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Adherence Measurements in Clinical Trials and Care

      Probably all practicing clinicians have encountered nonadherent patients. We used to say these patients were noncompliant, but this latter descriptor has largely been discarded because it has paternalistic connotations to some. It has also been suggested that calling patients noncompliant impugns their character. In a thoughtful commentary on this distinction, Emily Wolfe

      Wolfe E. What's the difference between patient adherence and compliance? 16 December 2016. https://www.twinehealth.com/blog/whats-the-difference-between-patient-adherence-and-compliance. Accessed 15 December 2017.

      noted that compliance is paternalistic, passive, and episodic, whereas adherence is collaborative, active, and continuous. Nevertheless, across countries and cross-sectional populations, my belief is that this semantic distinction is unimportant, because I cannot imagine that clinicians use either of these terms when speaking with patients. I have asked whether a patient has skipped or missed any doses. I have followed by asking why this has happened. Sometimes doses are forgotten, other times medications have been left at home, and still other times patients say they thought they were taking too much or were having side effects. I really doubt that any clinician-reader has said: “Have you been nonadherent since I last saw you?” Or, “one reason you are feeling worse is because you were nonadherent.”
      The most frequent problems with nonadherence are seen in patients with chronic illness (eg, hypertension, diabetes). One report suggests that 133 million patients in the United States have chronic conditions and that an estimated 50% who take medications do not take them as directed by their clinicians.

      Network for Excellence in Health Innovation. Medication adherence tools Class III. https://www.nehi.net/search?q=adherence. Accessed 15 December 2017.

      Other sobering estimates are that close to 2 billion instances of nonadherence occur yearly; that somewhere between 30% and 65% of all hospitalizations are attributable to nonadherence; that elderly patients, patients with low incomes, and patients labeled as minorities are particularly susceptible to nonadherence.

      Network for Excellence in Health Innovation. Medication adherence tools Class III. https://www.nehi.net/search?q=adherence. Accessed 15 December 2017.

      Furthermore, it is estimated that nonadherence costs ~$290 billion (USD) annually, largely because of avoidable usage of emergency departments, clinician office visits, and hospitalizations.
      • Cutler D.M.
      • Everett W.
      Thinking outside the pillbox — medication adherence as a priority for health care reform.
      Of note, this figure considers only medication adherence; it does not consider the economic burden of nonadherence to prescribed diet and exercise regimens, such as those discussed in this month’s Specialty Update on Exercise in Neurological Disorders.
      • Allendorfer J.B.
      • Bamman M.M.
      Getting the brain into shape: exercise in neurological disorders.
      • Amara A.W.
      • Memon A.A.
      Effects of exercise on non-motor symptoms in Parkinson's disease.
      • Motl R.
      • Sandroff B.
      Exercise as a countermeasure to declining central nervous system function in multiple sclerosis.
      • Allendorfer J.B.
      • Arida R.M.
      Role of physical activity and exercise in alleviating cognitive impairment in people with epilepsy.
      • Harnish S.
      • Rodriguez A.D.
      • Blackett D.S.
      • et al.
      Aerobic exercise as an adjuvant to aphasia therapy: theory, preliminary findings, and future directions.
      Nonadherence can complicate other conditions that are both chronic and episodic. It is generally better to treat these conditions by using preventive strategies. Examples include migraine headaches and certain seizure disorders. Given the debilitating effects of migraine headaches, some may feel surprised that migraineurs do not always take their preventive treatments. In a study of 8688 patients who met full criteria for chronic migraine, 71% to 74% of patients were nonadherent, depending on the criteria used to define nonadherence; at 12 months, the nonadherence rate ranged from 80% to 83%. This smaller cohort was chosen from a pool of 75,870 patients found in a large medical claims database.
      • Hepp Z.
      • Dodick D.W.
      • Varon S.F.
      • et al.
      Adherence to oral migraine-preventive medications among patients with chronic migraine.
      Here is another example. In a cross-sectional study of 450 patients with documented seizure disorders who were randomly selected from a larger pool of patients, nonadherence with antiepileptic agents was reported to be ~38%.
      • Getnet A.
      • Woldeyohannes S.M.
      • Bekana L.
      • et al.
      Antiepileptic drug nonadherence and its predictors among people with epilepsy.
      Factors considered to contribute to nonadherence included taking medication for >6 months, having to pay for medications, lack of information about their medications, inadequate support systems, stigma, and bothersome side effects. Among the methods used to assess adherence are pill counts and spot checks for blood or urine levels; each of these has its limitations. Finally, patients who are depressed have compromised adherence not just for their antidepressant medications but also for medications they may be taking for concurrent conditions.
      • Hansen R.A.
      • Dusetzina S.B.
      • Song L.
      • et al.
      Depression affects adherence measurement but not the effectiveness of an adherence intervention in heart failure patients.
      In addition to the reasons for nonadherence noted above, a key contributing factor is dosing regimen. Claxton et al
      • Claxton A.J.
      • Cramer J.
      • Pierce C.
      A systematic review of the association between dose regimens and medication compliance.
      found 76 reports in which adherence was tracked by using electronic monitoring. They defined adherence in two nonoverlapping ways: i) taking the prescribed amount of pills per day = “dose-taking,” and ii) consuming pills at a specified time = “dose-timing.” Dose-taking was correct in 71% of patients. What is most important from their analyses is that adherence worsened as a function of the number of times per day a drug was to be taken. Once-a-day dosing was associated with 79% adherence; results with schedules of twice a day, three times a day, and four times a day were 69%, 65%, and 51%, respectively. Only 14 of these 76 studies reported on dose-timing. The mean dose-timing adherence rate was 59%. To anyone who has taken medications long term, these findings are not at all surprising. A limitation to all electronic monitoring studies is that, although one can learn when and how often dispensing bottles are opened, there is no way of knowing whether the patient has actually swallowed the pill(s). Furthermore, although the size of these devices has diminished with each iteration, costs remain prohibitive.
      A champion of electronic monitoring was the late Dr. John Urquhart. Many consider him to be the father of this field of research. John was a friend of many years, and I had the opportunity to learn from him each year when he lectured on adherence in the postgraduate course on drug development that we, at the Center of the Study of Development at Tufts University, offer. John died at the age of 81, just a month after he taught for us in 2016. John developed the Medication Event Monitoring Systems (MEMS). On the basis of studies using this device, he described six patterns of adherence. For example, there are patients who only skip drugs on weekends; only 17% of patients fit the properly adherent pattern. Interested readers may find this review of electronic monitoring devices useful.
      • Checchi K.D.
      Technological Innovations in Medication Packaging to Improve Patient Adherence: A Systematic Review.
      I first learned about nonadherence during a medical school infectious diseases rotation; optimal responses were likely to occur only when all doses of an antimicrobial agent were taken for a specified duration. Later, in the 1980s, I learned about the importance of directly observed therapy (DOT) as an essential element in the treatment of tuberculosis (TB). Currently, the Centers for Disease Control and Prevention considers DOT to be the best and only way to ensure treatment adherence in patients with tuberculosis (TB).

