STEPWISE management of uncontrolled hypertension in primary care: A cluster randomised controlled trial

doi:10.21203/rs.3.rs-4939538/v1

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STEPWISE management of uncontrolled hypertension in primary care: A cluster randomised controlled trial

https://doi.org/10.21203/rs.3.rs-4939538/v1

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Background

Uncontrolled hypertension is common and a major health problem because it increases the risk of cardiovascular events. We aim to assess whether a stepwise work-up management strategy for patients with uncontrolled hypertension in primary care would result in better blood pressure control compared to usual care.

Methods

A pragmatic, cluster-randomised controlled trial (cRCT). General practitioners (GPs) from 22 practices (10 intervention arm; 12 usual care) recruited 106 patients aged 18-80 years who had an office blood pressure (BP) >140/90 mmHg and were prescribed three or more antihypertensive drugs from different therapeutic classes for three or more months in an adequate dose. This study was conducted between October 2018 and June 2021.

The intervention was a stepwise approach comprising of (i) 24-hour blood pressure measurements, (ii) dedicated attention on intake of blood pressure raising compounds, (iii) on lifestyle and on compliance to and (iv) optimalisation of medication, and (v) referral to specialist care, when appropriate. The control group received usual care. Primary outcome was the difference in 24-hours systolic BP between intervention and usual care measured at 8 months after baseline.

Results

Neither 24-hour nor office systolic BP 8 months after baseline did significantly differ between intervention and usual care arm: 136.9 mmHg versus 132.6 mmHg (p=0.15) and 146.1 mmHg versus 147.6 mmHg (p = 0.51), respectively. No significant differences across groups were seen in number of prescribed BP lowering medication: 2.98 versus 3.11, or controlled hypertension after 8 months: 22% versus 28%.

Conclusions

Our results are compatible with the notion that a pragmatic but structured stepwise treatment of uncontrolled hypertension does not result in lower 24 hour or office BP values as compared to usual primary care.

Trial registration: NTR7304 (www.trialregister.nl/trial/7099)

Antihypertensives

prevention

cardiovascular disease

uncontrolled hypertension

lifestyle

general practice

cluster randomised controlled trial

Elevated blood pressure -as one of the modifiable cardiovascular risk factors- ranks number one as cause for premature death and loss of quality adjusted life years globally (1). Worldwide, only around half of all patients managed for hypertension reach target levels (i.e. office systolic BP < 140 mmHg) (1). It is well documented that patients with uncontrolled hypertension are at increased risk for cardiovascular diseases (CVD) compared to those with controlled hypertension (2). A high prevalence in society coupled with an increased risk in morbidity and mortality clearly illustrates that there is an urgent need for better management of uncontrolled hypertension, notably in primary care, where the vast majority of patients with hypertension is managed (3).

There are several modifiable risk factors that, in addition to pharmacological treatment, are important in uncontrolled hypertension to reduce the blood pressure level and decrease the overall CVD risk. These include smoking, overweight, high salt intake, physical inactivity and alcohol use (4–9). In addition, opening the discussion on adherence to (non)pharmacological treatment is important (10). However, the current guidelines do not guide clinicians on how, and in what order to address the aforementioned modifiable factors and adherence issues (11). Implementation of an easy to follow, practical and stepwise work-up approach for uncontrolled hypertension in primary care that touches upon all aspects may result in improved BP control, and eventually in a reduction in cardiovascular diseases and healthcare costs. Most evidence on treatment effects in patients with elevated blood pressure comes from dedicated randomized controlled trials evaluating either pharmacological treatments, or lifestyle interventions, or combinations. We did not come across a stepwise approach tackling all potential blood pressure lowering aspects in a combined approach.

Therefore, we set out to assess whether the application of a practical work-up scheme including a training programme for general practitioners (GPs) and primary care practice nurses (PNs) based on the Dutch guidelines for cardiovascular risk management (CVRM) would result in a better blood pressure control compared to routine primary care in patients with uncontrolled hypertension.

