Whats New In

Hypertension

JNC VIII & Chlorthalidone

JNC VIII

An executive summary of the evidence

and designed to provide clear
recommendations
For
All Clinicians

More than

Panel List

400 nominees from various

expertise in

Cardiology,
Hypertension,
Endocrinology,
Pharmacology,
Nephrology ,
Clinical Trials etc.

Goal BP

Underlined Points different from JNC -7

Drug Prescribed
Population

Drug Prescribed

Non Black

Thiazide-type diuretic,
Calcium channel blocker (CCB),
Angiotensin-converting enzyme
inhibitor(ACEI), or
Angiotensin receptor blocker (ARB)

Black

Thiazide-type diuretic,
Calcium channel blocker (CCB)

Drug Prescribed
Population

Drug Prescribed

With
Diabetes
Mellitus

Thiazide-type diuretic,
Calcium channel blocker (CCB),
Angiotensin-converting enzyme
inhibitor(ACEI), or
Angiotensin receptor blocker (ARB)

With CKD

ACEI or ARB to improve kidney

outcomes.

2014 Hypertension Guideline

Management Algorithm

Adults aged 18

General Population

Diabetes or CKD Patients

Strategies to Dose
Antihypertensive Drugs

Strategies to Dose
Antihypertensive Drugs

A Start one drug, titrate to

maximum dose, and then add a
second drug
B Start one drug and then add

Strategies to Dose
Antihypertensive Drugs

Begin with 2 drugs at the same

time,
either as 2 separate pills or as
aBlood
single Pressure 160/100
pill combination

Role of Chlorthalidone

Thiazide vs Thiazide-like diuretics

Thiazide-like diuretics
Lacking thebenzothiadiazinering
Physiological action is similar but
clinical benefits are more

Evolution of Chlorthalidone
Use of doses of 200 to 600 mg daily.
Dose of 75, 50 or 25 mg daily - BP
reduction
12.5 mg and 25 mg daily, offer the
best efficacy-toside effect ratio
Landmark Trial: MRFIT,
SHEP
Landmark Trial: ALLHAT
Feasibility of 6.25 mg
dose

Dual Mode of action

Reduction in
plasma volume

Reduction in peripheral
vascular resistance (PVR)

Long term action

PVR reduction : theories

Interference with intracellular Ca2+ release

by nor- adrenaline

Inhibition of Rhokinase activity

Reduction in arterial edema

Reduction in vascular reactivity

Rao SS et al, Ind. J. Pharmac., 13(4) 349-351, Zhu Z et al, Hypertension. 2005 Feb;45(2):233-9, Braunwald - Heart Disease A
textbook of cardiovascular medicine, 5th Ed., 1997, Musso MN, Braz J Med Biol Res. 1990;23(10):999-1003

Long half life of chlorthalidone

o

Chlorthalidone has the longest elimination half-life

of 60 hrs.

The diuretic effect sets in after 2 to 3 hours,

reaches its maximum after 4 to 24 hours

Duration of action is 48-72 hr.

CTD- International
experience

The Systolic Hypertension in

the Elderly Program (SHEP)
Cohort
Age
Eligibility

4,736; 43% men

60 yrs old; mean 71.6 yrs old
Systolic BP 160219 mmHg and Diastolic BP <90 mmHg

Design

Double blind; placebo control

Therapy

Chlorthalidone (atenolol as step 2)

Duration

4.5 years

BP change

Systolic BP 12 mmHg

SHEP Research Group. JAMA. 1991;265:3255

SHEP
Change in Blood Pressure
Diastolic BP

Change in BP
(mmHg)

Systolic BP

Placebo
(n=2,371)

Placebo
(n=2,371)

Active Rx
(n=2,365)

Active Rx (n=2,365)

2 3 4
Years

2 3 4
Years

SHEP: Results
CHLORTHALIDONE VS. PLACEBO
Stroke

RR (95%
CI) (0.500.82)
0.64

CHD

0.73 (0.600.94)

CHF

0.46 (0.330.65)

CVD

0.68 (0.580.79)

Death

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

Favors chlorthalidone

0.87 (0.731.05)
Favors placebo

SHEP Cooperative Research Group. JAMA. 1991;265:32553264.