      Centers for Disease Control and Prevention. TB 101 for Health Care Workers. Lesson 6: Treatment of TB Disease. Directly Observed Therapy. https://www.cdc.gov/tb/webcourses/tb101/page3832.html. Accessed 15 December 2017.

      When DOT is implemented, the patient with TB meets on a specified schedule with a trained health care worker who hands the medication to the patient and watches while the medication is swallowed. There will always be some patients who will pretend to swallow their medications; they are purposely sequestering their medication under their tongues or in their cheek pockets. I have never seen data on how often this occurs for patients with TB; however, I did observe patients addicted to opioids do this with their methadone. The use of liquid formulations or having patients open their mouths may be the only way to ensure adherence with DOT; unfortunately, this can undermine the building of trusting relationships.
      In subsequent years, my interest in nonadherence was reinforced by several research experiences. We examined plasma level of alprazolam in 237 patients with panic disorder who were in the Cross-National Collaborative Panic Disorder Study.
      • Greenblatt D.J.
      • Harmatz J.S.
      • Shader R.I.
      Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder.
      • Ballinger J.C.
      • Burrows G.D.
      • DuPont Jr, R.L.
      • et al.
      Alprazolam in panic disorder and agoraphobia: results from a multicenter trial, I: efficacy in short-term treatment.
      This was a placebo-controlled randomized trial; patients who were randomly assigned to treatment were included only if they had not recently been on a benzodiazepine agent. However, in both screening and baseline plasma samples, 21% of the patients were found to have detectible levels of diazepam and desmethyldiazepam. This rate was found in both the alprazolam and placebo cohorts. Three weeks into the protocol, 6.7% of the alprazolam group still had levels comparable with their baseline values; this was true for 15.5% of the patients on placebo. At eight weeks, the values were 4.1% and 9.2%, respectively. A post hoc analysis that excluded the nonadherent patients did not alter the results; alprazolam was still clinically and statistically superior to placebo.
      We also participated in the National Institutes of Health Hypericum Depression Trial. Hypericum perforatum is commonly known as St. John’s wort. When this agent is ingested, hyperforin readily appears in the plasma. We obtained and studied usable plasma samples from 292 of the 340 patients with major depression who were treated in this randomized, placebo-controlled trial.
      • Vitiello B.
      • Shader R.I.
      • Parker C.B.
      • et al.
      Hyperforin plasma level as a marker of treatment adherence in the National Institutes of Health Hypericum Depression Trial.
      Sertraline served as an active control in this 3-arm study. Hyperforin was detected in 17% of patients in the placebo arm; none was found in the sertraline arm. Importantly, no hyperforin was detected in17% of the patients assigned to the H perforatum arm.
      Because of my interest in adherence, I continue to read about and explore new developments. In November 2017, the Food and Drug Administration (FDA) approved a new oral form of the antipsychotic agent, aripiprazole, whose trade name is Abilify MyCite.

