differentiating arbs-q1'12 (2)

8/22/2019 Differentiating ARBs-Q1'12 (2)

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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



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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



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Conclusion


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

differentiating arbs-q1'12 (2)

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