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

May combine two claims.

Poor medication adherence, lack of patient engagement, and therapeutic inertia are major contributors to patients not reaching their therapeutic targets.

“Poor medication adherence, lack of patient engagement, and therapeutic inertia are major contributors to patients not reaching their therapeutic targets [8-12].”

• cites [8] SabatéEAdherence to Long-Term Therapies: Evidence for Action2003GenevaWorld Health Organizationhttp://apps.who.int/iris/bitstream/10665/42682/1/9241545992.pdfNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [9] sourceNot checked — no full text of the source
• cites [10] sourcePartly supported

  The Background section links failure to reach blood-pressure targets to treatment adherence and clinical inertia. Results > Coding also discusses patients’ lack of enthusiasm and unwillingness to take medication or follow counseling, but says these attitudes were rarely explored as causes of inertia. The paper supports these factors in hypertension care, not the broader assertion that all three are major contributors to unmet therapeutic targets generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [11] Lee, WC, 2006, Manag Care InterfaceNot checked — no full text of the source
• cites [12] Balkrishnan, R, 2003, Clin Ther sourceNot checked — no full text of the source

May combine two claims.

Prior clinical studies suggested this DMO can identify reasons for uncontrolled hypertension and help patients achieve blood pressure control.

“and suggested this DMO can identify reasons for uncontrolled HTN and help patients achieve BP control [16-21].”

• cites [16] Au-Yeung, KY, 2011, Am J Manag CareNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [17] sourcePartly supported

  The Results report that the ingestible-sensor system detected medication ingestions in patients receiving tuberculosis therapy, and the Discussion says it could help identify poor adherence. The study did not investigate uncontrolled hypertension, determine its causes, or measure whether patients achieved blood-pressure control. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [18] sourceCould not verify

  The Study Design and Discussion describe an ingestible sensor used to assess medication adherence in kidney transplant recipients. Our copy does not address uncontrolled hypertension or blood-pressure control; searches for hypertension and blood pressure found no relevant passage. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [19] sourceNot checked — no full text of the source
• cites [20] sourceSupported
• cites [21] sourceSupported

Classified as probably not a substantial claim.

Blood pressure was recorded at each visit as the mean of two or more measurements obtained using the recommended measurement guidelines from the American Heart Association.

“Blood pressure recorded at each visit was the mean of two or more BP measurements obtained using the recommended measurement guidelines from the American Heart Association [22].”

• cites [22] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Hypertension and diabetes mellitus are major risk factors for cardiac diseases, stroke, and kidney diseases.

“Hypertension (HTN) and diabetes mellitus are major risk factors for cardiac diseases, stroke, and kidney diseases [1-5].”

• cites [1] 2011, MMWR Morb Mortal Wkly RepNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [2] sourceNot checked — no full text of the source
• cites [3] sourceNot checked — no full text of the source
• cites [4] sourcePartly supported

  The High Blood Pressure ‘Aftermath’ section reports higher risks of heart disease and stroke with elevated blood pressure, and the ‘Prehypertension’ section reports an association with end-stage renal disease; page numbers were not available in our copy. The retrieved Diabetes Mellitus passages do not establish diabetes as a risk factor for the three disease categories, so the full claim is not supported by the passages found. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [5] sourcePartly supported

  In “Potential Impact of CVD Prevention” (page unavailable), the paper calls hypertension a major risk factor for stroke, coronary heart disease, and heart failure. In “Commentary” (page unavailable), it identifies diabetes mellitus as a risk factor for cardiovascular disease. The cited passages do not establish the claim that both conditions are major risk factors for kidney disease, or that diabetes is a major risk factor for each listed cardiac and stroke outcome. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

The Patient Activation Measure (PAM) is a validated measure of patient activation that includes a person's beliefs, motivation, and actions for self-care.

“Participants also completed the 10-question Patient Activation Measure (PAM), a validated measure of patient activation that includes person’s beliefs, motivation, and actions for self-care at these visits [9,23,24].”

