Renale Denervatie
stand van zaken 2014 nieuwe poot in de hypertensie-behandeling
Hans-Otto Peels Interventiecardioloog MGG
Hypertensie
Global Prevalence of Hypertension
2000: 972 million people worldwide1
2025: 1.6 billion worldwide
9 out of 10 people are likely to develop hypertension in their lifetime2
30% of hypertension patients receive effective treatment3
Responsible for 13% of all deaths globally – 7.5M per year4
Hypertension-related costs consume approximately 10% of the world’s overall health expenditure5 The annual cost to treat hypertension and hypertension-related complications, US $150B, EU €192 annually The International Society of Hypertension estimates 54% of stroke, 47% of ischemic heart disease, 75% of hypertensive disease and 25% of other cardiovascular disease worldwide are attributable to hypertension6
1. 2. 3. 4. 5. 6.
Kearney PM. Whelton M. Reynolds K. et al. Global burden of hypertension: Analysis of worldwide data. Lancet. 2005. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-ages women and men. The Framingham Heart Study. JAMA. 2002. Wilkins K, Campbell N, Joffres MR, et al. Blood pressure in Canadian adults. Health Reports. Feb 2010. World Health Organization. Global health risks: Mortality and burden of disease attributable to selected major risks. 2009. Gaziano TA, Bitton A, Anand S, Weinstein MC; International Society of Hypertension. J Hypertens. 2009. Lawes CMM. Et al. Global burden of blood-pressure-related disease, 2001. Lancet. 2008.
Elevated Morbidity and Mortality Risk
The risk of cardiovascular death increases with rising blood pressure, every 20 mmHg rise in SBP doubles the risk of cardiovascular death 2-4
1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2011 update: A report from the American Heart Association. Circulation. 2011;123(4):e18-e209. 2. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: A metaanalysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903-13. 3. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA. 2003;289:2560-2572. 4. The graph on this page includes data from sources 2 and 3 and was adapted from www.hypertensiononline.org.
Definitions and Classification of Blood Pressure Levels Hypertension is defined as systolic blood pressure (BP) greater than 140 mmHg and a diastolic BP greater than 90 mmHg Systolic (mmHg)1
Diastolic (mmHg)
Optimal
< 120 and
< 80
Normal
< 130 and
< 85
High Normal
130 - 139 or
85 - 89
Hypertension
> 140 or
> 90
Stage 1 Hypertension
140 - 159 or
90 - 99
Stage 2 Hypertension
160 - 179 or
100 - 109
Goal BP for hypertension patients2 General Population: < 140/90 mmHg Individuals with diabetes mellitus or chronic kidney disease < 130/80 mmHg 1. 2.
Table modified from Carretero OA, Oparil S. Essential hypertension, Part 1: Definition and etiology. Circulation. 2000;101(3):329-35. Rosendorff C, Black HR, Cannon CP, et al. Treatment of Hypertension in the prevention and management of ischemic heart disease: A scientific statement from the American Herat Association Council for High Blood Pressure Research and the Councils on Clinical cardiology and Epidemiology and prevention. Circulation. 2007;115(21):2761-88.
Secondary causes:
Types of Hypertension
Renal parenchymal disease Renovascular hypertension Phaeochromocytoma Primair aldosteronisme (Conn’s disease) Cusching syndrome Obstructive sleep apnoe Coarctation of the aorta Drug/toxin induced Thyroid disease Hyperparathyroidism Acromegaly Pre-ecclampsia
Essential, primary or idiopathic hypertension1 High BP in which a secondary cause is not present Accounts for 90-95% of all cases of hypertension Secondary hypertension2 High BP that is a result of an identifiable underlying secondary cause Accounts for 5-10% of all hypertension
Resistant hypertension2 BP that remains above goal in spite of concurrent use of three antihypertensive agents of different classes This definition includes patients whose blood pressure is controlled but requires four or more medications 1. 2.
Carretero OA, Oparil S. Essential hypertension, Part 1: Definition and etiology. Circulation. 2000;101(3):329-35. 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(25):e510-26.
