Download Implantable carotid sinus baroreflex device for the treatment of drug

Health Policy Advisory Committee on
Technology
Technology Brief Update
Implantable carotid sinus baroreflex device for the
treatment of drug-resistant hypertension
July 2014
© State of Queensland (Queensland Department of Health) 2014
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TECHNOLOGY BRIEF UPDATE 2014
Technology, Company and Licensing
Register ID
WP066
Technology name
Rheos® Baroreflex Hypertension Therapy™ System
Patient indication
Patients with drug resistant hypertension
Stage of development in Australia
Yet to emerge
Established
Experimental
Established but changed indication
or modification of technique
Should be taken out of use
Investigational
Nearly established
Australian Therapeutic Goods Administration approval
Yes
ARTG number (s)
No
Not applicable
International utilisation
Country
Level of Use
Trials underway or
completed
Canada

Czech Republic

Germany

Latvia

Netherlands

United States of America

Poland

Switzerland

Limited use
Rheos® Baroreflex Hypertension Therapy™ System Update: July 2014
Widely diffused
1
2014 Evidence and Policy
2014 Safety and effectiveness
Two case series (level IV Interventional evidence) evaluating implantable baroreflex
stimulation for drug-resistant hypertension were included in this update. However, the
included studies used different iterations of the baroreflex stimulation devices. Bakris et al1
evaluated the safety and efficacy of the Rheos® Baroreflex Hypertension Therapy™ System
(CVRx®, Inc., Minneapolis, MN, USA), and Hoppe et al2 evaluated the Barostim neo™ (CVRx®,
Inc.), a second generation device that supersedes the Rheos® System. In contrast with its
predecessor, the Barostim neo™ system has a new unilateral 1 mm electrode and a smaller,
more advanced stimulator.
The case series study by Bakris et al1 enrolled participants from the Rheos Pivotal Trial3, a
multicentre, double-blind, randomised, placebo-controlled crossover trial of the Rheos® System,
to assess the long-term safety and efficacy of baroreflex activation therapy. The key
enrolment criterion for the original Rheos Pivotal Trial was drug-resistant hypertension, defined
as systolic blood pressure of at least 160 mmHg and a diastolic blood pressure of at least 80
mmHg after at least one month of maximally tolerated therapy with at least three
antihypertensive medications, including a diuretic. The primary efficacy outcomes for Bakris et
al1 were the mean change in systolic blood pressure and the mean number of blood
pressure medications taken per patient following device implantation. The primary safety
outcome was the number of deaths. Similarly, the primary outcomes in Hoppe et al 2 were
the mean change in systolic blood pressure and the mean number of adverse events six
months after the intervention. A summary of the studies is provided in Table 1.
Table 1 Characteristics of included studies evaluating implantable baroreflex stimulation for hypertension
Study
Bakris et al 2012
Hoppe et al 2012
Design (evidence level)
Case study (IV)
Case study (IV)
Prospective
Prospective
Device
Rheos® System
Barostim neo™
Number of patients
276
30
Length of follow-up
22 to 53 months
6 months
Conflict of interest
The first, second, fifth and last authors are paid
consultants or advisors for CRVx®, Inc.
The first six authors and the last author are paid
consultants for CRVx®, Inc.
The fourth author is an employee of CRVx®, Inc.
The seventh and eighth authors are employees
of CRVx®, Inc.
Rheos® Baroreflex Hypertension Therapy™ System Update: July 2014
2
Bakris et al 2012
The purpose of this study was to assess long-term blood pressure control in patients with
drug-resistant hypertension who participated in the original Rheos Pivotal Trial 3 (see
November 2011 technology update for study details).1 Of the original Rheos Pivotal Trial
cohort (n=322), 276 patients either consented to or remained eligible to consent to the
long-term follow-up. Twenty-one patients withdrew during the initial trial3 and a further 25
did not consent to further participation (two patients died, five had the device removed and
18 withdrew). Consenting patients were divided into three groups: clinically significant
responders (n=244), intermediate responders (n=32) and withdrawn (n=46). The inclusion
and exclusion criteria for each group are listed in Table 2. Patients were followed up for an
average of 28 months (standard deviation [SD] 9; range 22 to 53 months) after the Rheos
Pivotal Trial.
Table 2 Bakris et al1 study group categories
Study group
Inclusion/exclusion criteria
Clinically significant responders
Systolic blood pressure <140 mmHg or <130 mmHg in patients
with diabetes or renal disease
A sustained reduction in systolic blood pressure of 20 mmHg
following device activation
A sustained reduction in systolic blood pressure of 20 mmHg
following device deactivation
Received a replacement device following completion of the Rheos
Pivotal Trial
Did not receive a replacement device or have a sustained
decrease in systolic blood pressure
Intermediate responders
Withdrawn
Patients who withdrew from the Rheos Pivotal Trial
Safety
Two deaths occurred among the patients who were eligible but were not yet enrolled in the
long-term study (one unclassified death occurred during sleep and one as a result of
ischaemic encephalopathy). Two deaths occurred due to cardiopulmonary arrest during the
long-term follow-up. None of the deaths were attributed to the device.
Efficacy
The results for the primary efficacy endpoints are summarised in Table 3. Overall, there was
a sustained decrease in mean systolic and diastolic blood pressure in all three groups,
compared with baseline values (p<0.001). Importantly, 55 per cent of the clinically
significant responders maintained systolic blood pressures of less than 140 or less than 130
mmHg for patients with diabetes or kidney disease. By 12 months after device implantation,
the mean number of medications used per patient had dropped significantly compared with
baseline (p<0.001) in the clinically significant responder group, but it had returned to pre-
Rheos® Baroreflex Hypertension Therapy™ System Update: July 2014
3
implant levels by the last follow-up visit. The number of medications used per patient
decreased by an average of 0.6, making the clinical significance of this result unclear.
Table 3 Efficacy outcomes for patients with a Rheos® System implant (Bakris et al 2012)
Clinically significant responder (n=244)
Pre-implant
12-month
follow-up
Last visit†
Intermediate responder (n=32)
Withdrawn (n=46)
Pre-implant
12-month
follow-up
Last visit†
Pre-implant
12-month
follow-up
Last visit†
Mean blood pressure (SD) (mmHg)
Systolic
177 (22)
139 (27)*
142 (29)*
177 (27)
155 (27)*
157 (22)*
187 (22)
161 (33)*
152 (33)*
85 (16)*
86 (18)*
105 (18)
95 (21)*
95 (19)*
108 (14)
92 (18)*
91 (23)*
79 (12)
75 (13)
75 (14)
74 (15)
73 (15)
74 (14)
5.9. (2.2)
5.2 (1.6)
5.0 (2.0)
4.8 (2.0)
Diastolic
102 (15)
Mean heart rate (SD) (beats/minute)
73 (15)
71 (14)
72 (14)
Mean number of hypertensive medications used per patient
5.3 (1.9)
4.7 (2.1)*
5.0 (2.0)
6.2 (1.9)
5.4 (1.9)
SD: standard deviation, *p<0.001 compared with pre-implantation, †Last visit between 22 and 53 months after implantation
Hoppe et al 2012
Thirty adults with drug-resistant hypertension (defined as a systolic blood pressure ≥140
mmHg despite taking three antihypertensive medications, including a diuretic) were
enrolled into the case series study (level IV Intervention evidence).2 Patients were recruited
prospectively from seven centres within Canada and the European Union. Patients
diagnosed with secondary hypertension, unstable angina, syncope, known or suspected
baroreflex failure or autonomic neuropathy, previous myocardial infarction or cerebral
vascular accident three months prior to the predicted implant date were excluded from the
trial. All patients received a Barostim neo™ device, which was activated two weeks after
implantation. Six-month follow-up data are currently available.
Baseline patient demographics are outlined in Table 4. In general, patients were middle
aged, overweight and under intensive treatment for hypertension.
Safety
No deaths were reported. Four adverse events occurred throughout the study period: a
device pocket haematoma, a self-inflicted wound complication, intermittent pain lateral to
the device and intermittent pain near the device. All adverse events were attributable to the
procedure. However, each patient recovered with no recurrent side effects.
Rheos® Baroreflex Hypertension Therapy™ System Update: July 2014
4
Table 4 Baseline characteristics of patients (n=30) included in Hoppe et al 2012
Variable
Mean (SD) or n (%)
Women
16 (53%)
Age (years)
57 (12)
Weight (kg)
85 (16)
Body mass index (kg/m2)
30 (4.2)
Blood pressure (mmHg)
Systolic
172 (20)
Diastolic
100 (14)
