administration on lipid profile: a systematic review and meta-analysis. Journal of clinical lipidology, 11(4), 972-985.
- Brown, V. M. (2017). Managing patients with hypertension in nurse-led clinics. Nursing2020, 47(4), 16-19. doi: 10.1097/01.NURSE.0000513619.81056.60
- Crippa, G., Zabzuni, D., Cassi, A., & Bravi, E. (2016). Effect of bedtime dosing of barnidipine hydrochloride in non-dipper hypertensive patients with obstructive sleep apnoea not treated with continuous positive airway pressure. Eur Rev Med Pharmacol Sci, 20(2), 339-344.
- Davis, K. E. (2013). Expenditures for hypertension among adults age 18 and older, 2010: Estimates for the US civilian noninstitutionalized population. Agency for Healthcare Research and Quality. https://meps.ahrq.gov/data_files/publications/st404/stat404.shtml
- Del Giorno, R., Troiani, C., Gabutti, S., Stefanelli, K., Puggelli, S., & Gabutti, L. (2020). Impaired Daytime Urinary Sodium Excretion Impacts Nighttime Blood Pressure and Nocturnal Dipping at Older Ages in the General Population. Nutrients, 12(7), 2013.
- Fagard, R. H., Thijs, L., Staessen, J. A., Clement, D. L., De Buyzere, M. L., & De Bacquer, D. A. (2009). Night–day blood pressure ratio and dipping pattern as predictors of death and cardiovascular events in hypertension. Journal of human hypertension, 23(10), 645-653.
- Hermida, R. C., Ayala, D. E., Mojón, A., & Fernández, J. R. (2010). Influence of circadian time of hypertension treatment on cardiovascular risk: Results of the MAPEC study. Chronobiology International, 27(8), 1629-1651. doi: 10.3109/07420528.2010.510230
- Hermida, R. C., Ayala, D. E., Mojón, A., & Fernández, J. R. (2011a). Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. Journal of the American Society of Nephrology, 22(12), 2313-2321. doi: 10.1681/ASN.2011040361
- Hermida, R. C., Ayala, D. E., Mojón, A., & Fernández, J. R. (2011b). Influence of time of day of blood pressure–lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care, 34(6), 1270-1276. doi: 10.2337/dc11-0297
- Hermida, R. C., Crespo, J. J., Domínguez-Sardiña, M., Otero, A., Moyá, A., Ríos, M. T., ... & Salgado, J. L. (2019). Bedtime hypertension treatment improves cardiovascular risk reduction: The Hygia Chronotherapy Trial. European heart journal, ehz754. doi: 10.1093/eurheartj/ehz754
- Huangfu, W., Duan, P., Xiang, D., & Gao, R. (2015). Administration time-dependent effects of combination therapy on ambulatory blood pressure in hypertensive subjects. International Journal of Clinical and Experimental Medicine, 8(10), 19156-19161. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694448/
- Kaya, M. G., Yarlioglues, M., Gunebakmaz, O., Gunturk, E., Inanc, T., Dogan, A., ... & Topsakal, R. (2010). Platelet activation and inflammatory response in patients with non-dipper hypertension. Atherosclerosis, 209(1), 278-282.
- Khan, M. H., Kunselman, A. R., Leuenberger, U. A., Davidson Jr, W. R., Ray, C. A., Gray, K. S., ... & Sinoway, L. I. (2002). Attenuated sympathetic nerve responses after 24 hours of bed rest. American Journal of Physiology-Heart and Circulatory Physiology, 282(6), H2210-H2215.
- Kirkland, E. B., Heincelman, M., Bishu, K. G., Schumann, S. O., Schreiner, A., Axon, R. N., ... & Moran, W. P. (2018). Trends in healthcare expenditures among US adults with hypertension: national estimates, 2003–2014. Journal of the American Heart Association, 7(11), e008731. doi: 10.1161/JAHA.118.008731
- Kuhlman, S. J., Craig, L. M., & Duffy, J. F. (2018). Introduction to chronobiology. Cold Spring Harbor perspectives in biology, 10(9), a033613.
- Oba, Y., Kabutoya, T., Hoshide, S., Eguchi, K., & Kario, K. (2017). Association between nondipper pulse rate and measures of cardiac overload: The J‐HOP Study. The Journal of Clinical Hypertension, 19(4), 402-409.
- Okada, Y., Galbreath, M. M., Shibata, S., Jarvis, S. S., Bivens, T. B., Vongpatanasin, W., ... & Fu, Q. (2013). Morning blood pressure surge is associated with arterial stiffness and sympathetic baroreflex sensitivity in hypertensive seniors. American Journal of Physiology-Heart and Circulatory Physiology, 305(6), H793-H802.
- Rouch, L., Cestac, P., Hanon, O., Cool, C., Helmer, C., Bouhanick, B., ... & Andrieu, S. (2015). Antihypertensive drugs, prevention of cognitive decline and dementia: a systematic review of observational studies, randomized controlled trials and meta-analyses, with discussion of potential mechanisms. CNS drugs, 29(2), 113-130.
- Unger, T., Borghi, C., Charchar, F., Khan, N. A., Poulter, N. R., Prabhakaran, D., ... & Schutte, A.E. (2020). 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension, 75(6), 1334-1357. doi:10.1161/HYPERTENSIONAHA.120.15026
- Vanhook, P., Bosse, J., Flinter, M., Poghosyan, L., Dunphy, L., & Barksdale, D. (2018). The American Academy of Nursing on policy: Emerging role of baccalaureate registered nurses in primary care (2018). Nursing Outlook, 66(5), 512-517. doi: 10.1016/j.outlook.2018.09.003
- Wang, C., Ye, Y., Liu, C., Zhou, Y., Lv, L., Cheng, C., ... & Liu, X. (2017). Evening versus morning dosing regimen drug therapy for chronic kidney disease patients with hypertension in blood pressure patterns: a systematic review and meta‐analysis. Internal Medicine Journal, 47(8), 900-906. doi: 10.1111/imj.13490
- Winter, C., Silvestre-Roig, C., Ortega-Gomez, A., Lemnitzer, P., Poelman, H., Schumski, A., ... & Soehnlein, O. (2018). Chrono-pharmacological targeting of the CCL2-CCR2 axis ameliorates atherosclerosis. Cell metabolism, 28(1), 175-182.
- World Health Organization (2021, August 25). Fact Sheets: Hypertension. https://www.who.int/news-room/fact-sheets/detail/hypertension
- Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E., & Hogenesch, J. B. (2014). A circadian gene expression atlas in mammals: implications for biology and medicine. Proceedings of the National Academy of Sciences, 111(45), 16219-16224.
- Zhao, P., Xu, P., Wan, C., & Wang, Z. (2011). Evening versus morning dosing regimen drug therapy for hypertension. Cochrane Database of Systematic Reviews. doi: 10.1002/14651858.CD004184.pub2