Addressing Early Hypertension Control to Improve

PROFESSOR OF MEDICINE
UP College of Medicine
FELLOW AND DIPLOMATE
Philippine College of Physicians
Philippine College of Cardiology
HEAD OF CARDIOLOGY
Manila Doctors Hospital
FORMER HEAD OF CARDIOLOGY
University of the Philippine – Philippine General Hospital
National Kidney Institute and Transplant Foundation
PAST CHAIR, SPECIALTY BOARD OF CARDIOLOGY
PHILIPPINE COLLEGE OF CARDIOLOGY
MEMBER, INTERNATIONAL ATHEROSCLEROSIS SOCIETY
CONSULTANT IN CARDIOLOGY
University of the Philippines – Philippine General Hospital
Manila Doctors Hospital
Asian Hospital and Medical Center
POSITIONS HELD
Past President , Philippine Lipid and Atherosclerosis Society
Past President, Philippine Society of Hypertension
Past Chairman, Department of Medicine, Manila Doctors Hospital
Past Regent, Philippine College of Physicians
Past Chair, Council on Hypertension, Philippine Heart Association
NELSON S. ABELARDO, MD
DISCLOSURE
MEDICAL CONSULTANCY AND MEMBERSHIP IN
ADVISORY BOARD, SPEAKER /LECTURER
GX International, LRI Therapharma, Takeda
Pharmaceuticals, Otsuka Pharmaceuticals,
Menarini, MSD, AstraZeneca
RESEARCH PROJECTS FOR
GSK, BMS
Addressing Early Hypertension
Control to Improve Long Term
Outcomes
Nelson S. Abelardo, MD
University of the Philippines College of Medicine
A lecture delivered in fulfilment of the grant
Dr. Antonio de Leon Professorial Chair in Cardiology
blood-pressure trajectories in young adulthood,
characterized as a range from low and stable to
elevated and increasing, vary among individuals, and
the higher blood-pressure trajectories were associated
with a higher risk of subclinical atherosclerosis as
measured by coronary artery calcium (CAC) screening.
JAMA Feb 2014
CORONARY ARTERY RISK DEVELOPMENT
IN YOUNG ADULTS (CARDIA STUDY)
Population – 4681 black and white men and women aged 18 to 30 years
recruited from four US cities in 1985 to 1986 and followed for 25 years.
BP were taken at baseline and 2.5, 7, 10, 15, 20, and 25 years
Trajectories
low & stable BP
mod elevated BP relatively stable over time
moderately elevated & increasing over time
elevated but stable BP
elevated and increasing BP
21.8%
42.3%
12.2%
19.0%
4.8%
CAC >100
4.0%
7.9%
10.1%
17.4%
25.4%
Although individuals with higher BP were at greater risk for heart
disease, this population, the absolute BP were not actually meeting the
clinical threshold for HPN and were well below a level where medications
would be prescribed and yet they have this additional risk.
Allen NB, Siddique J, Wilkins JT, et al. Blood pressure trajectories in early adulthood
and subclinical atherosclerosis in middle age. JAMA 2014; 311:490-497.
Sarafidis PA, Bakris GL. Early patterns of blood pressure change and future coronary
atherosclerosis. JAMA 2014; 311:471-472.
Association of All-Cause Mortality and
Cardiovascular Mortality with Prehypertension

Meta analysis from PubMed EMBASE Cochrane Library
of 1,129,098 participants from 20 prospective cohort
studies for prehypertension and mortality
REL RISK

