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Recent advances in treatment of Hypertension -- Drugs inhibiting RAAS, Diuretics, Calcium channel blockers, Vasodilators
1. Dr Deepthi S VaggeDr Deepthi S Vagge
MD PharmacologyMD Pharmacology
BMCRIBMCRI
2. JNC 7 criteria for diagnosis of
HTN
BP classification Blood pressure levels
SBP mmHg DBP mmHg
Normal <120 and <80
Pre-hypertension 120-139 Or 80-89
Hypertension -I 140-159 Or 90-99
Hypertension -II >/= 160 Or >/= 100
3. Targets of drug action
Counter-regulatory mechanisms –fall in BP
7. vasoconstriction, cell growth in heart and
arteries
Aldosterone secretion
Reabsorption of Na
Enhances sympathetic activity
Vasodilation
Antiproliferative
promotes apoptosis
fetal tissue development
12. Comment Strength
of evidence
Conclusion
Aliskiren is
more
effective
than
ramipril
Low 1 RCT–842 pt. 26 weeks duration. Aliskiren 150mg /ramipril 5mg.
Mean reductions in BP: Aliskiren 150mg -17.9/13.3
ramipril 5mg. -15.2/12.
P<0.0001
Plasma renin concentration was increased in both groups , PRA was reduced in
aliskiren .
No SAE
Aliskiren is
as effective
as ARB
Low 2 RCTs compared aliskiren to ARB
1.aliskiren Vs losartan. 4 weeks, n=226. Randomized to
losartan 100mg. aliskiren 150mg, aliskiren 300mg
p=0.0002
Mean reduction in BP were losartan 100mg -11.4/-5.5;
aliskiren 150mg --10/-5.7; aliskiren 300mg -11.8/-5.7
Efficacy and evidence
13. Comment Strength of
evidence
Conclusion
2.aliskiren Vs irbesartan. 8week. n=652 randomised to receive
aliskiren 150mg /irbesartan 150mg
Mean reduction in BP: aliskiren 150mg:-10.9/-9.4
irbesartan 150mg: -12.5/-9.1
p<0.0001
BP control rate was similar in all groups
Aliskiren + valsartan
more effective than
either monotherapy
Low 1 RCT
Aliskiren +valsartan Vs aliskiren Vs valsartan
8week, n=1,797, randomized to either of the three groups
Mean reduction in BP
Aliskiren 300mg -13/9mmhg
Valsartan 320mg: -12.9/-9.7 mmhg
Aliskiren + valsartan: -17.2/ -12.2 mmhg
P<0.0001
14.
ADVANTAGES:
Efficacy greater than ACE inhi/ ARB, safety equal
The long t1/2
Most comprehensive inhibition of the RAAS, reducing PRA,
Ang I, Ang II, and aldosterone
No dose adjustment in elderly, liver or moderate renal
impairement
16. DIRECT RENIN INHIBITORS UNDER TRIAL:
DRUG TRIAL NO. of Pt INTERVENTIO
N
END POINTS RESULTS
SPP635
SPP1148
SPP800
A Phase IIa,
Double-Blind,
Placebo-
Controlled trial
-SPP635 in Mild
to Moderate
Hypertension
Phase I
Preclinical trial
n:35
mild to
moderate
HTN
SPP635 OD
(20)
Placebo(15)
For 4 weeks
Mean reduction in
sitting SBP
Mean reduction in
sitting DBP
SPP635
-17.9
-9.8
NO SAE
PLA
-3.1
-2.4
p<0.001
SPP635 Presently Phase IIa Study to Investigate the Efficacy and Safety
of SPP635 in Diabetic and Hypertensive Patients With Albuminuria
19.
lack of postural hypotension
No tachycardia
Safe in asthamatics, diabetes, PVD
Reduce the incidence of T2DM in high risk individuals
Renal blood flow is well maintained
ADVANTAGES
20. No deleterious effect on plasma lipid profile, no hyperuricemia
Delay development of diabetic glomerulopathy
Reverse left ventricular hypertrophy and increased wall:lumen ratio
No rebound hypertension on withdrawal
Reduce cardiovascular morbidity and increase life expectancy of
hypertensives
21.