SHEP: Fatal and Non-fatal Stroke

p=0.0003

Cumulative Stroke
Rate
Per 100 Persons

10
9
8
7
6
5
4
3
2
1
0

Placebo
(n=2,371)

Active Rx
(n=2,365)
0

12

24

36

48

Months of Followup
SHEP Cooperative Research Group. JAMA. 1991;265:32553264.

60

72

SHEP-X
Long Term Effect of Diuretic Based Therapy in
Subjects with Isolated Systolic Hypertension With
and Without Diabetes
Fourteen-Year Follow-up of the Systolic Hypertension in the Elderly
Program (SHEP)

Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR.
SHEP Investigators

Total Mortality (%)

14.3 yrs Follow up

p< 0.05 vs no diabetes

Kostis JB, Wilson AC, Freudenberger RS, et al. Am J Cardiol

Long follow up
Chlorthalidone based therapy reduced the incidence
of stroke significantly.

22 year follow up of SHEP (published 2011) increased

life expectancy with chlorthalidone based therapy

Alpesh B. Patel Stroke. 2008;39:1084

SHEP Long term follow up

Determine whether the effect of BP
lowering during SHEP is associated
with long-term (22 years) outcomes (CV
and all-cause mortality) and extended
life expectancy

Kostis JB, et al. JAMA. 2011;306:2588-259

Association Between Chlorthalidone Treatment

of Systolic Hypertension and Long-term (22
Years) Survival in SHEP 516 Days*
CV Death
Active Treatment
Control

* Survival during follow-up was longer with the

active treatment group (6501 days) than with the
control group (5985 days); p = .01

P=Systolic Hypertension in the Elderly Program; CV=cardiovascular

Kostis JB, et al. JAMA. 2011;306:2588-

Association Between Chlorthalidone Treatment of

Systolic Hypertension and Long-term (22 Years)
Survival in SHEP
Days*
All-Cause205Mortality

Active Treatment
Control
* Survival during follow-up was

longer with the active treatment

group (4212 days) than with the
control group (4007 days); p = .03

P=Systolic Hypertension in the Elderly Program; CV=cardiovascular

Kostis JB, et al. JAMA. 2011;306:2588-

1 day gain in life

22 year follow-up of SHEP trial
Higher survival and a gain in life
expectancy

Anti hypertensive and Lipid

Lowering treatment to
prevent Heart Attack Trial.
(ALLHAT)

ALLHAT
42418 patients

15255

9061
Chlorthalidone
Doxazosin

9048
Amlodipine

Follow-up visits were at 1

month,3, 6, 9, and 12 months;
and every 4 months thereafter.
The study lasted for 8 years

9054
Lisinopril

Discontinued

Barry Davis et al, ALLHAT 1994-2002 University of Texas Health Science Center

Systolic BP
(mmHg)

Chlorthalidone
Amlodipine
Lisinopril

Diastolic BP
(mmHg)

ALLHAT
Mean Systolic and Diastolic BP

6
0 1
Follow-up, yrs

SBP=systolic blood pressure

Chlorthalidone
Amlodipine
Lisinopril

DBP=diastolic blood pressure

% Patients with
BP <140/90 mmHg

BP Control: <140/90 mmHg

Chlorthalidone

Amlodipine

Lisinopril

Protects the heart

The risk of combined CVD events, which included

death from CHD,
nonfatal MI,
revascularization procedures,
angina,
congestive heart failure (CHF),
and peripheral arterial disease,
was significantly reduced for patients assigned to
chlorthalidone.