• cites [9] sourceNot checked — no full text of the source
• cites [23] sourcePartly supported

  The Conclusions describe PAM as a valid measure of activation encompassing beliefs, confidence, and action to manage health. However, the Methods report validation of a 22-item PAM, not the 10-question version participants completed; this source does not establish that version’s validity. The indexed passages do not provide page numbers. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [24] sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

A recent study demonstrated benefits of a pharmacist case management intervention to reduce BP using a telemonitoring BP device.

“In contrast, a recent study demonstrated benefits of a pharmacist case management intervention to reduce BP using a telemonitoring BP device [35].”

• cites [35] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Statin adherence, as evidenced by LDL-C reduction, has been associated with improved outcomes in diabetes patients.

“Statin adherence, as evidenced by LDL-C reduction, has also been associated with improved outcomes in diabetes patients [29,32,33].”

• cites [29] Lewington, S, 2002, Lancet sourceNot checked — no full text of the source
• cites [32] Farsaei, S, 2015, J Res Med SciNot checked — no full text of the source
• cites [33] sourcePartly supported

  In §3, “Assumptions and Definitions” (page unavailable), the pathway recommends statin therapy for patients with diabetes and advises monitoring both adherence and LDL-C response. It also discusses cardiovascular risk reduction, but does not report an association between measured statin adherence, LDL-C reduction, and improved outcomes specifically in patients with diabetes. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

In the Bloss et al study, no instructions were given to providers on use of the device data; this has been shown to make blood glucose monitoring less effective in non-insulin-using diabetes patients.

“In that study, no instructions were given to providers on use of the device data; this has been shown to make blood glucose monitoring less effective in non-insulin-using diabetes patients [30,34].”

• cites [30] sourceNot checked — no full text of the source
• cites [34] sourceCould not verify

  The Study enrollment section says HealthComp nurses could view device readings and describes instructions given to participants, but does not say whether providers received instructions on using the data. The Health self-management results report no difference in HbA1c, but do not test whether a lack of provider instructions made glucose monitoring less effective for non-insulin-using patients. Searches for provider instructions and that proposed effect found no decisive passage in our copy; page numbers were not available. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

In the pharmacist case management study, the intervention group had a statistically greater reduction in SBP at 6 months than usual care (mean difference -10.7, 95% CI -14.3 to -7.3 mm Hg).

“The intervention group had a statistically greater reduction in SBP at 6 months than usual care (mean difference –10.7, 95% CI –14.3 to –7.3 mm Hg), similar to the reductions in SBP observed in our pilot study on the DMO, except the pharmacist case management study only addressed hypertension, whereas this DMO study evaluated patients with both uncontrolled HTN and T2DM.”

• cites [35] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

A reduction in HbA1c of 0.5% or more is considered clinically significant to reduce the risk of microvascular complications.

“A reduction in HbA1c of 0.5% or more is considered clinically significant to reduce the risk of microvascular complications [30,31].”

• cites [30] sourceNot checked — no full text of the source
• cites [31] sourcePartly supported

  The Discussion (section 4.1; page unavailable) calls a 0.57% A1C improvement clinically meaningful. It separately reports that a 0.9% decrease was associated with fewer microvascular complications. It does not establish 0.5% or more as a threshold for reducing that risk. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

The inclusion criteria in the Bloss et al study were based on cost versus level of disease control and may have enrolled participants not needing additional interventions.

“Finally, the inclusion criteria were based on cost versus level of disease control and may have enrolled participants not needing additional interventions.”

• cites [34] sourcePartly supported

  The Methods (Study design and Study recruitment; pages not provided) say eligibility was based on a condition-related insurance claim, while recruitment was prioritized by the dollar amount of claims—not by measured disease control. This makes it plausible that some participants did not need additional intervention, but the paper does not establish that they were enrolled. The claim also conflates recruitment priority with inclusion criteria. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

The reductions in SBP observed in this pilot study on the DMO are similar to those in the pharmacist case management study, except the pharmacist study only addressed hypertension whereas this DMO study evaluated patients with both uncontrolled HTN and T2DM.