Heart rate (beats/min)
75 (12)
Number of medications used
6 (3)
History of sleep apnoea
2 (7%)
History of chronic kidney disease
3 (10%)
History of diabetes
7 (23%)
History of heart failure
1 (3%)
History of renal nerve ablation
6 (20%)
Efficacy
The implant procedure time was approximately 107 minutes (SD 28), of which 44 minutes
(SD 28) was spent mapping the procedure. There was a short learning curve associated with
the procedure. By the third implant procedure, the overall procedure time was reduced to
97 minutes (SD 29) (p<0.05). Of the 30 patients, 90 per cent (n=27) received the implant on
the right side, with most neck incisions being longer than 5 cm.
Twenty-nine patients completed the six-month follow-up and achieved the primary efficacy
objective of a reduction in office-cuff systolic blood pressure (Table 5). Interestingly,
implanting the device but not activating it also reduced blood pressure, but the statistical
significance of this effect was not reported. Additional endpoints included the mean change
in heart rate (5 beats/minute [SD 3]) and mean number of medications used (0.3 ± 0.3), but
these values were not statistically different from baseline (p>0.05 for both variables).
A subgroup analysis of patients with prior renal nerve ablation (another invasive treatment
for drug-resistant hypertension) showed that they also achieved a reduction in both blood
pressure and heart rate. Systolic and diastolic blood pressure decreased by a mean of 22.3
(SD 9.8) and 11.3 (SD 8.1) mmHg, respectively, while the heart rate dropped by a mean of 5
± 8 beats per minute. However, the statistical significance of these findings was not
reported.
Rheos® Baroreflex Hypertension Therapy™ System Update: July 2014
5
Table 5 Change in office-cuff systolic blood pressure in Hoppe et al 2012 (n=30)
Mean Systolic blood pressure
(SD) (mmHg)
Mean Diastolic blood
pressure (SD) (mmHg)
Statistical significance
Pre-implant
171.7 (20.2)
99.5 (13.9)
NR
Post-implant before
activation
160.6 (29.3)
94.6 (19.00)
NR
Mean change from baseline
at 3 months after activation
26.1 (3.3)
NR
P<0.001
Mean change from baseline
at 6 months after activation
26.0 (4.4)
NR
P<0.001
NR, not reported
2014 Economic evaluation
Borisenko et al 2013
The purpose of the economic evaluation was to compare the cost-effectiveness of Rheos®
Baroreflex Hypertension Therapy™ System as a second-line treatment for drug-resistant
hypertension with optimal medical therapy in a German population.4 The cost-effectiveness
of the Rheos® System was determined using a decision analytic model that combined a
decision tree with a Markov model. Data from the Rheos Pivotal Trial3 and the European
Device Based Therapy in Hypertension Trial (DEBuT-HT) trial5 were used for the efficacy inputs
of the model. Using a 50 year old patient with a high risk of end-organ damage as the
patient population, the Rheos® System was found to reduce the lifetime incidence of
myocardial infarction, stroke, heart failure and end-stage renal disease by 19, 35, 12 and 23
per cent compared with optimal medical management. Additionally, the Rheos® System
increased survival from 15.9 to 17.6 years and quality-adjusted life-years from 13.9 to 16.1,
with an incremental cost of AUD 26,012.14, compared with continued optimal medical
management. The incremental cost-effectiveness ratio (difference in average costs
compared with the difference in average quality-adjusted life-years between the study
cohorts) determined that the Rheos® System was cost effective (base case analysis was AUD
12,007.38, which was lower than the standard incremental cost-effectiveness ratio
threshold of EUR 35,000 [AUD 53,900] per quality-adjusted life-year used in European
studies).
Rheos® Baroreflex Hypertension Therapy™ System Update: July 2014
6
2014 Ongoing research
Table 6
Current clinical trials evaluating the Barostim neo™ system
Trial Identifier/
Location
Trial
status
N
Details
Diagnosis
Interventions
Estimated
completion
date
NCT01471834
Ongoing,
but not
recruiting
40
Case series
Drug-resistant
hypertension
Barostim neo™ system
July 2015
Recruiting
310
Drug-resistant
hypertension
Barostim neo™ system
July 2015
Canada,
Netherlands
NCT01679132
Multicentre
USA
RCT
Multicentre
Optimal medical management
NCT01471834: primary outcome is change in systolic blood pressure six months after the
intervention; secondary outcomes were not listed.
NCT01679132: primary outcomes are the number of adverse events 30 days after the
intervention and the change in office-cuff systolic blood pressure from baseline to six
months; secondary outcomes include the mean change in office-cuff and 24-hour
ambulatory systolic blood pressure from baseline to 12 months after the intervention and
the incidence of all hypertensive emergencies within six months of the intervention.
2014 Other issues
During the first 12 months of the Rheos Pivotal Trial, adjunct pharmacotherapies could be
altered at the discretion of the physician. Therefore, it was not clear whether this influenced
patient outcomes.
The Barostim Neo System has received CE mark approval in Europe.6
2014 Summary of findings
Baroreflex stimulation is a novel therapy for drug-resistant hypertension. The largest data
series (n=276) demonstrated a sustained reduction in both systolic and diastolic blood
pressure by the study end (22 to 53 months’ follow-up). However, the Rheos Pivotal Trial
was a randomised crossover trial, so the long-term efficacy of baroreflex stimulation
compared with optimal medical management (the current standard for drug-resistant
hypertension) remains undetermined. The other included study was small and had limited
follow-up. However, the study reported that baroreflex stimulation had a good safety
profile and few adverse events. In addition, there was a sustained decrease in systolic blood
pressure by the six-month follow-up. However, whether these surrogate outcomes of
reduced blood pressure and lowered heart rate translate to a lowered incidence of
cardiovascular or renal diseases remains unknown. Furthermore, the potential conflicts of
Rheos® Baroreflex Hypertension Therapy™ System Update: July 2014
7
interest, lack of appropriate comparators and long-term follow-up limits the conclusions
that can be made regarding baroreflex stimulation.
2014 HealthPACT assessment
Currently there is a lack of clinical and cost-effectiveness evidence to support the use of the
baroreflex stimulation to reduce hypertension. It should be noted that the Baroreflex Rheos
device has been superseded by the Barostim neo, which is not available in Australia. A large,
prospective RCT on the Barostim neo device is due for completion in 2015, the results of
which, if favourable, will be identified by horizon scanning activities. Therefore it is
recommended that no further research on behalf of HealthPACT is warranted at this time.
2014 Number of studies included
All evidence included for assessment in this Technology Brief has been assessed according
to the revised NHMRC levels of evidence. A document summarising these levels may be
accessed via the HealthPACT web site.
Total number of studies
2
Total number of Level IV studies:
2
2014 References
1.
Bakris, G. L., Nadim, M. K. et al (2012). 'Baroreflex activation therapy provides
durable benefit in patients with resistant hypertension: results of long-term followup in the Rheos Pivotal Trial'. J Am Soc Hypertens, 6 (2), 152-8.
2.
Hoppe, U. C., Brandt, M. C. et al (2012). 'Minimally invasive system for baroreflex
activation therapy chronically lowers blood pressure with pacemaker-like safety
profile: results from the Barostim neo trial'. J Am Soc Hypertens, 6 (4), 270-6.
3.
Bisognano, J. D., Bakris, G. et al (2011). 'Baroreflex activation therapy lowers blood
pressure in patients with resistant hypertension: results from the double-blind,
randomized, placebo-controlled rheos pivotal trial'. J Am Coll Cardiol, 58 (7), 765-73.
4.
Borisenko, O., Beige, J. et al (2014). 'Cost-effectiveness of Barostim therapy for the
treatment of resistant hypertension in European settings'. J Hypertens, 32 (3), 68192.
5.
Scheffers, I. J., Kroon, A. A. et al (2010). 'Novel baroreflex activation therapy in
resistant hypertension: results of a European multi-center feasibility study'. J Am Coll
Cardiol, 56 (15), 1254-8.
6.
CVRx® (2011). CVRx® Receives CE Mark Approval and Introduces New Implantable
Device for Hypertension, the Barostim neo™. [Internet]. CVRx®. Available from:
http://www.cvrx.com/intl_news/cvrx-receives-ce-mark-approval-and-introducesnew-implantable-device-for-hypertension-the-barostim-neo/ [Accessed 18 Mar
2014].
Rheos® Baroreflex Hypertension Therapy™ System Update: July 2014
8
PRIORITISING SUMMARY (UPDATE 2011)
REGISTER ID
S000091
NAME OF TECHNOLOGY
RHEOS HYPERTENSION THERAPY SYSTEMTM
PURPOSE AND TARGET GROUP
PATIENTS WITH DRUG RESISTANT HYPERTENSION
STAGE OF DEVELOPMENT (IN AUSTRALIA)


