CE: Namrta; HJH/203053; Total nos of Pages: 7; Eligibility for percutaneous renal denervation:the importance of a systematic screening Willemien L. VerloopÃ, Eva E. Ã, Michiel Evert-jan Maarten B. RookmaakerMichiel L. BotsPieter A. , Peter J. , andWilko Spiering Objective: Percutaneous renal denervation (pRDN) is anew and promising therapy for resistant hypertension.
Among patients suspected of having resistant G lobally,34%oftheadultpopulationhashyperten- sion, and this prevalence is still rising Hyper- hypertension, the actual presence of this condition needs tension is listed in the top three of modifiable to be well established; pseudoresistant hypertension and factors that impact the occurrence of disease burden glob- significant white-coat effect (WCE) should be excluded.
ally It is well established that lowering blood pressure This analysis presents the results of a standardized (BP) reduces cardiovascular risk Despite a broad avail- screening programme for patients referred for ability of effective pharmaceutical agents, only 32% of treated men and 37% of treated women reach treatment Methods: All patients referred to our centre for pRDN underwent a standardized stepwise screening and were Increased activation of the sympathetic nervous system subsequently discussed in a multidisciplinary team. The (SNS) is identified as an important factor in the develop- screening included a 24-h ambulatory blood pressure ment and progression of hypertension In this context, a measurement (ABPM), collection of plasma, urine and percutaneous, catheter-based approach has been devel- saliva, and finally imaging of the renal arteries.
oped to disrupt the renal sympathetic nerves, using radio-frequency energy The first clinical studies in a relatively Results: From August 2010 till October 2012, 181 small number of patients showed that this catheter-based patients were referred for pRDN. Mean blood pressure (BP) technique is efficacious. Office SBP/DBP values after bilat- was 182/100 mmHg, and median use was three eral percutaneous renal denervation (pRDN) were reduced antihypertensives. Ultimately, 121 patients (67%) were by À14/À10 to À27/À17 mmHg from 1 to 12 months of excluded from pRDN. Main reasons for exclusion were follow-up. Furthermore, the approach seems safe BP-related. Twenty-three patients (19%) had an office SBP According to the recently published European Society of less than 160 mmHg and 26 patients (22%) showed a Hypertension (ESH) position paper, pRDN is currently only WCE. Fourteen patients (12%) had a so far undetected indicated for patients with resistant hypertension In underlying cause of hypertension, the majority being 2008, the American Heart Association defined resistant primary aldosteronism (n ¼ 11). Nine patients had an hypertension as a BP that remains above treatment goals despite the concurrent use of medication from three differ- Conclusion: A high percentage of patients were excluded ent antihypertensive classes, one ideally being a diuretic, from treatment with pRDN due to secondary causes of with all agents prescribed at doses that provide optimal hypertension, WCE or a BP below the currently advised benefit Several reports provided insight into this thresholds. Treatment of these excluded patients would prevalence; however, numbers vary from 1.9 to 30% of lead to inappropriate use of pRDN, leading most likely tolittle benefit for the patients and a burden to healthcare.
Therefore, it is recommended to use a standardizedscreening before treatment with pRDN.
Journal of Hypertension 2013, 31:000–000aDepartment of Cardiology, bDepartment of Nephrology, cDepartment of Radiology, Keywords: ambulatory blood pressure measurement, dJulius Center for Health Sciences and Primary Care and eDepartment of Vascular blood pressure, renal denervation, resistant hypertension, Medicine, University Medical Center Utrecht, Utrecht, The Netherlands screening, secondary cause, white-coat effect Correspondence to Wilko Spiering, Department of Vascular Medicine, UniversityMedical Center Utrecht, F02.126, P.O. Box 85500, 3508 GA Utrecht, The Nether- Abbreviations: ABPM, ambulatory blood pressure lands. Tel: +31 88 755 5555; fax: +31 88 755 5488; e-mail: measurement; BP, blood pressure; CTa, computed ÃBoth Willemien L. Verloop and Eva E. Vink contributed equally to the writing of this tomography angiography; eGFR, estimated glomerular filtration rate; MRa, magnetic resonance angiography; Received 5 December 2012 Revised 21 February 2013 Accepted 10 April 2013 pRDN, percutaneous renal denervation; UMC, University J Hypertens 31:000–000 ß 2013 Wolters Kluwer Health | Lippincott Williams & Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: Namrta; HJH/203053; Total nos of Pages: 7; all patients who use at least three medications for hyper- treatment criteria. The standardized work-up consisted of a stepwise programme for every patient and the The potential success of pRDN as an adequate treatment option for hypertension depends on the ability to select patients were advised to reduce salt intake and to reduce patients most likely to benefit. Among patients suspected of having resistant hypertension, the actual presence of Subsequently after completion of the work-up, patients this condition needs to be well established. Individuals were discussed for the second time in the multidisciplinary with white-coat hypertension, with a BP that may still be meeting. Additional tests, for example to exclude secondary manageable with improved standard care and those with causes of hypertension, were performed whenever this was secondary forms of hypertension need to be excluded.
