456 - ARBs Over ACE-I?, Insomnia Treatment, Being Thought Of

From the Editorial Pages

1)  Should ARBs Be Preferentially Prescribed Over ACE-I?

For a long time, angiotensin converting enzyme inhibitors (ACE-I) inhibitors have enjoyed favored status amongst the renin-angiotensin system agents. They were developed first, and then angiotensin receptor blockers (ARBs) came along as an alternative if ACE-I were not tolerated.  The authors of an editorial in the journal Circulation would have us abandon those notions in favor of primarily prescribing ARBs, arguing equivalent effectiveness and better safety.

When I encounter a potentially practice-changing question like this, I try to remember to use a framework to slow me down and help me think through the question, so that I’m neither persuaded by elegant editorializing nor falling prey to therapeutic nostalgia. The STEPS framework – from the InfoPOEMS folks – encourages the systematic evaluation of Safety, Tolerability, Effectiveness, Price, and Simplicity when evaluating a drug. We can apply it to the question of the routine use of ACEs and ARBs.

Safety – The incidence of angioedema with ACE inhibitors is overall very low (<1%) but is several times as frequent as with ARBs.

Tolerability – The incidence of cough that necessitates stopping the medication is significantly lower with ARBs. The risk of withdrawing due to all adverse events (safety and tolerability) is just less than 2% with an estimated number needed to treat with ARBs to avoid a side effect of ~55.

Effectiveness – While there was some initial concern that the effects of ARBs were not as beneficial as ACEs, large studies and systematic reviews have nullified this concern, and shown them to have equivalent outcomes for hypertension, heart failure and kidney disease protection.

Price – There remains a small difference in average wholesale price between the generic versions of ACEs ($9-20) and ARBs ($14-33) at comparable dose, per goodrx.com. The larger price differentials between them have largely resolved, so the drivers for prescribing ACEs first are not impactful as they were.

Simplicity – Insurer formularies generally carry generic ACEs and ARBs without restrictions. Both have once-a-day versions. There was a significant shortage of losartan during the pandemic due to recalls, but that has resolved itself.

John’s Comments: 

We hold on to our prior practice patterns in the face of questions like this for a variety of reasons that are usually more related to our “System 1” thinking – heuristic, emotional, and inertial. Recognizing these cases and purposefully engaging our “System 2” thinking – rational, deliberative, and slower – using frameworks like STEPS can help us take a proactive approach to basing our practice on the best evidence. As I have seen my share of ACE inhibitor-related angioedema, I think I’ll try giving the ARBs top billing from now on.

References:

·       Messerli FH, Bavishi C, Bangalore S. Why Are We Still Prescribing Angiotensin-Converting Enzyme Inhibitors? Circulation. 2022;145(6):413-415. Link

·       Chen R, Suchard MA, Krumholz HM, et al. Comparative First-Line Effectiveness and Safety of ACE Inhibitors and Angiotensin Receptor Blockers: A Multinational Cohort Study. Hypertension. 2021;78(3):591-603. Link

·       Li EC, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. Cochrane Database of Systematic Reviews. 2014;(8). Link

From the Literature

2)  How Best to Treat Insomnia?

As we know, sleep difficulties are a common complaint in our medical practice.  These can include difficulty falling asleep (sleep latency), difficulty staying asleep (sleep maintenance), or not feeling rested by a night’s sleep (sleep quality).  Indeed, it is estimated that chronic insomnia (when the sleep difficulties occur at least three times a week for three months or longer) effects up to 10% of the US adult population and likely is more common in clinical practice.  

In 2016, the American College of Physicians published a guideline for the management of chronic insomnia disorder, recommending cognitive behavioral therapy for insomnia (CBT-I) as the initial treatment (Grade: strong recommendation, moderate-quality evidence) and for the use of a shared decision-making approach, including a discussion of the benefits, harms, and costs of short-term use of medications, to decide whether to add pharmacological therapy when CBT-I alone was unsuccessful. (weak/low-quality).

These recommendations were affirmed by a 2019 Department of Veterans Affairs and Department of Defense Guideline which in addition to CBT-I for first line therapy, added a recommendation for another form of behavioral therapy called brief behavioral therapy for insomnia (BBT-I).  In terms of medications, this guideline offered the following guidance:  “Pharmacotherapy with any medication is not recommended for long-term because of lack of proven effectiveness and known concern about adverse effects.  For short-term use, low dose doxepin (3 or 6 mg) or one of the “nonbenzodiazepine benzodiazepine receptor agonists” (BZRAs) such as zolpidem, zaleplon or eszopiclone can be used.  For all these, the lowest possible dose for the shortest possible duration is recommended, and a thorough discussion of adverse effects is warranted.”  

While cognitive behavioral therapy has continued to be considered the most evidence-based and effective intervention for this disorder, it is underutilized for many reasons, including cost, convenience, and access.  Attempts to overcome these limitations have included the development of a free mobile app, CBT-i Coach, underwritten by the US Department of Defense, the first version of which was released in 2013 (see reference).