Yet to emerge
Experimental




Investigational
Nearly established

Established
Established but changed indication
or modification of technique
Should be taken out of use
AUSTRALIAN THERAPEUTIC GOODS ADMINISTRATION APPROVAL



Yes
No
Not applicable
INTERNATIONAL UTILISATION
COUNTRY
Czech Republic
Germany
Latvia
Netherlands
United States
Poland
Switzerland
Trials Underway
or Completed







LEVEL OF USE
Limited Use
Widely
Diffused
2011 SAFETY AND EFFECTIVENESS ISSUES
Study description
Results from the multicentre, double-blind, randomised, placebo-controlled Rheos Pivotal
Trial were available for inclusion in this update (Bisognano et al 2011). The European Device
Based Therapy in Hypertension Trial (DEBuT-HT) also provided data on the safety and
efficacy of the Rheos® Baroreflex system (Scheffers et al 2010). Although numerous
supplementary articles have been published which present preliminary data on the
aforementioned trial, the publication by Scheffers et al (2010) presents the most detailed and
long-term dataset to date.
Rheos® Baroreflex Hypertension Therapy™ System Update: 2011
1
The Rheos Pivotal Trial (NCT00442286) was a Phase III clinical trial of 265 patients with
resistant hypertension, designed to assess the safety and efficacy of the Rheos system
(Bisognano et al 2011). The key enrolment criterion was resistant hypertension, defined as
systolic blood pressure (SBP) of ≥160 mm Hg and diastolic blood pressure (DBP) of ≥80 mm
Hg following at least one month of maximally tolerated therapy with at least three
antihypertensive medications, including a diuretic. Other enrolment criteria included an
ambulatory SBP of ≥135 mm Hg for a 24 hour average, and an absence of clinically
significant orthostatic blood pressure (BP) changes.
A total of 49 centres were used to screen 590 potential patients between March 2007 and
November 2009. After screening for eligibility, 264 patients were found to be ineligible. Of
the 326 patients who were eligible for implantation, four were not implanted with the device,
as they failed to exhibit an acute testing response during surgery. The device, consisting of a
pulse generator and leads attached to each carotid sinus, was implanted by either a vascular,
cardiothoracic, or neurosurgeon in a total of 322 patients. Of these patients, 265 were
randomised in a 2:1 fashion, 181 to group A and 84 to group B. Sample size was calculated
to adequately power all primary endpoints, with 148 patients required in group A and 74 in
group B. Following implantation, the device was switched off for one month in all patients.
Patients in Group A then received baroreflex activation therapy (BAT) for the first six
months, while BAT was delayed for six months in Group B patients. Subsequently, patients
in both groups received BAT for a further six months. Patients and investigators were blinded
to treatment until after the 12-month follow-up visit. The average patient follow-up was 21 ±
8 months, and one patient in group A was lost to follow-up before the 12-month visit
(Bisognano et al 2011). An intention to treat analysis was used in this study, with unblinded
and withdrawn subjects treated as failures.
Both treatment groups had similar baseline characteristics, with no significant differences
observed between the groups for age, sex, race, BP, heart rate, body mass index (BMI),
comorbidities, and number and type of BP medications. Group A consisted of 116 males
(64%) and 65 females (36%), with a mean age of 53.7 ± 10.5 years, mean SBP of 169 ± 26
mm Hg, mean DBP of 101 ± 17 mm Hg, taking a mean of 5.2 ± 1.6 BP medications. Group
B consisted of 46 males (55%) and 38 females (45%), with a mean age of 52.4 ± 9.8 years,
mean SBP of 168 ± 24 mm Hg, mean DBP of 100 ± 14 mm Hg, taking mean of 5.2 ± 1.8 BP
medications (Bisognano et al 2011).
The DEBuT-HT trial was a prospective, multicentre, nonrandomised feasibility study, which
aimed to assess the safety and efficacy of the Rheos system in resistant hypertensive patients
(Scheffers et al 2010). To be eligible for inclusion, patients were required to be over 21 years
of age with BP of ≥160/90 mm Hg, despite receiving at least three antihypertensive agents,
including a diuretic. All medications were kept constant two months prior, and three months
following, implantation. Exclusion criteria included baroreflex failure, significant orthostatic
hypotension, cardiac arrhythmias, chronic atrial fibrillation, clinically significant cardiac
valvular disease or hypertension secondary to a treatable cause, carotid artery atherosclerosis
with >50% stenosis, previous implants or radiation in the carotid sinus region, currently
implanted electrical medical devices, dialysis and pregnancy.
Rheos® Baroreflex Hypertension Therapy™ System Update: 2011
2
Scheffers et al (2010) included 45 patients who underwent Rheos implantation at nine clinical
centres between March 2004 and November 2007. The group consisted of 26 males and 19
females with a mean age of 54 ± 9 years, mean SBP of 179 ± 29 mm Hg, mean DBP of 105 ±
22 mm Hg, taking a median of five antihypertensive medications. The device was activated
one month after implantation, and patients were followed up monthly for the first three
months, and annually thereafter. Of the 45 patients who underwent Rheos implantation, three
were excluded from the safety and efficacy analyses (as per protocol), four dropped out and
one missed a visit, resulting in a dataset of 37 patients at three months. Twenty-six and 17
patients completed the 1-year and 2-year follow-up, respectively. An additional cohort of 10
eligible patients who declined to participate was followed up by regular care. Outcomes
measured included office and ambulatory BP, ability to exercise during a six minute hallwalk test, renal function, carotid artery stenosis and serious adverse events associated with
implantation (Scheffers et al 2010).
Safety
The study by Bisognano et al (2011) evaluated procedural safety, BAT safety, and device
safety. Some complications occurred prior to randomisation; four patients did not exhibit an
acute testing response and were not implanted with the device, and two patients had the
device explanted prior to randomisation due to infection. A total of seven deaths, none of
which were related to the procedure or device, were reported during the follow-up period.
The causes of death included three intracerebral haemorrhages, two cardiopulmonary arrests,
one ruptured aortic aneurysm, and one drug overdose. The authors suggested that the
majority of these deaths were due to the normal sequelae of long-term hypertension. With