deemed necessary. The final decision whether pRDN was Prevalence estimates of secondary causes in hypertensive indicated was unanimously made by the multidisciplinary patients ranging from 10 to 15% have been described team. This team consists of two hypertension specialists Secondary forms of hypertension are more preva- (vascular internist and nephrologist), an interventional lent in patients suspected of having resistant hypertension cardiologist and an interventional radiologist. Every meeting, all departments were represented.
In the current analysis, the results of our standardized stepwise screening of all patients referred to our tertiary centre for treatment with pRDN are evaluated.
Results are expressed as means with standard deviations oras absolute numbers and percentages unless otherwise stated. All analyses were performed with the SPSS statisticalpackage version 20 (IBM SPSS Data Collection, Chicago, Between August 2010 and October 2012, all patientsreferred to the University Medical Center (UMC) Utrecht ESH Excellence Center for treatment with pRDN werescreened using a standardized protocol. Primarily, patients From August 2010 till October 2012, 181 patients were with resistant hypertension were considered eligible for referred to the UMC Utrecht for pRDN. The majority of pRDN. This condition was defined as an office SBP of at patients were referred by a cardiologist (39%) or hyperten- least 160 mmHg, despite the use of at least three antihy- sion specialist (33%). shows the characteristics of pertensive drugs, preferably including a diuretic. Patients the patients. The majority (52%) of the patients was female; fulfilling the same BP criteria, but without optimal pharma- mean age of the screened patients was 60 Æ 12 years. At cological treatment due to recorded intolerance for anti- the first visit to the outpatient clinic, mean SBP was hypertensive drugs, were accepted. Major contraindications 182 Æ 30 mmHg and mean DBP was 100 Æ 15 mmHg.
for pRDN were an estimated glomerular filtration rate Patients used a median number of three (range: 0–8) BP- (eGFR) of less than 30 ml/min per 1.73 m2, known secon- lowering drugs. Twenty-four percent of patients used an dary causes of hypertension, a history of renal artery aldosterone antagonist at the moment of referral. A sub- stenting and severe comorbidity (defined as any serious stantial group had used aldosterone antagonists in the medical condition, which, in the opinion of the physician, past, but stopped due to side effects (i.e. hyperkalemia may adversely affect the safety of the patient or the effec- Of all the referred patients, 121 (67%) were excluded from treatment with pRDN. They were slightly older and had a lower office BP than the patients judged eligible for The departments of Nephrology, Cardiology, Vascular pRDN. In addition, comorbidity was more prevalent in the Medicine and Radiology collaborated closely and devel- group considered not eligible. In some patients, reason for oped a standardized stepwise protocol. The aims of this exclusion was multicausal. However, only the primary work-up were to confirm the diagnosis of resistant hyper- reasons are summarized in For example, a patient tension; to exclude secondary forms of hypertension with a WCE and comorbidity is formally excluded because (including sleep apnoea); to exclude significant white-coat of WCE. Out of the 121, 23 patients (19%) were excluded effect (WCE, defined as a difference between office BP and because of an office SBP of less than 160 mmHg. Twenty-six daytime ambulatory BP >20 mmHg SBP and/or >10 mmHg patients (22%) were excluded on the basis of an ABPM DBP leading to an ambulatory SBP <140 mmHg); and during antihypertensive treatment less than 140 mmHg or finally to determine whether the anatomy of the renal ABPM less than 150 mmHg during the medication-free interval. This last category of patients did have a clear All referral letters were checked before invitation to the WCE. Part of the patients appeared to be normotensive outpatient clinic. Patients with a renal artery stent were by ABPM, and the majority of the excluded patients excluded on forehand. After the first visit at the outpatient had white-coat resistant hypertension (ambulatory SBP department, all patients were discussed in a multidiscipli- 130–140 mmHg). The patients who did not meet the BP nary meeting to decide whether a patient was a potential criteria were excluded in this early phase from the remaining candidate for pRDN, and whether the patient can undergo the screening. A patient could be excluded from further One hundred patients (55%) continued with the full work-up due to comorbidity or an office BP below stepwise protocol after the first screening phase. After Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: Namrta; HJH/203053; Total nos of Pages: 7; Reasons for exclusion from renal denervation Exclusion of:- eGFR < 30 ml/min per 1.73 m2 - Known secondary hypertension- History of renal art. stenting- White-coat hypertension- Severe co-morbidity.
