Andrea Ferrucci Centro per la Diagnosi e la Cura dell’Ipertensione Arteriosa UOC di Cardiologia,...

Andrea Ferrucci

Centro per la Diagnosi e la Cura dell’Ipertensione ArteriosaUOC di Cardiologia, Dipartimento di Medicina Clinica e Molecolare,

Facoltà di Medicina, Università di Roma “Sapienza”Azienda Ospedaliera Sant’Andrea, Roma, Italia

e-mail: [email protected]

Resistant Hypertension

“Hypertension Paradox”

L’ipertensione resistente al trattamento è una condizione molto rara nella pratica clinica

Modified from Chobanian A. N Engl J Med. 2009 Aug 27;361(9):878-87

…. siamo sommersi dall’ipertensione resistente!

BP Stratification in Hypertensive Patients enrolled in 1995-2005 Hypertension Surveys in Italy

n=1.831 n=3.739 n=3.374 n=15.904 n=13.297 n=2.081

N=52.715

Volpe M, Tocci G, et al. J Hypertens 2007 Jul;25(7):1491-8

Rates of Awareness, Treatment, and Control of High Blood Pressure in the United States (1976–2004)

Chobanian AV. New Engl J Med 2009;361:878-87

Changes in the Prevalence and Control of Hypertension in the United States (1988-2004)


42

37

13

23

Resistant Hypertension

• Hypertension is usually defined resistant or refractory to treatment when a therapeutic plan that has included attention to lifestyle measures and the prescription of at least three drugs (including a diuretic) in adequate doses has failed to lower systolic and diastolic blood pressure to goal.

• According to this definition prevalence of resistant hypertension is relatively high (in ALLHAT 8% pts with 4 drugs and 15% with resistant hypertension).

• In such situations, referral to a specialist or a hypertension center should be considered, because resistant hypertension is recognized to be often associated with subclinical organ damage and a high or very high cardiovascular risk.

2007 ESH/ESC Hypertension Guidelines

Mancia G, et al. J Hypertens 2007;25:1105–1187

Clinical Features of 8295 Patients With Resistant Hypertension Classified on the Basis of 24-hour Ambulatory BP Monitoring

• The CARDIORISC-MAPAPRES project has been promoted by the Spanish Society of Hypertension with the support of an educational grant from Lacer Spain.

• More than 1000 investigators (primary care physicians and referral units) have participated by including patients with suspected hypertension or previously diagnosed hypertensives on pharmacologiacal treatment. The present analysis was performed in a cohort of 68045 patients.

• All the investigators were supplied by an automated ABPM monitor (SpaceLabs 90207). Data obtained were transferred to a central data base along with a case report form also common from all the participants.

De La Sierra A, et al, Hypertension 2011;57:898-902

CARDIORISC-MAPAPRES

Prevalence of Resistant Hypertension


CARDIORISC-MAPAPRES

Classification of Adults with Hypertension in the United States

Persel SD. Hypertension 2011;57:1076-1080

Resistant Hypertension or Challenging Hypertension?

Definizione comunque importante per selezionare quei pazienti che richiedono percorsi

diagnostici più approfonditi e decisioni terapeutiche più incisive

Is resistant hypertension really resistant ?Causes of Pseudo-Resistant Hypertension

• Improper blood pressure measurement• Heavily calcified or arteriosclerotic arteries that are difficult to compress

(in elderly persons)• White-coat effect• Poor patient adherence

– Side effects of medication – Complicated dosing schedules– Poor relations between doctor and patient– Inadequate patient education– Memory or psychiatric problems– Costs of medication

• Related to antihypertensive medication– Inadequate doses– Inappropriate combinations

• Physician inertia (failure to change or increase dose regimens when not at goal)

Sarafidis PA, et al. JACC 2008

Factors Contributing to Resistant Hypertension

• Drug-induced– Nonsteroidal anti-inflammatory drugs (including

cyclo-oxygenase-2 inhibitors)– Sympathomimetics (decongestants, anorectics)– Cocaine, amphetamines, other illicit drugs– Oral contraceptive hormones– Adrenal steroid hormones– Erythropoietin– Cyclosporine and tacrolimus– Licorice (included in some chewing tobacco)– Over-the-counter dietary and herbal supplements

