New Guidelines for the Management of Hypertension- Is the Pressure Off? Pranay Kathuria, MD, FACP, FASN, FNKF Director, Division of Nephrology Director, Nephrology Fellowship Professor of Medicine University of Oklahoma College of Medicine

Objectives Review the 2014 evidence-based guidelines for the management of hypertension in adults for patients aged 60 years or more Review the “The Minority View” on targeting systolic blood pressure goal of less than 150 mmHg in patients aged 60 years or older Summarize relevant studies Comment on other hypertension guidelines

Hypertension is a Major Health Problem • Affects 1 billion people worldwide • US – about 1 in 3 adults –73 million have hypertension (SBP >140/90) • A 55-yo normotensive person has up to a 90% lifetime risk of developing hypertension (Vasan 2001) • Number one reason listed for office visits • Causes/contributes to 457,000 admissions per year • A leading cause/contributor to death (MI, stroke, vascular disease)

Development of JNC-8 Commissioned by the NHLBI in 2008 Panel members appointed Developed focused critical questions relevant to practice In 2013, the NHLBI decides that it will no longer publish clinical guidelines Proposes to work collaboratively with other organizations The panel members appointed to the JNC-8 decided to publish their findings independently Published online in JAMA in December 2013 Received no endorsements from other organizations

And then we waited…and waited… Development of JNC-8 And then we waited…and waited…

also got known as JNC-Late Development of JNC-8 also got known as JNC-Late

2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults 2014 Hypertension Guideline Management AlgorithmSBP indicates systolic blood pressure; DBP, diastolic blood pressure; ACEI, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; and CCB, calcium channel blocker.aACEIs and ARBs should not be used in combination.bIf blood pressure fails to be maintained at goal, reenter the algorithm where appropriate based on the current individual therapeutic plan. JAMA. 2014;311(5):507-520. doi:10.1001/jama.2013.284427

New Hypertension Guidelines in 2013 A multitude of other hypertension guidelines were also published in 2013: AHA/ACC/CDC advisory algorithm American Society of Hypertension/International Society of Hypertension (ASH/ISH) European Society of Hypertension and European Society of Cardiology (ESH/ESC) Canadian Hypertension Education Program (CHEP)

Comparison of Recent Guideline Statements Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-8.

Recommendation 1 Patients aged 60+ Treatment threshold and BP goal 150/90+ Strong Recommendation – Grade A If treatment achieves BP <150/90, do not step- down medication (i.e. if already controlled <140, don’t change treatment) Expert Opinion – Grade E

Hypertension in the Elderly Fastest growing segment of the population Prevalence of hypertension is very high Several issues make managing HTN unique: Often present with isolated systolic HTN More likely to present with comorbidities Many clinical trials in HTN have excluded these patients (particularly for those 80 years and older) Elderly are more susceptible to certain adverse effects (orthostatic hypotension)

JNC-8 Implications for the USA ALL US Adults Ages 18-59 Ages 60+ JNC 7: HTN 66.6 M 32.8 M 33.8 M Controlled 26 (39.9%) 13.3 (40.5%) 13.3 (39.3%) JNC 8: HTN 60.8 M 30.8 M 30.0 M 34.3 (56.4%) 14.6 (47.4%) 19.7 (65.7%)

