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Health Policy Advisory Committee on
Technology
Technology Brief
ROX Coupler for Treatment-resistant Hypertension
March 2015
© State of Queensland (Queensland Department of Health) 2015
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This brief was prepared by Jonathan Henry Jacobsen from ASERNIP-S.
Summary of findings
The ROX Coupler is a novel therapeutic device indicated for patients with treatmentresistant hypertension. Evidence from the published literature is limited by the small
number of patients and short follow-up times. For patients treated with ROX, the relatively
small RCT reported significant reductions in all blood pressure measurements (office and
ambulatory) at six months follow-up, compared to baseline values. This reduction was not
observed in the control group. More patients in the ROX treated group reduced their antihypertensive medication compared to the control group, however some patients in both
groups needed to increase their medication. Larger patient numbers with an appropriate
sham control group is required to ascertain if these changes are significant. The two case
series demonstrated reduced systolic and diastolic blood pressure measurements at 6 and
12 months following the procedure. Despite the reductions, the average blood pressure
recording patients in all studies treated with ROX were still considered hypertensive. In the
case series, no mention was made as to whether the number of blood pressure medications
taken by these patients was reduced. Consequently, it is unclear whether the procedure
reduced the risk of developing cardiovascular and renal diseases. Although the majority of
adverse events were minor, the RCT did report one patient with deep vein thrombosis.
However, a similar procedure, arteriovenous fistula for vascular access has a relatively high
and severe complication rate. Three larger clinical trials are due to be completed within 24
months, two of which are randomised controlled trials.
HealthPACT Advice
The ROX Coupler is one of many therapeutic devices currently being marketed to reduce
treatment-resistant hypertension. The evidence-base supporting the use of this device is
limited, and although the small RCT reported reductions in all blood pressure measurements
in the treatment group compared to controls, this trial was not a blinded comparison and
did not include a sham arm. Studies have been conducted on a small number of patients
and different studies have used different patient inclusion criteria in particular regarding the
number of antihypertensive medicines used. The device is not registered by the TGA.
Concerns were also raised regarding the potential for harm with the use of this device, in
particular this has been demonstrated in COPD patients. Therefore HealthPACT recommend
that no further research on its behalf is necessary at this time, however should normal
horizon scanning activity detect TGA approval for the device or the results of the completed
RCTs are favourable, further research may be warranted.
ROX Coupler for treatment-resistant hypertension: March 2015
i
Technology, Company and Licensing
Register ID
WP195
Technology name
ROX Coupler
Patient indication
Treatment-resistant hypertension
Description of the technology
The ROX Coupler (ROX Medical, California, USA) is a novel treatment for patients with
treatment-resistant hypertension. The device consists of two components: a crossing needle
and a stent-like device made of nickel titanium alloy. The ROX coupler acts in a similar
manner to a paper clip, joining the femoral artery and vein in the upper thigh via a small
channel or anastomosis (Figure 1).
Figure 1
The ROX Coupler implanted to create a connection between the external iliac artery and vein,
increasing arterial compliance and reducing systemic arterial pressurea
Insertion of the ROX Coupler occurs in a cardiac or radiology catheterisation laboratory
under local anaesthesia. A spiral target wire is percutaneously inserted into the iliac artery
and advanced towards the femoral artery. The target wire marks the site of the vein-artery
anastomosis, and a guide wire and crossing needle are then inserted and positioned at the
site under fluoroscopic guidance. The crossing needle punctures the femoral vein and
artery. The ROX Coupler’s self-expanding stent is positioned at the puncture site, creating a
a
Diagram used with permission from ROX Medical (CA, USA) http://www.roxmedical.com/for-medicalprofessionals/professional-faqs/
ROX Coupler for treatment-resistant hypertension: March 2015
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connection between the vein and the artery. A balloon catheter is then used to expand the
anastomosis to a diameter of 4 mm. The procedure takes approximately one hour and is
fully reversible.2
The device creates a connection between the external iliac artery and vein, and it has been
hypothesised that this will increase arterial compliance whilst reducing systemic arterial
pressure in a similar manner as to that observed after the creation of an arterial-venous
fistula in end-stage renal disease patients.b A measured amount of blood is diverted from
the high pressure artery to the low pressure vein at a rate of 800 mL to 1000mL per minute.