regard to procedural safety, the event-free rate was 74.8%, which was less than the prespecified objective performance criterion of 82% (P=1.00). Procedural adverse events were
not presented by treatment group, and included surgical complications (n=13, 4.8%), nerve
injury with residual deficit (n=13, 4.8%), transient nerve injury (n=12, 4.4%), respiratory
complications (n=7, 2.6%), and wound complications (n=7, 2.6%). All other procedural
adverse events occurred at a rate of less than 2%, and the majority (76%) of procedural
adverse events resolved completely. With regard to BAT safety, the event-free rate was
91.7% in Group A and 89.3% in Group B (P<0.001), and the only adverse event that
occurred at a rate greater than 2% in either group was hypertensive emergency (Group A:
n=9, 5%; Group B: n=7, 8.3%). With regard to device safety, the event-free rate was 87.2%,
which exceeded the pre-specified objective performance criterion of 72% (P<0.001), and the
only event that occurred at a rate greater than 2% was hypertension-related stroke, which
occurred in a total of 6 patients (2.3%).
Scheffers et al (2010) reported that a total of seven patients (16.7%) experienced procedurerelated serious adverse events, while one patient (2.4%) experienced a device-related serious
adverse event. Procedural complications included explantation of the device following
infection (n=3), perioperative stroke with minimal residual effects (n=1), tongue paresis
attributed to intraoperative hypoglossal nerve injury (n=1) and moderate pulmonary oedema
that resolved in six days (n=1). One death due to angioneurotic oedema occurred in the
cohort, and while the specific cause could not be determined, the authors suspected an
adverse drug reaction. The sole device-related complication occurred as a result of movement
Rheos® Baroreflex Hypertension Therapy™ System Update: 2011
3
of the implantable pulse generator, which was resolved by further surgery to reposition the
device.
In terms of functional safety measures, the distance travelled during a six minute hall-walk
test improved by 48 meters (P=0.01, n=14) and serum creatinine levels increased
substantially (P=0.04, n=22), one year after implantation (Scheffers et al 2010). In addition,
carotid artery stenosis was absent in all patients at the 1-year follow-up visit. During the three
months after implantation, no cases of orthostatic hypotension or syncope were reported
(n=32).
Effectiveness
The primary efficacy endpoints reported by Bisognano et al (2011) included acute efficacy
and sustained efficacy. Acute efficacy was defined as the proportion of subjects in Group A
versus Group B that achieved at least a 10 mm Hg drop in SBP at month 6 compared with
month 0, with a superiority margin of 20%. This study reported that 54% of patients in Group
A and 46% in Group B were responders at six months, which was not significantly different
(P=0.97). An additional efficacy analysis did show that the percentage of subjects achieving a
SBP ≤140 mm Hg at six months was greater in Group A (42%) than Group B (24%)
(P=0.005). Sustained efficacy was defined as the sustained response in SBP at month 12 in
Group A patients who had a response at month 6, with an objective performance criterion of
65%. For this outcome, 88% of responders at six months maintained their response at 12
months (P<0.001). The mean change in SBP at six months, which was a secondary efficacy
endpoint, was 16 ± 29 mm Hg in Group A and 9 ± 29 mm Hg in Group B (P=0.08). However
at 12 months, at which point Group A had received BAT for 12 months and Group B six
months, the mean decrease in SBP was 25 ± 32 mm Hg for Group A and 25 ± 31 mm Hg for
Group B.
In the study by Scheffers et al (2010), significant reductions in both office BP and
ambulatory BP were observed at 3 months, 1 year, and 2 years post-implantation (Table 1).
The authors reported that at each study visit, when the device was temporarily switched off in
order to assess BP without carotid artery stimulation, BP immediately rose to baseline levels,
before falling again once the device was turned on.
Table 1: Blood pressure and heart rate measurements after implantation with the Rheos system
(Scheffers et al 2010)
Δ 3 months
Δ 1 year
Office Blood Pressure
n = 37
n = 26
SBP (mm Hg) -21 ± 4 (P<0.001)
-30 ± 6 (P<0.001)
DBP (mm Hg) -12 ± 2 (P<0.001)
-20 ± 4 (P<0.001)
HR (beats/min) -8 ± 2 (P<0.001)
-8 ± 2 (P=0.001)
Ambulatory Blood Pressure
n = 26
n = 15
SBP (mm Hg) -6 ± 3 (P=0.102)
-13 ± 3 (P<0.001)
DBP (mm Hg) -4 ± 2 (P=0.041)
-8 ± 2 (P=0.001)
HR (beats/min) -5 ± 2 (P=0.001)
-6 ± 2 (P=0.012)
All figures given are mean ± standard deviation. Baseline levels not reported.
SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HR: Heart rate.
Rheos® Baroreflex Hypertension Therapy™ System Update: 2011
Δ 2 years
n = 17
-33 ± 8 (P=0.001)
-22 ± 6 (P=0.002)
-11 ± 4 (P=0.008)
n=8
-24 ± 8 (P=0.017)
-13 ± 5 (P=0.049)
-11 ± 34 (P=0.005)
4
COST IMPACT
A recent study showed that the Rheos Baroreflex Stimulator may be cost effective, with an
incremental cost-effectiveness ratio (ICER) between $50,000 and $100,000 per QALY
(Young et al 2009). The characteristics of the cohort, such as age and SBP, were found to be
important in determining the cost-effectiveness of the implantable carotid body stimulator for
use in treating resistant hypertension. A Markov model was used in this study. Direct costs
(2007 dollars), utilities, and event rates for future myocardial infarction, stroke, heart failure,
and end-stage renal disease were included in the model.
ETHICAL, CULTURAL OR RELIGIOUS CONSIDERATIONS
No issues were identified from the retrieved material.
OTHER ISSUES
Numerous supplementary articles have been published reporting combined results from the
European DEBuT-HT and US feasibility studies. The majority of these publications were
excluded from this update, as the study published by Scheffers et al (2010) provides a more
comprehensive representation of patients enrolled in the DEBuT-HT study. Also in some
publications, data from the US Feasibility study has been pooled with the European study,
resulting in patient overlap with Scheffers et al (2010).
Despite this, several small case series provide additional data of interest. Sica et al (2009)
reported on the effects of Rheos implantation in patients with chronic kidney disease (using a
subset of data from the European DEBuT-HT trial). Results from this study demonstrated no
change in the estimated glomerular filtration rate (eGFR), and a reduction in left ventricular
