A New Way Of Treating Hypertension

Introducing NATEXAM as the only and newest

indapamide / amlodipine combination

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 1. Epidemiology
1.1 Older hypertensive patients are unlike others

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 Older hypertensive patients are unlike others ▪

Elevated systolic blood pressure

Hypertension affects at least
2 out of 3 patients over 65 years old

Prevalence of hypertension in adults in the US (NHANES: 2007-2012).1

1. Mozzafarian D et al. Circulation. 2015;e29-322. 3

 Older hypertensive patients are unlike others ▪

Elevated systolic blood pressure

Systolic blood pressure
increases with age
Mean systolic (A) and diastolic (B) blood pressure in the Health Survey for England
2011.1

1. Falaschetti E et al. Lancet. 2014;383:1912-1919. 4

 Older hypertensive patients are unlike others ▪

Elevated systolic blood pressure

Main reasons why
systolic blood pressure rises with age
Stiffening of the large arteries.1

The relationship between

increase in volume and
increase in pressure in five
different age groups. The
intra-aortic pressure rises
much higher with small
increases in volume in
elderly patients compared
with younger patients,
reflecting the rigidity of the
arteries in the elderly.

1. Hallock P, Benson IC. J Clin Invest. 1937;16:595-602 5

 Older hypertensive patients are unlike others ▪

Elevated systolic blood pressure

Main reasons why
systolic blood pressure rises with age

Reflected waves.1

Decreased distensibility
and increases pressure
wave amplitude, while
increased wave velocity
causes the reflected wave
to return during ventricular
systole.

1. O’Rourke M. Hypertension. 1995;26:2-9. 6

 Older hypertensive patients are unlike others ▪

Elevated systolic blood pressure

Systolic blood pressure
is the most difficult BP parameter to control

Mean BP results for 158 876 treated patients.1

Clinic blood pressure levels in

hypertensive patients
included in observational
studies or clinical surveys on
hypertension
between 2005 and 2011 in
Italy.
Histograms represent
average systolic BP and
diastolic BP levels in each
study included in the
analysis.
Data are expressed as mean
values.

1. Tocci G et al. J Hypertens. 2012;30:1065-1074. 7

 Older hypertensive patients are unlike others ▪

Elevated systolic blood pressure

Systolic blood pressure in older patients is
particularly difficult to control

Prevalence of BP control in patients ≥65 years old, aware of and treated for
hypertension; NHANES 2007-2012.1

1. Wozniak G et al. J Clin Hypertens (Greenwich). 2016;18(3):232-239. 8

 Older hypertensive patients are unlike others ▪

A high risk of stroke

Systolic blood pressure is the best predictor of
stroke risk for older hypertensive patients

Stroke mortality rate in each decade of age vs. usual systolic blood pressure at
the start of the decade.1

1. Rahimi K et al. Circ Res. 2015;116:925-936. 9

 Older hypertensive patients are unlike others ▪

A high risk of stroke

Stroke is the most devastating complication
for older hypertensive patients
Age-specific incidence rates of stroke
and acute myocardial infarction (MI)
in women.1
Age-specific incidence rates of stroke
and acute myocardial infarction (MI)
in men.1

1. Gentil A et al. J Neurol Neurosurg Psychiatry. 2009;80:1006-1010. 10

 Older hypertensive patients are unlike others ▪

A low level of renin activity

Older hypertensive patients have
a low level of renin activity

Low level of renin activity.1

Supine plasma renin activity

(PRA) and aldosterone
plasma level as a function of
age in healthy normotensive
people receiving an ad
libitum sodium diet.

1. Belmin et al. Drugs Aging. 1994;5(5):391-400. 11

1. Indapamide SR and amlodipine
are effective drugs at reducing
systolic blood pressure

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 Two complementary modes of action

Two complementary effects: renal and vascular.1-4

1. Waeber B et al. Expert Opin Pharmacother. 2012;13:1515-1526. 2. Leenen FH et al. Curr Med Res Opin. 1983;8(suppl 3):47-52. 3. Hamet P et al. J Hypertens. 2014;32(e-suppl 1):e269-e270.
4. Cappuccio FP et al. J Hum Hypertens. 1991;5:115-119. 13
 Two of the most effective drugs
at lowering systolic blood pressure
Baguet meta-analysis (2007)1

Indapamide SR and amlodipine effectively reduce systolic BP.

1. Baguet et al. Clin Drug Invest. 2007;27:735-753. 14

 Indapamide is more potent than HCTZ
at reducing systolic blood pressure
Roush meta-analysis (2015)1
Indapamide is significantly more potent than HCTZ at reducing systolic blood
pressure, which is not the case with chlorthalidone.

