Technology Note
Renal Denervation
April 2013
Introduction
Consequent to the 2011 National Health Committee (NHC) referral round, this Technology Note
considers the case for investing in renal denervation (the application of radio frequency energy via
a catheter to block renal nerves) to lower blood pressure in patients with resistant hypertension
(high blood pressure that is resistant to pharmaceutical treatment). The paper gives a high level
overview of the procedure, the prevalence and incidence of resistant hypertension, alternative
treatments, and the current evidence regarding the procedure’s safety, clinical effectiveness, cost
effectiveness and affordability.
The Procedure
Renal Denervation (RDN) (also known as renal nerve ablation or percutaneous transluminal
radiofrequency sympathetic denervation of the renal artery) is a percutaneous intervention for the
treatment of uncontrolled / resistant hypertension. The procedure does not involve an implant. A
catheter, with an electrode at its tip, is inserted through the femoral artery and guided using
fluoroscopy to the renal artery. The catheter is connected to a low-power radiofrequency (RF)
generator. Once inside the renal artery the electrode delivers RF energy to ablate (burn) the renal
sympathetic nerves at approximately five locations.1 Hyper-activation of the sympathetic nervous
system can cause hypertension [1-3]. Deactivation of the renal sympathetic nerves blocks
nervous-system signals from the kidneys to the brain that would otherwise raise blood pressure.
The procedure time is usually less than an hour and can be performed under local anaesthetic.
1
Alternatively methods such as ultrasound may be used for the ablation process
Renal Denervation
1
Prevalence and Incidence of Resistant Hypertension
The American Heart Association (AHA) defines resistant hypertension as office blood pressure2
greater than 140/90 mm Hg or 130/80 mm Hg in patients with diabetes or chronic kidney disease,
and patients prescribed three or more antihypertensive medications at optimal doses, including, if
possible, a diuretic; or normal office blood pressure but patients require four or more
antihypertensive medications [4]. No study has been conducted on the prevalence of resistant
hypertension in New Zealand. Overseas estimates suggest that between 5% and 30% of
individuals may be resistant to antihypertensive treatment [4-6].
International estimates of prevalence
The United States Joint National Committee on the Prevention, Detection, Evaluation, and
Treatment of high Blood Pressure [hence forth the US Joint National Committee] note that
prevalence of truly resistant hypertension is small [7]. Guidance issued by the American Heart
Association suggests that 20% to 30% of hypertensive individuals may be resistant to
antihypertensive treatment [4]. More recent research suggests a much lower prevalence of
resistant hypertension among US adults. Presell’s analysis of data from the National Health and
Nutrition Examination Survey between 2003-2008, which included a broadly representative
population of 15 968 non-pregnant adult participants, estimated population prevalence of 8.9% [6].
Participants in the study were classified as having resistant hypertension if their blood pressure
was ≥140/90 mm Hg (either systolic or diastolic) and they reported using antihypertensive
medications from 3 different drug classes in the past month or they reported using drugs from ≥ 4
antihypertensive drug classes in the past month regardless of blood pressure. It is unlikely that
medication was optimal for all patients in the study; in particular 14% of the study population were
not on a diuretic - diuretics can improve the effectiveness of antihypertensive medicines [8]. This
suggests the prevalence of truly resistant hypertension may be less than 8.9%. A recent
retrospective French study that followed hypertensive patients (n=144) in a specialised
hypertension unit found the frequency of resistant hypertension (failure to respond to triple therapy
plus a dietetic) was 5% [5].
2
Blood pressure measured in a clinic rather than at home.
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2
Estimating New Zealand‘s prevalence and incidence
The New Zealand Adult Nutrition Survey 2008/09 found 30% of adults, or 971,400 people aged 15
years or over, were currently taking medication for hypertension or had blood pressure ≥140/90
mm Hg.3 Assuming 5-9% of these adults have resistant hypertension, this equates to 48,570 –
87,426 individuals with resistant hypertension or between 111 and 200 per 10,000 individuals.
There is no published data on the incidence of hypertension in New Zealand. Nevertheless, in
2010/11 18,479 people were admitted to public hospitals in New Zealand and:


received a diagnosis of hypertension and;
had not previously had a diagnosis of hypertension in the secondary care setting (public
hospital discharge Jan 1988 - June 2010).
18,479 may serve as a rough indication of annual hypertension incidence (accepting it is likely to
undercount less severe cases of hypertension). Assuming resistant hypertension incidence
represents about 5-9% of hypertension cases, then this equates to 924 to 1663 cases annually.
Literature review methodology
The NHC undertook a systematic literature search to review available safety, efficacy,
effectiveness and cost-effectiveness evidence for RDN. The search strategy was adapted from an
early search strategy developed by the National Institute for Health and Clinical Excellence
(NICE)[9] (Appendix 1). MEDLINE, Embase, and Cochrane databases were searched from
January 1 2005 to 20 March 2013. Coupled with this was a search of available literature from
international health technology assessment agency websites using the keywords “renal
denervation”, “catheter ablation”, and “renal nerve ablation”. Abstracts and articles were screened
according to a pre-specified PICO research question and inclusion / exclusion criteria (Table 1).
Studies that met the inclusion criteria were retrieved and reviewed for use in the analysis.
Table One: PICO question and inclusion and exclusion criteria
Question
Inclusion Criteria
Exclusion Criteria
Population
Patients with resistant hypertension
Non-human/animal trials
Intervention
Renal denervation
Outcome
Safety, efficacy, effectiveness, cost-effectiveness
Other outcomes
Study type
HTAs, systematic reviews and meta-analyses,
RCTs, and observational studies
Case reports, single centre studies,
opinion pieces (other than editorials
to studies), abstracts only.
In line with recent literature reviews of renal denervation only one randomised control trial (RCT)
was identified along with an extended investigation of that trial [10-13]. The RCT, Renal
3
Source: Analysis conducted for the NHC from the 2008/09 Adult Nutrition Survey (n=4407). Blood pressure was not
measured in pregnant woman because pregnancy alters a woman’s blood pressure.
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3
Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-2), was for the
Symplicity™ Renal Denervation System. No other renal denervation system has published data
from a RCT; accordingly, the safety and efficacy evidence for RDN was limited to the Symplicity™
system. The phase I4 feasibility study was also included for the Symplicity™ system. One
systematic review, four health technology assessments, and two cost-effectiveness analyses were
included in the analysis. Of these works, one health technology assessment was provided to the
NHC through HealthPACT [14].
