09:12 AM

473 - BP Medication Timing, Menopausal Hormone Therapy, Thanks-Giving

Take 3 – Practical Practice Pointers©

From the Literature

1)  More on the Timing of Blood Pressure Medications


The issue of timing of blood pressure medications continues to be argued in the literature. So much so that the International Society for Hypertension published a systematic review and consensus statement about the state of the science. There are several timing-related arguments for worrying about this: the failure of blood pressure to “dip” at night while sleeping, outright nighttime hypertension, and a morning “surge” in blood pressure, all of which can lead to morning strokes and heart attacks. The statement authors noted that several studies have shown improved blood pressure control, and only two that showed benefit to cardiovascular outcomes. Because of reproducibility concerns, the statement authors advised waiting for the outcome of additional trials of medication timing that include cardiovascular outcomes.

One of these - from the UK, the TIME (Treatment in Morning vs. Evening) study – was recently published. Over 21,000 patients were randomized to morning (6-10 AM) vs. evening (8 PM – 12 AM) self-administration of all their antihypertensive medication. If patients took a diuretic as part of their regimen, they were instructed to take it in the early evening to avoid nocturia, or in the morning if the nocturia persisted.

Approximately thirteen percent of the cohort had a history of cardiovascular disease. The mean age of participants was 65 years, there were 42.5% women, 90.5% were white and, unfortunately, only 0.5% were Black, African, Caribbean, or Black British. Just over 4% of patients withdrew from each arm of the study. The median follow up was 5.2 years.

There was no difference in the primary composite cardiovascular event outcome (vascular death, non-fatal stroke, or non-fatal myocardial infarction) between the groups (3.4% in evening dose vs. 3.7% in morning dose, relative risk 0.95, 95% confidence interval 0.83 to 1.1). None of the secondary outcomes were significantly different either, including overall mortality. Interestingly, there were statistically significant decreases in side effects of falls, dizziness, upset stomach, diarrhea, and muscle aches in the evening dose group, and an increase in “excessive visits to the toilet” in the evening dose group but all without apparent effect on overall outcomes. The authors note the limitations of this study to be the pragmatic, “open-label” design, potentially incomplete adverse events data (fewer subjects in the evening-dose group responded to the questionnaires, potentially under-counting harms),

John’s Comments:

We covered one study on this topic back in early 2020 (pre-pandemic times!), which found benefit to evening dosing.  I said I would try it with patients and see how it worked. In my very small, non-systematically tracked sample, some took to it right away, and for some it seemed to cause confusion and non-adherence. The results of the TIME trial will make me rethink the recommendation for evening dosing since it was more demographically representative of the patients I see.

Interestingly, two of the authors of the systematic review were principal TIME investigators. The two outcome studies found by the systematic review (which include the one I reviewed in 2020) were both led by the same investigator (Hermida) in Spain and were very harshly criticized in the review (with repeated use of the word “implausibly”). The conflict of interest of the two TIME authors was mentioned at the end of the review, but not very well mitigated in the text.

I believe I’ll wait on the accumulation of data from the other cardiovascular outcomes trials and look for an impartial, rigorous systematic review of studies before I decide on a standard practice.


·         Stergiou G, Brunström M, MacDonald T, et al. Bedtime dosing of antihypertensive medications: systematic review and consensus statement: International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension. J Hypertens. 2022;40(10):1847-1858. Link

·         Mackenzie IS, Rogers A, Poulter NR, et al. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. The Lancet. 2022;400(10361):1417-1425. Link


From the USPSTF

2)  Hormone Therapy for Primary Prevention in Postmenopausal State


Menopause is defined as the cessation of a woman’s menstrual cycle. It is defined retrospectively, 12 months after the final menstrual period.  Perimenopause, or the menopausal transition, is the few-year time period preceding the final menstrual period and is characterized by increasing menstrual cycle length variability and periods of amenorrhea, and frequently symptoms such as vasomotor dysfunction.  The prevalence and incidence of most chronic diseases (eg, cardiovascular disease, cancer, osteoporosis, and fracture) increase with age, and women who reach menopause are expected on average to live more than another 30 years.  Menopausal hormone therapy (MHT) refers to the use of combined estrogen and progestin in women with an intact uterus, or estrogen alone those who have had a hysterectomy, taken at or after the time of menopause. 

The USPSTF recently updated and confirmed their 2017 recommendation for the use of hormone therapy in the postmenopausal state for the primary prevention of chronic conditions.  Specifically:

·         Recommends against the use of estrogen alone or combined estrogen and progestin for the primary prevention of chronic conditions in the postmenopausal state. (D Recommendation)

The review found that while MHT may reduce some health risks, such as osteoporotic fractures, it can also lead to serious harms such as an increase in the risk of blood clots and stroke, and that overall the potential harms were much greater than any potential benefits.