Systematic review and meta-

analysis; head-to-head RCTs
comparing HCTZ vs
indapamide (10 RCTS, n=813)
and HCTZ vs chlorthalidone (3
RCTS, n=70).

1. Roush et al. Hypertension. 2015;65:1041-1046. 15

 Two drugs providing full
24-hour blood pressure control
Maillon study (1998)1
BP change (32-hour ABPM) between M0 and M2, values beginning from subjects’
drug intake.1

Indapamide SR’s
antihypertensive effect
continued up to the 32nd
hour after the last dose,
even when the
subsequent dose was
forgotten.2

1. Mallion JM et al. J Cardiovas Pharmacol. 1998;32:673-678. 2. Jaillon P et al. J Hypertens. 2001;19:S234. 16

 Two drugs providing full
24-hour blood pressure control

Trough-to-peak ratios for different antihypertensive drugs.1-7

1. Lacourciere Y et al. Am J Hypertens. 1995;8:1154-1159. 2. Oparil MD et al. Clin Ther. 2010;32:1252-1269. 3. Staessen JA et et al. Hypertension. 1995;26:942-949. 4. Yusoff K et al. Int J Clin Pract. 1999;53:277-280. 5. Zannad F et
al. J Hypertens. 1999;17:137-146. 6. Hermida RC et al. Hypertension. 2003;42:283-290. 7. Mallion JM et al. Arch Mal Coeur. 1996;89;27-38. 17
 Two drugs providing full
24-hour blood pressure control

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 Two drugs that reduce BP variability
X-CELLENT ABPM sub-study (2011)1
Comparisons of 24-hour systolic blood pressure variability after 3 months of
antihypertensive treatment.

1. Zhang Y et al. J Hypertension. 2011;58:155-160. 19

Two drugs that reduce BP variability

For example, a patient (Mr A) is followed up with three recordings

at different visits. His systolic blood pressure (BP) values are 150
mm Hg, 130 mm Hg, and 140 mm Hg. His BP variability calculated
as the standard deviation (SD) of all BP measurements is 10 mm
Hg. Another patient (Mr B) is also followed up with three
recordings at different visits and his systolic BP values are 140 mm
Hg, 145 mm Hg, and 135 mm Hg. His mean BP will be the same as
for Mr A, 140 mm Hg, but his BP variability will be half that of Mr A
(5 mm Hg). If this pattern continues over the long term, Mr B may
have a lower risk of stroke than Mr A, since for the same target BP,
higher BP variability means higher risk of stroke.

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 CCB/thiazide-like diuretic combinations
are part of the most effective options
to reduce short-term BP variability
Levi-Marpillat study (1998)1

Mean differences ± SD (mm Hg)

in 24-hour, daytime and
nighttime BP between patients
treated with a given
antihypertensive class (alone or
in combination) and patients
not receiving the drug under
assessment, but receiving any
other type of antihypertensive
(control group).
*P≤0.005, ‡P≤0.001.

1. Levi-Marpillat N et al. Hypertension Res. 2014;37:585-590. 21

2. Indapamide SR and amlodipine
provide complete protection

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 Indapamide SR provides
effective protection against stroke
HYVET study (2008)1
Protection against stroke with indapamide (indapamide SR ± perindopril vs
placebo).

1. Beckett N et al. N Engl J Med. 2008;358:1887-1898. 23

 Thiazide-like diuretics are more effective than
thiazide-type diuretics in reducing stroke
Chen meta-analysis (2015)1
Stroke reduction with thiazide diuretics is mainly driven by thiazide-like diuretics
and not thiazide-type diuretics.

1. Chen P et al. Am J Hypertension. 2015;28:1453-1463. 24

 Effective protection against stroke
Wang meta-analysis (2007)1
Protection against stroke with amlodipine vs placebo, angiotensin receptor
blockers (ARBs), or angiotensin- converting enzyme (ACE) inhibitors.

Effects of antihypertensive
treatment on stroke in trials
comparing amlodipine with
placebo or other classes of
antihypertensive drugs,
including angiotensin receptor
blockers (ARBs) and
angiotensin-converting enzyme
(ACE) inhibitors.

