The document compares the efficacy of different angiotensin receptor blockers (ARBs). It provides an overview of the renin-angiotensin-aldosterone system (RAAS) and how RAAS modulators such as ARBs work. It then reviews clinical trial data comparing the blood pressure lowering effects, 24-hour blood pressure control, and ability to achieve blood pressure goals of various ARBs. The document also examines the evidence for using ARBs to treat heart failure, including several meta-analyses, with the conclusion being that ARBs do not reduce mortality or morbidity in heart failure beyond placebo or ACE inhibitors.

1. ARE ALL SARTANS
EQUAL ?
COMPARATIVE EFFICACY OF ARBs
Dr. Satyam Rajvanshi
Dept. of Cardiology, RML Hospital

2. Overview
 The RAAS
 RAAS Modulators
 ARB: Comparative Pharmacology
 ARB in HTN
 ARB in HF
 ARB in Diabetes
 ARB in CKD
 Are all sartans equal?

3. THE RAAS

4. THE RAAS
 The Renin-Angiotensin-Aldosterone System
 1898 - Physiologist Robert Tigerstedt and his
student, Per Bergman, experimented with
rabbits by injecting them with kidney extracts -
Results suggested the kidneys produced a
protein, which they named Renin
(renin = ren + in, ‘kidney’ + ‘compound’), that
caused a rise in blood pressure.

5. THE RAAS
 1930s – Goldblatt experimentally constricted
the renal blood flow in dogs – found
ischemic kidneys did in fact secrete a chemical
causing vasoconstriction
 1939 – Found Renin does not cause the rise in
blood pressure, but was an enzyme which
catalyzed the formation of the substances that
were responsible, namely, Angiotensin I (Ang
I) and Ang II.

6. THE RAAS
 1970s - Ang II harms the heart and kidneys,
and high plasma renin activity increases risk of
MI and stroke.

7. THE RAAS
 Renin-Angiotensin System (RAS) –
Peptidergic system which has endocrine
characteristics
 Simply defined-
 Substrate – Angiotensinogen, secreted by Liver
 Enzyme – Renin, secreted by JGA in kidney
 Product – Angiotensin I
 2nd enzyme – Angiotensin Converting Enzyme
(ACE)
 Final effector product – Angiotensin II

10. THE RAAS
Angiotensinogen (Liver)
Renin (kidney)
Angiotensin I
Non ACE Pathway ACE Pathway
Angiotensin II
AT1 receptors
AT2 receptors
Increase Aldosterone.
Increase Na+ and H2O
retention. Increase Venous
return. Increase Preload
Increase
Stimulation of SNS.
Thus heart rate and
CO Increase
Increase
Cell growth
Cardiac
remodelling
Increase
Vasoconstriction
and SVR

11. So, inappropriate activation of RAAS leads to…
 Hypertension
 Heart Failure
 Renal failure
 Progression of Metabolic Syndrome & Diabetes
 Obesity related complications
11

12. So, inappropriate activation of RAAS leads to…
 Stroke
 HF
 CAD, MI
 CKD
 CV DEATH
12

13. So, inappropriate activation of RAAS leads to…
... CV Morbidity and Mortality!
13

14. RAAS MODULATORS
Kidney
LVHHTN

15. RAAS modulators – The past & The
present
 1980s – First ACEI, Captopril introduced
 1990s – First ARB, Losartan introduced
Followed by Valsartan, Candesartan,
Irbesartan
 2000s – Telmisartan, Eprosartan, Olmesartan
DRI - Aliskiren
 2012 – Azilsartan introduced

16. Renin
Antagonists

17. RAAS modulators
Direct Renin Inhibitors
• Aliskiren
ACE Inhibitors
• Ramipril
• Enalapril
• Lisinopril
• Perindopril
Angiotensin Receptor
Blockers
• Losartan
• Valsartan
• Candesartan
• Irbesartan
• Eprosatan
• Telmisartan
• Olmesartan
• Azilsartan

18. ARB: COMPARATIVE
PHARMACOLOGY

19. Drug comparison and
pharmacokinetics
Olin BR, ed. Drug Facts and Comparisons. St. Louis: JB Lippincott Co, 2002:514–518.

