THE EVIDENCE BASED GUIDELINES
Rigorous,evidence based approach to recommend treatment thresholds,
goals,and medications in the management of HTN in adults.
Evidence was from RCTs,the gold standard for determining efficacy
1-5 –address questions 1 and 2 concerning thresholds and
goals for BP treatment.
6,7,8 – address question 3 concerning selection of
9 – summary of strategies based on expert opinion for starting
and adding antihypertensive drugs.
In the general population aged ≥60 years,
initiate pharmacological treatment to lower BP at
SBP of ≥150 mm Hg or
DBP of ≥ 90mm Hg and
treat to a goal
SBP < 150 mm Hg and
DBP <90 mmHg.
Strong recommendation – Grade A.
Goal BP evidence statement is from…
• Syst-Eur (The Systolic Hypertension in Europe Trial)
• SHEP(Systolic Hypertension in the Elderly Program)
• JATOS (Japanese Trial to assess Optimal Systolic blood pressure in
elderly hypertensive patients)
• VALISH (VALsartan in elderly Isolated Systolic Hypertension
High risk groups
• Black persons
• Those with CVD including stroke
• Multiple risk factors
In the General Population aged ≥60 yrs,
If pharmacological treatment for high BP results in lower
achieved SBP (for example <140 mm Hg) and
treatment is not assosciated with adverse effects on health or
quality of life,
treatment does not need to be adjusted.
Expert opinion – Grade E.
• In HYVET,SHEP trial,the average treated SBP was 143
to144mmHg.Many participants achieved an SBP lower than 140
mm Hg with treatment that was generally tolerated.
• Two other trials JATOS,VALISH suggest there was no benefit
for an SBP goal lower than 140 mmHg,but the confidence
intervals around the effect sizes were wide and did not exclude the
possibility of a clinically important benefit.
In the general population < 60 yrs,
Initiate pharmacological treatment to lower BP
at DBP of ≥90 mmHg and
treat to a goal
DBP of lower than 90 mmHg.
For ages 30-59 years,Strong recommendation -Grade A.
For ages 18-29 years.Expert opinion –grade E.
• HDFP(Hypertension Detection and Follow uP)
• Hypertension – Stroke Cooperative
• VA Cooperative
• Treatment to a lower DBP goal lower than 90 mm Hg reduces
cerebrovascular events,HF,overall mortality.
• No benefit of treatment to a target DBP of 80,85 mm Hg
compared to 90 mm Hg – HOT trial(not statistically significant in
In adults< 30 yrs
• There are no good or fair quality RCTs that assessed the benefits
of treating elevated DBP on health outcomes.
• DBP threshold and goal should be the same as in 30-59 yrs.
In the General Population younger than 60years,
initiate pharmacological treatment to lower BP
at SBP of ≥140 mm Hg and
treat to a goal SBP of < 140 mm Hg.
Expert opinion – Grade E.
Reasons for 140 mm Hg SBP
1.In the absence of any RCTs that compared the current SBP standard of
140 mm Hg with another higher or lower standard in this age group,there
was no compelling reason to change current recommendations.
2.In the DBP trials (the benefit of treating DBP to <90 mm Hg),many of
the study participants who achieved target DBP were also likely to have
achieved SBP <140 mmHg with Rx,not possible to determine the
outcome benefits were due to lowering of DBP,SBPor both.
In the Population aged 18 years or older with CKD,
Initiate pharmacological treatment to lower BP at
SBP of ≥ 140 mm Hg
DBP of ≥ 90 mmHg
treat to goal
SBP of < 140 mm Hg and
DBP < 90 mm Hg.
Expert opinion – grade E.
(Younger <70 yrs with eGFR or measured GFR <60 ml/min/1.73m2
People of any age with albuminuria >30mgalb/g of creatinine)
• In adults <70 yrs with CKD,the evidence is insufficient to determine
if there is a benefit in mortality,or cardiovascular or CV health
outcomes with antihypertensive drug therapy to a lower BP goal(ex
<130/80 mm Hg)compared with a goal of <140/90 mm Hg).
