1. Hypertension Update: Review of the 2014 HTN Guidelines Do Recent Guidelines Really Change Patient Management? Angela L. Brown, MD Associate Professor of Medicine Department of Medicine Cardiovascular Division

2. Department of Medicine Cardiovascular Division 2 Disclosure: Angela L. Brown, M.D. Angela L. Brown, M.D. has financial interests to disclose. Potential conflicts of interest have been resolved. Research Support / GrantsNIH. Medtronic Speakers Bureau / HonorariaArbor Pharmaceuticals

3. Department of Medicine Cardiovascular Division Objectives Understand the current hypertension treatment guidelines Understand implications of current guidelines Discuss current prescribing trends of antihypertensive medications

4. Department of Medicine Cardiovascular Division Why Are We Still Talking About Hypertension? It’s prevalent: NHANES 2010: Over 77.9 million adults in US 80 million adults have pre-hypertension Increasing prevalence with aging of population and epidemic of overweight/obesity Lowering BP leads to a reduction in events Approximately 50% reduction in heart failure Approximately 40% reduction in stroke Approximately 20-25% reduction in MI Go et al. Circ. 2013 Hebert PR et al. Arch Inten Med. 1993;153:578-81. Kannel WB. JAMA. 1996;275:1571-6. Moser M and Hebert P. J Am Coll Cardiol. 1996;27:1214-8.

5. Department of Medicine Cardiovascular Division Prevalence of Hypertension

6. Department of Medicine Cardiovascular Division 6 High Blood Pressure Remains One of the Most Important Multipliers for CV Risk BP >140/90 mm Hg associated with: 69% of first MIs 74% of cases of HF 77% of first strokes HBP is associated with a 2x to 3x higher risk for developing HF BP >140/90 mm Hg associated with: 69% of first MIs 74% of cases of HF 77% of first strokes HBP is associated with a 2x to 3x higher risk for developing HF Rosamond W et al. Circulation. 2007;115:e69-171.

7. Department of Medicine Cardiovascular Division Mortality From High Blood Pressure Higher in African Americans Overall Mortality Rates From Causes Related to Hypertension, 2003* *High blood pressure listed as a primary or contributing cause of death. High blood pressure=systolic ≥140 mmHg or diastolic ≥90 mmHg, taking antihypertensive medicine, being told ≥2 times by a physician that you have high blood pressure. Mortality Rate, % African American FemaleMaleFemale 20 10 30 40 50 49.7 14.9 40.8 14.5 0 60 Male White In hypertensive African Americans,  30% and  20% of all deaths in men and women, respectively, may be due to high blood pressure. Adapted from Thom T et al. Circulation. 2006;113:e85–e151.

8. Department of Medicine Cardiovascular Division 1972 1973 1976 1980 1984 1988 1993 1997 2003 2013 1972 1973 1976 1980 1984 1988 1993 1997 2003 2013 Development of Hypertension Guidelines: the JNCs and Drug Therapy NHBPEPSTARTS Earliest Guidelines 28 drugs DBP  105 Diuretics JNC I 43 drugs diuretics,  -blockers Added JNC III JNC II 34 drugs Diuretics JNC IV 50 drugs 50 drugs ACEI, CAs added JNC VI 84 drugs 7 options Low-dose 68 drugs Diuretics/  -blockers JNC V JNC 7 > 125 drugs Diuretics HR Black, 2003. JNC 8 >125 drugs Diuretics RAS blockers CAs

9. JNC V Optimal 110 120 130 140 150 160 170 180 190 200 210 220 JNC BP Classifications: SBP JNC I. JAMA. 1977;237:255-261. JNC II. Arch Intern Med. 1980;140:1280-1285. JNC III. Arch Intern Med. 1984;144:1045-1057. JNC IJNC IIJNC IIIJNC IVJNC VI Border - line ISH Stage 1 Stage 2 Stage 3 High- normal Normal Optimal SBP (mm Hg) Normal Border - line ISH Stage 4 No recommendations for SBP in JNC I or JNC II JNC 7 Stage 1 Stage 2 Prehyper- tension Normal Stage 3 Stage 2 JNC IV. Arch Intern Med. 1988;148:1023-1038. JNC V. Arch Intern Med. 1993;153:154-183. JNC VI. Arch Intern Med. 1997;157:2413-2446. JNC VII. JAMA. 2003;289:2560-2572.

