JNC 8 -Controversies. Sagren Naidoo Nephrologist CMJAH

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1 JNC 8 -Controversies Sagren Naidoo Nephrologist CMJAH

2 Joint National Committee (JNC) Panel appointed by the National Heart, Lung, and Blood Institute (NHLBI) First guidelines (JNC-1) published in 1977 Subsequent updates published in 3- to 6-year intervals Last edition (JNC-7) published in 2003 Chobanian AV et al. JAMA 2003;289:

3 Guidelines The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) Updated 2003 Succinct evidence-based recommendations. Published in JAMA May 21, 2003,

4 JNC-7 Blood Pressure Classification Blood Pressure Classification Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Normal < 120 < 80 Pre-hypertension Stage 1 hypertension Stage 2 hypertension > 160 > 100 Chobanian AV et al. JAMA 2003;289:

5 JNC-7 Treatment Algorithm

6 JNC-7 Compelling Indications Chobanian AV et al. JAMA 2003;289:

7 Development of JNC-8 Commissioned by the NHLBI in 2008 Panel members appointed Developed focused critical questions relevant to practiceconducted 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 James PA et al. JAMA 2014;311:

8 Development of JNC-8 3 critical questions for adults with hypertension: Does initiating antihypertensive pharmacologic therapy at specific blood pressure thresholds improve health outcomes? [When to start therapy?] Does treatment with antihypertensive pharmacologic therapy to a specified blood pressure goal lead to improvements in health outcomes? [How low should I go?] Do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? [What drug do I use?] James PA et al. JAMA 2014;311:507-20

9 Development of JNC-8 And then we wait and wait

10 JAMA published the long-awaited Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure-8 (JNC- 8) guidelines December 18, 2013.

11 JNC 8: Hypertension Management Evidence Review Limited to RCT s: Hypertensive adults > 18 years old Sample size > 100 Follow-up > 1 year Reported effect of treatment on important health outcomes (mortality, MI, HF, CVA, ESRD) January 1966 to December 2009 Separate criteria used of RCT s published after December 2009 Omitted observational, epidemiological and non randomised data

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13 JNC 8: Graded Recommendations A Strong evidence B Moderate evidence C Weak evidence D Against E Expert Opinion N No recommendation

14 JNC 8: Hypertension Management Evidence Review RCT s December 2009 August Major study in hypertension ACCORD, NEJM > 2,000 participants 3. Multicentered 4. Met all other inclusion/exclusion criteria

15 JNC 8: Graded Recommendations JNC-8 report matter-of-factly acknowledged 2 limitations-not a systemmatic review and not a thorough analysis of the dat Did not include observational studies, systematic reviews, or meta-analyses, panel did not conduct its own meta-analysis based on prespecified inclusion criteria. Thus, information from these types of studies was not incorporated into the evidence statements or recommendations. Although adverse effects and harms of antihypertensive treatment documented in the RCTs were considered when the panel made its decisions,, the review was not designed to determine whether therapy-associated adverse effects and harms resulted in significant changes in important health outcomes

16 But Wait There s More The last 3 RCTs (Jatos, Ogihara, and Verdecchia) involved almost exclusively stage 2 hypertension patients and had no placebo control arms. These studies tell us nothing about the efficacy and safety of drugs for mild hypertension. The JNC-8 authors referenced 5 RCTs as providing high quality evidence to support their strong (Grade A) recommendation for drug use above a threshold of DBP 90:

17 Trials that combined stage 1 and 2 Hypertension patients. The hypertension detection and follow up program (HDFP) The U.K. Medical Research Council Working Party trial (DBP ) The Hypertension-Stroke Cooperative Study Group study found no benefit from blood pressure lowering drugs in patients after a stroke The Australian therapeutic trial in mild hypertension combined stage 1 and stage 2 hypertension patients. The Effects morbidity of treatment on hypertension study mixed stage 1 and 2 patients.

18 But Wait There s More TheCochrane Database of Systematic Reviews found no evidence supporting drug treatment for patients of any age with mild hypertension (SBP: and/or DBP 90-99) and no previous cardiovascular disease, diabetes, or renal disease (i.e., low risk). The JNC-8 hypertension guidelines are not endorsed by the National Heart, Lung, and Blood Institute (NHLBI), the American Heart Association, the American College of Cardiology, nor any other authoritative body.