Potassium suppletion in case ofhypokalaemia • Exclusion of secondary hypertension: e.g. hypercortisolism, hyperparathyroidism, hyperaldosteronism, thyroid dysfunctions, pheochromocytoma• Exclusion of WCE• Non-invasive imaging of the renal arteries FIGURE 1 Flow chart of the stepwise screening protocol. ABPM, ambulatory blood pressure measurement; HTN, hypertension; WCE, white-coat effect.
completing the programme in these patients, 14 cases (12%) In total, 60 patients did meet the inclusion criteria for were diagnosed with secondary hypertension, the majority treatment with pRDN, and all were treated. Twenty (33%) of being primary aldosteronism (11 patients, 9%). Antihyper- them had additional renal arteries: 17 patients (28%) tensive treatment was successfully adjusted in 15 patients had additional arteries at one side, and three patients (i.e. BP <160 mmHg). Therefore, these patients were (5%) had dual arteries at both sides.
excluded from further screening. If a patient was not usinga diuretic, this was added, leading to an improved regula- tion in seven patients. In two patients, a fixed combinationdrug was prescribed with good result. Other adjustments Out of all 181 patients referred to the UMC Utrecht, only were addition of an alpha-blocker, renin inhibitor or an 33% were eligible to undergo pRDN. The main reasons for increase of prescribed dosage. Ten patients were excluded exclusion were an office SBP of less than 160 mmHg, from treatment with pRDN because of severe comorbidity.
pseudoresistant hypertension due to a WCE and a secon- For example, presence of a malignancy, vascular dementia or severe heart failure were reasons to discontinue the The developed screening programme has three aims.
First aim of the programme is to confirm the diagnosis of In some cases (n ¼ 8), the multidisciplinary team hypertension. More specifically, the office SBP has to be decided to exclude patients, as they had proven either at least 160 mmHg under at least three antihypertensives not to be compliant to prescribed medication or repeatedly (or confirmed intolerance to medication) to be treated did not show up for their visits to the outpatient clinic.
with pRDN. In addition, a 24-h ABPM was performed, as Because the current programme involves an extensive one-third of patients with suspected resistant hyperten- work-up and follow-up, full expected compliance of sion in fact had a WCE An ABPM offers a large patients is required. Finally, although referred, not all number of BP measurements, during both daytime and patients (n ¼ 12) or referring doctors (n ¼ 1) in the end night-time. This results in a more precise assessment of BP than can be obtained from single measurements Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: Namrta; HJH/203053; Total nos of Pages: 7; TABLE 1. Characteristics of referred patients Current use of an aldosteron-receptor blocker Continuous variables are displayed as a mean (SD), except the number of antihypertensives, which is displayed as median (range). Categorical variables are displayed as a number(percentage). CAD, coronary artery disease; eGFR, estimated glomerular filtration rate; PAD, peripheral arterial disease; pRDN, percutaneous renal denervation; TIA, transient ischaemicattack.
aCalculated on the basis of Modification of Diet in Renal Disease Study criteria.
ABPM is also recommended in the work-up before pRDN The second aim of the screening is to exclude secondary in the ESH position paper on pRDN This simple, forms of hypertension. In particular, among patients sus- inexpensive test excludes a considerable number of pected of resistant hypertension, secondary forms have patients from further, more expensive, screening. This shown to be more prevalent Various forms of may increase the cost-effectiveness of the screening secondary hypertension are unlikely to respond to pRDN.
For example, hypertension due to primary aldosteronism is TABLE 2. Reasons for excluding patients (n ¼ 121) from treatment with percutaneous renal denervation Mean 24-h ambulatory SBP <150 mmHg without antihypertensive treatment or SBP <140 mmHg during antihypertensive treatment Renal artery anatomy is ineligible for treatment with pRDN Options for pharmaceutical treatment of hypertension Patient did not want to be treated with pRDN Referring physician did not want his patient to be treated Adequate regulation of BP after lifestyle adjustments Results are displayed as number (percentage). BP, blood pressure; pRDN, percutaneous renal denervation.
