Hypertension Guidelines: Are We Pressured to Change? Oregon Cardiovascular Symposium Portland, Oregon June 6, Financial Disclosures

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1 Hypertension Guidelines: Are We Pressured to Change? Oregon Cardiovascular Symposium Portland, Oregon June 6, 2015 William C. Cushman, MD Professor, Preventive Medicine, Medicine, and Physiology University of Tennessee Health Science Center Memphis, Tennessee Financial Disclosures I have no financial relationships with any commercial interests relevant to this presentation James, et al. JAMA ;311:

2 This 2014 HTN evidence-based guideline focuses on the panel s 3 highest ranked questions related to HTN management 1. In adults with HTN, does initiating antihypertensive pharmacologic therapy at specific BP thresholds improve health outcomes? 2. In adults with HTN, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes? 3. In adults with HTN, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? This 2014 HTN evidence-based guideline focuses on the panel s 3 highest ranked questions related to HTN management 1. In adults with HTN, does initiating antihypertensive pharmacologic therapy at specific BP thresholds improve health outcomes? 2. In adults with HTN, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes? 3. In adults with HTN, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? Thresholds After reviewing the evidence, the JNC 8 panel decided that, although some trials had higher thresholds for eligibility than the goals tested, translation into practice should make the threshold for initiating antihypertensive treatment the same as the BP treatment goal. 2

3 This 2014 HTN evidence-based guideline focuses on the panel s 3 highest ranked questions related to HTN management 1. In adults with HTN, does initiating antihypertensive pharmacologic therapy at specific BP thresholds improve health outcomes? 2. In adults with HTN, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes? 3. In adults with HTN, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? VA Cooperative Morbidity Trial in Hypertension 67% RR 96% RR Stopped after 3.3 yrs Stopped after 1.5 years (N = 143) (N = 380) Blood pressure (BP) goal: DBP <90 mm Hg. Therapy: HCTZ + reserpine + hydralazine. NNT = 2.7 for both. RR = risk reduction. JAMA.1967;202(11): JAMA. 1970;213(7): Diastolic BP Goal Trials Several trials used DBP goal ~90 mm Hg and demonstrated consistent reduction of CVD events VA Cooperative Study -Entry: DBP mm Hg -Goal: DBP <90 mm Hg Hypertension Detection and Follow-up Program (HDFP) -Entry: DBP 90 mm Hg -Goal: DBP 90 mm Hg and at least 10 mm Hg Australian National Blood Pressure (ANBP) Trial -Entry: DBP 95 to <110 mm Hg -Goal: DBP 90 mm Hg initially, then after 1 year, lowered to 80 mm Hg STOP-Hypertension Trial -Entry: SBP mm Hg + DBP 90 mm Hg, or DBP mm Hg irrespective of SBP -Goal: BP <160/95 mm Hg 9 3

4 Hypertension Optimal Treatment (HOT) Trial Events by Target DBP Groups* Number of events DBP Target: N =18,790 0 Major All cardiovascular myocardial events Infarction All stroke Cardiovascular Mortality *The outcomes for different BP groups were not statistically significant Total Mortality Hansson L, et al. Lancet. 1998;351: Major Randomized Trials Testing SBP Goals in General (Older) Populations SHEP Syst-Eur HYVET JATOS VALISH Age >60 >60 > Number 4,736 4,695 3,845 4,418 3,260 Entry SBP >160 >160 Goal SBP <148 <150 <150 <140 <140 Achieved SBP Stroke 36% 42% ns ns ns CVD 32% 31% 34% ns ns Mortality ns ns 21% ns ns SBP = systolic blood pressure; CVD = cardiovascular disease Recommendation 1 In the general population 60 years of age, initiate pharmacologic treatment to lower BP at SBP 150 mm Hg or DBP 90 mm Hg and treat to a goal SBP <150 mm Hg and goal DBP <90 mm Hg. Strong Recommendation Grade A Corollary Recommendation: In the general population 60 years of age, if pharmacological treatment for high BP results in lower achieved SBPs (for example, <140 mm Hg) and treatment is not associated with adverse effects on health or quality of life, treatment does not need to be adjusted. Expert Opinion Grade E 4