19 But Wait There s More 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) J Hypertnsion 2013;31: Hypertension online November 15, J Hypertension 2014;32:3-15

20 JNC-8 Recommendations In patients >60 years of age, start medications at blood pressure of >150/90mm Hg and treat to goal of <150/90mm Hg In patients >60 years of age, treatment does not need to be adjusted if achieved blood pressure is lower than goal and well-tolerated James PA et al. JAMA 2014;311:

21 Hypertension in the Elderly

22 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

23 Hypertension in the Elderly They recommended blood pressure lowering drug treatment for patients 60-years-old with systolic blood pressure (SBP) 150 or diastolic blood pressure (DBP) 90 mm Hg. For patients < 60-years-old, they recommended medications for DBP 90 mm Hg. They classified both of these recommendations as Grade A (strong). To say the least, the evidence-basis for the drug treatment recommendations for mild hypertension in this report is in dispute.

24 Hypertension in the Elderly In relation to this changed drug treatment threshold recommendation, the JNC-8 panel cited 6 RCTs. The first 3 of these placebo controlled RCTs (Staessen,Beckett, and SHEP) involve only patients with stage 2 hypertension (SBP 160) rather than mild (stage 1) hypertension. RCTs of stage 2 patients say nothing about the important issue, which is whether the threshold to begin drug treatment should be at SBP = 140, 150, or 160. The widely acknowledged benefits of drugs for stage 2 hypertension were inappropriately extrapolated to apply to patients with stage 1 hypertension.

25 HYVET HYpertension in the Very Elderly Trial: Randomized, double-blind trial Included patients aged 80 or older with SBP>160mmHg Randomized to indapamide +/- perindopril or placebo Target BP of 150/80mmHg Primary outcome of fatal or nonfatal stroke Beckett NS et al. N Engl J Med 2008;358:

26 HYVET Results Mean BP at the end of the trial Indapamide +/- perindopril - 143/78 mm Hg Placebo 158/84 mm Hg 48.0% of indapamide patients achieved goal BP vs. 19.9% of placebo patients (p<0.001) Outcomes with indapamide +/- perindopril 30% reduction in stroke (p=0.06) 64% reduction in heart failure (p<0.001) 21% reduction in all-cause mortality (p=0.02) Beckett NS et al. N Engl J Med 2008;358:

27 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?

28 the International Verapamil- Trandolapril Study (INVEST) Analysis showing that patients over age 60 in who achieved an SBP target of >150 mm Hg had more deaths and cardiovascular events than those whose systolic blood pressure was reduced to below 140 mm Hg Among the more than 8350 patients included in the analysis, patients who achieved SBPs lower than 140 mm Hg over two years of follow-up had the lowest rates of the primary outcome (first occurrence of all-cause death, CV mortality, total MI, nonfatal MI, total stroke, nonfatal stroke, heart failure, or revascularization).

29 Hypertension in the Elderly Two treat-to-target trials in this age group: Japanese Trial to Assess Optimal SBP (JATOS) 4416 patients aged (average age of 74) Randomized to SBP<140 vs. SBP Achieved BP of 136/75 vs. 146/78 No difference in CV events or renal failure (p=0.99) VALISH trial 3079 patients aged (average age of 76) Randomized to SBP<140 or SBP No significant reductions in stroke, CV events, or renal failure Overall event rates were lower than anticipated in both of these studies JATOS Study Group. Hypertens Res 2008;31: Ogihara T et al. Hypertension 2010;56:

30 Hypertension in the Elderly Dissension among the ranks! Ann Intern Med. January 14, /17 authors (29%) Insufficient evidence to increase target SBP to 150 mmhg. Expertise vs. Scientific Evidence Wright JT Jr et al. Ann Intern Med 2014;160:

31 Hypertension in the Elderly The opposing arguments: The Japanese trials had low event rates and may not represent the risks in other populations Data from other studies suggests a goal SBP closer to 140mm Hg may be more appropriate for ages Methodology may have prevented JNC-8 panel from considering the results in their analysis The Speed Limit effect Wright JT Jr et al. Ann Intern Med 2014;160:

32 JNC-8 Recommendations In patients <60 years of age, start medications at blood pressure of >140/90mm Hg and treat to goal of <140/90mm Hg In all adult patients with diabetes or chronic kidney disease, start medications at blood pressure of >140/90mm Hg and treat to goal of <140/90mm Hg James PA et al. JAMA 2014;311:

33 JNC-8 Recommendations Controversy They classified both of these recommendations as Grade A (strong). To say the least, the evidence-basis for the drug treatment recommendations for mild hypertension in this report is in dispute.

