This Core IM Mind the Gap episode dives deeper into why we prescribe medications in the morning vs. at night (AND there is a part 2!)

Time Stamps

  • 2:45 Why do we dose warfarin at night?
  • 4:28 Back to the basics – what are the pharmacodynamics of warfarin and how does vitamin K intake matter?
  • 6:14 Practical matters – so what should we tell patients
  • 9:32 Dippers and non-dippers – what happens to blood pressure at night?
  • 11:15 The surprising link between dipping and cardiovascular outcomes 
  • 11:58 Timing is everything
 or is it? The evidence behind taking BP meds at night 
  • 15:58 Review of teaching points 

Show Notes

  1. Dosing warfarin at night is not in fact based in strong clinical data; it’s a question of practicality.
  2. Warfarin’s pharmacodynamics, including its long (20-60hr) half-life and 6-8 days needed to reach steady state, suggest that the timing of warfarin dosing should be irrelevant.
  3. However physiologically, it may help to time warfarin intake with the greatest intake of vitamin K of the day (e.g. with dinner, the largest meal) to help prevent fluctuations in INR.
  4. The pending results of the INRange trial, which studied the benefit of warfarin dosing in the morning, seeks to challenge this theory.
  5. Currently, we continue to dose warfarin at night in the hospital to make morning INRs more reliable, while outpatient the patient should simply focus on taking it at the same time every day.
  6. In hypertension, the data for dosing times relates to the phenomenon of “dipping” at night.
  7. Patients who have a blood pressure more than 10% lower at night are called dippers. Those with blood pressure 0-10% lower at night are non-dippers. And those with a blood pressure that rises are reverse dippers.
  8. Reverse dipping (aka rising) at night is correlated with increased mortality and cardiovascular morbidity to the tune of a 2.3 times relative risk compared regular dippers.
  9. Reverse dipping is thought to be due to underlying dysregulation, e.g. from OSA, CAD, diabetes, HLD)
  10. The MAPEC trial randomized patients to taking one of their antihypertensives at night vs. all in the morning. It showed that this restored the “dipping” effect AND led to reduced rates of cardiovascular disease, particularly statistically significant for cerebrovascular disease (e.g. stroke) and congestive heart failure.
  11. However, the MAPEC trial patients on average had a moderately high ASCVD risk (7.4%) but were not randomized based on aspirin and statin use; so this may be a fairly significant confounder undermining their outcomes.
  12. In addition, the smaller HARMONY trial (only 100 patients, not at RCT) did not see any improvement in night-time blood pressure after switching at least one BP medication to night-time dosing. It did not evaluate cardiovascular outcomes.
  13. Ultimately, the jury is still out, but in patients who likely experience “reverse dipping”, including those with CAD, OSA, and diabetes, clinicians can consider switching one of their blood pressure medications to taking them at night. 

Transcript

S: Janine, I have a really cool fact for you. It’s about warfarin…

J: wait, is this like a cool cool factor, or a nerdy cool fact, steve?

S: I’ll let you answer that one janine

J: well if it’s about how warfarin was named after the Wisconsin alumni Research foundation, I’ve heard that one before.

S: no no no, that’s old news. This is about warfarin dosing. Did you know that you don’t actually have to dose it at night?

J: wait, what? You mean those default order sets I put in as a resident were all wrong??

S: well, not exactly wrong, but it is overkill.

J: wait, stop. before we explain this any further, we should slow down and remind millenials what warfarin is all about. With all those DOACs out now, I feel like med students these days rarely see warfarin anymore

S: Yeah I was just at SHM, and they had a workshop for teaching millennials medicine. And well we recognize that a lot of our listeners are millennials.

J: Actually we are too Steve

S: Wait what?

J: Yep.

S: Mind. Blown. So I just learned how to teach
 myself?

J: Yep, super meta. So Steve’s mind doesn’t explode further, let’s move on.In today’s episode we cover why we prescribe certain medications in the morning or at night.

S: We’ll cover 1) the pharmacodynamics of warfarin, and why you don’t actually necessarily need to dose it at night , but should try to take it at the same time every day.

J: And 2) we’ll cover antihypertensive medications – what’s all this data suggesting that it’s actually better to take them at night?

S: And 3) — but we’ll actually save this one for part 2 — statins, and how night-time dosing may actually be more important than we thought.

J: And 4) what is the impact on the patient? Does taking meds at night help with adherence or hurt it?

S: So
 is the nighttime the right time?

J: Are you quoting music again, Steve?

S: Yup! So let’s take a deeper dive on why we make our patients take their medications at night and day, night and day.

J: No more – I can’t take it!

