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Hypertension
JNC VIII
More than
Panel List
Cardiology,
Hypertension,
Endocrinology,
Pharmacology,
Nephrology ,
Clinical Trials etc.
Goal BP
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
Adults aged 18
General Population
Strategies to Dose
Antihypertensive Drugs
Strategies to Dose
Antihypertensive Drugs
Strategies to Dose
Antihypertensive Drugs
Role of Chlorthalidone
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
Reduction in peripheral
vascular resistance (PVR)
CTD- International
experience
Design
Therapy
Duration
4.5 years
BP change
Systolic BP 12 mmHg
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
Favors chlorthalidone
0.87 (0.731.05)
Favors placebo
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
Long follow up
Chlorthalidone based therapy reduced the incidence
of stroke significantly.
Active Treatment
Control
* Survival during follow-up was
ALLHAT
42418 patients
15255
9061
Chlorthalidone
Doxazosin
9048
Amlodipine
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
Chlorthalidone
Amlodipine
Lisinopril
% Patients with
BP <140/90 mmHg
Amlodipine
Lisinopril
Heart Failure
Cumulative event
rate (%)
Chlorthalidone
Amlodipine
Lisinopril
Time to event,
yrs
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
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
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
Adapted from:
Dorsch MP, et al. Hypertension. 2011; 57
Chlorthalidone Safety
Electrolyte
imbalance
Hypokalemia
Lipid profile
Hyperglycemia
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
12 weeks
131
p value>0.05
49
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
Hypokalemia was not severe and returned towards baseline after 4 years of
treatment.
This was not associated with any increase in Cardiac events
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
-13.5
Hydrochlorothiazide 50 mg/day
-6.4
Pleiotropic benefits of
Chlorthalidone
Promotes angiogenesis
Better blood supply
Less load on heart
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
CTD -COMBINATION
Journal of American Society of hypertension-2010
75% of patients will
require combination
therapy to achieve
BP targets.
CTD- Offerings
ALLHAT-JNC 7 recognition