20000 fold

1000 fold

3000 fold

12500 fold

HTN

HTN

HTN

HTN
Pediatric HTN

HF
Post-MI Pediatric
HTN(US, 6-16 yrs)

HTN with LVH (reduce

CV risk reduction in patients 55 the risk of stroke) years of age or Nephropathy older at high risk in T2DM who are intolerant
to ACEi

VALIANT ValHeft JIKEI KYOTO

RENAAL LIFE OPTIMAAL ELITE II

ONTARGET, TRANSCEND

ROADMAP

56631

24481

52896

6577

No difference vs. captopril in all-cause mortality (primary) 14,703 post-myocardial infarction patients; Double- blind, randomized (valsartan is as effective as standard of care) study vs. captopril and vs. captopril + valsartan

VALIANT

Val-HeFT
5,010 heart failure IIIV patients; Double-blind, randomized study vs. placebo

13% 37% 28%

morbidity and mortality (primary) left ventricular remodeling atrial fibrillation occurrence heart failure signs/symptoms heart failure hospitalization

39% 3,081 Japanese patients on conventional treatment for hypertension, 40% 47% coronary heart disease, heart failure or combination of these; 65% Multicenter, randomized, controlled trial comparing addition of valsartan vs. non-ARB to conventional treatment

JIKEI HEART

composite CV mortality and morbidity Stroke/transient ischemic attack Hospitalization for heart failure Hospitalization for angina
Composite CV mortality and morbidity Stroke/transient ischemic attack (TIA) Angina pectoris New-onset diabetes

KYOTO HEART
3,031 Japanese patients on conventional treatment for hypertension and high CV risk; Multicentre PROBE trial comparing addition of valsartan vs non-ARB to conventional treatment

45% 45% 49% 33%

MARVAL
291 patients with Type 2 diabetes and microalbuminuria after 24weeks

44% in UAER Vs. 8% with amlodipine. 29.9% acheived normo albuminuria Vs 14.5% with amlodipine

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 those with CVD or DM in the absence of ventricular dysfunction or heart failure ACE-inhibitors are not tolerated by 15% to 25% of patients Will an ARB (telmisartan) be as effective and better tolerated? Is the combination superior?

2. 3. 4.

Questions:
1.
2.

Is telmisartan non-inferior to ramipril?

Is the combination superior to ramipril?

Outcome:
1. 2.

Primary: CV death, MI, stroke, CHF hosp 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

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 mg Full doses (Tel 80 mg daily, Ram 10 mg daily) for the 3 arms

Then

Change in BP (mmHg)

Ramipril Systolic Diastolic -6.0 -4.6

Telmisartan -6.9 -5.2

Combination -8.4 -6.0

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

Implications
Telmisartan is as effective as ramipril, with a slightly better tolerability. Combination therapy is not superior to ramipril, and has increased side effects.

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.

Telmisartan: No Significant Advantages

At 5 yrs, no significant difference in primary outcome: CV death, MI, CVA, or heart failure hosp No significant difference in secondary outcome (data not shown)

17% 15.7%

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

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<0.05)

The Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) trial

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 (<130/80 mm Hg). The primary outcome was the time to the first onset of microalbuminuria
1.Haller H, et al. Olmesartan for delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364:907-917.

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.

ROADMAP trial: Olmesartan delays onset of albuminuria, while increasing mortality

Olmesartan (n=2232) End point Placebo (n=2215)

Patients with events (%)

Hazard ratio (95% CI)

P value

Primary end point

Time to onset of microalbuminuria 178 (8.2) 210 (9.8) 0.77 (0.63-0.94) 0.01

Secondary end points

Composite of cardiovascular complications or death from cardiovascular causes Death from any cause 96 (4.3) 94 (4.2) 1.00 (0.75-1.33) 0.99

26 (1.2)

15 (0.7)

1.70 (0.90-3.22)

0.10

Death from cardiovascular causes Doubling of serum creatinine End stage renal disease
Composite of all cardiovascular complications

15 (0.7) 23 (1)
0% 81 (3.6)

3 (0.1) 4.94 (1.43-17.06)

23 (1) 0% 91 (4.1) 0.67 (0.37-1.19) 0.87 (.65-1.18)

0.01 p>0.05
0.17 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.

Conclusion
Olmesartan was associated with a delayed onset of microalbuminuria 23% reduction in new onset microalbuminuria The higher rate of fatal cardiovascular events with olmesartan
among 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)
1.Haller H, et al. Olmesartan for delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364:907-917.

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 incident diabetes (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

Does Valsartan, Telmi, Olme- ALL of them have similar/ comparable Cardiorenal benefits?

NO !

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 program that has led to cardio-protective indications for both HF and PostMI.

Telmesartan and Olmesartan are not indicated for HF and Post -MI

Updates

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