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20000 fold 1000 fold 3000 fold 12500 fold
HTN
HF
Post-MI
PediatricHTN(US, 6-16 yrs)
HTN
HTN with
LVH (reduce
the risk of stroke)
Nephropathyin T2DM
HTN
CV risk
reduction in
patients 55
years of age orolderat high riskwho are intolerant
to ACEi
HTN
Pediatric HTN
VALIANT
ValHeft
JIKEI
KYOTO
RENAAL
LIFE
OPTIMAAL
ELITE II
ONTARGET,
TRANSCEND
ROADMAP
56631 24481 52896 6577
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VALIANT
14,703 post-myocardial infarction patients; Double- blind, randomized
study vs. captopril and vs. captopril + valsartan
No difference vs. captopril in all-cause mortality
(primary)
(valsartan is as effective as standard of care)
Val-HeFT
5,010 heart failure IIIV patients; Double-blind, randomized study vs.
placebo
13% morbidity and mortality (primary) left ventricular remodeling
37% atrial fibrillation occurrence heart failure signs/symptoms
28% heart failure hospitalizationJIKEI HEART3,081 Japanese patients on conventional treatment for hypertension,
coronary heart disease, heart failure or combination of these;
Multicenter, randomized, controlled trial comparing addition of
valsartan vs. non-ARB to conventional treatment
39% composite CV mortality and morbidity40% Stroke/transient ischemic attack47% Hospitalization for heart failure65% Hospitalization for angina
KYOTO HEART
3,031 Japanese patients on conventional treatment for hypertensionand high CV risk; Multicentre PROBE trial comparing addition of
valsartan vs non-ARB to conventional treatment
45% Composite CV mortality and morbidity45% Stroke/transient ischemic attack (TIA)49% Angina pectoris33% New-onset diabetes
MARVAL
291 patients with Type 2 diabetes and microalbuminuria after 24-
weeks
44% in UAER Vs. 8% with amlodipine.29.9% acheived normo albuminuria Vs 14.5%
with amlodipine
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ONTARGET: The ONgoing Telmisartan Alone and in combination with
Ramipril Global Endpoint Trial
Background:
1. ACE-inhibitors (e.g. ramipril in the HOPE trial) reduces CV death, MI, stroke and HF hosp in thosewith CVD or DM in the absence of ventricular dysfunction or heart failure
2. ACE-inhibitors are not tolerated by 15% to 25% of patients
3. Will an ARB (telmisartan) be as effective and better tolerated?
4. Is the combination superior?
Questions:1. Is telmisartan non-inferior to ramipril?
2. Is the combination superior to ramipril?
Outcome:
1. Primary: CV death, MI, stroke, CHF hosp
2. Key secondary: CV death, MI, stroke (HOPE trial outcome)
Design:
1. Single blind run-in (n=29,019) ,Randomized, double blind, double dummy study conducted in
733 centers in 41 countries (n=25,620)2. 56 months follow-up
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Study Medications Titration
Run-in (Single Blind)Day 1-3 Ram 2.5 mg + Tel Placebo
Day 4-10 Ram 2.5 mg + Tel 40 mg
Day 11-18 Ram 5.0 mg + Tel 40 mg
Randomization (Double Blind)
2 weeks Ram Placebo + Tel 80 mg
Ram 5 mg + Tel Placebo
Ram 5 mg + Tel 80 mgThen Full doses (Tel 80 mg daily,
Ram 10 mg daily) for the 3 arms
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Change in BP (mmHg)
Ramipril Telmisartan Combination
Systolic -6.0 -6.9 -8.4
Diastolic -4.6 -5.2 -6.0
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Conclusions: Telmisartan vs. Ramipril
1. Telmisartan is non-inferior to ramipril Primary composite outcome (p=0.0038)
Most (>90%) of the benefits of ramipril are preserved
2. Consistent results on a range of:
Secondary outcomes
Subgroups
3. Telmisartan exhibits slightly superior tolerability
Less cough and angioneurotic edema
More mild hypotensive symptoms, but no difference in severe
hypotensive symptoms, such as syncope
4. Combination therapy does not reduce the primary outcome to a
greater extent compared to ramipril alone
5. Higher rates of adverse events:
hypotension related, including syncope renal dysfunction
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Implications
Telmisartan is as effective as ramipril, with a slightly better tolerability.
Combination therapy is not superior to ramipril, and has increased side
effects.
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TRANSCEND
Randomized close to 6000 individuals
With known CV disease or advanced DM
Who were intolerant of an ACE-I
Telmisartan 80 mg or placebo
Primary outcome: CV death, MI, CVA, or heart failure hosp.