• Moderate quality evidence with regard to no benefit in slowing the
progression of kidney disease from treatment with antihypertensive
drug therapy to a lower BP goal <130 /80 compared to <140/80 mm
Effect of antihypertensive drug therapy on
change in GFR or time to development of
• 3 trials
• 1 trial addressed cardiovascular disease end points.
• 2 trials AASK and MDRR used MAP and different targets by age.
• 1 trial(REIN 2) using only DBP goals.
• None of the trials showed that treatment to a lower BP goal (for
example,<130/80 mm Hg) significantly lowered Kidney or
CardioVascular Disease end points compared with a goal of
<140/90 mm Hg.
For patients with proteinuria > 3g/24,post hoc analysis from
MDRD indicated benefit from treatment to a lower BP goal
<130/80 mm Hg and this related to kidney outcomes only.
Age >70 yrs
• No recommendation for pts >70 yrs
with GFR < 60ml/min/1.73m2
• Commonly used estimating equations for GFR have not been
vaildated in older adults.
• Not significant number of patients in outcome trials analysed.
• Diagnostic criteria for CKD do not consider age related decline
in kidney function as reflected in estimated GFR.
• Antihypertensive treatment should be individualized based on
frailty,co morbidities and albuminuria.
In the Population aged 18 years or older with diabetes,
initiate pharmacological treatment to lower BP at
SBP of ≥ 140 mm Hg or
DBP of ≥90 mm Hg
and treat to a
goal SBP < 140 mm Hg
goal DBP < 90 mm Hg
Expert opinion Grade E.
• SBP of < 150 mm Hg improves cardiovascular and cerebrovascular
health outcomes and lowers mortality (SHEP,Syst –Eur,UKPDS).
No RCTs addressed whether Rx to <140mmHg is beneficial
compared to <150 mmHg.
• SBP <140 mm Hg is supported by ACCORD BP trial,in which the
control group used this goal and had similar outcomes compared with
a lower goal.
• ADVANCE trial tested the effects of Rx to lower BP on major
macrovascular and microvascular events in adults with diabetes who
were at increased risk of CVD,but the study didn’t meet the
inclusion criteria because participants were eligible irrespective of
baseline BP and there were no randomized BP treatment thresholds or
SBP goal of <130 mm Hg
• Not supported by any RCT.
• Only trial was ACCORD BP trial which compared an SBP treatment
goal of <120 mm Hg with a goal <140 mm Hg. – no difference in the
primary outcome,a composite of CV death,non fatal MI,and non
• No differences in any of the secondary outcomes except for a
reduction in stroke.
• Incidence of stroke in the group treated to <140 mm Hg was much
lower than expected,the difference being 0.21% per year.
• No sufficient evidence could be provided by the trial.
• In the HOT trial,which is frequently cited to support a lower
DBP goal,investigators compared a DBP goal of 90 mmHg or
lower vs a goal of 80 mm Hg or lower.
• The lower goal was associated with a reduction in a
composite CVD outcome,but this was a post hoc analysis of a
small group(8%) of the study population that was not
prespecified,as a result the evidence was graded as low quality.
• UKPDS,had a BP goal of <150/85 mm Hg in the more
intensively treated group compared with a goal of lower than
180/105 mmHg in the less intensively treated group.
• UKPDS did show that treatment in the lower goal BP group
was associated with a signficantly lower rate of
stroke,HF,diabetes related end points,and deaths related to
diabetes.(80 mm Hg vs 105 mmHg)(mixed SBP and DBP
In the General NonBlack population,including those with Diabetes,
initial AntiHypertensive treatment should include a
Thiazide -type Diuretic,
Calcium Channel Blocker(CCB),
Angiotensin Converting Enzyme inhibitor(ACEI),or
Angiotensin Receptor Blocker(ARB).
