Hypertension Guidelines 2016 Michael A. Weber, MD Division of Cardiovascular Medicine State University of New York Downstate Medical Center
Speaker Disclosures I disclose that I am a Consultant for: Ablative Solutions, Boston Scientific, Boehringer Ingelheim, Eli Lilly, Forest, Medtronics, Novartis, ReCor
What Are the Key Recommendations by a Hypertension Practice Guideline? The threshold blood pressure values that define hypertension and set treatment targets The optimal choice of drugs for reducing blood pressure and maximizing cardiovascular, stroke and renal protection
JNC 7 Algorithm for the 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 140 159 or DBP 90 99 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. *Compelling Indications Heart failure Post-MI High coronary artery disease risk Diabetes Chronic kidney disease Recurrent stroke prevention Chobanian AV et al. JAMA. 2003;289:2560 2572.
What is the appropriate blood pressure target? To adequately define hypertension, it is necessary to establish the evidence-based blood pressure threshold that should be achieved by treatment. Should it be < 150 mmhg, or < 140 mmhg, or <130 mmhg, or < 120 mmhg?
Systolic Hypertension in the Elderly Program (SHEP) Multicenter, randomized, double-blind, placebo-controlled, patients 60 years, systolic BPs 160 mm Hg & diastolic BPs <90 mm Hg, using 12.5-25 mg chlorthalidone + other drugs if needed (Starting SBP: 170 mm Hg; achieved SBP: Placebo 155 mm Hg, active treatment 143 mm Hg) Cumulative fatal and nonfatal stroke rate per 100 participants 10 8 6 4 2 0 Placebo (n=2371) 36% Active treatment (n=2365) 0 12 24 36 48 60 72 Months SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264.
James PA. et al. JAMA. 2013 Dec 18. doi: 10.1001/jama.2013.284427. [Epub ahead of print].
Authors of JNC 8 Panel: Recommendation 1 In the general population aged 60 years or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 150 mm Hg or higher or diastolic blood pressure (DBP) of 90 mm Hg or higher and treat to a goal SBP lower than 150 mm Hg and goal DBP lower than 90 mm Hg. Strong Recommendation Grade A Note: This was one of only two of the nine recommendations of the panelists that claimed to be Strong and Grade A
HYVET: 21% Reduced Mortality With Active Treatment in Patients Aged 80 or more Active (SBP: 143 mm Hg) versus placebo (SBP: 158 mm Hg) in patients aged 80 or older 30 No. of events per 100 patients 20 10 Placebo group Active treatment group No. at risk Placebo group Active-treatment group 0 0 1 2 3 Follow-up (yr) 1912 1933 1492 1565 814 877 379 420 4 202 231 Beckett NS et al. N Engl J Med. 2008;358:1887 1998.
Effective BP Control (SBP <140 mmhg) Reduces Cardiovascular Risk (VALUE Trial) HR (95% CI) of CV events in patients being followed up to 6 years Fatal and non-fatal cardiac events Fatal and non-fatal stroke All-cause death Myocardial infarction Heart failure hospitalizations 0.75 (0.67 0.83) 0.55 (0.46 0.64) 0.79 (0.71 0.88) 0.86 (0.73 1.01) 0.64 (0.55 0.74) 0.6 0.8 1.0 1.2 SBP controlled at 6 months (n=10,755) SBP not controlled at 6 months (n=4,490) * Pooled analysis of patients enrolled in the VALUE trial; blood pressure control defined as SBP <140 mmhg Statistically significant difference (p<0.05) vs SBP not controlled at 6 months BP=blood pressure; CI=confidence interval; CV=cardiovascular; HR=hazard ratio; SBP=systolic blood pressure; VALUE=Valsartan Antihypertensive Long-term Use Evaluation Weber MA, et al. Lancet 2004;363:2049-51.
ACCORD: Mean Systolic Pressures in Over Time (Patients with Diabetes) 140 Intensive Standard SBP (mm Hg) 130 120 110 100 Average : 133.5 Standard vs 119.3 Intensive, delta = 14.2 N = 4382 4050 2391 359 0 1 2 3 4 5 6 7 8 Years post-randomization Mean number of medications Intensive: 3.2 3.4 3.4 3.5 3.5 3.5 3.4 3.4 Standard: 1.9 2.1 2.1 2.2 2.2 2.3 2.3 2.3 Number of patients Intensive: 2,174 2,071 1,973 1,792 1,150 445 156 156 Standard: 2,208 2,136 2,077 1,860 1,241 504 203 201 Data shown are mean ± 95% CI. ACCORD study group. N Engl J Med. 2010;362:1575 1585.
