HYPERTENSION: WHEN TO TREAT & WHEN TO REFER Dr Charles Knight, Consultant Cardiologist BMI The London Independent Hospital Barts and the London NHS Trust

v  Diagnosis- ABPM, screening tests for primary causes / essential BP / secondary  Lifestyle modification  Medical therapy  Renal Denervation Why is hypertension important?

v Untreated hypertension 51 yrs- 136/78 54 yrs- 162/98 59 yrs- 188/ yrs- 226/118 short of breath at rest and LV strain BP at death aged /190

v Roosevelt’s blood pressure (Breunn) Messerli NEJM 1945

v Hypertension Major risk factor for stroke, myocardial infarction, heart failure, chronic kidney disease, cognitive decline and premature death. Untreated hypertension can cause vascular and renal damage leading to a treatment- resistant state.

v Normal Wall thicknessThickened heart muscle LVH

v Hypertension  One billion hypertensives worldwide  BP important in 50% of 17.5m deaths  4.5% of global disease burden  In the U.K. ~25% of all adults are hypertensive;  Hypertension is 12% of consultations in primary care  2 mm Hg increase in BP = 7% increase in CHD risk and 10% increase in stroke  Treatment ~£1billion P/A in drug costs alone.

v UK Epidemiology  Hypertension is common in the UK population.  Prevalence influenced by age and lifestyle factors.  At least 25% of the adult population in the UK have hypertension.  50% of those over 60 years have hypertension.  With an ageing population, the prevalence of hypertension and requirement for treatment will continue to increase.

v Cardiovascular Mortality Risk Doubles With Each 20/10 mm Hg Increase in BP* CV Mortality Risk SBP/DBP,mm Hg CV = cardiovascular SBP – systolic blood pressure DBP = diastolic blood pressure * In individuals aged 40 to 69 years (10-year study period starting at BP 115/75 mm Hg. SOURCE: Lewington S, et al. Lancet. 2002;360:

v ‘Double jeopardy’: type 2 diabetes and hypertension and cardiovascular risk CVD death rate (per 10,000 person-year) Systolic blood pressure (mmHg) SOURCE: Afbeelding 3 van 32, PACE

v Other CVRF, TOL, of established disease Normal SBP or DBP Normal – High SBP or DBP Grade 1 HT SBP or DBP Grade 2 HT SBP or DBP Grade 2 HT SBP≥180 or DBP≥110 No Other CVRFMedium Risk Low Added RiskModerate Added Risk High Added Risk 1-2 CVRFLow Added Risk Moderate Added Risk Very High Added Risk 3 or More CVRF, TOL, Diabetes or Metabolic Syndrome Moderate Added Risk High Added Risk Very High Added Risk Established Cardiovascular or Renal Disease Very High Added Risk Blood Pressure, mmHg

v  Diagnosis- ABPM, screening tests for primary causes / essential BP / secondary  Lifestyle modification  Medical therapy  Renal Denervation Why is hypertension important?

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v Secondary hypertension Consider particularly if: –Young –No FH hypertension –Severe HT –Unresponsive to treatment Tests –Renal ultrasound –Echo –24 hour urinary catecholamines –MR imaging

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v Diagnosis (1) If clinic BP is 140/90 mmHg or higher, offer ambulatory blood pressure monitoring (ABPM) to confirm the diagnosis of hypertension.

v Diagnosis (2) When using the following to confirm diagnosis, ensure: ABPM: – at least two measurements per hour during the person’s usual waking hours (usually 14/day). HBPM: – two consecutive seated measurements, 1 minute apart – BP is recorded twice a day for at least 4 days and preferably for 7 days – measurements on the first day are discarded – average value of all remaining is used.

v Definitions Stage 1 hypertension: Clinic blood pressure (BP) is 140/90 mmHg or higher and ABPM or HBPM average is 135/85 mmHg or higher. Stage 2 hypertension: Clinic BP 160/100 mmHg is or higher and ABPM or HBPM daytime average is 150/95 mmHg or higher. Severe hypertension: Clinic BP is 180 mmHg or higher or Clinic diastolic BP is 110 mmHg or higher.

v Assessing cardiovascular risk and target organ damage Updated recommendations: –Estimation of CV risk to discuss prognosis and healthcare options with people with hypertension. –For all with hypertension offer to: –test urine for presence of protein –take blood to measure glucose, electrolytes, creatinine, estimated glomerular filtration rate and cholesterol –examine fundi for hypertensive retinopathy –arrange a 12-lead ECG.

