Review of the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults – JNC 8 Eighth National Joint Committee Amanda Birnschein, PharmD candidate 2015 APPE 1: Magee Rehab Preceptor: Donna Peterson, PharmD

In the Past……JNC 7 Treatment Goals: 1st line agent – thiazide diuretic Other agents can be added on as needed for blood pressure control Treatment Goals: <140/80 for all patients without compelling indications <130/80 for patients with diabetes and CKD Hobanian AV, Bakris GL, Black HR, et al. JAMA. 2003;289(19):2560-2572.

JNC 7 – Compelling Indications Hobanian AV, Bakris GL, Black HR, et al. JAMA. 2003;289(19):2560-2572.

2014 Guidelines – JNC 8 Answered 3 main Questions about adults with hypertension: Does initiating antihypertensive pharmacologic therapy at specific blood pressure thresholds improve health outcomes? Does treatment with anithypertensive pharmacologic therapy to a specified blood pressure goal lead to improvements in health outcomes? Do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? The JNC 8 panel focused on when to begin treatment, how low to aim for, and which antihypertensive medications to use. James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

2014 Guidelines – JNC 8 Based on 9 recommendations: Recommendations 1 – 5 address thresholds and goals for blood pressure treatment Recommendations 6 – 8 address selection of antihypertensive drugs Recommendation 9 is a summary of strategies based on expert opinion for starting and adding antihypertensive drugs The panel made nine recommendations and one corollary recommendation based on a review of the evidence. Of the 10 total recommendations, five are based on expert opinion. Another two were rated as “moderate” in strength, one was “weak,” and only two were rated as “strong” (ie, based on high-quality evidence). James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation 1 – Threshold and Goals General population > 60 years old: Initiate pharmacologic treatment of SBP > 150 mm Hg or DBP > 90 mm Hg Reduces stroke, heart failure, and coronary heart disease (CHG) Setting a goal <140 mm Hg provides no additional benefit Though, if treatment was <140 mm Hg and not associated with adverse effects no adjustments made (corollary recommendation) High-risk groups (black persons, CVD including stroke, and multiple risk factors) insufficient evidence to raise the SBP target from <140 mm Hg to <150 mm Hg More research needed to identify optimal goals of SBP Strong recommendation (Grade A). Considered to have the greatest impact of all of the recommendations. The age cutoff of 60 years old for this recommendation is debatable. JATOS trial and VALISH trial both included patients > 60, with a mean age of 74 and 76.1 respectively. They found no difference in outcomes comparing a SBP of <140 or 140-160. Other guidelines: American Society of Hypertension and the International Society of Hypertension recommend a SBP <150 in patients > 80 years old, not 60 years old James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation 2 – Threshold and Goals General population < 60 years old: Initiate pharmacologic treatment for DBP > 90 mm Hg For ages 30 – 59 years Strong recommendation from 5 trials Decreasing DBP to < 90 mm Hg reduces cerebrovascular events, heart failure, and overall mortality For ages 18 – 29 years Expert Opinion, no good- or fair-quality RCTs Strength of Recommendation strong (grade A) for ages 30-59 & expert opinion (grade E) for ages 18-29 5 trials: HDFP, Hypertension-Stroke Cooperative, MRC, ANBP, and VA Cooperative These all demonstrated improvements in health outcomes among adults aged 30-69 years with elevated BP HOT trial: No benefit in treating patients to a goal of either 80 mm Hg or lower or 85 mm HG or lower compared with 90 mm Hg or lower Patients randomized to these 3 goals wihtout statisitically significant differences between treatment goups in the primary or secondary outcomes Reasonable to aim for the same diastolic goal in younger persons (under age 30), given the higher prevalence of diastolic hypertension in younger people. James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation 3 – Threshold and Goals General population < 60 years old Initiate pharmacologic treatment for SBP > 140 mm Hg Absence of RCTs that compared the current SBP standard of 140 mm Hg with another higher or lower standard in age group – no compelling reason to change Many trials for DBP also achieved a SBP lower than 140 mm Hg Similar recommendation for CKD and diabetic patients Strength of recommendation: Expert opinion Keep the same systolic goal for people younger than 60 as I the JNC 7 recommendations: Many study participants who achieved a diastolic pressure < 90 mm Hg, also achieved a systolic pressure < 140 mm Hg. Not possible to identify whether the outcome benefits were due to lower SBP or lower DBP or to both. Guidelines would just be simpler if the SBP were the same in the general population as in those