1. CURRENT MANAGEMENT OF
HYPERTENSION
DR.ANKIT JAIN
DR.G.KARTHIKEYAN

2. EPIDEMIOLOGY
 Worldwide prevalence is around 20% , and approximately
7.1 million deaths per year may be attributable to
hypertension
 The WHO reports that suboptimal BP (>115 mmHg SBP) is
responsible for 62 percent of cerebrovascular disease and
49 percent of ischemic heart disease (IHD)
 Suboptimal BP is top attributable risk factor for death
throughout the world
Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 19882000. JAMA 2003;290:199-206

3. Global Leading Risks for Death
Systolic blood
pressure > 115
mmHg
Global Burden of Disease Study 2010 , Lancet 2012; 380: 2224–60

4. Attributable Risk
54% stroke
47% IHD
25% other CVD
13.5% Total mortality
 Only half of the burden seen in people with hypertension
(BP > 140 mmHg); remainder in prehypertensives (BP > 115mmHg)
 > 80% of the burden seen in low-income and middle-income
regions
 Over half occurred in people aged 45-69 yrs
Study by Int Society of hypertension; Lancet May 2008;371:1513-8

5. Impact of a 5 mmHg Reduction
Overall Reduction
Stroke
14%
Coronary Heart Disease
9%
All Cause Mortality
7%
Hypertension 2003;289:2560-2572.

6. India- Soon Heading Towards Being
Hypertension Capital
No. of people with hypertension
in India (millions)
At least 1 out of every 5 adult Indians has hypertension
120
107.3
106.2
100
80
60.4
57.8
60
Hypertension is responsible for 57% of all stroke deaths
40
and 24% of all CHD deaths in India
20
0
2000
2025
Men
Women
Age > 20 yrs
J Assoc Physicians India 2007;55:323-4
Lancet 2005;365:217-23; JHH 2004;18:73-8

7. The Natural History of Untreated
Hypertension
 Untreated hypertension is a self-accelerating condition Evolving
arteriolar hypertrophy, and endothelial dysfunction facilitate the
later increase of BP transition to higher stage
 A summary of nearly all placebo- controlled early outcomes
trials in hypertension indicated that
 1493 of 13,342 (11.2%) subjects in the placebo groups
progressed in stages of hypertension,
 Compared with only 95 of 13,389 ( 0.7%) in the drug-treated
groups
Hansen TW, Staessen JA, Zhang H, et al. Cardiovascular outcome in relation to progression to hypertension in the
Copenhagen MONICA cohort. Am J Hypertens. 2007;20: 483-491

8. MAP/PP
 The BP can be divided into the steady [mean arterial
pressure (MAP)] and the pulsatile [pulse pressure (PP)]
components
 The MAP is determined by cardiac output (CO) and
vascular resistance and remain same throughout vascular
tree
 PP component is influenced by left ventricular ejection,
large artery stiffness, pulse wave reflection, and heart rate
and is an independent risk factor

10. Distribution of Hypertension Subtype in the
untreated Hypertensive Population in NHANES III b
Age
ISH (SBP 140 mm Hg and DBP <90 mm Hg)
SDH (SBP 140 mm Hg and DBP 90 mm Hg)
IDH (SBP <140 mm Hg and DBP 90 mm Hg)
17%
16%
<40
100
40-49
16%
20%
20%
11%
50-59 60-69
Age (y)
70-79
80+
80
Frequency of
hypertension 60
subtypes in all
untreated
40
hypertensives
(%)
20
0
Numbers at top of bars represent the overall percentage distribution of untreated hypertension by
age.
Franklin et al. Hypertension 2001;37: 869-874.

11. Blood Pressure Classification JNC 7
BP Classification
Normal
SBP mmHg*
<120
DBP mmHg
Lifestyle
Modification
Drug
Therapy**
and <80 Encourage
No
Prehypertension
120-139 or 80-89
Yes
No
Stage 1
Hypertension
140-159 or 90-99
Yes
Single
Agent
Yes
Combo
Stage 2
Hypertension
≥ 160
or ≥ 100
*Treatment determined by highest BP category; **Consider treatment for compelling
indications regardless of BP
JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

12. Prehypertension
 SBP 120–139 or DBP 80–89
 CV risk increases progressively from levels as low as 115
mmHg SBP
 54% of stroke and 46% of ischemic heart disease events
occurring in persons with blood pressures in this range
Lawes CM, Vander Hoorn S, Rodgers A; International Society of Hypertension. Global burden of blood pressure- related
disease, 2001. Lancet. 2008

13. Progress to HTN
 Among patients > 35 yr or more than 17% of those with normal
BP and 37% of those with BP in the prehypertensive range
progress to overt hypertension within 4 years without changes in
lifestyle or pharmacological intervention

Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in nonhypertensive participants in the Framingham Heart Study: a cohort study. Lancet. 2001; 358(9294):1682-1686

14. TROPHY
 Trial of treatment with candesartan 16 mg once daily pre
hypertensive subjects
 During the 2 years, hypertension developed in 154 /381 (40%)
participants in the placebo group and
 53/391(13.5%) of those in the candesartan group
 Relative risk reduction 66.3% P<0.001
 The PHARAO study with ramipril have similar findings

Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensinreceptor blocker.
N Engl J Med 2006

15. Proposed
New Definition of Hypertension
 Current guidelines define HTN according to measured BP
 Blood pressure serves as a biomarker for the disease
hypertension.
 Some patients may have elevated BP in the absence of
hypertension.
 Patients with the same levels of BP might be in different
hypertension stages
 So BP should be evaluated in the context of other
cardiovascular risk factors and disease markers
Expanding the Definition and Classification of Hypertension THE JOURNAL OF CLINICAL HYPERTENSION(WG-ASH)
VOL. 7 NO. 9 SEPTEMBER 2005

16. Writing Group of the American Society of
Hypertension (WG-ASH)

17. EVIDENCE OF TARGET ORGAN
DAMAGE
AND CARDIOVASCULAR DISEASE
 Cardiac 
LVH (moderate to severe)
Systolic or diastolic dysfunction
Ischemic heart disease
 Vasculature Peripheral arterial disease
Carotid arterial disease
Aortic aneurysm
 Renal
 Albuminuria (urinary albumin >300
mg/day)
CKD (estimated GFR <60 mL/min)
or
 Cerebrovascular  Stroke /Transient ischemic
attack

18. Writing Group of the American Society of
Hypertension (WG-ASH)

19. JNC 7 VS WG- ASH
 Many individuals designated as having pre-hypertension by
JNC 7 will be classified as normal in this system
 Because occasional BP elevation without presence of
cardiovascular risk factors/ disease markers is not
hypertension

20. PRE HYPERTENSION ??
PRE
HYPERTENSION
(JNC 7) WITH
EARLY SIGNS OF
VASCULAR
DAMAGE
PRE
HYPERTENSION(J
NC7) WITHOUT
SIGNS OF
VASCULAR
DAMAGE
• STAGE 1
HYPERTENSION
•
NORMOTENSIVES

21. Stratification of total CV risk in HTN
patients ESC 2013

22. Patient Evaluation
1. Two consecutive blood pressure measurements
2. Assess lifestyle and identify other CV risk factors or
concomitant disorders that affects prognosis and guides
treatment
3. Reveal identifiable causes of high BP
4. Assess the presence or absence of target organ damage and
CVD
http://hin.nhlbi.nih.gov/nhbpep_slds/menu.htm; Accessed October 20, 2003; 8:15AM

23. ABPM
 To collect information on BP during usual daytime
activities and during sleep
 Help in timing of drug therapy
 Help in correct prognosis of patients
 Latest NICE guidelines of hypertension management
recommend ABPM in every patient with clinic blood
pressure is >140/90

24. Indications
Pre hypertension
ii.
Variable clinic blood pressure
iii. White coat hypertension
iv. Masked hypertension
v.
Resistant hypertension
vi. Hypertension in elderly patients
vii. Postural hypotension
viii. BP evaluation in patients with the
suspected or confirmed autonomic
dysfunction
ix. As an overall guide to hypertension
treatment
x.
As a prognostic cardiovascular tool
i.

25. How valid are office BP
measurements?

26. ABPM – Diagnostic Thresholds
Category
24hr
systolic/diastoli
c
(mm Hg)
Daytime
(mm Hg)
Nighttime
(mm Hg)
Optimal
115/75
120/80
100/65
Normal
125/75
130/85
110/70
HTN
130/80
140/85
120/70

27. SEARCH FOR CAUSE
 Sleep apnea
 Drug-induced or related causes
 Chronic kidney disease
 Primary aldosteronism
 Renovascular disease
 Chronic steroid therapy and Cushing’s syndrome
 Pheochromocytoma
 Coarctation of the aorta
 Thyroid or parathyroid disease

28. Most Common Causes of
Secondary Hypertension by Age*
Am Fam Physician 2010 Dec 15;82(12):1471-8.

29. Search Target Organ Damage
 Predict
CV mortality independently
Framingham risk score stratification
of
SCORE
 Change drug treatment
 Prevention of TOD reflect adequate management
/

30. TOD
 Heart
•
•
•
•
Left ventricular hypertrophy
Angina or prior myocardial infarction
Prior coronary revascularization
Heart failure
 Brain
• Stroke or transient ischemic attack, cognitive disturbances
 Chronic kidney disease
 Peripheral arterial disease
 Retinopathy
 PWV

31. IMPORTANCE
 Adequate control of BP and other risk factors can
facilitate the regression of TOD.
 Preliminary data indicate that regression of
albuminuria and of left ventricular hypertrophy are
followed by a decrease in the number of
cardiovascular events.
 Increase in the urinary excretion of albumin
predicts cardiovascular events or death.