The Autonomic Nervous System Sympathetic
Parasympathetic Constricts pupils
Dilates pupils
Stimulates salivation
Inhibits digestive activity Stimulates glucose release by liver Epinephrine—adrenal glands Norepinephrine—kidney
Thoracic
Accelerates heart
Lumbar
Relaxes bronchi
Cervical
Inhibits salivation
Constricts bronchi
Inhibits heart Stimulates digestive activity
Stimulates gall bladder Stimulates bladder
Relaxes bladder Contracts rectum
Relaxes rectum
Campbell WW. DeJong’s The Neurologic Examination: Incorporating the Fundamentals
Sympathicus en hypertensie
Myat Circ Cardiovasc Interv 2013
Renal Sympathetic Efferent Nerve Activity Kidney as Recipient of Sympathetic Signals
Afferent signals Renal Efferent Nerves ↑ Renin Release RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↑ Proteinuria ↑ Glomerulosclerosis
Renal Sympathetic Afferent Nerves: Kidney as Origin of Central Sympathetic Drive
Vasoconstriction Vascular effects
Other effects
Hypertrophy Arrhythmia Oxygen Consumption
Renal Afferent Nerves
Kidney injury / ischemia
↑ Renin Release RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↑ Proteinuria ↑ Glomerulosclerosis
Renal denervation
Sympathectomie
1952
Dr. Reginald H. Smithwick
Renal Nerves as a Therapeutic Target • Arise from ~ T10-L2 • Follow the renal artery to the kidney • Primarily lie within the adventitia
Medtronic Symplicity Catheter
Renal Procedure Goal: Effective Denervation
* Animal study. Results on file at St. Jude Medical
Percutane renale denervatie Symplicity-1 •Observationeel •Office systole >160 ondanks ≥3 antihypertensiva inclusief diureticum •RR 177/101 (SD 20/15) op 4,7 (SD 1,5) antihypertensiva •∆ office bloeddruk -26/-11 (SD 10/5) mm Hg na 6 mnd (p<0,001) •Extended studie 3 jaars followup
Krum Lancet 2009, Symplicity-1 investigators Hypertension 2011, Krum Lancet 2013
Percutane renale denervatie Symplicity-2 •Gerandomiseerd, multicenter •Office systole >160 ondanks ≥3 antihypertensiva •Primaire eindpunt na 6 maanden •Daarna crossover •N=106 •Eindpunt office bloeddruk
Symplicity HTN-2 investigators Lancet 2010, Esler Circulation 2012
∆ Bloeddruk Baseline-6 mnd
p<0.0001
April 2014
Percutane renale denervatie Symplicity-3 •Blinded (sham procedure), randomized controlled trial •n = 535 in 88 centra VS •Office systolische bloeddruk ≥160 mmHg ondanks ≥3 antihypertensiva incl. diureticum in maximaal getolereerde dosis •Exclusie: ABPM gemiddelde systole <135 mm Hg, eGFR <45 ml/min/m2, nierarterie <4 mm diameter of <20 mm lengte •Primaire eindpunt ∆ office bloeddruk 6 mnd •Secundair eindpunt ∆ ABPM 6 mnd
Percutane renale denervatie Symplicity-3: primair en secundair eindpunt
Office bloeddruk Bhatt NEJM 2014
ABPM
Percutane renale denervatie Symplicity-3: secundair eindpunt
∆ office systole na 6 mnd
∆ ABPM na 6 mnd
∆SBP at 6 mo
∆ ABPM at 6 mo
Symplicity-3: primair eindpunt
P=0.26
P=0.98
HTN-3 Results: Primary Safety Endpoint Major Adverse Event (MAE) Rate
Performance Goal = 9.8%
Safety Measures MAE
P < 0.001
Renal Denervation (N = 364)
Sham Procedure (N = 171)
Difference (95% CI)
P
1.4% (5/361)
0.6% (1/171)
0.8% (-0.9%, 2.5%)
0.67
Speculations Around HTN-3
Percutane renale denervatie Symplicity-3: subgroepanalyses
Bhatt NEJM 2014
Percutane renale denervatie Symplicity-3: subgroepanalyses
Percutane renale denervatie Waarom doorgaan met RDN na Symplicity-3?
• • •
Pathofysiologie grondig onderzocht Grote bloeddrukverlagingen gerapporteerd Wisselend effect – –
• •
Betere patiëntselectie bijv. nierziekte, <65 jaar, blank ras, metingen (RAAS, NA) Mogelijkheid ‘mislukte’ interventies: intraprocedurele meting? meer ervaren interventioloog? betere catheter?