with CKD and diabetes. James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation 4 – Threshold and Goals Patients > 18 years old with CKD: Initiate pharmacologic treatment for SBP > 140 or DPB > 90 mm Hg CKD as defined by GFR < 60 mL/min/1.73 m2 in patients up to age 70 years old OR Albuminuria as defined as > 30 mg/g of creatinine at any GFR at any age Need to weigh the benefits vs risks for individuals > 70 years old and a GFR < 60 mL/min/1.73 m2 Consider factors such as frailty, comorbidities, and albuminuria Based on the inclusion criteria used in the RCTs reviewed by the panel, this recommendation applies to individuals younger than 70 years with an estimated GFR or measured GFR less than 60 mL/min/1.73 m2 and in people of any age with albuminuria defined as greater than 30 mg of albumin/g of creatinine at any level of GFR. James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation 5 – Threshold and Goals Patients > 18 years old with diabetes Initiate pharmacologic treatment for SBP > 140 mm Hg or DBP > 90 mm Hg Moderate-quality evidence that treatment to an SBP < 150 mm Hg improves cardiovascular and cerebrovascular health outcomes and lowers mortality < 140 based on expert opinion from ACCORD-BP trial Goal not supported of SBP < 130 mm Hg or DBP < 80 mm Hg Strength of recommendation: Expert opinion (Grade E) Not based on RCTs The ACCORD-BP trial: The control group had a goal SBP < 140 mm Hg and had similar outcomes compared with a lower goal. No evidence to support a lower blood pressure goal <130/80 as in JNC 7. Showed no differences in outcomes with a systolic goal <140 vs <120 EXCEPT for a small reduction in stroke. They stated that the risks of trying to achieve intensive lowering of blood pressure may outweight the benefit of a small reduction in stroke. James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation 6 - Treatment Nonblack population with diabetes – initial antihypertensive treatment should include 1 of the following: Thiazide-type diuretic (hydrochlorothiazide, chlorthalidone, and indapamide) Calcium channel blocker (CCB) Angiotensin-converting enzyme inhibitor (ACEI) Angiotensin receptor blocker (ARB) Each of the 4 drug classes yielded comparable effects on overall mortality and cardiovascular, cerebrovascular, and kidney outcomes One exception: heart failure In order of efficacy (top to bottom): Thiazide-type ACEI CCB Patients needing more than 1 agent: Any of the 4 classes would be good choices as add-on agents Strength of recommendation: moderate (grade B) The panel did not recommend β-blockers for the initial treatment of hypertension because no differences in outcomes: in one study use of β-blockers resulted in a higher rate of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to use of an ARB, a finding that was driven largely by an increase in stroke Though in other studies, outcomes the same as the other 4 classes The panel did not address preferential use of chlorthalidone as opposed to HCTZ, or the use of spironolactone in resistant hypertension α-Blockers were not recommended as first-line therapy because in one study initial treatment with an α-blocker resulted in worse cerebrovascular, heart failure, and combined cardiovascular outcomes than initial treatment with a diuretic There were no RCTs of good or fair quality comparing the following drug classes to the 4 recommended classes: dual α1- + β-blocking agents (eg, carvedilol), vasodilating β-blockers (eg, nebivolol), central α2 adrenergic agonists (eg, clonidine), direct vasodilators (eg, hydralazine), aldosterone receptor antagonists (eg, spironolactone), peripherally acting adrenergic antagonists (reserpine), and loop diuretics (eg, furosemide) Therefore, these drug classes are not recommended as first-line therapy. In addition, no eligible RCTs were identified that compared a diuretic vs an ARB, or an ACEI vs an ARB. ONTARGET was not eligible because hypertension was not required for inclusion in the study. this recommendation is specific for thiazide-type diuretics, which include thiazide diuretics, chlorthalidone, and indapamide; it does not include loop or potassium-sparing diuretics. Third, it is important that medications be dosed adequately to achieve results similar to those seen in the RCTs. Fourth, RCTs that were limited to specific nonhypertensive populations, such as those with coronary artery disease or heart failure, were not reviewed for this recommendation. JNC 8 did not consider randomized controlled trials in a specific nonhypertensive populations (CAD or HF)  beta blockers should be individualized as to use of beta-blocker in these two conditions James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation 7 - Treatment Black population with diabetes – initial antihypertensive treatment should include 1 of the following: Thiazide-type diuretic CCB Thiazide-type diuretic more effective in improving cerebrovascular, heart failure, and combined cardiovascular outcomes