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CE: Namrta; HJH/203053; Total nos of Pages: 7; Reasons for exclusion from renal denervation volume dependent and is characterized by a decreased radiation and contrast agent exposure, but is also an accu- sympathetic activity On the basis of the working rate noninvasive imaging technique . Doppler Duplex mechanism of pRDN, it is unlikely that these patients will ultrasonography is another alternative that provides func- tional, as well as some anatomical, information. This tech- The current screening is a stepwise work-up that allows nique is relatively inexpensive, but it is time-consuming exclusion of a patient from further screening in an early and operator dependent, especially in obese patients phase. This resulted in a fully completed screening in only 93 patients. In these 93 patients, 14 patients were diagnosed We are among the first to provide an overview of with a secondary form of hypertension. Thirty-four percent screening results of patients referred for pRDN in clinical of this preselected population was diagnosed with resistant practice. Savard et al. performed a retrospective hypertension. This is in line with previous studies analysis. They applied the inclusion and exclusion criteria The majority of patients with an identified secondary of the ESH position paper to a cohort of hypertensive cause had been diagnosed with primary aldosteronism patients referred to their tertiary care hypertension depart- (77% of all secondary causes). It is remarkable that all ment and concluded that only 1.5% of this population referred patients had an extensive history of hypertension would be fully eligible for treatment with pRDN This and the majority had already been screened in some way for is clearly in contrast with our results, but is explained by the secondary causes before referral. The guidelines of the different patient population. Our population comprised Endocrine Society recommend screening for primary aldos- patients specifically referred for treatment with pRDN.
teronism in particular in all patients with resistant hyper- The discrepancy between prevalence of secondary causes tension The aldosterone-renin ratio is currently the for hypertension in our population compared with the most reliable manner to screen for primary aldosteronism population of Savard et al. may be explained by our Washout of all interfering medication is preferred selected population. Most of our patients were previously and patients should have an unrestricted dietary salt intake screened by their referring physician. Although exclusion before testing Temporary treatment with antihyper- rates between the population of Azizi and our population tensives, for example diltiazem or doxazosin, with neutral may differ, the overall conclusion is comparable; a sub- effects on plasma renin and aldosterone levels can be used stantial number of patients are excluded from treatment.
in severe hypertension. The standardized scheme of treat- Furthermore, the number of excluded patients in the ment tapering is given in the online supplement 2, Symplicity HTN-2-trial is comparable with our current clinical data, although we did not exclude patients with The prevalence of pheochromocytoma is about 0.2% of additional renal arteries. Surprisingly in the HTN-2 trial patients with hypertension In the screened patient no patients were excluded due to a secondary form cohort, pheochromocytoma was not diagnosed. During the screening, four false-positive cases with elevated One of the aims of this article is to give some metanephrines levels in 24-h urine were obtained.
recommendations for screening and selection of patients However, all patients had normal levels at repeated candidate for pRDN. Multiple additional articles with recom- investigation. As the majority of the patients diagnosed mendations for proper patient selection were published with a secondary cause of hypertension were diagnosed However, these articles only give general recom- with primary aldosteronism in our cohort, it is open for mendations and are not based on actual patient data. In debate whether patients should only be screened for this contrast to the ESH position paper, a slightly different secondary cause of hypertension. More extensive screen- patient selection and modified exclusion criteria were ing for rare causes, for example pheochromocytoma, applied by us. The position paper states that pRDN is might be performed only in patients suspected for such currently only indicated for patients with resistant essential hypertension . However, we decided to treat some According to the ESH position paper, it is recommended patients (n ¼ 10) with documented intolerance for antihy- to obtain renal artery imaging to assess renal artery pertensive drugs. Most of these patients experienced serious anatomy before treatment with pRDN As stated, side effects such as angioedema from angiotensin-convert- this is the third aim of the screening programme. Three ing-enzyme (ACE)-inhibitors, gout from diuretics or asthma out of 181 referred patients did have a history of renal from beta-blockers. These patients often pose dilemmas to artery stenting and were therefore not suitable for treat- the treating physician, and especially for these patients, ment and were excluded on the basis of the referral pRDN can be of potential benefit. This approach is partly letter. Six patients were not eligible due to a significant supported by the German Consensus Document, arguing renal artery stenosis, as shown by magnetic resonance patients intolerant for the combination of three antihyper- tensive drugs are also eligible for treatment The Swiss Multiple noninvasive techniques are available to obtain Consensus Document is more conservative and states that imaging of the renal arteries. In the current work-up, MRa patients should at least use four different antihypertensive was chosen because of excellent vascular imaging without drugs and that both a diuretic and a mineralocorticoid radiation exposure. In addition, MRa uses a gadolinium-like receptor antagonist should have been tried The French contrast agent, which can be applied safely in patients with Consensus Document gives a more general approach for kidney failure (eGFR >30 ml/min per 1.73 m2) . When patients suspected of resistant hypertension without discus- MRa was contraindicated, computed tomography angiog- sing specific details on inclusion and exclusion criteria for raphy (CTa) was performed. CTa not only has both pRDN. Authors advice addition of aldosterone antagonist Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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