5 2014 Eighth Joint National Committee Panel Recommendation For Blood Pressure Targets Revisited: Results From The INVEST Study Bangalore, et al. JACC 2014;64: Recommendation 2 In the general population <60 years of age, initiate pharmacologic treatment to lower BP at DBP 90 mm Hg and treat to a goal DBP <90 mm Hg. For ages years, Strong Recommendation Grade A For ages years, Expert Opinion Grade E Recommendation 3 In the general population <60 years of age, initiate pharmacologic treatment to lower BP at SBP 140 mm Hg and treat to a goal SBP <140 mm Hg. Expert Opinion Grade E BP Targets in Chronic Kidney Disease (CKD) 3 RCTs (8 reports), total of 2272 participants: MDRD(Modification of Diet in Renal Disease) Study AASK(African American Study of Kidney Disease and Hypertension) Trial REIN-2(Ramipril Efficacy in Nephropathy 2) trial No conclusive evidence favoring a BP target of <125/75 to 130/80 mm Hg rather than <140/90 mm Hg. Upadhyay A, et al (Tufts). Annals Intern Med

6 Recommendation 4 In the population 18 years of age with CKD, initiate pharmacologic treatment to lower BP at SBP 140 mm Hg or DBP 90 mm Hg and treat to goal SBP <140 mm Hg and goal DBP <90 mm Hg. Expert Opinion Grade E James, et al. JAMA ;311: Systolic Blood Pressure Intervention Trial SPRINT (NHLBI) To test whether SBP goal <120 mm Hg reduces CVD events compared with SBP goal <140 mm Hg in nondiabetic high CVD risk population: Primary outcome: composite of MI, stroke, HF, ACS, CV death. Other outcomes: renal, cognition/dementia, MRI changes. Known CVD, stage 3 CKD, and combinations of risk factors or other indications for high risk; enriched with seniors ( 75 years old) SBP mm Hg on 0-3 medications (depending on level of SBP). Completed enrollment of 9,361 participants in March years follow-up (2016). RCTs Testing BP Goals In Hypertensive Diabetic Patients Trial n Duration (years) SBP goal, mmhg DBP goal, mmhg Mean BP, less intense, mmhg Mean BP, more intense, mmhg SHEP <148 none 155/72 146/68 Outcome Risk Reduction Stroke 22% (ns) CVD 34% CHD 56% Syst-Eur <150 none 162/82 153/78 HOT 1,501 3 none <80 148/85 144/81 UKPDS 1, <150 <85 154/87 144/82 ABCD none <75 138/86 132/78 ACCORD 4, <120 none Stroke 69% CVD 62% CVD 51% MI 50% Stroke 30% (ns) CV death 67% DM-related 34% deaths 32% Stroke 44% Microvasc 37% Renal (1º) nc Microvasc nc Death 49% CVD ns CVD (1º) 12% (ns) Stroke 41% Ferrannini, Cushman. Lancet 2012;380:

7 ADVANCE BP Trial 11,140 patients with type 2 diabetes randomized to addition of indapamide + perindopril vs PBO on usual therapy. Significant 14% reduction in mortality (stopped early) and 9% reduction of combined macro- and microvascular outcomes, but neither significant alone. Mean SBP in intensive group was 135 mm Hg, similar to mean SBP in ACCORD standard BP group. Patel, et al. Lancet 2007;370: Recommendation 5 In the population 18 years of age with diabetes, initiate pharmacologic treatment to lower BP at SBP 140 mm Hg or DBP 90 mm Hg and treat to a goal SBP <140 mm Hg and goal DBP <90 mm Hg. (Expert Opinion Grade E) BP Targets/Goals: Summary Best evidence from trials: <150/90 Most current guidelines recommend: <140/90 for most patients Consensus for age 80 years: <150/90 JNC 8/?ESH/ESC: 60/65 years: <150/90 <140/90 OK, if tolerated DM: <140/ CKD: <140/90 (some: <130/80 if proteinuria) Other populations: insufficient evidence or included in these recommendations 7