compared to an ACEI No difference in outcomes between CCB and diuretic CCB over ACEI 51% higher rate of stroke in black patients with the use of an ACEI as initial therapy compared with a CCB ACEI less effective in BP reduction Consider using ACEI/ARB on an individual basis, especially for proteinuria Strength of recommendation: moderate (grade B) for the general black population; weak (grade C) for blacks with diabetes ALL—HAT trial: Thiazide-type diuretic (chlorthalidone) better than an ACEI (lisinopril) in terms of cerebrovascular, heart failure, and composite outcomes, but similar for mortality rates and cardiovascular, and kidney outcomes. CCB (amlodipine) better than ACEI for cerebrovascular outcomes There were no outcome studies meeting our eligibility criteria that compared diuretics or CCBs vs β-blockers, ARBs, or other renin-angiotensin system inhibitors in black patients. James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation 8 - Treatment Patients > 18 years old with CKD – initial or add-on antihypertensive treatment should include 1 of the following: ACEI or ARB Improve kidney outcomes Applies to all CKD patients with hypertension, regardless of race or diabetes status No evidence in patients > 75 years old Can consider thiazide-type diuretic or CCB Neither ACEIs nor ARBs improve cardiovascular outcomes compared with a CCB or Beta-blocker Strength of recommendation: moderate (grade B) ***regardless of race, diabetes, or proteinuria*** This recommendation is based primarily on kidney outcomes because there is less evidence favoring ACEI or ARB for cardiovascular outcomes in patients with CKD. The panel noted the potential conflictbetween thisrecommendation to use an ACEI or ARB in those with CKD and hypertension and the recommendation to use a diuretic or CCB (recommendation 7) in black persons: what if the person is black and has CKD? To answer this, the panel reliedonexpert opinion. In black patients with CKD and proteinuria, an ACEI or ARB is recommended as initial therapy because of the higher likelihood of progression to ESRD. In black patients with CKD but without proteinuria, the choice for initial therapy is less clear and includes a thiazide-type diuretic, CCB, ACEI, or ARB. If an ACEI or ARB is not used as the initial drug, then an ACEI or ARB can be added as a second-line drug if necessary to achieve goal BP. James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation 9 - Summary Goal BP not reached within 1 month of treatment Increase dose of initial drug OR Add a second drug from one of the 4 recommended classes (thiazide-type diuretic, CCB, ACEI, or ARB) Do not use an ACEI and an ARB together in the same patient Continue to assess BP and adjust the regimen until goal BP is reached If not reached with 2 drugs, add and titrate a third drug If goal BP cannot be reached using the recommended classes because of contraindications or the need to use more than 3 drugs to reach goal Use antihypertensives in other classes Strength of recommendation: Expert opinion (grade E) Blood pressure should be monitored and assessed regularly, treatment adjusted as needed, and lifestyle modifications encouraged. The panel did not recommend any monitoring schedule before or after goal blood pressure is achieved, and this should be individualized. Target doses usually can be achieved within 2 – 4 weeks, and generally should not take longer than 2 months. James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Strategies to Dose Antihypertensive Drugs Strategy Description A Start one drug, titrate to maximum dose, and then add a second drug B Start one drug and then add a second drug before achieving maximum dose of the initial drug C Begin with 2 drugs at the same time, either as 2 separate pills as a single pill combination 3 strategies to dose antihypertensive drugs: These strategies were not compared with each other, nor is it known if one is better than the others in terms of health outcomes. In all cases, avoid combining an ACE inhibitor and an ARB. Some committee members recommend starting therapy with ≥2 drugs when SBP is >160 mm Hg and/or DBP is >100 mm Hg, or if SBP is >20 mm Hg above goal and/or DBP is >10 mm Hg above goal. If goal BP is not achieved with 2 drugs, select a third drug from the list (thiazide-type diuretic, CCB, ACEI, or ARB), avoiding the combined use of ACEI and ARB. Titrate the third drug up to the maximum recommended dose. James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Recommendation Summary Patients > 60 years old, initiate pharmacologic treatment to lower SBP > 150 mm Hg or DBP > 90 mm Hg Treat to a goal < 150/90 mm Hg Patients < 60 years old, initiate pharmacologic treatment to lower SBP > 140 mm Hg or DPB > 90 mm Hg Treat to a goal < 140/90 mm Hg Patients > 18 years old with diabetes or CKD initiate pharmacologic treatment to lower SBP > 140 or DBP > 90 Treat to a goal < 140/90 James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427.

