The impact of new technology on medication adherence: finally breaking the nonadherence barrier?

by M. Burnier, Switzerland

Jana BRGULJAN, MD, PhD, FESC
Secretary of the ESC Council
on Hypertension
President of the Slovenian
Hypertension Society
Medical Director
Division of Hypertension
Dpt. of Internal Medicine
Dr Peter Držaj Hospital
University Medical Centre Ljubljana
Ljubljana, SLOVENIA

In the treatment of hypertension, good medication adherence is crucial to achieve optimal blood pressure control and reduce the risk of cardiovascular events and the costs related to antihypertensive treatment. Medication adherence is a complex issue that goes beyond pill consumption and is actually a reflection of a patient’s overall behavior toward his/her health. However, adherence is not exclusively the responsibility of the patient as it is an interplay between the various components of the treatment process: patients, doctors, pharmacists, and health care systems. The use of modern technology to improve adherence is an interesting and promising concept, especially as technological interventions can be implemented at all stages of the treatment process. Technical solutions include the use of mobile phones and the internet to communicate with patients and share information, medication event monitoring systems, text messaging, home telemonitoring, mobile devices, electronic health records, electronic blisters, ingestible biosensors, long-acting medications, and fixed-dose combinations. While technological interventions have the potential to improve adherence, their use calls for an evolution of the physician’s role in advocating for and educating patients. Ultimately, nothing can replace the relationship between doctor and patient, which should be at the center of any effort to improve adherence using technological interventions.

Medication adherence is not a simple process. It is an interplay between patients, their habits, their awareness of their illness, their doctor’s awareness and medical knowledge; the health care system, and finally, medications themselves. Medications are usually prescribed to recover homeostasis. History taking and clinical examination are fundamental processes that influence treatment decisions and medication prescription.

Blood pressure control and adherence

The sphygmomanometer is a very useful tool that was first introduced into clinical practice some 120 years ago, followed decades later by the concept of high blood pressure as a disease.1 It took several more decades before antihypertensive medications became available, and today there are several classes of blood pressure– lowering drugs. Yet, despite having the basic tools to diagnose and treat hypertension at our disposal for over half a century, high blood pressure remains one of the leading contributors to morbidity and mortality worldwide. Many people with hypertension do not have their blood pressure adequately controlled. This is partly due to the fact that hypertension is undiagnosed in many patients, but also because only about a third of those diagnosed are adequately controlled.2

So why do we find ourselves in this situation when so many new technological developments are currently available? Nonadherence in chronic diseases has been an issue for several years, but it is not getting better according to the latest available data.3 Adherence is key to therapeutic success; however, it is a multifaceted issue. Medication adherence goes beyond pill consumption and is a reflection of a patient’s overall healthy behavior.4 Since adherence is an interplay of different factors within the treatment process, we need to define what would be the ideal situation in this process and then implement new technology. This article will thus describe how new technology can be applied to the “treatment circle” (ie, patients, doctors, nurses or technicians, pharmacists, and the healthcare system) to improve adherence.

Patients

The patient is the main component in the treatment process. From the doctor’s perspective, the perfect patient is a patient who is very well informed about his/her chronic illness and follows the doctor’s recommendations. Hypertensive patients should understand that hypertension is an illness which is really harmful to the whole body and that its consequences can be dramatic. They should realize that blood pressure readings are not just numbers and that hypertension is a silent killer. More generally, patients should be aware that regular blood pressure measurements are the perfect way do diagnose hypertension, and that a high percentage of people with prehypertension actually have masked hypertension and should be treated immediately.5

If we consider the patient’s perspective, it is important to note that patients are sometimes afraid of their illness and do not want to think about it and, as a result, are reluctant to get their blood pressure measured. In addition, some patients lead such busy lives that they forget to look after themselves. Therefore, new technologies can become useful tools to share information about this silent problem and help diagnose it. As doctors, we should understand how the different generations use new technologies. The younger generation is proficient in the use of computers and mobile phones and, therefore, it is feasible to share information with them using sources like Facebook, YouTube, Twitter, with the caveats that this information should be prepared by health care specialists, so it could not be used for commercial proposes. The older generations are not as comfortable with these electronic devices, but are usually able to use them to a lesser extent.