mass index (LVMI) (data not reported). Based on these findings, the authors concluded that
BAT may confer renoprotective effects, in addition to cardioprotective effects, in patients
with resistant hypertension (Sica et al 2009).
Karunaratne et al (2010) assessed whether the Rheos baroreflex stimulator had any
deleterious interactions with pacemakers in four patients. This study demonstrated no
oversensing at any pacemaker voltage setting, even when both devices were programmed to
provoke interaction. This subset of patients had a mean follow up of 8.3 ± 4.6 months at the
time of publication, during which no occurrence of observed or suspected oversensing was
reported (Karunaratne et al 2010).
Wustmann et al (2009) examined the effect of Rheos baroreflex stimulation on
cardiovascular regulation in 21 patients. In addition to demonstrating a mean decrease in BP,
this study also reported a fall in mean heart rate (P=0.001) and heart rate turbulence onset
(P=0.004), and altered heart rate variability frequency domain parameters (P<0.001). The
authors indicated that these cardiovascular changes were consistent with inhibition of
sympathetic activity and increased parasympathetic activity, corresponding to the observed
decrease in BP (Wustmann et al 2009).
Including the European DEBuT-HT and US feasibility trials, there are currently six ongoing
clinical trials evaluating the Rheos system (Table 2).
Rheos® Baroreflex Hypertension Therapy™ System Update: 2011
5
Table 2: Ongoing and currently recruiting clinical trials using the Rheos® system
ClinicalTrials.gov id
n (estimated)
Description
NCT01077180
(ongoing)
16
NCT00710190
(ongoing)
45
NCT00710294
(ongoing)
50
NCT00442286
(ongoing)
300
NCT00718939
(ongoing)
60
NCT00957073
(recruiting)
540
United States Rheos® Feasibility Trial;
case series to demonstrate the safety and
efficacy of the Rheos® system. 13 month
follow-up period.
Device Based Therapy in Hypertension
Trial (DEBuT-HT); case series to
demonstrate the safety and efficacy of
the Rheos® system. Continuous followup.
European DEBuT-HT extension trial;
collection of long-term safety and
efficacy data to support regulatory
approval and market release of the
Rheos® baroreflex stimulator.
Rheos® Pivotal Trial; prospective
randomised controlled trial comparing
clinical results between Rheos ‘ON’ and
Rheos ‘OFF’ arms. 12 month follow-up
period.
Rheos® Diastolic Heart Failure Trial;
prospective randomised double-blind
controlled trial comparing Rheos®
patients to non-implanted patients. 12
month follow-up period.
Rheos® HOPE4HF Trial; prospective
randomised controlled trial. Outcomes of
primary interest are death and
complications.
Estimated date of
completion
March 2012
December 2010
December 2010
December 2009
January 2011
December 2014
2011 SUMMARY OF FINDINGS
Although a significant number of articles have been published with regards to the safety and
efficacy of the Rheos Baroreflex Stimulator, the majority of such articles are in the form of
supplementary reports relating to several main trials. The study (Rheos Pivotal Trial) by
Bisognano et al (2011), and the two year safety and efficacy data (DEBuT-HT study)
presented by Scheffers et al (2010), represent the most comprehensive analysis of the Rheos
system to date. At six months, Bisognano et al (2011) did not demonstrate a significant
difference in the primary endpoint, number of acute responders, between the group that
received stimulation and the group that did not have the device switched on; however, an
additional analysis did show that more subjects in the stimulation group achieved SBP below
140 mm Hg. The device and stimulation therapy were found to meet pre-defined safety
criteria, while for procedural safety the event-free rate was less than the pre-specified
objective. In the study by Scheffers et al (2010), patients showed a reduction in office and
ambulatory BP measurements following implantation, and these values continued to decrease
two years post-implantation. Several serious complications were noted.
2011 HEALTHPACT ASSESSMENT
The safety and effectiveness of the Rheos Baroreflex Stimulator remain under investigation.
Several large clinical trials are ongoing. As these trials have the potential to expand
Rheos® Baroreflex Hypertension Therapy™ System Update: 2011
6
knowledge relating to the safety and effectiveness of the Rheos system, it is recommended
that this technology be monitored for 24 months.
2011 INCLUDED STUDIES
Total number of studies
Level II interventional evidence
Level III-3 interventional evidence
2
1
1
2011 REFERENCES
Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, de Leeuw PW, Sica
DA. Baroreflex activation therapy lowers blood pressure in patients with resistant
hypertension. Journal of the American College of Cardiology 2011; 58 (7): 765–773.
Karunaratne H, Muluk S, Papademetriou V, Park M, Sample R, Irwin E. Implantation of a
Carotid Baroreceptor Stimulator in Patients with Pacemakers and Hypertension. Pacing and
Clinical Electrophysiology 2010;[Epub ahead of print]
Scheffers IJM, Kroon AA, Schmidli J, Jordan J, Tordoir JJM, Mohaupt MG, Luft FC, Haller
H, Menne J, Engeli S, Ceral J, Eckert S, Erglis A, Narkiewicz K, Philipp T, de Leeuw PW.
Novel Baroreflex Activation Therapy in Resistant Hypertension – Results of a European
Multi-Center Feasibility Study. Journal of the American College of Cardiology 2010; 56
(15): 1254–1258.
Sica D, Rothstein M, Bisognano JD, Nadim MK, Lovett EG, Maufman D, de Leeuw P, for
the DEBuT-HT and Rheos Feasibility Investigators. Baroreflex Activation Therapy preserves
eGFR in hypertensive patients with Stage 2 and 3 chronic kidney disease: results from
European and United States Trials of the Rheos® System. Journal of the American Society of
Nephrology 2009; 20: 227A.
Wustmann K, Kucera JP, Scheffers I, Mohaupt M, Kroon AA, de Leeuw PW, Schmidli J,
Allemann Y, Delacrétaz E. Effects of chronic baroreceptor stimulation on the autonomic
cardiovascular regulation in patients with drug-resistant arterial hypertension. Hypertension
2009; 54 (3): 530–536.
Young KC, Teeters JC, Benesch CG, Bisognano JD, Illig KA. Cost-effectiveness of treating
resistant hypertension with an implantable carotid body stimulator. Journal of Clinical
Hypertension (Greenwich) 2009; 11 (10): 555-563.
Rheos® Baroreflex Hypertension Therapy™ System Update: 2011
7
PRIORITISING SUMMARY (2008)
REGISTER ID
S000091
NAME OF TECHNOLOGY
RHEOS HYPERTENSION THERAPY SYSTEMTM
PURPOSE AND TARGET GROUP
PATIENTS WITH DRUG RESISTANT HYPERTENSION
STAGE OF DEVELOPMENT (IN AUSTRALIA)