v  Diagnosis- ABPM, screening tests for primary causes / essential BP / secondary  Lifestyle modification  Medical therapy  Renal Denervation Why is hypertension important?

v SOURCE: Analysis by London Health Observatory using Office for National Statistics data. Diagram produced by Department of Health. Parliamentary copyright images are reproduced with the permission of Parliament.

v Lifestyle and adherence Lifestyle interventions –Offer guidance and advice about: –diet (reduce sodium and caffeine intake), weight reduction and exercise –alcohol consumption –smoking. Patient education and adherence –Provide: –information about benefits of drugs and side effects –details of patient organisations –an annual review of care.

v CBPM ≥160/100 mmHg & ABPM/HBPM ≥ 150/95 mmHg Stage 2 hypertension Consider specialist referral Offer antihypertensive drug treatment Offer lifestyle interventions If younger than 40 years If target organ damage present or 10-year cardiovascular risk > 20% Offer annual review of care to monitor blood pressure, provide support and discuss lifestyle, symptoms and medication Offer patient education and interventions to support adherence to treatment CBPM ≥140/90 mmHg & ABPM/HBPM ≥ 135/85 mmHg Stage 1 hypertension

v  Diagnosis- ABPM, screening tests for primary causes / essential BP / secondary  Lifestyle modification  Medical therapy  Renal Denervation Why is hypertension important?

v Treatment of hypertension 19 million with hypertension in UK (2.6 million with CAD) 500 per GP surgery (70 with CAD)

v Step 4 Summary of antihypertensive drug treatment Aged over 55 years or black person of African or Caribbean family origin of any age Aged under 55 years C* A A + C* A + C + D Resistant hypertension A + C + D + consider further diuretic or alpha- or beta-blocker Consider seeking expert advice Step 1 Step 2 Step 3 Key A – ACE inhibitor or low-cost angiotensin II receptor blocker (ARB) 1 C – Calcium-channel blocker (CCB) *D – Thiazide-like diuretic

v First Line Antihypertensives ARB’s Thiazide diuretics Calcium antagonists ACE Inhibitors

v Second Line Antihypertensives Alpha blockers Beta blockers

v Monitoring drug treatment (1) Use clinic blood pressure measurements to monitor response to treatment. Aim for target blood pressure below: –140/90 mmHg in people aged under 80 –150/90 mmHg in people aged 80 and over

v Monitoring drug treatment (2) For people with a ‘white-coat effect’ consider ABPM or HBPM as an adjunct to clinic BP to monitor response to treatment. Aim for ABPM/HBPM target average of:  below 135/85 mmHg in people aged under 80  below 145/85 mmHg in people aged 80 and over. White-coat effect: a discrepancy of more than 20/10 mmHg between clinic and average daytime ABPM or average HBPM blood pressure measurements at the time of diagnosis.

v BP still high…  Measurement correct?  Compliance?  Weight loss/salt reduction  Untreated secondary cause?  Stop drugs that raise BP  NSAI  Cocaine  Alcohol

v Step 4: - Resistant Hypertension  Step 4 is patients >140/90 on at least 3 medicines (steps 1-3) and still hypertensive  Spironolactone 25 mg can be considered for patients with K less than 4.5 mMol/L and eGFR >45  Or more thiazide diuretics  alpha blockers and betablockers Consider Specialist Referral…

v  Diagnosis- ABPM, screening tests for primary causes / essential BP / secondary  Lifestyle modification  Medical therapy  Renal Denervation Why is hypertension important?

v Standard interventional technique 4-6 two-minute treatments per artery Proprietary RF Generator −Automated −Low-power −Built-in safety algorithms Percutaneous Renal Denervation SOURCE: Frontiers in Physiology and Professor Markus Schlaich MD, Nephrologist & Hypertension Specialist Adjunct Professor, Central Clinical SchoolFaculty of Medicine, Nursing & Health Sciences, Monash University. Reproduced with permission. 37

v Initial Cohort – Reported in the Lancet, 2009: -First-in-man, non-randomized -Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a diuretic; eGFR ≥ 45 mL/min) - 12-month data \ Expanded Cohort – This Report (Symplicity HTN-1): -Expanded cohort of patients (n=153) -24 and 36 -month follow-up Symplicity HTN-1 Symplicity HTN-1 Investigators. Hypertension. 2011;57: Sobotka P, ACC 2012

v Change in Office BP Through 36 Months BP change (mmHg) P<0.01 for ∆ from BL for all time points Sobotka P, ACC 2012