      Food and Drug Administration. FDA approves pill with sensor that digitally tracks if patients have ingested their medication. 13 November 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584933.htm. Accessed 15 December 2017.

      This product’s sponsor is Otsuka Pharmaceuticals, Inc. The company is moving forward with clinical studies of the MyCite formulation; the currently available package insert for MyCite uses data from standard aripiprazole tablets.

      Abilify MyCite [package insert]. Otsuka America Pharmaceutical, Inc. https://www.otsuka-us.com/media/static/ABILIFY-MYCITE-PI.pdf?_ga=2.26204989.163628188.1512762694-1945964039.1512762694. Accessed 15 December 2017.

      Each pill contains a grain of sand sized sensor that emits a biogalvanic signal once it reaches the stomach.

      Abilify MyCite [package insert]. Otsuka America Pharmaceutical, Inc. https://www.otsuka-us.com/media/static/ABILIFY-MYCITE-PI.pdf?_ga=2.26204989.163628188.1512762694-1945964039.1512762694. Accessed 15 December 2017.

      Each sensor’s signal is unique. The signal is then detected by a patch worn on the skin in the area of the distal sternum. When a properly programmed and Bluetooth-enabled smartphone is placed over the patch, a signal is sent to the prescribing clinician’s office. In this way, the treating clinician can be assured that the agent has been ingested. This unique electronic monitoring system was developed by Proteus Digital Health, Inc.

      Proteus Digital Health, Inc. http://www.proteus.com. Accessed 15 December 2017.

      The sensor, which is made of silicon, copper, and magnesium, is called an Ingestion Event Monitor (IEM); the patch is called the Proteus Personal Monitor. Extensively tested, it appears that the only adverse experiences with the system are local skin inflammation and irritation from the patch in 17.7% of patients, according to the sponsor’s FDA filing. The system has also been used by embedding the IEMs in larger capsules that also contain other therapeutic agents or as a co-ingested agent in studies of patients with diabetes or hypertension.

      Naik R, Macey N, West RJ, et al. First use of an ingestible sensor to manage uncontrolled blood pressure in primary practice: The UK Hypertension Registry. J Community Med Health Ed. https://www.omicsonline.org/open-access/first-use-of-an-ingestible-sensor-to-manage-uncontrolled-blood-pressure-inprimary-practice-the-uk-hypertension-registry-2161-0711-1000506.php?aid=86075. Accessed 15 December 2017

      Frias J, Virdi N, Raja P, et al. Effectiveness of digital medicines to improve clinical outcomes in patients with uncontrolled hypertension and type 2 diabetes: Prospective, open-label, cluster-randomized pilot clinical trial. July 11, 2017. J Med Internet Res. 19(7), e246, 2017. https://www.ncbi.nlm.nih.gov/pubmed/28698169. Accessed 15 December 2017

      If the added expense from using this system is not prohibitive, it may turn out to be a valuable aid to identifying nonadherent patients; it may also reveal adherence as a factor in some patients’ lack of responsiveness to treatment.
      My thought is that the Proteus system could also make a great contribution to the Proof of Concept stage (Phase IIA) of drug development and to the dose-determining stage in Phase IIB. Findings will be more reliable if investigators can be assured that all doses have been ingested.

      A New Editorial Team for Pharmacoeconomics, Outcomes, and Health Policy

      Looking back at 2017, we published 27 manuscripts that focused on Pharmacoeconomics, Outcomes, and Health Policy. An equal number of manuscripts did not meet our peer-review standards. Internally, we call this area POHP; it is an area that grows with each new volume. The accepted manuscripts covered POHP topics from 10 different countries. To manage this growing area and to expand coverage of therapeutic medical devices and drug/diagnostic combinations, we have recruited three new Editors from Università Commerciale Luigi Bocconi (UB) in Milano, Italy: Patrizio Armeni, PhD, Giuditta Callea, PhD, and Carlo Federici, MSc. UB is highly regarded internationally, especially for its programs in economics, finance, management, and marketing. I believe our three new colleagues will further strengthen our efforts in POHP and will help Clinical Therapeutics expand its coverage internationally. I also want to thank departing Editors, Sean Candrilli, PhD, and James Eaton, MSc, who are completing their service in POHP.

      Welcome to 2018 and Volume 40!