Use of mobile phones
Many people now use mobile phones. In addition to being very useful tools for communication, mobile phones can also be used for educational purposes, but are more useful in monitoring a patient’s blood pressure and its response to antihypertensive treatment. A Korean study evaluated the benefits of mobile phones in helping patients to monitor their blood pressure and bodyweight using a weekly web-based diary along with remote support. Participants were recruited from the family medicine outpatient department of a tertiary care hospital located in an urban city of South Korea. Twenty eight patients were assigned to an intervention group and 21 to a control group. The intervention’s goal was to bring blood pressure, body weight, and serum lipid levels close to normal ranges. Patients in the intervention group were requested to record their blood pressure and body weight in a weekly web based diary or by using their mobile phones. The researchers sent weekly recommendations to each patient by SMS and Internet. The intervention took place over 8 weeks. After 8 weeks, the systolic and diastolic blood pressure in the intervention group decreased significantly from the baseline by 9.1 mm Hg and 7.2 mm Hg, respectively (P<0.05); in contrast, there was no significant change in the control group.6

In a pragmatic, single-blind, 3-arm, randomized trial (SMSText Adherence Support [StAR]) undertaken in South Africa, patients treated for high blood pressure were randomly allocated in a 1:1:1 ratio to information-only SMS text messaging, interactive SMS text messaging, or usual care. The number of patients included was 457:458:457. A slight reduction in systolic blood pressure was found for the patients getting text messages compared with usual care at 12 months. There was no evidence that an interactive intervention increased this effect.7

In their study, Kiselev and colleagues included 97 hypertensive patients under active ambulatory care management— including SMS and mobile phone technology—and 102 patients under traditional ambulatory care management. The blood pressure, body mass, and smoking history of patients were analyzed in the study, which lasted 1 year. In the active ambulatory care management group, 36% of patients were withdrawn from the study. At the end of the study, 77% of patients from the active care management group had achieved the blood pressure level goal, which was over 5 times more than in the traditional ambulatory care management group (P<0.001). The risk ratio of achieving and maintaining the goal blood pressure in the active care management group was 5.44, (CI, 3.2-9.9; P=0.005). It was concluded that active ambulatory care management supported by SMS and mobile phone technology improves the quality of ambulatory care for hypertensive patients.8

Today, innovative digital technologies have the potential to redefine blood pressure management, eliminating not only the cuff, but also the century-old approach that necessitates monitoring, decision-making, education, and treatment to be tied to a visit to the doctor. A wide variety of devices ranging from handheld devices, to wristbands and weighing scales are currently being developed to simplify and improve blood pressure measurement. These emerging technologies use techniques such as photoplethysmography (the optical sensing of changes in light absorption with each heartbeat, as in pulse oximetry) or radar to measure blood pressure. Probably the greatest advancement these non-cuff sensing technologies will bring is in enabling the development of wearable sensors for continuous and noninvasive measurement of blood pressure, but they still need to be tested in real practice.

Medication Event Monitoring Systems (MEMS)
A medication event monitoring system (MEMS) consists of a conventional medicine container fitted with a special closure that records the time and date each time the container is opened and closed. It is generally acknowledged that electronic monitoring of adherence to treatment improves blood pressure control by increasing patients’ awareness of their treatment; however, the effect is questionable in the long term. In their observational study of 470 patients with mild to- moderate hypertension, van Onzenoort et al measured adherence in 228 patients by means of both a MEMS and pill count (intervention group), and in 242 patients by means of pill count alone (control group). During a follow-up period of 1 year consisting of seven visits to the physician’s office, blood pressure measurements were performed and medication was adjusted based on the blood pressure achieved. In addition, adherence to treatment was assessed at each visit.