“similar to the reductions in SBP observed in our pilot study on the DMO, except the pharmacist case management study only addressed hypertension, whereas this DMO study evaluated patients with both uncontrolled HTN and T2DM.”

• cites [35] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

The final modified-ITT group included 109 participants (40 in 4-week DMO, 40 in 12-week DMO, and 29 in usual care).

“The final modified-ITT group included 109 participants (40 in 4-week DMO, 40 in 12-week DMO, and 29 in usual care) (Figure 2).”

May combine two claims.

Mean ingestion adherence was 86% during the first 4 weeks (combined DMO) and 84% for the entire 12 weeks (12-week DMO).

“The mean ingestion adherence was 86% during the first 4 weeks (combined DMO) and 84% for the entire 12 weeks (12-week DMO) (see Figure 4).”

May combine two claims.

DMO participants had a greater reduction in diastolic blood pressure than usual care participants, but the difference was not statistically significant.

“DMO participants also had a greater reduction in DBP compared with usual care, but the results were not significant.”

May combine two claims.

The 4-week DMO group had greater reductions in systolic and diastolic blood pressure at week 12 than usual care, but the differences were not statistically significant.

“The 4-week DMO group also had greater reductions in SBP and DBP at week 12 than usual care, but the results were not statistically significantly different”

May combine two claims. The quote only partly states this claim.

At week 4, DMO participants with uncontrolled BP who were medication adherent (≥80%) appeared to be 4 times more likely than usual care participants to receive an antihypertensive titration, but the difference was not statistically significant.

“At week 4, DMO participants with uncontrolled BP, who were medication adherent (≥80%), appeared to be 4 times more likely than usual care participants to receive an antihypertensive titration.”

• Also stated in: § Secondary Outcomes · hedged

  “this finding should be interpreted with caution because the actual number of medication changes that occurred was small and the difference was not statistically significant.”

May combine two claims.

At week 12, the combined DMO groups had a greater reduction in systolic blood pressure than usual care, but the difference was not statistically significant (mean change -20.9 vs -15.2 mm Hg; mean difference -4.6, 95% CI -14.3 to 5.1 mm Hg).

“Week 12, mean change (SE) | –15.2 (2.0) | –20.9 (3.4) | –4.6 (4.9); (–14.3, 5.1)”

May combine two claims.

Most participants agreed the DMO was easy to learn (92%, 69/75) and to incorporate in their daily routine (91%, 68/75).

“In general, participants agreed the DMO was easy to learn (92%, 69/75) and to incorporate in their daily routine (91%, 68/75)”

May combine two claims.

DMO participants had a nonsignificantly greater increase in PAM score compared with usual care; changes were mean 7.9 (SE 3.8) for 4-week DMO, mean 7.9 (SE 3.0) for 12-week DMO, and mean 1.7 (SE 3.3) for usual care at week 12.

“The DMO participants had a nonsignificantly greater increase in PAM score compared with usual care; the changes were mean 7.9 (SE 3.8) for 4-week DMO, mean 7.9 (SE 3.0) for 12-week DMO, and mean 1.7 (SE 3.3) for usual care at week 12 (see Table 6).”

May combine two claims.

Most participants agreed using the DMO data was useful to manage (91%, 68/75) and improved their health (93%, 70/75).

“and that using the data was useful to manage (91%, 68/75) and improved their health (93%, 70/75)”

May combine two claims.

12 participants reported study medication-related AEs (14 events total) with gastrointestinal AEs (9 events in 8 participants; 7 mild, 2 moderate, 1 moderate event led to study withdrawal, 10%) being the most common.

“Additionally, 12 participants reported study medication-related AEs (14 events total) with gastrointestinal AEs (9 events in 8 participants; 7 mild, 2 moderate, 1 moderate event led to study withdrawal, 10%) being the most common.”

May combine two claims.

Participants using the DMO showed lower trends in HbA1c (as much as a 1% greater reduction) and LDL-C (33 mg/dL greater reduction) compared to usual care.

