2/10/2014. Hypertension: Highlights of Hypertension Guidelines: Making the Most of Limited Evidence. Issues with contemporary guidelines

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1 Hypertension: 214 Highlights of Hypertension Guidelines: Making the Most of Limited Evidence Michael A, Weber, MD Editor-in-Chief, The Journal of Clinical Hypertension, Professor of Medicine, Division of Cardiovascular Medicine, SUNY Downstate College of Medicine Michael Weber, MD, Disclosures Research: Boston Scientific; Medtronics; Astra Zeneca Consulting: Medtronics, Novartis, Boehringer Ingelheim, Forest Speakers Programs: Arbor Issues with contemporary guidelines Strong focus on evidence Belief that only prospectively defined primary endpoints from randomized, controlled, blinded clinical trials should be considered in decision-making As a result, only a very small fraction of available information can be used in making the guidelines Inevitably, many important issues that depend on other types of evidence, or the experience and judgment of experts, are now omitted 1

2 JNC 7: algorithm for the treatment of hypertension Lifestyle modifications Not at goal blood pressure (<14/9 mmhg) (<13/8 mmhg for those with diabetes or chronic kidney disease) Initial drug choices Without compelling indications With compelling indications Stage 1 hypertension (SBP or DBP 9 99 mmhg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination Stage 2 hypertension (SBP >16 or DBP >1 mmhg) 2 drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Not at goal blood pressure Drug(s) for the compelling indications* Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist *Compelling Indications Heart failure; post-mi; high coronary artery disease risk; diabetes; chronic kidney disease; recurrent stroke prevention Chobanian, AV et al. JAMA 23;289: CHD rates by SBP, DBP and age IHD mortality (Floating absolute risk and 95% CI) A: Systolic blood pressure Age at risk: IHD mortality (Floating absolute risk and 95% CI) B: Diastolic blood pressure Age at risk: Usual systolic blood pressure (mmhg) Usual diastolic blood pressure (mmhg) Adapted from Lewington et al. Lancet. 22; 36: What made traditional antihypertensive therapy traditional: initial placebo-controlled VA studies CV event rate (%) VA-1 DBP mmhg VA-2 DBP mmhg Placebo Active On assigned meds at study end: VA-1 92% VA-2 85% Active treatment: HCTZ 5-1 mg, reserpine.1.2 mg, hydralazine 1 2 mg Veterans Administration Cooperative Study Group 1. JAMA 1967;22: Veterans Administration Cooperative Study Group 2. JAMA 197;213:

3 Systolic Hypertension in the Elderly Program (SHEP) Multicenter, randomized, double-blind, blind, placebo-controlled, controlled, patients aged 6, systolic BPs >16 mmhg & diastolic BPs <9 mmhg, using mg chlorthalidone + other drugs if needed (Starting SBP: 17 mmhg; achieved SBP: Placebo 155 mmhg, active treatment 143 mmhg) 1 Placebo (n=2371) Active treatment (n=2365) Cumulative fatal and nonfatal stroke rate per 1 participants % Months SHEP Cooperative Research Group. JAMA ;265: Systolic Hypertension in Europe Trial (Syst-Eur) Randomized, double-blind blind placebo trial of patients aged 6 with isolated systolic hypertension, placebo vs nitrendipine 1-4 mg ± enalapril 5-2 mg ± HCTZ. Goal: Lower SBP by 2 mm Hg to <15 mm Hg: In reality, placebo = 161 mmhg; active = 151 mmhg Events per 1 patients Fatal and Nonfatal Strokes 42% reduction P= Time since Randomization randomization (Yrs) (y) Fatal and Nonfatal Myocardial Infarction % reduction P= Time since Randomization randomization (Yrs) (y) Staessen JA et al. Lancet ;35: HYVET (Patients Aged >8): BP Effects During Trial Patients with isolated systolic hypertension; baseline SBP 174 mmhg; Target BP <15 mmhg; Achieved BP: placebo = 158 mmhg; active = 143 mmhg Blood pressure (mmhg) mmhg 6 mmhg Follow-up () Placebo Indapamide SR ± perindopril Median follow-up 1.8 Beckett NS, et al. N Engl J Med 28;358:

4 HYVET: 21% reduction in total mortality with active treatment versus placebo a9 p=.19 Beckett NS, et al. N Engl J Med 28;358: United Kingdom Prospective Diabetes Study (UKPDS): Results BP Control Glucose Control Any diabetes- Diabetes- Micro- related end point related death vascular endpoints (144/82 vs 154/87 mm Hg) Any diabetes- Diabetes- Micro- related Stroke endpoint related vascular death endpoints % (P<.1) -1% (P=.34) -25% (P<.1) UKPDS Group 38. BMJ. 1998;317: UKPDS Group 33. Lancet. 1998;352: % (P<.5) -32% (P=.19) -44% (P=.13) -37% (P=.9) VALUE: analysis of results based on BP control at six months Patients treated with valsartan Patients treated with amlodipine Odds ratio Odds ratio Fatal/nonfatal cardiac events.76 (.66.88).73 (.63.85) Fatal/nonfatal stroke.6 (.48.74).5 (.39.64) All-cause death.79 (.69.91).79 (.69.92) Myocardial infarction.83 ( ).91 ( ) Heart failure hospitalizations.62 (.5.77).64 (.52.79) Controlled Non-controlled patients* patients (n=5,253) (n=2,396) Hazard ratio 95% CI Controlled Non-controlled patients* patients (n=5,52) (n=2,94) Hazard ratio 95% CI *SBP <14 mmhg at 6 months; p<.1 Weber MA, et al. Lancet 24;363:

5 Slide 1 a9 image so unable to amend author, 6/27/212

6 Methods Patients with diabetes at baseline grouped according to mean on-treatment SBP Tight Control Usual Control Not Controlled <13 mm Hg 13-<14 mm Hg 14 mm Hg Results: Outcomes During INVEST 28 Major Outcomes by Achieved Systolic Blood Pressure Category in ACCOMPLISH (1) Primary Endpoint* Cardiovascular (CV) Death p-values versus >14 1 p-values versus >14 Events per 1, patient <.1 <.1 NS Events per 1, patient to <12 12 to <13 13 to <14 >14 n=1329 n=3593 n=3429 n=2354 Systolic Blood Pressure Category (mmhg) 4 11 to <12 12 to <13 13 to <14 >14 n=1329 n=3593 n=3429 n=2354 Systolic Blood Pressure Category (mmhg) * CV Death or Non-fatal MI or Non-fatal Stroke Weber et al. Amer J Med 213; 126:

7 Effects of intensive blood pressure control on cardiovascular events in type 2 diabetes mellitus: The Action to Control Cardiovascular Risk In Diabetes (ACCORD) blood pressure trial William C Cushman, MD, FACP, FAHA Veterans Affairs Medical Center, Memphis, TN For The ACCORD Study Group ACCORD: mean systolic pressures in treatment groups with time a5 14 Intensive Standard 13 Average : Standard vs Intensive, delta = N = Years Post-Randomization Mean number of medications Intensive: Standard: SBP (mm Hg) Number of patients Intensive: 2,174 2,71 1,973 1,792 1, Standard: 2,28 2,136 2,77 1,86 1, Data shown are mean ± 95% CI ACCORD group. Med 21;362: study N Engl J ACCORD: primary outcome and total stroke Primary outcome (Nonfatal MI, nonfatal stroke or CVD death) Nonfatal stroke Patients with Events (%) HR =.89 95% CI ( ) Patients with Events (%) HR =.59 a6 95% CI ( ) NNT for 5 = 89 Intensive Standard Years Post-Randomization Years Post-Randomization ACCORD study group. N Engl J Med 21;362:

8 Slide 17 a5 Jennie - I can't access graph to sentence case the x axis, add commas to thousands etc. Original also has axis break marked author, 6/27/212 Slide 18 a6 graphs are images and therefore not able to amend case for axes titles author, 6/27/212