The diversion of blood reduces vascular resistance (the force that opposes blood flow
through the blood vessels) while increasing arterial compliance (the ability of the vessels to
expand and contract with changes in blood pressure), thereby improving systolic and
diastolic blood pressure.1 Figure 2 is a schematic of the proposed mechanism of action of
the ROX Coupler.
Figure 2
A schematic describing the proposed mechanism of action of the ROX Couplerc
b
Eng, MH & Klein, AJ (2015). 'The path of least resistance to success in chronic hypertension?'. Catheter
Cardiovasc Interv, 85 (5), 887-8.
c
http://perruchenautomne.eu/wordpress/?p=3039
ROX Coupler for treatment-resistant hypertension: March 2015
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Company or developer
ROX Medical, California, USA.
Reason for assessment
At present there is no proven therapy available for patients with treatment-resistant
hypertension. These patients are at significant risk of cardiovascular morbidity and
mortality.
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
Licensing, reimbursement and other approval
The ROX Coupler is not listed on the ARTG and is considered an investigational device by the
United States Food and Drug Administration. The device has received the CE mark and is
commercially available in Europe.
Australian Therapeutic Goods Administration approval
Yes
ARTG number (s)
No
Not applicable
Technology type
Device
Technology use
Therapeutic
Patient Indication and Setting
Disease description and associated mortality and morbidity
Hypertension is defined as abnormally high arterial blood pressure indicated by an adult
systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg.
Hypertension is a major factor in the progression of cardiovascular disease and is a
contributing factor in the rising morbidity and mortality rates associated with coronary
heart disease, chronic kidney disease and stroke. Multiple blood pressure measurements
should be taken, at least twice, one or more weeks apart, to diagnose hypertension.
Lifestyle factors that contribute to an increased risk in the development of hypertension
include smoking, moderate to high alcohol intake, a body mass index >25 kg/m2, lack of
physical activity and a high salt intake. Treatment for patients diagnosed with hypertension
ROX Coupler for treatment-resistant hypertension: March 2015
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would depend on the absolute cardiovascular risk and other concomitant conditions;
however modification of lifestyle factors would be advised. Patients not responding to
lifestyle modification alone would be candidates for pharmacological options. ACE inhibitors
(or angiotensin II receptor antagonists (sartans)), dihydropyridine calcium channel blockers
or low-dose thiazide diuretics (for patients aged >65years) may be considered as first-line
pharmacological options. Thiazide diuretics should be used with caution as they have been
associated with an increased risk of new-onset diabetes. Beta-blockers are no longer
recommended as a first-line therapy due to an increased risk of developing diabetes.
Monotherapy with antihypertensives is recommended, however combination drug therapy
may be required.d
Treatment-resistant hypertension is defined by the American Heart Association as
persistent, elevated blood pressure that remains above blood pressure goals despite the use
of three antihypertensive agents. Ideally, one of the antihypertensive agents should be a
diuretic (a drug that promotes urine production). A patient whose blood pressure is
controlled using four or more medications is also considered to have treatment-resistant
hypertension.3 The long-term prognosis for patients with treatment-resistant hypertension
is unknown. Persistent, uncontrolled, elevated blood pressure is a leading risk factor for
stroke, myocardial infarction, obstructive sleep apnoea, and heart and kidney failure.