“Participants using the DMO also showed lower trends in HbA1c (as much as a 1% greater reduction), and LDL-C (33 mg/dL greater reduction) compared to participants who received usual clinical care.”

May combine two claims.

Participants with uncontrolled HTN and T2DM who used the DMO had significantly greater reductions in SBP within 4 weeks than usual care (9 mm Hg greater reduction), which was maintained at 12 weeks with a significantly greater proportion achieving BP goal.

“In this study, participants with uncontrolled HTN and T2DM who used the DMO had significantly greater reductions in SBP within 4 weeks than the usual care group (9 mm Hg greater reduction), which was maintained at 12 weeks with a significantly greater proportion of patients achieving their BP goal.”

May combine two claims.

32 of 82 DMO participants (39%) reported 59 adverse events, of which 33 were unrelated to DMO; 8 of 36 usual care participants (22%) reported 17 AEs.

“There were 32 of 82 DMO participants (39%) who reported 59 adverse events (AEs), of which 33 were unrelated to the DMO; 8 of 36 usual care participants (22%) reported 17 AEs.”

May combine two claims.

In participants with baseline LDL-C ≥70 mg/dL, the mean change in LDL-C was -37.2 mg/dL at week 4 and -30.1 mg/dL at week 12 for DMO, and -4.0 mg/dL at week 4 and -10.9 mg/dL at week 12 for usual care.

“In participants with baseline LDL-C of 70 mg/dL or higher (n=54; 4-week DMO: n=6, 12-week DMO: n=28, usual care group: n=20), changes in LDL-C were mean –37.2 (SE 7.9) mg/dL at week 4 and mean –30.1 (SE 8.0) mg/dL at week 12 for DMO and mean –4.0 (4.3) mg/dL at week 4 and mean –10.9 (SE 5.9) mg/dL at week 12 for usual care.”

May combine two claims.

The differences in change in LDL-C between DMO and usual care were -33.2 (95% CI -50.6 to -15.8) at week 4 and -19.2 (95% CI -36.4 to -2.0) at week 12, and these differences were statistically significant.

“The differences in change in LDL-C between DMO and the usual care group were –33.2 (95% CI –50.6 to –15.8) at week 4 and –19.2 (95% CI –36.4 to –2.0) at week 12. These differences were statistically significant (see Table 5 for complete results).”

May combine two claims.

There were 14 device-related AEs in 11 participants, most commonly mild skin reactions to the wearable sensor (13 events in 10 participants, 12%).

“There were 14 device-related AEs in 11 participants, most commonly mild skin reactions to the wearable sensor (13 events in 10 participants, 12%).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Most participants (81%, 61/75) did not mind wearing the patch.

“Most (81%, 61/75) did not mind wearing the patch (see Table 7).”

Classified as probably not a substantial claim.

Differences between groups were calculated using a mixed-effects regression model that incorporated covariates found to be significant in the model: baseline value, gender, age (<65 vs ≥65 years), and race (African American vs other).

“Differences between groups were calculated using a mixed-effects regression model that incorporated covariates found to be significant in the model: baseline value, gender, age (<65 years vs ≥65 years), and race (African American vs other).”

Probably not a substantial claim: may not pass S3 (load-bearing).

One usual care site with five participants was not included in the final analysis over concern about violation of the cluster randomization.

“One usual care site with five participants was not included in the final analysis over concern about violation of the cluster randomization.”

May combine two claims.

A sensitivity analysis showed that excluding the one usual care site did not impact the primary outcome; the change in SBP for usual care with the excluded site was mean -14.0 (SE 2.7; difference from combined DMO: -7.8, SE 2.8, 95% CI -13.3 to -2.3 mm Hg).

“A sensitivity analysis showed that excluding the one usual care site did not impact the primary outcome; the change in SBP for usual care with the excluded site was mean –14.0 (SE 2.7; difference from combined DMO: –7.8, SE 2.8, 95% CI –13.3 to –2.3 mm Hg).”

Classified as probably not a substantial claim. May combine two claims.