(e.g., ginseng, yohimbine, ma huang, bitter orange)

• Excess alcohol intake

• Volume overload– Excess sodium intake– Volume retention from kidney disease– Inadequate diuretic therapy

• Associated conditions– Obesity– Diabetes mellitus– Older age

• Identifiable causes of hypertension– Renal parenchymal disease– Renovascular disease– Primary aldosteronism– Obstructive sleep apnea– Pheochromocytoma– Cushing’s syndrome– Thyroid diseases– Aortic coarctation– Intracranial tumors

Sarafidis PA. JACC 2008

Leonetti G, et al.G Ital Cardiol 2001;11:1161-1169

The challenge of lowering BP in elderly:Prospective data from mega-trials

Prevalence of PA

0

5

10

15

20

25

30

35

40

45

50

11.3% 11.2%

17%20%

23%19%

Prev

alen

ce (%

)

Doum

a S.

Lanc

et 20

08

Ross

i GP.

JA

CC 20

06

Calh

oun

DA Hyp

ert.

2002

Gallay

BJ

Am J

Kidne

y Dis

2001 Eid

e IK J

Hyp

ert

2004 Stra

uch B

J Hum

Hyp

ert

2003

Sospetto clinicoSospetto clinico

Dosaggio renina (PRA) ed aldosterone plasmatici; aldosterone urinario

Dosaggio renina (PRA) ed aldosterone plasmatici; aldosterone urinario

ALDO/PRA ≥ 40 ALDO/PRA ≥ 40 ALDO/PRA < 40ALDO/PRA < 40

Ipertensione essenzialeIperaldosteronismo secondario

Ipertensione essenzialeIperaldosteronismo secondario

test dinamico(carico salino)

test dinamico(carico salino)

Aldosterone < 75 pg/mlAldosterone < 75 pg/mlAldosterone > 75 pg/mlAldosterone > 75 pg/ml

Iperaldosteronismo primarioIperaldosteronismo primarioCateterismo vene surrenaliche

-Scintigrafia surrenalica

Cateterismo vene surrenaliche-

Scintigrafia surrenalica

lateralizzazione(APA)

lateralizzazione(APA)

assenza di lateralizzazione(BAH)

assenza di lateralizzazione(BAH)

TC/RMNTC/RMN

ChirurgiaChirurgia

Terapia medicaTerapia medica

Algoritmo diagnostico dell’ iperaldosteronismo primitivo

Ferrucci A, 2010

When your hypertensive’s patient BP is challenging you

New Options from studies and practice

Potential Upcoming Options for Treating Resistant Hypertension

• Direct Renin Inhibitors (Aliskiren)

• Aldosterone Synthase Inhibitors• NEP inhibitors (Omapatrilat- compassionate use)• New Aldosterone Antagonists (Eplerenone, others)• Clonidine Extended Release • Endothelin Antagonists

• …Combination Algorhytms

Monotherapy versus combination therapy strategies in the clinical management of hypertension

If BP goals not achieved

Mild BP elevationLow/Moderate CV riskConventional BP target

Single AgentAt low dose

Previous Agent at full dose

Marked BP elevationHigh/Very High CV risk

Lower BP target

Two Drug CombinationAt low dose

Switch to other Agent at low dose

Previous Combination at full dose

Add a third Agent at low dose

Full DoseMonotherapy

Two-to-Three Combination at full dose

Two-to-Three Combination at full dose

Choose between

If BP goals not achieved

Mancia G et al. J Hypertens 2007;25:1105–1187


Possible combinations between some classes of antihypertensive drugs

The preferred combinations in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to be beneficial in controlled intervention trials.