Patients with treatment-resistant hypertension are more likely to develop organ damage,
such as left ventricular hypertrophy, retinal lesions, kidney disease and heart failure, and
atherosclerosis (hardening of the arteries), compared with hypertensive patients who have
achieved blood pressure goals.4
Risk factors for the development of treatment-resistant hypertension include high body
mass index, protein in the urine (albuminuria), impaired kidney function, history of
cardiovascular disease and black ethnicity.4
Number of patients
The prevalence of treatment-resistant hypertension is difficult to determine. A review of
population-based studies within the United States concluded that 9 to 12 per cent of all
hypertensive adults meet the American Heart Association’s criteria for treatment-resistant
hypertension. This figure decreases to eight per cent when at-home blood pressure
measurements are considered. This highlights the impact of the white-coat effect, in which
patients exhibit elevated blood pressure in a clinical setting, but not in other settings.4
Approximately 4.6 million adults in Australia have hypertension.5 Using the prevalence of
treatment-resistant hypertension identified for the United States, it is estimated that
414,000 to 552,000 Australians could be classified as having treatment-resistant
d
Guide to management of hypertension 2008, Australian Heart Foundation. Available from:
http://www.heartfoundation.org.au/SiteCollectionDocuments/A_Hypert_Guidelines2008_2009Update_FINAL.
pdf
ROX Coupler for treatment-resistant hypertension: March 2015
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hypertension. Within Australia, approximately 47,243 Aboriginal and Torrens Strait Islanders
have hypertension.6 It is therefore estimated 4252 to 5669 Aboriginal and Torrens Strait
Islanders may be classified as having treatment-resistant hypertension.
In New Zealand, 1.4 million adults have hypertension.7 It is therefore estimated 126,000 to
168,000 New Zealand adults may be classified as having treatment-resistant hypertension.
However, it is unclear how many patients would be eligible for the ROX Coupler as the
inclusion and an exclusion criterion has not been firmly established.
Speciality
Cardiovascular disease and vascular surgery
Technology setting
General Hospital
Impact
Alternative and/or complementary technology
The ROX Coupler is used in conjunction with conventional medical management of
hypertension. It may potentially be used with other novel therapeutic technologies aimed at
reducing blood pressure, such as renal denervation and baroreceptor stimulation.
Current technology
Patients with treatment-resistant hypertension do not respond to conventional medical
management. These patients are at significant risk of cardiovascular morbidity and
mortality. Two novel devices previously evaluated by HealthPACT are currently being trialled
for treatment-resistant hypertension: the Rheos® Baroreflex Hypertension Therapy™
System (CRVx®, Inc., Minnesota, USA) and renal denervation. The Rheos system reduces
blood pressure by electrically stimulating the baroreceptors and carotid sinus, which
modulates the control of blood pressure by the sympathetic nervous system. Use of the
Rheos System is limited due to a lack of follow-up data and the use of inappropriate controls
in current clinical trials.
Renal denervation removes the sympathetic nerve terminals in the renal arteries by gently
heating the inside wall of the artery using radio frequencies emitted by a catheter. This
reduces the stimulation of kidney function by the sympathetic nerves, lowering blood
pressure. A phase three clinical trial for the leading renal denervation device, the
Symplicity™ Renal Denervation System (Medtronic, Inc., Minnesota, USA), failed to meet its
primary endpoint of reduced blood pressure at six months.8
Diffusion of technology in Australia
The ROX Coupler is not used in Australia.
ROX Coupler for treatment-resistant hypertension: March 2015
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International utilisation
Country
Level of Use
Trials underway or
completed
Belgium

Germany

Greece

Ireland

Netherlands

Poland

UK

USA

Limited use
Widely diffused
Cost infrastructure and economic consequences
Insertion of the ROX Coupler is an additional procedure for patients with treatmentresistant hypertension. Increased costs attributable to the procedure include the cost of the
device, imaging systems (fluoroscopy) and routine cardiac or radiology catheterisation
laboratory costs.
Table 1 lists the MBS items associated with the creation of an arteriovenous fistula for
vascular access and can be used as a cost estimate for the arteriovenous fistula created by
the ROX Coupler.
Table 1
MBS fees related to the creation of arteriovenous fistulas
MBS Item number
Descriptor
Fee
Benefit
34503
ARTERIOVENOUS ANASTOMOSIS OF UPPER OR LOWER LIMB, in
conjunction with another venous or arterial operation (Anaes.) (Assist.)
$413.55
75% = $310.20
34509
ARTERIOVENOUS ANASTOMOSIS OF UPPER OR LOWER LIMB, not in
conjunction with another venous or arterial operation (Anaes.) (Assist.)