Alternative Treatments
Hypertension is an important risk factor for heart disease, as well as stroke and renal failure.
Modifiable risk factors for high blood pressure include physical activity, salt intake, obesity and
alcohol intake (Fisher and Williams 2005). First line treatment for hypertension is lifestyle change,
while antihypertensive medication may be used in concert if required. New Zealand guidelines
recommend antihypertensive medication if blood pressure is ≥170/100 [15]. NICE recommends
that if hypertension proves resistant to regular treatment further diuretics, alpha or beta-blockers
should be considered (see appendix 2) [16]. The US Joint National Committee found resistant
hypertension almost always treatable provided the cause is correctly identified (Appendix 3) [7].
As a major developed world health condition, there is no lack of private incentive for companies to
develop new technologies to address refractory hypertension. As such, irrespective of any effect
RDN may have, it should be expected that new medicines and alternative technologies, including
means of improving medication compliance5, will reduce the pool of patients defined as having
refractory hypertension over-time. An alternative to RDN is Baroreflex activation therapy (BAT),
where an implanted device electrically stimulates the carotid sinus to reduce blood pressure. The
procedure was shown to be efficacious in a double-blinded RCT but appears less efficacious than
RDN (disused below) [17]. Currently BAT is costly relative to health outcomes with an incremental
cost-effectiveness ratio, relative to medical therapy, estimated at $US64,400 (NZ$77,600) per
quality-adjusted life-year (QALY) for a 50 year old US cohort without a history of cardiovascular
events [18].
An overview of percutaneous renal denervation devices by the Cardiovascular Centre Frankfurt
notes more than 60 companies are working on new devices for renal denervation[19]. However,
most of these procedures appear to be in the preclinical stages of development with little published
data available. The U.S. National Institute of Health’s clinical trials registry, Clinicaltrials.gov, lists
57 current or planed clinical trials for renal denervation (Appendix 4). Mercy Angiography Unit in
4
A Phase I trial tests the safety and feasibility of an intervention.
5
Technically if a patient has uncontrolled hypertension due to failure to comply with optimal medical therapy, then they
cannot be said to have resistant hypertension. But as the wide range of prevalence estimates demonstrate, it is difficult to
disentangle truly resistant hypertension from lack of compliance.
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4
Auckland is a registered trial site for a multicentre international phase two trial of the OneShot™
RDN device (NCT01520506). They have previously trialled the Symplicity device. The trial is a
small (n=40) safety/efficacy observational study over 13 locations. Twelve RDN procedures which
have undergone, or are in the process of clinical trials, are identified in Table Two.
Table 1 Competing RDN devices
Device and Developer
Medtronic
Symplicity™ Renal Denervation
System
THERMOCOOL Irrigated Tip
Catheter and Integrated Ablation
System
Mechanism of Action
Radiofrequency ablation of renal
sympathetic nerves
Status
CE Marking, WAND notification,
and TGA approval
Phase III trial underway
Radiofrequency ablation of renal
sympathetic nerves
Nonrandomised / non-controlled
Phase I and II trial underway
Radiofrequency ablation of renal
sympathetic nerves
CE Marking, WAND notification,
and TGA approval
Johnson & Johnson
St. Jude Medical EnligHTN™
System
Feasibility (observational) trial
underway
Kona Medical
Externally Focused (non-invasive)
Ultrasound Therapy
Feasibility (observational) trial
underway
Ultra-sound ablation of renal
sympathetic nerves
Animal and first-in-human
Mercator MedSystems
Chemical Ablation
Animal trials
Cricket and Bullfrog Systems
Allows drug delivery to renal
sympathetic nerve sheath
Vessix
Radiofrequency ablation of renal
sympathetic nerves
CE Marking
Radiofrequency ablation of renal
sympathetic nerves
CE Marking
Ultra-sound ablation of renal
sympathetic nerves
CE Marking
Radiofrequency ablation of renal
sympathetic nerves
FIH completed and recruiting for
prospective, non-randomised
open label feasibility study
Surround SoundTM system
CardioSonic
TIVUS system
V2™ Renal Denervation System
Covidien
OneShot™ System
Recor
Paradise™ System.
Medtronic
Multi-Electrode Radiofrequency
(RF) – Next generation simplicity
system
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Post market approval clinical
surveillance study
Phase II study Currently
underway
Phase I trial
5
Device and Developer
Medtronic
MDT-2211
Sound Intervention
Mechanism of Action
Status
Delivers radiofrequency (RF)
energy through the luminal
surface of the renal artery.
Recruiting for RCT
Unfocused Ultrasound
Completed FIH trial
Renal Denervation System
Regulatory status
Under current New Zealand legislation there is no pre-market scrutiny of devices and no approval
is required before a device can be supplied. However, for medical devices to be legally supplied in
New Zealand they must be notified to MedSafe’s Web Assisted Notification of Devices (WAND)
Database.6 The Symplicity™device was notified to the WAND database on 4 July 2012, and the
EnligHTN™ device was notified on 20 April 2012. Both devices have also been approved by the
Australian Therapeutic Goods Administration (TGA).
No RDN device has received FDA approval, though we are aware of five percutaneous RDN
systems with CE marking7. These include Medtronic’s Symplicity™ Renal Denervation System, St.
Jude Medical’s EnligHTN™ System, Vessix's V2™ Renal Denervation System, Covidien’s
OneShot™ System, and Recor’s Paradise™ System. Of these only Medtronic’s Symplicity device
has been subjected to a RCT.
Safety and Effectiveness
The primary literature on the safety and effectiveness of RDN has come from two clinical trials for
Medtronic’s Symplicity™ Renal Denervation System. These are the Symplicity HTN-1 phase
one (observational) trial with 153 patients, and the Symplicity HTN-2 phase two RCT (106
patients).
