OUR VISION To be a globally-acknowledged centre of excellence for clinical care, education

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OUR VISIONTo be a globally-acknowledged centre
of excellence for clinical care,
education training, and research
in diabetology and endocrinology.
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ARBs vs. ACEI

• Dr SANJAY KALRA
• BHARTI HOSPITAL
• KARNAL

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TAKE HOME MESSAGES

• Read the fine print
• Familiarize yourself with side-effects, kinetics,
  doses
• Give ACEI if cardiac morbidity is a concern
• Give ARB if renal morbidity is a concern, in type
  2DM ACEI in type 1
• Give both if both are a concern
• Make sure you control BP

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WHY CONTROL B.P ?

• Decreased risk of
• stroke
• cardiovascular disease
• nephropathy
• Decreased mortality
• BOTH SYSTOLIC DIASTOLIC BP ARE IMPORTANT (JNC
  7, MONICA 94,BHRC 90)

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Questions Unanswered

• A specific endpoint
• Blood pressure
• Cardiac morbidity
• Renal morbidity
• Cerebrovascular morbidity
• Mortality
• class effect
• Specific dose

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Class effect

• All drugs of a particular class have a common
  minimum structure or common effect
• Extra elements may add other unknown effects or
  take away beneficial effects

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Class effect

• Development of a molecule is expensive
• It is much easier and economical to market a
  me-too molecule, based on class effect
• Studies may not be available to show a particular
  effect

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Dose effect

• 10 mg of ramipril is not equal to 5 mg of
  ramipril
• 10 mg of ramipril is certainly not equal to 10 mg
  of quinapril
• 4 mg perindopril PROGRESS shows different
  results from 8 mg EUROPA

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PHYSIOLOGY

• RENIN-ANGIOTENSIN SYSTEM
• Vasoconstrictor system
• Activation leads to hypertension
• Blockade of angiotensin II or its receptors leads
  to normotension
• This also prevents cerebrovascular,
  cardiovascular and renal events

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Actions of RAS

• Circulating RAS
• Vasoconstriction
• Aldosterone release
• AVP release
• Stimulate thirst and sodium appetite
• Renal sodium and water reabsorption

• Tissue-based RAS
• Hypertrophy
• Hyperplasia
• Remodelling
• Cytokine activation
• Collagen deposition/ fibrosis

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Angiotensin
Endopeptidase
Chymase
ACE
Angiotensin (1-7)
Angiotensin II
Bradykinin
Inactive peptides
AT 1 AT 2 NO, prostaglandins
Non-AT1/ non-AT2
Vasoconstriction Vasodilation Growth
promotion Growth inhibition Sodium
reabsorption Natriuresis
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Endothelium and Ang II

• Vasoconstriction
• Inflammation
• Remodelling
• Thrombosis
• Oxidative stress
• Stimulation of metalloproteinases which break
  down extracellular matrix

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Tissue angiotensin II
Oxidative stress Cytokines Adhesion
molecules Growth factors
Cathepsin G from granulocytes Chymase from mast
cells ACE from monocytes
Inflammation Progression of lesion Smooth muscle
cells Foam cells Thrombosis
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Rationale for ARBs/combinattion

• ACEI dont suppress Ang II production over 24 h
• Partial recovery of Ang II occurs ACE escape
• Ang II is also produced by cathepsin G, elastase,
  tPA, chymase, chymostatin-sensitive Ang II
  generating enzyme CAGE, tonin
• Cough and angioedema are less common with ARBs as
  they do not increase bradykinin levels
• 18 pts respond only to ACEI, 15 only to ARB
  Stergiou , 2001

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ACEI

• Reduce morbidity and mortality in heart failure
  patients
• Meta-analysis of 7105 patients in 32 trials gt 8
  weeks duration showed 0.77 OR for all-cause
  mortality, 0.65 OR for mortality
  hospitalization due to CCF

• Meta-analysis of 12763 patients of LV dysfunction
  /- MI in 5 trials showed 0.80 OR for all-cause
  mortality, 0.67 OR for hospitalization due to
  failure, 0.79 OR for reinfarction

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ACEI

• Meta-analysis of 98496 patients in 4 trials
  treated within 0-36 hrs of MI with ACEI showed
  7 reduction in 30-day mortality and significant
  decrease in nonfatal heart failure

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ACEI IN DIABETIC HYPERTENSIVES

• FACET 380 pts. Fosinopril vs. amlodipine. HR
  0.49 for acute MI, stroke and hospitalization due
  to angina. B.P control was better with amlodipine
  -19 mm SBP vs. 13 mm SBP with fosinopril -8
  mm DBP with both
• ABCD 470 pts. Enalpril vs. nisoldipine had lower
  risk for MI, though BP control was same.
• UKPDS no difference b/w captopril and atenolol