ACCORD: Primary Outcome and Total Stroke 20 Primary Outcome (Nonfatal MI, nonfatal stroke or CVD death) HR = 0.89 95% CI (0.73-1.07) 20 HR = 0.59 95% CI (0.39-0.89) Nonfatal Stroke Patients with events (%) 15 10 5 15 10 5 NNT for 5 years = 89 0 Intensive Standard 0 0 1 2 3 4 5 6 7 8 Years post-randomization 0 1 2 3 4 5 6 7 8 Years post-randomization ACCORD study group. N Engl J Med. 2010;362:1575 1585.
SPRINT Research Question Examine effect of more intensive high blood pressure treatment than is currently recommended Randomized Controlled Trial Target Systolic BP Intensive Treatment Goal SBP < 120 mm Hg Standard Treatment Goal SBP < 140 mm Hg SPRINT design details available at: ClinicalTrials.gov (NCT01206062) Ambrosius WT et al. Clin. Trials. 2014;11:532-546.
Systolic BP During Follow-up Year 1 Mean SBP 136.2 mm Hg Standard Average SBP (During Follow-up) Standard: 134.6 mm Hg Mean SBP 121.4 mm Hg Intensive Intensive: 121.5 mm Hg Average number of antihypertensive medications Number of participants
SPRINT Primary Outcome and its Components Event Rates and Hazard Ratios Intensive Standard No. of Events Rate, %/year No. of Events Rate, %/year HR (95% CI) P value Primary Outcome 243 1.65 319 2.19 0.75 (0.64, 0.89) <0.001 All MI 97 0.65 116 0.78 0.83 (0.64, 1.09) 0.19 Non-MI ACS 40 0.27 40 0.27 1.00 (0.64, 1.55) 0.99 All Stroke 62 0.41 70 0.47 0.89 (0.63, 1.25) 0.50 All HF 62 0.41 100 0.67 0.62 (0.45, 0.84) 0.002 CVD Death 37 0.25 65 0.43 0.57 (0.38, 0.85) 0.005
Participants with CKD at Baseline Renal Disease Outcomes Intensive Standard Events %/yr Events %/yr HR (95% CI) P Primary CKD outcome 14 0.33 15 0.36 0.89 (0.42, 1.87) 0.76 50% reduction in egfr * 10 0.23 11 0.26 0.87 (0.36, 2.07) 0.75 Dialysis 6 0.14 10 0.24 0.57 (0.19, 1.54) 0.27 Kidney transplant 0-0 - -. Secondary CKD Outcome Incident albuminuria** 49 3.02 59 3.90 0.72 (0.48, 1.07) 0.11 Participants without CKD at Baseline Secondary CKD outcomes 30% reduction in egfr* 127 1.21 37 0.35 3.48 (2.44, 5.10) <.0001 Incident albuminuria** 110 2.00 135 2.41 0.81 (0.63, 1.04) 0.10 *Confirmed on a second occasion 90 days apart **Doubling of urinary albumin/creatinine ratio from <10 to >10 mg/g
Major Outcomes by Achieved Systolic Blood Pressure Category in ACCOMPLISH Increased Serum Creatinine (>50%) 70 p-values versus >140 Events per 1,000 Patient-Years 60 50 40 30 20 0.0156 0.0000 0.0000 0.0507 0.6240 0.0359 Patients with diabetes Patients without diabetes 10 p-values versus >140 110 to <120 120 to <130 130 to <140 >140 Achieved Systolic Blood Pressure (mmhg)
How to Interpret SPRINT Could result be due to more intensive treatment rather than more intensive BP control? Mean systolic BP in Intensive group was 121.5 mmhg, with >50% of patients above 120 mmhg. ----- So, despite the original intention to test < 120 mmhg, do these findings better support a target of < 130 mmhg? Measurement of BP by rigorous use of automated device in SPRINT (to minimize white coat effect) such that SPRINT readings might have been 5-10 mmhg lower than typical practice readings, again suggesting a <130 mmhg rather than <120 mmhg target
Clinical Trials Where Different Drug Treatments Produced Differing Outcomes Independent of Blood Pressure LIFE ASCOT ACCOMPLISH ALLHAT In SPRINT the Intensive Group had significantly greater use of ACEi, ARBs, CCBs, thiazides, spironolactone