Yet to emerge
Experimental




Investigational
Nearly established

Established
Established but changed indication
or modification of technique
Should be taken out of use
AUSTRALIAN THERAPEUTIC GOODS ADMINISTRATION APPROVAL



Yes
No
Not applicable
INTERNATIONAL UTILISATION
COUNTRY
Czech Republic
Germany
Latvia
Netherlands
United States
Poland
Switzerland
Trials Underway
or Completed







LEVEL OF USE
Limited Use
Widely
Diffused
IMPACT SUMMARY
CVRx Inc. has developed the Rheos Hypertension Therapy System to treat people with drug
resistant hypertension. At the time of writing, this technology is not available in Australia and
is limited by Federal law in the United States to investigational use only.
BACKGROUND
Hypertension, also referred to as high blood pressure, is defined as systolic blood pressure
(SBP) more than 140 mm Hg and/or diastolic blood pressure (DBP) more than 90 mm Hg
(Illig et al 2006). It is a major risk factor for heart disease, stroke, peripheral vascular disease
and kidney disease failure (Berlowitz et al 1998; Spranger et al 2006).
Rheos® Baroreflex Hypertension Therapy™ System Update: 2008
1
Treatment of hypertension depends on its severity and whether the patient is in a high risk
group. For those stratified as being at high or very high risk (five year risk of cardiovascular
event 15% or greater), drug treatment is required in addition to lifestyle modifications (Vial
2004). There are many classes of medications used to treat hypertension including low-dose
thiazide diuretics, beta blockers, calcium channel blockers, ACE inhibitors and angiotensin-II
receptor antagonists (Vial 2004). The choice is influenced by the presence of
contraindications for particular classes or the presence of co-indications for drugs of a
particular class (Vial 2004). Most patients with hypertension requiring drug therapy need
combination therapy with medications from two or more classes to achieve target blood
pressure levels (Vial 2004). In Australia in 2005-06, agents acting on the rennin-angiotensin
system were by far the most popular medicines prescribed or supplied for hypertension (53.4
per 100 problems), followed by calcium-channel blockers (18.9 per 100 problems), betablocking agents (11.9 per 100 problems) and diuretics (7.4 per 100 problems), while
antihypertensives were seldom prescribed (1.7 per 100 problems) (AIHW 2007).
Despite the vast number of oral medications designed to help control hypertension, not all
patients are able to achieve desired blood pressure targets. There are numerous reasons for
blood pressure being inadequately controlled including issues of compliance to prescribed
medication, cost and incorrectly chosen medication combinations (Sica and Lohmeier 2006).
However, a significant number of patients fail to achieve adequate blood pressure control
despite adherence to maximal doses of several pharmacological agents (Fillipone and
Bisognano 2007). These patients are said to have resistant hypertension, defined as failure to
achieve a blood pressure of < 140/90 mmHg despite taking three anti-hypertensive
medications, including a diuretic for at least one month (Fillipone and Bisognano 2007;
Johnson 2007). In such patients new treatment options are sought to reduce hypertension
induced cardiovascular morbidity.
The Rheos Hypertension (HT) Therapy System (Rheos, CVRx. Inc., Maple Grove, MN,
USA) is a new device based treatment for drug resistant hypertension which works by
electrically activating the baroreceptors in the carotid arteries. Activation of the baroreceptors
initiates the baroreflex - a series of responses to physiologic stimuli that determine the
balance of sympathetic and parasympathetic activity in the heart and peripheral vasculature,
and thereby participate in both short and long term control of blood pressure (Braunwald et al
2001). The Rheos Hypertension (HT) Therapy System is made up of three components - the
Rheos Implantable Pulse Generator, Rheos Carotid Sinus Leads and the Rheos Programmer
System. Electrodes implanted on the exterior surface of the carotid sinus wall are connected
to the battery powered, programmable, impulse generator. The carotid sinus leads conduct the
activation energy from the impulse generator to stimulate the baroreceptor fibres in the vessel
walls of both carotid sinuses. These impulses are transmitted to the brainstem, where the
increased nerve traffic originating from the baroreceptor afferents is interpreted as an
elevated blood pressure and results in central nervous systems modulation of sympathetic and
vagal outflows which reduce blood pressure and heart rate (Tordoir et al 2007). The
programmable system is linked telemetrically to the impulse generator and allows the
physician to non-invasively adjust the stimulation parameters delivered to the carotid sinus
leads (Tordoir et al 2007).
Rheos® Baroreflex Hypertension Therapy™ System Update: 2008
2
The degree to which cardiovascular risk is reduced with treatment of resistant hypertension is
unknown. However, Calhoun et al (2008) suggest the benefits of successful treatment, are
likely to be substantial as suggested by hypertension outcome studies in general and by the
early Veterans Administration cooperative studies, which demonstrated a 96 % reduction in
cardiovascular events over 18 months with use of triple antihypertensive regimens compared
with placebo in patients with severe hypertension (diastolic blood pressure 115 to 129 mm
Hg) (Veterans Administration cooperative study group on antihypertensive agents, 1967).
CLINICAL NEED AND BURDEN OF DISEASE
The number of Australians with hypertension in 2004-05 was 2,100,700 (AIHW 2008a). It is
the most common problem managed in general practice, at 6.5 % of all problems in 2005-06
(AIHW 2007). Nearly 8 % of the burden of disease in Australia in 2003 could be attributed
to hypertension (AIHW 2008b). A recent population based survey of 11,247 Australian
adults found that the overall prevalence of hypertension was 29 % (Johnson 2007). However,
only 47 % of these people were receiving antihypertensive medications, and less than 20 %
had adequate blood pressure control (BP < 140/90 mm Hg) (Johnson 2007). The prevalence
of resistant hypertension ranges from 3 to 5 % in primary health care to 21 % in groups of
patients referred to tertiary institutions (Johnson 2007).
DIFFUSION
At the time of writing the CVRx Rheos Hypertension System was an investigational device
