Hypertension: Update Meenakshi A Bhalla MD,FACC Associate Professor of Medicine Director Preventive Cardiology Advanced Heart Failure and Transplant Cardiology University of Kentucky Faculty Disclosure None relevant. 1
Introduction Why are we still talking about hypertension? Guidelines Discrepancy How low is too low? Define Resistant Hypertension What is the data, how to treat it? Introduction Most common reason for office visits and use of prescription medications. NHANES (2005-2008) estimated 29-31% of adults with hypertension. Approx. 76.4 million Americans over the age 20 years have hypertension. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA 2010; 303:2043. Mean systolic and diastolic blood pressure in adults aged 18 and over in the United States, 2001-2008. Natl Health Stat Report 2011; :1. 2
Prevalence of Hypertension in United States Egan BM, Zhao Y JAMA 2010; 303:2043 CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment* CV mortality risk 8 7 6 5 4 3 2 1 0 115/75 135/85 155/95 175/105 SBP/DBP (mm Hg) *Individuals aged 40-69 years, starting at BP 115/75 mm Hg.CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressurelewington S, et al. Lancet. 2002; 60:1903-1913. JNC VII. JAMA. 2003. 3
IHD Rates by SBP, DBP, and Age IHD Mortality (Floating Absolute Risk and 95% CI) 256 128 64 32 16 8 4 2 1 A: Systolic Blood Pressure Age at risk: 80-89 years 70-79 years 60-69 years 50-59 years 40-49 years IHD Mortality (Floating Absolute Risk and 95% CI) 256 128 64 32 16 B: Diastolic Blood Pressure 8 4 2 1 Age at risk: 80-89 years 70-79 years 60-69 years 50-59 years 40-49 years 120 140 160 180 Usual SBP (mm Hg) 70 80 90 100 110 Usual DBP (mm Hg) Lewington et al. Lancet. 2002;360:1903-1913. Stroke mortality rates by SBP, DBP and Age Data from Prospective Studies Collaboration, Lancet 2002; 360:1903. 4
Cumulative absolute risk of CVD at five years Reference: Non diabetic, Non smoking, 50 yo Female with TC 154 mg/dl, HDL 62 mg/dl Jackson R, Lawes CM, etal. Lancet 2005; 365:434 Trends in the awareness, treatment & control of high blood pressure in adults in the United States Data for adults 18-74 yo of age with SBP 140 mm of Hg and/or DBP 90 mm of Hg Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003; 289:2560, and from US Trends in Prevalence, Awareness, Treatment, and Control of Hypertension 1988-2008, JAMA 2010; 303:2043. 5
Potential reasons for low rates of blood pressure control 1. Access to healthcare and medications 2. Lack of adherence with long-term therapy 3. Therapeutic inertia 6.Wang TJ, Vasan RS. Epidemiology of uncontrolled hypertension in the United States. Circulation 2005; 112:1651. 7.Egan BM et al. Initial monotherapy and combination therapy and hypertension control the first year. Hypertension 2012; 59:1124. JNC 7 Classification of Hypertension 6
JNC 8 Hypertension Guideline Algorithm Adult aged 18 years with HTN Implement lifestyle modifications Set BP goal, initiate BP lowering medication based on algorithm General Population (no diabetes or CKD) Diabetes or CKD present Initial Drugs of Choice for Hypertension ACE inhibitor (ACEI) Angiotensin receptor blocker (ARB) Thiazide diuretic Calciumchannel blocker (CCB) Age 60 years Age < 60 years All Ages Diabetes present No CKD BP Goal < 150/90 Nonblack Initiate thiazide, ACEI, ARB, or CCB, alone or in combo BP Goal < 140/90 Black Initiate thiazide or CCB, alone or combo At blood pressuregoal? No Reinforce lifestyle and adherence Titrate medications to maximum doses or consider adding another medication (ACEI, ARB, CCB, Thiazide) At blood pressure goal? No No BP Goal < 140/90 All Ages and Races CKD present with or without diabetes BP Goal < 140/90 Initiate ACEI or ARB, alone or combo w/another class Reinforce lifestyle and adherence Add a medication class not already selected (i.e. beta blocker, aldosterone antagonist, others) and titrate above medications to max (see back of card) At blood pressuregoal? Reinforcelifestyle and adherence Titrate meds to