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Device-Guided Breathing as Treatment for Hypertensionin Type 2 DiabetesMellitusA Randomized, Double-blind, Sham-Controlled TrialGijs W. D. Landman, MD, PhD; Iefke Drion, MD; Kornelis J. J. van Hateren, MD, PhD; Peter R. van Dijk, MD;Susan J. J. Logtenberg, MD, PhD; Jan Lambert, MD, PhD; Klaas H. Groenier, PhD; Henk J. G. Bilo, MD, PhD, FRCP;Nanne Kleefstra, MD, PhD

IMPORTANCE Biofeedback with device-guided lowering of breathing frequency could be analternate nonpharmacologic treatment option for hypertension. Evidence from trials withhighmethodologic quality is lacking.

OBJECTIVE To evaluate the effects of device-guided lowering of breathing frequency onblood pressure in patients with type 2 diabetes mellitus and hypertension.

DESIGN Single-center, double-blind, sham-controlled trial.

SETTING A large nonacademic teaching hospital in the Netherlands.

PARTICIPANTS Patients with type 2 diabetes mellitus and hypertension.

INTERVENTION Fifteen-minute sessions with either the device that guides breathing throughmusical tones to a lower breathing frequency (aiming at

T ype 2 diabetes mellitus (T2DM) and hypertensioncommonly occur together.1 Management of hyperten-sion through pharmacologic as well as nonpharmaco-logic interventions is effective in preventing cardiovascularevents.2

An example of a nonpharmacologic intervention is abreathing-focused biofeedback device approved by the Foodand Drug Administration and available without prescription(RESPeRATE; InterCureLtd).3-5 Throughuseof biofeedback 15minutes eachday, theobjective for thedevice is to lowerbloodpressure (BP) by guiding breathing frequency with musicaltones to less than 10 breaths/min.4,6 The mechanisms pro-posedareanadaptationof thepulmonarystretchreceptorsandbaroreceptor reflex, which lead to vascular and cardiacrelaxation.4,7 Slowbreathing also could lead to stimulation ofthe parasympathetic system or reduced sympatheticactivation.7-9

A recent systematic review and meta-analysis3 of 8 ran-domized clinical trials showed a potential small benefit ofdevice-guided breathing on systolic BP after short-termfollow-up. However, the methodologic quality of theincluded studies was variable. An editorial10 and systematicreview3 emphasized that an independent double-blindstudy design with a proper control group would be neces-sary to determine whether device-guided breathing has anyeffect on BP. Therefore, we reevaluated the effects of theRESPeRATE device on office-measured BP in patients withT2DM and hypertension in an investigator-initiated, double-blind, sham-controlled trial.

MethodsStudy DesignThe present study was a single-center, randomized (1:1),double-blind, sham-controlled trial conducted inpatientswithT2DMandhypertension (Figure) and aimed to investigate theeffects on hypertension of biofeedback by lowering breath-ing frequency with musical tones (with the RESPeRATE de-vice). The device was to be used 15 min/d during an 8-weekintervention period.

Study SamplePatients were recruited from the internal medicine outpa-tient clinic of the Isala Clinics in Zwolle, the Netherlands. Eli-gibility criteriawere age 18years or older, adiagnosis ofT2DM,hypertension treated with 1 or more antihypertensive drugs,systolic BP between 130 and 170 mm Hg at the previous andlast visits (the same day as baseline measurement) to the in-ternist, andunchangedhypertension treatmentduring thepre-ceding 3months. The systolic BPbefore randomizationhad tobe between 140 and 160 mm Hg. Exclusion criteria were or-thostatic hypotension (because it theoretically could miti-gate the effects of the device10), heart failure (NewYorkHeartAssociation class III or IV), severe lung disease, hospitaliza-tion in the past 3 months, deafness, blindness, and insuffi-cient cognitive abilities or knowledge of the Dutch language.Orthostatic hypotension was defined as a fall in BP of at least

20mmHg systolic or 10mmHgdiastolic pressure either 1 or 3minutes after changing from a supine to upright position.11,12

Study Groups and ProceduresTheRESPeRATEdevice consists of a control box, a sensor thatattaches around theusers chest, and a set of headphones.Us-ers listenedtoamelodythroughtheheadphones,whichguidesthem to slow their breathing rate, preferably to less than 10breaths/min. The control group used a visually identical de-vice guiding users to a breathing frequency of approximately14 breaths/min.

Patients visited the clinic twice. The first investigator(G.W.D.L.) performed baseline measurements and deter-minedeligibility for inclusion (not randomization). Theuseofthe device and home BP monitor was explained by a secondinvestigator (I.D.). All patients were informed that the objec-tive was to study the effects of music therapy. All instruc-tions were given both verbally and in writing and were re-peated after 1 week by telephone. Patients were asked toperformtheexercise 15minutes eachdayat approximately thesame time of day for 8 weeks. During the second visit, pa-tientswere seenbya third investigator (K.J.J.v.H. andP.R.v.D.)blinded to treatment allocation. Data on home BP measure-ments fromthestudydiarywerecollected,andquestionsaboutknowledge of the working mechanism and the brand nameRESPeRATE were asked to test the success of blinding.