Based on pill counts, median adherence to treatment did not differ between the intervention group and the control group (96.1% vs 94.2%; P=0.97). In both groups, systolic and diastolic blood pressure decreased similarly: 23/13 mm Hg vs 22/12 mm Hg in the intervention and control group, respectively. In this study, the use of a MEMS did not lead to better long-term blood pressure control, nor did it result in fewer drug changes and the use of fewer drugs. Recently, it was shown that patients are more inclined to take their drugs as prescribed when they are faced with an upcoming consultation. This phenomenon—known as white coat compliance— emphasizes the importance of clinical visits for patients with hypertension. So, in the study of van Onzenoort et al, the absence of an effect on blood pressure control of the MEMS intervention and the high adherence may be explained by the frequent visits that the patients participating in the study had to attend.9

Health care system organization

The use of mobile computing and communication technologies in health care and public health—known as mobile health—is a rapidly expanding area of e-health. The potential of mobile-health interventions to have beneficial effects on health care and health care service delivery processes is huge, especially in resource-poor settings. Understandably, there is considerable enthusiasm for these interventions.

Text messaging
Missed appointments are one of the important problems in daily practice. The effectiveness of mobile health technology in improving health care service delivery processes was assessed in a systematic review and meta-analysis. The pooled effect on appointment attendance using text message (SMS) reminders versus no reminder was increased, with a relative risk (RR) of 1.06 (95% confidence interval [CI], 1.05-1.07; I2= 6%). The pooled effect on the number of cancelled appointments was not significantly increased (RR, 1.08; 95% CI, 0.89-1.30). There was no difference in attendance using SMS reminders versus other reminders (RR, 0.98; 95% CI, 0.94- 1.02, respectively).10

Home telemonitoring
Home telemonitoring of blood pressure has been proven to be effective in regulating blood pressure. Using this technique would be useful in the future even though, as shown in 401 primary care patients aged 29-95 years with uncontrolled daytime ambulatory blood pressure (≥135/85 mm Hg, but <210/135 mm Hg), it costs significantly more than usual care (mean difference per patient £115.32 (95% CI, 83.49-146.63; P<0.001). Increased costs were due to telemonitoring service costs, patient training, and additional general practitioner and nurse consultations. The mean cost of systolic blood pressure reduction was £25.56/mm Hg per patient (95% CI, 16.06-46.89). Over the 6-month trial period, supported telemonitoring was more effective at reducing blood pressure than usual care, but also more expensive. If clinical gains were maintained, these additional costs would be very likely to be compensated for by reductions in the cost of future cardiovascular events. Longer-term modeling of costs and outcomes is required to fully examine the cost-effectiveness implications.11

Use of mobile devices
Topol and Steibuhel have done a lot of investigations and work on the development of electronic possibilities to follow patients remotely to achieve better health outcomes, improve communication, and decrease hospital admissions. They conducted a prospective randomized controlled trial of adults who had submitted a 2012 health insurance claim associated with hypertension, diabetes, and/or cardiac arrhythmia. The intervention involved receipt of one or more mobile devices that corresponded to their condition(s) (hypertension, Withings Blood Pressure Monitor; diabetes, Sanofi iBGStar Blood Glucose Meter; arrhythmia, AliveCor Mobile ECG) and an iPhone with linked tracking applications for a period of 6 months. The control group received a standard disease management program. In addition, participants in the intervention group received access to an online health management system that provided them with detailed device tracking information over the course of the study. They also examined health self-management. Surprisingly, there was little evidence of differences in health care costs or utilization as a result of the intervention. They even found evidence that the control and intervention groups were equivalent with respect to most health care utilization outcomes. This result suggests there are no large short-term increases or decreases in health care costs or utilization associated with monitoring chronic health conditions using mobile health or digital medicine technologies. Among the secondary outcomes there was some evidence of improvement in health self-management, which was characterized by a decrease in the propensity to view health status as due to chance in the intervention group.12

Electronic health records
Establishing electronic health records is another option that offers better treatment control and adherence and also gives useful information for further treatment. In their recent study, Ravindrarajah et al examined the primary care electronic health records from 2001 to 2014 of 265 225 participants aged 80 years and over from the UK Clinical Practice Research Datalink, and found that, in octogenarians, blood pressure treatment had intensified, and that blood pressure values had declined, with a substantial increase in the proportion of patients achieving conventional blood pressure targets.13 However, we need to be very careful regarding data protection, because distrust in the use of personal information may render patients reluctant to visit their doctor.