20.  Losartan, Irbesartan, and Candesartan are CYP
450 metabolized
 Losartan needs CYP450 for conversion to active
metabolite
 Candesartan converts to active metabolite while
absorption from gut – CYP needed for elimination
only
 None of the ARBs requires dose modification in
Renal dysfunction
 Telmisartan needs to be used cautiously in
hepatic failure – other ARBs safer in CLD

22. Insurmountable
antagonism is
characterised by long-
lasting inhibition, slow
dissociation,
irreversible binding,
conformational
changes.
Surmountable
antagonism is
characterised by short-
lasting inhibition and
fast, reversible binding.
Even between ARBs
having high
insurmountability –
½

23. Dosage comparison
Drug Starting Dose
(mg/d)
Maintenance
Dose (mg/d)
Dose Frequency
Losartan 50 25-100 OD – BD
Valsartan 80 80-320 OD
Irbesartan 150 150-300 OD
Candesartan 16 8-32 OD – BD
Telmisartan 40 20-80 OD
Olmesartan 20 20-40 OD
Some patients may require lower starting doses
Some patients may require total maintenance dose to be split into twice daily dosin
Note - Candesartan despite most noncompetitive inhibition has shorter t1/2,
may require twice daily dosing!
- Olmesartan despite shorter t1/2 requires only once a day dosing!

24.  Losartan: Only ARB with Uricosuric action
 Telmisartan: Has PPAR-gamma activity and hence
improves Insulin sensitivity
 Olmesartan: Decreases CRP
 Eprosartan: short acting (5 hr Half life), not much
data
 Azilsartan: newest, structurally related to
candesartan, Intermediate acting (11 hr Half life)
24

25. ARB in HTN

26. Why to use ARB for HTN?
 Highly effective as first line agents against HTN –
similar to ACEIs
 Upto 50% pts achieve goal BP with ARB
monotherapy alone
 Excellent tolerability – AE profile almost similar to
placebo – Significantly lower Cough incidence
than ACEIs
 Slow progression of HTN & DM associated renal
disease – apparently independent of BP lowering
– Like ACEIs
 Long term efficacy does not decrease over time –
ACEIs suffer from “Ang-II escape” phenomenon

27. ARB in HTN

28. ARB in HTN
 Several head to head trials between ARBs
 No single study directly assesses all ARBs
 Summary of trial findings to reach a conclusion

29. BP Reduction - Monotherapy
 Losartan
 First ARB
 50-100 mg/d
 On systematic upward titration, combining
different studies -
 Mean SBP reduction: 10-14 mmHg
 Mean DBP reduction: 6-12 mmHg

30. BP Reduction - Monotherapy
 Candesartan
 Most studies: 8-16 mg/d
 8 mg/d dose – equivalent to Losartan 50 mg/d
– inferior to Olmesartan 20 mg/d
 16 mg/d dose – better than Losartan
 Current starting dose recommendation: 16 mg/d
 Mean SBP reduction: 13-19 mmHg
 Mean DBP reduction: 8-13 mmHg

31. BP Reduction - Monotherapy
 Irbesartan
 Most studies: 8-16 mg/d
 150 mg/d – equivalent to Losartan 100 mg/d
 300 mg/d – better than Losartan 100 mg/d
– equivalent to Valsartan 160 mg/d
 Mean SBP reduction: 10-12 mmHg
 Mean DBP reduction: 10 mmHg

32. BP Reduction - Monotherapy
 Telmisartan
 40 mg/d dose – better than Losartan 50 or 100
mg/d
– better than Valsartan 80 mg/d
 Mean SBP reduction: 10-21 mmHg
 Mean DBP reduction: 9-19 mmHg

