Renal Denervation in Hypertension - The Story Told With Skepticism - Prof. Sverre E. Kjeldsen, MD, Dr. Med., FAHA, FESC Department of Cardiology Oslo University Hospital, Oslo, Norway, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan Past-President of European Society of Hypertension
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Renal Denervation in Hypertension...Renal Denervation in Hypertension - The Story Told With Skepticism - Prof. Sverre E. Kjeldsen, MD, Dr. Med., FAHA, FESC Department of Cardiology
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Renal Denervation in Hypertension - The Story Told With Skepticism -
Prof. Sverre E. Kjeldsen, MD, Dr. Med., FAHA, FESC Department of Cardiology
Oslo University Hospital, Oslo, Norway, Division of Cardiovascular Medicine, University of Michigan,
Ann Arbor, Michigan Past-President of European Society of Hypertension
Arterial Plasma Noradrenaline During Mental Stress Predicts Future BP
Resting SBP at 18-Year Follow-Up
SB
P (m
m H
g)
Arterial noradrenaline tertile at baseline during mental stress test
P=.004
Flaa A et al. Hypertension. 2008;32:336-341.
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KEY POINTS In this study, BP, arterial plasma epinephrine, and NE concentrations were measured in 99 healthy men at rest, during a mental arithmetic test, and during a cold pressor test. After approximately 18 years of follow-up, resting BP was measured. Epinephrine and NE concentrations during mental arithmetic at baseline predicted almost 13% of the variation of future SBP after adjusting for initial resting BP, family history, body mass index, and SBP during the stress test (adjusted R2=0.651; P<.001). This study shows that SNS activity during mental arithmetic predicts future blood pressure, indicating a possible causal factor in the development of essential hypertension independent of the initial BP REFERENCE Flaa AF, Eide IK, Kjeldsen SE, Rostrup M. Sympathoadrenal stress reactivity is a predictor of future blood pressure: An 18-year follow-up study. Hypertension. 2008;32:336-341.
Dr. Reginald H. Smithwick
Oslo RDN study
Sympathectomy: An Early Surgical Precedent
1952
Photo of Dr. Smithwick reproduced with permission from JAMA.
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Purpose: To highlight the early clinical studies of the effects of sympathectomy in the treatment �of hypertension. Key Points: Between 1930 and 1960, Dr Reginald Smithwick and other pioneering surgeons developed surgical methods of lowering BP in patients with hypertension1 Smithwick developed a surgical procedure, known as thoracolumbar splanchnicectomy, for patients with severe forms of hypertension1 Early studies using this approach showed that the 5-year mortality rate of patients with malignant hypertension and Grade IV retinopathy decreased from 99% to 66.5% in those undergoing sympathectomy compared with untreated patients; similar decreases in 5-year mortality rates were reported in patients with Grade III retinopathy2 Although highly effective, the extended hospitalization and recovery period, safety profile, and the inability to predict the BP response made physicians, at the time, increasingly skeptical. The advent of antihypertensive medications and the complications from the procedure eventually led to discontinuation of the procedure2
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The autonomic nervous system controls and regulates the internal organs mainly unconsciously. This system consists of two antagonistic sets of nerves, the sympathetic and parasympathetic nervous systems, and this schematic representation shows distribution of sympathetic and parasympathetic nerves to the head, trunk, and limbs. Together they regulate activity as pupillary response, , resiratory rate, heart rate, blood pressure, digestion, urination.
Rate
of sp
illove
r of n
oradre
nalin
efro
m the
kidn
eys t
o plas
ma (n
g/min)
0
100
200
300
400
NormalBP
20-39 40-59 60-79
EssentialHypertension
**
*
Increased Spillover of Noradrenaline into the Renal Veins in Essential Hypertension
M. Esler, G. Lambert, G. Jennings. J. Hypertension 1990; 8:S53-57 (updated)
15 patients
• Standard interventional technique • 4-6 two-minute treatments per artery • Proprietary RF Generator
● Upper age range ● No ambulatory BP ● No evidence of drug adherence
Symplicity HTN-2 Trial: Office BP Reduction
P≤0.005 for changes in SBP and DBP at all time points between Symplicity RDN and control groups; error bars represent 95% CIs. Symplicity HTN-2 Investigators (Esler M et al.) Lancet. 2010;376:1903-1909.
Total n=106 (intervention group n=52, control group n=54)
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KEY POINTS At all time points following the procedure significant reductions in both SBP and DBP (P≤.005 for changes in SBP and DBP at all time points) were seen in the RDN group vs control patients Among patients in the RDN group, office BP measurements slowly declined over time. These reductions were achieved despite the fact that many patients remained on a stable antihypertensive regimen REFERENCE Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.