Safety
Available evidence suggests the procedure is associated with a low incidence of adverse events,
but long-run evidence on the procedure’s safety is still in its formative stage. The Symplicity HTN1 observational study of 153 patients found the procedure was without complications in 97% of
patients (149 of 153 patients)[20]. All four patients who experienced complications were treated
without subsequent problems. Three patients developed a pseudoaneurysm/hematoma (internal
6
Devices must be notified to the WAND database within 30 calendar days of a person or organisation becoming the
sponsor of the device. A sponsor is a person or organisation that imports or exports a device or that manufactures or
arranges the manufacture of a device in New Zealand.
7
The CE mark indicates a product's compliance with EU legislation and enables the free movement of products within the
European market: http://www.bvmed.de/stepone/data/downloads/9c/bc/00/CE%20Flyer%20english%202008.pdf
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bleed) in the femoral access site, and one patient experienced renal artery dissection on
placement of the treatment catheter before delivery of RF energy.
Initial results from the Symplicity HTN-2 randomised controlled trial reported no serious
complications related to the device or the procedure [21]. However, the following serious events
requiring hospital admission were reported for patients who underwent RDN:

one patient had nausea and oedema possibly related to underlying hypertension

one patient had a hypertensive crisis after abrupt stopping of clonidine

one patient had a transient ischaemic attack

one patient had a hypotensive episode resulting in a reduction of antihypertensive drug use

one patient received a coronary stent for angina
An extended investigation of the trial involving 46 patients to investigate the effect of RDN on
cardiorespiratory response to exercise found RDN and cardiopulmonary exercise testing were
performed without any serious adverse events in all patients [22].
Efficaciousness
The results from the Symplicity HTN-2 RCT reported an average reduction in office based blood
pressure of 32/12 mm Hg (p<0.0001) at six months for the 52 patients that underwent RDN,
whereas there was no change for the control group (n=54) [21]. The Symplicity HTN-1
observational study (n=153) reported an average reduction in office based blood pressure
compared to baseline of 25/11 mm Hg at six months (n=86), 23/11 mm Hg at 12 months (n=64),
and 32/14 mm Hg at 24 months (n=18) [20]. Medtronic have marketed two year follow-up data for
the HTN-2 study and three year follow-up data for the HTN-1 studies, but these data are yet to be
published in peer reviewed journals.
Figure two summarises the potential biases and limitations of the HTN-1 and HTN-2 studies. Of
note, both studies were sponsored by the manufacturer and the number of patients studied is still
relatively small. Published data does not extend beyond two years, so we cannot be confident of
the long term safety, efficacy or effectiveness of the procedure.
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Figure 1 Appraisal of HTN-1 and HTN-2 studies
Appraisal of HTN-1 and HTN-2
The U.S. Preventive Services Task Force grades the quality of the overall evidence for a service or
intervention on a 3-point scale (good, fair, poor):
Good: Evidence includes consistent results from well-designed, well-conducted studies in representative
populations that directly assess effects on health outcomes.
Fair: Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is
limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or
indirect nature of the evidence on health outcomes.
Poor: Evidence is insufficient to assess the effects on health outcomes because of limited number or power
of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information
on important health outcomes.
The HTN-1 study is fair quality with the following potential biases and limitations:




The device’s manufacturer, Atrian (now Medtronic), funded the trial and had input into the design,
analysis and publication of the study.
There was confounding in terms of the suite of medications that the participants took during the
trial. No separate analysis was done to assess if RDN was more or less safe versus various
types/combinations of antihypertensive medications.
31% of patients changed their medical therapy during the trial. There appears to have been little
effect when patients receiving increased medication were excluded from the analysis, but changes
in the use of diuretics may have influenced results.
Follow-up rates were low - 64 patients (42%) at 12 months and just 18 patients (12%) at 24
months.
The HTN-2 study is fair quality with the following potential biases and limitations:






The Symplicity HTN-2 RCT was not blinded, and the control group did not undergo sham
procedures. No placebo treatment was used. Having a placebo RDN treatment may not have been
feasible for ethical reasons during this study but could have limited the chance of the Hawthorne
Effect affecting the results.
The control group was not checked for optimal medical therapy. The enrolment criteria required
patients to have an elevated office systolic BP (≥160 mm Hg) despite taking ≥ 3 antihypertensive
drug classes, 1 of which was a diuretic, at target or maximal tolerated dose. But 5 percent of
patients at baseline were not using a diuretic.
35 percent of the control group had a reduction in systolic blood pressure of 10mm Hg or more at 6
months, the corresponding figure was 84% for the RDN group (p<0.0001). That is, a third of the
studies population may not be considered to have truly resistant hypertension, and the marginal
benefit of the procedure may be substantially less than the raw improvement figure (↓84% BP)
suggests.
The exposed group (RDN) and the control group were not necessarily comparable as there
seemed to be differences in the risk factors between the groups. Notably, the RDN group had a
higher proportion of patients with coronary artery disease, eGFR of 45-60 mL/min per 1.73 m2, and
taking beta and alpha-1 blockers. The study claimed that there were no significant differences
between the groups; however, it did not publish any significance tests to back up that claim.
Patients were asked to monitor their own blood pressure at home. This could have encouraged
user error and affected the readings. This problem though, was mitigated through a combination of
taking the average of three readings as well as recording blood pressure over a 24 hour period
using an automated device.
67% of the centres in this study were considered hypertension centres of excellence according to
the European Society of Hypertension, so these results may not carry over to centres with less
experience dealing with hypertension. No subgroup analysis by centre was reported.
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Reviews of RDN
A systematic review concluded that ‘data from short-term studies suggest that RDN is a
safe and effective therapeutic option’, though there remain ‘unanswered questions about
patient selection’, and a need for ‘long-term studies with large patient populations….to
study whether this benefit is sustained with a demonstrable difference in cardiovascular
disease’[10].
The Ludwig Boltzmann Institute, an Austrian think-tank, recommended against the adoption
of the technology in Austria given the current lack of evidence regarding mortality, longterm efficacy, and quality of life [11]. The Queensland Policy and Advisory Committee on
New Technology (QPACT) published a due diligence report on renal denervation in October
2011[13]. They found that preliminary cost-effectiveness analysis supports the adoption of
RDN, where it was expected the device and procedure could easily integrate into existing
hospital infrastructure. QPACT have subsequently approved funding for renal denervation
at the Princess Alexandra Hospital under the New Technology Funding and Evaluation
Program [23]. They aim to study short and long-run outcome indicators (including central
aortic pressure, aortic stiffness, left ventricular mass, and quality of life, reduction in
adverse cardiovascular outcomes and cardiac arrhythmic risk), and collect primary costeffectiveness data. NICE issued guidance on RDN in January 2012. NICE found inadequate
evidence of long-run safety and efficacy, hence it only supports the procedure’s use with
“special arrangements for clinical governance, consent, and audit or research” [12]. DLA
Piper reviewed RDN for the Australian-New Zealand health technology advisory body
HealthPACT, concluding that RDN was likely to become main-stream in the next decade.