CONF INTER
STATUS
CVD
1.28
1.16 – 1.40
INC
CHD
1.12
1.02 – 1.23
INC
STROKE
1.41
1.28 - 1.56
INC
ALL-CAUSE M
1.03
0.97 – 1.10
NC
CONCLUSION: HPN is associated with CV, CHD and
stroke mortality especially driven by high range pre-HPN
but not all cause mortality
Yuli Huang et al
Am Heart J 2014 167(2):160-168
JNC 7 Blood Pressure Classification
Based on the mean ≥2 measurements at each of ≥2 visits
BP Classification
SBP mm Hg
DBP mm Hg
Normal
<120
and
<80
Prehypertension
120-139
or
80-89
Stage 1 Hypertension
140-159
or
90-99
Stage 2 Hypertension
≥160
or
≥100
When SBP and DBP fall into different categories, use the highe
Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
JNC 7 Re-Classification of SBP/DBP
JNC VI (1997)
JNC 7 (2003)
Optimal
Normal
< 120 and <80
< 120 and < 80
Normal
< 130 and < 85
Prehypertension
High-normal
120-139 or 80-89
130-139 or 85-89
Stage 1
Stage 1
140-159 or 90-99
140-159 or 90-99
Stage 2
160-179 or 100-109
Stage 2
Stage 3
> 160 or > 100
> 180 or > 110
JNC VI. Arch Intern Med. 1997;157:2413-2446.
JNC 7. JAMA, May 21, 2003-Vol 289, No.19, 2560-2572.
WHY PREHYPERTENSION?
Rx?
Genetic
Factors
Wellness
(Absence of
Disease)
Predisposition
to disease
Non-Genetic
Factors
e.g., age, sex,
activity level.
Environment,
other lifestyle
issues
Rx?
Diagnosed by
Biomarker
Testing
Diagnosed
PreDisease
Diagnosed by
Medical
Imaging
Rx!
Diagnosed by
Conventional
Techniques
Diagnosed
Disease
Examples of Conditions & Their “Predisease” States
Condition
AIDS
Cervical cancer
Colon cancer
Dementia
Diabetes
Hypertension
Hypo- or hyperthyroidism
Osteoporosis
1⁰ open-angle glaucoma
Tuberculosis
“Predisease”
HIV infection
Cervical dysplasia
Adenomatous polyp
Mild cognitive impairment
Prediabetes
Prehypertension
Subclinical thyroid dysfunction
Osteopenia
Increased IOP
Latent TB infection
Predisease: When Does It Make Sense?
•Discriminating ability
When people designated as having predisease
are much more likely to develop disease than those
not so designated.
•Effective intervention
When there is a feasible intervention targeted
to those with predisease that effectively reduces the
likelihood of developing disease
•Benefits exceed harms
When the benefits of intervening in the
predisease stage outweigh the harms in the
population?
Anthony J. Viera, Epidemiol Rev (2011) 33 (1): 122-134.
"It is a capital mistake to
theorize before one has
data. Insensibly one
begins to twist facts to
suit theories instead of
theories to suit facts.“
Sherlock Holmes
Risk of Progressing to Hypertension
Framingham Heart Study
4-year rates of hypertension (95% CI)*
Base BP Category
Optimum
Age 35-64 years
Age 65-94 years
5.3 (4.4-6.3)
16.0 (12.0-20.9)
Normal
17.6 (15.2-20.3)
25.5 (20.4-31.4)
High-normal
37.3 (33.3-41.5)
49.5 (42.6-56.4)
N=9845.
Rates are per 100 and are adjusted for sex, age, body mass index, baseline examinations, and baseline systolic
and diastolic BP
Vasan RS, et al. Lancet. 2001;358:1682-1686.
Kidney International 2010 ISN
Cardiovascular Mortality Risk Doubles
with each 20/10 mmHg Increase in
Systolic/Diastolic BP*
Cardiovascular mortality risk
8
8X
risk
6
4
4X
risk
2
0
1X risk
2X
risk
115/75
135/85
155/95
175/105
Systolic BP/Diastolic BP (mmHg)
*Individuals aged 40–69 years
Lewington et al. Lancet 2002;360:1903–13
…the projected NNTs are similar for Stage 2 preHTN and Stage 1
HTN when the two groups are matched for concomitant risk factors
[Ogden et al. 2000]. Unlike Stage 1 HTN, however, there is a dearth
of outcome data for treating Stage 2 preHTN, which accounts for
the current lifestyle only recommendation for most patients in this
group [Chobanian et al. 2003].
Cumulative CVD incidence during 12 years of follow-up by
prehypertension and diabetes status in the Strong Heart Study cohort.
Segura J , Ruilope L M Dia Care 2009;32:S284-S289
Why Prehypertension?