2003 2007

Modified from Mancia G et al. J Hypertens 2007;25:1105–1187


ARBs

ACE Inhibitors

Average reductions in BP over 24 hours (treated minus placebo) according to category of drug and dose

Fall in BP (mmHg) (95% CI)

Category of DrugHalf

Standard DoseStandard Dose

Twice Standard Dose

Two Drugs

SBP reduction 7.1 (6.8-7.5) 9. 1 (8.8-9.3) 10.9 (10.7-11.2) 13.3 (12.4-14.1)

DPB reduction 4.4 (4.2-4.6) 5.5 (5.4-5.7) 6.5 (6.3-6.7) 7.3 (6.2-8.3)

Modified from Law MR, et al. BMJ 2003;326;1427-35

-4.8

-11.5

-13.8

-16.1-14.9

-19.7

*-24.2

*-23.6

*

-25.4*

-25.3

*

-29.2

*

-30.1

Me

an

ch

an

ge

in S

eS

BP

(m

mH

g)

5 1010 20 40PBO

Drug and dose (mg/d)

AMLOLM OLM/AML

10/5 20/5 40/5 10/10 20/10 40/10

Combining OLM with AML increases efficacy more than doubling the dose of each monotherapy

SeSBP reduction after 8 weeks’ treatment in patients with mild-to-severe hypertension

*p<0.001 vs. corresponding monotherapy Chrysant et al. Clin Ther 2008;30:587–604

BP CRUSH: Triple combination therapy enablesthe great majority of patients to get to goal

Weir et al. Late breaker presentation at ASH 2010

● Mean age = 55.6 years● Proportion males = 50.9%

● Mean SeSBP/SeDBP = 153.7/91.9 mmHg● Body mass index = 31.0 kg/m2

Total cohort N = 999

49.5

63.8

77.1

86.790.3

0

20

40

60

80

100

Pat

ien

ts w

ith

BP

<14

0/90

mm

Hg

(%

)

OLM/AML20/5 mg

OLM/AML40/5 mg

OLM/AML40/10 mg

OLM/AML/HCTZ40/10/12.5 mg

OLM/AML/HCTZ40/10/25 mg

n=965n=962 n=965 n=965 n=965

Potential Upcoming Options for Treating Resistant Hypertension

• Direct Renin Inhibitors (Aliskiren)

• Aldosterone Synthase Inhibitors• NEP inhibitors (Omapatrilat- compassionate use)• New Aldosterone Antagonists (Eplerenone, others)• Clonidine Extended Release • Endothelin Antagonists

• …Combination Algorhytms

-21.2***§

§

p<0.0001

***

**

192 183 183 180 194 188 173 187 189 186 173 184 187 180 173

-7.5

-9.4

-12.2

-15.7

-11.0

-13.9 -14.3 -14.3

*

*** *** ***§

-19.8***

-19.5***§

-15.3

-17.6

***§

***§

-15.6*** -17.3

***§

Aliskiren provides additional SBP lowering when combined with HCTZ

Villamil A, et al. 2007 (Study 2204)

†Overall significance of HCTZ effect not testedPairwise comparisons:*p<0.05; **p<0.001; ***p≤0.0001 vs placebo;§p<0.05 vs each component monotherapy

–22

–18

–14

–10

Aliskiren HCTZ†

75

Combination

150 300 75 150 300 30075 15075 150

6.25 12.5 25 6.25 12.5 25 6.25 12.5 25 12.5 25

Aliskiren (mg)

HCTZ (mg)

n=

Mea

n ch

ange

fro

m b

asel

ine

in m

ean

sitt

ing

SB

P (

mm

Hg) Placebo

Aliskiren significantly improves BP control when added to Amlodipine 5 mg

Munger M, et al. 2006 (Study 2305)

Mean change from baseline in mean sitting BP (mmHg)

−12

0

−8

DBP SBP

−2

−4

−6

−10

−14***

n=187n=178n=180

−8.46

−4.84

−8.04

−10.98

−4.96

−9.63***

n=187n=178n=180

**p=0.002, ***p<0.0001 vs amlodipine 5 mg

Aliskiren/amlodipine150/5 mg

Amlodipine 10 mgAmlodipine 5 mg

**

**

Aliskiren/ramipril combination provides significantly greater reductions in BP than component monotherapies