This recommendation statement applies to asymptomatic postmenopausal women who are considering hormone therapy for the primary prevention of chronic medical conditions.  It does not apply to those who are considering hormone therapy for the management of perimenopausal symptoms, such as hot flashes or vaginal dryness.  It also does not apply to those who have had premature menopause (primary ovarian insufficiency) or surgical menopause.

It should be noted that the American College of Obstetricians and Gynecologists (ACOG) recommends against the use of menopausal hormone therapy for primary and secondary prevention of coronary heart disease.  ACOG also notes that evidence suggests that women in early menopause who are in good cardiovascular health and at low risk of adverse cardiovascular outcomes should be considered candidates for the use of estrogen therapy or conjugated equine estrogen plus a progestin for relief of menopausal symptoms and that menopausal hormone therapy is approved for use in women with an increased risk of osteoporosis and fracture.  The American Academy of Family Physicians has endorsed the previous USPSTF recommendation on hormone therapy the postmenopausal state. 

Mark’s Comments:

A thoughtful editorial accompanying the release of this recommendation notes that despite the efforts of the USPSTF to draw a clear distinction between MHT for prevention vs symptom management, many patients and clinicians don’t distinguish between these 2 different indications. The notion that “the net harms of MHT outweigh the benefits,” originally intended to explain the limitations of MHT for routine prevention, is now widely adopted as a rationale for not using MHT for symptomatic treatment.  It’s important to note that many of the other treatments for perimenopausal and postmenopausal symptoms have not gone through the rigor of MHT, and therefore there are many unknowns for them for long-term treatment.  As such, a dialogue between a woman and her clinician about the pros and cons of various options to treat these symptoms is appropriate. 


USPSTF.  Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons. USPSTF Recommendation Statement.  JAMA. 1 November 2022;328(17):1740-1746. Link

From PeerRxMed ( www.PeerRxMed.org )

3)  Celebrating Our “Angels” this Thanks-Giving


“Sometimes our light goes out but is blown again into instant flame by an encounter with another human being.  Each of us owes the deepest thanks to those who have rekindled this inner light.”   Albert Schweitzer, MD, Humanitarian and Nobel Peace Prize Recipient

There is a drawer where I keep cards, letters, and pictures that have been given to me over the years from patients, students, residents and colleagues, and when I’m feeling the need to be reminded of why I do this incredible but also demanding and emotionally draining work, I go through that drawer and pick out a few in order to be reminded again.  This ritual allows me to reflect on the many people who have spoken into my professional life and in doing so, helped make me “better than I am.”  Though I don’t remember someone ever advising me to save these items, I’ve learned over the years that many other colleagues have such a memento collection as well.    

Recently, after a particularly challenging day in clinic, including having to share some very sobering news about a likely terminal diagnosis with one patient and having another patient and her son expressing their anger to me regarding something that I had no control over, I was feeling in need of an uplift.  In response, I opened that drawer and allowed some of the notes and pictures to speak love and encouragement to me from across the miles and years.      

One of notes was from a dear friend and colleague, Elizabeth Vogel, PhD, with whom I worked from 2006-2009 as we created the Carilion Office of Professional Development and whose life ended very suddenly, and senselessly.  Elizabeth was one of those people whose inner light shone brightly, and her “can-do” attitude helped teach me to listen to and trust my instincts.  Her encouragement inspired the foundation for much of the work I am doing today.  The quote above was one of her favorites, and we often spoke of those people, whom she called her “Angels,” who had positively impacted our lives with their ability to see something in us that we couldn’t yet see in ourselves.  Though I didn’t tell her often enough, she was such a person for me. 

One of Elizabeth’s legacies was the inspiration she helped provide for what is now the PeerRxMed process.  She and I spoke often of the challenges of working in healthcare and of how very isolating it can be, both by choice and by design.  She often stated what has now become the obvious for me – that it is “crazy” that anyone should try to navigate this professional journey on their own.  In doing so, she helped plant the seeds for the PeerRx vision that “No one cares alone.”    

All of which has left me thinking about other “Angels” in my life, past and present, and wondering about yours as well.  When was the last time we’ve thanked them for how they have positively impacted our lives?  In this season of Thanks-giving, perhaps we can all take a moment to express our gratitude to and for them.  For me, that would include my PeerRxMed partners, who weekly fan the flames of my life with their presence and their encouragement.  Now more than ever we all need to show up as the “better versions” of ourselves, and there’s no way that’s going to happen on our own.  Fortunately, we all have “Angels” in our midst.  That’s something worth celebrating every day ….


Mark and John

Carilion Clinic Department of Family and Community Medicine

Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.

Email: mhgreenawald@carilionclinic.org