Relationship between the Frequency of Blood Pressure Self

ORIGINAL RESEARCH ARTICLE

Clin Drug Invest 2006; 26 (8): 439-446 1173-2563/06/0008-0439/$39.95/0 © 2006 Adis Data Information BV. All rights reserved.

Relationship between the Frequency of Blood Pressure Self-Measurement and Blood Pressure Reduction with Antihypertensive Therapy Results of the OLMETEL (OLMEsartan TELemonitoring Blood Pressure) Study Silke Ewald,1 Johannes vor dem Esche,2 Sakir Uen,3 Fabian Neikes,3 Hans Vetter3 and Thomas Mengden3 1 2 3

Sankyo Pharma GmbH, Munich, Germany TeleMed-Project GmbH, Bergisch-Gladbach, Germany Division of Hypertension and Vascular Medicine, University Clinic, Medizinische Poliklinik, Bonn, Germany

Abstract

Objectives: This subanalysis of the OLMETEL (OLMEsartan TELemonitoring blood pressure) study in patients with essential hypertension assessed the relationship between the frequency of blood pressure self-measurement (BPSM) and the response to blood pressure (BP)-lowering therapy with olmesartan medoxomil, and the number of BP readings per week necessary to detect a mean systolic or diastolic BP reduction ≥5mm Hg. Methods: A total of 53 patients with essential hypertension received treatment with olmesartan medoxomil 10, 20 or 40mg daily for 12 weeks. BPSM was performed for the first 9 weeks using a TensioPhone TP2 device. Patients were instructed to measure BP at least twice daily (morning and evening). Results: After the first 9 weeks of the 12-week treatment period, the extent of BP reduction correlated with the number of BPSMs. Systolic/diastolic BP reductions in patients with a 100% adherence to at least two BP measurements daily were –16.6/–8.0mm Hg compared with –0.2/–3.3mm Hg in patients with only a 75% adherence to at least one BP measurement daily. Obtaining five home BP readings per week resulted in a sensitivity of 94.8% and a specificity of 90.0% to detect a BP reduction of ≥5mm Hg. Conclusion: Patients adhering to the instructions for BPSM (at least two measurements daily) had a better response to antihypertensive treatment with olmesartan medoxomil. Whether BPSM per se resulted in an improved adherence to therapy or whether the number of recordings was an indicator of already

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existing adherence remains to be determined. Obtaining at least five home BP readings per week was identified as the threshold for correctly predicting response to olmesartan medoxomil treatment.

Introduction The goal of treating hypertension is the prevention of morbidity and mortality, which should be accomplished by achieving and maintaining normalised blood pressure (BP).[1] It has been recognised for >50 years that BP pressure self-measurement (BPSM) values at home are lower than those recorded by a physician.[2,3] The discrepancy between BP values recorded in the home and the clinic, which has been confirmed repeatedly, is primarily a result of the ‘white-coat effect’.[4] Measuring BP in the home environment under similar everyday conditions avoids the white-coat effect and reduces BP variability.[5-7] Recently published international guidelines for the management of hypertension have acknowledged the need to look for alternative methods of BP measurement such as BPSM in order to quantify more precisely the contribution of hypertension to cardiovascular risk.[1,8,9] However, the number of measurements needed for (1) optimal adherence and (2) to identify responders to antihypertensive treatment is still a matter for debate. Olmesartan medoxomil is a selective and potent angiotensin II type 1 receptor antagonist that has been proven to be effective and safe for once-daily treatment of hypertension.[10-14] Results of the OLMETEL (OLMEsartan TELemonitoring blood pressure) study in patients with essential hypertension have been published recently.[15] This telemonitoring study in 53 patients with essential hypertension demonstrated not only the effective and reliable BP-lowering effects of olmesartan medoxomil, which were maintained throughout a 24-hour period, but also that in a real-life clinical © 2006 Adis Data Information BV. All rights reserved.

practice setting, telemonitoring of BPSM is an effective technique. The present study had two main objectives: (1) to investigate the relationship between the frequency of BP measuring (as an indicator of patients’ adherence) and response to antihypertensive treatment; and (2) to investigate how many regular BP readings per week are necessary to detect a mean systolic or diastolic BP reduction of ≥5mm Hg. Methods