The Data Behind the JNC 8 Recommendations

HYpertension in the Very Elderly Trial International, multi-centre, randomised, double-blind, placebo-controlled Inclusion Criteria: Exclusion Criteria: Aged 80 or more, Standing SBP < 140mmHg Systolic BP; 160 -199mmHg Stroke in last 6 months + diastolic BP; <110 mmHg, Dementia Informed consent Need daily nursing care Primary Endpoint: All strokes (fatal and non-fatal) Background Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear. It has been suggested that antihypertensive therapy may reduce the risk of stroke, despite possibly increasing the risk of death. Full Text of Background... Methods We randomly assigned 3845 patients from Europe, China, Australasia, and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide (sustained release, 1.5 mg) or matching placebo. The angiotensin-converting–enzyme inhibitor perindopril (2 or 4 mg), or matching placebo, was added if necessary to achieve the target blood pressure of 150/80 mm Hg. The primary end point was fatal or nonfatal stroke. Full Text of Methods... Results The active-treatment group (1933 patients) and the placebo group (1912 patients) were well matched (mean age, 83.6 years; mean blood pressure while sitting, 173.0/90.8 mm Hg); 11.8% had a history of cardiovascular disease. Median follow-up was 1.8 years. At 2 years, the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group. In an intention-to-treat analysis, active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke (95% confidence interval [CI], −1 to 51; P=0.06), a 39% reduction in the rate of death from stroke (95% CI, 1 to 62; P=0.05), a 21% reduction in the rate of death from any cause (95% CI, 4 to 35; P=0.02), a 23% reduction in the rate of death from cardiovascular causes (95% CI, −1 to 40; P=0.06), and a 64% reduction in the rate of heart failure (95% CI, 42 to 78; P<0.001). Fewer serious adverse events were reported in the active-treatment group (358, vs. 448 in the placebo group; P=0.001). Full Text of Results... Conclusions The results provide evidence that antihypertensive treatment with indapamide (sustained release), with or without perindopril, in persons 80 years of age or older is beneficial. (ClinicalTrials.gov number, NCT00122811.) Target blood pressure 150/80 mmHg

HYVET: ITT Analysis HR 95% CI 0.70 (0.49, 1.01) 0.61 (0.38, 0.99) 0.79 (0.65, 0.95) 0.81 (0.62, 1.06) 0.77 (0.60, 1.01) 0.71 (0.42, 1.19) 0.36 (0.22, 0.58) 0.66 (0.53, 0.82) All Stroke Stroke Death All cause mortality NCV/Unknown death CV Death Cardiac Death Heart Failure CV events 0.1 0.2 0.5 2

Hypertension in the Elderly HYVET demonstrated that treatment of HTN to goal BP less than 150/80 mm Hg in patients >80 years old was safe and effective But…what about a lower BP goal? And…what about the patients age 60-80?

Hypertension in the Elderly Trials – Stroke, HF, & CHD Reduction SHEP Syst-Eur Year 1991 1997 Sample Size (N) 4, 736 4,695 Sample Characteristics Adults ≥60 yo SBP 160-219 DBP <90 DBP <95 Goals SBP >180: <160 SBP 160-179: ↓20 SBP <150 AND↓≥20 Median f/u 4.5 years 2 years Quality Rating Good* *Good = least risk of bias, results considered valid JAMA. 2013;():doi:10.1001/jama.2013.284427.

Results – Cardiovascular Disease Combined fatal and non-fatal stroke SHEP ↓36% (p=0.0003) Syst-Eur ↓42% (p=0.003) Combined fatal and non-fatal HF SHEP ↓49% (p<0.001) Syst-Eur ↓29% (p=0.12) Combined fatal/non-fatal MI, CHD death, sudden death SHEP CHD events ↓25% (95% CI 0.60, 0.94) Non-fatal MI ↓33% (95% CI 0.47, 0.96) Non-fatal MI+CHD death ↓27% (95% CI 0.57, 0.94) Syst-Eur - CHD component outcomes not significant w/o HF inclusion JAMA. 2013;():doi:10.1001/jama.2013.284427.

Trials Addressing SBP <150 vs <140 JATOS* VALISH** Year 2008 2010 Sample Size (N) 4,418 3,260 Sample Characteristics Adults 65-85 SBP ≥ 160 DBP <120 Adults 70-85 SBP ≥160 DBP <90 Goals Strict: <140 Moderate: ≥140-<160 Strict: SBP <140 Moderate: ≥140-<150 Median f/u 2 years 2.85 years Quality Rating Good *Japanese Trial to Assess Optimal SBP (JATOS) **Valsartan in Elderly Isolated Systolic Hypertension JAMA. 2013;():doi:10.1001/jama.2013.284427.