8 This 2014 HTN evidence-based guideline focuses on the panel s 3 highest ranked questions related to HTN management 1. In adults with HTN, does initiating antihypertensive pharmacologic therapy at specific BP thresholds improve health outcomes? 2. In adults with HTN, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes? 3. In adults with HTN, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? Network Meta-analysis of Antihypertensive Drugs Low-dose Diuretics* versus Placebo Outcome RR 95% CI P CHD Heart failure <0.001 Stroke <0.001 CVD events <0.001 CVD mortality Total mortality * Low-dose Diuretics (examples): HCTZ mg/d chlorthalidone mg/d Low-dose diuretics better Low-dose diuretics worse Psaty, et al. JAMA 2003; 289:2534 Proportion of patients with first event (%) LIFE Study Primary Composite Endpoint* Intention-to-treat Adjusted risk reduction 13 0%, P=0 021 Unadjusted risk reduction 14 6%, P=0 009 Atenolol Losartan * CV mortality, MI, and stroke Study Month Losartan (n) Atenolol (n) Dahlof B, et al. Lancet. 2002;359: Reprinted with permission from Elsevier Science. 8

9 ALLHAT Hypertension Trial 42,418 high-risk hypertensive patients 90% previously treated 10% untreated STEP 1 AGENTS (Double-blind) Chlorthalidone mg Amlodipine mg Lisinopril mg Doxazosin 1-8 mg N=15,255 N=9,048 N=9,054 N=9,061 Blinded drugs titrated and atenolol, clonidine, reserpine, and/or hydralazine added as needed to achieve BP goal: <140/90 mm Hg ALLHAT CHD Final Outcomes Results Doxazosin vs. Chlorthalidone Relative Risk and 95% Confidence Intervals 1.03 ( ) All-Cause Mortality Combined CHD Stroke Heart Failure 1.03 ( ) 1.07 ( ) 1.26 ( ) 1.80 ( ) Combined CVD, p< ( ) Favors Doxazosin Favors Chlorthalidone Hypertension 2003;42: ALLHAT Major Outcomes Relative Risks and 95% Confidence Intervals Amlodipine/Chlorthalidone CHD 0.98 ( ) All-Cause Mortality 0.96 ( ) Stroke 0.93 ( ) Combined CVD 1.04 ( ) Heart Failure 1.38 ( ) Lisinopril/Chlorthalidone 0.99 ( ) 1.00 ( ) 1.15 ( ) 1.10 ( ) 1.19 ( ) ESRD 1.12 ( ) 1.11 ( ) Favors Amlodipine Favors Chlorthalidone Favors Lisinopril Favors Chlorthalidone JAMA 2002;288:

10 ALLHAT Only Subgroup Differences: Lisinopril vs Chlorthalidone in Blacks/Non-Blacks for CVD & Stroke Blacks Non-Blacks CHD Mortality Combined CVD Stroke Heart Failure ESRD 1.10 ( ) 1.06 ( ) 1.19 ( ) 1.40 ( ) 1.32 ( ) 1.29 ( ) 0.94 ( ) 0.97 ( ) 1.06 ( ) 1.00 ( ) 1.15 ( ) 0.93 ( ) Favors Favors Lisinopril Chlorthalidone Favors Favors Lisinopril Chlorthalidone Recommendation 6 In the general non-black population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, CCB, ACEI or ARB. Moderate Recommendation Grade B Drug Considerations Each of the 4 drug classes recommended by the panel yielded comparable effects on overall mortality and CV, cerebrovascular, and kidney outcomes, with one exception: HF. Initial treatment with a thiazide-type diuretic was more effective than a CCB or ACEI, and an ACEI was more effective than a CCB in improving HF outcomes. While the panel recognized that improved HF outcomes was an important finding that should be considered when selecting a drug for initial therapy for HTN, the panel did not conclude that it was compelling enough within the context of the overall body of evidence to preclude the use of the other drug classes for initial therapy. 10

