Treating Hypertension With a Catheter..Wait What? COI 5/3/2013. Worldwide Prevalence of Hypertension Is Increasing

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1 Treating Hypertension With a Catheter..Wait What? David P. Lee, M.D. 4 May 2013 Stanford University COI Medtronic: Research Grant, Consultant Boston Scientific: Research Grant, MAB Worldwide Prevalence of Hypertension Is Increasing In 2000, 972 million (26%), of the adult population had hypertension Prevalence of Hypertension by World Region By year 2025, 1.56 billion (29%) are projected to have hypertension Most of the expected increase will be in economically developing regions Number of People With Hypertension (millions) Kearney PM, et al. Lancet. 2005;365:

2 Despite Hypertension Treatment, Many Patients are Not Controlled Established Market Economies (EME) Treated Hypertension Hypertensives Country Study Year Age Range Aware (%) Treated (%) Controlled (%) Controlled (%) United States Canada Spain England Germany Greece China* (M) 24 (M) 56 (M) _ Japan (W) 36 (W) 65 (W) M = men. W = women. *Based on World Bank criteria used in this study, China was not considered an established market economy at time of publication. Adapted and reproduced with permission from Kearney PM, et al. J Hypertens. 2004; 22: Blood Pressure Classification BP Classification SBP mmhg DBP mmhg Normal <120 and <80 Prehypertension or Stage 1 Hypertension or Stage 2 Hypertension >160 or >100 CVD Risk HTN prevalence ~ 50 million people in the United States. The BP relationship to risk of CVD is continuous, consistent, and independent of other risk factors. Each increment of 20/10 mmhg doubles the risk of CVD across the entire BP range starting from 115/75 mmhg. Prehypertension signals the need for increased education to reduce BP in order to prevent hypertension. 2

3 Benefits of Lowering BP Average Percent Reduction Stroke incidence 35 40% Myocardial infarction 20 25% Heart failure 50% In stage 1 HTN and additional CVD risk factors, achieving a sustained 12 mmhg reduction in SBP over 10 years will prevent 1 death for every 11 patients treated. BP Control Rates Trends in awareness, treatment, and control of high blood pressure in adults ages National Health and Nutrition Examination Survey, Percent II II II (Phase 1) (Phase 2) Awareness Treatment Control Sources: Unpublished data for computed by M. Wolz, National Heart, Lung, and Blood Institute; JNC 6. BP Measurement Techniques Method In-office Ambulatory BP monitoring Self-measurement Brief Description Two readings, 5 minutes apart, sitting in chair. Confirm elevated reading in contralateral arm. Indicated for evaluation of white-coat HTN. Absence of 10 20% BP decrease during sleep may indicate increased CVD risk. Provides information on response to therapy. May help improve adherence to therapy and evaluate white-coat HTN. 3

4 Office BP Measurement Use auscultatory method with a properly calibrated and validated instrument. Patient should be seated quietly for 5 minutes in a chair (not on an exam table), feet on the floor, and arm supported at heart level. l Appropriate-sized cuff should be used to ensure accuracy. At least two measurements should be made. Clinicians should provide to patients, verbally and in writing, specific BP numbers and BP goals. Ambulatory BP Monitoring ABPM is warranted for evaluation of white-coat HTN in the absence of target organ injury. Ambulatory BP values are usually lower than clinic readings. Awake, individuals id with hypertension have an average BP of >135/85 mmhg and during sleep >120/75 mmhg. BP drops by 10 to 20% during the night; if not, signals possible increased risk for cardiovascular events. Self-Measurement of BP Provides information on: 1. Response to antihypertensive therapy 2. Improving adherence with therapy 3. Evaluating white-coat HTN Home measurement of >135/85 mmhg is generally considered to be hypertensive. Home measurement devices should be checked regularly. 4

5 Hypertension* Cigarette smoking Obesity* (BMI >30 kg/m 2 ) Physical inactivity Dyslipidemia* id i CVD Risk Factors Diabetes mellitus* Microalbuminuria or estimated GFR <60 ml/min Age (older than 55 for men, 65 for women) Family history of premature CVD (men under age 55 or women under age 65) *Components of the metabolic syndrome. Identifiable Causes of Hypertension Sleep apnea Drug-induced or related causes Chronic kidney disease Primary aldosteronism Renovascular disease Chronic steroid therapy and Cushing s syndrome Pheochromocytoma Coarctation of the aorta Thyroid or parathyroid disease Laboratory Tests Routine Tests Electrocardiogram Urinalysis Blood glucose, and hematocrit Serum potassium, creatinine, or the corresponding estimated GFR, and calcium Lipid profile, after 9- to 12-hour fast, that includes high-density and low-density lipoprotein cholesterol, and triglycerides Optional tests Measurement of urinary albumin excretion or albumin/creatinine ratio More extensive testing for identifiable causes is not generally indicated unless BP control is not achieved 5