Wachtell, K. et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive
therapy and reduction in sudden cardiac death. Circulation

32. Urine Albumin Predicts CV and Non-CV
Mortality in the General Population
(Hillege et al Circ 2002; 106: 1777)
6
Cardiovascular
5
Hazard
Ratio for
Death
4
Noncardiovascular
3
2
1
0
10
100
Urinary Albumin (mg/L)
1000

33. Microalbuminuria and CHD risk in
Hypertension (Borch-Johnsen et al AJH 1999;19:92)
Relative
risk of CHD
6
4
Hi
2
Nl
0
Low
<140
140-160
Systolic Pressure
>160
High
Urine
albumin

35. Benefits of Therapy
 Reductions in
(1) stroke incidence- 35–40 %
(2) Myocardial infarction (MI)- 20–25 %
(3) HF averaging >40 %
Blood Pressure Lowering Treatment Trialists' Collaboration. Lancet 2000

36. Benefits of Therapy
.Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 45:907, 2005

37. What are the goals of therapy?
 <140/90 for patients without diabetes or renal disease
 Most patients who achieve their systolic goal will also
achieve their diastolic goal
 <130/80 for patients with diabetes or renal disease
JNC 7

38. HOW LOW TO GO
 Data from observational studies have indicated that death from CV
diseases increases progressively from levels as low as 115 mmHg
SBP and 75 mmHg DBP upward in patients free from CV disease
 For every 20 mmHg systolic or 10 mmHg diastolic increase in BP,
there is a doubling of mortality from both IHD and stroke
Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: A metaanalysis of individual data for one million adults in 61 prospective studies. Prospective Studies Collaboration. Lancet 2002;360:190313

39. J- curve
 The “J-curve” describes the shape of the relationship
between BP and the cardiovascular risk
 Whether this J-curve exists in the range of BP at which
patients might be exposed to further BP lowering by
treatment is unknown
 Various studies showed that J-curve exists for DBP for
patients with coronary artery disease (CAD) not for
renal disease or stroke prevention

40. Does J- curve exist for DBP??
 Data showing associations between low in-trial DBP
and risk do not prove that the lowering of DBP caused
that risk
 low baseline DBP would automatically identify a
cohort of patients at high cardiovascular disease risk
 The cohort of patients with low in-trial DBP are most
likely to be older and have diabetes and more likely to
have coronary heart disease and a Stiff aorta and
higher SBP and pulse pressure

Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive
patients with coronary artery disease be dangerous? Ann Intern Med 2006;144:884–93

41. Goal in Coronary Artery Disease and
“High Risk” Groups
 AHA/ACC Guidelines say: Treat to <130/80
 High risk includes any vascular disease, Framingham
risk score >10%
 Evidence Level 5 (Expert Opinion)

42. Goal in Coronary Artery Disease and
“High Risk” Groups
 Lower Achieved BP has been associated with no benefit or
worsened outcomes in post hoc analysis of trials
 INVEST DM and CAD
 ONTARGET Vascular disease or DM
 ACCORD DM with high CV risk
JAMA July 7,2010;304(1)61-68,
N Engl J Med 2008;359:2456–67
NEJM 358:1547-1559

44. ACCORD Study Design
• Randomized multi-center clinical trial
• BP question: does a therapeutic strategy targeting SBP
<120 mmHg reduce CVD events compared to a strategy
targeting SBP <140 mmHg in patients with type 2 diabetes
at high risk for CVD events?

45. ACCORD BP Trial Eligibility
• Stable Type 2 Diabetes >3 months
• HbA1c 7.5% to 11% (or <9% if on more meds)
• High CVD risk = clinical or subclinical disease or ≥2 risk
factors
• Age (limited to <80 years)
≥ 40 yrs with history of clinical CVD (secondary prevention)
≥ 55 yrs otherwise
• Urine protein <1.0 gm/24 hours or equivalent
• Serum Creatinine ≤1.5 mg/dl