maximum doses, add another med and/or refer to hypertension specialist Yes Yes Yes Strategy A B C Continue tx and monitoring Description Start one drug, titrate to maximum dose, and then add a second drug. Start one drug, then add a second drug before achieving max dose of first Begin 2 drugs at same time, as separate pills or combination pill. Initial combination therapy is recommended if BP is greater than 20/10mm Hg above goal Lifestyle changes: Smoking Cessation Control blood glucose and lipids Diet Eat healthy (i.e., DASH diet) Moderate alcohol consumption Reduce sodium intake to no more than 2,400 mg/day Physical activity Moderate to vigorous activity 3 4 days a week averaging 40 min per session. Reference: James PA, Ortiz E, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: (JNC8). JAMA. 2014 Feb 5;311(5):507-20 Indication Heart Failure Post MI/ClinicalCAD CAD Diabetes CKD Recurrent strokeprevention Pregnancy Compelling Indications Treatment Choice ACEI/ARB + BB + diuretic + spironolactone ACEI/ARB AND BB ACEI, BB, diuretic, CCB ACEI/ARB, CCB, diuretic ACEI/ARB ACEI, diuretic labetolol (first line), nifedipine, methyldopa Hypertension Treatment Beta 1 Selective Beta blockers possibly safer in patients with COPD, asthma, diabetes, and peripheral vascular disease: metoprolol bisoprolol betaxolol acebutolol Drug Class Agents of Choice Comments Diuretics HCTZ 12.5 50mg, chlorthalidone 12.5 25mg, indapamide 1.25 2.5mg triamterene 100mg K+ sparing spironolactone 25 50mg, amiloride 5 10mg, triamterene 100mg furosemide 20 80mg twice daily, torsemide 10 40mg ACEI/ARB ACEI: lisinopril, benazapril, fosinopril and quinapril 10 40mg, ramipril 5 10mg, trandolapril 2 8mg ARB: candesartan 8 32mg, valsartan 80 320mg, losartan 50 100mg, olmesartan 20 40mg, telmisartan 20 80mg Beta Blockers Calcium channel blockers Vasodilators metoprolol succinate 50 100mg and tartrate 50 100mg twice daily, nebivolol 5 10mg, propranolol 40 120mg twice daily, carvedilol 6.25 25mg twice daily, bisoprolol 5 10mg, labetalol 100 300mg twice daily, Dihydropyridines: amlodipine 5 10mg, nifedipine ER 30 90mg, Non dihydropyridines: diltiazem ER 180 360 mg, verapamil 80 120mg 3 times daily or ER 240 480mg hydralazine 25 100mg twice daily, minoxidil 5 10mg Monitor for hypokalemia Most SE are metabolic in nature Most effective when combined w/ ACEI Stronger clinical evidence w/chlorthalidone Spironolactone gynecomastia and hyperkalemia Loop diuretics may be needed when GFR <40mL/min SE: Cough (ACEI only), angioedema (more with ACEI), hyperkalemia Losartan lowers uric acid levels; candesartan may prevent migraine headaches Not first line agents reserve for post MI/CHF Cause fatigue and decreased heart rate Adversely affect glucose; mask hypoglycemic awareness Cause edema; dihydropyridines may be safely combined w/ B blocker Non dihydropyridines reduce heart rate and proteinuria Hydralazine and minoxidil may cause reflex tachycardia and fluid retention usually require diuretic + B blocker terazosin1 5mg, doxazosin1 4mg given at bedtime Alpha blockersmay cause orthostatic hypotension Centrally acting clonidine 0.1 0.2mg twice daily, methyldopa 250 500mg twice daily Clonidine available in weekly patch formulation for Agents resistant hypertension guanfacine 1 3mg Reference: James PA, Ortiz E, et al. 2014 evidence based guideline for the management of high blood pressure in adults: (JNC8). JAMA. 2014 Feb 5;311(5):507 20 7
Comparison of International Guidelines on HTN Goals (mm Hg) HTN Guideline Controversy; Age at which the blood pressure goal should be increased to less than 150/90 mm of Hg Blood Pressure Management PSAP 2016 Treatment Of Hypertension in Patients with CAD; ACC/AHA guideline recommendation 1. <140/90 mm Hg reasonable target for the secondary prevention of cardiovascular events in patient with hypertension and CAD ( Class IIa; level of evidence B) 2. Lower target BP (<130/80 mm of Hg) may be appropriate in some individuals with CAD, previous MI, CVA or CAD risk equivalents ( Class IIb; level of evidence B) 3. Patients with elevated DBP and CAD with evidence of myocardial ischemia, BP should be lowered slowly, and caution advised in decreasing DBP<60 mm Hg in any patient with diabetes or age >60 yrs. ( Class IIa; level of evidence C) A scientific statement from the A scientific statement from the AHA/ACC/ASH. Circulation 2015 8