only, undergoing clinical evaluation in Europe and the United States to demonstrate its safety
and effectiveness. The data collected from this study by the FDA will be used to evaluate
whether this device should be made available to patients with drug resistant hypertension in
the US.
COMPARATORS
Lifestyle modifications (reduction in salt and alcohol intake and weight loss) combined with
drug therapy are the current methods used to control resistant hypertension.
SAFETY AND EFFECTIVENESS ISSUES
Four case series studies (level IV intervention evidence) were selected for inclusion in this
prioritising summary. Three of these are 1 page summary articles from supplement issues of
journals (Bisognano et al 2008; De Leeuw et al 2008; Scheffers et al 2008).
Bisognano et al (2008) recorded ambulatory blood pressure in 16 patients with resistant
hypertension during 1 year of Baroreflex Hypertension TherapyTM. Ambulatory pressure was
measured using an automated cuff programmed to inflate every 30 minutes during the day
and every 60 minutes during the night. Only tests of at least 21 hours duration and with 70%
of more available readings were used in their analysis. No mention was made of the patient’s
details in the paper including whether they were taking any hypertension medication in
addition to undergoing the Baroreflex Hypertension TherapyTM.
Scheffers et al (2008) report the first two year data (blood pressure and heart rate) on 16
patients with resistant hypertension (8f /8m, age: 52 ± 9 yrs, BMI: 31 ± 6 lg/m2) enrolled in
the DEBuT-HT trial (Device Based Therapy in Hypertension). The DEBuT-HT Clinical Trial
is a multi-center European clinical evaluation of the Rheos Hypertension System in patients
Rheos® Baroreflex Hypertension Therapy™ System Update: 2008
3
with drug resistant high blood pressure.The patients were a cohort from a total of 45 patients
implanted with Baroreflex Hypertension Therapy SystemTM. At the time Scheffer et al (2008)
were writing their paper the mean duration of the patient’s treatment with the device was 33
± 5 months. The number of antihypertensive medications taken by the patients remained
constant throughout the trial starting at 4.8 at baseline (when the device was activated) and
4.8, 4.7 and 4.6 at 3 months, 1 year and 2 years respectively.
De Leeuw et al (2008) investigated changes in blood pressure, heart rate, left ventricular
structure and number of anti-hypertension medications in 16 patients with resistant
hypertension (12 Europe/4 US, 7 M/9 F, Age 50.4±11.5 yrs, BMI 33.1±7.8 kg/m2) during 12
months of Baroreflex Hypertension TherapyTM. The patients, who were implanted at 4
different centers, had stage II hypertension (systolic BP ≥ 160 mmHg) and were taking ≥ 3
anti hypertension drugs (≥ diuretic) at the time of implantation of the device. The patients
continued to take the drugs whist undergoing the Baroreflex Hypertension TherapyTM.
Tordoir et al (2007) report the short term outcome of 16 patients implanted with the
Baroreflex Hypertension Therapy SystemTM as part of a multi-center feasibility trial for the
treatment of resistant hypertension. The patients (8m/8f, age: 52.3±8.6 yrs, BMI: 31.0±6.2
kg/m2) all had severe hypertension despite a multi drug therapy with a mean of >5
concomitant antihypertensive drugs. Tests of hemodynamic responses (heart rate and blood
pressure) to acute device activation were conducted. The settings for the tests included:
continuous bilateral stimulation with a frequency of 100Hz and an impulse width of 480 µs.
Stimulus amplitude (voltage) was increased in steps of 1V from 1-6V, each for 5 minutes.
Patient responses to the device were monitored for 3 months of therapeutic electrical
activation. It is not stated in the paper as to whether the patients remained on the
antihypertensive drugs during the evaluation of the device.
Safety
Safety outcomes were not reported in the study by Bisognano et al (2008), it is therefore
unclear if any adverse events occurred. Scheffers et al (2008) reported that no unexpected
system or procedure related serious adverse events occurred during the observation period in
their study (534 patient months). The only mention of safety outcomes by De Leeuw et al
(2008) was that no unanticipated adverse events occurred.
In the study by Tordoir et al (2007) the implantation of the baroreflex activating system was
reported to have been well tolerated with no unexpected serious procedure or device related
adverse events or perioperative deaths occurring. In the perioperative period (the time during
which the procedure was being implanted and a 30 day period following the procedure) there
were 38 procedure related adverse events reported in 17 patients. Of these events three were
classified as serious adverse events: 1. Infection, which led to the complete surgical removal
of the device in one patient. The implantable pulse generator was infected with a spreading
infection along the leads to the neck incision at both sides. High fever and serious pain with
redness necessitated surgical intervention. 2. Procedure related hypoglossal nerve injury with
symptoms of hoarseness and eating disturbances which improved during follow up. In this
patient the electrodes had to be placed high on the carotid bifurcation which resulted in an
accidentally injury to the nerve and 3. One case of intraoperative bradycardia (to 20
Rheos® Baroreflex Hypertension Therapy™ System Update: 2008
4
beats/min), which recovered spontaneously without any sustained effect. Details of all
adverse events are summarised in Table 1.
Table 1: Perioperative device and/or procedure related adverse events (Tordoir et al 2007)
Adverse event
Device related
Procedure related
N events
Infection
Hypoglossal nerve
injury
Introperative
bradycardia
Pain
Wound
complication
Extravascular
tissue stimulation
Anaesthesia
complications
Injury to local
tissue
Other
Total
0
0
1
1
1
1
N patients with
event
1
1
2
1
2
2
1
0
6
3
7
3
5
3
0
1
1
1
0
2
2
2
1
1
1
22
38
23
41
16
17
3
Effectiveness
In the study of 16 patients by Bisognano et al (2008) significant reductions from baseline in
24 hour mean blood pressure, daytime systolic blood pressure, nighttime systolic blood
pressure, pulse pressure, blood pressure load (percent of time systolic blood pressure
exceeded 140 mmHg), and trough:peak ratio (ratio of mean systolic pressure for the first 2
hours after wake-up to the last two hours before going to bed) were observed following 12