10. Department of Medicine Cardiovascular Division JNC 7 Treatment Goals ConditionGoal BP, mmHg Uncomplicated hypertension<140/90 Diabetes mellitus<130/80 Chronic renal disease<130/80 Chobanian AV et al. Hypertension. 2003;42:1206-1252;

11. Department of Medicine Cardiovascular Division NHLBI Approach: Adult CVD Guideline Reports Advisory group recommendations Update risk factor guidelines Develop an integrated guideline (including JNC 8) Use evidence-based approach Development process Increase rigor and minimize bias Utilize new IOM standards (decision making based on evidence) Strictly evidence based Only RCTs assessing important health outcomes No use of intermediate or surrogate measures

12. Department of Medicine Cardiovascular Division NHLBI Systematic Review and Guideline Development Process Literature Searched; Eligible Studies Identified Studies Quality Rated; Data Abstracted Evidence Tables Developed; Body of Evidence Summarized External Review of Recommendation Drafts; Revised as Needed Guidelines Disseminated & Implemented Graded Evidence Statements & Recommendations Developed Expert Panel Selected Topic Area Identified Critical Questions &Study Eligibility Criteria Identified

13. Department of Medicine Cardiovascular Division NHLBI Evidence Quality Rating and Recommendation Strength Evidence Quality High Well-designed and conducted RCTs Moderate RCTs with minor limitations Well-conducted observational studies Low RCTs with major limitations Observational studies with major limitations Recommendation Strength A – Strong B – Moderate C – Weak D – Against E – Expert Opinion N – No Recommendation

14. Department of Medicine Cardiovascular Division Levels of Evidence 1A 1B 2A 2B 2C 2D

15. Department of Medicine Cardiovascular Division JNC 8: Questions to Address Among adults with hypertension, does initiating antihypertensive pharmacological therapy at specific BP thresholds improve health outcomes? (When to initiate drug treatment?) Among adults, does treatment with antihypertensive pharmacological therapy to a specific BP goal lead to improvements in health outcomes? (How low should you go?) In adults with hypertension, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? (How do we get there?)

16. Department of Medicine Cardiovascular Division Inclusion/Exclusion Criteria for Studies Randomized Controlled trials 1966-present Minimum one year follow-up Studies with samples size <100 excluded

17. Department of Medicine Cardiovascular Division Among adults with HTN, does initiating drug therapy at a particular level lead to improvement in health outcomes? Articles screened = 1496 Included = 44Excluded = 1452 Good = 8Poor = 18 Total abstracted = 26 Fair = 18

18. Department of Medicine Cardiovascular Division Among adults with HTN, does treating to a specific goal lead to improvements in health outcomes? Articles screened = 1978 Included = 92Excluded = 1886 Good = 17Poor = 36 Total abstracted = 56 Fair = 39

19. Department of Medicine Cardiovascular Division Among adults with HTN, do various anti-hypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? Articles screened = 2662 Included = 101Excluded = 2561 Good = 15Poor = 35 Total abstracted = 66 Fair = 51

20. Department of Medicine Cardiovascular Division JNC 8-RECOMMENDATIONS In the general population 60 years of age or older, initiate pharmacologic treatment to lower blood pressure at SBP >150 mmHg or DBP > 90 mmHg and treat to a goal of <150/90 mmHg (Strong Recommendation-Grade A) In the general population less than 60 years of age, initiate Pharmacological treatment to lower BP at SBP > 140 mmHg and treat to goal < 140/90 mmHg (Expert Opinion-Grade E) In the population with nondiabetic chronic kidney disease initiate pharmacological treatment at BP >140/90 mmHg and treat to <140/90 mmHg (Expert Opinion-Grade E)