1. Wang et al. Hypertension. 2007;50:181-188. 25

 CCBs are still one of the
most effective classes for reducing stroke
Mukete meta-analysis (2015)1
Risk ratios for stroke comparing treatment with calcium channel blockers versus
other antihypertensive agents(ACE) inhibitors

1. Mukete B et al. Am J Cardiovasc Drugs. 2015;15:243-257. 26

 CCB/thiazide-like diuretic combinations are more
effective at reducing stroke than other combinations
Rimoldi meta-analysis (2015)1
Risk ratios for stroke comparing treatment with combination CCB/thiazide-like
diuretic vs other combinations.

CCB, calcium channel blocker; CI, confidence interval, Diu, diuretic; RR, risk ratio.
1. Rimoldi SF et al. J Clin Hypertens (Greenwich). 2015;17:193-199. 27
 CCB and thiazide-like diuretic are two
of the most effective drugs for reducing stroke
in black hypertensive patients

Risk of primary outcome (composite of death, myocardial infarction, and stroke)

with ACEi vs CCB and ACEi vs thiazide in black hypertensive patients.

1. Bangalore et al. Am J Med. 2015;128(11):1195-203. 28

 CCB and thiazide-like diuretic are two
of the most effective drugs for reducing stroke
in black hypertensive patients

Comparison of stroke rate with RAAS blocker vs CCB or diuretic.

1. Palla et al. J Clin Hypertens (Greenwich). 2016. doi: 10.1111/jch.12867. Epub ahead of print. 29
 Indapamide SR provides
effective protection against heart failure
HYVET study (2008)1

Indapamide SR reduces the risk of heart failure.

1. Beckett et al. N Engl J Med. 2008;358:1887-1898. 30

 Thiazide-like diuretics have
strong evidence of cardiac protection
Olde Engberink meta-analysis (2015)1

1. Olde Engberink RH et al. Hypertension. 2015;65:1033-1040. 31

 Indapamide SR reduces
left ventricular hypertrophy
LIVE study (2000)1

Indapamide SR significantly reduces left ventricular hypertrophy.

1. Gosse P et al. J Hypertens. 2000;18:1465-1475. 32

 Indapamide SR reduces
left ventricular hypertrophy
LIVE study (2000)1
Indapamide SR significantly decreases left ventricular diameter and wall
thickness.

These data support the

previous hypothesis, which
was based on a meta-
analysis, that indapamide SR
may produce a greater
regression in left ventricular
hypertrophy than other
diuretics, particularly with
regard to its action on wall
thickness.

1. Gosse P et al. J Hypertens. 2000;18:1465-1475. 33

 Amlodipine
effectively reduces myocardial infarction
Wang study (2007)1
Protection against myocardial infarction with amlodipine vs placebo, angiotensin
receptor blockers (ARBs), or angiotensin-converting enzyme (ACE) inhibitors.

1. Wang JG et al. Hypertension. 2007;50:181-188. 34

 Amlodipine
effectively reduces myocardial infarction
Wang study (2007)1

Effects of antihypertensive
treatment on myocardial
infarction in trials comparing
amlodipine with placebo or
other classes of
antihypertensive drugs,
including angiotensin
receptor blockers (ARBs)
and angiotensin-converting
enzyme (ACE) inhibitors

1. Wang JG et al. Hypertension. 2007;50:181-188. 35

 Amlodipine
effectively reduces myocardial infarction
VALUE trial (2004)1
Reduction in myocardial infarction with an amlodipine-based regimen vs a
valsartan-based regimen.

CI, confidence interval, HR, hazard ratio.

1. Julius S et al. Lancet. 2004;363:2022-2031. 36
 Amlodipine
effectively reduces myocardial infarction
VALUE trial (2004)1

End points (first occurrence in each category).

1. Julius S et al. Lancet. 2004;363:2022-2031. 37

 Amlodipine
effectively reduces myocardial infarction
ACCOMPLISH trial (2008)1
Hazard ratios for the primary outcome and the individual components in
ACCOMPLISH.

1. Jamerson K et al. N Engl J Med. 2008;359:2417-2428. 38

 Indapamide SR provides
effective renal protection
NESTOR study (2004)1

Reduction in microalbuminuria and return to normoalbuminuria in NESTOR.

Focus on older patients.

Similar results were observed in
the subgroup of 187 elderly
(over 65) type 2 diabetic
hypertensive patients. The
UACR decreased by 46% in the
indapamide SR group and 47%
in the enalapril group. The
noninferiority of indapamide SR
versus enalapril was
demonstrated (P=0.02; 35% limit
of noninferiority) with a ratio of
0.95 (95% CI, 0.68 to 1.34).
Mean blood pressure
decreased by 18 and 15 mm
Hg in the indapamide SR and
the enalapril groups,
respectively (P=0.11).2

1. Marre M et al. J Hypertens. 2004;22:1613-1622. 2. Puig JG et al. Am J Hypertens. 2007;20:90-97. 39

 Indapamide SR provides
effective renal protection
Madkour study (1996)1
Effects of long-term therapy with indapamide SR or hydrochlorothiazide on
creatinine clearance in patients with impaired renal function and hypertension.