months Baroreflex Hypertension TherapyTM (Table 2).
Table 2: Changes in ambulatory measures following 12 months BHT (N=16) (Bisognano et al 2008)
Measure
Baseline
12-months BHT
24-hour mean (mm Hg)
171 ± 22
157 ± 24
Daytime SBP (mm Hg)
174 ± 22
159 ± 24
Nighttime SBP (mm Hg)
160 ± 26
148 ± 28
Pulse Pressure (mm Hg) 70 ±14
65 ± 13
BP load > 140 (%)
90 ± 16
71 ± 33
SD 24-hr SBP (mm Hg)
20 ± 4
18 ± 5
Trough:Peak
0.93 ± 0.11
1.04 ± 0.15
*p < 0.05
It is not stated in the paper as to what the error bars represent
∆ 12 months
-14*
-14*
-11*
-5*
-19*
-2
0.11*
Scheffers et al (2008) observed significant blood pressure and heart rate reductions compared
to baseline after 3 months, 1 year and 2 years of Baroreflex Hypertension TherapyTM (Table
3). A drop in systolic blood pressure of at least 20 mmHg was achieved in 12 of 16 (75 %)
patients at 2 years and 5 of 16 (31%) achieved a systolic blood pressure of less than 140
mmgHg at 2 years.
Rheos® Baroreflex Hypertension Therapy™ System Update: 2008
5
Table 3: Office based mean ± SD baseline and mean ± SE deltas (Scheffers et al 2008)
N=16
Systolic BP (mm Hg)
Diastolic BP (mm Hg
Heart rate (bpm)
*P<0.001
**P= 0.004
Baseline
191 ± 32
116 ± 22
81 ± 11
∆ 3 months
-34 ± 7*
-20 ± 4*
-14 ± 3*
∆ 1 year
-38 ± 7*
-27 ± 5*
-12 ± 3*
∆ 2 year
-35 ± 8*
-24 ± 6*
-12 ± 4**
De Leeuw et al (2008) reported significant reductions in office cuff systolic blood pressure,
office cuff diastolic blood pressure, septal wall thickness, left ventricular posterior wall
thickness, left ventricular mass index and relative wall thickness from baseline after 3 months
and 12 months of Baroreflex Hypertension TherapyTM. Left ventricular mass index decreased
in 15 out of 16 patients after a year of Baroreflex Hypertension TherapyTM.
Tordoir et al (2007) reported significant mean maximal reductions (p ≤ 0.0001) in systolic
and diastolic blood pressure and heart rate in system tests conducted 1-3 days
postoperatively. The tests, which were repeated monthly, showed consistent acute dose
dependent reductions in systolic and diastolic blood pressure and heart rate in that the degree
of change was directly related to the amplitude (voltage) of stimulation (Table 4). Reductions
in blood pressure and heart rate were also observed within amplitudes between the 1 month
(baseline values) and 4 month (3 months of baroreflex activation therapy) measurements
(Table 4). A repeated measures ANOVA of blood pressure and heart rate readings during
testing across voltage increments (0 volts to 6 volts) and visits (1 and 4 months) demonstrated
significant differences across doses (p < 0.0001 for each) and by visit (p = 0.003 for systolic
blood pressure, p = 0.0001 for diastolic blood pressure and p < 0.0001 for heart rate.
Table 4: Blood pressure and heart rate during 1 and 4 month system tests, n = 16 (Tordoir et al 2007)
Parameter and
Baroreflex Activation IPG Stimulation Amplitude (V)
Time Point
0
1
2
3
4
SBP (mm Hg)
1-month
184 ± 28
180 ± 29
176 ± 30
167 ± 32
160 ± 36
4-month
165 ± 21
164 ± 21
163 ± 27
160 ± 23
155 ± 27
DBP (mm Hg)
1-month
105 ± 17
104 ± 18
105 ± 17
98 ± 21
94 ± 22
4-month
95 ± 17
94 ± 16
93 ± 17
92 ± 15
89 ± 17
HR (BPM)
1-month
80 ± 14
78 ± 14
77 ± 15
74 ± 14
72 ± 14
4-month
68 ± 11
67 ± 10
68 ± 11
65 ± 11
65 ± 11
SBP; systolic blood pressure
DBP; diastolic blood pressure
HR; heart rate
BPM; beats per minute
It is not stated in the paper as to what the error bars represent
5
6
153 ± 31
147 ± 30
144 ± 36
143 ± 30
92 ± 21
84 ± 17
84 ± 24
81 ± 17
71 ± 15
64 ± 12
68 ± 14
62 ± 12
COST IMPACT
At the time of writing a price for the Rheos Hypertension Therapy System had not been
established as the product was still under clinical investigation.
ETHICAL, CULTURAL OR RELIGIOUS CONSIDERATIONS
No issues were identified from the retrieved material.
Rheos® Baroreflex Hypertension Therapy™ System Update: 2008
6
OTHER ISSUES
Each of the four case series had a person from the company manufacturing the Rheos
Hypertension Therapy System (CVRx Inc.) as a co-author on the paper. In the paper by
Tordoir et al (2007) the authors from CVRx, RK and RC, declare potential conflicts of
interest as employees and shareholders of the sponsor CVRx Inc. and the authors EI and TP
are consultants for the sponsor.
SUMMARY OF FINDINGS
The four papers reviewed all reported that Baroreflex Hypertension TherapyTM resulted in
sustained reductions in blood pressure over the period the patients were monitored. The
longest time investigated was two years (Scheffers et al 2008). Another outcome reported by
De Leeuw et al 2008 was that left ventricular hypertrophy, a factor that increases risk of
myocardial ischemia, regressed with Baroreflex Hypertension TherapyTM. Serious
complications were reported in one of the studies which conducted a safety analysis (Tordoir
et al 2007). It is important to note that these are only case series studies (level IV
intervention evidence) that have presented preliminary results from feasibility clinical trials.
Long term randomised controlled trials are required to further investigate the effectiveness
and safety of Baroreflex Hypertension TherapyTM. Several long term clinical trials sponsored
by CVRx Inc. are due to finish in 2009/2010 (http://clinicaltrials.gov; search term
baroreflex).
HEALTHPACT ACTION
Given the promising results to date and that the Rheos Hypertension Therapy System is still
under clinical investigation it is recommended that this system is monitored for 24 months.
NUMBER OF STUDIES INCLUDED
Total number of studies
4
Level IV intervention evidence
REFERENCES
Australian Institute of Health and Welfare. 2007. Medicines for cardiovascular health: are
they used appropriately? Senes S & Penm E. Cardiovascular Disease Series Number 27. Cat.
No. 36. Canberra: AIHW.
Australian Institute of Health and Welfare. High Blood Pressure in Australia. 2008a
http://www.aihw.gov.au/cvd/high_blood_pressure.cfm (Accessed September 2008).
Australian Institute of Health and Welfare. 2008. Australia’s health 2008. Cat. No. AUS 99.
Canberra: AIHW.
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SOURCES OF FURTHER INFORMATION
http://www.cvrx.com/medpros/index.php?id=15
http://www.cvrx.com/patients/index.php?id=33
SEARCH CRITERIA TO BE USED
Rheos, baroreflex, carotid sinus AND resistant hypertensio
Rheos® Baroreflex Hypertension Therapy™ System Update: 2008
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