21. Department of Medicine Cardiovascular Division JNC 8-RECOMMENDATIONS In the population with diabetic chronic kidney disease initiate pharmacological treatment at BP >140/90 mmHg and treat to <140/90 mmHg (Expert Opinion-Grade E) In the general, non-black population initial antihypertensive treatment should include a thiazide-type diuretic, CCB, ACEI or ARB (Moderate recommendation-Grade B) In the general, non-black population with diabetes initial antihypertensive treatment should include a thiazide-type diuretic, CCB, ACEI or ARB (Moderate recommendation-Grade B)

22. Department of Medicine Cardiovascular Division JNC 8-RECOMMENDATIONS In the general black population initial antihypertensive treatment should include a thiazide- type diuretic or CCB (Moderate recommendation-Grade B) In the general black population with diabetes initial antihypertensive treatment should include a thiazide- type diuretic or CCB (Weak recommendation-Grade C) In the population 18-80 years of age with chronic kidney disease and hypertension initial (or add-on) antihypertensive treatment should include and ACE inhibitor or ARB to improve kidney outcomes (Moderate Recommendation-Grade B)

23. Department of Medicine Cardiovascular Division James PA, Oparil S, Carter BL et al. JAMA 2014: 311 (5):507-520, Feb 5, 2014. JNC 8 Hypertension Guideline Management Algorithm

24. Department of Medicine Cardiovascular Division Evidence Supporting a Systolic Blood Pressure Goal of Less Than 150 mm Hg in Patients Aged 60 Years or Older: The Minority View Jackson T. Wright Jr., MD, PhD; Lawrence J. Fine, MD, DrPH; Daniel T. Lackland, DrPH; Gbenga Ogedegbe, MD, MPH, MS; and Cheryl R. Dennison Himmelfarb, PhD, RN, ANP Annals of Internal Medicine Annals of Internal Med January 2014 Conclusion: These five dissenters believe that the threshold and goal BP should be 60 years of age

25. Department of Medicine Cardiovascular Division Benefit of Treatment of Stage 2 Isolated Systolic HTN: Final BP <150 mmHg but not <140 mm Hg TrialBpBP Change in BP v PChange in CVE SHEP170/77143/6812/40.67 (0.56–0.80) Syst-Eur174/86152/7810/50.69 (0.55–0.86) Syst-China170/86150/818/30.61 (0.39–0.96) HYVET170/91144/8015/60.66 (0.53–0.82) SHEP Cooperative Research Group. JAMA. 1991;265:3255. Staessen JA et al. Lancet. 1997;350:757. Liu L et al. J Hypertens. 1998;16:1823. Beckett NS et al. N Engl J Med. 2008;358:1887. Bp,=initial BP BP=treatment BP P=placebo CVE=cardiovascular event

26. Department of Medicine Cardiovascular Division Major Randomized Trials Testing SBP Goals in General (Older) Populations SHEPSyst-EurHYVETJATOSVALISH Age>60 >8065-8570-84 Number4,7364,6953,8454,4183,260 Entry SBP 160-219 160-199 >160 Goal SBP <148<150<150<140<140 Achieved SBP 142151144136137 Stroke  36%42%nsnsns CVD  32%31%34%nsns Mortality  ns 21%nsns SBP = systolic blood pressure; CVD = cardiovascular disease

27. Department of Medicine Cardiovascular Division Denardo et al. Am J Med 123:719-726, 2010 Risk of Adverse Outcomes Among Elderly CAD Patients in INVEST by Age and BP-“Is There a Sweet Spot for BP”