Design and study population

The rationale and design has been described in detail elsewhere (12). In short, a cluster randomized controlled trial was conducted in Dutch general practices (10 intervention and 12 usual care). Eligible were people enlisted with the GP, 18 to 80 years of age, with an office BP >140/90 mmHg, while managed with three or more antihypertensive drugs from different therapeutic classes simultaneously for three or more months in an adequate dose based on the current Dutch guideline on cardiovascular risk management (13). Detailed inclusion and exclusion criteria are presented in table 1.

The study protocol was approved by the Research Ethics Committee of the University Medical Center Utrecht in the Netherlands. All patients provided written informed consent. This study was conducted between October 2018 and June 2021 partly during the full COVID-19 epidemic.

Randomisation and blinding

Randomisation was done at GP practice level, enabling uniform care of GPs working in one practice (the so-called cluster). The randomization was 1:1, stratified by region (Utrecht/Nijmegen) and practice size (1 norm practice, 2 norm practices 3 ≥ norm practices, 2350 patients are the norm for one “standard GP practice”), using a web-based randomization program (Julius Center, UMC Utrecht, Utrecht, the Netherlands)(14,15). Due to the nature of the intervention, blinding was not possible. A cluster randomized design was adopted to avoid contamination between the intervention and usual care group. Patients in the control group were not informed about the intervention, and were asked to participate in a study to monitor the treatment of patients with uncontrolled hypertension.(16)

Interventions

The stepwise treatment of patients in the intervention group (figure 1) consisted of 5 steps: (i) excluding a white coat effect using 24-hour blood pressure measurement, (ii) re-evaluation of lifestyle, (iii) re-evaluation of adherence, (iv) optimalisation of medication, and (v) referral to a hospital specialist to rule out secondary hypertension. A more detailed description of these five steps of the intervention group has been described elsewhere (12). When participants achieved a controlled BP level at a certain step, the next steps were not performed and only a 8 months end of study assessment was performed. In the mean time, patients received care as usual. Participants in the usual care group were in principle seen at least once a year for cardiovascular risk management consultation in the general practice and were managed according to the Dutch guideline for cardiovascular risk management (13).

For the usual care, follow-up information was obtained at the end of study visit (at 8 months) and/or through the linkage of the GP information in Electronic Health Care records with the study database. The latter holds for information on co-morbidity, medication prescription and office SBP and BMI measurements and laboratory values.

Outcomes

The primary outcome was the difference in the mean 24–hour systolic BP between the intervention and usual care group assessed 8 months after the enrolment. Secondary outcome measures after 8 months were: (1) The percentage of patients achieving a controlled BP, that is an office BP ≤140/90 mmHg or a mean 24-hour BP ≤130/80 mmHg, measured at the end of study (8 months); (2) The time window (time from baseline) to reach a controlled BP during the study, defined as twice an office BP of ≤140/90 mmHg, or a mean 24-hour BP of ≤130/80 mmHg; (3) The number and/or dosage prescribed of BP lowering drugs, measured during the study time; (4) Referral to the medical specialist during the study time; (5) Health care use during the study period; (6) The difference in health-related quality of life as measured with the EQ5D and EQ-VAS at baseline and after 8 months between both arms (7) Self-reported weight/body mass index.

Sample size

The sample size calculation for the primary endpoint was based on an estimated standard deviation (SD) of 16 mmHg around a group mean systolic blood pressure based on 24-hour systolic blood pressure measurements as described elsewhere (12). We needed 233 participants to detect a clinically relevant difference of 7.5 mmHg in the mean 24 hour systolic BP between both groups, with an intracluster correlation coefficient of 0.05, a 2-sided alpha of 5% and 90% power.

We estimated the prevalence of eligible patients to be 15 per GP practice. Anticipating a conservative 50% response for participation, and a drop-out rate of around 20%, we needed to enrol 39 GP practices to be sure to end up with 583 participants to be invited to participate (i.e., 233 * 2 * 1.25). Rounded up, we planned to include 40 general GP practices (20 in the intervention and 20 in the care as usual arm) and 240 patients (40 * 15 * 0.50 * 0.80).