$977.55
75% = $733.20
34512
ARTERIOVENOUS ACCESS DEVICE, insertion of (Anaes.) (Assist.)
$1,075.40
75% = $806.55
Ethical, cultural or religious considerations
No ethical, cultural or religious issues for the ROX Coupler were identified.
Evidence and Policy
Safety and effectiveness
Two case series evaluating the ROX Coupler, one prospective and one retrospective were
originally included in this brief (level IV interventional evidence). However, since this Brief
was finalised an RCT describing the use of the ROX coupler compared to normal medical
management was published (level II interventional evidence). For completeness, the results
ROX Coupler for treatment-resistant hypertension: March 2015
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of this study have subsequently been added. The two case series evaluated the safety and
efficacy of the ROX Coupler in patients with treatment-resistant hypertension and chronic
obstructive pulmonary disease (COPD) (Table 2).
Table 2
Characteristics of included studies
Study
Number of
participants
Length of follow
up
Lobo et al 20159
United Kingdom
RCT
Level II interventional
83
6 months
Industry sponsored
Faul et al 201410
24
12 months
The first author is the founder of ROX
Medical, holds several patents, has stock
ownership in and has received consultant
fees from ROX medical.
United States of America
Prospective case series
Level IV interventional
Brouwers et al 201411
Conflicts of interest
The seventh author is an employee of
ROX medical.
8
6 months
Not reported
Ireland
Retrospective case series
Level IV interventional
RCT, randomised controlled trial
Lobo et al 20159
The study conducted by Lobo et al. (2015) is an industry sponsored randomised controlled
trial to assess the safety and efficacy of the ROX Coupler. The study’s primary endpoint was
mean change in office and ambulatory systolic blood pressure at six months. Secondary
endpoints included mean office and ambulatory diastolic blood pressure and any
complications attributable to the ROX coupler at six months.
One hundred and ninety-five adults with treatment resistant hypertension were screened
across 16 centres in Europe for eligibility into the trial. Patients were excluded if they had
secondary hypertension (unless it was related to sleep apnoea), renal denervation within six
months, chronic kidney disease, type one diabetes mellitus, unstable cardiac disease, or a
recent history of heart conditions, severe cerebrovascular disease, a stroke within the
previous year, or severe peripheral arterial venous disease.
One hundred and twelve patients were subsequently excluded from the trial. Eighty three
patients were randomised in a 1:1 ratio via a computer generated process to either the
intervention (ROX coupler, n=44) or control (normal medical management, n=39) groups. Six
month follow-up data is currently available.
ROX Coupler for treatment-resistant hypertension: March 2015
7
Patient details are outlined in Table 3. In general, the included cohorts were middle aged,
overweight, stage two hypertensive and were taking between four to five antihypertensive
medications. Approximately 20 per cent of patients had prior previous renal denervation.
Table 3
Baseline characteristics of patients in Lobo et al 20159
ROX coupler group (n=44)
Mean (SD or %)
Normal medical management (n=39)
Mean (SD or %)
Age (years)
59 (9)
58 (9)
Body mass index (kg/m2)
30 (4)
30 (5)
Estimated glomerular filtration rate
(mL/min per 1.73m2)
76 (20)
77 (18)
Previous renal denervation
10 (23%)
7 (18%)
Coronary artery disease
7 (16%)
10 (26%)
Previous cerebrovascular events
5 (11%)
8 (21%)
Type 2 diabetes mellitus
9 (20%)
5 (13%)
175 (18)
100 (13)
171 (22)
100 (18)
157 (15)
93 (11)
156 (14)
93 (13)
4.6 (1.5)
5.0 (1.6)
21 (48%)
23 (59%)
Variable
Baseline office BP (mm Hg)
Systolic
Diastolic
Baseline ambulatory BP (mm Hg)
24hr systolic
24hr diastolic
Number of antihypertensive medications
Patients taking ≥5 medications
SD, standard deviation; BP, blood pressure
Safety
There were no deaths at the six month follow-up. Thirteen procedure-related and twelve
device-related adverse events occurred throughout the study period (Table 4). Each patient
recovered with no recurrent side effects.
There were no adverse events reported in the control group.