28. Department of Medicine Cardiovascular Division Source >60 years >80 yearsCKD ASH/ISH<140/90<150/90130-140/80-90 ESH/ESC<140/90<150/90130-140/90 2014 HTN guidelines <150/90 <140/90 ADA 2015-— Contrasts in Goal BP Recommendations American Diabetes Association. Diabetes Care. 2015;38(suppl 1):S49-57; ASH-ISH Weber MA, et al. J Clin Hypertension. Dec. 17, 2013 [Epub ahead of print]; 2014 HTN Guidelines James PA, et al. JAMA. 2014;311:507-520. ESH/ESC Mancia G, et al. J Hypertens. 2013;.31: 1281-1357

29. Department of Medicine Cardiovascular Division What is the Goal BP and Initial Therapy in Kidney Disease or Diabetes to Reduce CV Risk? * Indicates use with diuretic Group Goal BP (mmHg) Initial Therapy ADA (2013)<140/80ACE Inhibitor/ARB* KDIGO/KDOQI (NKF) (2012)<140/90ACE Inhibitor/ARB ESH (2007+ 2009)<130/80ACE Inhibitor/ARB* KDOQI (NKF) (2004)<130/80ACE Inhibitor/ARB* JNC 7 (2003)<130/80ACE Inhibitor/ARB* Am. Diabetes Assoc (2003)<130/80ACE Inhibitor/ARB* Canadian HTN Soc. (2002)<130/80ACE Inhibitor/ARB* Am. Diabetes Assoc (2002)<130/80ACE Inhibitor/ARB* Natl. Kidney Foundation (2000)<130/80ACE Inhibitor* British HTN Soc. (1999)<140/80ACE Inhibitor WHO/ISH (1999)<130/85ACE Inhibitor JNC VI (1997)<130/85ACE Inhibitor 29

30. CategoriesNICE* 2011 ESH/ESC 2013 ASH / ISH 2014 AHA/ACC/CDC 2013 JNC 8* 2014 Definition of Hypertension ≥140/90 and daytime ABPM (or home BP) ≥135/85 ≥140/90 Not addressed Drug therapy/ low risk patients after non-pharm treatment ≥160/100 or day-time ABPM ≥ 150/95 ≥140/90 < 60 y. ≥140/90 ≥ 60 y. ≥150/90  -blockers - first line drug NoYesNo Diuretic Chlorthalidone - indapamide thiazides chlorthalidone, indapamide thiazidesthiazides chlorthalidone, indapamide Initial single pill combo Rx Not mentionedmarkedly elevated BP ≥160/100 BP targets < 140/90 ≥ 80 y. < 150/90 <140/90 ; < 80, SBP 140-150 SBP <140 in fit patients Elderly ≥ 80 y. SBP 140- 150 <140/90 ≥ 80 y. < 150/90 <140/90 Lower targets may be appropriate in some patients, including the elderly < 60 y. <140/90 ≥ 60 y. <150/90 BP target in Diabetes Not addressed< 140/85<140/90<140/90 – Consider lower <140 /90

31. IHD mortality (absolute risk and 95% CI) Usual SBP (mm Hg) Lancet. 2002;360:1903-1913. Ischemic Heart Disease Mortality Rate in Each Decade of Age 120140160180 256 128 64 32 16 8 4 2 1 SBP 40-49 y Age at risk: 70-79 y 60-69 y 50-59 y 80-89 y Usual DBP (mm Hg) 708090110100 256 128 64 32 16 8 4 2 1 DBP

32. Department of Medicine Cardiovascular Division 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

33. Department of Medicine Cardiovascular Division ACCORD Adverse Events Adverse Events Intensive N (%) Standard N (%) P value Serious AE77 (3.3)30 (1.3)<0.0001 Hypotension17 (0.7)1 (0.04)<0.0001 Syncope12 (0.5)5 (0.2)0.10 Bradycardia or Arrhythmia12 (0.5)3 (0.1)0.02 Hyperkalemia9 (0.4)1 (0.04)0.01 Renal Failure5 (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 ESRD59 (2.5)58 (2.4)0.93 Dizziness on Standing † 217 (44)188 (40)0.36 N Engl J Med. 2010;362:1575-85