Because of this, medication continues to often be used as the first line treatment in clinical practice, despite the paucity of long-term studies.  A recently published systematic review and network meta-analysis adds to our understanding of the effectiveness and cautions for the use of medications for the treatment of acute and chronic insomnia.  This extensive analysis included 170 trials (36 interventions and 47,950 participants) in the systematic review and 154 double-blind, randomized controlled trials (30 interventions and 44,089 participants) for the network meta-analysis.  In terms of acute treatments, the authors found that benzodiazepines, doxylamine, eszopiclone (Lunesta), lemborexant (Dayvigo), and zolpidem (Ambien) were more efficacious than placebo (moderate to high certainty).  Benzodiazepines, eszopiclone, and zolpidem were more efficacious than melatonin, ramelteon (Rozerem), and zaleplon (Sonata) (moderate to low certainty).  Daridorexant (Quviviq), suvorexant (Belsomra), and trazodone can also be effective, but comparative data is limited.

For long-term treatment, eszopiclone and lemborexant were more effective than placebo (very low certainty) and eszopiclone was more effective than ramelteon and zolpidem (very low certainty).  Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (very low certainty);  however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (very low certainty).  Doxepin and zaleplon (Sonata) were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions.  Benzodiazepines have known long-term risks.  Melatonin, ramelteon (Rozerum), and non-licensed drugs did not show overall material benefits long-term.

Mark’s Comments:

The more we learn about sleep, the more we recognize how essential it is for our health and well-being.  CBT continues to be the favored first line treatment for chronic insomnia because of its consistent and robust evidence of effectiveness across many outcomes, as well as the fact that it has no identified side-effects.  Unfortunately, it is greatly underutilized in clinical practice due to what I believe is a pill bias (“pill for every ill”) by both clinicians and patients as well as challenges with CBT access.  This is particularly concerning given the paucity of long-term safety and efficacy data for these medications.  Mobile apps such as CBT-I hold promise as a way to close that gap.       

References:

·       Qaseem M, et al for the American College of Physicians.  Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline.  Ann Intern Med 2016 Jul 19;165(2):125-33.  Link

·       Mysliwiec V et al.  The Management of Chronic Insomnia Disorder and OSA: Synopsis of the 2019 U.S. Department of Veterans Affairs and DoD Clinical Practice Guidelines. Ann Intern Med. 2020 Mar 3;172(5):325. (article link) (VA/DoD site link)

·       CBT-i Coach Mobile App:  US Department of Veterans Affairs National Center for PTSD:  Link

Crescenzo F et al.  Comparative Effects of Pharmacological Interventions for the Acute and Long-Term Management of Insomnia Disorder in Adults:  Systematic Review and Network Meta-analysis.  Lancet.  July 16 2022; 400(10347):170-184.  

From PeerRxMed ( www.PeerRxMed.org )

3)  The Power of Being Thought Of

“Reach out, reach out and touch someone … reach out, call up and just say ‘hi.’”  Award-winning Bell System/AT+T commercial jingle, 1979-1987 *

For some of you, reading the words above will immediately bring a tune to mind, and if so, your “age is showing.”  For 8 years, a series of groundbreaking television commercials touched the hearts of millions, portraying emotionally moving scenarios that at some point involved people using the telephone to connect with each other, even if only to say “hi.”

Of course, with the evolution of technology and social media, it’s easy to imagine that reaching out to “just” say hi, by whatever means, has become rather trite or passe  – that perhaps we have become sensitized or even overwhelmed by the constant barrage of social outreach.   And certainly, those past a certain age will realize that for a younger generation, “saying” hi has been replaced by texting hi, or even replaced by an emoji, a GIF or even a “TOY.” 

But has just saying “hi” really lost its connecting power?  Not necessarily reports a team of researchers in a recently published study in the Journal of Personality and Social Psychology.  Through a series of simple experiments, lead author Peggy Liu and colleagues wanted to determine if there was congruence for the perception of the value of an outreach (a brief call, text, e-mail, or small gift) between “sender” and “receiver” within a social circle.  They discovered that there was a significant and consistent underestimation by the “sender” as to how much people appreciate being reached out to.  They also found that this effect was magnified when there was an element of surprise with regard to the context for the outreach (“just because”) and when the outreach occurred between individuals who were more socially distant from each other (“haven’t seen or heard from you for a while”). 

This study was very affirming for a practice I have up to this point done inconsistently over the past few years.  When someone “comes to mind” during my day, I try to remember to send them an e-mail with the heading “Thought-Of” and a message which includes a brief greeting (“to let you know you were ‘thought-of’ today”) as well as something I’m appreciating about them that day that precipitated my outreach (“Remembering that incredible trip we took together”).  And in line with the findings of the authors, I continue to be surprised at how often there is a reply, frequently accompanied by a request for a more substantive connection by video … or even phone (there’s that jingle playing in my head again).

What about you?  Who are some people in your life for whom it’s time to “reach out … and just say ‘hi’”?  Why not do an experiment this week and briefly reach out to at least one of them.  Then consider it making it a regular habit – now knowing that sharing with someone that they are being “thought of” matters more than you likely realized … significantly more.   

*NOTE:  For those who would like to relive a bit of advertising nostalgia, or perhaps experience it for the first time, here’s the original advertisement: Reach Out Ad 1979

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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