Statistical analyses

The baseline characteristics were provided as percentages or means with corresponding standard deviation. No statistical testing for differences at baseline was conducted since all potential difference are considered to be due to chance since a central randomization procedure was applied. The primary outcome was the difference in 24-hour systolic BP between groups measured at 8 months follow-up. The end-of-study 24-hour systolic BP values were presented for each treatment arm using a modified intention to treat approach, i.e., taking those with end of study measurements available. The difference between treatment arms was assessed using a linear regression model and presented as mean difference with standard errors (SE). We did not collect baseline 24-hour blood pressure measurements in the usual care group, since these measurements were considered the first step in the intervention. Therefore we could not adjust the end of study measurements for the baseline level as recommend to do so (17). Yet, based on the assumption that baseline office systolic pressure is a major determinant to end of study 24-hour blood pressure, we ran an analysis for end of 24-hour blood pressure with baseline adjustment for office blood pressure.

For the secondary outcomes, we applied regression models with end of study value adjusted for the baseline value (for blood pressure and body weight). The difference in EQ-5D score parameters between intervention groups at 8 months was evaluated using a Spearman correlation coefficient. A similar approach was taken for health care use. SPSS 25.0 was used as for the above mentioned analyses. Statistical significance was based on a two-sided p value of 0.05.

As this is a cluster randomized trial we additionally performed analyses taking clustering by GP practice into account in a linear mixed model approach with a random intercept using SAS statistical package. These results did not differ in direction, magnitude or significance from the results presented.

Enrolled study population

Figure 2 shows the flow of the participants at each step up to the end of the study. A total of 106 participants were randomised, 50 to the intervention arm and 56 to the usual care arm. In 35 participants in the intervention arm, 24-hour SBP end of study measurements and 47 office SBP measurements were available. For the usual care arm the corresponding numbers were 45 and 48, respectively.

Baseline characteristics

Table 2 provides information on the baseline characteristics of the studied population by treatment arm. The mean number of prescribed blood pressure lowering medication was 3.20 (SE 0.06) in the intervention group and 3.09 (SE 0.09) in the usual care group. The proportion of patients with a medical history of comorbidity was comparable. Table 3 depicts relevant blood pressure data on 24-hour and office blood pressure. We observed higher mean office systolic blood pressure than 24-hour systolic blood pressure values in the intervention group (154.6 versus 139.3 mmHg, respectively).

Table 2

Baseline characteristics of the study population subdived in intervention and usual care arm
	Intervention (n = 50) Mean (SD)	Usual care (n = 56) Mean (SD)
Women (%)	50	41
Mean age in years	66.6 (8.6)	67.6 (7.8)
Higher vocational education or higher (%)	25	25
Any family member with CVD < 65 YEARS (%)	50	60
Current smoker (%)	17	6
Former smoker (%)	40	66
Medical history
Hypercholesterolemia (%)	28	16
Obesity (%)	8	9
Diabetes mellitus (%)	50	41
OSAS (%)	14	20
Stroke (%)	4	9
Coronary heart disease (%)	10	18
Chronic kidney disease (%)	14	14
Height (in centimeters)	170 (11)	171 (13)
Weight in kg	86 (16)	89 (18)
BMI in kg/m²	29.8 (4.6)	30.8 (7.3)
Average of 2 office SBP measurements in mmHg	155 (11.5)	158(13.7)
Average of 2 office DBP measurements in mmHg	82 (10.3)	81 (9.9)
Fasting glucose in mmol/l	7.8 (8.8)	7.2 (3.0)
Total cholesterol in mmol/l	4.7 (0.89)	4.6 (1.0)
LDL cholesterol in mmol/l	2.6 (0.81)	2.5 (0.9)
HDL cholesterol in mmol/l	1.3 (0.4)	1.2 (0.3)
Triglyceriden in mmol/l	1.7 (1.0)	1.7(0.9)
Creatinine in mmol/l	83.8 (22.0)	82.0 (23.0)
eGFR in ml/min/1.72 m²	72.2 (16.9)	72.5 (15.0)
Serum potassium level in mmol/l	4.0 (0.4)	3.9 (0.4)
*BMI = Body Mass Index, SBP = systolic blood pressure, DBP = diastolic blood pressure