33. BP Reduction - Monotherapy
 Olmesartan
 20 mg/d dose – better than Losartan 50 mg/d
– better than Candesartan 16 mg/d
– better than Irbesartan, Valsartan
 Mean SBP reduction: 11-21 mmHg
 Mean DBP reduction: 11-16 mmHg

34. BP Reduction – Combination
therapy
 ARB/HCTZ
 Rationale: HCTZ activates RAS and SNS
Increases sensitivity to ACEI/ARB
Incidence of HCTZ ind.
Hypokalemia decreases

35. BP Reduction – Combination
therapy
 ARB/HCTZ
 All ARB/HCTZ combinations > better than
MonoRx
 Olmesartan/HCTZ potency and efficacy > better
than other combinations
 High dose Olmesartan/HCTZ – 40/25 mg/d
 Mean SBP reduction: 26-35 mmHg
 Mean DBP reduction: 14-21 mmHg
 Least potent is Losartan/HCTZ

36. BP Reduction – Combination
therapy
 ARB/CCB
 Rationale: Incidence of CCB ind. edema
decreases
CCB ind. renal hyperfiltration
decreases
 All ARB/CCB combinations > better than MonoRx
 No head to head trials

37. 24-hour BP control
 Maximum CV risk reduction is with effective
24-hr BP control
 Specially important for drugs with once-a-day
dosing in morning – final 4 hrs of interdosing
period coincide with ‘Early morning surge’
 Early morning BP surge strongly associated
with incease in Cardiovascular (MI/SCD) and
Caerebrovascular (Stroke) events

38. 24-hour BP control
 Maximum CV risk reduction is with effective
24-hr BP control
 Specially important for drugs with once-a-day
dosing in morning – final 4 hrs of interdosing
period coincide with ‘Early morning surge’
 Early morning BP surge strongly associated
with incease in Cardiovascular (MI/SCD) and
Caerebrovascular (Stroke) events

39. 24-hour BP control
Mean changes in systolic and diastolic blood pressure (SBP; DBP)
assessed by ambulatory blood pressure monitoring over (a) 24
hours (b) the last four hours of the dosing interval. Values are
adjusted by initial dose, age, number of patients, clinic blood
pressure.

40. 24-hour BP control
 Some trials show Telmisartan better than
Olmesartan
 Clearly – Telmisartan, Olmesartan better than
others
 Olmesartan despite 13 hr half life, has proven
DOA over 24 hrs – maybe due to receptor
binding characteristics

41. BP reduction: Speed of onset
 For maximum CV benefit – BP must be
normalized as quickly as possible after starting
Rx
 Amlodipine faster than Valsartan
 Olmesartan equivalent to Amlodipine
 Olmesartan and Telmisartan faster than older
ARBs in BP reduction at 1 and 2 weeks

42. BP goal achievement
 Very few studies compare BP goal
achievement across ARBs – only
retrospectove analyses present
 MonoRx at Starting doses achieving goal BPOlmesartan Telmisatan Irbesartan Losartan Valsartan
20 mg/d 40 mg/d 150 mg/d 50 mg/d 80 mg/d
33% 32% 26% 16% 14%

43. BP goal achievement
 Combination Rx: Similar results
 Olmesartan and Telmisartan/HCTZ and CCB
 70-90% achieve goal BP
 More than 80% achieve <130/85

44. ARB in HF

45. ARB in HF
 ACEIs have proven benefit in HF with reduced
EF
 ARBs in HF….
…. Evidence is conflicting!

46. ARB in HF
 ARCH-J 2003
 CHARM-Alternative 2003
 Crozier 1995
 Mitrovic 2003
 Sharma 2000, III-Int’l; Sharma
2000, III-US
 SPICE 2000
 STRETCH 1999),
 Dickstein 1995
 ELITE 1997; ELITE II 2000
 HEAVEN 2002
 Lang 1997
 REPLACE 2001
 ADEPT 2001
 CHARMAdded 2003
 Hamroff 1999
 Tonkon 2000
 V-HeFT 1999
 Val-HeFT 2001
 Mazayev 1998
 RESOLVD 1999
Total of about 22 RCTs published including
HFrEF