Stage I HTN :first choice if thiazides are not being used
Stage II HTN: in combination with thiazides
Drug of choice: in HTN associated with diabetics, LVH, CHF,
post MI, renovascular HTN
CURRENT STATUS
22.
MC-4232 is a combination of MC-1 and lisinopril.
MC-1 is a naturally occurring small molecule, a metabolite of
vitamin B6
Presently under Phase II MATCHED study (MC-1 and ACE
Therapeutic Combination for Hypertensive Diabetics),
evaluating the effects of MC-4232 in patients with coexisting
diabetes and hypertension.
DRUG UNDER TRIAL
25.
Similar to ACE , but with better tolerability profile
Complete inhibition of AII actions
Result in indirect AT 2 receptor activation
Advantages
26.
Intolerance to ACEI therapy and as an important option in the
treatment of patients with concurrent disorders such as heart
failure and type 2 diabetes
CURRENT STATUS:
27.
Azilsartan medoxomil is an angiotensin receptor
blocker, approved in 2011the US Food and Drug
Prodrug
Azilsartan - active moiety
Newer drugs
28.
Trial No.of pt Intervention End points Results
Phase III
Double-blind,
randomized,
placebo-
controlled
trial-
azilsartan,
olmesartan,
valsartan, and
placebo.
1285
SBP 150–180
mm Hg
Placebo
Azilsartan
20 mg
( titr 40 mg)
Azilsartan
40mg
(titr 80mg )
olmesartan 20
mg
( titr 40 mg)
valsartan 160
mg
(titr 320mg)
for 6 weeks
reductions in
24-hour mean
SBP at 6weeks
azilsartan
40mg
–14.3 mm Hg
valsartan 320
mg
–10.0 mmHg;
P 0.001
olmesartan 40
mg
–11.7 mm Hg
P 0.009
29.
Trial No pt Intervention End points Results
Phase III
Double-blind,
randomized
trial -azilsartan
Vs valsartan
984
SBP
150-180mm
Hg
Placebo
Azilsartan 20mg
(titr 40 mg)
Azilsartan 40mg
(titr 80 mg)
Valsartan 160 mg
(titr 320 mg)
24 weeks.
reductions
in 24-hour
mean SBP at
study
end
Azilsartan 40 mg
–14.9 mm Hg
Azilsartan 80mg
-15.3 mm Hg
valsartan 320 mg
–11.3mmHg
30.
Drugs under trial: LCZ696 (valsartan + AHU337 neprolysin
inhibitor)
Trial Pt Efficacy end
point
Intervention Result
Phase II
Randomized,
Double Blind,
active comparator
trial
1328 More than
20mmhg
reduction in the
SBP
LCZ696
100mg (156)
200mg (169)
400mg (172)
Valsartan
80mg (163)
160mg (166)
320mg (164)
47 (31%)
76 (45%)
87 (51%)
51 (31%)
49 (30%)
53 (33%
31.
Trial Particip
ants
Interventions and
duration
Primary end
point
Results
Irbe PS
200
400 800 Place
bo
A phase II
Randomized,
Double-Blind,
Placebo And
Active-
Controlled-
PS433540 In
Hypertension
261 Drug:
irbesartan
300 mg OD (58)
PS433540
200 mg OD (58)
400 mg OD (58)
800 mg OD (28)
Placebo (59)
The duration
12weeks
Primary :
Chage from
baseline in
mean SBP.
Secondary:
Chage from
baseline in
mean DBP.
Percentage of
patients
achieving BP
<140/90mmhg
-10.7 -13.2 -14.2 -23.4 1.8
-7.1 -7.2 -9.2 -14.3 0.2
17% 21% 16% 28% 5%
PS433540 : a dual acting angiotensin and endothelin receptor antagonist
32.