ROX Coupler for treatment-resistant hypertension: March 2015
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Table 4
Adverse events in the ROX Coupler group
Adverse events
Number (%)
Procedural adverse events
Arterial deployment
3 (7.1)
Intimal dissection iliac artery
1 (2.4)
Transient bradycardia
1 (2.4)
Contrast reaction
1 (2.4)
Urinary retention
1 (2.4)
Anaemia
1 (2.4)
Transient or localised pain
2 (4.8)
Nausea or lethargy
1 (2.4)
Deep venous thrombosis
1 (2.4)
Lower limb pain
1 (2.4)
Device-related adverse events
Venous stenosis
12 (28.6)
Efficacy
The ROX coupler was successfully implanted in 98% (n=42/43) patients. One patient was
excluded at the implantation stage due to unsuitable anatomy.
Forty-two and thirty-six patients completed the six-month follow-up in the ROX coupler and
control groups respectively. The primary and secondary outcomes of reduced home and
office systolic and diastolic blood pressure was achieved in the ROX coupler group but not
the control group (Table 5). All patients, however, were still considered hypertensive.
Further, it was not reported whether there were differences in blood pressure between the
two groups at six months.
A sub-analysis of patients, who received renal denervation more than six months prior to
the ROX Coupler, had significantly reduced blood pressure at six months compared to
control patients (Table 6).
Anti-hypertensive medication was reduced in eleven and two patients in the ROX Coupler
and control groups respectively (p=0.0303). Four patients in the ROX Coupler group required
an increase in the number of anti-hypertensive medications consumed at six months, in
contrast to ten in the control group (p=0.0382). Adherence to anti-hypertensive medication
throughout the study period was not measured.
There were no changes in kidney function in either group at six months.
ROX Coupler for treatment-resistant hypertension: March 2015
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Table 5
Mean change in systolic and diastolic blood pressure from baseline Lobo et al 20159
Mean (SD)
change in Blood
pressure
recording (mm
Hg)
ROX Coupler
(n=42)
p-value
Normal medical
management
(n=36)
p-value
Systolic
-26.9 (NR)
p<0.0001
-3.7 (NR)
p=0.31
Diastolic
-20.1 (NR)
p<0.0001
-2.4 (NR)
p=0.26
Systolic
-13.5 (NR)
p<0.0001
-0.5 (NR)
p=0.86
Diastolic
-13.5 (NR)
p<0.0001
-0.1 (NR)
p=0.96
Systolic
-13.9 (20)
p<0.0001
-1.5 (16.7)
p=0.60
Diastolic
-14.7 (9.8)
p<0.0001
-1.1 (10.5)
p=0.56
Systolic
-11.5 (17.6)
p<0.0001
3.0 (16.8)
p=0.30
Diastolic
-10 (9.7)
p<0.0001
2.5 (9.7)
p=0.14
Office
Ambulatory
Daytime
ambulatory
Night time
NR, not reported
Table 6
Mean
change in
blood
pressure
recording
(mm Hg)
Mean change in blood pressure from baseline at six months in patients with previous renal
denervation in Lobo et al 20159
ROX Coupler
(n=42)
p-value
Normal
medical
management
(n=36)
p-value
Net mean
difference
p-value
Systolic
-34.3
p=0.0024
3.2
p=0.70
-37.5
p=0.0029
Diastolic
-21.6
p=0.0012
-4.6
p=0.39
-17.0
p=0.0041
Systolic
-13.6
p=0.0066
5.2
p=0.52
-18.8
p=0.0368
Diastolic
-14.6
p=0.0006
5.2
p=0.36
-19.8
p=0.0086
Office
24hr
Ambulatory
SD, standard deviation
Faul et al 201410
Twenty-four adults with hypertension and COPD were prospectively enrolled into the study.
Patients were included if they were between 50 and 80 years of age, had stable COPD of
Global Initiative for Obstructive Lung Disease stage II or higher, and had been on the same
medication for at least four weeks prior to enrolment. Patients were excluded from the trial
if they were obese or had a mean pulmonary arterial pressure of more than 35 mm Hg; liver
cirrhosis; recent stroke or heart failure (within 6 months); unstable coronary artery disease;
peripheral vascular disease; or cancer that might affect their safety. All patients were
ROX Coupler for treatment-resistant hypertension: March 2015
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implanted with the ROX Coupler and received repeat cardiac catheterisation three to six
months following the implant. Data from the twelve-month follow-up was provided.