Doctors

Doctors are at the center of the medical team, and as such, keep the “treatment circle” going. It is important that doctors are highly educated and keep themselves up-to-date with all the possible treatments, as they are developing really fast. First of all, doctors need to be absolutely positive about the treatments and procedures they recommend to their patients. Due to lack of time and financial support, attending congresses is not always possible. However, thanks to new technology, doctors can now benefit from e-learning and can “attend” webinars. There is a wide range of continuing medical education courses available, but due to lack of time, doctors often do not make the most of what’s on offer. In any case, even though we can read about all the biggest medical achievements on the internet, nothing can replace personal communication and the sharing of personal clinical experience.

Medications

Electronic blister packs
Electronic medication blisters were tested in a randomized single- blinded (doctor-blinded), controlled, single-center study with a crossover design performed on 53 patients with increased cardiovascular risk—defined as the presence of at least two out of three health risks such as type 2 diabetes, hypertension or hypercholesterolemia. To objectively track the dosage and timing of medication intake, electronic medication blister packs (OtCM, DSM TCG B.V., Mauritslaan, the Netherlands) were used as add-ons to standard medication blister packs. Labels with printed circuitry were applied to the aluminum foil cover of the blister (bottom side) and were linked to a small printed circuit board (positioned on the blister’s upper side). Taking out a pill broke the conductive track inside the label directly underneath that pill. This event was recognized and led to the storage of the corresponding data (position and time) in the microcontroller’s internal memory. These data could be interrogated wirelessly by a near-field communication (NFC)–enabled reader device (Figure 1). Although a statistically significant difference (P=0.04) between the monitoring and control phase was observed for the diabetes medication only, the results indicate that mHealthbased adherence management is feasible and well accepted by patients with increased cardiovascular risk. It may help to increase adherence, even in patients with high baseline adherence and, subsequently, lead to improved control of indicators, including blood pressure and cholesterol concentrations.14

Figure 1. Electronic blister packaging: gesture of touching the
blister pack with a mobile phone to read out data.
From reference 14: Brath et al. Br J Clin Pharmacol. 2013;76(Suppl 1):47-55.
© 2013, John Wiley & Sons, Inc.

Ingestible biosensor systems
Another medication-based approach to assess drug adherence is the use of ingestible biosensor systems, such as radio- frequency identification (RFID)-tagged gelatin capsules. Once the capsule dissolves in the stomach, the RFID tag activates to transmit a unique signal to a relay device, which transmits a time-stamped message to a cloud-based server that functions as a direct measure of medication adherence.15

Fixed-dose combinations
To date, the most important achievements in medication based technologies are fixed-dose combinations and longacting medications. The use of single-pill combinations of two antihypertensive agents is associated with substantially better adherence than the same two drugs given separately.16 In addition, single-pill combinations are much more effective at lowering blood pressure.17 We are still waiting for long-lasting medications (ie, 1 month or more) for the treatment of hypertension.

Where are we today?

The ACCOMPLISH trial (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension) achieved the best blood pressure control ever attained in a large outcome trial in hypertension, with more than 80% of the 11 440 patients getting to their blood pressure target. Various motivation items routinely used in outcome trials, including clearly marked pill boxes and blister packages, may have contributed to better adherence and blood pressure control in white patients18 or in African-American patients as shown in the meta-analysis of Ruppar et al.19 Efforts to improve adherence to antihypertensive medications is extremely important and may involve multiple methods.20-22

Therapeutic drug monitoring is an evolving and useful tool for detecting and reducing nonadherence, and leads to effective blood pressure control. Therapeutic drug monitoring is a cost-effective health care intervention in patients diagnosed with apparent treatment-resistant hypertension, and this finding is valid for a wide range of patients, independent of sex and age. In general, therapeutic drug monitoring enables objective surveillance of patient adherence by repeatedly measuring concentrations of antihypertensive drugs in blood and urine. Moreover, a retrospective study looking at the impact of therapeutic drug monitoring on adherence found that when nonadherent patients were confronted with low or undetectable drug levels and were given additional counseling to overcome barriers to adherence, blood pressure control improved considerably without intensification of drug therapy.23 During the follow-up, systolic blood pressure was reduced by 46± 10 mm Hg in nonadherent patients, and only by 12±17 mm Hg in adherent patients, without intensification of the antihypertensive therapy. An essential benefit of therapeutic drug monitoring is that it identifies the source of the problem and may lead to its resolution, ie, getting patients to take the drugs they were prescribed.24