Hypertension Guidelines Table Thomas G, Shishehbor MH, Brill D, et al. Cleveland Clinic Journal of Medicine. 2014;81(3):178-188.

Lifestyle Modification Diet Dietary Approaches to Stop Hypertension (DASH) diet and reduction of sodium intake (< 2,400 mg/day) Greater blood-pressure-lowering effect when the both are combined Physical activity Moderate to vigorous physical activity for 160 minutes/week 4 sessions/week, ~40 minutes in length Weight loss No review of blood-pressure-lowering effect of weight loss Maintain a healthy weight in controlling blood pressure Alcohol intake No specific recommendation Sodium: noting that limiting intake to 1,500 mg can result in even greater reduction in blood pressure, and that even without achieving these goals, reducing sodium intake by at least 1,000 mg per day lowers blood pressure. Thomas G, Shishehbor MH, Brill D, et al. Cleveland Clinic Journal of Medicine. 2014;81(3):178-188.

Strengths and Limitations of JNC 8 Simplified algorithm of when to treat and treatment goals Only RCT data was included Utilized information with different age groups Relaxed blood pressure goals in elderly patients Based recommendations on clinically significant endpoints instead of surrogate markers for blood pressure Treatment adherence and medication costs were thought to be beyond the scope of review Only RCT data was included The review was not designed to determine risk-benefit of therapy-associated adverse effects and harms Blood pressure targets in some subgroups not clearly addressed History of stroke Simplifed The studies had to be randomized controlled trials. NO observational studies, systematic reviews, or meta-analyses were allowed in the JNC 8 guidelines. Though, these were allowed in JNC 7. Clinical significant endpoint: cerebrovascular events compared to surrogate marker of just blood pressure James PA, Oparil S, Carter BL, et al. JAMA. 2013;doi:10.1001/jama:284-427. Thomas G, Shishehbor MH, Brill D, et al. Cleveland Clinic Journal of Medicine. 2014;81(3):178-188.

What are the differences from JNC 7? Focused on evidenced based recommendation Higher target SBP for patients > 60 years old Limited data support either SBP 150 mm Hg or 140 mm Hg Removed special lower target BP for those with CKD or diabetes Liberalized initial drug treatment choices Thiazide-type diuretics no longer recommended as the only first line therapy ACEI/ARBs do not have cardiovascular benefits Thomas G, Shishehbor MH, Brill D, et al. Cleveland Clinic Journal of Medicine. 2014;81(3):178-188.