Moderate recommendation –GradeB.
• Only RCTs that compared one class of antihypertensive
medication to another and assessed the effects on health outcomes
• Placebo controlled trials were not included.
• Treatment of HTN with antihypertensive medications reduces CV
mortality or CV events.(VA cooperative trial,HDFP,SHEP) all
trials used thiazide type diuretics compared with placebo.
• Additional evidence that BP lowering reduces risk comes from
trials of B blocker vs placebo and CCB vs placebo.
• Initial treatment with a thiazide type diuretic was more effective
than a CCB or ACEI.
• ACEI was more effective than a ARB in improving HF outcomes.
• B blockers are not recommended as initial treatment of HTN
because in one study use of B blockers resulted in a higher rate of
primary composite outcome of CV death,MI,or Stroke compared
to use of an ARB,a finding that was largely driven by an increase
in stroke.(LIFE study : Losartan vs Atenolol).
• Alpha blockers were not recommended as first line
Not recommended as first line drugs
• Dual alpha1 +b blocking agents (Carvedilol)
• Vasodilating b blocking agents (Nebivolol)
• Central a2 adrenergic agonists (Clonidine)
• Direct vasodilators (Hhydralazine)
• Alodsterone receptor antagonists (Spironolactone)
• Peripherally acting adrenergic antagonists (Reserpine)
• Loop diuretics(Furosemide)
ONTARGET trial was not eligible because Hypertension was not
required for inclusion in the study.(Telmisartan,Ramipril).
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 –GradeB.
For black patients with diabetes:Weak recommendation –GradeC.
• A thiazide type diuretic was shown to be more effective in
improving CerebroVascular,HF,combined CardioVascular outcomes
compared to an ACEI in the black subpatient group(diabetic and
non diabetics)ALLHAT trial.
• CCB not effective over thiazide diuretic in preventing HF in black
• CCB preferred over ACEI in blacks – 51% higher rate (relative
risk,1.51:95%CI,1.22-1.86) of stroke in pts with the use of ACEI
• ACEI less effective than CCB in reducing BP in blacks.
• No studies comparing diuretics,CCBs vs BB,ARBs,Renin
angiotensin inhibitors in black population.
In the population aged 18 years or older
with CKD and hypertension,
initial (or add-on) antihypertensive treatment should include
ACEI or ARB to improve kidney outcomes.
This applies to all CKD patients with hypertension regardless
of race or diabetes status.
Moderate Recommendation – GradeB.
• Recommendation applies to CKD pts with or without proteinuria.
• Less evidence favouring ACEI/ARB for cardiovascular outcomes in
patients with CKD.
• Neither ACEI/ARBs improved CV outcomes for CKDpts compared
with a BB or CCB.
• ARB improved HF outcomes compared with a CCB(IDNT) trial –
population was restricted to pts with diabetic nephropathy with
• No RCTs in the evidence review that compared directly ACEI./ARB
for any CV outcome.
• AASK study showed the benefit of an ACEI on kidney outcomes
in black patients with CKD and provides additional evidence that
supports ACEI use in that population.
• Trials not restricted to patients with Hypertension,showing
benefits of ACEI/ARBs are not included.
• Direct renin inhibitors are not included – no studies demonstrated
their benefits on kidney or CV outcomes.
What if patient is a black and having
• 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. AASK trial.
• 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.
• ACEI /ARB can be used as an initial drug or second line drug.
Patients older than 75 yrs
• No evidence to support renin angiotensin system inhibitor
treatment in those older than 75 yrs.
• Use of thiazide type diuretic or CCB is also an option for
individuals with CKD in this age group.
If goal BP is not reached within a month of treatment,
Increase the dose of the initial drug or
add a second drug from one of the classes in recommendation6
(thiazide- type diuretic,CCB,ACEI,ARB).
If goal BP cannot be reached with 2 drugs,
add and titrate a third drug from the list provided.
Donot use an ACEI and ARB together in the same patient.