Influence of medication nonadherence on patient prognosis

As far as target organ damage is concerned, nonadherence to medications is associated with a high risk of cardiovascular events in the general hypertensive population. In a survey of 18 806 newly diagnosed hypertensive patients in whom drug adherence was assessed using data from a medical database, it was shown that high drug adherence was associated with a long-term reduction in acute cardiovascular events (hazard ratio: 0.62; 95% CI 0.40-0.96; P=0.032, vs low drug adherence).25

In other retrospective studies that used the same methodology to assess adherence, it was also shown that compared with patients with low drug adherence (medication possession ratio [MPR] <80%), patients with high drug adherence (MPR>80%) showed a relative risk (RR) reduction of 11% in chronic heart failure (RR, 0.89; 95% CI, 0.80-0.99), 10% in coronary events (RR, 0.90; 95% CI, 0.84-0.95), and 22% in cerebrovascular events (RR, 0.78; 95% CI, 0.70-0.87).26-28

Interestingly, a recent meta-analysis of 44 individual studies, involving nearly 2 million participants, showed that high adherence to antihypertensive treatment was associated with a 29% RR reduction in all-cause mortality (RR, 0.71; 95% CI, 0.64-0.78).29 Taken together, these results indicate that nonadherence is an important factor that leads to drastically worse clinical outcomes in hypertension.

Practical conclusion

Good medication adherence is crucial to achieve optimal blood pressure control and reduce the risk of cardiovascular events and the costs related to antihypertensive treatment. Doctors worry about target organ damage and end point events of untreated hypertension, whereas patients only worry about the possible drug side effects that they may experience in the short term.30

Doctors need to be convinced that they are prescribing the right treatment, should be up-to-date with the latest medical achievements, have enough time to talk to their patients, and be interested in getting their patients to the blood pressure goal. Patients need to be aware of the harmful impact of elevated blood pressure and have a trustful connection with their doctor. They also need to be able to contact their doctor as soon as they have any doubt about their treatment or feel that they are experiencing side effects, so that they have an opportunity to discuss the problem rather than stopping the treatment of their own accord.

Health care systems need to be organized in a way that offers a close relationship between doctors and patients, and also between family physicians and hypertension specialists so they can join their forces in the battle against the silent killer that is hypertension. The way health care systems are organized is heavily dependent on government policies, so politicians should consult with health care professionals and listen to their professional advice before making decisions.

New technologies
New technology is useful and in permanent development. It is clear from both consumer-level pricing and marketing that many wearable medical devices are being marketed directly to patients themselves. Whether this technology can really empower patients or is simply another market for medical device manufacturers remains to be seen. However, it is undeniable that the growth of technology calls for an evolution of the physician’s role in advocating for and educating patients. In such a fast-moving field it is more important than ever for physicians to stay up-to-date with what devices manufacturers are offering—not only to advise patients on what works, how to access it, and how to get the best out of it, but also to evaluate the effectiveness and cost-efficiency of these devices, to push device companies to deliver the best possible product, and to ensure that government regulations protect patients as consumers.31

Figure 2. The smart home.
From reference 32: Muse et al. Lancet. 2017;389(10067):358. © 2017, Elsevier Ltd.

Waking up in a smart house (Figure 2),32 where all the sensors in the house would, each morning, detect our temperature, blood pressure, heart rate, analyze our urine and feces, and analyze our mood when we look in the mirror could be nice as we would get all the possible medical analyses performed every morning. But is this really how we want to live?

The patient-doctor relationship
Although self-blood pressure measurement as an adjunct to office blood pressure measurement was shown to lead to somewhat better adherence to treatment in the study of van Onzenoort et al, the difference was only small and not clinically significant. The time relative to a visit to the doctor actually seemed to be a more important predictor of adherence.9

In her book What Patients Say, What Doctors Hear, in which she analyzes the complexities and miscues of the patient– doctor exchange, Danielle Ofri argues that “For all the sophisticated diagnostic tools of modern medicine, the conversation between doctor and patient remains the primary diagnostic tool.”33,34 Only based on this conversation and personal contact can we apply new technology to improve adherence to medication.

As Hippocrates said “it is far more important to know what person the disease has than what disease the person has.”

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