đŸŽ”INTRO MUSIC đŸŽ”

J: Hi I’m Janine Knudsen

S: And I’m Steve Liu

J: Welcome to Mind the Gap

S: A CoreIM podcast

J: We’d like to thank Dr. Matthew Sparks, Nephrologist at Duke, and Tania Ahuja, one of our favorite pharmacist at NYU Langone Health. for peer-reviewing this episode.

S: Subscribe for our show notes at CoreIMPodcast.com

J: And follow us on insta and twitter.

S: Let’s get back to tackling warfarin. Let me explain why it doesn’t matter if you dose it in the morning or at night.

J: Ok, you really have to convince me here. I’ve been dosing it at night for years.

S: Well, the thing is there’s just no clinical outcome data to support taking it at night. It’s not even mentioned in the AHA guidelines!  Yet, most anticoagulation clinics and hospital systems recommend nightly warfarin.

J: Wait, that’s our teaching?? Just no data at all? Give me one paper Steve, just one! We are doing a podcast on evidence-based medicine

S: Well call me George Washington cuz I cannot tell a lie! But if you really want something, I guess there’s at least a couple places that mention it. There’s a study protocol and the Cleveland clinic website that both basically say that we do it to help providers


J: Are you serious? That’s not convincing me a lot

S: Well, there is some utility to that

J: Ok well I could see that since inpatient labs are done in the morning, that gives providers all day to adjust the warfarin dose because it’s given at night. If it were given in the morning, by the time you got the INR results it would be too late to change that day’s dose.  

S: In the event you need to do a procedure in-patient, and if they took their warfarin in the morning there’s a chance their INR could be a little different by the afternoon. So you’d have to recheck it. Taking it at night and measuring their morning trough gets rid of all that.

J: Well, that is the best worst explanation for “why we do what we do” that I’ve heard so far. I guess that why anticoagulation clinics do it that way too – it’s just easier.

S: Ha, yeah. And if you look at warfarin pharmacodynamics it kind of gets dumber than that. So Janine, if I can convince you even less..

J: Yeah, data shows that its half-life is estimated between 20 and 60 hours, and even more, it takes 6 to 8 days to reach a stable therapeutic dose.

S: Exactly, so implied in all of this is it really doesn’t matter what time of day you’re taking it, because it’s effect is supposed to plateau, not these big spikes all over the place.

J: Ok, that’s in an ideal world. But doesn’t warfarin have a small spike in the first few hours after you take it? After it goes through first pass metabolism in the liver?

S: True. And some researchers think that if you take it at night, when you’re also eating the biggest meal and therefore of vitamin K intake of the day, that timing those two together might be helpful.

J: So just to repeat, what you are saying is that you’re timing your mini INR spike with your vitamin K spike. Like an insulin bolus to match your sugar.

S: That’s a great analogy, Janine. It’s pretty hypothetical, but that’s a least the pharmacological argument for taking it at night. The study protocol we mentioned earlier is meant to study that specifically. It’s the cleverly named INRange trial.

J: INRange? So bad but so good.

S: So they’re looking at whether or not patients should warfarin in the morning or at night!

J: To challenge whether this vitamin K idea really matters

S: Data collection has been completed on the clinical trial websites, and we’ll have to eagerly await their findings.

J: Obviously this will be at the top of our collective reading lists in the coming year.

S: I’m checking my twitter feed every second! But for now, we just have to go of basic pharmacodynamics and the total lack of data to make our recommendation – which is that warfarin probably be taken at any time of day, as long as it’s around the same time every day.

J: Amazing. Consider me convinced with that interesting review of the data.  I’m going to tell all my clinic patients on warfarin that they should take their warfarin at the SAME time every day
. But night or day, whichever is more convenient.

S: As long as they’re taking it

J: Exactly

S: Ok, our next medication timing to tackle: we’re going to talk about anti-hypertensives, the so-called “dipping” phenomenon, and the data behind reducing mortality by prescribing blood pressure meds at night.

J: Woah, hypertension and blood pressure are some weighty topics.

S: Spoken like a true primary care physician. I pulled out an ancient textbook

J: Woah, a book!

S: Its called the Principles of Ambulatory Medicine For millennials, books are things we used to read back in the day to learn knowledge

J: We need to tone that down, Steve. Also this book was published in 2003 so really not that long ago

S: But covered in dust. Anyway I didn’t find much. Maybe because I didn’t have my control F function to help me find it!

J: Haha ok I agree with you on that one. Digital is better for that one.

S: But I did manage to find a section that said “the lowest blood pressures occur during sleep”

S: Which they pulled from a Lancet paper from 1978

J: Ok I didn’t need a textbook to tell me that if you’re ever the night resident fielding calls about low nighttime blood pressures, you know that this happens

S: Ok, but let me tell you more about this Lancet paper. In 1978, three scientists in England did what any self-respecting doctor researching hypertension would do.