However, they noted that trials with larger numbers of patients and longer follow-up were
required before the therapy becomes widespread [14]. In the absence of this evidence, the
review noted that RDN ‘should be reserved for selected patients with resistant hypertension
and accessed through health care facilities that are collecting long-term data using rigorous
methods.’
Cost-effectiveness
Two cost-effectiveness analyses (CEA) were identified; one based in the United States, the other
in Germany. The U.S. CEA estimates RDN has an incremental cost-effectiveness ratio (ICER) of $
NZ 3,624 per QALY when compared with medical therapy for a population (43% female) with a
mean age of 58 [24]. The German CEA estimates RDN has an ICER of $NZ4,095 per QALY and
$3,600 per QALY compared with medical therapy for men and woman aged 60, respectively[25].
Costs and QALYs were discounted at 3% in both studies, and both took the healthcare payer
perspective; that is they didn’t account for wider societal costs and benefits outside the health
system. Whilst deriving similar ICERs the U.S. CEA assumes a much greater upfront material and
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procedural cost than the German CEA ($NZ14, 806 vs $NZ 6,855), larger net lifetime savings ($NZ
12,423 vs $NZ 2,842 -$NZ 3,687), a greater reduction in systolic blood pressure (SBP) (32mm Hg
vs 20 mm Hg) and attributes fewer incremental QALYS (0.66 vs 0.88-0.98) to RDN (Table 3).
Table 3 Key Parameters and outputs of two CEAs
Parameters / Outputs
U.S. Study
German Study
Sex
43 % female
M
F
Age
58 (45-70)
60
Base case reduction in systolic blood pressure
32mm Hg
20 mm Hg
Procedure cost
(not including lifetime costs and savings)
$NZ14,806
$NZ 6,891
Incremental Cost
$NZ 2,385
$NZ 4,013
$NZ 3,168
Implied net lifetime discounted savings
$NZ 12,423
$NZ 2,878
$NZ 3,723
Implied savings as a % of procedural cost
84%
42%
54%
Incremental QALY
0.66 QALY
0.98 QALY
0.88 QALY
ICER
$NZ 3,624
$NZ 4,095
$NZ 3,600
Implied ICER assuming no savings
$NZ 22,433
$NZ 6,995
$NZ 7,790
Currency conversions are based on following exchange rates: $1USD =$NZ1.18, 1EURO = $NZ1.55. Source: [24, 25]
Implied savings and ICERs excluding savings were calculated from reported data in these studies.
The German study shows cost-effectiveness decreases with age due to the shorter postintervention survival time. That is, downstream cost savings/QALY gains attributed to reduced
hypertension-related adverse events and death decline with increasing age (table 4).
Table 4 Estimated ICERs for RDN by age in Germany
Age
Men
Woman
50
$2,344
$2,418
60
$4,095
$3,601
70
$6,653
$6,603
80
$18,017
$20,460
85
$29,433
$40,706
90
$96,746
$196,281
Source:[25]
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The results of both studies are most sensitive to the assumed reduction in SBP, the cost of RDN,
and the discount rate. The German study also found the non-response rate an important variable.
Using a willingness to pay threshold of about $NZ 38,000, and employing probabilistic sensitivity
analysis8, both studies report a 95% probability that RDN is cost-effective. In the U.S. study, RDN
ranged from being cost saving to costing NZ$37,000 per QALY when compared to medical
management. In the German study the credibility interval never shows cost savings, but shows the
RDN is cost-effective for men and woman aged up to 76 and 75, respectively.
Critical review of CEA studies
While the reported cost-effectiveness results look promising there are significant issues with the
analysis in both studies. Issues include, but are not limited to the following:
Limited clinical trials data
In absence of long-run data both studies had to estimate long run reductions in morbidity and
mortality from the Symplicity trials above. As such the validity of the results is limited by the
limitations outlined for those studies. In particular, the clinical data is short-term and from a small
population sample.
Absence of real world data
The effectiveness of the procedure is yet to be reported in a large registry trial, so we do not know
how the procedure will perform outside strict trial protocols in the general population.
Estimated savings are large and speculative
As shown in table three, the U.S. CEA indicates that 84% of the procedure’s cost will be recouped
from net lifetime savings. In the German study the net savings are between 42-54% of the original
cost of the procedure. Savings are attributed to estimated improvements in long-term morbidity and
mortality which have yet to be proven in real world conditions (i.e. reduced or delayed treatment
costs).
Estimated QALYs are speculative
As with savings, QALYs are attributed to estimated improvements in long-term morbidity and
mortality which have no real hard evidence from clinical trials of RDN. Of note the German study
derives a third to a half more QALYs from a baseline reduction in SBP which is two-thirds lower
than the U.S. study (table 3). It is not clear from published data why this is the case other than the
studies using different risk estimation for cardiovascular disease (CVD) events.
8
PSA sensitivity analysis differs from regular sensitivity analysis in that it is based on randomly drawn values from known
or estimated distributions for all input parameters - rather than selective variation by researchers of one or two
parameters at a time.
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Inaccurate comparator
The German study reports the ICER relative to ‘best medical therapy’, but the Symplicity trials did
not adequately check for compliance to optimal therapy. For example, fourth-line treatment using
an aldosterone antagonist combined with other diuretics has recently been shown to control blood
pressure in about 60% of patients with resistant hypertension [26]. An independent randomised
open label trial is currently underway to determine if renal denervation can do better on-top of
optimal treatment (Clinical trials number: NCT01570777).
The Cost of RDN is uncertain
The German study reports a procedural cost of $NZ 6,891 including further costs for periprocedural
bleeding complications. The cost is based on a diagnostic related group (DRG)9 code for similar
percutaneous interventional procedures. The U.S. estimate is substantially higher at $NZ14,806 for
material and procedure costs, which is in-line with a recent Australian estimate [14]. There is little
detail on either cost estimate.