v Chronic Safety Out to 3 Years  One progression of a pre-existing stenosis unrelated to RF treatment (stented without further sequelae)  One new moderate stenosis which was not hemodynamically relevant and no treatment  3 deaths within the follow-up period; all unrelated to the device or therapy  No hypotensive events that required hospitalization  There were no observed changes in mean electrolytes or mean eGFR to 18 months Symplicity HTN-1 Investigators. Hypertension. 2011;57: Sobotka P, ACC 2012

v Purpose: To demonstrate the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with uncontrolled hypertension in a prospective, randomized, controlled, clinical trial Patients: 106 patients randomized 1:1 to treatment with renal denervation vs. control Clinical Sites: 24 centers in Europe, Australia, & New Zealand (67% were designated hypertension centers of excellence) Symplicity HTN-2 Symplicity HTN-2 Investigators. Lancet. 2010;376: Lancet. 2010;376:

v Symplicity HTN-2 Trial Inclusion Criteria: –Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus) –Stable drug regimen of 3+ more anti-HTN medications –Age years Exclusion Criteria: –Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention –eGFR < 45 mL/min/1.73m 2 (MDRD formula) –Type 1 diabetes mellitus –Contraindication to MRI –Stenotic valvular heart disease for which reduction of BP would be hazardous –MI, unstable angina, or CVA in the prior 6 months Symplicity HTN-2 Investigators. Lancet. 2010;376: Treatment-resistant HTN population BL OBP 178/97 mmHg 49 RDN, 51 Control Age 58 years BMI 31 kg/m² 40% with Diabetes eGFR 77* Mean no of drugs 5.2 RDN and Control groups generally well-matched *MDRD, ml/min/1.73m 2

v Procedural Safety RDN Group (n=52) No serious device or procedure related adverse events Minor adverse events (n-5) 6-month renal imaging (n=43) No vascular abnormality at any RF treatment site 1 MRA indicates possible progression of a pre-existing stenosis unrelated to RF treatment (no further therapy warranted) Cross Over Group (n-35) One renal artery dissection following injection of contrast through the guide catheter during angiography. The lesion was stented without further consequence One hospitalization prolonged in a crossover patient due to hypotension following the RDN procedure. IV fluids administered, anti-hypertensive medications decreased and patient discharge without further incident Esler M, ACC 2012

v Symplicity HTN-2: Primary Endpoint and Latest Follow-up Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.) ∆ from Baseline to 6 Months (mmHg) Primary Endpoint: 84% of RDN patients had ≥10 mmHg reduction in SBP 10% of RDN patients had no reduction in SBP Systolic Diastolic SystolicDiastolic RDN (n= 47) ∆ from Baseline to 12 Months (mmHg) Systolic Diastolic Primary Endpoint (6M post Randomisation) Latest Follow-up (12M post Randomisation) Latest Follow-up: Control crossover (n = 35): -24/-8 mmHg (Analysis on patients with SBP ≥ 160 mmHg at 6 M) p <0.01 for  from baseline p <0.01 for difference between RDN and Control

v SYMPLICITY HTN-3  Larger trial against sham procedure in US  535 patients  Did not meet primary endpoint  Fall in office BP at 6/12  Met safety endpoints  Details not yet available

v Scott’s parabola – the rise and fall of a surgical technique Promising Idea “Of possible value but only as a research tool” Encouraging reports Widespread enthusiasm Strong media pressure for universal acceptance General introduction Doubts creep in Standard treatment Damaging survey reported Condemned by several authorities Falls into disuse Very old surgeons amaze their juniors with rollicking stories of the old days Widely publicised medicolegal case Used only in highly specialised circumstances Operating theatre staff ponder possible uses for large quantities of expensive, obsolete equipment SOURCE: J W Scott consultant gynaecologist, Poole Hospital NHS Trust, Poole, Dorset.

v Pre - FL O 2 w Procedure Post - FL O 2 w Procedure

v ROX Preliminary results

v Conclusions (1)  Hypertension a huge global health problem  Mostly primary hypertension  ABPM key in diagnosis  Lifestyle measures very important  Treat all the patient’s Cv risks  Medication usually controls without significant side effects  But many patients not treated/undertreated  New technologies becoming available for resistant hypertension

v Conclusions (2)  Vast majority of hypertensives treated easily in primary care  Referral for  BP not controlled on 2/3 drugs  Multiple drug intolerance/poor compliance  Concern about white coat  Concern re secondary causes  Young patients  Consideration of BP interventions (research at present)