The standard error was adjusted for cluster (study site) effects as well as the intracluster correlation coefficient (ICC) calculated using a one-way analysis of variance to adjust for any imbalances between and within clusters.

“The SE was adjusted for cluster (study site) effects as well as the intracluster correlation coefficient (ICC) calculated using a one-way analysis of variance to adjust for any imbalances between and within clusters.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Medication nonadherence alone costs US $290 billion annually in the United States and is difficult to assess and improve.

“Medication nonadherence alone costs US $290 billion annually in the United States and is difficult to assess and improve [13,14].”

• cites [13] New England Healthcare InstituteThinking Outside the Pillbox: A System-Wide Approach to Improving Patient Medication Adherence for Chronic Disease200908http://www.nehi.net/writable/publication_files/file/pa_issue_brief_final.pdfNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [14] sourceNot checked — no full text of the source

May combine two claims.

For patients failing hypertension and diabetes oral therapy, this DMO, which provides dose-by-dose feedback on medication ingestion adherence, can help lower blood pressure, HbA1c, and LDL-C, and promote patient engagement and provider decision making.

“For patients failing hypertension and diabetes oral therapy, this DMO, which provides dose-by-dose feedback on medication ingestion adherence, can help lower BP, HbA1c, and LDL-C, and promote patient engagement and provider decision making.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Target enrollment in this pilot study was 120 participants to ensure at least 90 evaluable participants at the end of the study.

“Target enrollment in this pilot study was 120 participants to ensure at least 90 evaluable participants at the end of the study.”

Classified as probably not a substantial claim.

Participants with at least one follow-up blood pressure were included in this modified intention-to-treat analysis, which represented the minimal data needed for a pre/post comparison for each participant.

“Participants with at least one follow-up BP were included in this modified intention-to-treat (ITT) analysis, which represented the minimal data needed for a pre/post comparison for each participant.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Missing data were handled using last observation carried forward.

“Missing data were handled using last observation carried forward.”

Classified as probably not a substantial claim.

A comparison of adherence to treatment was not included among the goals of this study.

“A comparison of adherence to treatment was not included among the goals of this study.”

May combine two claims.

No objective assessment of adherence to treatment was attempted in the usual care arm because there are only indirect methods of measuring adherence as an alternative to DMO and none of these methods have been established to be inherently reliable or accurate.

“No objective assessment of adherence to treatment was attempted in the usual care arm because there are only indirect methods of measuring adherence as an alternative to DMO and none of these methods have been established to be inherently reliable or accurate.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Each 2 mm Hg reduction in SBP or 1 mm Hg reduction in DBP has been associated with lowering mortality from stroke and ischemic heart disease by 10% and 7%, respectively.

“Each 2 mm Hg reduction in SBP or 1 mm Hg reduction in DBP has been associated with lowering mortality from stroke and ischemic heart disease by 10% and 7%, respectively [29].”

• cites [29] Lewington, S, 2002, Lancet sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ambulatory BP monitoring was not used; therefore, BP fluctuations may be potentially related to the context of in-clinic measurement.

“In order to demonstrate use of the DMO in the real-world primary care clinic workflow, ambulatory BP monitoring was not used; therefore, BP fluctuations may be potentially related to the context of in-clinic measurement (outside of the participant’s natural context).”

May combine two claims.

This study had a small sample size and included only 13 sites, which likely contributed to discrepancies noted in participant demographic and baseline characteristics.

“This study had a small sample size and included only 13 sites, which likely contributed to discrepancies noted in participant demographic and baseline characteristics.”

Probably not a substantial claim: may not pass S4 (based).

The results should be generalizable given the diversity of the study population.

“The results should be generalizable given the diversity of the study population.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A 1-point increase in PAM score is associated with a 1.8% increased likelihood of decreasing HbA1c to less than 8%.

“a 1-point increase in PAM score is associated with a 1.8% increased likelihood of decreasing HbA1c to less than 8% [9].”

• cites [9] sourceNot checked — no full text of the source