46. Outcomes
Intensive
Standard
Events (%/yr) Events (%/yr)
Primary
HR (95% CI)
P
208 (1.87)
237 (2.09)
0.88 (0.73-1.06)
0.20
Total Mortality
150 (1.28)
144 (1.19)
1.07 (0.85-1.35)
0.55
Cardiovascular
Deaths
60 (0.52)
58 (0.49)
1.06 (0.74-1.52)
0.74
Nonfatal MI
126 (1.13)
146 (1.28)
0.87 (0.68-1.10)
0.25
Nonfatal Stroke
34 (0.30)
55 (0.47)
0.63 (0.41-0.96)
0.03
Total Stroke
36 (0.32)
62 (0.53)
0.59 (0.39-0.89)
0.01

47. Serious AE
Hypotension
Syncope
Bradycardia or
Arrhythmia
Hyperkalemia
Renal Failure
eGFR ever <30
mL/min/1.73m2
Any Dialysis or ESRD
Dizziness on Standing†
Intensive Standard
N (%)
N (%)
77 (3.3)
30 (1.3)
17 (0.7)
1 (0.04)
12 (0.5)
5 (0.2)
P
<0.0001
<0.0001
0.10
12 (0.5)
3 (0.1)
0.02
9 (0.4)
5 (0.2)
1 (0.04)
1 (0.04)
0.01
0.12
99 (4.2)
52 (2.2)
<0.001
59 (2.5)
217 (44)
58 (2.4)
188 (40)
0.93
0.36
† Symptom experienced over past 30 days from HRQL sample of
N=969 participants assessed at 12, 36, and 48 months post-randomization

48. Conclusions
 No conclusive evidence that the intensive BP control strategy
reduces the rate of a composite of major CVD events
 Assuming that this finding
related to stroke were real, the
number needed to treat to the lower SBP level to prevent one
stroke over 5 years was 89.

49. INVEST Study
International Verapamil-Trandolapril Study
 Diabetic Subgroup 6400, all with CAD
Achieved SBP <130, 130-139, 140+
OUTCOME
TIGHT
CONTROL
USUAL
CONTROL
UNCONTROLLED
12.7
12.6
19.8 *
%
Death, MI,
Stroke
CI 1.01-1.31
11.0
Mortality
JAMA July 7,2010;304(1)61-68
10.2
15.4

52. RESULTS
 In the high-CV-risk patients of ONTARGET, it appears that
this may have beneficial effects for stroke, renal , but not
for myocardial infarction, heart failure, or overall CV
events.
 This suggests that protection against stroke is generally
governed by the lower the BP, the better rule. This rule also
appears to apply to renal protection

53. IMPLICATION
 More aggressive BP lowering might be justified when the
risk of stroke clearly exceeds that of a cardiac event.
 In Asian countries where stroke accounts for 80% of the
overall CV events
 Aggressive BP control may also be considered in
individuals with severe hypertension because the relative
contribution of stroke to the overall incidence of CV events
may be greater

54. Hypertension in CKD
 Guidelines say: Treat to <130/80
 Relevant clinical trials: AASK 2002
 RCT 1094 African American patients with hypertensive
nephropathy assigned to MAP<93 vs 102-107
 Achieved BP 130/78 vs 141/86
 4 year result no benefit
 10 year Cohort follow up: No benefit overall
 Proteinuria subgroup 27% reduction in doubling of GFR
at 10 years

55.  Three trials with a total of 2272 participants were included
 Analysis did not show that a BP target of less than 125/75 to
130/80 mm Hg is more beneficial than a target of less than
140/90 mm Hg.
 low target may be beneficial in subgroups with proteinuria
greater than 300 to 1000 mg/d.
Ann Intern Med. 2011;154:541-548.

56. Hypertension in CKD
 Guidelines say: Treat to <130/80
 Evidence says: No renal or cardiovascular benefit in this
overall group
 Long term renal benefit in patients with proteinuria
(>300mg/dl)
 New ESC guideline: <140/90, consider <130/80 in patients
with proteinuria

57. Evidence Based Goals JNC 8??
 <140/90 for almost everybody
 Perhaps <130/80 in patients with
Proteinuric renal disease at risk for ESRD
2. Patients with recurrent stroke
 perhaps a bit higher (<150 systolic) in older patients with
isolated systolic HTN
1.

58. ESC 2013

59. ESC 2013
 In summary, the goal BP <130/80 mmHg has
been discarded for two reasons:
1. Because no concluding evidence exists that
would support it
2. Goal BP <130/80 mmHg can be accompanied
by an increased risk of cardiac events in
patients with established CAD and in whose
with diabetes.