The included cohort were middle aged, had severe to very severe COPD and were
hypertensive. Two-thirds of the patients (n=16) had a systolic blood pressure of more than
140 mm Hg at baseline, and five patients had a reading of more than 160 mm Hg. On
average the patients were taking two antihypertensive medications. Further demographic
information is outlined in Table 7.
Table 7
Baseline characteristics of patients (n=24) in Faul et al 201410
Demographic
Mean (SD)
Age (years)
Body mass index
65 (6)
(kg/m−2)
25 (5)
Systolic blood pressure (mm Hg)
145 (12)
Diastolic blood pressure (mm Hg)
86 (13)
Mean arterial blood pressure (mm Hg)
105 (12)
Post-broncholdilator forced vital capacity (% predicted)
68 (22)
Post-broncholdilator forced expiratory volume (% predicted)
30 (11)
PaO2 mm Hg on room air
63 (9)
PaCO2 mm Hg on room air
42 (6)
PaCO2, partial pressure of carbon dioxide in the blood; PaO2, partial pressure of oxygen in the blood
Safety
There were no deaths at the 12-month follow-up. There were a number of adverse events,
and these were classified as early (those occurring within seven postoperative days) or late
(those occurring more than three months after the procedure). Four early adverse events
were attributable to the creation of the anastomosis, including a pseudoaneurysm at the
femoral access site (n=2), mild chest pressure and chest pain (n=1) and a clot around the
shunt (n=1). Late adverse events attributable to the device included: deep venous
thrombosis (n=4), closure of the shunt due to lack of clinical improvement (n=1) and venous
stenosis of the iliac vein (n=4). All patients were successfully treated.
Efficacy
The median procedure time was 53 minutes (range, 20 to 135 minutes), and was completed
without technical difficulty in 20 patients. The types of difficulties encountered while
undertaking the procedure on the remaining four patients were not reported.
All patients completed the 12-month follow-up. A sustained reduction in both systolic and
diastolic blood pressure was found (Table 8); however, all patients remained hypertensive.
Between three and six months the patients exhibited improved oxygen delivery and cardiac
output, and lowered systemic and pulmonary vascular resistance. These improvements may
have contributed to the reduction in blood pressure (Table 9).
ROX Coupler for treatment-resistant hypertension: March 2015
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Table 8
Change in systolic and diastolic BP compared with baseline, Faul et al 201410
BP mm Hg
Mean (SD) systolic
pressure mmHg
Mean (SD) diastolic
pressure mm Hg
Baseline
145 (12)
3 months
139 (NR)
p<0.05
76
p<0.01
6 months
130 (NR)
p<0.01
71
p<0.01
9 months
132 (NR)
p<0.05
74
p<0.01
12 months
132 (18)
p<0.01
67 (13)
p<0.001
Systolic p-value
Diastolic p-value
86 (13)
All p-values represent difference from baseline; NR, not reported; BP, blood pressure
Table 9
Change in haemodynamic outcomes, Faul et al 201410 (3-6 months postoperatively)
Mean (SD) values at
baseline
Mean (SD) values between
three and six months’
follow-up
p-value
Heart rate (beats/minute)
91 (16)
92 (16)
p=0.85
Mean arterial pressure (mm Hg)
106 (12)
97 (12)
p=0.001
Right atrial pressure (mm Hg)
8 (4)
9.5 (4)
p=0.17
Cardiac output (L/minute)
6 (2)
8.4 (3)
p<0.01
Oxygen delivery (mL/minute)
1091 (432)
1441 (518)
p<0.01
Systemic vascular resistance
(dynes)
1457 (483)
930 (335)
p<0.01
Mean pulmonary arterial
pressure (mm Hg)
25 (5)
29 (6)
p<0.01
Mixed venous oxygen saturation
(%)
73 (6)
79 (5)
p<0.01
12.2 (5)
15.5 (7)
p<0.01
190 (117)
140 (77)
p<0.01
Haemodynamic outcomes
Pulmonary capillary wedge
pressure (mm Hg)
Pulmonary vascular resistance
(dynes)
All p-values represent difference from baseline
Brouwers et al 201311
Eight patients, pooled from two-treatment centres in Belgium and Ireland, with treatmentresistant hypertension (taking an average of four anti-hypertensive drugs) and COPD were
retrospectively analysed for this case series. All patients underwent creation of an iliofemoral anastomosis using the ROX Coupler. Patients were followed up for six months
postoperatively with appointments at one, three and six months. No inclusion or exclusion
criteria were reported.