J: They got 5 healthy patients and 20 patients with untreated hypertension and put L brachial a-lines in them and sent them out into the world and said “you do you.”

S: But they were English so it was probably all proper like “jolly good old man, go about your day”

J: And so these 25 people did go about their day, including going to work

S: But let’s remember they had freaking a-lines in their arms


J: And the docs recorded the results.

S: For two days. (slowly)

J: And this was done with informed consent and somehow approved by a hospital ethics committee.

S: So thank you to these brave volunteers, they found that there is a clear dip in both heart rate and blood pressure measurements at night, followed by a clear rise in the morning that remains relatively stable throughout the day.

J: I don’t understand why they didn’t just use BP cuffs

S: Ignore that Janine. They noted reasonably that this mimics the rise of catecholamines in the body in the early morning hours that also peak by mid-day.

J: Physiologically makes sense.

S: But this still doesn’t explain why we tell people to take antihypertensives at night. Based on your observation and theirs, you would think taking your BP meds in the early morning.

J: These doctors would have agreed with you, noting that “it seems that from 6AM until 9AM, when the arterial blood-pressure is increasing rapidly, active hypotensive therapy is crucial. … perhaps [it should] be designed to give more satisfactory blood-pressure control during that part of the day.”

S: So this is where dipping comes in. Later evaluations of populations of hypertensive patients noted that some patients – particularly the elderly and patients with autonomic failure – you don’t see a drop in blood pressure overnight.

J: So group of Irish doctors lead by Dr. Eoin O’Brien (pronounced “Owen” apparently) coined the term dippers and non-dippers to describe both of these groups of patients.

S: Dr O’Brien went on to join and lead the European Society of Hypertension’s working group on blood pressure monitoring.

J: And coined later more language including “dippers,” “nondippers,” “reverse dippers,” and “extreme dippers.”

S: So we’re gonna try to parch through all of that, dippers (what we would call “normal”) are folks who have at least a 10% drop in blood pressures from daytime to nighttime.

J: But then, there’s the non-dippers, unlike their name suggests they can also dip

S: Nooooo

J: Yeahhhh but they only dip between 0 and 10%

S: Extreme dippers dip more than 20% at night.

J: Meanwhile, last but not least, the reverse dippers

S: I would call them risers

J: No don’t be silly, that name would be stupid, these guys are reverse dippers. Another accepted term is inverted dipping.

S: So as their blood pressure reverse dips, upwards
??

J: Their blood pressure is higher at nighttime.

S: We swear this naming scheme is a real thing. I guess it makes sense that every specialty has its special vocab and turns out, hypertension is no different


J: So, what types of patients are in this abnormal category of “non-dipping” at night?

S: Yeah, you’re more likely to see that in patients with diabetes, coronary disease, hyperlipidemia, etc.

J: But there’s also a category of people of whether we’re just not measuring it right, for example patients with abnormal sleep habits like teenagers or Mediterranean people who take a siesta.

S: True – make sure  you’re not misdiagnosing someone just because their sleep schedule is off!

J: But wait
 Why do we care so much about dipping again?

S: There is a clear correlation between worsening cardiovascular prognosis and patients who did not have normal dipping at nighttime.

J: From one meta-analysis, there was a 2.5-fold increase in both non-fatal and fatal cardiovascular events in reverse dippers compared to the regular dippers.

S: Reverse dipping (or rising) is also worse than just non-dipping

J: Again that’s when BP just stays the same or dips less than 10% at night

S: In this comparison reverse dippers still had a 2.1 fold increase in poor outcomes over non dippers.

J: So I think by now you see where we’re going with this. Clearly people that don’t dip do worse.

S: Just remember that failure to dip probably correlates to other dysregulation, and is a sign, not necessarily purely a cause of disease.

J: So all this population level data led other researchers to ask whether giving  anti-hypertensive at nighttime to recreate that dip would help with mortality?

S: So they did that in a study called MAPEC, which actually suggests it might.

J: This trial prospectively looked at 2156 people with either untreated hypertension or resistant hypertension.

S: They wanted to see if by using ambulatory blood pressure monitoring and actigraphs – this is a device worn on the wrist that monitors physical activity –

J: So like a fitbit.

S: Well it’s definitely not a freaking a-line.  They used blood pressure monitoring and activity to measure dippers vs nondippers

J: They gave participants the task of changing at least one of their blood pressure meds to night-time dose.

S: Couple caveats: Allocation was randomized, but the trial was not blinded.

J: And they looked at a combined primary outcome of death from all causes, MI, angina, coronary revascularization, heart failure, acute arterial occlusion of the lower extremities, rupture of aortic aneurysms, thrombotic occlusion of the retinal artery, hemorrhagic stroke, ischemic stroke and TIA.