Characteristic Benazepril + Amlodipine Benazepril + HCTZ Hazard Ratio (95% CI) p-value Number of Patients Mean BP after Titration Primary endpoint CV death + MI + stroke 2,266 132/73 mmhg 2,293 133/73 mmhg 118(5.2) 161(7.0) 0.73 (0.57-0.92) 0.008 Fatal and non-fatal MI 48 (2.1) 68 (3.0) 0.70 (0.49 1.02) 0.059 Stroke 48 (2.1) 63 (2.8) 0.76 (0.52 1.10) 0.143 CV death 45 (2.0) 60 (2.6) 0.75 (0.51 1.10) 0.137 Hospitalized HF 26 (1.2) 29 (1.3) 0.89 (0.54 1.52) 0.679 All-cause death 95 (4.2) 123 (5.4) --- 0.77 (0.59 1.00) --- 0.052 SPRINT Endpoint* 165 (7.3) 213 (9.3) 0.77 (0.62 0.95) 0.0140 ACCOMPLISH: Endpoints for the Non-diabetes Cohort Values are absolute numbers (percentages). Abbreviations: HCTZ=hydrochlorothiazide; MI=myocardial infarction; UA=unstable angina; CV=cardiovascular; HF=heart failure *Composite of MI, other acute coronary syndromes, stroke, heart failure or CV death, added to this Table following publication of SPRINT Trial Adapted from: Weber et al. JACC 2010;56:77-85
Therapy Most evidence now supports 3 drug types: the RAS blockers (ACE inhibitors or ARBs); calcium channel blockers; and diuretics. Evidence for beta blockers weaker, except if HF, post-mi, angina, AF Chlorthalidone & indapamide seen as alternatives to HCTZ; growing interest in spironolactone for difficult-to-control hypertension Combination treatment is required in >50% of patients and can be used to start therapy
LIFE Trial: Losartan vs Atenolol as Initial Therapy Proportion of patients (%) 8 7 6 5 4 3 2 1 0 Cardiovascular Mortality Atenolol Losartan Adjusted risk reduction: 11.4%, P=0.206 Unadjusted risk reduction: 13.3%, P=0.136 8 7 6 5 4 3 2 1 0 Stroke (Fatal and Nonfatal) Adjusted risk reduction: 24.9%, P=0.0010 Unadjusted risk reduction: 25.8%, P=0.0006 No. at risk Losartan Atenolol Reprinted from The Lancet, 359(9311), Dahlöf B et al, Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, 995-1003, 2002, with permission from Elsevier. Dahlöf B et al. Lancet 2002; 359: 995 1003.
Chlorthalidone (CLD) Had Positive Effects on Cardiovascular Outcomes in Landmark Studies Clinical study HDFP 1 MRFIT 2,3 SHEP 4 ALLHAT 5 Population studied and duration of study Comparators Significant findings 10,940 adults with HTN Over 5 years 12,866 high risk males with HTN Over 10.5 years 4,736 adults >60 years of age with ISH Over 5 years 33,357 high risk adults with HTN Over 4.9 years CLD Usual care CLD HCTZ Usual care CLD Placebo CLD Amlodipine Lisinopril CLD reduced mortality by 17% vs usual care CLD reduced mortality rate vs HCTZ CLD lowered risk for CV events by 21% vs HCTZ CLD lowered risk for CVD by 32% vs placebo CLD was similar to amlodipine and lisinopril in prevention of fatal and nonfatal coronary events ALLHAT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CLD=chlortalidone; CVD=cardiovascular disease; CV=cardiovascular; HCTZ=hydrochlorothiazde; HDFP=Hypertension Detection and Follow-up Program; HTN=hypertension; ISH=isolated systolic hypertension; MRFIT=Multiple Risk Factor Intervention Trial; SHEP=Systolic Hypertension in the Elderly Program 1. Hypertension Detection and Follow-up Program Cooperative Group. JAMA. 1979;242:2562-71. 2. Multiple Risk Factor Intervention Trial Research Group. Circulation. 1990;82:1616-28. 3. Dorsch MP, et al. Hypertension. 2011;51:689-94. 4. SHEP Cooperative Research Group. JAMA. 1991;265:3255-64 5. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-97.