Barry Davis, ALLHAT 1994-2002 University of Texas Health Science Center

Heart Failure
Cumulative event
rate (%)

Chlorthalidone
Amlodipine
Lisinopril

Time to event,
yrs

ALLHAT Combined CV Disease

RR
RR
Favors
Favors
Favors
(95% CI) amlodipine chlorthalidone (95% CI) lisinopril

TOTAL

1.04
(0.99-1.09)

Favors
chlorthalidone

1.10
(1.05-1.16)

Age <65

1.03
(0.94-1.12)

1.05
(0.97-1.15)

Age 65

1.05
(0.99-1.12)

1.13
(1.06-1.20)

Men

1.04
(0.98-1.11)

1.08
(1.02-1.15)

Women

1.04
(0.96-1.13)

1.12
(1.03-1.21)

Diabetic

1.06
(0.98-1.15)

1.08
(1.00-1.17)

Nondiabetic

1.02
(0.96-1.09)

1.12
(1.05-1.19)

0.5

0.5

ALLHAT Conclusions
There was no difference in the primary outcome
between amlodipine, chlorthalidone and lisinopril
Similar reduction of risk for CHD death and
nonfatal MI
Chlorthalidone was associated with lower risk for
Stroke, combined CVD, and HF compared with lisinopril
HF compared with amlodipine

ALLHAT Research Group. JAMA. 2002;288:2981-299

Multiple Risk Factor Intervention Trial

(MRFIT)
Objective
To test the effect of a special interventions
(chlorthalidone or hydrochlorothiazide)
versus usual care in 12,866 high-risk men
aged 35 to 57 years
Main Outcome Measures
Primary: Coronary heart disease mortality
Adapted from:
Multiple Risk Factor Intervention Trial Research Group. JAMA.
1982;248:1465-77.

Mortality Reduction
MRFIT
9 centres HCTZ and 6 centres chlorthalidone
HCTZ group had a 44% higher mortality.
Patients were shifted to chlorthalidone
Later with chlorthalidone the trend was reversed and
the same group had a 28% lower risk.
Circulation. 1990 Nov;82(5):1616-28

MRFIT: Impact on Outcomes After

Switching From HCTZ to Chlorthalidone
Difference Between SI Versus UC

MRFIT = Multiple Risk Factor

Intervention Trial; SI=special

Multiple Risk Factor Intervention Trial

Research Group. Circulation.

Multiple Risk Factor Intervention Trial

Changes From Baseline at 48 Months

p for Interaction < .001

p for Interaction = .002

p for Interaction = .001

Adapted from
Ernst ME, et al. Hypertension. 2011;58:1001-1007.

Multiple Risk Factor Intervention Trial

Comparison of Diuretic Therapies

Chlorthalido
ne
HCTZ
Drug
Stopped
Adjusted estimates were controlled
for by age, race, smoking status,
MRFIT randomized group, diuretic
dose, SBP, LDL, HDL, and baseline

Chlorthalidone vs Drug Stopped; p

< .0001
HCTZ vs Drug Stopped; p < .0001
Chlorthalidone vs HCTZ; p = .0016

Adapted from:
Dorsch MP, et al. Hypertension. 2011; 57

Chlorthalidone Safety
Electrolyte
imbalance
Hypokalemia
Lipid profile
Hyperglycemia

Indian Experience with low dose

chlorthalidone (CTD)
Nature of study

Duration

No. of patients in
trial

6.25 mg Chlorthalidone
6.25 mg Chlorthalidone + atenolol

24 weeks

300

6.25 mg Chlorthalidone +
Metoprolol XL

12 weeks

130

6.25 mg Chlorthalidone + Losartan

12 weeks

131

SBP reduction with monotherapies

p value>0.05

49

DBP reduction with monotherapies

p value >0.05

Electrolyte change
Study Groups
Chlorthalidone

Visit

Sodium

Potassium

Chloride

Baseline

138.37

4.21

102.50

End

138.29

3.97

98.75

Pareek et al, Current Medical Research and Opinions, vol 24, no. 6, 2008

ALLHAT report on hypokalemia

Hypokalemia was not severe and returned towards baseline after 4 years of
treatment.
This was not associated with any increase in Cardiac events

Effect on lipid profile

Trials lasting less than a year have shown some

change in lipid levels, Long term studies have failed
to show adverse effect on lipid concentrations.
Smaller doses now in use do not alter lipid profile.