47. ARB in HF
 2 RCTs published in HFnEF
 CHARM-Preserve 2003 (candesartan)
 I-PRESERVE 2008 (Irbesartan)

48. ARB in HF
 Several meta-analysis published
 Jong 2002; Lakhdar 2008; Lee 2004; Shah
2010;Sharma 2000; Shibata 2008
 Jong 2002 & Lee 2004 were the largest
metaanalysis

49. Jong 2002

50. Jong 2002
 Compared ACEIs and ARBs in patients with symptomatic HF.
The pooled outcomes were all-cause mortality and
hospitalization for HF.
 17 trials included.
 ARBs were not superior to controls in rates of death or
hospitalization
 Nonsignificant trend in benefit of ARBs over placebo in
reducing mortality and hospitalization when given in the
absence of background ACEI therapy.
 When compared directly with ACEIs, ARBs were not superior
in reducing either mortality or hospitalization
 Combination therapy of ARBs and ACEIs was superior to
ACEIs alone in reducing hospitalization but not mortality

51. Lee 2004

52. Lee 2004
 24 trials included
 ARBs reduced all-cause mortality and heart failure
hospitalizations as compared with placebo
 ARBs versus ACE inhibitors, all-cause mortality
and heart failure hospitalization did not differ
 Combinations of ARBs plus ACE inhibitors versus
ACE inhibitors alone, all-cause mortality was not
reduced but heart failure hospitalizations were
reduced
 High-risk acute MI, 2 randomized trials compared
ARBs withACE inhibitors but did not reveal
differences in all-cause mortality or heart failure
hospitalization

53.  Both Metanalysis concluded
 ARBs and ACEIs cause similar mortality and
morbidity reduction in HF
 ARBs should be regarded as suitable alternative
to ACEI in HF

54. Heran et al 2012

55. Heran et al 2012
 Most recent (2012) meta-analysis
 22 studies evaluated the effects of ARBs in
LVEF ≤40%
 ARBs did not reduce total mortality or total morbidity
as measured by total hospitalisations compared with
placebo.
 Total mortality, total hospitalisations, and stroke did
not differ between ARBs and ACEIs but withdrawals
due to adverse effects were lower with ARBs.
 Combinations of ARBs plus ACEIs increased the risk
of withdrawals due to adverse effects but did not
reduce total mortality or total hospital admissions

56. Heran et al 2012
 2 studies evaluated ARBs LVEF >40%
 ARBs did not reduce total mortality or total
morbidity as measured by total hospitalisations
compared with placebo.
 Withdrawals due to adverse effects were
higher with ARBs versus placebo when all
patients were pooled irrespective of LVEF

57. Heran et al 2012
 Concluded -
 In patients with symptomatic HF and systolic
dysfunction or with preserved ejection fraction, ARBs
compared to placebo or ACEIs do not reduce total
mortality or morbidity.
 ARBs are better tolerated than ACEIs but do not
appear to be as safe and well tolerated as placebo in
terms of withdrawals due to adverse effects.
 Adding an ARB in combination with an ACEI does not
reduce total mortality or total hospital admission but
increases withdrawals due to adverse effects
compared with ACEI alone.

58. ARB in HF
 Even Meta-analysis conflict!

59. ARB in DM

60. ARB in DM

61. Cheng et al 2014
 Most recent meta-analysis (2014) concluded
 ACEIs and ARBs differentially affect the risk of all-
cause mortality, CV deaths and CV events in
patients with diabetes.
 ACEIs reduce the risk of mortality, myocardial
infarction and heart failure, while ARBs does not
affect risk of mortality and major CV events.
 ARB therapy did reduce the risk of heart failure.
 No effect on stroke was seen with either
treatment.
 Based on these data, ACEIs should be
considered first-line treatment in patients with
diabetes mellitus, to reduce mortality and