      “…of peace on earth, and good will to men.…”

      Longfellow HW. Christmas Bells. http://www.potw.org/archive/potw118.html. Accessed 15 December 2017

      Henry Wadsworth Longfellow penned these words in 1863, not too long after his wife died and his eldest son, Charles, was wounded while fighting for the Union in the American Civil War. This was a positive, forgiving, and healing sentiment from a man dealing with painful experiences. It seems likely that Longfellow took this phrase from the Gospel of Luke 2:14, for which a common wording is “…peace on earth, good will toward men.”

      Luke 2:14. King James Version. Bible Hub. http://biblehub.com/luke/2-14.htm. Accessed 15 December 2017

      However, according to one Bible scholar, the actual translation from the Greek is much less all-encompassing: “…on the earth peace among whom He is pleased.”

      Sanidopoulos J. What does “peace on earth, good will toward men” mean? 24 December 2015. Mystagogy Resource Center. http://www.johnsanidopoulos.com/2015/12/what-does-peace-on-earth-good-will.html. Accessed 15 December 2017

      In 2018, we need to strive for the more all-encompassing interpretation; one that does not separate us on the basis of religious beliefs, ethnicity, sexual preference, country of origin, or power-driven tribalism. We at Clinical Therapeutics will continue our efforts to promote sharing and healing through the publication of clinically useful ideas and information; our international readership has no boundaries.

      References

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      2. Network for Excellence in Health Innovation. Medication adherence tools Class III. https://www.nehi.net/search?q=adherence. Accessed 15 December 2017.

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        • Everett W.
        Thinking outside the pillbox — medication adherence as a priority for health care reform.
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        Getting the brain into shape: exercise in neurological disorders.
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        • Memon A.A.
        Effects of exercise on non-motor symptoms in Parkinson's disease.
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        • Sandroff B.
        Exercise as a countermeasure to declining central nervous system function in multiple sclerosis.
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        Role of physical activity and exercise in alleviating cognitive impairment in people with epilepsy.
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        • Rodriguez A.D.
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        Adherence to oral migraine-preventive medications among patients with chronic migraine.
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        Technological Innovations in Medication Packaging to Improve Patient Adherence: A Systematic Review.
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      3. Centers for Disease Control and Prevention. TB 101 for Health Care Workers. Lesson 6: Treatment of TB Disease. Directly Observed Therapy. https://www.cdc.gov/tb/webcourses/tb101/page3832.html. Accessed 15 December 2017.

        • Greenblatt D.J.
        • Harmatz J.S.
        • Shader R.I.
        Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder.
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        • Burrows G.D.
        • DuPont Jr, R.L.
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        Arch Gen Psychiatry. 1988; 45: 413-422
        • Vitiello B.
        • Shader R.I.
        • Parker C.B.
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        Hyperforin plasma level as a marker of treatment adherence in the National Institutes of Health Hypericum Depression Trial.
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      4. Food and Drug Administration. FDA approves pill with sensor that digitally tracks if patients have ingested their medication. 13 November 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584933.htm. Accessed 15 December 2017.

      5. Abilify MyCite [package insert]. Otsuka America Pharmaceutical, Inc. https://www.otsuka-us.com/media/static/ABILIFY-MYCITE-PI.pdf?_ga=2.26204989.163628188.1512762694-1945964039.1512762694. Accessed 15 December 2017.

      6. Proteus Digital Health, Inc. http://www.proteus.com. Accessed 15 December 2017.

      7. Naik R, Macey N, West RJ, et al. First use of an ingestible sensor to manage uncontrolled blood pressure in primary practice: The UK Hypertension Registry. J Community Med Health Ed. https://www.omicsonline.org/open-access/first-use-of-an-ingestible-sensor-to-manage-uncontrolled-blood-pressure-inprimary-practice-the-uk-hypertension-registry-2161-0711-1000506.php?aid=86075. Accessed 15 December 2017

      8. Frias J, Virdi N, Raja P, et al. Effectiveness of digital medicines to improve clinical outcomes in patients with uncontrolled hypertension and type 2 diabetes: Prospective, open-label, cluster-randomized pilot clinical trial. July 11, 2017. J Med Internet Res. 19(7), e246, 2017. https://www.ncbi.nlm.nih.gov/pubmed/28698169. Accessed 15 December 2017

      9. Longfellow HW. Christmas Bells. http://www.potw.org/archive/potw118.html. Accessed 15 December 2017

      10. Luke 2:14. King James Version. Bible Hub. http://biblehub.com/luke/2-14.htm. Accessed 15 December 2017

      11. Sanidopoulos J. What does “peace on earth, good will toward men” mean? 24 December 2015. Mystagogy Resource Center. http://www.johnsanidopoulos.com/2015/12/what-does-peace-on-earth-good-will.html. Accessed 15 December 2017