60. Lifestyle Modification
Modification
Weight reduction
Approximate SBP Reduction
(range)
5-20 mmHg/ 10 kg weight loss
Adopt DASH eating plan
8-14 mmHg
Dietary sodium reduction
2-8 mmHg
Physical activity
4-9 mmHg
Moderation of alcohol
consumption
2-4 mmHg
JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

61. The Salt Controversy and
Hypertension
 The WHO recommends a sodium intake of less than 2 g per
day, based on projections made from small clinical trials in
primary prevention populations
 Recent studies suggest that both low and high sodium
intake are harmful and salt intake should be limited to 4 g
⁄d to 5 g⁄d

Stolarz-Skrzypek K, Kuznetsova T, Thijs L, et al; European Project on Genes in Hypertension (EPOGH)
Investigators. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in
relation to urinary sodium excretion. JAMA. 2011

62. OPTIMAL SODIUM INTAKE IN
HIGH RISK PATIENTS
 A recent publication in high CV risk patients demonstrated
the association between urinary sodium excretion and CV
events may be J-shaped, based on data from ONTARGET
and TRANSCEND studies
O’Donnell MJ, Yusuf S, Mente A, et al. Urinary sodium and potassium excretion and risk of
cardiovascular events. JAMA. 2011;306:2229–2238

63. Reasons proposed
 Increase in sympathetic nervous system
activation
 Decreased insulin sensitivity,
 Activation of the renin-angiotensin-aldosterone
system

64.  Salt reduction is associated with a small physiological
increase in plasma renin activity, aldosterone, and
noradrenaline and no significant change in lipid
concentrations
 Their results showed larger reductions in salt intake will
lead to larger falls in systolic blood pressure
 Further Reduction to 3 g/day will have a greater effect and
should become the long term target for population salt
intake

65. CONCLUSION
 Slow reduction in salt intake, as currently recommended,
has a significant effect on blood pressure both in
individuals with raised blood pressure and in those with
normal blood pressure
 Measurement error in assessing daily salt intake, Sudden
reduction in salt intake with neuro harmonal activation and
Reverse causality may be responsible for J curve

66. DRUG THERAPY

67. AHA 2013

68. Compelling Indications for
Individual Drug Classes
 Coronary artery disease/Post MI: BB, ACEI
 Systolic heart failure: ACEI or ARB, BB, ALDO ANTAG,

thiazide
Diastolic heart failure: ACEI or ARB, BB, thiazide
Diabetes: ACEI or ARB, thiazide, BB, CCB
Kidney disease: ACEI or ARB
Stroke or TIA: Thiazide, ACEI

Hypertension. published online November 15, 2013




69. Should therapy be given to a patient with
CAD and ISH with low DBP
 Concerns about the impact of further DBP lowering on
coronary perfusion
 With aging, the predominant effect of treatment is to
lower SBP, because the ratio of DBP/SBP lowering
with therapy progressively declines with age and low
baseline DBP
Wang J-G, Staessen JA, Franklin SS, Fagard R, Gueyffier F. Systolic and diastolic blood pressure lowering as
determinants of cardiovascular outcome. Hypertension 2005

70. • Meta analysis that tested antihypertensive treatment against placebo or
no treatment in 18500 patients across a spectrum of age and baseline
DBP
 Antihypertensive treatment reduced
SBP/DBP by 8.3/4.6 mm Hg in young patients (30-59)
II. By 10.7/4.2 mm Hg in old patients (60-79)
III. By 9.4/3.2 mm Hg in very old patients ( >80)
IV. Ratios of DBP to SBP lowering of 0.55, 0.39, and 0.32, respectively
I.

71. Contd..
 In spite of the differential lowering of SBP and DBP, treatment reduced
the risk of all cardiovascular events to a similar extent.
 Absolute benefit increased with age and with lower ratio of DBP to
SBP lowering.
 Suggests that antihypertensive drug treatment improves outcome
mainly through lowering of SBP irrespective of the decrease in DBP or
the achieved DBP.
 These findings remained consistent if the achieved DBP averaged < 70
mm Hg.

72. What to choose first?
 Initial antihypertensive therapy without compelling
indications
• JNC 6: Diuretic or a beta-blocker
• JNC 7: Thiazide-type diuretics
 Most outcome trials base antihypertensive therapy on
thiazides
JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

73. Comparing NICE with JNC 7 First
Medication Therapy Used.
 NICE:
 < 55 years: ACE
inhibitor or ARB
 > 55 years: Calcium
Channel Blocker
 If CCB not tolerated or
contraindicated, use
diuretic.
 JNC 7:
 Thiazide diuretic for
most
 Unless diuretic cannot
be used or if compelling
indication requires use
of another class of
antihypertensive.