1. Madkour et al. Am J Cardiol. 1996;77:23B-25B. 40

 Indapamide SR provides effective
protection against heart failure
HYVET study (2008)1
Indapamide SR–based treatment reduces the risk of death from cardiovascular
causes.

Focus on older patients.

The double-blind phase of
HYVET was followed by an
extension phase during
which all patients received
active treatment. The
HYVET-extension results
confirm the importance of
long-term treatment
because total mortality
and cardiovascular
mortality both decreased
with time, with respective
reductions after 3 years of
52% (intention-to-treat [ITT],
P=0.016) and 81% (ITT,
P=0.033) compared with
treatment for 1 year.2

1. Beckett N et al. N Engl J Med. 2008;358:1887-1898. 2. Beckett N et al. BMJ. 2012;344:d7541. 41

 Amlodipine reduces mortality
ACCOMPLISH study (2008)1
Kaplan-Meier curves for time to first primary composite end point in
ACCOMPLISH.

1. Jamerson K et al. N Engl J Med. 2008;359:2417-2428. 42

3. Going further with NATEXAM

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 Natexam further reduces
systolic blood pressure versus placebo
EFFICIENT study (2014)1
Baseline characteristics of hypertensive patients eligible to receive fixed-dose
combination indapamide SR/amlodipine 1.5 mg/5 mg.

1. Jadhav U et al. PLoS One. 2014;9:e92955. 44

 Natexam further reduces
systolic blood pressure versus placebo
EFFICIENT study (2014)1

Efficient and rapid blood pressure (BP) decrease (global population).

BP, blood pressure.

1. Jadhav U et al. PLoS One. 2014;9:e92955. 45
 Natexam further reduces
systolic blood pressure versus placebo
EFFICIENT study (2014)1
Blood pressure (BP)–lowering efficacy of Natexam in grade 3 hypertensive
patients.

BP, blood pressure.

1. Jadhav U et al. PLoS One. 2014;9:e92955. 46
 Natexam further reduces
systolic blood pressure versus placebo

Systolic blood pressure (BP) decrease for 10 mm Hg decrease of diastolic BP.1

BP, blood pressure.

1. Safar M et al. Am J Cardiovasc Drugs. 2014;14(6):423-432. 47
 Natexam further reduces systolic blood pressure
versus ARB/CCB combinations
006 study (2016)1
Reduction in office SBP at week 12 in 216 patients with sustained hypertension
(baseline ambulatory blood pressure monitoring >130/80 mm Hg.

1. Dominiczak A, Asmar R et al. ESH Abstract 2016. 48

 Natexam further reduces systolic blood pressure
versus ACEI/CCB combinations
NESTOR CCB substudy (2015)1
Long-term efficacy of indapamide SR + amlodipine 10 mg vs enalapril +
amlodipine 10 mg.

BP, blood pressure.

1. Hanon O et al. Am J Hypertens. 2015;28:1064-1071. 49
 Natexam further reduces
systolic blood pressure in older patients
NESTOR CCB over 65 years old substudy (2016)1
Reduction in systolic blood pressure from baseline to 52 weeks in patients aged
≥65 years.

1. Hanon O. NESTOR CCB over 65. ESH Congress (Paris, 2016). Abstract. 50
 A good safety profile
NESTOR CCB substudy (2015)1
Superiority of indapamide + amlodipine over enalapril + amlodipine in reducing
edema.

1. Hanon O et al. Am J Hypertens. 2015;28:1064-1071. 51

 Indapamide is metabolically neutral

Indapamide SR preserves lipid and glucose metabolism in the short and long
term.1-4

1. Beckett NS et al. N Engl J Med. 2008;358:1887-1898. 2. ADVANCE Collaborative Group. Lancet. 2007;370:829-840. 3. Ambrosioni E et al. J Hypertens.
1998;16:1677-1684. 4. Marre M et al. J Hypertens. 2004;22:1613-1622. 52
 Indapamide SR is metabolically neutral

Frequency of hypokalemia with indapamide SR in the 6th week of treatment.1

1. Ambrosioni E et al. J Hypertens. 1998;16:1677-1684. 53

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