11 Diuretics Used to Treat Hypertension Thiazide and Thiazide-like Diuretics Loop Diuretics Potassium-Sparing Diuretics BA (%) T ½ (hours) DOA (hours) Hydrochlorothiazide Chlorothiazide Chlorthalidone Bendroflumethiazide Indapamide Metolazone Bumetanide Furosemide Torsemide Amiloride Triamterene 83 (55) * 3.0 (3.0) * 7-9 Spironolactone > Eplerenone NA *Parentheses denote active metabolite. The half-life of one active metabolite, potassium canrenoate, is 15 h. BA = bioavailability; T½ = half-life; DOA = duration of action: NA = unknown. Reprinted from Brater DC. In: Principles of Pharmacology: Based Concepts and Clinical Applications. 1995: , with permission from Springer Science and Business Media; Delyani JA, et al. Cardiovasc Drug Rev. 2001;19: ; Rosenberg J, et al. Cardiovasc Drug Ther. 2005;19: ; Sica DA. Congest Heart Fail. 2003;9: Recommendation 7 In the general Black population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic or CCB. For general Black population: Moderate Recommendation Grade B For Blacks with diabetes: Weak Recommendation Grade C Recommendation 8 In the population 18 years of age with CKD and HTN, initial (or add-on) antihypertensive treatment should include an ACEI or ARB to improve kidney outcomes. This applies to all CKD patients with HTN regardless of race or diabetes status. Moderate Recommendation Grade B 11

12 ALLHAT Cumulative Percent Controlled (BP <140/90 mm Hg) at Five Years Percent or 2 Any Number of Prescribed Drugs Derived from Cushman et al. J Clin Hypertens. 2002;4: Recommendation 9 The main objective of HTN treatment is to attain and maintain goal BP. If goal BP is not reached within a month of treatment, increase the dose of the initial drug or add a 2 nd drug from one of the classes in Recommendation 6 (thiazide-type diuretic, CCB, ACEI or ARB). Continue to assess BP and adjust the treatment regimen until goal BP is reached. If goal BP cannot be reached with 2 drugs, add and titrate a 3 rd drug from the list provided. Do not use an ACEI and an ARB together in the same patient. Initial Choices of Medications Diuretics Diuretics or CCBs in Blacks β-blockers should be included in the regimen if there is a compelling indication for a β-blocker ACE inhibitors or ARBs* Calcium antagonists * Recommended for CKD Combining ACEI with ARB discouraged 12

13 Recommendation 9, cont If goal BP cannot be reached using the drugs in Recommendation 6 because of a contraindication or the need to use more than 3 drugs to reach goal BP, antihypertensive drugs from other classes can be used. Referral to a hypertension specialist may be indicated for patients in whom goal BP cannot be attained using the above strategy or for the management of complicated patients where additional clinical consultation is needed. Expert Opinion Grade E From the 2014 U.S. Hypertension Guidelines by the JNC 8 Panel James, et al. JAMA ;311: JNC 8 Panel option C (Expert Opinion): Begin with 2 drugs at the same time, either as 2 separate pills or as a single pill combination Initiate therapy with 2 drugs simultaneously, either as 2 separate drugs or as a single pill combination. 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, et al. JAMA ;311:

14 Drugs to Add to Initial 2-3 Drug Combinations spironolactone or amiloride: especially if K + low or 1 aldosteronism. reserpine: best choice of adrenergic inhibitor, well tolerated, very long duration of action alpha blocker: especially if LUTS alternative CCB: don t combine non-dhp c BB beta-blocker: safe to combine (except c non- DHP CCB), but doesn t add much efficacy. vasodilator: hydralazine or minoxidil alpha-beta blocker: labetolol or carvedilol central agonist: most side effects frequency JNC 2014 Report The JNC 2014 report addresses whether pharmacologic treatment of hypertension at particular BP thresholds, and to particular BP goals, or with particular antihypertensive drug(s)/drug classes improves important health outcomes, including mortality (overall and CVD), myocardial infarction and coronary revascularization, heart failure, stroke, peripheral revascularization and progression of CKD compared to other thresholds, goals, or treatment regimens. Thank you! 14