Safety
No deaths were reported. A lower leg oedema was the only adverse event recorded. There
was no information provided regarding treatment for the oedema.
ROX Coupler for treatment-resistant hypertension: March 2015
12
Efficacy
Both at-home and office-based blood pressure measurements exhibited a sustained
reduction at six months following the procedure (Table 10). These findings were
independent of changes in heart rate and kidney function. The statistical significance of
changes in at-home blood pressure recordings was not reported.
A sub analysis of five patients treated at the Belgium centre demonstrated a significant
increase in left ventricular function (p<0.05).
Table 10
Change in systolic and diastolic blood pressure, Brouwers et al 20138
Mean (SEM) change in
blood pressure
recoding (mm Hg)
Baseline
3 month follow-up
6 month follow-up
p-value (baseline
to 6-months)
Systolic
175.3 (6.8)
162.8 (8.5)
160.3 (9.0)
p=0.027
Diastolic
87.3 (5.1)
75.5 (5.7)
68.5 (4.7)
p=0.005
Systolic
151.9 (5.9)
146.3 (7.3)
145.5 (5.7)
Not reported
Diastolic
82.0 (5.4)
72.0 (5.5)
68.5 (4.7)
Not reported
Office
Ambulatory
SEM, standard error of mean
Economic evaluation
The costs associated with treatment-resistant hypertension have not been widely explored
in the Australian and New Zealand context. As such, an approximation has been made
regarding the yearly cost of antihypertensive medication. The average cost of medication
(Table 11) was calculated by determining the most frequently prescribed antihypertensive
of each drug class in the 2013-2014 financial year, the number of repeats required for a year
and then multiplying by the cost of the medication as listed on the Pharmaceutical Benefits
Scheme.
Table 11
Summary of the average costs of single and multi-medication antihypertensive regimes
Anti-hypertensive
regime
Average (range ) cost
of dispensed price for
maximum quantity
per year
Average (range ) cost
of maximum price to
consumer per year
One anti-hypertensive
medication
$128.99
($45.73 – $224.96)
$193.88
($65.23 – $289.93)
Two anti-hypertensive
medications
$260.87
($182.79 – $404.90)
$357.68
($477.39 - $267.25)
Three anti-hypertensive
medications
$406.29
($340.32 – $483.67)
$482.97
($482.97 – $547.21)
Four anti-hypertensive
medications
$519.30
($425.29 – $585.75)
$644.90
($574.72 – $714.64)
Physician
consultation every 3
months for blood
pressure
measurements
Total medical
management cost for
hypertension in
Australia per year
$51,309,720 $117,270,720
Professional
Attendances
(MBS item 3) $67.87
ROX Coupler for treatment-resistant hypertension: March 2015
$118,911,240 $158,548,320
$132,385,050 $190,121,400
$173,195,820 $230,927,760
13
For multi-medication regimes, the most common combination of anti-hypertensive drugs
was determined by the Heart Foundations guidelines. The cumulative cost of medication
was produced by adding the most commonly prescribed combination of medication, and
accounting for the number of repeats required for a year.
An estimated cost of the medical management required for hypertension within Australia
was determined by summating the average cost of maximum price to consumer per year
and the cost of four physician consultations, and then multiplying by the range of
hypertensive adults in Australia.
It is unclear whether the ROX Coupler will reduce the number of antihypertensive
medications required by the patient. As such, the ROX Coupler is an additional expenditure
with the cost estimate provided in Table 1.