74. Is it appropriate to start 2 agents?
 Additional data from other trials suggest that delays of 3
months to 2 years in starting antihypertensive therapy can
increase the risk of certain cardiovascular end points,
particularly stroke.
 Current data support more aggressive treatment to get
patients to BP goal faster. Not slow uptritation of single
agent as recommended in previous guidelines
 So in addition to adequate BP control , prompt BP control
is an additional goal

75. Benefits of antihypertensive therapy
with early onset of effect
 Various trials suggest that the risk of vascular events is significantly
influenced by the time it takes to achieve BP control
 The VALUE trial, which compared BP-lowering and clinical event
rates between patients who achieved immediate vs delayed BP control
provides the Evidence evidence of this to date
 The combination treatment is more likely to achieve early BP control
1.
2.
3.
VALUE:The Lancet, 2004; 363: 2022–2031
The study on cognition and prognosis in the elderly (SCOPE) . J Hypertension 2003
Staessen JA, et al. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic
Hypertension in Europe Trial. J Hypertens 2004; 22: 847–857

76. How to start treatment
 Starting with at least two drugs from the start of treatment is
recommended in the guidelines particularly in patients in
whom actual BP and target BP differ by >20 mmHg
 Patients with DM or CKD require even more intensive
treatment to achieve a recommended BP goal
 Contributes to the maintenance of adequate long-term BP
control, as shown in the ACCOMPLISH study

77. Step 2 Treatment
 ACE inhibitor/ARB + Calcium Channel Blocker
 For those intolerant to CCBs or at high risk of heart
failure: ACE inhibitor/ARB + Thiazide-like diuretic.
 ACCOMPLISH trial and updated cost-effectiveness
analysis both favored CCB

78. Step 3 Treatment
 ACEi/ARB + CCB + Thiazide-like diuretic
 Based on the recommendations and analyses
performed in the first two steps.
 Thiazide diuretic examples: chlorthalidone
(Hygroton), indapamide (Lozol), hydrochlorothiazide
(Hydrodiuril), metolazone (Zaroxolyn)

79. Step 4
 Addition of low-dose Spironolactone
 Considered when potassium level is <4.5 mmol/L
 Higher-dose thiazide-like diuretic treatment
 Considered when potassium level is >4.5 mmol/L
 Other options for add-on therapy: alpha blockers
or beta blockers

80. Combinations

82. ACCOMPLISH Hypothesis
 ACCOMPLISH
tested a new strategy for the treatment of
hypertension –
 Assigned 11,506 patients with hypertension
 Evidence of cardiovascular or renal disease or target organ damage
 Either
benazepril
hydrochlorothiazide
plus
amlodipine
or
benazepril
plus

83. RESULTS
 Absolute risk reduction of 2.2% with amlodipine-
benazepril combination

85. ACE INHIBITOR ARB
COMBINATION

86. ACEI/ARBs: One or the other, not both
The ONTARGET Study
 RCCT N=17,118 high risk patients with DM or vascular
disease
 Ramipril, Telmisartan or both for 56 months
 No additional benefit in combined vascular events
 Combination therapy caused higher rate of adverse events
1.
Hypotensive symptoms (4.8% vs. 1.7%, P<0.001),
2.
Syncope (0.3% vs. 0.2%, P=0.03)
3.
Renal dysfunction (13.5% vs. 10.2%, P<0.001)
NEJMVolume 358:15471559, April 10, 2008

87. Chronotherapy
 Chronotherapy means changing the time of medicine administration
 In a study - 52 patients >65 years with resistant HT and non-dipper
circadian pattern taking 4 or more anti-HT drugs in the morning were included
 All drugs were given at night for a 24-week period
 After 24 weeks, control of the ambulatory BP was achieved in 22
patients (42.3%) and circadian variability reversed to a dipper pattern
in 30 patients (57.7%)
Journal of Hypertension : June 2010 - Volume 28 - Issue - p e264

88. Chronotherapy…
 Another cross-sectional study investigated the impact of treatment
time on the BP pattern in 700 patients with resistant HT.
 Percentage of patients with controlled ambulatory BP was double in
patients taking 1 drug at bedtime compared with those taking all
medication on awakening.
 Also, prevalence of non-dipping reduced from 82% to 57% when
patients received 1 drug at bedtime
Hermida RC et al. : Hypertension. 2005;46:1053–1059.

90. HYPOTHESIS
 Prospective MAPEC study was designed to test the
hypothesis that
1. Bed time chronotherapy with ≥1 hypertension
medications exerts better BP control and
2. CVD risk reduction than conventional therapy, i.e., all
medications ingested in the morning

91. METHODS
 A total of 2156 hypertensive subjects were randomized to




ingest all their antihypertensive drugs
Upon awakening or ≥1 of them at bedtime
No differences in ambulatory BP between groups at
baseline
Sleep-time relative BP decline (an index of BP dipping)
(Awake BP mean −Asleep BP mean)/Awake BP mean
Patient was defined as dipper if the sleep-time relative SBP
decline was ≥10%, and as non-dipper otherwise

92. RESULTS
 Patients ingesting medication at bedtime showed
Significantly lower mean sleep-time BP
2. Reduced prevalence of non-dipping (34% versus 62%; p
< .001)
3. higher prevalence of controlled ambulatory BP (62%
versus 53%; p < .001).
1.

