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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)
Chobanian AV. New Engl J Med 2009;361:878-87
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
De La Sierra A, et al, Hypertension 2011;57:898-902
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
2007 ESH/ESC Hypertension Guidelines
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
2007 ESH/ESC Hypertension Guidelines
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.
2007 ESH/ESC Hypertension Guidelines
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
Bisognano JD, et al. J Am Coll Cardiol 2011;58:765–73
RHEOS Pivotal Trial
RHEOS Pivotal Trial
Bisognano JD, et al. J Am Coll Cardiol 2011;58:765–73
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
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
Moser M. N Engl J Med 2006
Ipertensione Clinica Isolata
Ferrucci A, Personal Data 2005
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
Chobanian AV. New Engl J Med 2009;361:878-87
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
Volpe et al. Clin Drug Invest 2009;29:11–25
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
De La Sierra A, et al, Hypertension 2011;57:898-902
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)
Volpe et al. Clin Drug Invest 2009;29:381–91