HypertensionRole of New Combination Therapy
Aziz-ur-RehmanServices Institute of Medical Sciences
Lahore
Hypertension is very prevalent
Hypertension is one of the easiest condition to diagnosis
Uncontrolled hypertension may be asymptomatic but has lot of CV
morbidity & mortality
End-stageRenal Disease
CoronaryHeart Disease
Stroke
Heart failure
Left VentricularHypertrophy
Atherosclerosis
PersistentlyElevated BP
Lewington et al. Lancet 2002;360:1903–13
CV Mortality Risk Doubles with Each 20/10 mmHg Increment in BP*
Cardiovascular mortality risk
0
2
4
8
115/75 135/85 155/95 175/105
6
Systolic BP/Diastolic BP (mmHg)
*Individuals aged 40–69 years
2X risk
4X risk
8X risk
1X risk
Treatment of Hypertension reduces CV morbidity & mortality
Benefits of Blood Pressure Reduction
• Meta-analysis of 61 prospective, observational studies
• 1 million adults• 12.7 years
2 mmHg decrease in mean SBP 10% reduction in risk
of stroke mortality
7% reduction in risk of ischemic heart disease mortality
Lewington et al. Lancet 2002;360:1903–13
Treatment of hypertension is very cost-effective
Majority of the patients are either not diagnosed or not treated
adequately
Law of 50%
Pakistan< 3%
Hypertension is a multifactorial disease
HTN
SNS
RAAS
Vessels
Psy
Na + W
Blockage of one pathway tends to stimulate others
Limitations of Agents with a Single Mechanism of Action (MoA)
• Inadequate in 4060% of hypertensive patients1
• In majority two or more antihypertensive agents are required to achieve the recommended target BP of <130/80 mmHg2
• Multiple channels are needed to be blocked3
1Materson et al. N Engl J Med 1993;328:914212Bakris et al. Am J Kidney Dis 2000;36:64661
3Milani. Am J Manag Care 2005;11:S2207
• Components of multiple-mechanism therapy can add the desirable effects but not the undesirable ones1,2
• Neutralize adverse events.1,2
– Hyperkalaemia of ACEIs & ARBs neutralised by diuretics
– RAAS blockers may attenuate the oedema that is caused by CCBs
1Sica. Drugs 2002;62:443622Quan et al. Am J Cardiovasc Drugs 2006;6:10313
Advantages of Multiple-mechanism Therapy: Safety/Tolerability
Multiple-mechanism therapy may have an improved tolerability profile compared with its single-mechanism components1,2
Current Guidelines Recommend Combination Therapy
• JNC 7 guidelines state1:“When BP is more than 20/10 mmHg above goal, consideration should be given to initiate therapy with 2 drugs...”
• ESH/ESC guidelines state2:“A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or when CV risk is high.”
1Chobanian et al. Hypertension 2003;42:1206–52 2Mancia et al. J Hypertens 2007:25:110587
ESH = European Society of HypertensionESC = European Society of CardiologyJNC = Joint National Committee
Amlodipine has a Wealth of CV Outcomes Data
1Pitt et al. Circulation 2000;102:1503–10; 2Nissen et al. JAMA 2004;292:2217–26; 3Dahlof et al. Lancet 2005;366:895–906 4Williams et al. Circulation 2006;113:1213–25; 5Leenen et al. Hypertension 2006;48:374–84
PREVENT1
825 CAD patients (≥30%):
35% hospitalization for heart failure + angina43% revascularization procedures
CAMELOT2
1,991 CAD patients (>20%):
42% hospitalization for angina27% coronary revascularization
ASCOT-BPLA/CAFE3,4
19,257 HTN patients
16% total CV events and procedures30% new-onset diabetes23% stroke11% all-cause mortality
ALLHAT5
18,102 HTN patients
6% combined CVD23% stroke
Valsartan has a Wealth of CV Outcomes Data
1Julius et al. Lancet 2004;363:2022–31; 2Pfeffer et al. N Engl J Med 2003;349:1893–9063Maggioni et al. Am Heart J 2005;149:548–57; 4Wong et al. J Am Coll Cardiol 2002;40:970–55Cohn et al. N Engl J Med 2001;345:1667–7; 6Mochizuki et al. Lancet 2007;369:1431–9
VALUE1 15,245 patients: HTN 23% new-onset diabetes
VALIANT2 14,703 patients: Post-MI(valsartan is as effective as standard of care)
Val-HeFT3–5
5,010 patients: Heart failure II–IV patients
13% morbidity and mortality (primary)
left ventricular remodeling
37% atrial fibrillation occurrence
heart failure signs/symptoms28% heart failure hospitalization
JIKEI HEART6
3,081 Japanese patients: HTN plus other risk factors
39% composite CV mortality and morbidity
40% Stroke/transient ischemic attack
47% Hospitalization for heart failure
65% Hospitalization for angina
Valsartan also has a Wealth of CV Protection Data
1Viberti et al. Circulation 2002;106:672–82Ridker et al. Hypertension 2006;48:73–9
MARVAL1
332 patients with T2D + microalbuminuria ± HTN: Multicenter, randomized, double-blind, active-controlled study vs. amlodipine
Primary endpoint: % change in urinary albumin excretion rate (UAER) over 6 months
44% in UAER vs. baseline with valsartan vs. 8% with amlodipine
15.4% between-group difference favoring valsartan in patients returning to normoalbuminuria