34. Department of Medicine Cardiovascular Division Systolic Blood Pressure Intervention Trial: SPRINT RCT to test whether a treatment strategy aimed at reducing systolic blood pressure to  lower goal (SBP < 120 mmHg) compared with  currently recommended (SBP < 140 mmHg) will reduce the occurrence of cardiovascular disease (CVD) N = 9250, age 50 and over 28% > age 75 years

35. Department of Medicine Cardiovascular Division Primary Outcome Composite (CVD) CVD mortality Myocardial infarction Non-MI acute coronary syndrome Stroke Heart Failure

36. Department of Medicine Cardiovascular Division Key Secondary Objectives Total mortality Progression of CKD Probable dementia Cognitive impairment White matter lesions detected by MRI

37. Department of Medicine Cardiovascular Division SPRINT: Results Planned completion 2017 Stopped early September 2015 “Lower blood pressure target greatly reduces CV complications and deaths in older adults” – NIH Cardiovascular events  ⅓ Death  ¼ NIH Press Release, Sept 11, 2015

38. Department of Medicine Cardiovascular Division Other Planned Analyses Achieved blood pressure Adverse events Health related quality of life Cost Various laboratory assays Chemistry profile, fasting glucose, lipid profile

39. Department of Medicine Cardiovascular Division Op-Ed: European Society of Hypertension Clyde Yancy, MD, Northwestern University “The management of hypertension now falls within the camp of primary care physicians, internists, and a dedicated community of hypertension clinician scientists.” Unanswered questions?  Clear targets of blood pressure lowering  Risk algorithms to guide decision-making regarding risk/benefit of antihypertensive therapy  Clear algorithm to inform stepwise progression of care  Old adage of simply lowering BP - May matter how we lower BP and to what thresholds

40. Department of Medicine Cardiovascular Division PATHWAY Clinical Trials(ESH) 335 subjects with resistant hypertension Standard therapy plus spironolactone 25-50mg, doxazosin 4-8mg, bisoprolol 5-10mg, or placebo BP reduction: 8.7 mmHg vs 4.03 mmHg vs 4.48 mmHg BP control: 58% vs 43.7% (p<0.001) 440 subjects with 1 other component of MetS Role of potassium in glucose intolerance Amiloride 10-20mg, HCTZ 25-50mg, ½ dose both Amiloride vs HCTZ 55 mmol/L change from baseline; ½ dose - neutral change in glucose (0.42 mmol/L) but greatest BP reduction 17mmHg

41. Department of Medicine Cardiovascular Division Spironolactone Induced Reduction in Systolic Blood Pressure (BP) Diastolic BP at 6-weeks, 3- and 6-months Follow-up in Subjects with Resistant Hypertension (N=76) BP reduction was significant at all time points compared to baseline Nishizaka MK, et al. American Journal of Hypertension 2003;16(11):925-930. -12 -23 -10 -21 -10 -25 0 -10 -20 -30 6wk3mo6mo BP Response (mm Hg)

42. Department of Medicine Cardiovascular Division Additional BP Reduction with Spironolactone in Resistant Hypertension Pimenta, Calhoun, Oparil. Arq Bras Cardiol 2007; 88(6) : 604-613

43. Department of Medicine Cardiovascular Division Lifestyle Modification—Especially Diet and Exercise BP Control using Multiple or Fixed-Dose Combination Agents Not at Goal All Patients RAS Blocker (ACEI or ARB) + Thiazide Diuretic or Amlodipine Amlodipine or Chlorthalidone Amlodipine or Chlorthalidone (using alternative not used above) Additional Agents (consider Mineralocorticoid Receptor Blocker) Additional Agents (consider Mineralocorticoid Receptor Blocker) Not at Goal

44. Department of Medicine Cardiovascular Division PARAMETER Trial (ESH) Pulse pressure independent risk factor for vascular events in the elderly Valsartan/sacubitril (LCZ696) 400mg vs olmesartan 40mg 454 subjects – SBP > 150 mmHG, PP > 60mmHg Central Ao SBP reduction: 12.6 mmHg vs 8.9 mmHg Pulse pressure reduction: 6.4 mmHg vs 4.0 mmHg