Drug combinations Rationale
RAAS Inhibitor + a low-dose, thiazide Improves efficacy and side
effect profile
RAAS Inhibitor + CCB improves the tolerability
profile of the CCB
Renin inhibitor with an ARB More complete inhibition of
RAAS
RAAS Inhibitors + beta Blocker Combination may result in
severe bradycardia.
ACE Inhibitors + ARB More SE
Combination therapy with RAAS
inhibitors:
33.
ACEIs, ARBs, and Direct Renin Inhibitors
for Treating Essential Hypertension ?
Evidence on the comparative long-term benefits and harms of
ACEIs, ARBs, and direct renin inhibitors, focusing on their use
for treating essential hypertension in adults*
* Advancing excellence I n health care ahrq.gov/reports/final.cfm 2011
34. Efficacy Strength of evidence Evidence
ACE in & ARBs
have similar long
term effects on BP
control
Aliskiren more
effective than
ramipril and as
effective as ARB
High (ACEI vs.
ACEIs )
Low
(DRI vs.
ACEI,ARB )
77 studies (70 RCTs, 5 nonrandomized
controlled clinical trials, 1 retrospective
cohort study, and 1 case-control study)
1,26,170 patients receiving an ACEI or an
ARB were followed for periods from 12
weeks to 5 years (median 24 weeks).
Based on 3 RCT
These studies found the direct renin
inhibitor to
have a greater reduction in blood pressure
compared to the ACEI ramipril (1 study )
and no significant difference compared to
the ARB losartan (2 study).
35. Reducing
mortality and
major
cardiovascular
events:
Strength of
evidence
Evidence
ACE inhi = ARBs
??
Low (ACEI vs.
ARBs )
Insufficient
(DRI vs. ACEI,ARB
)
In 21 studies that reported mortality, MI, or
clinical stroke as outcomes
among 38,589 subjects, 38 deaths and 13
strokes were
reported.
3 of these 21 studies (including 1 death)
evaluated
36. Safety profile Strength of evidence Evidence
Incidence of cough is more
with ACE inhi compared to
ARBs
High
(ACEI vs. ARBs )
Insufficient
(DRI vs. ACEI,ARB )
difference rates of cough
7.8 percent
4% higher in ACE
inhibitors
Withdrawals due to AE
were more in ARB
High (ACEI vs. ARBs )
Low
(DRI vs. ACEI,ARB )
Withdrawals were 2.3%
more with ARBs (5.4%
vs. 3.1%).
No statistically
significant difference in
the withdrawal rate
39. Advantages
More beneficial in elderly
Safe in asthama, PVD
Lipid profile, uric acid levels or glucose metabolism not effected
No renin release
No postural hypotension , rebound phenomenon
No tolerance
Renal or cerebral perfusion, male sexual activity, physical work capacity
not impaired
Used in pregnancy
40.
Preferred in elderly hypertensives
They have stroke prevention potential
Next to ACE inhi in reducing albuminuria and slowing disease
progression in hypertensive / diabetic nephropathy
cyclosporin induced hypertension in renal transplant
Current Status :
41. Clevidipine
Newer drugs
Trial No pt Intervention End points Results
ESCAPE-1
Phase III,
double-
blind,
randomized,
placebo-
controlled
study
-clevidipine
in
preoperative
hypertensio
n
105
hypertensive
scheduled for
cardiac
surgery with
hypertension
Clevidipine
(53)
placebo (52)
Preoperative
ly
incidence of
treatment
failure (to
decrease SBP
by >15% from
baseline at
any time
within the 30-
minute
BP target
levels
reached
Clevidipine :
92.5% (49 of
53 patients
placebo
(7.5%)
P<0.0001).
42.
Trial No pt Intervention End points Results
ESCAPE-2
Phase III,
double-blind,
randomized,
placebo-
controlled,
multi-center
study
-clevidipine
in
postoperativ
e
hypertension
after cardiac
surgery
110 patients
with
SBP>140
mm Hg
within 4
hours of
admission to
a
postoperativ
e setting,.
clevidipine
(61)
placebo (49)
the
incidence of
treatment
failure (the
inability to
decrease
SBP by
>15% from
baseline).
