Are all sartans equal

ARE ALL SARTANS EQUAL ?COMPARATIVE EFFICACY OF ARBs

Dr. Satyam RajvanshiDept. of Cardiology, RML Hospital

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

THE RAAS

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.

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.

THE RAAS 1970s - Ang II harms the heart and

kidneys, and high plasma renin activity increases risk of MI and stroke.

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

THE RAAS Angiotensinogen (Liver)

Renin (kidney)

Angiotensin I

Non ACE Pathway ACE Pathway

Angiotensin II

AT1 receptorsAT2 receptors

Increase Aldosterone. Increase Na+ and H2O

retention. Increase Venous return. Increase Preload

IncreaseStimulation of SNS.Thus heart rate and

CO Increase

IncreaseCell growth

Cardiac remodelling

IncreaseVasoconstriction

and SVR

So, inappropriate activation of RAAS leads to…

Hypertension Heart Failure Renal failure Progression of Metabolic Syndrome &

Diabetes Obesity related complications

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Stroke HF CAD, MI CKD CV DEATH

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... CV Morbidity and Mortality!

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RAAS MODULATORSKidney

LVHHTN

RAAS modulators – The past & The present

1980s – First ACEI, Captopril introduced

1990s – First ARB, Losartan introducedFollowed by Valsartan,

Candesartan, Irbesartan

2000s – Telmisartan, Eprosartan, Olmesartan

DRI - Aliskiren

2012 – Azilsartan introduced

Renin Antagonists

RAAS modulators

Direct Renin Inhibitors

• Aliskiren

ACE Inhibitors• Ramipril• Enalapril• Lisinopril• Perindopril

Angiotensin Receptor Blockers

• Losartan• Valsartan• Candesartan• Irbesartan• Eprosatan• Telmisartan• Olmesartan• Azilsartan

ARB: COMPARATIVE PHARMACOLOGY

Drug comparison and pharmacokinetics

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

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

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 – marked difference in t ½ present

Dosage comparisonDrug Starting Dose

(mg/d)Maintenance Dose (mg/d)

Dose Frequency

Losartan 50 25-100 OD – BD Valsartan 80 80-320 ODIrbesartan 150 150-300 ODCandesartan 16 8-32 OD – BDTelmisartan 40 20-80 ODOlmesartan 20 20-40 OD

Some patients may require lower starting dosesSome patients may require total maintenance dose to be split into twice daily dosing

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!

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)

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ARB in HTN

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

ARB in HTN

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

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

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

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

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

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

BP Reduction – Combination therapy

ARB/HCTZ Rationale: HCTZ activates RAS and SNS

Increases sensitivity to ACEI/ARB

Incidence of HCTZ ind. Hypokalemia decreases


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


ARB/CCB Rationale: Incidence of CCB ind. edema

decreasesCCB ind. renal

hyperfiltration decreases All ARB/CCB combinations > better than

MonoRx No head to head trials

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

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

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.

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

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

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/d33% 32% 26% 16% 14%

BP goal achievement Combination Rx: Similar results Olmesartan and Telmisartan/HCTZ and

CCB 70-90% achieve goal BP More than 80% achieve <130/85

ARB in HF

ARB in HF ACEIs have proven benefit in HF with

reduced EF

ARBs in HF….…. Evidence is conflicting!

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

ARB in HF 2 RCTs published in HFnEF

CHARM-Preserve 2003 (candesartan) I-PRESERVE 2008 (Irbesartan)

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

Jong 2002

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

Lee 2004

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

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

Heran et al 2012

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 versus ACEI alone.

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

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.

ARB in HF Even Meta-analysis conflict!

ARB in DM

ARB in DM

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 morbidity.

Cheng et al 2014 Again questions the ‘alternative’ status

of ARBs in diabetics!

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)

ARB in CKD

ARB in CKD KDIGO meeting 2012, 2013, 2014

proceedings concluded In Nephropathy patients

Contd..

No head to head comparison amongst ARBs available

ARB: Side effects

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

ARE ALL SARTANS EQUAL?

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

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!)

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.

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 – IRBESARTANFDA approved for diabetic nephropathy

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 – LOSARTANFDA approved for stroke prophylaxis

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!

References

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

ACEI vs ARB: High CV risk without HF

ACEI vs ARB: High CV risk without HF

Health & Medicine

Are all sartans equal