9 Blood pressure criteria Achieving SBP <16 mmhg is of benefit Achieving SBP <15 mmhg is also of benefit Achieving SBP <14 mmhg also appears to be justified (though evidence not as rigorous as for <15 mmhg) Achieving SBP <13 mmhg doesn t provide better outcomes, but appears safe. Is around 13 mmhg optimal? Achieving SBP <12 mmhg is beneficial only for stroke. The SPRINT study in the US is now examining this target in high risk non-diabetic patients James PA, et al. JAMA. 213 Dec 18. doi: 1.11/jama [Epubahead of print]. Authors of JNC 8 Panel: Recommendation 1 In the general population aged 6 or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 15 mmhg or higher or diastolic blood pressure (DBP) of 9 mmhg or higher and treat to a goal SBP lower than 15 mmhg and goal DBP lower than 9 mmhg. Strong Recommendation Grade A Note: This was one of only two of the nine recommendations of the panelists that claimed to be Strong and Grade A 7

10 Authors of JNC 8 Panel: Recommendation 1 Concern #1 In the general population aged 6 or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 15 mmhg or higher or diastolic blood pressure (DBP) of 9 mmhg or higher and treat to a goal SBP lower than 15 mmhg and goal DBP lower than 9 mmhg. Strong Recommendation Grade A NOTE: In none of the 3 studies (SHEP, Syst-Eur, HYVET) underlying this recommendation was a general population studied: They all rigorously excluded the majority of patients aged 6 or more who did not have isolated systolic hypertension Authors of JNC 8 Panel: Recommendation 1 Concern # 2 In the general population aged 6 or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 15 mmhg or higher or diastolic blood pressure (DBP) of 9 mmhg or higher and treat to a goal SBP lower than 15 mmhg and goal DBP lower than 9 mmhg. NOTE: Only 2 of the 3 studies achieved SBP below 15 mmhg: HYVET (in patients aged 8 or more) and the definitive SHEP: Treatment =143 vs. placebo =155 mmhg. THUS, recommending the15 mmhg goal gives back about half the 36% stroke benefit. Wouldn t <145 or <14 mmhg been more in keeping with the evidence? Authors of JNC 8 Panel: Recommendation 1 Concern # 3 In the general population aged 6 or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 15 mmhg or higher or diastolic blood pressure (DBP) of 9 mmhg or higher and treat to a goal SBP lower than 15 mmhg and goal DBP lower than 9 mmhg. NOTE: With the exception of a few patients in Syst EUR none of the patients studied in the 3 studies had pre-treatment diastolic values > 9 mmhg, so there is no evidence whatever to support this part of the recommendation 8

11 How these concerns played out (1) The 15/9 mmhg threshold recommended by the panelists has been claimed to reduce the use of drugs and other resources and thus save money. But, if the generally-used 14/9 mmhg threshold is more correct, then these savings in money would be at the expense of increased major cardiovascular events in the large high risk group of hypertensive people aged 6 or more. How these concerns played out..(2) Following critiques of the panelists recommendation by external reviewers, the NHLBI (which was the original sponsor of the guidelines) announced it was quitting the guidelines business and handing it over to the AHA and the ACC. After reviewing the JNC panel s draft paper, the AHA and ACC also expressed concerns. After a failed negotiation the JNC panelists decided to simply publish their document independently, explicitly acknowledging that it is unsponsored by any federal agency or professional society. How the JNC Panelists Modified their Statement As a corollary to the 15/9 mmhg recommendation, they state that 14/9 mmhg is acceptable if it occurs during treatment and is well tolerated The panelists acknowledge in their publication that the panel was unable to achieve unanimity on the recommendation of a goal SBP of lower than 15 mmhg and that some members of the panel had argued that the evidence was insufficient to increase the diagnostic threshold from 14 to 15 mmhg in people aged 6 or more. Thus the following statement was made: The panel agreed that more research is needed to identify optimal goals of SBP for patients with high BP. The Conclusion to the publication states: It is important to note that this evidence-based guideline has not re-defined BP, and the panel believes that the 14/9 mmhg definition from JNC 7 remains reasonable. 9