Mea

n ch

ange

fro

m b

asel

ine

in m

ean

sitt

ing

BP

(m

mH

g)

Aliskiren/ramipril

combinationRamipril

monoAliskiren

mono

−18

−6

0

−14

DBP SBP

−8

−10

−12

−16

Aliskiren/ramipril

combinationRamipril

monoAliskiren

mono

*p<0.05 for superiority vs ramipril monotherapy; †p<0.05 for superiority vs aliskiren monotherapy;‡p<0.05 for non-inferiority for aliskiren monotherapy vs ramipril monotherapyError bars indicate standard error from the mean Uresin Y, et al. 2006 (Study 2307)

−20 *

n=274n=279n=275 n=274n=279n=275

−12.8

−10.7 −11.3

−16.6

−12.0

−14.7*

‡

†

* ‡

Aliskiren/valsartan combination therapy provides significantly greater BP reductions than either component monotherapy

**p<0.0001 vs placebo; ‡p<0.0001 vs aliskiren/valsartan combination therapy

–12.8

–20

–15

–10

–5

0

Mean change from baseline in mean sitting BP after 8 weeks (mmHg)

–4.6

–13.0

–17.2

** **

n=455 n=430 n=453 n=438

–4.1

–9.0 –9.7

–12.2** **

n=455 n=430 n=453 n=438

2.5‡

3.2‡

**

4.4‡4.2‡

**

Oparil S, et al. 2007 (Study 2327)

DBP SBP

Placebo

Aliskiren 300 mg

Valsartan 320 mg

Aliskiren/valsartan 300/320 mg

Pharmacological Treatmentof Resistant Hypertension

• Ultimately, many patients will need administration of more than three drugs.

• At present, the optimal choice of the 3rd, 4th and 5th line antihypertensive agents has not been addressed by proper randomized trials.

• However, recent observational studies suggest that the aldosterone antagonist spironolactone provides significant additional blood pressure lowering efficacy.


Mancia G, et al. J Hypertens 2007;25:1105–1187

Chapman N, et al. Hypertension 2007 Apr;49(4):839-45

BP reductions after addition of spironolactone in patients with resistant hypertension

Box-plot graphic representation of office and ambulatorysystolic BP before (clear box) and during (dark box)

spironolactone administration

Segura J, et al. J Am Soc Hypertens 2011 Nov-Dec;5(6):498-504

Non pharmacological options

Schematic Representation of the Catheter Ablation of Renal Arteries

Simplicity HTN-1

Krum H, et al. Lancet 2009; 373: 1275–81

Simplicity Long-Term Follow-Up

Symplicity HTN-1 Investigators. Hypertension 2011; 57:911-917

Distribution of office systolic BP levels in patients with resistant hypertension at baseline, 12 months, and 24 months

Symplicity HTN-1 Investigators. Hypertension 2011; 57:911-917

Schematic representation of the device for carotid baroreceptor stimulation

Proportion of Subjects That Achieved SBP control (defined as <140 mmHg)

Bisognano JD, et al. J Am Coll Cardiol 2011;58:765–73

RHEOS Pivotal Trial

Observed Mean Change in SBP


RHEOS Pivotal Trial

RHEOS Pivotal Trial


Summary of Adverse Events

• Procedural 68 (25.5)– Surgical complication 13 (4.8)– Nerve injury with residual deficit 13 (4.8)– Transient nerve injury 12 (4.4)– Respiratory complication 7 (2.6)– Wound complication 7 (2.6)

• BAT– Hypertensive crisis (Group A) 9 (5.0)– Hypertensive crisis (Group B) 7 (8.3)

• Device 34 (12.8)– Hypertension-related stroke 6 (2.3)

BP >140/90 mmHg in hypertensive patients receiving at least 3 antihypertensive drugs, including a diuretic, at adequate (full) doses