OutcomeMeasuresThe primary and secondary outcome measures were changein office-measured systolic anddiastolic BP, respectively. Ad-ditional outcomemeasures were changes in home-measuredsystolicanddiastolicBP.Health-relatedqualityof lifewasorigi-nally planned as a secondary outcome, but prior to inclusionthe protocol was amended because of logistic reasons.

MeasurementsBaseline data consisted of medical history, smoking status,laboratory data, medication use, height, BP, and body

Figure. Participant FlowDiagram

48 Randomized

24 Analyzed 21 Analyzed

0 Lost to follow-up 3 Lost to follow-up2 Dyspnea, refused second

study visit1 Died

24 Allocated to sham group24 Received allocated intervention

24 Allocated to intervention group24 Received allocated intervention

244 Excluded91 Did not meet inclusion

criteria153 Declined to participate

292 Assessed for eligibility

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weight. Blood pressure was measured following a standard-ized protocol, using a validated digital BP monitor (UA-767Plus 30; A&D Medical).13,14 Home BP was measured on thefirst and last day of the study, after patients remainedseated for a minimum of 5 minutes before performing theexercise. Data on the number and duration of treatment ses-sions were uploaded from the intervention and shamdevices to determine adherence.

Randomization and Sample Size CalculationBlock randomization (blocks of 8) was done by a third partyusing sealed, nontransparent envelopes. Sample size wascalculated with G*Power 3.0 software (http://www.psycho.uni-duesseldorf.de/abteilungen/aap/gpower3/download-and-register).TheSDsof thechange insystolicBP inpreviousstud-ies were 9.4 mm Hg15 and 10.9 mm Hg.14 To detect a 10mmHg absolute reduction in systolic BP, with a power of 0.85, a2-tailed value of .05, and an SD of 11 mm Hg (assuming acorrelation of 0.5 between baseline and end-of-treatmentmeasures), the total sample size would be 44. For possibleloss to follow-up, we increased the sample size to 48. A10mm Hg margin in systolic BP was predefined as clinicallysignificant.

Statistical AnalysisData entry was performed in duplicate. Analyses were car-ried out by a statistician (K.H.G.) blinded to treatment alloca-tion.Mixed-effectmodels were used to estimate the effect ofthe interventiononBPafter 8weekswith andwithout adjust-ment for age, sex, bodymass index (calculated asweight in ki-lograms divided by height in meters squared) and hemoglo-bin A1c level. Analyses were performed according to theintention-to-treat principle.

Two per-protocol analyses were carried out. The first ex-cludedpatientswhodidnot reach the targetbreathing rateandthesecondexcludednonadherent (performing.99

Macrovascular disease, No. (%) 10 (42) 16 (67) .08

Smoker, No. (%) 5 (21) 4 (17) .71

Abbreviations: HbA1c, hemoglobinA1c; BMI, bodymass index (calculatedas weight in kilograms divided byheight in meters squared); BP, bloodpressure; IQR, interquartile range.

SI conversion factor: To convertHbA1c to a proportion of totalhemoglobin, multiply by 0.01.

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lead to significant differences in home-measured BP com-pared with the control group (Table 2).

Per-protocol analysis in adherent patients (14 in the inter-ventiongroup [67%]and18 in thecontrol group [75%]) showeda nonsignificant difference in systolic BP of 2.67mmHg (95%CI, 6.97 to 12.32, in favor of the control group), and the dif-ference in diastolic BPwas 1.14mmHg (95%CI, 6.27 to 4.00,in favor of the intervention group). Two patients (10%) in theinterventiongrouphadanaveragebreathing frequencygreaterthan 10breaths/min.Whenexcluding thesepatients, thenon-significant difference in office-measured systolic BPwas 2.19mmHg (95% CI, 6.49 to 10.87; P = .61, in favor of the controlgroup).

SafetyTherewere3adverseevents, all in the interventiongroup.Onepatient diedof respiratory failuredue tounderlyingheart fail-ure. Another patient reported shortness of breath. The thirdpatient had atypical chest pain with shortness of breath andsought care at the emergency department. Both individualsrefused to continueusing thedevice andwereunavailable forfurther BP measurements.

DiscussionTo our knowledge, this is the first randomized, double-blind, sham-controlled trial investigating short-term effectsof device-guided slowing of breathing in patients withT2DM and hypertension. Our study did not show beneficialeffects of device-guided slowing of breathing on office- andhome-measured BP. Per-protocol analyses excludingpatients not reaching the target breathing frequency andanalyses excluding nonadherent patients showed similarresults. We observed 3 adverse events in the interventiongroup; 2 of these could have been related to the use of theRESPeRATE device.