Antihypertensive Therapy Recommendations for Patients with Ischemic Heart Disease Treatment of hypertension in patients with coronary artery disease. A scientific statement from the AHA/ACC/ASH. Circulation 2015 How low is the Target?? 9
Clinical Trial Evidence of Lower SBP Goals is Unclear ACCORD BP question: Does a strategy targeting systolic blood pressure (SBP) <120 mm Hg reduce CVD events compared to a strategy targeting SBP <140 mm Hg in 4,700 participants with type 2 diabetes at high risk for CVD events? Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med 2010; 362:1575-1585 Acaa ACCORD Results are Mixed Outcome Intensive Events (%/yr) Standard Events (%/yr) HR (95% CI) P CVD (Primary) 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20 Cardiovascular Deaths 60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74 Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01 Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med 2010; 362:1575-1585 10
ACCORD Adverse Events Adverse Events Intensive Standard N (%) N (%) P value Serious AE 77 (3.3) 30 (1.3) <0.0001 Hypotension 17 (0.7) 1 (0.04) <0.0001 Syncope 12 (0.5) 5 (0.2) 0.10 Bradycardia or Arrhythmia 12 (0.5) 3 (0.1) 0.02 Hyperkalemia 9 (0.4) 1 (0.04) 0.01 Renal Failure 5 (0.2) 1 (0.04) 0.12 egfr ever <30 ml/min/1.73m 2 99 (4.2) 52 (2.2) <0.001 Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93 Dizziness on Standing 217 (44) 188 (40) 0.36 Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med 2010; 362:1575-1585 ACCORD- Summary No difference in the primary outcome composite of nonfatal MI, nonfatal stroke or CVD death. Secondary outcome of nonfatal and fatal stroke was improved in the intensively treated verses standard groups (numbers of events small 32 Int vs 62 Std) Side effects of syncope and hypotension was greatest in the intensively treated group (2.6 fold) Hypokalemia more common in the intensively treated group Same number in both groups progressed to ESRD End of study intensively treated group had lower GFR than standard group Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med 2010; 362:1575-1585 11
SPRINT Research Question Examine effects of more intensive high blood pressure treatment than recommended Randomized Controlled Trial Target Systolic BP Total N= 9,361 Intensive Treatment Goal SBP < 120 mm of Hg N= 4,678 Standard Treatment Goal SBP < 140 mm of Hg N= 4,683 Median follow up 3.26 years SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016. Inclusion Criteria 50 years old SBP 130-180 mm of Hg ( treated or untreated) Additional cardiovascular disease( CVD) risk - Clinical or subclinical CVD (excluding stroke) - CKD, defined as egfr 20-60 ml/min/1.73 m2 - Framingham Risk Score for 10-year CVD risk 15% Exclusion Criteria Stroke Diabetes mellitus Polycystic kidney disease Congestive heart failure ( symptoms or EF<35%) Proteinuria >1 g per day CKD with egfr < 20 ml/min/1.73 m² ( MDRD) Adherence concerns - Age 75 years SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016. 12
SPRINT Primary Outcome and its Components Event Rates and Hazard Ratios SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016. Serious Adverse Events (SAE) During Follow-up SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016. 13
Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged 75 Years: A Randomized Clinical Trial Objective: To evaluate the effects of intensive (<120 mm Hg) vs standard(<140 mm Hg) SBP in patients 75 years with hypertension but without diabetes. Study Design: Patients 75 years who participated in SPRINT. Study duration 2010-2015. Conclusions: Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Williamson JD et al. JAMA 2016;315:2673-2682. Summary Primary composite outcome (myocardial infarction, acute coronary syndrome, stroke, CHF, CV death) decreased 25% with intensive Rx. All cause mortality significantly lower in intensive Rx group: HR 0.73%; 95% CI 0.60 to 0.90; P=0.003. Hypotension, syncope, electrolyte abnormalities, and renal injury all higher in intensive Rx group (but not injurious falls). Application of results dependent on clinical judgment, tolerance of Rx, avoidance of associated problems, probable limitation to 4 BP medications. Fewer patients to meet SPRINT goals vs. 2014 but will have CV events. + Same intensive BP Rx benefits adults 75 years with CV events. # *SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016. + Ko MJ et al. J Am Coll Cardiol 2016;67:2821-2831. # Williamson JD et al. JAMA 2016;315:2673-2682. 14
Resistant Hypertension Defined as either a BP of 140/90 mm of Hg while using optimally dosed antihypertensive agents from 3 different drug classes( including a diuretic); or blood pressure that requires 4 or more medications to achieve control Differentiate from Pseudo resistance - Inaccurate BP measurements - Poor adherence to BP medications - Suboptimal antihypertensive therapy i.e inadequate doses or exclusion of diuretic. - White coat resistance ( 35% in Spanish study- well controlled via ambulatory monitoring) Causes Of True Resistant Hypertension Extracellular volume expansion Increased sympathetic activation Ingestion of substances ex NSAIDs/stimulants Secondary or contributing causes of hypertension. 15
Treatment; General Principles Identify and treat secondary hypertension Stop medications that raise the blood pressure Out-of-office blood pressure monitoring Non-pharmacologic therapy Pharmacological Therapy Diuretics: Persistent volume expansion contributes to resistant hypertension, even among patients who have been on conventional doses of thiazides. Mineralocorticoid Receptor Antagonists: provide significant antihypertensive benefit when added to existing multiple-drug regimens in patients with resistant hypertension. Gaddam KK et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med 2008; 168:1159. Chapman N et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007; 49:839. 16
EXPERIMENTAL THERAPIES Catheter-based radiofrequency ablation of renal sympathetic nerves ( renal denervation) has not been established in patients with resistant hypertension A blinded randomized trial (SYMPLICITY-HTN-3) failed to demonstrate benefit. EXPERIMENTAL THERAPIES Electrical stimulation of carotid sinus baroreceptors- or baroreflex activation therapy (BAT), may decrease blood pressure in patients with resistant HTN. Rheos Pivotal Trial failed in two of its five primary endpoints, it remains unapproved by the FDA for the indication of resistant hypertension in the United States. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: Bisognano JD etal J Am Coll Cardiol. 2011;58(7):765 17
Differences in LV mechanics drive differential response to therapy in HFpEF and HFrEF Margaret M. Redfield et alpflugers Arch. 2014 Jun; 466(6): 1037 1053. Conclusions There is Much Established Benefit from the Treatment of Hypertension. The age at which the goal BP< 150/90 mm of Hg remains controversial. Selection of the Optimal Regimen Requires Experience, Judgement, Trial/Error. There is diminishing support for starting with β-blocker. Aggressive blood pressure target of 120/80 mm of Hg safe in carefully monitored patients. Direct renal artery surgery has not had good results. 18
Lifestyle Modifications Not at goal BP <140/90, or <130/80 for diabetes, CKD or CAD, or <120/80 for LV dysfunction Initial Drug Choices No Compelling Indications Stage 1 HTN 1. Thiazides for most 2. Consider ACEI, ARB, BB, CCB or combo Stage 2 HTN Two-drug combo for most; usually thiazide and ACEI, ARB, BB, or CCB Compelling Indications Drugs for compelling indications; others as needed 19