End point ASCOT: Primary and Secondary End Points Amlodipine/Perindopril vs Atenolol/Bendroflumethiazide Hazard Ratio P Value All-cause mortality Primary end point: nonfatal MI and fatal CHD Total coronary end point: primary end point + new-onset angina + fatal and nonfatal heart failure Fatal and nonfatal stroke All CV events and revascularization procedures CV mortality 0.005 0.12 0.0048 0.0007 <0.0001 0.0017 0.5 1 1.5 Favors Amlodipine/Perindopril Favors Atenolol/Bendroflumethiazide ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; MI = myocardial infarction; CHD = cardiovascular heart disease; CV = cardiovascular. Sever PS, Dahlöf B. American College of Cardiology 2005 Scientific Sessions; March 6-9, 2005; Orlando, FL.
Hypertension Guideline Headlines 2016 Likely that 140 mmhg will remain threshold for many patients (including those with diabetes), but 120 mmhg, or more likely 130 mmhg, will have a growing role Defining thresholds for important groups of patients non-high risk, young adults still not achieved Drug choice/selection of combinations may be critical in maximizing CV protection RAS blockers/ccbs/thiazides are core; beta blockers, unless indicated, are less proven; chlorthalidone & spironolactone getting attention Growing focus on home BPs, even ABPM
Causes of Treatment Resistant Hypertension White coat hypertension Poor drug selection/clinical inertia Poor drug compliance Secondary hypertension (aldo/osa) BP-raising drugs (eg NSAIDs, cold remedies) High salt diet/volume overload; alcohol excess True resistance a rare entity
1/3 of Office Resistant Hypertension Is Actually White-Coat Hypertension by ABPM Spanish APBM Registry of 8295 Patients Entire Cohort Apparent Treatment Resistant Percentage of treated hypertensives de la Sierra A. Hypertension 2011;57:898-902.
Drug-Induced (Medications) that Can Interfere with BP Control NSAIDs/COX-2 inhibitors Oral contraceptives (estrogen predominant) Sympathomimetic agents (decongestants, diet pills, cocaine) Stimulants (amphetamines, methylphenidate) Alcohol Anti-depressants (TCAs and SNRIs) Cyclosporine Erythropoietin Natural licorice Herbal compounds (ephedra or ma huang) Calhoun et al. AHA Scientific Statement: Hypertension 2008;51:1403-1419.
BP Response with Spironolactone 25-50 mg as 4 th Drug: ASCOT Results SBP = -21.9 170 N=1411 156.9 Mean BP (mm Hg) 150 130 110 135.1 6% discontinuation rate due to adverse effects DBP = -9.5 90 85.3 75.8 70 Pre Post Pre Post SBP DBP Chapman et al. Hypertension 2007;49:839.
Resistant hypertension? Assessment of Adherence by Urine Sample Analysis 375 Patients Referred for Uncontrolled HTN on 3 Drugs 108 Uncontrolled Maximized Doses Excluded White Coat Exclude Pseudoresistant 76 Uncontrolled 15 with Secondary HTN 17 Controlled on 4 Drugs 40 Non-Adherent (30% taking no meds and 85% <half) 36 True Resistant HTN (10% of all 375 referred patients) Jung O. et al. J Hypertension 2013;31:766-774.
Treatment Resistant Hypertension Conclusion In the hands of experienced clinicians willing to systematically evaluate and treat their patients, treatment resistant hypertension is a relatively rare condition
How does renal denervation reduce BP? Destruction of the renal nerves Inhibits renal release of renin Enhances renal sodium excretion Works centrally to reduce sympathetic outflow Causes renal microvascular dilation Question: Is this something that drugs cannot do?
REDUCE-HTN: Vessix Catheter (Radio Frequency Ablation): Treatment Resistant Hypertension 0-5 Systolic Diastolic Systolic Diastolic Systolic Diastolic Systolic Diastolic BP change (mm Hg) FIM 13 + PMS -10-15 -20-25 -30-10 -23-23 -13-27 -10-14 -35-40 -36 2 Weeks F/U (n=44) 1 Month F/U (n=34) 3 Month F/U (n=18) 6 Month F/U (n=6) Margolis, TCT 2012. * Vessix is an investigational device and not available for sale in the US.
