JNC 8 & Chlorthalidone

1. What’s New In Hypertension
JNC VIII & Chlorthalidone

2. JNC VIII
An executive summary of the evidence and
designed to provide clear recommendations
For
All Clinicians

3. Panel List
More than 400 nominees from various expertise in
•Cardiology,
•Hypertension,
•Endocrinology,
•Pharmacology,
•Nephrology ,
•Clinical Trials etc.

4. Goal BP
Underlined Points different from JNC -7

5. 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)

6. 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.
Drug Prescribed

7. 2014 Hypertension Guideline
Management Algorithm

8. Adults aged ≥ 18

9. General Population

10. 2

11. Diabetes or CKD Patients

12. Strategies to Dose
Antihypertensive Drugs

13. A Start one drug, titrate to maximum
dose, and then add a second drug
B Start one drug and then add a
second drug before achieving
maximum dose of the initial drug
Strategies to Dose Antihypertensive Drugs

14. C
Begin with 2 drugs at the same time,
either as 2 separate pills or as a single
pill combination
Strategies to Dose Antihypertensive Drugs
Blood Pressure ≥ 160/100

15. Role of Chlorthalidone

16. Thiazide vs Thiazide-like diuretics
Thiazide-like diuretics
•Lacking the benzothiadiazine ring
•Physiological action is similar but clinical
benefits are more

17. 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-
to–side effect ratio
Landmark Trial: MRFIT, SHEP
Landmark Trial: ALLHAT
Feasibility of 6.25 mg dose

18. Dual Mode of action
Reduction in peripheral
vascular resistance (PVR)
Reduction in
plasma volume

19. 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

20. Long half life of chlorthalidone
o Chlorthalidone has the longest elimination half-life of 60 hrs.
o The diuretic effect sets in after 2 to 3 hours, reaches its
maximum after 4 to 24 hours
o Duration of action is 48-72 hr.
Carter BL et al Hypertension . 2004; 4-9

21. CTD- International experience

22. The Systolic Hypertension in
the Elderly Program (SHEP)
SHEP Research Group. JAMA. 1991;265:3255-3264.
Cohort 4,736; 43% men
Age  60 yrs old; mean 71.6 yrs old
Eligibility Systolic BP 160219 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

23. 65
70
75
80
140
150
160
170
180
Change
in
BP
(mmHg)
Years
SHEP
Change in Blood Pressure
Placebo
(n=2,371)
Active Rx (n=2,365)
Years
0 1 2 3 4 5 0 1 2 3 4 5
Systolic BP Diastolic BP
Placebo
(n=2,371)
Active Rx
(n=2,365)

24. SHEP: Results
CHLORTHALIDONE VS. PLACEBO
SHEP Cooperative Research Group. JAMA. 1991;265:3255–3264.
RR (95% CI)
0.64 (0.50–0.82)
0.73 (0.60–0.94)
0.46 (0.33–0.65)
0.68 (0.58–0.79)
0.87 (0.73–1.05)
Stroke
CHD
CHF
CVD
Death 0.2 1.6
1.0
0.4 0.6 0.8 1.2 1.4
Favors chlorthalidone Favors placebo

25. Cumulative
Stroke
Rate
Per
100
Persons
Months of Follow-up
SHEP: Fatal and Non-fatal Stroke
p=0.0003
Placebo
(n=2,371)
Active Rx
(n=2,365)
SHEP Cooperative Research Group. JAMA. 1991;265:3255–3264.
10
9
8
7
6
5
4
3
2
1
0
0 12 24 36 48 60 72

26. 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
SHEP-X

27. 47
54
39
47
40
40
0
10
20
30
40
50
60
PLACEBO ACTIVE
%
B-L DM F-U DM NO DM
*
*
*
Total Mortality (%) –
14.3 yrs Follow up
p< 0.05 vs no diabetes
Kostis JB, Wilson AC, Freudenberger RS, et al. Am J Cardiol 2005;95:29-35