Japanese Trial to Assess Optimal SBP (JATOS) Hypertens Res. 2008;31(12):2115-2127

Valsartan in Elderly Isolated Systolic Hypertension

Dissension among the ranks! Wright JT Jr et al. Ann Intern Med 2014;160:499-504.

JNC 8 Methodology Excluded Most Studies Conducted a systematic search of pertinent literature Limited to randomized controlled trials (RCTs) published between 1966 and 2009 Included patients age 18 or older with hypertension Sample size of 100 patients or more Results must have included “hard” outcomes Subsequent search of studies from 2009 to 2013 required samples of 2000 or more patients Only 2.05% of reviewed studies formed the basis of the recommendation Five of the 9 guidelines were opinion-based or “by expert advise only”

Other Trials Targeting SBP < 140 mm Hg Felodipine Event reduction (FEVER) Trial Chinese population; age range 50-79; mean age 62 yrs Significant reduction in CVD, mortality, CAD, HF Secondary Prevention of Subcortical Stroke (SPS3 Trial) Significant reduction in stroke 2 recent meta-analyses Observational studies

Achieved BP in Studies Included by the JNC 8 was Lower SHEP Syst-Eur HYVET Year 1991 1997 2008 Sample Size (N) 4, 736 4,695 3,845 Sample Characteristics Adults ≥60 yo SBP 160-219 DBP <90 DBP <95 Adults ≥80 yo SBP ≥160 DBP <110 Goals SBP >180: <160 SBP 160-179: ↓20 SBP <150 AND↓≥20 <150/80 BP achieved 143 mm Hg 150 mm Hg 144 mm Hg Median f/u 4.5 years 2 years 2.1 years Quality Rating Good* *Good = least risk of bias, results considered valid JAMA. 2013;():doi:10.1001/jama.2013.284427.

Problems with JATOS and VALISH Studies Performed in Japanese populations Low number of events Trial (n) Total Endpoints Composite CVD Stroke JATOS (n=4418) 172 Rate per 1000 patient year: 22.6 vs 22.7 (p=.99) 13.7 vs 12.9 VALISH (n=3260) 99 HR: 0.89 P=0.383 HR: 0.68 P=o.237

Lack of Harm with SBP < 140 VALISH JATOS HYVET SHEP

The age group 60 years and older is a high risk population

U.S. Cardiovascular Disease Death Rates for Persons Younger and Older Than 65 yrs Ann Intern Med. 2014;160(7):499-503. doi:10.7326/M13-2981

NHANES Data Showing Progress in Treatment of Hypertension Smoothed Weighted Frequency Distribution, Median and 50th Percentile of SBP for persons aged 60-74 years Reproduced from Lackland and colleagues (4). NHANES = National Health and Nutrition Examination Survey; NHES = National Health Examination Survey. Ann Intern Med. 2014;160(7):499-503. doi:10.7326/M13-2981

Population Impact of Changing BP Goals <150 for Age 60 or Older High risk population Risk range for white and AA men aged 60 is 9-30% depending on risk profile Risk Range for white and AA aged 70 without known CVD or DM with SBP < 140 exceeds 20% at 10-yrs The “Speed Limit” effect

What will resolve the controversy? BP< 140/90 or < 150/90 More data is needed

BP Treatment Targets Have Risks Both Ways If one votes to keep all at 140/90 PM’s and incentives may encourage over-treatment Worse symptoms, falls, costs in elderly • If one votes to move to 150/90 in elderly Risk of under-treatment Despite existing guideline goals/PM’s, <50% of public reaches goal!

Summary Significant controversy over targets of initiating and goals of hypertension therapy in elderly patients I recommend the following: Risk factor stratification Frail versus non-frail Chronologic versus physiologic age Risk of falls Consideration of adverse effects of anti-hypertensives and polypharmacy