The risk of CVD increases as the blood pressure
increases even at prehypertension levels

The risk of progression to hypertension increases as
the level of non-hypertensive BP increases

HTN is a leading risk factor for cardiovascular
disease
Why Prehypertension?
“ intended to identify people who are at higher cardiovascular risk
based on BP and higher risk for developing sustained hypertension
within a few years
in order to encourage them to initiate or continue healthy lifestyle
practices, such as weight reduction, if appropriate, or regular
exercise, rather than to begin antihypertensive drug therapy.”
-Public health goal: Prevent hypertension and
cardiovascular disease
William C. Cushman, MD
Clinician Review 13(7):59-70, 2003.
Prehypertension Recommendations




Identify prehypertensives
Advise patients on lifestyle modifications and nondrug therapy to reduce risk of hypertension
Prehypertensive individuals are not candidates for
drug therapy on the basis of their BP alone
Prehypertensive individuals at high risk i.e., with
CAD, diabetes or CKD should be considered for
drug therapy if TLC and non-drug therapy fail to
reduce their BP to 130/80 mm Hg or less
Chobanian AV, et al. Hypertension. 2003;42:1206-1252; JNC 7. JAMA. 2003;289(19):2560-2574
JNC 7: Lifestyle Modifications to Manage HTN
Approximate SBP
Reduction
Modification
Recommendations
Weight Reduction
Maintain normal body weight
(BMI 18.5-24.9)
Adapt DASH
eating plan
Consume diets rich in fruits,
vegetables, low fat dairy and
low saturated fat
Dietary sodium
reduction
Reduce sodium to no more
than 2.4 g/day sodium or
6 g/day NaCl
2-8 mm Hg
Increase physical
activity
Engage in regular aerobic
activity such as walking
(30 min/day on most days)
4-9 mm Hg
Moderate alcohol
consumption
Limit alcohol to no more than
2 drinks/d for men and 1
drink/d for women.
2-4 mm Hg
5-20 mm Hg /
10 kg wt loss
8-14 mm Hg
Source: The Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure JNCVII. JAMA. 2003;289:2560-2572.
Overview of the Non-Drug
Armamentarium
Broadly applicable non-drug strategies well
supported by scientific evidence:
•
•
•
•
•
Weight loss in the overweight
Healthy diet (DASH diet)
Reduced sodium intake
Regular aerobic activity
Moderation in alcohol intake
Overview of the Non-Drug
Armamentarium
Other therapies with “some” scientific evidence in
their favor
• Stress reduction, behavior modification,
meditation and breathing exercises, biofeedback
• Smoking cessation
• Increased calcium intake
• Increased magnesium intake
• Increased potassium intake
Drug Therapy for Prehypertension?
Arguments in favor of the use of
antihypertensive drugs for prehypertension
Drugs


more convenient and more likely to be adhered to than
complex lifestyle-modifying regimens
already accepted for use in high-risk individuals with
prehypertension.
Patients at high risk of CV events, e.g., with DM, CKD or CAD,
clearly benefit from aggressive intervention, and
pharmacological treatment should be administered to these
patients if BP exceeds 130/80 mmHg.
Arguments against the use of
antihypertensives for prehypertension

The lack of evidence for the following:
>that they reduce target organ damage and
cardiovascular morbidity and mortality in
these patients;
>that they are cost-effective for the
treatment of patients with low absolute risk
of CV disease.