When Stringent Definitions are Used, 7.6% to 18% of Patients Have True Treatment-Resistant Hypertension
• Spanish ABPM Monitoring Registry definition:1
– Use of 3 antihypertensive drugs (with 1 diuretic)
– Clinic BP ≥140 and/or ≥90 mm Hg – Daytime BP ≥130 and/or ≥80 mm Hg
• Pierdomenico et al definition:2
– Use of triple therapy – Clinic BP ≥140 or ≥90 mm Hg
at ≥2 visits – Daytime BP ≥135 or ≥85 mm Hg
• Both studies excluded patients at BP target being treated with ≥4 drugs1,2
– True prevalence of treatment-resistant hypertension may therefore be somewhat higher
Large prescription registry in Israel suggests prevalence of 1-2 % only
ABPM=ambulatory blood pressure monitoring; BP=blood pressure. 1. de la Sierra A et al. Hypertension. 2011;57:898-902; 2. Pierdomenico SD et al. Am J Hypertens. 2005;18:1422-1428.
7.6%
18%
Spanish ABPM Monitoring Registry1
(N=8295)
Italy: Pierdomenico et al2
(N=742)
Pat
ient
s (%
) 1-2 % ?
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KEY POINTS When stringent definitions of resistant hypertension are used, between 7.6% and 18% of patients have true treatment-resistant hypertension1,2 REFERENCES de la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57:898-902. Pierdomenico SD, Lapenna D, Bucci A et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens. 2005;18:1422-1428.
Ray W. Gifford: Hypertension 1988 Proceedings From Course at the Cleveland Clinic in
How Many Patients Are Actually Adherent to Their Antihypertensive Medication?
A quantitative analysis based on serum drug levels in patients taking free combination multidrug therapy*
Patie
nts (
%)
Fully Compliant With Treatment
No Drugs Detectable in
Serum
N=84 Number of antihypertensives: 5.0±1.2
34.5%
65.5%
34.5%
Poor drug adherence in apparent treatment resistant hypertension makes these patients wide open for Hawthorne effect: Patients start taking their prescribed medication when getting attention with subsequent fall in BP
Fulfilled Criteria for
Nonadherence *All patients except 3 were taking agents as free combinations. Ceral J et al. Hypertens Res. 2011;34:87-90.
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KEY POINTS Difficult to control hypertension—or failure to achieve BP targets—can be attributable to severe hypertension or to failure to adhere to prescribed medications Data suggest that many patients taking multidrug therapy for hypertension are nonadherent. This slide shows one of the first studies to assess adherence in patients taking multiple drugs using quantitative analysis of serum drug levels In this study, serum drug levels were evaluated in a laboratory among 84 patients with a history of difficult-to-control hypertension, defined by documented BP elevations despite recommended antihypertensive therapy consisting of a combination of 3 or more antihypertensives from different classes [Ceral, p 88/c1/¶4] Of the 84 patients included in the study, 29 (34.5%) were compliant because all antihypertensives prescribed were identified in their blood samples. Nonadherence was identified in 65.5% of patients, of whom no prescribed antihypertensives were identified in 34.5% [Ceral, p 88/c2/¶5] This study illustrates a key issue involved in multidrug treatment of hypertension: Few patients who are taking free combination therapy are compliant with all drugs in complicated antihypertensive regimens Reference�Ceral J, Habrdova V, Vorisek V, Bima M, Pelouch R, Solar M. Difficult-to-control arterial hypertension or uncooperative patients? The assessment of serum antihypertensive drug levels to differentiate non-responsiveness from non-adherence to recommended therapy. Hypertens Res. 2011;34:87-90.
The Hawthorne Effect
People change their behaviour when being under observation
Fractions (%) of apparent treatment resistant HT patients detected to be non-adherent by therapeutic drug monitoring
(TDM) or direct observed treatment (DOT)
Ceral et al. 2011 N=84 TDM, blod 65.5 % Jung et al. 2013 N=76 TDM, urin 53.0 % Strauch et al. 2013 N=163 TDM, blod 47.0 % Strauch et al. 2013 N=176 TDM, blod 19.0 %
Fadl Elmula et al. 2013 and 2014 N=83 DOT + 24t ABM 29.3 %
Brinker et al. 2014 N=56 TDM, blod 54.0 %
Tomaszewski et al. 2014 N=208 TDM, urin 25.0 % Florczak et al. 2015 N=36 TDM, blod 86.1 %
Hameed et al 2015 N=50 DOT + 24t ABM 50.0 %
Eskås PA, Heimark S et. al. Blood Press 2016; 25: in press.
Therapeutic Drug Monitoring Facilitates BP Control in Resistant Hypertension
Written patients’ reports, home BP Electronic pill boxes
Blood measurements of drugs Urine measurements of drugs
Prescription registries Witnessed intake of drugs
(directly observed therapy = DOT)
Methods 2 Inclusion criteria Exclusion criteria Office SBP >140mmHg (measured per guidelines) Daytime ambulatory SBP >135mm/Hg (after witnessed intake of anti-hypertensiv drugs prior to ABPM) Age 18-80 years At minimum, 3 antihypertensive medications must meet one of them must be a diuretic.