If goal BP cannot be reached using the drugs in recommendations,
because of a contraindication or the need of > 3 drugs to reach goal
BP,antihypertensive drugs from other classes can be used.
Referral to a hypertension specialist.
Expert opinion –GradeE.
Peculiarities of recommendation 9
• In response to a perceived need for further guidance to assist
in implementation of recommendation 1-8.
• Based on strategies used in RCTs that demonstrated improved
patient outcomes,expertise and clinical experience of panel
• Not developed in response to 3 critical questions.
• No evidence about which strategy improved outcomes.
• The recommendations based on RCT evidence in this
guideline differ from recommendations in other currently
used guidelines supported by expert consensus.
• JNC7 and other guidelines recommend treatment to lower BP
goals in patients with diabetes and CKD based on
• ADA have raised the SBP goals to values that are similar to
those recommended in this evidence based guideline.
Patients want to be assured that
BP treatment will reduce their
Clinicians want guidance on
using the best scientific
Clinical guidelines are at
the intersection between
research evidence and
clinical actions that can
improve patient outcomes.
Expertise in HTN
Primary care (n=6),
Clinical trials n =6,
Senior scientist from
Senior medical officer
Review in January 2013 NHLBI
20 reviewers 16 federal agencies
Reviewed and discussed by panel
MARCH TO JUNE 2013
Questions guiding the Evidence review
3 highest ranked questions related to high BP management
identified through a modified DELPHI technique.
Nine recommendations were made.
1.Thresholds for pharmacological management
2.Goals for pharmacological management.
3.Whether particular antihypertensive drugs or drug classes
improve important health outcomes compared with other drug
The Evidence Review
• Adults aged 18yrs or older with HTN
• Prespecified sub groups –
adults,men and women,racial and ethnic groups,smokers.
• Sample sizes smaller than 100 were excluded.
• Follow up < 1 yr were excluded.(unlikely to yield enough
information regarding health related outcomes to permit
• Important health outcomes information
• Overall mortality ,CVD mortality,CKD related mortality.
• MI,HF,hospitalization for HF,stroke.
• Coronary revascularization (CABG,coronary angioplasty,stent
placement),doubling of creatinine level,halving of GFR.
1.Study was a major study in hypertension (ACCORD-BP,SPS3)
2.Study had atleast 2000 participants.(low event rates in ACCORD)
3.Study was multicentered.
4.Study met all other inclusion/exclusion criteria.
• No additional clinical trials met the previously described
• Studies were included if rated as good or fair.
Why only RCTs ?????
Less subject to bias
Gold standard for determining efficacy and effectiveness.
Original publications of eligible RCTs.
January 1,1966 through December 31,2009.
PubMed and CINAHL between December 2009 and August 2013.
HISTORY OF JNC8
• Originally constituted as the “EIGHTH JOINT NATIONAL COMMITTEE
ON THE PREVENTION,DETECTION,EVALUATION,AND TREATMENT
OF HIGH BLOOD PRESSURE(JNC 8)”.
• In June 2013,NHLBI announced its decision to discontinue developing
clinical guidelines including those in process,instead partnering with selected
organizations that would develop the guidelines.
Not an NHLBI sanctioned report and does not reflect the views of NHLBI.
Not a comprehensive guideline
Limited in scope ( focused evidence review to address the 3
Numerous comorbidities with HTN not addressed.
Adherence and medication costs.
Observational studies,systematic reviews,or meta –analysis.
RCTs with participants with normal BP were excluded.
Recommendations donot apply to those without HTN.
Treatment related adverse effects on health outcomes.
• Not redefined high BP .
• Relationship between natural occuring BP and risk is linear
down to very low BP,but the benefit of treating to these lower
levels with antihypertensive drugs is not established.
• For all patients with HTN ,the benefits of a healthy diet,wt
control,regular exercise cannot be overemphasized. – reduce
• Recommendations by 2013 Lifestyle Work Group.
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