Table 3

Blood pressure findings, by treatment arm
	Intervention (n = 50)					Usual care (n = 56)			Mean difference intervention – control group in mmHg (SE)
Primary outcome: 24-hour systolic blood pressure measurement
	N		Mean SBP		SD	N	Mean SBP	SD
Step 1 of intervention	50		139.3		15.8	--	---	--	--
End of study (T8)	35		136.9		12.3	45	132.6	12.3	4.4 (2.8) 3.9 (2.8) 4.7 (2.8)*
Secondary outcome: office systolic blood pressure measurement
		N		Mean SBP	SD	N	Mean SBP	SD
Baseline		50		154.6	11.5	56	157.8	13.7
Visit T8		35		143.1	11.4	45	146.7	15.8	-2.3 (3.0) -2.3 (2.9) *
LOCF + HIS		47		146.1	12.5	48	147.6	16.1	-0.40 (2.8) -0.30 (2.8)***
N = number of patients; SD = standard deviation; T8 = 8 month visit since baseline; SE = standard error; LOCF: Last Observation Carried Forward, LOCF + HIS for the intervention arm the latest office blood pressure measurement before T8 visit when the T8 measurement was missing, but also measurement added from the electronic health records of the GP adjusted for age and sex. * adjusted for baseline office systolic blood pressure

Primary outcome measurement

Table 3 provides the observed findings with respect to 24-hour and office systolic BP at baseline and at the end of the study (8 months). We found no statistically significant differences in both 24-hour and office systolic blood pressure measurements between intervention and usual care

Secondary outcome measurements

Table 3 shows a considerable reduction in office systolic BP for all patients occurring in both arms during the study after an 8 month period. The number of prescribed classes of BP lowering agents at the end of the study (8 months after baseline) did not differ between the intervention group versus the usual care group: 2.98 (SE0.10) versus 3.11 (SE 0.13). With respect to controlled hypertension, we observed a prevalence at the end visit of 22% in the intervention arm and 28% in the usual care arm, not reaching statistical significance. At the end of the study, the mean weight of participants in the usual care group was higher than that in the intervention group: 91.5 kg versus 84.4 kg (Table 4).

Table 4

Several secondary outcomes across treatment groups, baseline and end of study, means and SD or percentages
	Baseline usual care	end of study usual care	Baseline intervention	End of study intervention
EQ-5D score
Mobility (1–3)	1.36	1.38	1.28	1.14
Self-care (1–3)	1.02	1.00	1.02	1.03
Usual activities (1–3)	1.08	1.16	1.19	1.08
Pain (1–3)	1.30	1.42	1.49	1.28
Mood (1–3)	1.09	1.07	1.11	1.14
General VAS (0-100)	78 (11)	79 (10)	74 (14)	77 (14)
Weight (kg)	N = 53	N = 50	N = 45	N = 36
	89.5 (18.7)	91.5 (18.5)	86.2 (16.1)	84.4 (14.2)
*EQ-5D = Euro Quality of life, VAS = Visual Analogue Scale

We observed lower mobility scores, pain scores and daily activity scores based on the EQ-5D questionnaire at 8 months in the intervention group compared to the usual care group without reaching statistical significance (Table 4).

The total number of contacts, irrespective of cause between the participant and the general practitioner such as consults, visits, telephone calls, and e-consults, were higher in the intervention group compared to the usual care group (median per participant 24 vs. 7, p < 0.001) (Table 5). In the intervention group there were in total 7 encounters with a hospital specialist during the conduct of the study, of which 2 were with a vascular specialist (defined as an internist, cardiologist, neurologist, nephrologist, or vascular surgeon). In the usual care group this was in total 8. Four hospitalisations occurred during the study: 1 in the intervention group (hip replacement), and 3 in the usual care group (acute myocardial infarction, rhythm disorder, peripheral artery stent placing).