S: Phew, that’s a lot. We have warned you guys about combined primary outcomes before. Yeah, so essentially what they were looking at was cardiovascular events including all cause mortality

J: Why did you give me that line? Yeah. So if you had to summarize their biggest finding, how would you summarize it?

S: Well, to start they demonstrated that there was a clear improvement in blood pressures not only throughout the day, but most specifically at nighttime. Patients who were previously non-dippers became dippers.

J: And related to this, they found that there was a pretty big decrease in their primary outcome of cerebrovascular events and heart failure. They showed a general improvement actually in all outcomes, but cerebrovascular events and heart failure were statistically significant.

S: After adjusting for sex, age, and diabetes, they found a relative risk reduction in folks taking at least one medication at night-time of 0.33 in the intervention group.

J: Wow! Well there’s one pretty satisfying data point in favor of taking meds at night if i’ve ever seen one.

S: Hold your horses janine. There’s one gigantic caveat to their trial. They did not ensure that all patients were treated with a standardized protocol for medications that are known to treat other clear risk factors for cardiac risk, I’d say namely ASA or statins.

J: That’s concerning, so that could easily be a confounder. If patients aren’t taking aspirin and statins, maybe they had worse outcomes just because of that? Or vice versa. Not related to the blood pressure meds.

S: Yes, it could’ve made a big difference. If you look at their average patient and plug them into an ASCVD risk score, you end up with a borderline 7.4% risk of ASCVD outcomes at 10 years.

J: Most patients would have qualified for a moderate intensity statin, and maybe a statin, and current guidelines suggest consideration of aspirin.

S: So if we are not sure what providers did, we gotta question a little bit of their data. But this doesn’t invalidate their findings, but we’d probably want to check other places first.

J: So we did look at other trials, the answer remains as you might guess is 
 it’s just  not really clear.

S: One of those trials was the HARMONY trial – it was published in Hypertension in 2018 which argued against the data presented in MAPEC.

J: The HARMONY trial looked at daytime or nighttime dosing and argued that night-time dosing is not actually better

S: This was a far smaller trial with just over 100 participants.

J: They did a crossover trial which was designed to look at whether or not dosing medications at nighttime for about 12 weeks impacted mean blood pressure readings.

S: And they found it didn’t affect blood pressure readings during the daytime, the nighttime, or over 24 hours.

J: So this contradicts the MAPEC findings that mean blood pressures, improved with taking at least one medication at night.

S: And this is especially important in the contradiction in data that there was no change in nighttime BP control. In other words, there was not restoration of our dip.

J: Unfortunately in this trial did not look at cardiovascular outcomes.

S: For that we’ll have to wait for the “treatment in the morning versus evening” trial

J: The aptly named TIME trial

S: Something something nighttime is the right time.

J: And that will show us if the data from MAPEC will be replicated or not.

S: So that’s all for today.

J: You guys may have noticed that we haven’t talked about the practicality of taking meds at nighttime, but we figured we’d address that next time when we talk about the use of statins at night.

S: So, Janine, take it away with the summaries

J: Thanks Steve. We have a few. For warfarin, the biggest takeaway is that there’s no data to support night-time dosing, and the long half-life of the drug makes timing of the dose particularly irrelevant.

S: Yeah ultimately the timing is based on the needs of the medical team
 which you could argue isn’t better for patients. We’ll have to wait on that INRange trial data to come out to confirm this, though.

J: But for blood pressure meds, taking them at night may have a huge impact on morbidity and mortality.

S: At least that’s what the folks from the MAPEC trial suggested. They claim that Dippers (people with night-time BPs more than 10% lower than daytime BPs) have lower cardiovascular disease and mortality. Reverse dippers are 2.1x more likely to have cardiovascular disease and death.

J: And, as the MAPEC trial suggests, taking BP meds at night can restore this “dipping” effect in non-dippers (commonly patients with diabetes, OSA, HLD) and may lead to reduced mortality and cardiovascular disease.

S: But I’m not sure I trust the MAPEC trial since they didn’t control for patient aspirin or statin use, and most patients had a moderate ASCVD risk score and should have been on those meds.

J: Major confounder. Also, the HARMONY trial had opposite results to the MAPEC trial
 but it was small, not randomized, and only looked at blood pressure, not mortality.

S: Ok, so the jury is still out, but it’s definitely worth consider switching at least 1 BP med to night-time dosing if you have a patient who can handle it and may be a non-dipper

J: Aka those with diabetes, OSA, etc.

S: Sounds good. At least thats what some cardiologist and nephrologist do. Tell us what do you do? Tweet us or share with on insta and let’s try to learn from each other’s practice.

References

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  • ACC cardiotool
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