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ACEI IN HYPERTENSION

• STOP 6614 patients 70 84 yrs old. ACEI
  better than CCB RR 0.77 but not different from
  BB or diuretic w.r.t risk for MI
• CAPPP 10985 pts. No difference b/w captopril and
  BB-diuretic groups w.r.t risk of MI

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ACE INHIBITORS

• HOPE STUDY
• marked reduction in complications of diabetes RR
  0.84
• Reduction in new cases of diabetes RR 0.66

• Improved insulin sensitivity
• decreased hepatic clearance of insulin
• antiinflammatory effect
• improved pancreatic blood flow

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HOPE

• 9297 patients at high risk of CV events
• Risk of MI, stroke, death from cardiovascular
  causes lower for ramipril group RR 0.68 to 0.84
• 20 risk reduction in MI is more than the 5 RR
  expected with a 3 mm redction in SBP

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Different ACEI

• 4 ACEIs have not been shown to reduce
  morbidity/mortality in any indication
  benazepril, fosinopril, moexipril, quinapril
• A 5th perindopril has shown benefit at 8 mg but
  not at 4 mg
• ramipril has the broadest approval

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ARBs and blood pressure

• CCBs are taken to be potent anti-hypertensives
• 24 hour coverage is needed to protect against
  early morning activation of RAS
• Telmisartan is more potent than amlodipine for
  DBP control and control during 4 hours prior to
  dosing Lacourciere et al, 1998

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ARBs and nephropathy

• IRMA2 trial irbesartan reduced overt nephropathy
  by 71 in diabetics with microalbuminuria
  (Parving, 2001)
• Similar results by Brenner in RENAAL (losartan,
  2001), Lewis in IDNT (irbesartan, 2001), Viberti
  in MARVAL (valsartan, 2002) in type 2 diabetics
  with overt nephropathy

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ACE(I) or ARBs for the kidney ?

• Best results for type 2 renoprotection seen with
  ARBs
• IRMA2 71 RR with 300 mg irbesartan
• Ravid 94 30 with enalapril
• MICRO-HOPE 25 with ramipril

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ARBs and heart failure

• ELITE losartan better tolerated, reduced
  mortality, with better compliance w.r.t captopril
  1997
• ELITE II no difference in mortality 2000

• ValHeFT addition of valsartan reduced endpoint
  by 13.2 in all pts by 45 in pts not on ACEI
  2001
• LIFE losartan and atenolol equipotent for BP
  control losartan RR 0.75 for stroke, 0.87 for
  combined endpoint 2002

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ARBs

• SCOPE candesartan reduces risk of stroke by 28
  no change in cognitive function 2002
• ACCESS candesartan reduced mortality/
  complications by 47.5 in stroke survivors

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Different ARBs

• Losartan, eprosartan b.d dose
• Rifampicin induces, fluconazole reduces
  metabolism of losartan
• Losaretan is uricosuric
• Avoid digoxin telmisartan
• Can give valsartan, telmisartan with food
• Avoid losartan in hepatic dysfunction
• Prefer telmisartan in severe renal failure
• Candesartan most potent telmisartan longest t 1/2

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Combination

• RESOLVD candesartan enalapril , but
  combination is better for 6MWD, ventricular
  function, NYHA-FC and QOL. Optimum dose
  enalpril 20 mg cande 8 mg 1999

• OPTIMAAL losartan 50 mg captopril 150 mg/d
  2002
• Pfeffer et al, 2003 valsartan captopril
  combination.
• CHARM candesartan reduced endpoint by 15

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ARBs optimal dose

• Higher doses provide more benefit various
• Valsartan 160 mg
• Losartan 100 mg
• Candesartan 8 mg

• Valsartan 160 mg lisinopril 20 mg amlodipine
  10 mg
• Valsartan 160 mg better than enalapril 20 mg,
  benazepril 20 mg

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ACEI ARBs (DUAL BLOCKADE)

• Rossing, 2000 candesartan 8 mg
  enalapril/lisinopril 20 mg or captopril 100 mg
• CALM study, 2000 candesartan 16 mg lisinopril
  20 mg greater decline in DBP, SBP but no
  significant reduction in urinary albumin
  creatinine ratio

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COMBINATION THERAPY

• gt65 of diabetics require combination therapy to
  achieve B.P.lt 130/80
  (Nat Kid Fnd Ht Diab Exec Com Work Gp, 2000
  Sep)
• Diabetics require 2nd 3rd drugs 40 100
  more frequently than non-diabetics (Brown et al,
  2000 May)
• Similar guidelines from JNC 7 ESH, 2003

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ACEI BETA-BLOCKERS

• Both lower sympathetic drive
• Both act on high- renin hypertension
• Combination is not synergistic
• No such combination available in market

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CONCLUSION

• Control B.P. aggressively
• CONVINCE YOURSELF BEFORE CONVINCING THE PATIENT
• Use appropriate monotherapy or combination
  therapy
• Increase compliance

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