6 Treatment Overview Goals of therapy Lifestyle modification Pharmacologic treatment Algorithm for treatment t t of hypertension Classification and management of BP for adults Followup and monitoring Goals of Therapy Reduce CVD and renal morbidity and mortality. Treat to BP <140/90 mmhg or BP <130/80 mmhg in patients with diabetes or chronic kidney disease. Achieve SBP goal especially in persons >50 years of age. Lifestyle Modification Modification Weight reduction Adopt DASH eating plan Dietary sodium reduction Physical activity Moderation of alcohol consumption Approximate SBP reduction (range) 5 20 mmhg/10 kg weight loss 8 14 mmhg 2 8 mmhg 4 9 mmhg 2 4 mmhg 6

7 Algorithm for Treatment of Hypertension Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmhg) (<130/80 mmhg for those with diabetes or chronic kidney disease) Initial Drug Choices Without Compelling Indications With Compelling Indications Stage 1 Hypertension (SBP or DBP mmhg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 Hypertension (SBP >160 or DBP >100 mmhg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist. Definition of Resistant Hypertension Uncontrolled Hypertension Includes all patients who lack BP control on treatment, including those on inadequate treatment regimens, those with poor adherence, those with undetected secondary hypertension, as well as those with true treatment resistance 1 Uncontrolled Hypertension Resistant Hypertension Resistant Hypertension BP that remains above goal in spite of compliance with full doses of 3 antihypertensive medications of different classes; ideally, 1 of the 3 agents should be a diuretic 1 The treatment plan must include attention to lifestyle measures 2 Includes those patients who achieve BP control but require 4 antihypertensive agents to do so 1 1. Calhoun DA, et al. Circulation. 2008;117:e510 e Mancia G, et al. Eur Heart J. 2007;28: M people worldwide are estimated to have treatment-resistant hypertension 1,2,3 Percentage of patients resistant to treatment has increased by 62% in the last 20 years* 4,5 * Between vs , the proportion of treated uncontrolled hypertensive patients reportedly taking 3 BP medications increased from 16% to 28%. 1. Persell, S. Hypertension. 2011;57: Hypertension and cardiovascular disease. World Heart Federation Accessed March 2, Lloyd-Jones D, et al. Circulation. 2010;121:e46-e Calhoun DA, et al. Circulation. 2008;117:e510-e Egan BM, et al. Circulation. 2011;124:

8 Resistant Hypertension Causes of Pseudoresistant Hypertension 1,2 Suboptimal dosing of antihypertensive agents White coat effect Suboptimal BP measurement technique Physician inertia Lifestyle factors Medications that interfere with BP control Pseudoresistance caused by poor adherence to prescribed medication 1. Calhoun DA, et al. Circulation. 2008;117;e510 e Makris A, et al. Int J Hypertens. 2011;doi: /2011/ Papademetriou V, et al. Int J Hypertens. 2011;doi: /2011/ Secondary Causes of Hypertension 1,2 Obstructive sleep apnea Primary aldosteronism Renal artery stenosis However, a majority of patients with resistant hypertension and no identifiable secondary causes have an activated sympathetic nervous system and increased sympathetic outflow 3 Caution: The Symplicity Renal Denervation System is an Investigational Device. Limited by U.S. law to investigational use. Consequences of Resistant Hypertension Patients with resistant hypertension have approximately 3 fold increased risk for CV events compared with that of patients with controlled hypertension 1 No longitudinal study has specially evaluated the prognosis of resistant hypertension 1 The degree to which CV risk is reduced with treatment is unknown, however the benefits of successful treatment are likely substantial 2 DBP = diastolic blood pressure. 1. Doumas M, et al. Int J Hypertens. 2011;doi: 4061/2011/ Calhoun DA, et al. Circulation. 2008;117:e510-e526. Causes of Resistant Hypertension Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication Inadequate doses Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives) Over-the-counter (OTC) drugs and herbal supplements Excess alcohol intake Identifiable causes of HTN 8