Potential industry bias
Authors of the German study received funding from Medtronic. The relationship of the company
with the authors of the U.S. study is unclear.
The studies are not immediately applicable to New Zealand
Using New Zealand data the procedure is likely to be less cost-effective than indicated as the price
of antihypertensive medication is likely to be lower in New Zealand due to Pharmac. Given the
current paucity of published clinical data, the benefit of producing a New Zealand specific costeffectiveness model is limited.
Both cost-effectiveness studies used a 3% percent discount rate. The discount rate used by
Pharmac and NICE is 3.5% - roughly the long run government cost of debt (real 10 year
government bond rate), representing the opportunity cost of government spending. Since costs
are paid up front, but savings and QALYs predominate in later years, a greater discount rate will
reduce the present value / cost-effectiveness of the procedure. Remodelled the U.S. CEA using a
3.5% discount rate reduces incremental QALYs from 0.66 to 0.60, and increases the ICER from $
NZ 3,624 to $4,930 per QALY. These results do not indicate a material difference. In deriving the
estimate we fitted the distribution of future savings and QALYs to a Poisson distribution, as the
actual distribution was not evident in the U.S CEA report. Comparative QALYs and ICERs at
different discount rates are presented below (table 5).
9
DRGs are a system of classifying patients for the purpose of reimbursement.
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Table 5: Incremental QALYs and ICERs for under various discount rates
Discount Rate
0%
3%
5%
3.5%
IQALY – U.S
1.09
0.66
0.48
NA
IQALY remodelled
1.09
0.66
0.473
0.604
$NZ 3,624
$NZ 9,499
NA
ICER – U.S
-$ NZ 2,081
(incremental cost only)
ICER remodelled
-$NZ 2,081
(incremental cost only)
$NZ 3,626
$NZ 9,668
$NZ 4,930
ICER –
remodelled
without savings
NA
$NZ 22,433
$NZ 31,302
$NZ 24,513
Source:[24] with remodelling by the NHC
Given the limitations outlined, the most defensible estimate of cost-effectiveness may be derived
from the U.S. study, given its more conservative procedural cost and incremental QALY estimates,
excluding its significant down-stream savings estimates. This gives an ICER of about $24,513
(table 5).
The NHCs affordability model is subject to change: however, our current estimate is that the
technology could cost the health sector an additional (in excess of standard treatment) $7-16
million over five years.
The developing evidence base
Appendix 4 shows that there are a large number of studies (n=57) planned or underway which
should help clarify the safety, effectiveness and cost effectiveness of the procedure over the next
few years. The largest of these is Medtronic’s global registry which aims to collect data on 5,000
patients between 2012 and 2021. The company is recording outcomes for patients with various
health conditions including heart failure, diabetes, chronic kidney disease, and obstructive sleep
apnea. Expansion of RDNs treatment scope is also being trialled in patients with arterial fibrillation,
ventricular tachycardia, and metabolic syndrome. Medtronic’s other major trial is called Symplicity
HTN-3 – a multi-centre, single-blind (patients) RCT with an enrolment of 530 patients. Two studies
are assessing the cost-effectiveness of RDN [NCT01570777 (n=120), NCT01673516 (n=60)]
where both appear to be government funded. There is a series of RCTs planned or underway,
including several single and double blinded studies that do not appear to be industry sponsored.
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Conclusion
The available evidence for RDN suggests it may significantly reduce hypertension with relatively
little risk of adverse events. The evidence base for the long term safety and effectiveness of the
procedure is however, still in its formative stages. Recent cost effectiveness analyses claim the
procedure has an ICER of about $NZ 5,000 per QALY. Whilst indicating the procedure may be
highly cost-effective, the analyses assume large down-stream savings and health benefits for
which we currently have insufficient evidence. At a minimum the savings component of the ICER
should be regarded as speculative. With no savings assumed the ICER is roughly $24,500 per
QALY. The potential budgetary impact of the procedure is not predictable with any degree of
certainty but estimated to be between $7- 16 million over five years.
Renal Denervation
14
Appendix 1: Search Strategy
The following search strategy was used to find literature on the safety, efficacy, effectiveness, and
cost-effectiveness of RDN:
Database searched 1 January 2005 to 20 March 2013: Ovid MEDLINE(R) In-Process & Other Non-Indexed
Citations and Ovid MEDLINE(R), adapted for Cochrane Library, Embase.Search Strategy:
1hypertension/ (182440)
31 economics/ (26426)
55 randomized controlled trial/
(343710)
2 exp hypertension renal/ (17931)
32 "costs and cost analysis"/
(40245)
56 random allocation/ (76613)
3 (hypertension or hypertensive).tw.
(293377)
33 cost allocation/ (1920)
57 double blind method/ (118545)
4 ((high or raise*) adj3 blood adj3
pressure).tw. (12945)
34 cost-benefit analysis/
(55706)
58 single blind method/ (17181)
5 1 or 2 or 3 or 4 (347570)
35 cost control/ (19546)
59 clinical trial/ (475196)
6 exp sympathectomy/ (9179)
36 cost savings/ (7989)
60 clinical trial, phase i.pt. (12811)
7 *sympathetic nervous system/ (21502)
37 cost of illness/ (15827)
61 clinical trial, phase ii.pt. (20560)
8 denervation/ (12816)
38 cost of sharing/ (0)
62 clinical trial, phase iii.pt. (7651)
9 catheter ablation/ (18880)
39 value of life/ (5271)
63 clinical trial, phase iv.pt. (777)
10 6 or 7 or 8 or 9 (60230)
40 cost effective*.tw. (68435)
64 randomized controlled trial.pt.