Check any discrepancies amongoffice, home and 24-hour ambulatory BP measurements

Check patient’s adherence to antihypertensive drug prescriptions

Check patient’s assumption of any interfering drug or substance

Identify and treat possible causes of secondary hypertensionand any concomitant condition that may persistently keep BP levels elevated *

Optimize and titrate pharmacologic and non-pharmacologic therapies

Refer patient to Hypertension Center

All BP above limits

Modified from Volpe M, et al. Expert Review CV Therapy 2010 Jun;8(6):811-20

Hypertension Unit: How to properly diagnose and treat Resistant Hypertension

Grazie per la Vostra Attenzione!

E: [email protected]: [email protected]

Simplicity HTN-2

Responder rates higher with aliskiren and HCTZ combination therapy than with component monotherapies

Villamil A, et al. 2007 (Study 2204)

Pairwise comparisons: *p<0.05; **p<0.001; ***p≤0.0001 vs placebo;§p<0.05 vs each component monotherapy

Aliskiren HCTZ

75

Combination

150 300 75 150 300 30075 15075 150

6.25 12.5 25 6.25 12.5 25 6.25 12.5 25 12.5 25

Aliskiren (mg)

HCTZ (mg)

40

50

60

70

80

90Responder rate (%)

192 183 183 180 194 188 173 187 189 186 173 184 187 180 173

45.8

51.9 51.9

63.9

53.6

60.659.0

61.563.5

70.4

58.4

69.671.1

80.6

76.9

***

*** **

*

*** ***

***

***

**

§§

§

§

n=

Placebo

A global perspective on BP treatment and control in a referred cohort of hypertensive patients

Bramlage P, Volpe M, et al. J Clin Hypertens 2010

N=22,282

I-SEARCH Survey

Veglio F et al. Clin Exp Hypertension 2001

True resistant hypertension White-coat resistant hypertension

SBP

DBP

SBP

DBP

153

97

12476m

mH

g

28% Normal ABPM profile

(< 135/85 mmHg)

Brown MA et al. Am J Hypert 2001

118 patients with resistant

hypertension at visit

24-hour Ambulatory Blood Pressure Monitoring

Moser M. N Engl J Med 2006

Ipertensione Clinica Isolata

Ferrucci A, Personal Data 2005

Rate of major CV morbid events in a normotensive group (A), 2 groups with WCH defined with a restrictive (B) or liberal (C) criterion, and a group with

ambulatory hypertension (D).

Verdecchia P, et al. Lancet 1996;348:1444 –1445

Clinical Inertia

12,3

23

29,9

25,9

9,9

43,4

29,929,7

37,2

24,9

49,3

36,5

0

10

20

30

40

50

60Baseline

Reassessment

Diureti

cs

Calci

um ch

anne

l

block

ers

Beta

-blo

cker

s

Alpha-

block

ers

ACE in

hibito

rs +/

-

diure

tic

ARB +/

- diur

etic

42,4%

% of physicians who decide to modify therapy when BP control was not controlled

Patie

nts

(%)

REACT StudyREACT StudyVolpe M. et al HBPCVP 2004

Algorithm for Management of Hypertension

Lifestyle modificationAlcohol restrictionDASH dietExerciseSalt reductionWeight control

Single drug treatmentACE inhibitorARBCalcium-channel blockerDiuretic

Add second drug of different classACE inhibitorARBBeta-blockerCalcium-channel blockerDiuretic

Add third drug of different classAssess adherenceOptimize doses

Stage 1 Hypertension(blood pressure, 140–159/90–99mmHg)

Stage 2 Hypertension(blood pressure, 160/100mmHg)

Two-drug regimen for most patients plus lifestyle changesACE inhibitorARBBeta-blockerCalcium-channel blockerDiuretic