28. 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

29. 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;306:2588-2593

30. Association Between Chlorthalidone Treatment of Systolic
Hypertension and Long-term (22 Years) Survival in SHEP
CV Death
Active Treatment
Control
516 Days*
* Survival during follow-up was longer with the active treatment group
(6501 days) than with the control group (5985 days); p = .01
Kostis JB, et al. JAMA. 2011;306:2588-2593.
SHEP=Systolic Hypertension in the Elderly Program; CV=cardiovascular

31. Association Between Chlorthalidone Treatment of Systolic
Hypertension and Long-term (22 Years) Survival in SHEP
All-Cause Mortality
Active Treatment
Control
205 Days*
* Survival during follow-up was longer with the
active treatment group (4212 days) than with the
control group (4007 days); p = .03
Kostis JB, et al. JAMA. 2011;306:2588-2593.
SHEP=Systolic Hypertension in the Elderly Program; CV=cardiovascular

32. 1 day gain in life
• 22 year follow-up of SHEP trial
• Higher survival and a gain in life expectancy

33. Anti hypertensive and Lipid Lowering
treatment to prevent Heart Attack
Trial.
(ALLHAT)

34. ALLHAT
42418 patients
15255 9048 9054 9061
Chlorthalidone Amlodipine Lisinopril Doxazosin
Discontinued
Follow-up visits were at 1 month,3, 6, 9,
and 12 months; and every 4 months
thereafter. The study lasted for 8 years
Barry Davis et al, ALLHAT 1994-2002 University of Texas Health Science Center

35. 70
75
80
85
90
130
135
140
145
150
ALLHAT
Mean Systolic and Diastolic BP
Systolic
BP
(mmHg)
Follow-up, yrs
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Diastolic
BP
(mmHg)
Chlorthalidone
Amlodipine
Lisinopril
Chlorthalidone
Amlodipine
Lisinopril
SBP=systolic blood pressure DBP=diastolic blood pressure

36. 0
10
20
30
40
50
60
70
Baseline Year 1 Year 2 Year 3 Year 4 Year 5
BP Control: <140/90 mmHg
Lisinopril
Amlodipine
Chlorthalidone
%
Patients
with
BP
<140/90
mmHg

37. 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

38. 0
3
6
9
12
15
Heart Failure
0 1 2 3 4 5 6 7
Cumulative
event
rate
(%) Chlorthalidone
Amlodipine
Lisinopril
Time to event,
yrs

39. RR
(95% CI)
RR
(95% CI)
TOTAL
1.04
(0.99-1.09)
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 2 0.5 2
ALLHAT Combined CV Disease
Favors
amlodipine
Favors
chlorthalidone
Favors
lisinopril
Favors
chlorthalidone
1 1

40. 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;288:2981-2997.

42. 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.

43. 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

44. Difference Between SI Versus UC
MRFIT: Impact on Outcomes After
Switching From HCTZ to Chlorthalidone
-6.2
+6.3
+1.2
-7.6
+39.0
-20.2
-13.5
-17.6
-32.2
-5.7 -7.6 -8.1
-50
-40
-30
-20
-10
0
10
20
30
40
50
Total All CV Acute MI Other IHD Other CVD All non-CV
Percent
Change
HCTZ Group (Before Change)
CLD Group (After Change)
Multiple Risk Factor Intervention Trial Research Group.
Circulation. 1990;82;1616-1628.
MRFIT = Multiple Risk Factor Intervention Trial;
SI=special intervention; UC=usual care

45. Multiple Risk Factor Intervention Trial
Changes From Baseline at 48 Months
Adapted from
Ernst ME, et al. Hypertension. 2011;58:1001-1007.
p for Interaction = .002
p for Interaction = .001
p for Interaction < .001

46. Multiple Risk Factor Intervention Trial
Comparison of Diuretic Therapies
Adapted from:
Dorsch MP, et al. Hypertension. 2011; 57 689-694
Chlorthalidone
HCTZ
Drug Stopped
Chlorthalidone vs Drug Stopped; p < .0001
HCTZ vs Drug Stopped; p < .0001
Chlorthalidone vs HCTZ; p = .0016
Adjusted estimates were controlled for by age, race,
smoking status, MRFIT randomized group, diuretic
dose, SBP, LDL, HDL, and baseline hypertension
treatment.