Onverwachte bloeddrukdaling in shamgroep: effecten therapietrouw? Veiligheid geen issue
ESH 2014 Statement on Symplicity HTN-3 Progress continues with the scientific leaders desire to proceed with renal denervation
Global Symplicity Registry (GSR) Consecutive patients treated in real-world population 5000 patients
GREAT Registry N = 1000
Korea Registry* N = 102
South Africa Registry* N = 400
Rest of GSR N ≈ 3500
Canada and Mexico*
231 international sites in 37 countries Min. 10% randomly assigned to 100% monitoring
Follow-up schedule
3M
* Limited to resistant hypertension only
6M
1Y
2Y
3Y
4Y
5Y
Change in Office SBP at 6 Months for GSR and Non– African American Patients in SYMPLICITY HTN-3
Opzet •Multicenter, gerandomiseerd onderzoek •Randomisatie met 2:1 ratio RD vs. controle •Stratificatie naar centrum en eGFR 20-60 vs. >60 ml/min/1.73m² •Minimaal 300 deelnemers met uitloop naar 570 •Follow-up 2 jaar Primaire doel: vaststellen of renale denervatie toegevoegd aan gebruikelijke medicamenteuze behandeling de bloeddruk verlaagt vergeleken met gebruikelijke medicamenteuze behandeling alleen, gemeten 6 maanden na randomisatie door middel van ABPM als gemiddelde systolische bloeddruk in het daginterval
Secundaire eindpunten: •Effect bij chronische nierinsufficientie als eGFR 20-60 vs. >60 ml/min/1.73m² •Effect bij minder ernstige therapieresistente hypertensie als office systole 140-160 vs. >160 mmHg •Veranderingen in antihypertensiva gebruik als daily defined doses van alle gebruikte antihypertensiva •Effect op office bloeddruk Overige analyses: •Effect op nierfunctie en veiligheid in het algemeen •Cardiovasculaire events •Kosteneffectiviteit •Effect op kwaliteit van leven •Klinische en procedurele predictors van effect
Inclusiecriteria •Individual has a mean day-time SBP ≥ 135 mmHg, as determined with the use of ABPM, while the patient uses 3 or more antihypertensive agents for at least 3 months prior to inclusion or with documented intolerance to 2 or more of the 4 major classes antihypertensive drugs (ACE/ARB, CCB, BB, diuretic) and no possibility to take 3 anithypertensive drugs. •Individual is ≥18 years of age
Exclusiecriteria •Individual is unable or unwilling to sign informed consent •Individual has a treatable secondary cause of hypertension •Individual has an eGFR below 20 mL/min/1.73m2 using the MDRD calculation •Individual has renal artery anatomy that is ineligible for treatment •Individual has any serious medical condition, which in the opinion of the investigator, may adversely affect the safety and/or effectiveness of the participant or the study. •Individual is pregnant, nursing or planning to be pregnant •Individual has a known, unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions or would be unlikely or unable to comply with study follow-up requirements •Individual is currently enrolled in another investigational drug or device trial
Deelnemende centra Maasstad ZH, Rotterdam
AMC, Amsterdam
LUMC, Leiden
VUMC, Amsterdam
MC Alkmaar
OLVG, Amsterdam
Catharina ZH, Eindhoven
Rijnstate ZH, Arnhem
Canisius W. ZH, Nijmegen
Scheper ZH, Emmen
MC Haaglanden, den Haag
Twee Steden ZH, Tilburg
Isala klinieken, Zwolle
Maastricht UMC
Amphia ZH, Breda
Jeroen Bosch ZH, Den Bosch
MC Leeuwarden
IJsselland ZH, Capelle a/d IJssel
Antonius ZH, Nieuwegein
Zorgsaam ZH, Terneuzen
Albert Schweitzer ZH, Dordrecht
Haga ZH, Den Haag
Martini ZH, Groningen
Ziekenhuis groep Twente, Almelo UMC Utrecht
Renale denervatie goed voor alles… Diabetes II Nierfalen Sleep apnoe Hartfalen Atriumfibrilleren Ventriculaire ritmestoornissen LVH ……
Conclusies • • • •
Hypertensie is een groot gezondheidsprobleem Een meerderheid van patiënten met hypertensie wordt niet of onvoldoende behandeld Het sympathisch zenuwstelsel speelt een essentiële rol in (de behandeling van) hypertensie Renale denervatie is veelbelovend: – Theoretisch – Vele studies, met name in “resistant hypertension” – Grote variatie in effect, research nodig! – HTN III studie negatief – Meer studies nodig (patiënten selectie) – Wellicht ook werkzaam bij: • DM, AF, HF, SA, CKD, metabool syndroom……. – Goede screening patiënten essentieel
Voorstel: •
Opzetten van een (1,5 lijns-) hypertensie kliniek in de regio Alkmaar – Huisartsen en specialisten samen (SSIZ) – Veel winst te halen voor alle hypertensie-patiënten • Eenduidige behandeling van alle patiënten in de regio HONK • Mogelijkheden voor goede research
•
– Sterke huisartsen organisatie, HONK – Juiste 2de lijns expertise aanwezig Opzet: – –
• •
Eenduidige protocollen voor RR behandeling 1ste en 2de lijn • Medicatie, lab, beeldvorming etc MDO (huisarts, vasculair geneeskundige, radioloog, interventiecardioloog)
Politiek “correct” Kortom: het opzetten van de Alkmaar standaard!!
Renale Denervatie-FIH in Alkmaar 12-’13