Using the Guidelines – Patient Case #1 AC is a 64 year old female with a PMH of HTN, DM, and hyperlipidemia Medications: amlodipine 10 mg PO daily, atorvastatin 20 mg PO daily, lisinopril 10 mg PO daily (same medications for last 3 months) BP on exam: 136/82 Repeat – 138/82 According to JNC 7, what would you do in terms of AC’s antihypertensive therapy? According to JNC 8, what would you do in terms of AC’s antihypertensive therapy?

Using the Guidelines – Patient Case #2 LZ is an 82 year old man with a PMH of GERD, HTN, and COPD Current medications: hydrochlorothiazide 25 mg PO daily, pantoprazole 40 mg po daily, Advair 250/50 PO BID, Spiriva 18 mcg PO daily, and albuterol inhaler PO Q4H PRN SOB BP on exam: 148/86 Repeat-148/84 According to JNC 7, what would you do in terms LZ’s antihypertensive therapy? According to JNC 8, what would you do in terms of HN’s antihypertensive therapy?

Therapy Overview Patient Population Initial Drug Therapy General nonblack population, including comorbid conditions Thiazide-type diuretic ACEI/ARB CCB Hypertension with CKD, regardless of race or diabetes status ACEI ARB Black patients with HTN + Diabetes Black patients with comorbid CKD With proteinuria: ACEI or ARB Without proteinuria: ***Use ACEI or ARB as add-on agent if not already present as initial therapy*** Wojtaszek D, Dang DK. Drug Topics. 2014;158(5):33-42.

Antihypertensive Medications Initial Daily Dose (mg) Target Dose in RCTs Reviewed (mg) Number of doses/day Common and/or Major Adverse Effects ACEI Captopril Enalapril Lisinopril 50 5 10 150-200 20 40 2 1-2 1 Hyperkalmia, angioedema, acute kidney failure, SCr, dry cough ARB Losartan Valsartan Irbesartan 40-80 75 5100 160-320 300 Hyperkalmia, angioedema, acute kidney failure, SCr CCB Amlodipine Diltiazem ER 2.5 120-180 360 Dihydropyridines Reflex tachy, peripheral edema, dizziness, HA, flushing,  cardiac contractility Nondihydropyridines Bradycardia, heart block,  cardiac contractility, constipation, gingival hyperplasia Thiazide-type diuretics Chlorthalidone Hydrochlorothiazide Indapamide 12.5 12.5-25 1.25 25-100 1.25-2.5 Electrolyte abnormalities, hyperuricemia, hyperglycemia, hypercalcemia, hyperlipidemia Beta-Blockers Atenolol Metoprolol 25-50 100 100-200 Bradycardia, heart block, rebound HTN, masking hypoglycemia, transient  chol, bronchospasm Electrolyte abnormalities: hypokalemia, hypomagnesemia, hyponatremia Wojtaszek D, Dang DK. Drug Topics. 2014;158(5):33-42.

In Conclusion Guidelines are not rules Only provide framework Formulate antihypertensive plan on the basis of individual patient characteristics Co-morbidities Lifestyle factors Medication side effects Patient preferences Cost issues Adherence Thomas G, Shishehbor MH, Brill D, et al. Cleveland Clinic Journal of Medicine. 2014;81(3):178-188.

References Hobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572. James PA, Oparil S, Carter BL, et al. 2014 Evidenced-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2013;doi:10.1001/jama:284-427. Thomas G, Shishehbor MH, Brill D, et al. New hypertension guidelines: one size fits most? Cleveland Clinic Journal of Medicine. 2014;81(3):178-188. Wojtaszek D, Dang DK. MTM essentials for hypertension management, Part 2: drug therapy considerations. Drug Topics. 2014;158(5):33-42.