47. Chlorthalidone Safety
•Electrolyte imbalance
•Hypokalemia
•Lipid profile
•Hyperglycemia

48. Indian Experience with low dose
chlorthalidone (CTD)
Nature of study Duration No. of patients in trial
1 6.25 mg Chlorthalidone
6.25 mg Chlorthalidone + atenolol
24 weeks 300
2 6.25 mg Chlorthalidone +
Metoprolol XL
12 weeks 130
3 6.25 mg Chlorthalidone + Losartan 12 weeks 131

49. 49
SBP reduction with monotherapies
M e an fall in SBP for thre e bas e line
tre atm e nts
110
115
120
125
130
135
140
145
150
0 4 8 12 16 20 24
We e k s
BP(mm
of
Hg)
A TN 25 mg
CTN 6.25 mg
A M L 2.5 mg
p value>0.05

50. DBP reduction with monotherapies
Me an fall in DBP for thre e bas e line
tre atm e nts
70
75
80
85
90
95
100
0 4 8 12 16 20 24
We e k s
BP
(mm
og
Hg)
A TN 25 mg
CTN 6.25 mg
A M L 2.5 mg
p value >0.05

51. Electrolyte change
Study Groups Visit Sodium Potassium Chloride
Chlorthalidone
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

52. ALLHAT report on hypokalemia
Chlorthalidone & Hypokalemia
3.8
3.9
4
4.1
4.2
4.3
4.4
Baseline 2 Years 4 Years
serum
K+
mEq/L
Potassium mEq/L
• Hypokalemia was not severe and returned towards baseline after 4 years of treatment.
• This was not associated with any increase in Cardiac events

53. 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.

54. Effect on blood sugar in Indian trial
Study Groups Visit FBS PPS
Chlorthalidone
Baseline 101.49 137.13
End 105.78 135.24
Pareek et al, Current Medical Research and Opinions, vol 24, no. 6, 2008

55. 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

56. CTD vs HCTZ
Which way?

57. Potency
Chlorthalidone is 1.5 to 2.0 times as potent as
hydrochlorothiazide.
Carter BL et al Hypertension . 2004; 4-9
HCTZ 50mg 25mg 12.5mg
Chlorthalidone 25mg 12.5mg 6.25 mg

58. 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.
Superior to HCTZ
24-hour mean BP
Chlorthalidone 25 mg/day -12.4 mm of Hg
HCTZ 50 mg/day - 7.4 mm of Hg
Barry LC, Hypertension 2006; 47; 352-358.

59. 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 early morning
blood pressure surge.
Barry LC, Hypertension 2006; 47; 352-358.

60. Pleiotropic benefits of Chlorthalidone
Reduces platelet aggregation
Less potential of clot formation
Better blood flow
Promotes angiogenesis
Better blood supply
Less load on heart
Reduces vascular permeability
Better blood supply
Less load on heart
Better circulatory performance
Less load on heart
Ryan Woodman et al; Hypertension 2010

61. 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

62. Clinical expert opinion
Dr Henry Black
Chlorthalidone – We missed its superior benefits compared with
Thiazides
Medscape cardiology
Clinical professor of internal medicine at the New
York University

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

65. Clinical expert opinion
Dr Messerli
Not all diuretics are equal……… Chlorthalidone significantly reduce
CV mortality
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)

66. Clinical expert opinion
Dr Norman Kaplan
Chlorthalidone……………..Class apart diuretic
Hypertension October 24, 2011
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

67. Clinical expert opinion
Dr G Bakris
ARBs mix best with Chlorthalidone……
American Society of Hypertension 2010
Professor of Medicine and Director, Hypertensive
Diseases at the University of Chicago
Has served many national committees
including JNC 6, JNC 7

68. 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