Table 5

Number of contacts per participant not nessearily related to high blood pressure treatment (absolute number) between health care provider and participant during the conduct of the study, by assignment group.
Type of contact	Usual care		Intervention		P value (Spearman)
	Median	Mean (SD)	Median	Mean (SD)
Consult	6	10 (12)	19	20 (14)	< 0.001
e-consult	--	0.07 (0.3)	--	0.06 (0.24)
Telephone	0	4.8 (8.8)	4	6.4 (7.0)	0.003
Visit	--	0.9 (0.3)	--	0.16 (0.3)
Any of above	7	15 (20)	24	26 (18)	< 0.001

The present study in primary care patients with uncontrolled blood pressure levels showed no statistically significant improvement in 24-hour or office systolic blood pressure between the stepwise targeted care compared to usual care. On average 1 out of 4 patients had controlled blood pressure levels 8 months after inclusion in both arms, without increase in the number of antihypertensive medication. Another important finding is that in both arms there is a large reduction in office SBP between baseline and after 8 months. This large difference may be due to ‘regression to the mean’, but could also be explained by extra attention to blood pressure lowering in both groups. The latter implies that there might have been contamination between the groups despite the cluster randomised design. An alternative explanation could be that usual care was already at such a relatively good level that implementation of an additional stepwise intervention is not effective.

Strengths

The main appeal of the randomized controlled trial (RCT) in health care comes from its potential to reduce confounding by indication and selection bias. Furthermore, by choosing for a cluster randomised trial instead of a controlled trial in which individuals are randomised, we potentially avoided ‘contamination’ or lack of contrast (usual care becoming similar to intervention) (16). Moreover, we applied primary outcome assessment, i.e., 24-hour BP measurement measured with an automated device, which reduces measurement-bias and allows comparison with international studies that also use 24-hour BP measurements. In Stepwise-HTN, measures were taken to reduce potential bias due to differential collection of the data across the groups. This was done using information from the Electronic Health Records that was collected uniformly for the intervention and for the usual care group in order to. These extractions included only coded data.

Another strength is that the study was done in a relevant patient-group in primary care including patients with multimorbidity. This approach enables extrapolation to everyday primary practice and thus, increases the external validity of the study. Further this was the first study on uncontrolled hypertension in primary care that focuses on implementation of the guideline using a clear stepwise approach and training of health care workers.

Limitations

A clear limitation of the study is that the recruitment rate was substantially lower than originally planned. Recruitment was severely hampered by the Covid-19 pandemic. A lower recruitment rate than planned in general affects the precision (i.e., standard error of the difference in blood pressure between the treatment arms becomes larger) of the study results. A lower recruitment rate, however, generally does not affect the mean estimates in the treatment arms. Another limitation is that GPs and PNs were not blinded for the intervention, however, the primary outcome (24-hour SBP) was an assumed unbiased outcome. Due to the nature of the intervention, blinding was not possible in this study. Finally, we had complete follow-up in over 80% of the participants, with a difference between the groups. As no information is currently present on whether those with a controlled or those with an uncontrolled blood pressure level selectively provided 24-hour blood pressure assessment, there is no way to quantify whether this selection, may have biased the findings.

Our study shows that repeating 24 hour blood pressure measurements within a short period of time as done in the intervention arm (as step 1 in the intervention and as end point) results in reluctance to participate in the second measurement, which fits with the knowledge that 24-hour blood pressure is considered at least by part of patients as inconvenient or unpleasant.