62. Cheng et al 2014
 Again questions the ‘alternative’ status of
ARBs in diabetics!

63. ARB in DM
 Though various studies have shown ARBs to
be beneficial
 No head to head trial comparing ARBs
 Telmisartan and Olmesartan
 May increase insulin sensitivity (activate PPAR
Gamma)
 May decrease systemic inflammation (decrease
CRP)

64. ARB in CKD

65. ARB in CKD
 KDIGO meeting 2012, 2013, 2014
proceedings concluded
 In Nephropathy patients

66.  Contd..
 No head to head comparison amongst ARBs
available

67. ARB: Side effects

68. ARB: Side effects
 Most studies show excellent tolerability of
ARBs
 Significantly less discontinuation rate than
ACEIs – Mainly because of Cough
 No evidence to suggest any significant
difference between ARBs in AEs rates

69. ARE ALL SARTANS EQUAL?

70. ARE ALL SARTANS EQUAL?
 Hypertension
 No head to head trials
 Many trials compare only DBP or only SBP
reduction
 Many trials used lesser starting doses than
recommended curently
 Many trials do not titrate dose upwards – Fixed
doses
 Few trials show conflicting evidence in efficacy

71. ARE ALL SARTANS EQUAL?
 Hypertension
 Despite these Shortcomings
 All ARBs are approved for use in HTN
 Newer ARBs (Telmisartan and Olmesartan)
- probably better than older ones!
 OLD is NOT always GOLD!
(In Medicine! And in ARBs!)

72. ARE ALL SARTANS EQUAL?
 HF
 No head to head trials
 Most meta-analysis conclude ARB use as an
alternative to ACEI
 Though guidelines do not particularly specify -
VALSARTAN and CANDESARTAN
- FDA approved for heart failure, to reduce
cardiovascular mortality in clinically stable
patients with left ventricular failure, left ventricular
dysfunction following myocardial infarction.

73. ARE ALL SARTANS EQUAL?
 CKD and DM
 No head to head trials
 Metaanalysis show superiority of ACEI over ARB;
ARB better than Placebo; conclude ARB use as
an alternative to ACEI
 Though guidelines do not particularly specify –
IRBESARTAN
FDA approved for diabetic nephropathy

74. ARE ALL SARTANS EQUAL?
 High CV risk without HF
 No head to head trials amongst ARBs
 Some Metaanalysis show superiority of ACEI over
ARB; conclude ARB use as an alternative to ACEI
 Though guidelines do not particularly specify –
LOSARTAN
FDA approved for stroke prophylaxis

75. ARE ALL SARTANS EQUAL?
 HF
 CKD
 DM
 High CV risk without HF
OLD (ACEIs) is GOLD!
NEW (ARBs) is SILVER!
… (probably!)
Amongst ARBs - No evidence to say!

76. References

77.  Comparison of Angiotensin II Type 1 Receptor Antagonists in the Treatment
of Essential Hypertension. David H.G. Smith. Drugs 2008; 68 (9): 1207-
1225
 Efficacy in angiotensin receptor blockade: a comparative review of data
with olmesartan. Josep Redon, Maria Jose Fabia. Journal of the Renin-
Angiotensin-Aldosterone System (Including other Peptidergic systems);
September 2009 Volume 10 Number 3
 Angiotensin Receptor Blockers - Advantages of the New Sartans. Zia Al
Sabbah, Aijaz Mansoor. JAPI • july 2013 • VOL. 61
 Angiotensin receptor blockers for heart failure (Review). Heran BS The
Cochrane Library; 2012, Issue 4
 ACE inhibitors and ARBs differentially affect CV morbidity and mortality in
diabetics • Cheng J et al., JAMA. 2014
 A Meta-Analysis Reporting Effects of Angiotensin-Converting Enzyme
Inhibitors and Angiotensin Receptor Blockers in Patients Without Heart
Failure. JACC Vol. 61, No. 2, 2013
 KDIGO proceedings 2012-2014

79. ACEI vs ARB: High CV risk without
HF

80. ACEI vs ARB: High CV risk without
HF