(343710)
11 exp kidney/ (286454)
41 cost utility.tw. (2156)
65 multicenter study.pt. (152917)
12 renal artery/ (14880)
42 cost minimi*.tw. (837)
66 clinical trial.pt. (475196)
13 (kidney or renal).tw. (589285)
43 quality-adjusted life years/
(6033)
67 exp clinical trials as topic/
(262606)
14 11 or 12 or 13 (688451)
44 cost minimi*.tw. (837)
68 epidemiologic studies/ (5585)
15 10 and 14 (4519)
45 quality-adjusted life years/
(6033)
69 exp case control studies/ (589584)
16 5 and 15 (1147)
46 (qaly or daly or icer or
haly).tw. (4965)
70 exp cohort studies/ (1234345)
17 rsd.tw. (10142)
47 decision analy*.tw. (4694)
71 case control.tw. (68056)
18 ((renal or kidney) adj3 sympathe* adj3
(denervat* or ablation* or activ*)).tw. (1843)
48 models, economic/ (5486)
72 (cohort adj (study or studies)).tw.
(71440)
19 symplicity.tw. (22)
49 (cost or costs or
economic*).tw. (390451)
73 cohort analy*.tw. (3146)
20 (catheter* adj3 (renal or kidney) adj3
(denervat* or ablation*)).tw. (87)
50 meta-analysis as topic/
(12504)
74 (follow up adj (study or
studies)).tw. (35074)
21 enlightn*.tw. (2)
51 meta analy*.tw. (49231)
75 (observational adj (study or
studies)).tw. (37195)
22 vessix v2*.tw. (0)
52 metaanaly*.tw. (1213)
76 longitudinal.tw. (124918)
23 oneshot*.tw. (7)
53 (systematic adj (review*1
or overview*1)).tw. (41418)
77 retrospective.tw. (241669)
24 paradise system*.tw. (0)
54 randomized controlled
trials as topic/ (83877)
78 cross sectional.tw. (144394)
25 bullfrog microinfusion.tw. (0)
55 randomized controlled
trial/ (343710)
79 cross-sectional studies/ (152704)
26 kona.mp. and externally applied
focussed ultrasound.tw. [mp=title, abstract,
56 random allocation/
(76613)
80 or/31-79 (2833017)
Renal Denervation
15
31 economics/ (26426)
55 randomized controlled trial/
(343710)
27 tivus.tw. (0)
57 double blind method/
(118545)
81 30 and 80 (121)
28 17 or 18 or 19 or 20 or 21 or 22 or 23 or
24 or 25 or 26 or 27 (12025)
58 single blind method/
(17181)
82 limit 81 to (humans and yr="2005 Current") (63)
29 5 and 28 (613)
59 clinical trial/ (475196)
30 16 or 29 (1412)
60 clinical trial, phase i.pt.
(12811)
1hypertension/ (182440)
original title, name of substance word,
subject heading word, keyword heading
word, protocol supplementary concept, rare
disease supplementary concept, unique
identifier] (0)
HTA agencies searched for available literature: Agency for Healthcare Research and Quality,
AHTA - Adelaide Health Technology Assessment, Australia and New Zealand Horizon Scanning
Network - Technologies Assessed, MSAC, CADTH, DACEHTA - Danish Centre for Evaluation
and Health Technology Assessment, HSAC (New Zealand), Belgian Health Care Knowledge
Centre, Institute of Health Economics (Canada), Ontario Health Technology Advisory Committee
(Canada), NCCHTA - National Coordinating Centre for Health Technology Assessment, Quality
Improvement Scotland, NHSC (relationship to Euroscan) (University of Birmingham), VA
Technology Assessment, California Technology Assessment Forum, Health Technology
Assessment – Washington, Ludwig Boltzmann Institut für Health Technology Assessment, Haute
Authorité de Santé (primarily French, but some English content), Norwegian Knowledge Centre for
the Health Services, Swedish Council on Technology Assessment in Health Care, Catalan Agency
for Health Technology Assessment and Research, Blue Cross Technology Evaluation Center,
AETMIS, Ontario Health Technology Advisory Committee, McGill Technology Assessment Unit,
and the Monash – Center for Clinical Effectiveness, NICE
Renal Denervation
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Appendix 2: NICE guidance for antihypertensive drug treatment
Renal Denervation
17
Appendix 3: Causes of Resistant hypertension [7]
Improper BP measurement
Volume overload
Excess sodium intake
Volume retention from kidney disease
Inadequate diuretic therapy
Drug-induced or other causes
Nonadherence
Inadequate doses
Inappropriate combinations
Nonsteroidal anti-inflammatory drugs; cyclooxygenase 2 inhibitors
Cocaine, amphetamines, other illicit drugs
Sympathomimetics (decongestants, anorectics)
Oral contraceptive hormones
Adrenal steroid hormones
Cyclosporine and tacrolimus
Erythropoietin
Licorice (including some chewing tobacco)
Selected over-the-counter dietary supplements and medicines (eg,
ephedra, ma haung, bitter orange)
Associated conditions
Obesity
Excess alcohol intake
Identifiable causes of hypertension
Chronic kidney disease
Coarctation of the aorta
Cushing syndrome and other glucocorticoid excess states including chronic
steroid therapy
Obstructive uropathy
Pheochromocytoma
Primary aldosteronism and other mineralocorticoid excess states
Renal Denervation
18
Appendix 4: Current and planned RDN clinical trials
(Results current to 19 May 2013)
Condition
Sponsor
Phase
Enrolment
Design
Start
Finish
NCT01534299
RH HF D
CKD OSA
Medtronic
Vascular
4
5000
NR SB
01/02/12
01/07/21
BP
NCT01417221
EH
Other
1,2
800
NR OL
01/08/11
01/08/16
CCE
NCT01733901
CHD
Other
_
600
R SB
01/11/12
01/07/15
RSD4CHD2PRE
BP M
NCT01418261
RH
Medtronic
Vascular
3
530
R SB
01/09/11
_
SYMPLICITY
HTN-3
BP AE
NCT01705080
RH
St. Jude M
edical
_
500
OP
01/01/13
01/06/18
EnligHTN II
BP AE
NCT01628198
RH
Other
_
500
NR OL
01/05/12
01/12/19
SAVE
BP
NCT01635998
RH AF
Other
_
300
R SB
01/09/12
01/07/17
H-FIB
BP AF
QOL
NCT01790906
HF
Other
_
200
R SB
01/01/13
01/04/17
RSD4CHF
BP M
NCT01747837
VT
Other
_
200
R SB
01/10/12
01/10/15
RESCUE-VT
OM
NCT01417247
MS
Other
1,2
200
NR OL
01/08/11
01/08/16
CCE
NCT01402726
HF
Other
1,2
200
NR OL
01/07/11
01/04/17
CCE
NCT01418560
CKD
Other
1,2
200
NR OL
01/08/11
01/08/16
O
NCT01560312
RH
Other
3
150
R OL
01/10/11
_
PRAGUE-15
BP AE
NCT01541865
RH CKD
Vessix Vas
cular, Inc
_
150
NR OL
01/02/12
01/12/14
REDUCE-HTN
BP O
NCT01570777
RH
Other
4
120
R OL
01/04/12
01/07/14
DENER-HTN
BP AE CE
NCT01588795
D
Other
4
120
R OL
01/04/12
01/04/13
DERENEDIAB
O
NCT01522430
RH
Other
3
120
R DB
01/01/12
01/12/16
DEPART
BP O
NCT00888433
RH
Medtronic
Vascular
2
106
R OL
01/06/09
01/12/15
Symplicity
HTN-2
BP AE
NCT01814111
RH AF
Other
_
100
R SB
01/07/12
01/06/15
RSDforPAF
AF BP
NCT01628172
RH
Biosense
Webster, In
c.