Study Population

Patients ≥18 years of age with essential hypertension requiring antihypertensive therapy were eligible for inclusion in this study. Patients with untreated hypertension, or whose hypertension was uncontrolled or insufficiently treated, received olmesartan medoxomil 10, 20 or 40mg once daily for 12 weeks according to the instructions of their respective physicians. It was at the discretion of the attending physician to use monotherapy with olmesartan medoxomil or to add other antihypertensive medications. Patients underwent office BP measurements at baseline, then conducted BPSM for a period of 12 weeks. The reminder system of the BPSM device was activated during the entire observation period. Because of decreasing measurement adherence at the end of the study, analysis for BPSM was performed only for weeks 1 and 9 of the study.[15] The mean of all BPSM values collected during days 1–3 constituted the baseline BPSM measurement. Mean BPSM values were then calculated weekly at weeks 1–9. At week 12, patients attended the clinic Clin Drug Invest 2006; 26 (8)

Blood Pressure Self-Measurement in OLMETEL

and the physician performed a second office BP measurement. Patients gave written informed consent for personal patient data (name, address and phone number) to be transmitted from the physician to the remote service centre for telemonitoring devices. The service centre ensured that no patient-related data were handed to third parties to rule out backtracking of data to individual patients. All patientrelated data relating to phone protocols were deleted by the service centre after completion of the study. Study Design

This was a post-authorisation study (PAS), in which patients received open-label olmesartan medoxomil (Olmetec®; Sankyo Pharma GmbH, Germany)1 in accordance with the summary of product characteristics of the marketed drug. The PAS was performed in accordance with German health authority recommendations[16] and the requirements of the European Directive 2001/83.[17] Blood Pressure Self-Measurement

For BPSM, patients were supplied with a TensioPhone 2 telemonitoring BP device (Tensiomed Hungary), which stored BP measurement data. The Tensiophone is an upper-arm oscillometric device with a built-in modem for data teletransmission via standard telephone lines. After instruction in the technique of self-measurement, patients were advised to perform at least one recording in the morning (between 6am and 10am) and one recording in the evening (between 6pm and 10pm) every day during the observation period. However, the exact time of medication intake was unknown. An integrated modem automatically transmitted measured BP values to a remote service centre (TeleMed-Project GmbH, Germany) every fourth night. This system in 1

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general allows bilateral communication between patient and physician with a signal to remind patients to take their measurements and/or drugs.[18] In the OLMETEL study, we analysed morning and evening BP values separately to calculate the morning/evening BP ratio at baseline and after 9 weeks.[15] The respective values (systolic/diastolic) were 0.99/1.00 and 1.02/1.01. These data are reflective of a 24-hour duration of the antihypertensive medication and it appears unlikely that BP reduction in the morning influenced BP data. The number of home measurements needed to identify treatment responders was analysed. To estimate the predictive power of different numbers of home measurement to identify a BP reduction (defined as systolic BP or diastolic BP reduced by ≥5mm Hg), random samples of size 1, 2, 3, …, 14 and 21 were drawn from the measurements of each patient at week 9. BP reduction then was determined according to the average of these values. This procedure was repeated 1000 times for each sample size, resulting in rates of correct prediction of BP reduction (sensitivity) or correct prediction of non-reduction (specificity) in comparison to reduction and non-reduction determined, and on the basis of all available measurements in week 9. A sensitivity of ≥90% and a specificity of ≥90% to detect a BP reduction >5mm Hg were defined as providing reliable data. A BP reduction ≥5mm Hg refers to the mean of morning and evening reductions (although a separate analysis did not demonstrate a difference between morning and evening values). A detailed user procedure for BPSM has already been published and addresses methodology, practical recommendations regarding protocol and procedure for measurement, documentation and analysis of data, choice and provision of devices, and education of patients and physicians.[19]

The use of trade names is for product identification purposes only and does not imply endorsement.

© 2006 Adis Data Information BV. All rights reserved.

Clin Drug Invest 2006; 26 (8)

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Ewald et al.

Table I. Demographics of the patients included in the study (n = 53) Demographic variable Sex (M/F) [no.]

29/24

Age (y) [mean (range)]

57.7 (33–90)

Weight (kg) [mean (range)]

81.3 (48–140)

Height (cm) [mean (range)]

169.6 (150–187)

BMI (kg/m2) [mean (range)]

28.1 (19–41)

Duration of hypertension (y) [mean 6.4 (0–23) (range)] BMI = body mass index; F = female; M = male.

Statistical Analysis

Mean BPSM values at week 9 were compared with the respective mean baseline values using descriptive statistical methods, i.e. calculating arithmetic means and SDs. No other statistical analyses were performed. Results OLMETEL was conducted between February and October 2003 in 27 clinical practices in Germany. A total of 53 patients with previously untreated or inadequately treated hypertension were enrolled in the study (table I). Overall, more men than women were enrolled in the study. The mean age of the study participants was 57.7 years, the mean weight was 81.3kg, the mean height was 169.4cm, and the mean body mass index was 28.1 kg/m2. Hypertension had been known in the patients for a mean 6.4 years. The mean daily olmesartan medoxomil dose prescribed was 23.5mg.