A recent systematic review andmeta-analysis3 including8 trials investigating the RESPeRATE device showed that allprevious studieswere subject tomethodologic flaws.Noneofthesestudieshadasham-controlled,double-blinddesign.Only4studieshadadesignwithacontrol groupqualifyingasarea-sonable control group.4,14-16 Three studies claimed to have adouble-blind design but used either aWalkman4,16 or no con-trol device.17 Only 1 of the 8 studies included in the system-atic review and meta-analysis reported a significantly lower

office-measured systolic BP,18 and 2 studies reported a signifi-cantly lower office-measured diastolic BP.16,19 The meta-analysis indicated that there could be a modest beneficialeffect of short-term use of the RESPeRATE device, with adecrease in systolic BP of 3.1 mm Hg (95% CI, 1.4-4.7).3 Thestudy18 with the largest effect on the results of the meta-analysis also had the highest risk of bias; that study had noadequate control group, was not blinded, and was carriedout by the manufacturer. The manufacturer was involved inall but 3 studies.14,15,20 All studies that reported a beneficialeffect of the RESPeRATE device were initiated or sponsoredby the manufacturer.3,16,18,19 A sensitivity analysis excludingsponsored studies showed no effect of device-guidedbreathing on BP. The authors of the aforementionedmeta-analysis3 postulated a possible conflict of interest intheir results.

Our study was investigator-initiated and its strength liesin the use of a sham device by the control group and thesuccessful double-blinding procedure. Our trial was limitedby a short duration of 8 weeks and was relatively small.18

We predefined a 10mm Hg margin as clinically significant,arguing that this margin was acceptable for a device requir-ing a tremendous amount of effort and persistence.Although we were able to exclude an advantage of 10 mmHg with 85% power, this 10mm Hg margin used for thesample-size calculation is subject to debate. Given the rela-tively wide 95% CI of the difference in systolic BP, we alsocould not exclude a relevant harmful effect of theRESPeRATE device. Furthermore, only 16% of eligiblepatients were included. We had to extend the inclusionperiod by 2 years because of this low participation rate.Most patients refused participation because of the time-consuming nature of the device, indicating that the targetpopulation of RESPeRATE will likely be small. Several otherrecruited patients did not meet our inclusion criteria, whichindicates that our study population is representative for afew of the Dutch population of patients with T2DM andhypertension. The generalizability was further limited to awhite population.

In conclusion, this study showed no beneficial effects ofthe RESPeRATE device on BP in patients with T2DM andhypertension. Furthermore, possible harmful effects wereseen. By confirming the results of 7 of the 8 previous trials,the promotion of the RESPeRATE device as an effective bio-feedback modality for hypertension treatment should bereevaluated, at least for white patients with T2DM.

Table 2. Estimated Changes inMeasurements of BP

Characteristic

Mean Change in BP

Difference in BP, Mean (95% CI)bIntervention(n = 21)

Control(n = 24)a

Office-measured BP, mm HgSystolic 6.03 8.38 2.35 (6.50 to 11.20)

Diastolic 5.92 3.67 2.25 (6.67 to 2.16)

Home-measured BP, mm Hg

Systolic 3.66 0.64 3.02 (13.22 to 7.17)

Diastolic 1.38 1.48 0.10 (6.88 to 7.08)

Abbreviation: BP, blood pressure.a Ten patients did not perform homeBPmeasurements.

bDifference is control intervention,unadjusted for baseline values.

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ARTICLE INFORMATION

Accepted for Publication: February 28, 2013.

Published Online: June 10, 2013.doi:10.1001/jamainternmed.2013.6883.

Author Contributions:Dr Landman had full accessto all the data in the study and takes fullresponsibility for the integrity of the data andaccuracy of the data analysis.Study concept and design: Landman, van Hateren,Logtenberg, Bilo, and Kleefstra.Acquisition of data: Landman, Drion, van Hateren,van Dijk, and Lambert.Analysis and interpretation of data: Landman,Lambert, Groenier, and Bilo.Drafting of the manuscript: Landman and Drion.Critical revision of the manuscript for importantintellectual content: All authors.Statistical analysis: van Hateren and Groenier.Obtained funding: Bilo.Administrative, technical, andmaterial support:Landman, Drion, van Dijk, and Lambert.Study supervision: Bilo and Kleefstra.

Conflict of Interest Disclosures:None reported.

Funding/Support: InterCure Ltd provided theRESPeRATE and sham devices.

Role of the Sponsors: The trial was sponsored bytheMedical Research Foundation Zwolle.

Additional Contributions:We thank all thepatients who participated in this trial. InekeKloppenberg, as well as Sabine Diepeveen, MD,PhD, Ad Kamper, MD, PhD, and Jan-Evert Heeg,MD, PhD, assisted with the inclusion.

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