Change in Office BP By 36 Months in Treatment Resistant Hypertension: Symplicity 2 0-5 -10 BP change (mmhg) -15-20 -25-30 -35-40 -19-9 -10-10 -21-22 -27-14 -14-29 -34-17 -31-16 SBP mmhg DBP mmhg -45 P<0.01 for from BL for all time points 1 mo (n=143) 3 mo (n=148) 6 mo (n=144) 12 mo (n=132) 24 mo (n=105) 30 mo (n=44) 36 mo (n=34)* Schlaich M, TCT 2012 Reported as mean with 95% confidence intervals *Number of patients represents data available at time of data-lock
Symplicity 3: RDN vs. Sham in Treatment Resistant HTN Δ = -2.39 (95% CI, -6.89 to 2.12) P=0.26* 200 Δ = -14.1±23.9 P<0.001 Δ = -11.7±25.9 P<0.001 Office SBP (mm Hg) 150 100 50 180 mm Hg 166 mm Hg 180 mm Hg 168 mm Hg Baseline 6 Months 0 (N=364) (N=353) Denervation (N=171) Sham (N=171) *P value for superiority with a 5 mm Hg margin; bars denote standard deviations
Symplicity HTN 3: Explaining An Unexpected Result - Sham procedure design raised question: Did previous uncontrolled trials produce misleading data? - Unresolved issues of renal nerve anatomy, catheter design, operative technique - Patients selected for Treatment resistant Hypertension -- a poorly defined clinical entity
Global Symplicity Registry: Office SBP 20 15 All Patients* <140 mm Hg* 140-159 mm Hg 160 mm Hg* 12.9 14.2 10 5 0-5 -10-15 N=769 N=751 N=227 N=222 N=448 N=433 N=94 N=96-2.0-4.6-10.0-11.9 3 Mo 6 Mo -20-25 -18.9-21.4 Bohm et al, Hypertension 2015;65:766-74 *P<0.0001 for both 3 and 6 month change from baseline ; P=0.14 at 3 months and P=0.0006 at 6 months
Our View of Renal Nerve Distribution Has Changed Renal nerves may have a positional bias on radial distance from arterial lumen: distal nerves are closer Distal Proximal Prior concept Uniform radial distribution Distal Proximal Current concept Non-uniform radial distribution Sakakura K, et al., JACC 2014; 64:634-43
DENER HTN: The First Successful Controlled Trial of Renal Denervation in Treatment Resistant Hypertension* 0 : 5.9 mm Hg (95% CI: 11.3 to 0.5) p = 0.0329 : 6.3 mm Hg (95% CI: 12.0 to 0.6) p = 0.0296 SBP Change from Baseline to 6 Months (mm Hg) 10 20 Denervation Control Daytime Nighttime Primary endpoint *It required 1416 referred resistant patients to yield 106 eligible for the trial (1:13) Azizi M et al. The Lancet. 2015 Jan 23. http://dx.doi.org/10.1016/s0140-6736(14)61942 1945.
Lessons Learned in Renal Denervation Cannot get reliable results when an inconsistent technique is applied to an ill-defined clinical condition Solution Optimize catheter designs to ensure full circumferential ablation effects Establish rigorous standards of procedural technique: branches as well as main renal artery Study carefully defined hypertensive populations Use trial designs that effectively measure the effects of treatment on high blood pressure
Indication Indications for Renal Denervation (1) Looking to the Future 1.Treatment-resistant hypertension (TRH) 2. Patients with poor drug compliance Comment Condition poorly defined True TRH is rare No consistent evidence that RDN superior to expert drug therapy Improved RDN studies are ongoing Improvement in long term BP control could justify RDN intervention 3. Systolic hypertension in the elderly SNS is a factor Condition responds well to drugs RDN could simplify care if ablation energy can cross atherosclerotic renal artery walls SNS=sympathetic nervous system Weber MA. TCT Meetings, 2015
Indication Indications for Renal Denervation (2) Looking to the Future 4. Hypertension in young adults Comment High SNS activity often characterizes this condition Early evidence for left ventricular changes, arterial stiffness etc. RDN could potentially improve lifelong natural history of hypertension 5. Hypertension associated with CKD 6. Atrial fibrillation and heart failure Early evidence that RDN can reduce rate of loss of renal function These indications already being studied independently of hypertension SNS=sympathetic nervous system; CKD=chronic kidney disease Weber MA. TCT Meetings, 2015
Summary The task of renal denervation trials now under way or about to start is to demonstrate in well defined hypertensive patient populations that this procedure reduces BP and is efficacious when combined with drug therapy A second critical task is to demonstrate short and long-term safety in these patients When these data are obtained we can start to define the potential of renal denervation in the clinical practice of hypertension