Target BP
reached
Clevidipine :
91.8%
Placebo:
20.4%
43.
Trial No pt Intervention End point results
VELOCITY
The phase III
prospective,
open-label,
single-arm
study -
clevidipine in
Treatment
Acute Severe
Hypertension
117 patients
the ER or ICU
with SBP>180
and/or
DBP>115 mm
Hg
The initial
dose of
clevidipine
was 2 mg/hr
for 3 minutes
the dose was
doubled every
3 minutes as
needed to a
maximum
dose of 32
mg/hr, which
was then
continued for
18-96 hours
Achieving of
a patient-
specific
systolic blood
pressure
range the first
30 minutes of
infusion;
88.9% of
patients
(104/117)
receiving
clevidipine
achieved their
target SBP
range within
30 minutes of
treatment
initiation,
with a median
time-to-target
of 10.9
minutes
46.
Current status:
Thiazides Loop K+ sparing
First choice in
treatment of
essential HTN esp.
in elderly.
Overcoming
resistance to other
antihypertensives
Severe HTN
associated with
CRF, CHF
Used with thiazides
to prevent K loss
Current Status
47. COMBINATION RATIONALE
Diuretic and a CCB results Side effect profile improved.
b-Blockers+ Diuretics Efficacy improved
Thiazide Diuretics + Potassium-
sparing
Diuretics
Side effect profile improved.
Combination therapy
49.
Drugs MOA Role in HTN AE
Hydralazine Activate K channels
Generate NO &
stimulate cGMP
Moderate HTN not
controlled by beta
blocker /diuretic
Headache, nausea,
nasal congestion,
angina attack (due to
tachycardia
: reversible
dessiminated lupus
erythematosus
Minoxidil Converted to active
metabolite minoxidil
sulfate which activates
K channels
Severe HTN, life
threatening HTN,
resistant HTN
Hirsutism
Diazoxide activates K channels HTN emergencies Na, water retention
50.
Drugs MOA Role in HTN AE
Fenoldopam D1 receptor agonist—
dilation of peripheral
arteries and natriuresis
Hypertensive
emergencies esp in
those with renal
impairement
Tachycardia,
headache, flushing
Increase intraocular
pressure
Hypokelemia,
electrolyte
disturbances
Sodium nitroprusside Activates guanylyl
cyclase either directly
or through the release
of NO---increase in
intracellular cGMP---
vascular smooth
muscle relaxation
Hypertensive
emergencies
Tachycardia,
headache, flushing
Toxicity due to
accumulation of
cyanide/ thiocyanate
Disadvantage: long term efficacy and safety studies not available, safety in childreen and early pregnanacy not available CI in pt allergic to it
Recommended dose for starting, ot included in any guideline as it a new drug, as an added om drug rather than a substitution for well esstablished drug
No potural hypo, as it does not interfere with cardiac reflexes . No reflex stimulation sympathtic---used in IHD
do not interfere with degradation of bradykinin or other ACE substrates
Dis ad with ACE and ARB aldosterone escape. Indirect activation of AT2 may have antigrowth & antiproliferative ctions
See if OD dose , phase of study
vAlsartan 80 mg ??????????? Phase
interchange column 3 and 4 phase mst common AE diarrhoea, back pain
Useful in pt of low renin levels, as its efficacy not depended on it as RAAS inhibitore. PRC is ususally low in elderly
CI in heart failure, angina
Write when approved clevidipine 0.5 mg/mL in 20% lipid or 20% lipid emulsion (placebo) by infusion over a minimum 30 minutes immediately before anesthesia induction for cardiac surgery (Efficacy Study of Clevidipine Assessing its Preoperative
Antihypertensive Effect in Cardiac Surgery
TY (Evaluation of the Ultra-ShortActing
Clevidipine in the treatment of patients with
severe hypertension) tr