Hemodynamically or anatomically significant renal artery abnormalities or stenosis (>50%) or prior renal artery intervention eGFR < 45 mL/min/1.73m² (MDRD formula) Alb/creat ratio > 50 mg/mmol Type 1 diabetes mellitus Known alcohol/drug abuse MI, unstable angina, or CVA in the prior 6 months Known secondary cause of hypertension Known chronic serious disease
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Office SBP > 140 mmHg and daytime ambulatory BP >135 mmHg after witnessed intake of anti-hypertensiv drugs prior to ABPM were mandatory for inclusion. Exclusion criteria almost similar to that in Symplicity trials
Witnessed Intake of Antihypertensive Drugs
• Patients were asked to bring their prescribed medication to the clinical visit • Medication was documented and administered by the investigator and swallowed by the patient under continuous observation
• Patients were then continuously under the observation by the investigator
Methods 3
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- Reffered pasients were asked to bring their blood pressure medications in their original packaging or medication boxes. Pills boxes not accepted because one can not identify what in them! Medication was documented and administered by the investigator and swallowed by the patient under continuous observation - Patients were then continuously under the observation by the investigator (in order to prohibit throwing up again of the pills) until 24-hour ambulatory BP device had been mounted and tested out
Daytime ambulatory mean systolic and diastolic blood pressures at baseline and 3 and 6 months after renal denervation (n=6).
F. Elmula et al. Hypertension 2014;63:991-999.
Control Methods: Integrated Non-Invasive Hemodynamic Management Using the HOTMAN® System to guide improvement and adjustment of drug treatment
Methods: Integrated Non-Invasive Hemodynamic Management Using the HOTMAN® System
Methods: Integrated Non-Invasive Hemodynamic Management Using the HOTMAN® System
Clinical Case 2 (of 53) Hemodynamic Measurements at Baseline
Clinical Case 2 (of 53) 24h ABPM at Baseline and 6 Month Follow-up
Baseline 6 Month
The Oslo RDN Study Inclusion criteria Exclusion criteria Average SBP ≥140mmHg (measured per guidelines) 24 hour average ABPM SBP >135mm/Hg (witnessed intake of all meds prior to AMBP) Age 18-80 years At minimum, 3 antihypertensive medications must meet one of them must be a diureticum.
Hemodynamically or anatomically significant renal artery abnormalities or stenosis (>50%) or prior renal artery intervention eGFR < 45 mL/min/1.73m2 (MDRD formula) Alb/creat ratio > 50 mg/mmol Type 1 diabetes mellitus Known alcohol/drug abuse MI, unstable angina, or CVA in the prior 6 months Known secondary cause of hypertension Known chronic serious disease
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Purpose: To provide an overview of the consequences of resistant hypertension. Key Points: Clinical evidence to date suggest that resistant hypertension carries a greater risk for CV events compared with that of controlled hypertension1 Data from small clinical studies and observational cohorts show that patients with resistant hypertension have approximately 3-fold increased risk for CV events including stroke, transient ischemic attacks, myocardial infarction, death, heart failure, renal failure, new onset diabetes, compared with that of patients with controlled hypertension1 Early VA Cooperative studies demonstrated that successful treatment of severe hypertension with triple antihypertensive regimens conferred a remarkable reduction in the incidence of CV events1,2,3 Sources: Doumas M, Papademetriou V, Douma S, et al. Benefits from treatment and control of patients with resistant hypertension. Int J Hypertens. 2011;doi:10.4061/2011/318549. Calhoun DA, Jones D, Textor S, 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. Circulation. 2008;117:e510-e526. Veterans Administration Cooperative Study Group on Antihypertensive Agents: effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA.1967;202:1028-1034.
F. Elmula et al. Hypertension 2014
Change in The Mean Ambulatory Daytime BP after Witnessed Intake of Antihypertensive
Drugs (n=13)
164
130
102
81
60
80
100
120
140
160
180
Referral BPs BPs after witnessed drugs intake
Ambu
lato
ry B
lood
Pre
ssur
e, m
mH
g Amb. daytime SBP
Amb. daytime DBP
Office BPs at 3 and 6 months
F. Elmula et al. Hypertension 2014;63: 991-999.
Individual office BPs at 3 and 6 months
Daytime Ambulatory BPs at 3 and 6 months
F. Elmula et al. Hypertension 2014;63: 991-999.
Individual daytime ambulatory BPs at 3 and 6 months
F. Elmula et al. Hypertension 2014;63: 991-999.
Online March 3, 2014
For Full Details, Please Go to WWW.NEJM.ORG
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Online March 31, 2014
Effect of RDN on 6 Months Office SBP
FEM Fadl Elmula et al. Blood Press 2015; 24: 263-274
Effect of RDN on 6 Months 24-hour BP
FEM Fadl Elmula et al. Blood Press 2015; 24: 263-274
Effect of RDN on 6 Months eGFR
FEM Fadl Elmula et al. Blood Press 2015; 24: 263-274
Persu A, Jin Y, Fadl Elmula FEM, Renkin J, Høieggen A, Kjeldsen SE, Staessen JA 2014
Incident Renal Artery Stenosis Following RDN
+ Symplicity HTN-2 - Oslo RDN - Symplicity HTN-3 - Prague-15 - French Dener-HTN - Symplicity Flex