Comparisons with existing literature

We came across two cluster randomised trials ongoing in primary care on patients with uncontrolled hypertension with three or more antihypertensive medications drugs. The first evaluates the effectiveness of an evidence-based, physician manager-centered, educational intervention on treatment success.(18) A second study aims to assess the effectiveness of a comprehensive intervention, consisting of self-management and self-monitoring hypertension, re-evaluation of lifestyle, and optimization of pharmacotherapy, and control in patients prescribed two or more antihypertensive drugs(19). The results from these studies are not available yet. A third trial has published its results. It was an open, cluster randomised trial in 326 villages in China in which 33,995 individuals aged 40 years or older with an untreated blood pressure of 140/90 mm Hg or higher (≥ 130/80 mm Hg among those with a history of cardiovascular disease, diabetes, or chronic kidney disease) or a treated blood pressure of 130/80 mm Hg or higher were randomised to enhanced usual care or trained village doctors. In the intervention, antihypertensive medications were initiated and titrated according to a standard protocol with supervision from primary care physicians, with additionally conducted health coaching on home blood pressure monitoring, lifestyle changes, and medication adherence (20). Usual care consisted of training health care professionals in measuring BP and referring patients to trained GPs when the BP is higher higher than 140/90 mm Hg. After 18 months a group difference of 37.0% (95% CI 34.9 to 39.1%) was found in controlled blood pressure in favor of the intervention group (57% controlled versus 20%). Mean SBP decreased − 26.3 mmHg from baseline to 18 months in the intervention group and by -11.8 mmHg in the control group, with a group difference of -14.6 mmHg (95% CI -15.7 to -13.3 mmHg, p < 0.001) (20). Importantly, this was an open label cluster RCT in which office blood pressures were used which could have affected the outcome. At 18 months the intervention-group took on average 2.1 types of antihypertensive medication whereas this number was was 0.9 in the enhanced usual care group (group difference 1.2% (95% CI 1.1 to 1.3%, p < 0.001). Although, conducted in a complete different context than the Netherlands, not selectively in uncontrolled hypertension patients, the results do indicate that an approach tackling several important aspects helps in controlling blood pressure levels. However, it may apply to domains where usual care is inadequate which means that there is sufficient room for improvement of both lifestyle issues and antihypertensive medication treatment.

Implications for research and practice:

Given that this trial was clearly underpowered, we are hesitant to draw conclusions based on our findings. Lessons learned are that complex interventions that are labour-intensive and that need substantial adjustments to routine care are difficult to perform in general practice, which leads to the risk of underpowerment. Further research should focus either on short and simple interventions that can easily be performed by health care workers, or on interventions that can be carried out by redundant staff.

In addition, the burden for patients should also be taken in account as we observed reluctance to participate in second 24-hour BP measurements.

Finally, since bloodpressure levels decreased in both groups, we think that wake up calls or increasing awareness for treatment of hypertension among both lay people and general practices may have a beneficial effect.

Uncontrolled hypertension is prevalent in general practice and guidelines recommend to touch upon its various contributing factors.

Our study findings are compatible with the notion that a stepwise approach with practical steps to address the contributing factors in general practice does not seem to be effective if usual care is already at a rather high level considering the refractoriness of managing hypertension.

Our results suggests that in The Netherlands a pragmatic but structured stepwise treatment of uncontrolled hypertension does not result in a lower 24-hour or office BP values as compared to usual care.

Ethics approval and consent to participate

The trial was approved by the medical Ethics Committee of the University Medical Center (UMC) Utrecht (NL61553.041.17) and was registered in the Dutch Trial register (reference: NTR7304). Registration date: May 4^th, 2018.

Consent for publication

All participants in the study signed informed consent to participate in the study and publication

Availability of data and materials

Unfortunately, the raw data cannot be made publicly available due to ethical and legal restrictions. However, all interested readers may request data from Monika Hollander, MD, PhD, general practitioner ([email protected]), the PI of the study.

Competing interests

The authors have declared no competing interests.

Funding

The study was conducted with an unrestricted research grant from The Netherlands Organization for Health Research and Development (ZonMw, project number: 839110013) and an additional grant from the Dutch Kidney foundation (project code: KF3P0lA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors’ contributors

MLB, MH and FR conceived the study idea, and designed the study. BK coordinated the study. BK, MH, and MCJB recruited the practices. BK, MH and MCJB managed the study and data collection. MLB performed the data-analysis. BK and MLB drafted the manuscript. All authors contributed to the revision of the manuscript and MLB is guarantor of the study. All authors read and approved the final manuscript.

Acknowledgments

We thank all participating GPs and PNs and the patients for their willingness to participate in Stepwise-HTN. We also want to thank Janneke Giele-Eshuis from Research Online and RTC Health Data for their excellent help with the data management of the Stepwise-HTN study.

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Table 1 is available in the Supplementary Files section.

No competing interests reported.

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STEPWISE management of uncontrolled hypertension in primary care: A cluster randomised controlled trial

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Primary outcome measurement

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Discussion

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Comparisons with existing literature

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Conclusions

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Version 1