_
100
R SB
01/01/11
01/01/15
RELIEF
BP
NCT01737138
CKD
Other
_
100
R SB
01/11/12
01/04/18
RSD4CKD
BP M O
NCT01644604
RH
Medtronic
Vascular
3
100
R OL
01/07/12
01/12/17
HTN-J
BP AE
NCT01686542
AF
Other
1,2
100
R OL
01/06/12
01/12/16
NCT01713270
RH AF
Other
_
100
R SB
01/07/12
01/07/15
RSDforAF
BP AF
NCT01639378
HF
Other
3
100
R DB
01/08/12
_
REACH
S
NCT01442883
RH CKD
Other
_
100
OP
01/11/10
01/12/13
BP
NCT01390831
RH
Other
1,2
100
NR OL
01/11/11
01/06/15
BP
NCT01505010
RH
Other
2
84
R SB
01/11/12
01/11/15
NCT00483808
RH
Medtronic
Vascular
1
73
NR OL
01/06/07
01/05/13
BP AE
NCT01656096
RH
Other
4
70
R SB
01/07/12
01/07/14
BP
NCT01762488
RH
Other
3
70
R DB
01/01/13
_
Renal Denervation
Acronym
Main
outcome
measures
NCT Number
O
INSPiRED
ReSET-2
19
BP
BP
Enrolment
Design
Start
Finish
Acronym
Main
outcome
measures
70
R DB
01/09/11
01/05/13
ReSET
BP
2,3
60
R OL
01/04/12
_
DIASTOLE
BP AE
Other
2
60
R OL
01/07/11
01/12/13
RH
Other
2
60
R OL
01/08/12
01/10/13
OsloRDN
BP CE
NCT01785732
IS RH
Other
60
R OL
01/01/13
01/01/16
RENSYMPIS
BP IS
NCT01630928
RH
Other
50
NR OL
01/03/13
01/12/15
NCT01789918
RH
ReCor Med
ical, Inc.
_
50
NR OL
01/02/13
01/02/15
NCT01699529
RH
Medtronic
Vascular
_
50
NR OL
01/09/12
01/08/16
BP AE
NCT01704170
RH
Kona Medi
cal Inc.
_
50
NR OL
01/11/12
01/06/14
BP AE
NCT01520506
RH
Maya Medi
cal,
Covidien,
Meditrial E
urope LTD
2
50
NR OL
01/05/12
01/03/15
RAPID
BP AE
NCT01438229
RH
St. Jude M
edical
_
47
NR OL
01/10/11
01/03/14
EnligHTN I
BP AE
NCT01632943
RH
Medtronic
Vascular
3
45
NR OL
01/05/13
01/01/14
HTN-India
BP AE
NCT00664638
RH
Medtronic
Vascular
_
45
NR OL
01/04/08
01/05/13
HTN-1
BP AE
NCT01392196
HF
Medtronic
Vascular
4
40
NR OL
01/10/11
01/01/17
SymplicityHF
AE
NCT01617551
EH
Other
_
30
R DB
01/03/12
01/06/14
RENO
O
NCT01427049
RH
Other
_
30
OP
01/08/11
01/08/13
BP O
NCT01499810
RH
Other
3
30
NR SB
01/03/10
01/01/13
BP AE
NCT01756300
RH
Biosense
Webster, In
c.
1
30
NR OL
01/12/12
01/03/18
BP
NCT01465724
IS RH
Other
3
30
NR OL
01/11/11
01/05/14
DREAMS
BP IS
NCT01355055
RH
Other
_
26
OP
01/03/11
_
ReD
_
NCT01689415
RH S
Other
_
25
OP
01/09/12
_
_
NCT01747382
RH
Other
2
20
NR OL
01/04/12
01/09/14
BP O
NCT01529372
RH
ReCor Med
ical, Inc
_
20
NR OL
01/05/12
01/07/14
NCT01638195
RH
Kona Medi
cal Inc.
1
20
NR OL
01/06/12
01/09/13
BP
NCT01538992
HF
Other
3
20
NR OL
01/04/13
01/04/14
AE
NCT01631370
IS RH
Other
8
NR OL
01/06/12
01/06/14
IS
NCT Number
Condition
Sponsor
NCT01459900
RH
Other
NCT01583881
RH HF
Other
NCT01366625
RH OSA
NCT01673516
Phase
BP OSA O
BP QOL
ACHIEVE
REALISE
Source: ClinicalTrials.gov
KEY: Condition: RH = resistant hypertension; EH = essential hypertension; HF = heart failure; AF = atrial fibrillation; D= diabetes;
CKD= chronic kidney disease; OSA = obstructive sleep apnea; S= Stroke; IS = insulin resistance; VT = ventricular tachycardia; MS=
Renal Denervation
20
BP AE
BP AE
metabolic syndrome. Sponsor: specified, or other = university, institute, hospital. Design: R= randomised; NR= not randomised; SB=
single blind; DB= double blind; OL= open label; OP = observational prospective; Outcomes: BP = blood pressure, usually SBP; AE
= adverse events, CE = cost effectiveness, QOL = quality of life; M= all-cause mortality; CCE = composite cardiovascular even; IS =
insulin resistance; OSA = obstructive sleep apnea; AF = atrial fibrillation; O= other
Renal Denervation
21
References
1.