Effect on blood sugar in Indian

trial
Study Groups
Chlorthalidone

Visit

FBS

PPS

Baseline

101.49

137.13

End

105.78

135.24

Pareek et al, Current Medical Research and Opinions, vol 24, no. 6, 2008

Hyperglycemia with
chlorthalidone
ALLHAT
There was no effect of change in FG level on CVD
and renal outcomes.

SHEP
New cases of diabetes 8.6% vs 7.5% in placebo
No significant increase in CVD mortality compared

Gurwitz et al Ann Int Med 118: 273, 1992, Paul K whelton et al ALLHAT group

CTD vs HCTZ

Which way?

Potency
Chlorthalidone is 1.5 to 2.0 times as potent as
hydrochlorothiazide.

HCTZ

12.5mg

50mg

Chlorthalidone 25mg
6.25 mg

25mg

12.5mg
Carter BL et al Hypertension . 2004; 4-9

Superior to HCTZ
A randomized, single blinded clinical trial showed
that, after 8 weeks patients who were taking 25
mg/day chlorthalidone experienced a greater
reduction in blood pressure than those taking 50
mg/day of hydrochlorothiazide.
24-hour mean BP
Chlorthalidone 25 mg/day
HCTZ 50 mg/day

-12.4

mm of Hg

- 7.4 mm of Hg

Barry LC, Hypertension 2006; 47; 352-358

Better night time control of BP

Night-time mean SBP
(mm of Hg)
Chlorthalidone 25 mg/day

-13.5

Hydrochlorothiazide 50 mg/day

-6.4

The higher potency of chlorthalidone resulted in longer

duration of action that provided night time blood pressure
control and hence was effective in providing additional
protection from stroke and myocardial infarction during
Barry LC, Hypertension 2006; 47; 352-358.

Pleiotropic benefits of
Chlorthalidone
Promotes angiogenesis
Better blood supply
Less load on heart

Reduces platelet aggregation

Less potential of clot formation
Better blood flow
Reduces vascular permeability
Better blood supply
Less load on heart

Better circulatory performance

Less load on heart
Ryan Woodman et al; Hypertension 2010

Chlorthalidone .. Class
Apart
Millions of hypertensive patients have been given
a less effective drug (HCTZ) that almost certainly
did not protect them as well as CTD would have
Norman Kaplan Hypertension October 24, 2011

Clinical expert opinion

Dr Henry Black
Clinical professor of internal medicine
at the New York University

Chlorthalidone We missed its superior benefits

compared with Thiazides
Medscape cardiology

CTD -COMBINATION
Journal of American Society of hypertension-2010
75% of patients will
require combination
therapy to achieve
BP targets.

Clinical expert opinion

Dr Messerli
Expert in hypertensive CVD and
preventive cardiology, Director of the
Hypertension Program at Columbia
University in New York.
Has served on committees for the Food
and Drug Administration (FDA)

Not all diuretics are equal Chlorthalidone

significantly reduce CV mortality

Clinical expert opinion

Dr Norman Kaplan
Clinical Professor of Internal Medicine
at the University of Texas and for the
last twenty years
Member of the third, fourth, fifth, and
sixth JNC

Chlorthalidone..Class apart diuretic

Hypertension October 24, 2011

Clinical expert opinion

Dr G Bakris
Professor of Medicine and Director,
Hypertensive Diseases at the
University of Chicago

Has served many national committees

including JNC 6, JNC 7

ARBs mix best with Chlorthalidone

American Society of Hypertension 2010

CTD- Offerings

Dual action: Blood volume reduction + PVR reduction in long term

Better goal BP achievement

Good night time BP control

Superior target organ protection

Suited for rising ISH population

ALLHAT-JNC 7 recognition

Safe in low doses