Add third drug of different classAssess adherenceOptimize doses

Add fourth drug of different classAssess alcoholic excessAssess salt retention

Evaluate for secondary hypertension


Control other

CV risk

factors

Mean change in seated DBP (SeDBP) at the end of 4 and 8 weeks

Volpe et al. Clin Drug Invest 2009;29:11–25

Mean change in seated SBP (SeSBP) at the end of 4 and 8 weeks


Box-plot graphic representation of office and ambulatorysystolic BP at baseline (clear box) and during aliskiren, amlodipine, and

chlorthalidone administration (dark box) in resistant hypertensivepatients not responding to spironolactone

Segura J, et al. J Am Soc Hypertens 2011 Nov-Dec;5(6):498-504

Efficacy of Low-Dose* Spironolactone inSubjects With Resistant Hypertension

Nishizaka MK. et al. Am J Hypert 2003

* 12,5 to 50 mg/die

Establish the Diagnosis

Is blood pressure > 140/90 mmHg or > 130/80 mmHg in patients with diabetes or renal disease?

Is the patients receiving 3 drugs, including a diuretic, at full doses?

In older patients, is pseudohypertension present?

Is office-resistant hypertension a consideration?Check home, workplace or

ambulatory readings

Does the patient adhere to the medical program?

Does the patient take interfering substances? ( e.g. sympathomimetic agents, hebal supplements, NSAIDs and corticosteroids)

Is the patient obese or it is there a diagnosis of metabolic syndrome?

Are there secondary causes?

Optimize and intensify pharmacologic therapy

Yes

Yes

Yes

Yes

Yes

NoNo

No

No

No

Address concerns about side effects or economic, cultural, literacy, language, or educational issues

Discontinue or minimize interfering or competing substance, or maximize

antihypertensive medications

Recommend diet and aerobic exercise

Diagnose and treat the following conditions: renal parenchimal disease, renovascular disease, aldosteronism,thyroid disease,

cushing’s disease, pheocromocytoma, aortic coarctation, sleep apnea

Management of resistant hypertension

Moser M. N Engl J Med 2006

Prevalence of hypokalaemia in PA

23%

Mulatero P. JCEM 2004

28%

Nishikawa T. Biomed & Pharmacother. 2000

39,4%

20,5%

Rossi E. Am J Hypert 2002

Douma S. Lancet 2008 Gallay BJ. Am J Kidney Dis 2001 Born-Frontsberg E. JCEM 2009

67% 56,1%

An Approach to Achieve BP Goal in Resistant Hypertension

NSAIDsNSAIDs

CiclosporinCiclosporin

Mechanisms of drug-induced hypertension

HYPERTENSION

Endothelin

Nitric oxide

Increased renin production

Activation of the sympathetic nervous

system

Vasoconstriction and glomerular ischaemia

Reduction of hypoxia-mediated vasodilation

Increased vascular tone

Reduced production of PGE2 and PGI2

Reduced renal blood flow

Retention of salt and water

Sodium retention

Direct vasoconstrictor effect

Erythropoiesis Erythropoiesis stimulating agentsstimulating agents

Glucocorticoids and Glucocorticoids and mineralocorticoidsmineralocorticoids

Clinical Characteristics of Resistant Hypertension in the Spanish ABPM cohort

• Resistant hypertension (RH): – 8295 hypertensive patients

– Treated with at least 3 antihypertensive drugs (from different classes) one of them being a diuretic (thiazide or loop diuretic)

– Office BP ≥ 140 and/or 90 mmHg


CARDIORISC-MAPAPRES

Patients with more severe hypertension at baseline needed HCTZ

Treatment at Week 52/Early Termination

OLM/AML/HCTZ40/10/12.5 mg

(n=68)

OLM/AML40/10 mg

(n=144)

OLM/AML40/5 mg(n=452)

OLM/AML/HCTZ40/10/25 mg

(n=27)


Andrea Ferrucci Centro per la Diagnosi e la Cura dell’Ipertensione Arteriosa UOC di Cardiologia,...

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Transcript of Andrea Ferrucci Centro per la Diagnosi e la Cura dell’Ipertensione Arteriosa UOC di Cardiologia,...