93. RESULTS

94. Relative risks (with 95% confidence
intervals) of CVD events

95. CURRENT
STATUS OF BETA
BLOCKERS

96. BETA BLOCKERS
 Beta blockers are not recommended as initial treatment of
uncomplicated hypertension
 beta-blockers had a reduced ability to protect against
stroke, though being equally effective for protection from
coronary events and mortality
 Administration of beta-blockers is beneficial in patients
with angina pectoris, heart failure and a recent myocardial
infarction

97. •Double-blind, randomized trial
•Losartan (upto 100mg od) Vs atenolol(upto 100mg od) on
cardiovascular morbidity and mortality
• 9,193 patients (55 to 80 years old)
– previously treated or untreated essential
hypertension (systolic BP 160–200 mmHg or
diastolic BP 95–115 mmHg)
– ECG LVH
•1,195 patients (13%) had diabetes at baseline
•BP CHANGE:- -30/16(LOSARTAN) Vs -29/17(ATEN.)
Dahlof B, et al. Lancet. 2002;359:995-1003.

98. LIFE: Primary Composite Endpoint
Composite of CV Death / MI / Stroke
P=0.021
15%
12.8%
11.0%
10%
5%
0%
Rate 23.8/1,000
patient yrs
Adjuste
d
Hazard
Ratio =
0.87
Rate 27.9/1,000
patient yrs
n=508
n=588
Losartan
Atenolol

99. LIFE: Individual Endpoint Results
Cardiovascular Death
P=0.206
8%
6%
Myocardial
Infarction
P=0.001
P=0.491
8%
Adjuste
d HR
0.89
Stroke
8%
Adjusted
HR 1.07
5.1%
6%
4.4%
6%
4.3%
Adjuste
d HR
0.75
6.7%
5.0%
4.1%
4%
4%
4%
2%
2%
2%
0%
0%
0%
Losartan Atenolol
Losartan Atenolol
Losartan
Atenolol

100. LIFE: New-onset diabetes
P=0.001
10%
8%
6%
4%
5.2%
Rate 13.0/1,000
patient yrs
Adjuste
d
Hazard
Ratio =
0.75
7.0%
Rate 17.4/1,000
patient yrs
2%
0%
n=241
n=319
Losartan
Atenolol

101. ASCOT-BPLA: Additional reductions in group
receiving the amlodipine-based regimen
Amlodipine-based*
(n = 9639)
Atenolol-based
(n = 9618)
Rate/1000
patient years
†
Rate/1000
patient years
Amlodipine-based
better
Secondary endpoints
Nonfatal MI (excluding silent)
+ fatal CHD
Total coronary endpoint
Total CV events and procedures
All-cause mortality
CV mortality
Fatal/nonfatal stroke
Fatal/nonfatal HF
7.4
8.5
14.6
27.4
13.9
4.9
6.2
2.5
16.8
32.8
15.5
6.5
8.1
3.0
Tertiary endpoints
Development of diabetes
Development of renal impairment
11.0
7.7
Atenolol-based
better
15.9
9.1
0.50
*Amlodipine 5–10 mg ± perindopril 4–8 mg prn
†Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn
Unadjusted risk reduction
P
<0.05
<0.01
<0.0001
<0.05
0.001
<0.001
NS
<0.0001
<0.05
0.70
1.00
1.45
2.00
Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

102. ASCOT-BPLA: Summary
• Amlodipine perindopril showed reductions in:
– Major CV events 16%
– New-onset diabetes 30%
– Stroke 23%
– Mortality 11%
• Improved BP control* with amlodipine perindopril may explain some,
but not all, of the benefit
Dahlöf B et al. Lancet. 2005;366:895-906.
Poulter NR et al. Lancet. 2005;366:907-13.