On the basis of evidence from preclinical hypertensive
models, inhibitors of the renin-angiotensin-aldosterone
system would seem most promising. This hypothesis
remains to be validated.
TROPHY
Objective
• Determine whether treatment with an ARB of
subjects with prehypertension will:
» suppress clinical hypertension during active
treatment
» delay the onset of clinical hypertension after
discontinuation of active treatment
Julius, Stevo, et. al. JAMA 2006; 354:1-13
TROPHY: Study design
Patients with untreated prehypertension
Ages 30–65 years
N = 772
Candesartan 16 mg qd
n = 391 (134/85)
Randomized
Double-blind
Years 1 & 2
Placebo
n = 381 (134/85)
Placebo
Years 3 & 4
Study end points:
Development of HTN at years 2 and 4
Julius S et al. N Engl J Med. 2006;354:1685-97.
TROPHY
Reduction in new-onset hypertension
N = 772
Candesartan vs Placebo
Placebo only
16%*
80
66%*
60
Patients
(%)
‡
63.0
53.2
40.4
40
†
13.6
20
0
Year 2
Placebo
*Relative risk reduction
†P < 0.001; ‡P = 0.007
Year 4
Candesartan 16 mg qd
Julius S et al. N Engl J Med. 2006;354:1685-97.
TROPHY
Reduction in new-onset hypertension
N = 772
100
Candesartan vs
placebo
80
Placebo only
RRR 16%
HR = 0.84 (0.75–0.95)
P = 0.007
Cumulative 60
incidence
(%)
40
RRR 66%
20
HR = 0.34 (0.25–0.44)
P < 0.001
0
0
Placebo
1
2
Study year
3
4
309
184
191
118
127
85
Candesartan 16 mg qd
Number of patients without HTN
Candesartan
Placebo
391
381
356
269
Julius S et al. N Engl J Med. 2006;354:1685-97.
TROPHY: Summary
Efficacy
• Candesartan significantly delayed new-onset HTN vs placebo:
» RRR: 66% (yr 2); 16% (yr 4)
» ARR: 26.8% (yr 2); 9.8% (yr 4)
» New-onset HTN at 2 years: 13.6% vs 40.4%
Safety
• Candesartan was safe and well tolerated
• Serious AE rates: 3.5% (candesartan) vs 5.9% (placebo)
Julius S et al. N Engl J Med. 2006;354:1685-97.
TROPHY: Summary

Aggressive BP-lowering with
candesartan can reduce the incidence of
HTN in prehypertensive patients at risk
for CV disease
Julius S et al. N Engl J Med. 2006;354:1685-97.
The PHARAOH Study: Prevention of HPN with ACE-I Ramipril in
Patients with High Normal BP: A Prospective, Randomized
Controlled Prevention Trial of the German HPN League
Schrader, L et al J Hypertens 2008 Jul26(7) 1487-96

Methods
N=1008 pts with high normal BP randomized to Ramipril (505) and
Control (503) followed for 3 years with primary end point of delay of
progression to manifest HPN

Results
Ramipril 155 pts (30.7%) Control 216 (42.9%) reached primary end-point
(RRR of 34.4% p=0.0001). Ramipril reduced incidence of manifest
office HPN in pts with baseline ABPM high normal BP. Cerebro and
cardio vascular events showed no significant statistical difference.

Interpretation:
There is now good clinical evidence to suggest that pts with high normal
BP are more likely to progress to manifest HPN than pts with optimal
BP. ABPM seems to be essential for correct diagnosis. Treatment
with ACE-I significantly reduced risk of progression to manifest HPN
What Is Challenging About
Hypertension?
39
Public Health Challenges of
Hypertension
1.
2.
3.
4.
5.
Decrease the existing prevalence of hypertension
Increase hypertension awareness & prevention
Improve hypertension control
Reduce cardiovascular risks
Improve opportunities for treatment (welltolerated & affordable, improved adherence)
SHOULD WE INVEST IN IT?
Early Intervention for
Lifetime Risk Management

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