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Telmisartan: No Significant Advantages
15.7%
17%
At 5 yrs, nosignificant difference
in primary outcome:
CV death, MI, CVA, or
heart failure hosp
No significant
difference in
secondary outcome
(data not shown)
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TRANSCEND- Conclusion
At best, there was only a modest benefit of telmisartan
over placebo among individuals with known CVD or
advanced DM who were intolerant to ACE-I
When compared to similar studies of ACE-I, telmisartan
appears to have a less robust impact upon outcomes
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DIOVAN Messages:
Powerful blood pressure-lowering efficacy
The VALIANT (n=14,703 )patients,
Similar to an ACE-inhibitor regimen in reducing mortality in
high-risk post-MI patients
The ValHeFT (n= 5,010)
Significant reduction in the combined endpoint of mortality and
morbidity in patients with heart failure
JIKEI HEART (n= 3,081) Japanese patients
9% relative risk reduction in the combined CV
morbidity/mortality endpoint
KYOTO HEART (n=3,031)Japanese patients
significantly reduced the primary composite CV endpoint by
45% compared to conventional therapy (p=0.00001), including a
45% reduction in the risk of stroke (p
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The Randomized Olmesartan And Diabetes
MicroAlbuminuria Prevention (ROADMAP) trial
1.Haller H, et al. Olmesartan for delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med.2011;364:907-917.
Design: Randomized, double-blind, multicenter, controlled trial.
Population: 4447 patients with type 2 diabetes and at least one
additional cardiovascular risk factor, but with no evidence of renal
dysfunction
Medication: Olmesartan (at a dose of 40 mg once daily) versus
placebo for median 3.2 years
Other antihypertensive drugs (except ACE inhibitors and ARBs)
were used as required for BP control (
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ROADMAP trial: Occurrence of microalbuminuria during the
48-month follow-up period in the two study groups
1.Haller H, et al. Olmesartan for delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med.2011;364:907-917.
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ROADMAP trial: Olmesartan delays onset of albuminuria, while
increasing mortality
End point
Olmesartan(n=2232)
Placebo(n=2215) Hazard ratio
(95% CI) PvaluePatients with events (%)
Primary end point
Time to onset of microalbuminuria 178 (8.2) 210 (9.8) 0.77 (0.63-0.94) 0.01
Secondary end pointsComposite of cardiovascular
complications or death fromcardiovascular causes
96 (4.3) 94 (4.2) 1.00 (0.75-1.33) 0.99
Death from any cause 26 (1.2) 15 (0.7) 1.70 (0.90-3.22) 0.10
Death from cardiovascular causes 15 (0.7) 3 (0.1) 4.94 (1.43-17.06) 0.01
Doubling of serum creatinine 23 (1) 23 (1) - p>0.05
End stage renal disease 0% 0% 0.67 (0.37-1.19) 0.17
Composite of all cardiovascularcomplications
81 (3.6) 91 (4.1) 0.87 (.65-1.18) 0.37
1.Haller H, et al. Olmesartan for delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med.2011;364:907-917.
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Conclusion
1.Haller H, et al. Olmesartan for delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med.2011;364:907-917.
Olmesartan was associated with a delayed onset of
microalbuminuria
23% reduction in new onset microalbuminuria
The higher rate of fatal cardiovascular events with
olmesartanamong patients with pre-existing coronary heart disease
The study failed to meet its secondary composite renal
endpoint
comprising doubling of serum creatinine, end stage renal disease
and worsening of renal function as assessed by changes in
estimated glomerular filtration rate (eGFR)
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Diovan Messages
ROADMAP -Olmesartan can delay the onset of MAU in diabetic
patients with normoalbuminuria at randomization The nephroprotective potential of DIOVAN has been demonstrated in the
MARVAL and DROP trials (up to 51% reductions in albuminuria in diabetic
patients)
In people with IGT and CV disease or risk factors, valsartan in addition to
lifestyle modification,14% relative (3.8% absolute) reduction in incidentdiabetes (median follow-up 5 yrs)- NAVIGATOR
The ROADMAP failed to demonstrate a CV benefit in favor of
olmesartan
DIOVAN-based therapy provides powerful BP-lowering efficacy
DIOVAN has been extensively studied in CV outcome trials (ValHeFT / VALIANT
/ JIKEI HEART / KYOTO HEART)
DIOVAN remains the only ARB indicated in both post-MI and heart failure
populations
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Does Valsartan, Telmi, Olme- ALL of them have similar/
comparable Cardiorenal benefits?
NO !
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The reason health authorities around the world require robust
outcomes-based studies to gain approval for cardio-protective
indications is simply due to the fact that drugs are different .
Only VALSARTAN has a massive mega-trial evidence-based programthat has led to cardio-protective indications for both HF and Post-
MI.
Telmesartan and Olmesartan are not indicatedfor HF and Post -MI
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Updates
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Thank You
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