103. Journal of Hypertension 2006,
24:2131–2141

104. BETA BLOCKER VS DIURETIC

105. BETA BLOCKER VS CCB
FAVORS CCB

106. BETA BLOCKER VS ACEI/ARB

107. CONCLUSION
 Beta-blockers are inferior to CCBs and to RAS inhibitors
and RAS inhibitors for reducing several important hard end
points.
 Hence beta-blockers are generally suboptimal first-line
antihypertensive drugs

108. EXPLANATION ?
 ASCOT trial Suggested that BP in the central aorta might
be an explanation for increase stroke in beta blocker group
 In this trial atenolol based regimen was less efficacious in
reducing central aortic pressure than amlodipine based
regimen

Williams Bet al: differential impact of blood pressure lowering drugs on central aortic pressure and clinicaL outcomes
CAFÉ study . CIRCULATION 113:1213,2006

109. CAFE-Heart Rate
 The difference in central aortic pressure is largely explained
by heart rate lowering effect of beta blockers
 Slowing heart rate will increase central augmentation
index and in turn diminish central BP lowering effect of
beta blockers

Williams B, Lacy PS. Impact of heart rate on central aortic pressures and
hemodynamics: analysis from the CAFE (Conduit Artery Function Evaluation)
study: CAFE-Heart Rate. J Am Coll Cardiol 2009;54:705–713.

110. NEW BETA BLOCKERS
 These findings cannot be directly extrapolated to other β-blockers,
such as nebivolol and carvedilol
 They have vasodilating effect in the peripheral circulation and less
heart-rate–slowing effect in the heart
 They reduces central pulse pressure and aortic stiffness better than
atenolol or metoprolol
metoprolol

and affect insulin sensitivity less than
Impact of Heart Rate on Central Hemodynamics and Stroke: A Meta-Analysis of β-Blocker Trials Feng-Hua Ding1, Yan Li1, Li-Hua Li1, Ji-Guang Wang1 American Journal of
Hypertension 26(1) January 2013

111. JNC 8 WHAT IS EXPECTED
 BP goal in all patients with hypertension should be 140/80
except:
very elderly  < 150
Significant proteinuria  <130/80
 In addition to good BP control prompt BP control should be
the goal
 One drug at bed time can be considered in patients with
hypertension especially in non dippers
 ACE inhibitors and ARB combination is not useful

112. JNC 8 WHAT IS EXPECTED
 Chlorthalidone or indapamide should be highlighted as the
evidence-based thiazide-type diuretic of choice
 Reduced role for Beta-Blockers as initial therapy
 Recommendation for low dose aldosterone antagonist as
add-on therapy in resistant HTN.
 Delineation of role for ambulatory/home BP monitoring

113. THANK YOU

114. hypertension in the elderly
 PREVELENCE

115. PATHOPHYSIOLOGY
 Increased arterial stiffness (reduction of elasticity), with the
resultant increase in PWV and alteration in wave reflection,
is largely responsible for the age-related rise in the
prevalence of hypertension
Y
O

116. Evaluation
 Polypharmacy, OSA, ARAS, CKD very common
 Exclude pseudohypertension
 Postural hypotension very common because of increased
stiffness of the carotid arteries leads to blunting of the
carotid baroreflex
 Postprandial hypotension, defined as a decrease in systolic
BP of ≥20 mmHg within 2 h after a meal, is a common and
often unrecognized cause of syncope among the elderly
 Rx- Avoid diuretics/ alpha glucosidase inhibitors

117. GOAL
 Less then 80 years- 140/80 with Close watch on
adverse responses
 More then 80 years, the target systolic BP should
be <150 mmHg which reflects the findings of the
Hypertension in the Very Elderly Trial (HYVET)
 HYVET was the first prospective trial in patients
with hypertension who were >80 years of age

118.  Randomly assigned 3845 ,>80 years of age
 Had a sustained SBP of 160 mm Hg or more
 Receive either the diuretic indapamide +-prindopril
added if necessary to achieve the target blood
pressure of 150/80
 The primary end point was fatal or nonfatal stroke

119. RESULTS
HR
95% CI
All Stroke
0.70
S(0.49, 1.01)
Stroke Death
0.61
(0.38, 0.99)
All cause
mortality
0.79
(0.65, 0.95)
NCV/Unknown
death
0.81
(0.62, 1.06)
CV Death
0.77
(0.60, 1.01)
Cardiac Death
0.71
(0.42, 1.19)
Heart Failure
0.36
S(0.22, 0.58)
CV events
0.66
S(0.53, 0.82)
0.1
0.2
0.5
0
2

120. Conclusions
 Antihypertensive treatment based on indapamide (SR) 1.5mg (
perindopril) reduced
 stroke mortality and total mortality in a very elderly cohort
 Large and significant benefit in reduction of heart failure
 NNT (2 years) = 94 for stroke and 40 for mortality

121. DRUG THERAPY IN ELDERLY
 No specific drug by JNC7/ESC 2013
 NICE guidelines CCBs or (for those intolerant of CCBs)
thiazide-like diuretics preferred as initial therapy for
patients aged >55 years,
 Also recommend
that more-potent and longer-acting
thiazide-like diuretics (chlorthalidone/ indapamide ) should
be be used in preference to HCZ