Table II summarises information on BP changes for office measurements at week 12 and BPSM measurements at week 9 versus baseline. BPSM data were missing for three patients who failed to connect the BPSM device properly to the telephone system, and for one patient who performed BPSM only after the end of the study. In total, 49 patients were eligible for analysis of BPSM. The mean number of daily BP readings was 2.3 between days 1 and 63 and 1.8 between days 64 and 84, indicating decreasing adherence over time. Figure 1 and figure 2 display BP changes from baseline to week 9 as a function of the number of daily BPSMs and adherence to scheduled BPSM recordings. Forty-seven patients with available BPSM data had at least 50% BP recordings as scheduled, i.e. two or more BPSMs daily; however, only five patients had actually adhered to the scheduled two BPSMs per day. Patients with two or more BPSMs per day had greater systolic and diastolic BP reductions than those with only one or more BPSMs per day (figure 2). In addition, BP-lowering effects correlated with adherence to scheduled BPSMs, i.e. patients complying 100% with scheduled BPSMs and having at least two BPSMs daily had the largest BP reductions (–16.6/–8.0mm Hg). Patients with at least one BPSM daily and a 75% adherence to device use had the least reductions in BP (–0.2/–3.3mm Hg). In addition, the number of home measurements needed to identify treatment responders was analysed. Five to seven BPSM measurements per

Table II. Office blood pressure changes (mm Hg) in the efficacy population at week 12 versus baselinea Time-point

Systolic blood pressure (mm Hg)

Diastolic blood pressure (mm Hg)

absolute

absolute

difference vs baseline

difference vs baseline

Office measurements Baseline (visit 1)

162.6 ± 18.7

Week 12 (visit 2)

133.5 ± 7.7

96.3 ± 13.5 29.1 ± 16.9

79.8 ± 5.8

16.5 ± 13.2

BPSM Baseline (days 1–3)

147.8 ± 16.1

Week 9 (days 57–63)

138.6 ± 13.2

a

85.7 ± 11.6 9.2 ± 16.9

79.0 ± 10.7

6.7 ± 8.9

All values are means ± SD.




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Adherence to BPSM: 100% 90% 75% 50% ≥ 1 BPSM per day

≥ 2 BPSM per day

0 n=9

−4 −6 −8

n = 11 n = 12

−10

n = 19

n = 12

−12 n = 25

−14 −16 n=5

−18

Fig. 1. Changes in systolic blood pressure (BP) from baseline at week 9. BPSM = BP self-measurement.

Adherence to BPSM: 100% 90% 75% 50% ≥ 1 BPSM per day

≥ 2 BPSM per day

0

BP reduction/mm Hg (%)

−2 −4

n=9

−10

Sensitivity Specificty

n = 11

−6 −8

This subanalysis of OLMETEL demonstrates that more regular BPSM is associated with a greater reduction in BP compared with less regular BPSM. Although the overall number of patients per strata (between 5 and 19) was limited, a clear correlation between adherence to device use and the intended BP-lowering effects of the trial medication olmesartan medoxomil was observed. The reductions in systolic/diastolic BP of 16.6/8.0mm Hg in the very compliant group contrasted with a BP reduction of 0.2/3.3mm Hg in patients with the least adherence to device use. The reasons for this observation are by no means certain and leave room for interpretation. One explanation for the observed phenomenon is that patients who meticulously follow the instructions for BPSM may equally meticulously follow their physicians’ recommendation for antihypertensive drug intake, or vice versa. This means that once the physician is dealing with an a priori compliant patient, it may not necessarily make a difference whether the patient uses BPSM to achieve the intended effect concerning BP-lowering since the number of BPSM recordings are just an indicator of good compliance. Similarly, other authors have concluded that physi-

n = 19 n = 12

n = 25

100

n=5 n = 12

−12 −14

93.2

Percentage

BP reduction/mm Hg (%)

−2

Discussion

90

−18

60


89

90

95.6

95.9

90.4

91.1

82.1

70

week were needed to detect a BP reduction by ≥5mm Hg with a specificity and sensitivity of ≥90% (see figure 3 for details).

86.3

94.8

80

−16

Fig. 2. Changes in diastolic blood pressure (BP) from baseline at week 9. BPSM = BP self-measurement.

94.8

94

90

66.7

1

2

3

4

5

6

7

Readings per week Fig. 3. Sensitivity and specificity of the number of blood pressure (BP) home readings per week as a means of correctly predicting a ≥5mm Hg BP reduction. Between five and seven measurements per week (see boxed-off section of figure) were needed to detect a BP reduction of ≥5mm Hg with a specificity and sensitivity of ≥90%.