Wang, Z.V. and P.E. Scherer, Adiponectin, cardiovascular function, and hypertension.
Hypertension, 2008. 51(1): p. 8-14.
2.
Schlaich, M.P., et al., Renal Denervation as a Therapeutic Approach for Hypertension.
Hypertension, 2009. 54(6): p. 1195-1201.
3.
Katholi, R.E. and K.J. Rocha-Singh, The Role of Renal Sympathetic Nerves in Hypertension: Has
Percutaneous Renal Denervation Refocused Attention on Their Clinical Significance? Progress in
cardiovascular diseases, 2009. 52(3): p. 243-248.
4.
Calhoun, D.A., et al., Resistant hypertension: diagnosis, evaluation, and treatment. A scientific
statement from the American Heart Association Professional Education Committee of the Council for High
Blood Pressure Research. Hypertension, 2008. 51(6): p. 1403-19.
5.
Rosenbaum, D., et al. Frequency of hypertension resistant to treatment and indication for renal
denervation. in Annales de cardiologie et d'angeiologie. 2012: Elsevier.
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Persell, S.D., Prevalence of resistant hypertension in the United States, 2003–2008.
Hypertension, 2011. 57(6): p. 1076-1080.
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Chobanian, A.V., et al., Seventh report of the joint national committee on prevention, detection,
evaluation, and treatment of high blood pressure. Hypertension, 2003. 42(6): p. 1206-1252.
8.
Frohlich, E.D., Renal Denervation Using an Irrigated Radiofrequency Ablation Catheter for
Management of Drug-Resistant Hypertension: A Demonstrated Value? JACC: Cardiovascular
Interventions, 2012. 5(7): p. 766-768.
9.
NICE, NICE Interventional Procedures Programme: Interventional procedure overview of
percutaneous transluminal radiofrequency sympathetic denervation of renal artery for resistant
hypertension, NICE, Editor. 2012.
10.
Gosain, P., et al., Renal Sympathetic Denervation for Treatment of Resistant Hypertension: A
Systematic Review. The Journal of Clinical Hypertension, 2013. 15(1): p. 75-84.
11.
Wegman, M., S. Thomas., and H. Deuber, Renal denervation in patients with essential
hypertonia. Decsion Support Document 45., L.B. Institute, Editor. 2011.
12.
NICE. Percutaneous transluminal radiofrequency sympathetic denervation of the renal artery for
resistant hypertension. 2012; Available from:
http://www.nice.org.uk/nicemedia/live/13340/57923/57923.pdf.
13.
QPACT, Due Diligence on Catheter-based radiofrequency sympathetic renal denervation for
resistant hypertension, Q.P.a.A.C.f.N. Technology, Editor. 2011.
14.
DLA-Piper, New and Emerging Cardiac Technologies in Austrlian and New Zealand Public Health
Services Over the next Decade. 2013.
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MoH, New Zealand Primary Care Handbook 2012. 2012.
16.
NICE. Hypertension - Clinical management of primary hypertension in adults. 2011; Available
from: http://www.nice.org.uk/nicemedia/live/13561/56008/56008.pdf.
Renal Denervation
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17.
Bisognano, J.D., et al., Baroreflex activation therapy lowers blood pressure in patients with
resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial.
Journal of the American College of Cardiology, 2011. 58(7): p. 765-73.
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Young, K.C., et al., Cost‐Effectiveness of Treating Resistant Hypertension With an Implantable
Carotid Body Stimulator. The Journal of Clinical Hypertension, 2009. 11(10): p. 555-563.
19.
Horst, S., H. IIona, and V. Laura. Catheter-Based Technology Alternatives for Renal Denervation.
2012; Available from: http://www.tctmd.com/txshow.aspx?tid=208&id=113839&trid=198.
20.
Krum, H., et al., Catheter-based renal sympathetic denervation for resistant hypertension:
durability of blood pressure reduction out to 24 months. Hypertension, 2011. 57: p. 911-917.
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Esler, M.D., et al., Renal sympathetic denervation in patients with treatment-resistant
hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lance, 2010. 376(9756): p.
1903-1909.
22.
Ukena, C., et al., Cardiorespiratory response to exercise after renal sympathetic denervation in
patients with resistant hypertension. Journal of the American College of Cardiology, 2011. 58(11): p.
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CHI, Newsletter - Access Improvement Service, C.f.H. Improvement, Editor. 2012.
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Geisler, B.P., et al., Cost-Effectiveness and Clinical Effectiveness of Catheter-Based Renal
Denervation for Resistant Hypertension. Journal of the American College of Cardiology, 2012.
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Dorenkamp, M., et al., Potential lifetime cost-effectiveness of catheter-based renal sympathetic
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Bobrie, G., et al., Sequential nephron blockade versus sequential renin–angiotensin system
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Renal Denervation
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National Health Committee (NHC) and Executive
The National Health Committee (NHC) is an independent statutory body which provides advice
to the New Zealand Minister of Health. It was reformed in 2011 to establish evaluation systems
that would provide the New Zealand people and health sector with greater value for the money
invested in health. The NHC Executive are the secretariat that supports the Committee. The
NHC Executive’s primary objective is to provide the Committee with sufficient information for
them to prioritise interventions and make investment and disinvestment decisions. They do this
through a variety of products including Prioritising Summaries, Technology Notes, EpiNotes,
CostNotes, Rapid Reviews, and Health Technology Assessments which are chosen according
to the nature of the decision required and time-frame within which decisions need to be made.
Citation: National Health Committee 2012 Renal Denervation.
Wellington: National Health Committee.
Published in October 2012 by the National Health Committee
PO Box 5013, Wellington, New Zealand
This document is available on the National Health Committee’s website:
http://www.nhc.health.govt.nz/
Disclaimer
The information provided in this report is intended to provide general information to clinicians,
health and disability service providers and the public, and is not intended to address specific
circumstances of any particular individual or entity. All reasonable measures have been taken to
ensure the quality and accuracy of the information provided.
If you find any information that you believe may be inaccurate, please email to
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The contents of this report should not be construed as legal or professional advice and specific
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trademark, manufacture, or otherwise does not constitute an endorsement or recommendation
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Renal Denervation
24