12 Wright JT Jr, et al. Ann Intern Med. Published online 14 January 214. doi: /M Therapy Most evidence now supports 3 drug types: the RAS blockers (ACE inhibitors or ARBs); calcium channel blockers; and thiazide diuretics. Evidence for beta blockers weaker, except in HF, post-mi or angina Among the major classes, ethnicity, age and concomitant conditions will influence the selection of drugs Combination treatment is required in >5% of patients: most patients finish up with 2- or 3- drug combinations utilizing a RAS blocker, a calcium channel blocker and a thiazide From these 3 types of drugs, does it matter which are chosen for 2-drug combinations? For instance, is there a CV outcomes difference between the very popular RAS blocker/thiazide combination and a RAS blocker/calcium channel blocker combination? ACCOMPLISH Kaplan-Meier curve for time to primary composite CV endpoint.16 Cumulative event rate Benazepril/amlodipine (552 patients with events: 9.6%) Benazepril/HCTZ (679 patients with events: 11.8%) 2% risk reduction* p= Time to first CV mortality/morbidity (months) Patients at risk (N) Benazepril/amlodipine 5,512 5,317 5,141 4,959 4,739 2,826 1,447 Benazepril/HCTZ 5,483 5,274 5,82 4,892 4,655 2,749 1,39 *Hazard ratio (95% confidence interval):.8 (.72,.9) CV=cardiovascular; HCTZ=hydrochlorothiazide Jamerson K, et al. N Engl J Med 28;359:

13 Differential Effects of Hypertension Therapies on Cardiovascular Event Rates: The Role of Body Size Michael A. Weber, Kenneth Jamerson, George L. Bakris, Matthew Weir, Richard Devereux, Shawna Nesbitt, Dion Zappe, Ying Zhang, Bjorn Dahlof, Eric Velazquez, Bertram Pitt Weber et al. Lancet 213; 381: Rates for Primary Endpoint* for the Pooled ACCOMPLISH Cohort 25 (24.6) Events per 1 patient- 2 p =.66 (19.5) p (overall) =.25 (17.2) 15 Normal Overweight Obese * CV death or non-fatal MI or stroke BMI Categories Differing Effects of the Thiazide and Amlodipine Combinations on Primary Event Rates in BMI Categories 32 (3.7) Events per 1 patient % risk reduction p =.37 Benazepril+Hydrochlorothiazide Benazepril+Amlodipine p (overall) =.34 (21.9) 24% risk reduction (18.2) p = (18.2) (16.9) NS (16.5) Normal Overweight Obese BMI Categories 11

14 British Hypertension Guidelines (NICE): Summary of antihypertensive drug treatment Age <55 Aged over 55 or black person of African or Caribbean family origin of any age Step 1 Step 2 Step 3 Step 4 A C A + C A + C + D Resistant hypertension A + C + D + consider further diuretic or alpha- or beta-blocker Consider seeking expert advice Key A angiotensin converting enzyme inhibitor or low-cost angiotensin II receptor blocker C calcium channel blocker D thiazide-like diuretic NICE 211 guidelines. Available at: accessed 18 June 212 NICE 211 CG127 Hypertension slide set. Available at: accessed 18 June 212 Blood pressure in mm Hg Definition of Hypertension Drug therapy in low risk patients after non-pharmacologic treatment NICE 211[2] 14/9 and daytime ABPM (or home BP) 135/85 16/1 or day-time ABPM 15/95 Comparison of Hypertension Guidelines ESH/ESC ASH/ISH Go A. et al. AHA/ACC/CDC 214 Hypertension 213[3] 214 [4] 213 [5] guidelines, US JNC 8 [6] 14/9 14/9 14/9 Not addressed 14/9 14/9 14/9 < 6 y. 14/9 6 y. 15/9 Beta-blockers as first line drug No Yes No No No (Step 4) (Step 4) (Step 3) (Step 4) Diuretic chlorthalidone, indapamide thiazides chlorthalidone, indapamide thiazides chlorthalidone indapamide thiazides thiazides chlorthalidone, indapamide Initiate drug therapy with two Not mentioned drugs Blood pressure targets < 14/9 In patients with markedly elevated BP <14/9 16/1 16/1 16/1 <14/9 <14/9 < 6 y. <14/9 8 y. < 15/9 Elderly < 8 y. SBP SBP <14 in fit patients 8 y. < 15/9 Lower targets may be appropriate in some patients, including the elderly 6 y. <15/9 Elderly 8 y. SBP Blood Pressure target in patients with diabetes mellitus Not addressed < 14/85 <14/9 <14/9 Lower targets may be considered <14 /9 Lindholm LH, Carlberg B. HT News 214, Opus 35 Weber MA, et al. J ClinHypertens(Greenwich). 214 ; 16:

15 Blood Pressure >14/9 in Adults Aged >18 (For age >8, pressure >15/9 or >14/9 if high risk (diabetes, kidney disease) Start Lifestyle Changes (Lose weight, reduce dietary salt and alcohol, stop smoking) Start Drug Therapy (Consider a delay in uncomplicated Stage 1 patients)* Start Drug Therapy (In all patients) Stage /9-99* Stage 2 >16/1* Special Cases Black Patients CCB orthiazide If Needed, Add ACE-iorARB OR combine CCB+Thiazide If Needed Age <6 Years ACE-iorARB If Needed, Add CCB orthiazide If Needed CCB+Thiazide+ACE-i(orARB) If Needed, Refer to a Hypertension Specialist non-black Patients Age 6 Years CCB orthiazide If Needed, Add ACE-iorARB If Needed If Needed, add other drugs e.g. spironolactone; centrally acting agents; β-blockers All Patients Start With 2 Drugs CCB orthiazide + ACE-iorARB If Needed CCB+Thiazide+ACE-i(orARB) At any stage it is entirely appropriate to seek help from a hypertension expert if treatment is proving difficult. Kidney disease Diabetes Coronary disease Stroke history Heart failure *In stage 1 patients without other cardiovascular risk factors or abnormal findings, some months of regularly monitored lifestyle management without drugs can be considered. Weber MA, et al. J ClinHypertens On-line 213; Dec 17. J Hypertens. 214;32:3 15. Hypertension 214 For most people, 14/9 mmhg defines hypertension and its treatment targets; for those aged >8, 15/9 mmhg is appropriate Patients with diabetes or kidney disease have the same BP criteria (14/9 mmhg) as other patients RAS blockers (ACE inhibitors or ARBs) and calcium channel blockers are emerging as preferred drugs, with thiazides to be used as CCB alternatives or as part of 3-drug regimens Treatment resistant hypertension is the current hot topic, but care should be taken not to over-diagnose this condition 213 ESH/ESC Hypertension Guidelines Blood pressure goals in hypertensive patients Recommendations Class Level A SBP goal < 14 mmhg: a) is recommended in patients at low-moderate CV risk I B b) is recommended in patients with diabetes IIa A c) should be considered in patients with previous stroke or TIA IIa B d) should be considered in patients with CHD I B e) should be considered in patients with diabetic or non-diabetic CKD B In elderly hypertensives less than 8 old with SBP 16 mmhg there is solid evidence to recommend reducing SBP to between 15 and 14 mmhg In fit elderly patients less than 8 old SBP values < 14 mmhg may be considered wheras in the fragile elderly population SBP goals should be adapted to individual tolerability In individuals older than 8 and with initial SBP 16 mmhg, it is recommended to reduce SBP to between 15 and 14 mmhg provided they are in good physical and mental conditions A DBP target of <9 mmhg is always recommended except in patients with diabetes, in whom values <85 mmhg are recommended. It should nevertheless be considered that DBP values between 8 and 85 mmhg are safe and well tolerated IIa IIa IIa A C B A 13