45. Effect of BP on CHD Mortality: MRFIT 100+90–9980–8975–7970–74<70 <120 120–139 140–159 160+ DBP (mm Hg) SBP (mm Hg) Adapted with permission from Neaton JD et al. Arch Intern Med. 1992;152:56 CHD death rate per 10,000 person-years 9 99 12 10 21 24 17 14 13 12 25 25 25 26 25 31 48 37 35 44 38 81

46. Department of Medicine Cardiovascular Division Age Differences in Treatment and Control of HTN in US Physician Offices, 2003- 2010 (NAMCS) 2003 - 20042009 - 2010 Prescriptions69.2%78.8%p<0.001 BP Control39.1%48.8%p<0.001 Beta-blockers in older patients 25.4%34.7%p<0.001 ARBs17%22.1%p=0.042 NAMCS - National Ambulatory Medical Care Survey Gu A, Yue, et al. Am J Med. Aug 2015

47. Department of Medicine Cardiovascular Division Age Differences in Treatment and Control of Hypertension in US Physician Offices, 2003-2010 Gu A, Yue, et al. Am J Med. Aug 2015

48. Department of Medicine Cardiovascular Division Antihypertensive Prescribing Trends 2003-2010 National Ambulatory Medical Care Survey (NAMCS), Diuretics most commonly prescribed and consistent between groups HCTZ > chlorthalidone and indapamide ACE-I > in younger patients Beta-blocker use persisted in the elderly after excluding compelling indications Gu A, Yue, et al. Am J Med. Aug 2015

49. Department of Medicine Cardiovascular Division Chlorthalidone Lowers Ambulatory Systolic Blood Pressure More than Hydrochlorothiazide at Week 8 (N=30) Chl (25 mg)HCTZ (50 mg) Ernst ME, et al. Hypertension 2006;47:352-358.  mm Hg 24 hr ABPM  Nighttime ABPM  p = 0.054 p = 0.009 Office BP reductions in SBP trended greater for Chlorthalidone -17.1 vs. 10.8 mm Hg (P=NS)

50. Department of Medicine Cardiovascular Division β-blockers as 1 st Line Therapy in HTN β-blockers vs other drugs RR stroke 16% all cause mortality 3% MInot significant β-blockers vs placebo or no treatment stroke 19% all cause mortalitynot significant MInot significant Lindholm, Carlberg Samuelsson. Lancet 2005

51. Department of Medicine Cardiovascular Division Implications of JNC-8 on HTN Management for Aging Adults Atherosclerosis Risk in Communities Study (ARIC) 6088 subjects, mean age 75.6 years, 2011-2013 16.6% reclassified as at goal blood pressure (1 in 6) 20.6% reclassified with DM and CKD 11.6% reclassified without DM and CKD Despite less aggressive goals, >20% patients remained uncontrolled by the new criteria JNC 762.8% JNC 879.4% Miedema MD et al. Hypertension. Sept 2015

52. Department of Medicine Cardiovascular Division The prevalence of at-goal blood pressure according to Seventh Joint National Committee (JNC7) and Eighth Joint National Committee Panel (JNC8P) blood pressure guidelines in black and white individuals stratified by diabetes mellitus (DM) or chronic kidney disease (CKD) in 6088 participants from the fifth visit of the Atherosclerosis Risk in Communities Study, 2011–2013. Michael D. Miedema et al. Hypertension. 2015;66:474-480 Copyright © American Heart Association, Inc. All rights reserved.

53. Department of Medicine Cardiovascular Division Summary The 2014 HTN guidelines are controversial regarding the appropriate BP target in older adults SPRINT may give us a more definitive answer Need more comprehensive algorithms that include risk/benefit of antihypertensive therapy For those with resistant HTN, consider addition of mineralocorticoid antagonist Expect new set of guidelines in the near future Guidelines are just that – guidelines. Treat the patient in front of you!

54. Thank you!