Val-MARC2
1,668 stage 2 HTN patients: Multicenter, open-label, randomized study vs valsartan/hydrochlorothiazide (HCTZ)
Primary endpoints: change in systolic BP and in high-sensitivity C-reactive protein (hsCRP) between randomization and Week 6
Drop in systolic BP was greater with the combination
13% hsCRP (marker of inflammation) vs. valsartan/HCTZ
ARB (Val)• ↓ RAS ↓ SNS• Arterio- and venodilation• Effective in high-renin patients• Congestive heart failure and renal benefits• Attenuates peripheral edema• No effect on cardiac ischemia
CCB (Aml)• ↑ SNS ↑ RAS• Arteriodilation• Effective in low-renin patients• No renal or congestive heart failure benefits• Peripheral edema• Reduces cardiac ischemia
negative sodium balance
reinforces the effects of the
ARB
Vasodilation Arterial +Venous
CCBs and ARBs compliment each other’s functions
Natriuresis
Arterial
SNS = sympathetic nervous system; RAS = renin-angiotensin system
Amlodipine/Valsartan Provides Powerful BP Reductions
¶DBP 9099 mmHg, SBP 140159 mmHg‡DBP ≥100 mmHg, SBP ≥160 mmHgBP = blood pressure; DBP = diastolic BP; SBP = systolic BP; MSSBP = mean sitting SBP
1Smith et al. J Clin Hypertens 2007;9:355–64 (Dose 10/160 mg)2Poldermans et al. Clin Ther 2007;29:279–89 (Dose 5–10/160 mg)
Mild HTN1¶
Mea
n ch
ange
in M
SSBP
from
bas
elin
e (m
mH
g)
0
–10
–20
–30
–40
–50
n=69 n=140 n=15
–20
–43
–30
Moderate HTN1‡Baseline SBP≥180 mmHg2
10/160 (aml+val)
Amlodipine/Valsartan vs. Amlodipine
LSM Change in MSSBP from baseline (mmHg) LSM Change in MSSBP from baseline (mmHg)
p=0.1
−20
−10
0
Amlodipine/Valsartan10/160 mg
Amlodipine10 mg
p=0.0018
−40
−30
N=55
−31.7
N=46
–40.1
LSM=least square meanMSSBP=mean sitting systolic blood pressure
EX-EFFeCTS1
Patients with Stage 2 Hypertension
−20
−10
0N=42
Amlodipine/Valsartan10/160–320 mg
Amlodipine10 mg
–43.5
−40
−30
−50
−37.2
N=38
EX-STAND2
Black Patients with Stage 2 Hypertension
1.Destro et al. J Am Soc Hypertens 2008;2:294–3022.Flack et al. J Hum Hypertens 2009 (E-pub ahead of print).
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
Amlodipine 10 mg
DiabetesElderly
(65 yrs)
Mea
n ch
ange
in M
SSBP
at W
eek
4 (m
mH
g)
86 89 78 98 46 55 134 145 34 36
*p<0.05 amlodipine/valsartan vs. amlodipine monotherapy
Amlodipine/Valsartan: Superior BP Across Diverse Patient Populations (EX-EFFECTS)
ISH†Severe
(180 mmHg) Obese‡
**
*
* *–29.7
–21.7
–30.2
–22.0
–40.1
–31.7
–27.2
–22.9
–29.5
–22.7
Amlodipine/valsartan 10/160 mg
MSSBP = mean sitting systolic BP†ISH = isolated systolic hypertension (140 and <90 mmHg)‡Obese defined as body mass index 30 kg/m2
–5
–10
–15
–20
–25
–30
–35
–40
–45
Destro et al. J Am Soc Hypertens 2008;2:294–302
Amlodipine/Valsartan Reduces Albuminuria Versus Amlodipine in Black Patients with Stage 2 Hypertension (EX-STAND)
Chan
ge fr
om b
asel
ine
in U
ACR
(%)
Amlodipine5+5 mg
Amlodipine/Valsartan5+160 mg
n=157
n=160
Post-hoc analysis (Week 12 data)UACR = urinary albumin-to-creatinine ratio
–30
101510
50
–5–10–15–20–25–30–35
Flack et al. J Hum Hypertens 2009 (E-pub ahead of print)
Complementary Effects of a CCB/ARB Reduction of CCB-associated Edema
I.
II.
III.
Edema
Arterial hypertension
Constricted blood vessels, high resistance
CCBs BP reduction due to arterial vasodilation Tendency towards edema due to absent venodilation BP reduction stimulates RAAS & causes venoconstriction
CCBs + RAS inhibitors* Blockade of RAAS inhibits effects of angiotensin II,
giving rise to additional BP reduction Additional venodilation by RAS inhibitors reduces
edema
Edema
*Angiotensin receptor blockers or angiotensin-converting enzyme inhibitors
Messerli. Am J Hypertens 2001;14:978–9
Amlodipine/Valsartan: Fewer Patients Experience Peripheral Oedema*
Prop
ortio
n of
pati
ents
exp
erie
ncin
g pe
riphe
ral e
dem
a (%
)
p<0.00140
30
20
10
0
Amlodipine/Valsartan 5/160 mg
Amlodipine10 mg
31%
7%
n=184/591n=39/592
Schrader et al. J Int Clin Pract 2009;63:217225*Week 8 data
SUMMARY- CCB/ARB COMBO
• Amlodipine/Valsartan provides powerful BP reductions
–across hypertension severities• Up to 43 mmHg systolic BP (SBP) drop
– in diverse patient types• Elderly (≥65 years), ISH, obese and diabetics
– in patients uncontrolled with monotherapy• ~21 mmHg SBP drops
–with fewer patients experience peripheral edema
Single-pill combinations of Amlodipine and Valsartan approved as first-line treatments for HTN
• Approvals consistent with current treatment guidelines
• Up to 80% of patients may need multiple medications
• Single-pill combinations offer effective, convenient medications
• Single pill combination improves compliance
Amlodipine + Valsartan Combo
Make use of this powerful tool to control the menace of
hypertension
Combination is Better
Thank youAziz-ur-Rehman