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cians should recommend home BP measurement to patients being treated with antihypertensive drugs because there is the possibility that home BP measurement might improve medication compliance.[20] On the other hand there is strong support for the notion that self-measurement per se increases compliance with antihypertensive therapy.[21,22] This has been demonstrated in the Self-Measurement for the Assessment of the Response to Trandolapril study that was performed in general practice and enrolled 1710 patients.[21] Furthermore, not only did BPSM increase compliance compared with usual management, it also resulted in fewer clinic visits. The assumption that self-measurement increases compliance is also supported by other studies using home telemonitoring that showed that the mean arterial pressure reduction in the telemedical patient group was superior to that observed in the usual care group (in whom an increase in mean arterial pressure was observed).[22,23] While it is also possible that more intensive medication adjustment by the attending physician may contribute to improved BP control, only a few medication changes of this nature occurred in the OLMETEL study and patients without medication changes also showed decreases in BP in the aforementioned study.[23] Such findings suggest a beneficial effect of telemedical monitoring of BP control through other mechanisms, possibly involving an improvement in patient adherence to medication.[24] This is also supported by observations in another study showing that the ability to transmit home BP data by phone maintained good patient compliance.[25] The reminder system of the BPSM device was activated during the entire observation period. This may improve compliance in daily practice; however, the study design did not allow this question to be answered. The issue of why BPSM compliance decreased substantially towards the end of the study, with meaningful results being available for only up © 2006 Adis Data Information BV. All rights reserved.

Ewald et al.

to 9 weeks of the observation period, also remains unsolved. Similar observations have been made by other groups using telemetry (personal communication). In the present study most patients had a rather rapid BP response after the start of treatment with olmesartan medoxomil.[15] If BP does not change further in responders as well as in non-responders, measurement compliance decreases (personal observation, Dr Mengden). The results of this analysis do not provide the answer to the question of whether BPSMs per se resulted in improved compliance with antihypertensive therapy or whether the number of recordings was an indicator of already existing compliance. Such relationships will have to be determined by investigating patients’ attitudes and behaviours and correlating these with actual study outcomes. Since to our knowledge such assessments have not been conducted, a definitive evaluation is currently not possible. The question of how many home measurements are needed in pharmacological trials or for clinical use is still a matter of debate. Obviously, a higher number of readings performed with BPSM increases reproducibility and statistical power in comparison to office readings.[26-28] However, until now, limited data have been available with regard to the number of measurements needed to identify responders in pharmacological studies. Our study demonstrated that at least five BPSM measurements per week are needed to detect a relevant BP reduction with a high specificity and sensitivity and to give a correct prediction of response to olmesartan medoxomil treatment. Therefore, inclusion of twice-daily BPSMs yielded robust results, even when BPSM compliance was as low as 50%. There was no difference in the effect of morning or evening readings on the sensitivity/specificity of BPSM. However, such a difference could not be expected since morningevening ratios of BPSM ranged between 0.987 and Clin Drug Invest 2006; 26 (8)


1.028, with no change occurring between baseline and week 9 (data not included). As confirmed in the primary publication of OLMETEL, BPSM using telemonitoring is a useful means for BP management that can be effectively applied in ‘real-life’ clinical practice. The Tensiophone system performed well in this study, and no data loss occurred as a result of technical failure.[15] Non-adherence to drug intake is one of the most common causes of treatment-resistant hypertension.[9] Patients’ non-adherence to therapy is increased by misunderstanding of the condition or treatment, denial of illness because of lack of symptoms or perception of drugs as symbols of ill health, lack of patient involvement in the care plan, or unexpected adverse effects of medications.[9] Therefore, any means to improve patient compliance should be welcome. Using BP telemonitoring not only may improve compliance but has also been proven to be a very useful tool in the assessment and follow-up of BP in hypertensive patients.[20-24] Conclusion Patients adhering to the instructions for BPSM (at least two measurements daily) had a higher response to antihypertensive treatment with olmesartan medoxomil than those who were not adherent to these instructions. Whether BPSMs per se resulted in improved compliance with antihypertensive therapy or whether the number of recordings was an indicator of already existing compliance remains to be determined. Furthermore, a number of at least five BP home readings per week was identified as being able to correctly predict response to olmesartan medoxomil treatment. Acknowledgements This study was supported by Sankyo Pharma GmbH, Munich, Germany. Silke Ewald is an employee of Sankyo Pharma GmbH. The other authors have no potential conflicts


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of interest that are directly relevant to the contents of this manuscript.

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Correspondence and offprints: Dr Silke Ewald, Sankyo Pharma GmbH, Zielstattstrasse 48, Munich, D-81379, Germany. E-mail: [email protected]