Ongoing research
Searches of ClinicalTrials.gov and the Australian and New Zealand Clinical Trials Register
identified three clinical trials investigating the ROX Coupler for treatment-resistant
hypertension (Table 12). All three trials are being conducted in Europe, predominately in the
United Kingdom.
Table 12
Clinical trials evaluating the ROX Coupler
Trial Identifier/
Study
design
Indication
Interventions
Outcomes
Estimated
completion date
NCT01642498
Prospective
Multicentre
ROX Coupler +
continuing standard
antihypertensive
medication
Primary: change in mean office
systolic blood pressure at 6
months.
September 2016
Belgium,
Germany,
Greece, Ireland,
Netherlands,
Poland, United
Kingdom
Treatmentresistant
hypertension
Location
RCT
Standard
antihypertensive
medication
N=100
Secondary: change in mean
office diastolic blood pressure at
6 months.
6 month follow-up
Ongoing, but
not recruiting
NCT01885390
Prospective
United Kingdom
Single
centre
Recruiting
Treatmentresistant or
uncontrolled
hypertension
ROX Coupler +
continuing standard
antihypertensive
medication
Case
series
N=100
Primary: change in daytime
systolic blood pressure and
mean daytime ambulatory
systolic blood pressure at 6
months.
June 2016
Secondary: change in daytime
diastolic blood pressure and
mean daytime ambulatory
diastolic blood pressure at 6
months.
6 month follow-up
AF, atrial fibrillation; RCT, randomised control trial
Other issues
The device is also indicated for patients with COPD.
ROX Coupler for treatment-resistant hypertension: March 2015
14
Arteriovenous fistulas are routinely created as vascular access points for haemodialysis, and
are a similar procedure to creating an ilio-femoral fistula. As such, it can be used to highlight
potential complications and risks associated with ROX Coupler in the absence of any highlevel evidence. The rate of complication for arteriovenous fistula for vascular access ranges
from 16 to 26 per cent with aneurysms, cardiac failure, infection and thrombosis the most
frequently encountered complications.12, 13 Complications are more likely to arise in the
elderly and in patients with comorbidities such as diabetes.14 Further, high-flow
arteriovenous fistulas (>2000ml/min) increase the risk of adverse structural and functional
cardiac changes, for example, ventricular hypertrophy, left ventricular dilatation, elevated
left ventricular diastolic filling pressure and high-output cardiac failure. However, it is
presently unclear whether these changes occur only in patients with an underlying
cardiomyopathy or in all patients with a high-flow fistula.15
A study evaluating the ROX Coupler for patients with COPD was excluded from this technical
brief; however, it highlights significant issues regarding safety. Fourteen of the fifteen
patients enrolled in the study experienced adverse events (93%) attributable to the device.
Some patients experienced multiple adverse events (Table 13).16 Six patients were
successfully treated following an adverse event by using conservative methods, while eight
patients had their anastomosis closed. One patient died following the last follow-up from
right-sided heart failure, and this was likely related to the creation of the anastomosis.
Table 13
Number of adverse events reported by Bertog et al 201216
Adverse event
Number or events
Right heart failure
4
Oedema
10
Venous stenosis
7
Venous thrombosis
4
Haematoma
4
Pseudoaneurysm
1
Gum or nose bleeding
2
Passage of dark, tarry stools
1
Mild coughing up of blood
1
Contrast reaction (rash)
1
There was no difference in the study’s primary outcome (six minute walking distance) or
secondary outcome (quality of life), compared with baseline values, at the 12-week followup (p>0.05 for both variables). Despite this, surrogate markers of lung and heart function,
such as the New York Health Association Class, were improved at the 12-week follow-up
(p<0.01).
ROX Coupler for treatment-resistant hypertension: March 2015
15
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 website.
Total number of studies
2
Total number of Level IV studies
2
Search criteria to be used (MeSH terms)
Pulmonary Disease, Chronic Obstructive
Arteriovenous Shunt, Surgical
References
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ROX Coupler for treatment-resistant hypertension: March 2015
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