GIM Journal Club: On or Off Target

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GIM Journal ClubOn or Off Target?

• Telmisartan, Ramipril, or Both in Patients at
  High Risk for Vascular Events. N ENGL J MED 2008,
  3581547-1549.the ONTARGET Group
• Amit Kakkar, R1
• June 17th, 2008

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Background

• Numerous RCT that prove benefit of ACEI (HOPE,
  SOLVD, SAVE) in reducing rates of death, MI, CVA,
  and HF in pts w/ LVD, DM, or PVD.
• ARBs proven to reduce death/hospitalization for
  HF patients unable to tolerate ACEI or already on
  one (CHARM, RESOLVD, RENAAL, Val-Heft)

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Angiotensin II The Bad Guy

• Some effects
• Vasoconstriction
• Salt/water retention (via aldosterone)
• vasopressin/norepi release
• Renal efferent arteriolar vasconstriction
• Cardiac myocyte hypertrophy
• Myocyte necrosis
• Fibroblast proliferation, migration, and collagen
  production
• Free O2 radicals
• 2nd growth factors (TGF-beta, endothelin)
• Vascular smooth muscle proliferation and
  hypertrophy

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The HOPE Trial- Heart Outcomes Prevention
Evaluation

• Inclusion Criteria agegt55, hx CAD, CVA, PVD, or
  DM one of the following (HTN, high TC, low HDL,
  tobacco use, microalbuminuria)
• Exclusion HF, EF lt.4, on ACEI or vitamin E,
  uncontrolled HTN, nephropathy, MI/CVA within
  4weeks.
• Trial terminated early at 4.5yrs due to outcomes
• HOPE looked at highest risk patients, at 4.5yrs
  cardiovascular mortality in 8.1 and nonfatal MI
  4.8

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Verdecchia et al. Do ARBs increase the risk of
MI. European Jouranl of Cardiology. 2005
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Study Design - Goals

• 1) examine if telmisartan (80mg qd) was not
  inferior to the ACEI ramipril (10mg qd)
• 2) if combination of telmisartan ramipril was
  superior to ramipril alone in high risk patients
  with CVD or DM but no HF

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Study Design

• Overall, the ONTARGET program consists of 2
  large, randomized, double-blind, multicenter
  international trials
• a principal trial
• ONTARGET
• parallel trial TRANSCEND

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Study Design - Methods

• Patients recruited at 733 centers in 40 countries
• Data organized/analyzed by 3 coordinating
  centers.
• Progress evaluated regularly by 3 centers
  Boehringer Ingelheim
• Study outcomes abjudicated by central committee
  who were blinded to study group assignments.

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Inclusion Criteria
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Exclusion Criteria
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Study Design - Methods

• Run-In Period 29, 019 enrolled, but 11.7 were
  excluded at this point
• 25,620 left for randomization
• 8542 got telmisartan 80mg po qday
• 8576 got ramipril 5mg po qday, then increased to
  10mg at 2wks
• 8502 got combination
• f/u visits at 6wks, 6months, then q6monthly

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Endpoints

• Primary endpoint death caused by CVD, acute MI,
  CVA, and hospitalization for HF
• Secondary endpoints new HF, revascularization,
  new-onset DM2, angina, renal impairment/renal
  failure requiring HD, and new dx afib

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Results

• Similar characteristics in each treatment group
  (see Table 1)
• 99.8 were followed until a primary event
  occurred or the end of the study

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Results

• No significant difference in of deaths between
  ramipril group and telmisartan group
• Total number of deaths higher in the combination
  therapy group, but not significant
• 2nd outcomes significant findings seen in renal
  dysfunction.

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Discussion

• Telmisartan not inferior to Ramipril for the
  primary outcome
• High rates of adherence to both regimens
• Similar population to reference study (HOPE)
• Combination group showed decreased in BP 2 to
  3mmHg compared to ramipril, but result not
  significant (similar to VALIANT, but not CHARM)

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Strengths

• Large, multi-ethnic population
• High adherence rates
• Similar characteristics to comparator trial
  (HOPE)
• SubGroup Analyses possible (Cardiac MRI trial)
• Dosage regimen fixed

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Concerns

• Choice of ARB? Telmisartan ?
• Reproducibility with other ACEI/ARBs
• Variable dosing of ACEI (CHARM)
• Role of pharma in overseeing results
• Combo effect of ACE/ARBs? Potential?

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References

• Anderson C Rationale and design of the cardiac
  magnetic resonance imaging substudy of The
  ONTARGET Trial Programme. Clinical Trial,
  Journal Article, Multicenter Study, Randomized
  Controlled TrialJ Int Med Res 2005.50A-57A.
• Greenberg and Herman. Contemporary Diagnosis and
  Management of Heart Failure. Handbooks in Health
  Care Co. Newton, PA 2002.
• Heart Outcomes Prevention Evaluation Study
  Investigators Effects of an ACEI on
  cardiovascular events in high risk patients. N
  ENG J MED 2000 342.
• Verdecchia et al. Do ARBs increase the risk of
  MI. European Jouranl of Cardiology. 2005.