9 Renal Nerves and the SNS Efferent Sympathetics Afferent Renal Sympathetics Sympathetic signals from the CNS modulate the physiology of the kidneys The kidney is a source of central sympathetic activity, sending signals to the CNS Adapted from Schlaich MP, et al. Hypertension. 2009;54: Central Sympathetic Drive in Hypertension Sympathetic drive is elevated in multiple types of hypertension Sympathet tic Activity per Minute * * * * # Baseline activity (normotensives) s MSNA=single unit efferent sympathetic nerve activity. LVH=left ventricular hypertrophy. *P<0.05 Compared with borderline hypertension. P<0.05 Compared with white coat hypertension. P<0.05 Compared with normal pressure. P<0.05 Compared with high normal pressure. P<0.05 Compared with essential hypertension stage 1. # P<0.05 Compared with essential hypertension stage 2/3. Adapted from Smith P, et al. Am J Hypertens. 2004; 17: Renal Nerve Anatomy Allows a Catheter-Based Approach Standard interventional technique 4 6 two minute treatments per artery Caution: The Symplicity Renal Denervation System is an Investigational Device. Limited by U.S. law to investigational use. 27 9

10 Symplicity Investigational Catheter Device Generator will automatically control RF energy delivery: Power automatically ramped and maintained (5 8W) Continuously monitors temperature and impedance Automatically shuts off after 2 min or when either impedance or temperature exceed program limits 5mm Flexible Tip (self orienting) 12mm Deflectable Shaft Caution: The Symplicity Renal Denervation System is an Investigational Device. Limited by U.S. law to investigational use. St. Jude EnligHTN Boston Scientific/Vessix V2 Covidien OneShot ReCor Paradise 10

11 Six Month Post Procedure Histology (Porcine Model) Movat s Pentachrome Stain An area of medial injury (yellow) is located between the arrows on the left. An enlargement of the boxed region is shown on the right Findings: minimal intimal thickening and minimal internal elastic lamina injury overlying areas of mild full thickness medial fibrosis (yellow [fibrosis] with green [proteoglycan deposition]) and adventitial fibrosis (yellow) Reproduced with permission from Rippy MK, et. al. Clin Res Cardiol. 2011;doi:101007s Six Month Post Procedure Nerve Histology (Porcine Model) H&E Nerve from untreated vessel: Periarterial nerve bundle surrounded by a thin fibrous connective tissue sheath (perineurium) Nerve from treated vessel: Periarterial nerve bundle has a hypercellular appearance and the perineurium has a thickened and fibrotic appearance. Nerve from Untreated Vessel Nerve from Treated Vessel Reproduced with permission from Rippy MK, et. al. Clin Res Cardiol. 2011;doi:101007s Symplicity Staged Evaluation in Hypertension and Beyond Symplicity HTN 1 2 First-in-Man 1 Series of Pilot Studies Symplicity yhtn 2 3 EU/AU Randomized Clinical Trial USA Symplicity HTN 3 4 US Randomized Clinical Trial Sources: 1. Krum H, et al. Lancet. 2009;373: Symplicity HTN 1 Investigators. Hypertension. 2011;57: EU/AU Other Areas of Research: 4 Insulin Resistance, HF/Cardiorenal, Sleep Apnea, More 3. Symplicity HTN 2 Investigators. Lancet. 2010;376: Data on file, Medtronic. 11

12 The Symplicity HTN-1 Trial: Overview Design Multicenter (19 sites in Europe, Australia, and the United States), nonrandomized, open label, proof of concept study Population 153 patients with treatment resistant hypertension Treatment Endovascular catheter based RDN using the Symplicity Renal Denervation System plus baseline antihypertensive medications Duration 36 months (assessments at 1, 3, 6, 12, 18, 24, and 36 months) Outcome Measures Primary efficacy measure: change in office BP Primary safety measures: based on physical examination, basic blood chemistries, and anatomic assessment of renal vasculature Source: Symplicity HTN-1 Investigators. Hypertension. 2011;57: Symplicity HTN-1 Trial: Key Inclusion/Exclusion Criteria * Inclusion Criteria >18 years of age Elevated office systolic blood pressure (SBP) 160 mm Hg 3 antihypertensive medications (including 1 diuretic) Exclusion Criteria Estimated glomerular filtration rate (egfr) <45 ml/min/1.73m 2 Type 1 diabetes mellitus Known secondary cause of hypertension other than sleep apnea or chronic kidney disease Significant renovascular abnormalities * Inclusion/exclusion criteria in the trial settings were stringent and conservative in order to ensure a homogenous population in clinical practice, individual patient characteristics and physician judgment should guide patient selection Source: Symplicity HTN-1 Investigators. Hypertension. 2011;57: Symplicity HTN-1 Trial: 24 Month Results * Change (mm Hg) Office BP SBP DBP 50 1M (n=138) 3M (n=135) 6M (n=86) 12M (n=64) 18M (n=36) 24M (n=18) * Changes in SBP and diastolic blood pressure (DBP) were significant at all time points; error bars represent 95% CIs. Symplicity HTN-1 Investigators. Hypertension. 2011;57:

13 Symplicity HTN-1 Trial: Results for 18 Patients with 2-year Follow-Up Office BP Change (mm Hg) M (n=18) 3M (n=16) 6M (n=16) 12M (n=16) 18M (n=17) 24M (n=18) SBP DBP Symplicity HTN-1 Investigators. Hypertension. 2011;57: Symplicity HTN-2 Trial Overview Design Multicenter (24 sites in Europe, Australia, and New Zealand), prospective, randomized, controlled study Population 106 patients with treatment resistant hypertension Treatment Intervention group (endovascular catheter based RDN with the Symplicity Renal Denervation System plus baseline antihypertensive medications) Control group (baseline antihypertensive medications alone) Duration 6 months (for the primary endpoint) with follow up to 3 years Outcome Measures Primary endpoint: between group changes in average office SBP from baseline to 6 months Secondary endpoints: acute and chronic procedural safety, a composite cardiovascular endpoint, occurrence of 10 mm Hg SBP reductions, achievement of target SBP, change in 24 hour ambulatory BP, and change in home BP Symplicity HTN-2 Investigators. Lancet. 2010;376: Symplicity HTN-2 Trial Key Inclusion/Exclusion Criteria * Inclusion Criteria years of age Elevated office SBP 160 mm Hg (or 150 mm Hg for type 1 diabetics) Documented compliance with 3 antihypertensive medications Exclusion Criteria egfr <45 ml/min/1.73m 2 Type 1 diabetes mellitus Contraindications to MRI Substantial stenotic valvular heart disease Pregnancy or planned pregnancy during the study Myocardial infarction, unstable angina, or cerebrovascular accident in previous 6 mo Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention * Inclusion/exclusion criteria in the trial settings were stringent and conservative in order to ensure a homogenous population in clinical practice, individual patient characteristics and physician judgment should guide patient selection. Symplicity HTN-2 Investigators. Lancet. 2010;376:

14 ( 5/3/2013 Symplicity HTN-2 Trial: 1-, 3-, and 6-Month Office BP Reduction * ffice BP Change (mm Hg) Mean Of SBP DBP -50 Symplicity RDN Group Control Group Symplicity RDN Group Control Group Symplicity RDN Group Control Group 1M 3M 6M (Primary Endpoint) * P 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. Lancet. 2010;376: Symplicity HTN 2 Trial: Distribution of Office SBP at 6 Months 1,2 1. Data on file, Medtronic. 2. Symplicity HTN-2 Investigators. Lancet. 2010;376: Symplicity HTN 2 Trial: Short Term Procedure Safety No serious device or procedure related adverse events Minor complications in 5 of 52 patients: 1 access site complication (femoral artery pseudoaneurysm); treated with manual compression 1 post procedural drop in BP 1 urinary tract infection 1 extended hospital admission for assessment of parasthesias 1 case of back pain; treated with pain medication and resolved after 1 month Symplicity HTN-2 Investigators. Lancet. 2010;376:

15 Symplicity HTN-2 Trial: Chronic Safety 43 RDN patients underwent CTA, MRA, or duplex evaluation at 6 months No new vascular abnormalities or stenoses at any site of RF delivery 1 possible progression of a pre existing stenosis unrelated to RF treatment; no further therapy warranted Serious adverse events at 6 months requiring hospital admission: Symplicity RDN Control Group Group (n=49) (n=51) Composite Cardiovascular Events Hypertensive event unrelated to non-adherence to 3 2 medication Other cardiovascular events 0 0 Other Serious Adverse Events Transient ischemic attack 1 2 Hypertensive crisis after abruptly stopping clonidine 1 0 Hypotensive episode resulting in reduction of medications 1 0 Coronery stent for angina 1 1 Temporary nausea/edema 1 0 Symplicity HTN-2 Investigators. Lancet. 2010;376: Design Symplicity HTN 3: Overview Multicenter (60 sites in the United States), prospective, randomized, blinded, controlled study Population 530 patients with treatment resistant hypertension Treatment Treatment group (endovascular catheter based RDN with the Symplicity Renal Denervation System plus baseline antihypertensive medications) Control group (sham procedure * plus baseline antihypertensive medications) Primary Outcome Measures Change in office SBP from baseline to 6 months Safety * The renal angiogram also acts as the sham procedure for patients in the control group. Data on file, Medtronic. Symplicity HTN 3 Trial: Study Design Office SBP? 160 mmhg Full doses of? 3 meds Initial Initial Screening past 2 wks Screening No plan to change meds for 6 M 2 weeks Home BP & Med Diary Confirmatory Screening ABPM Treatment Renal Angiogram Control 1M 3M 1M 3M 2 weeks 6M Home BP & Med Confirmation Primary Endpoint 2 weeks Home BP & Med Confirmation 6M 12 36M Patient and Research staff assessing BP are blinded to treatment status No changes in medications for 6M 45 15

16 Symplicity HTN 3 Trial: Inclusion Criteria Average SBP 160mmHg (measured per guidelines) On stable medication regimen of full tolerated doses of 3 or more antihypertensive meds, with one being a diuretic No changes for a minimum of 2 weeks prior to screening No planned medication changes for 6 months Age years Source: Data on file, Medtronic. Symplicity HTN 3 Trial: Antihypertensive Medications At minimum, 3 antihypertensive medications must meet one or more of the following full dose criteria: Highest labeleddosedose according to medication s labeling Highest usual dose per clinical guidelines (JNC 7) Highest tolerated dose Highest appropriate dose for the patient per the PI s best clinical judgment Symplicity HTN 3 Trial: Exclusion Criteria Hemodynamically or anatomically significant renal artery abnormalities or stenosis (>50%) or prior renal artery intervention egfr < 45 ml/min/1.73m 2 (MDRD formula) In patient hospitalization for HTN Crisis in past year 24 hour average ABPM SBP <135mm/Hg Type 1 diabetes mellitus Symptomatic orthostatic hypotension in past year Stenotic valvular heart disease for which BP would be hazardous MI, unstable angina, or CVA in the prior 6 months Planned surgery or CV intervention within the next 6 months Known primary pulmonary HTN Known pheochromocytoma, Cushing's disease, coarctation of the aorta, hyperthyroidism or hyperparathyroidism Known alcohol or drug abuse 16

17 Symplicity HTN 3 Trial: Referral to Randomization Steps Initial Screening Confirmatory Screening Renal Angiogram Referred Office SBP 160mmHg to trial Full tolerated doses of 3 site meds (diuretic) No HTN meds Δin past 2 weeks No plan Δ HTN meds in next 6 M Home Office diary SBP 160mmHg 2 wks Documented compliance on meds (diary) egfr 45 ml/min 24-hr ABPM ABPM 135 mmhg Renal angiogram Symplicity HTN-3: Schematic 530 uncontrolled hypertensive pts Treatment 1 mo 3 mo 2:1 randomization 6 months 1 o endpoint: ΔOffice SBP 6 mo Pt can crossover* Follow-up to 3 years 12, 18, 24, 30, 36 Control (renal angio) 1 mo 3 mo 6 mo 12, 24, 36 +1, 3, 6, 12, 18, 24, 30 Patient is blinded for 6 months No medication changes unless medically necessary: An adverse event or symptom change, OR SBP <115mmHg, OR SBP increase >15mmHg above baseline Symplicity HTN-3: Summary Office SBP >160mmHg 3 antihypertensive medications (one must be a diuretic) On stable, 3 full tolerated dose antihypertensive medication regimen for at least 2 weeks No significant renal insufficiency (egfr < 45 ml/min) Meets inclusion/exclusion criteria by general medical review No known renal artery anatomy exclusion (i.e. dual renal arteries, known RA stenosis >50%) Until 6 month primary endpoint: Patients must remain blinded No changes in medication unless medically necessary After 6 mo endpoint, control patients can crossover if still meet all initial criteria 17

18 Summary We can do a better job with HTN recognition and management Data for renal denervation thus far is very positive Renal denervation is coming (already approved in Europe) for refractory/resistant HTN Questions? 18