34 Hypertension in Diabetics Action to Control CV Risk in Diabetes (ACCORD) Randomized, double-blind trial Included patients with T2DM and high CV risk Randomized to SBP<120 or SBP<140 Primary outcome of CV death, MI, or stroke Results: Mean SBP of 119 mm Hg vs. 133 mm Hg No significant difference in primary outcome (HR=0.88, p=0.2) Incidence of stroke was lower with intensive treatment (HR 0.59, p=0.01) Significant increase in serious adverse events

35 JNC-8 Recommendations For the non-black population (including diabetes), initial antihypertensive treatment may include a thiazide, ACEI, ARB, or CCB For the black population (including diabetes), initial antihypertensive treatment should include a thiazide or CCB For all patients with CKD, initial (or add-on) therapy for hypertension should include an ACEI or ARB James PA et al. JAMA 2014;311:

36 Initial Drug Selection for HTN ALLHAT: Randomized, double-blind trial Enrolled 33,357 patients age 55 or older Chlorthalidone Amlodipine Lisinopril Doxazosin (this arm stopped early 2 worse outcomes) Primary outcome of CHD death or nonfatal MI No significant difference in primary outcome among the thiazide, ACEI, or CCB The ALLHAT Collaborative Research Group. JAMA 2002;288:

37 Initial Drug Selection for HTN African-American patients: High risk for CV events Less responsive to drugs that act on the renin-angiotensinaldosterone system ACEI, ARB, BB Subgroup analysis of black patients in ALLHAT Less BP reduction with lisinopril than amlodipine Risk of stroke was significantly higher with lisinopril than with amlopdipine (RR 1.51, 95% CI ) Lisinopril less effective than chlorthalidone in preventing heart failure, stroke, and combined CHD The ALLHAT Collaborative Research Group. JAMA 2002;288:

38 Initial Drug Selection for HTN What happened to the beta-blockers (BB)? Most evidence for BB is from atenolol Does not meet current FDA criteria for a once-daily drug Losartan Intervention for Endpoint reduction (LIFE) study Compared losartan vs. atenolol in pts. with HTN & LVH Primary outcome of CV death, MI, or stroke Overall 13% RRR with losartan vs. atenolol (p=0.021) Driven mainly by 25% reduction in risk of stroke (p=0.001) BB still recommended for many patients with comorbid conditions (CHF, CAD, etc.) Dahloff B et al. Lancet 2002;359:

39 Comparisons to Other Guidelines BP Goal JNC-7 JNC-8 ASH/ISH ESC/ES H CHEP Age < 60 <140/90 <140/90 <140/90 <140/90 <140/90 Age <140/90 <150/90 <140/90 <140/90 <140/90 Age 80+ <140/90 <150/90 <150/90 <150/90 <150/90 Diabetes <130/80 <140/90 <140/90 <140/85 <130/80 CKD <130/80 <140/90 <140/90 <130/90 <140/90 Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-8

40 Comparisons to Other Guidelines JNC-7 JNC-8 ASH/ISH ESC/ESH CHEP Non-black (no DM or CKD) Thiazide Thiazide, ACEI, ARB, CCB <60:ACEI,A RB >60:CCB, thiazide Thiazide, ACEI, ARB, CCB, BB Thiazide, ACEI, ARB (BB if <60) Black (no DM or CKD) Thiazide Thiazide, CCB Thiazide, CCB Thiazide, ACEI, ARB, CCB, B Thiazide, ARB (BB if <60) Diabetes ACEI, ARB, CCB, BB, thiazide CCB, thiazide ACEI, ARB, CCB, thiazide ACEI, ARB ACEI, ARB, CCB, thiazide CKD ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-8

41 2013 ESH/ESC Guidelines for the management of arterial hypertension Blood pressure goals in hypertensive patients Recommendations SBP goal for most Patients at low moderate CV risk Patients with diabetes Consider with previous stroke or TIA Consider with CHD Consider with diabetic or non-diabetic CKD SBP goal for elderly Ages <80 years Initial SBP 160 mmhg SBP goal for fit elderly Aged <80 years SBP goal for elderly >80 years with SBP 160 mmhg DBP goal for most DB goal for patients with diabetes <140 mmhg mmhg <140 mmhg mmhg <90 mmhg <85 mmhg SBP, systolic blood pressure; CV, cardiovascular; TIA, transient ischaemic attack; CHD, coronary heart disease; CKD, chronic kidney disease; DBP, diastolic blood pressure. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) - J Hypertension 2013;31: Medical Education & Information for all Media, all Disciplines, from all over the World Powered by

42 What is the goal BP?