Hypertension: New drugs? New treatments? . Fausto J Pinto, MD, PhD, FESC, FACC, FSCAI, FASE Lisbon University, Portugal
Fausto J. Pinto, MD, PhD, FESC, FASE, FACC, FSCAI
• Disclosures: • Consultancy, advisory boards and lecture fees: Astra Zeneca, Bayer, Bial, Boehringher Ingelheim, Covidien, GE, Irokio, Menarini, Pfizer, Servier
Global Mortality 2000: Hypertension is the major risk factor High BP Tobacco High cholesterol
7.6 million deaths
Underweight Unsafe sex High BMI Physical inactivity Alcohol
Developing regions Developed regions
0 1 2 3 4 5 6 7 8 Attributable mortality in millions (total: 55 861 000) Adapted from Ezzati et al. Lancet 2002;360:1347-1360.
Hypertension Epidemiology • Single largest contributor to death worldwide 30% Untreated
35% Treated but Uncontrolled
35% Treated & Controlled
• Every 20/10 mmHg increase in BP correlates with a doubling of 10-year cardiovascular mortality • Dramatically increases risk of stroke, heart attack, heart failure, & kidney failure • Only half of all treated hypertensives are controlled to established BP targets • High prevalence: • Affects 1 in 3 adults • 1B people worldwide 1.6 B by 2025
Chobanian et al. Hypertension. 2003;42(6):1206–1252.
Relationship between BP reduction and cardiovascular outcomes
Relative risk of outcome event
All-cause mortality
Systolic blood pressure difference between randomized groups (mm Hg ) BPLTT Collaboration. Lancet. 2003;362:1527-1535.
Renal Nerve Anatomy • Nerves arise from T10-L2 • The nerves arborize around the artery and primarily lie within the adventitia Vessel Lumen Media
Adventitia Renal Nerves
Renal Nerve Anatomy Allows a Catheter-Based Approach
• Standard interventional technique • 4-6 two-minute treatments per artery • Proprietary RF Generator − Automated − Low-power − Built-in safety algorithms
In the United States: Caution: Investigational Device. Limited by U.S. law to investigational use.
Symplicity HTN-1
Lancet. 2009;373:1275-1281
Hypertension. 2011;57:911-917.
Initial Cohort – Reported in the Lancet, 2009: -First-in-man, non-randomized -Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a diuretic; eGFR ≥ 45 mL/min) - 12-month data \
Expanded Cohort* – This Report (Symplicity HTN-1): -Expanded cohort of patients (n=153) -36-month follow-up *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)
Symplicity HTN-1: BP Reductions 3 years
BP change (mmHg)
P<0.01 for â&#x2C6;&#x2020; from BL for all time points
*Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)
Symplicity HTN-1: Percentage Responders Over Time Responder was defined as an office SBP reduction â&#x2030;Ľ 10 mmHg
(n=143)
(n=148)
(n=144)
(n=130)
*Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)
(n=107)
(n=59)
(n=24)
(n=24)
Symplicity HTN-2 Trial • Treatment-resistant HTN population
Inclusion Criteria: –
• BL OBP 178/97 mmHg
–
• 49 RDN, 51 Control
–
• Age 58 years • BMI 31 kg/m² • 40% with Diabetes • eGFR 77* • Avg # meds 5.2 • RDN and Control groups generally well-matched *MDRD, ml/min/1.73m2 Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.
Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus) Stable drug regimen of 3+ more anti-HTN medications Age 18-85 years
Exclusion Criteria: –
– – – – –
Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention eGFR < 45 mL/min/1.73m2 (MDRD formula) Type 1 diabetes mellitus Contraindication to MRI Stenotic valvular heart disease for which reduction of BP would be hazardous MI, unstable angina, or CVA in the prior 6 months
Symplicity HTN-2: Primary Endpoint and Latest Follow-up Primary Endpoint (6M post Randomisation)
Latest Follow-up (12M post Randomisation) RDN (n= 47)
∆ from Baseline to 6 Months (mmHg)
Systolic Diastolic Diastolic
Systolic
p <0.01 for difference between RDN and Control
Primary Endpoint: •84% of RDN patients had ≥10 mmHg reduction in SBP •10% of RDN patients had no reduction in SBP Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)
∆ from Baseline to 12 Months (mmHg)
Diastolic
Systolic p <0.01 for ∆ from baseline
Latest Follow-up: •Control crossover (n = 35): -24/-8 mmHg (Analysis on patients with SBP ≥ 160 mmHg at 6 M)
Home & 24 Hour Ambulatory BP
Systolic
Diastolic
Diastolic
Systolic
24-h ABPM: • Analysis on technically sufficient (>70% of readings) paired baseline and 6-month • RDN (n=20): -11/-7 mmHg (SD 15/11; p=0.006 SBP change, p=0.014 for DBP change) • Control (n=25): -3/ -1 mmHg (SD 19/12; p=0.51 for systolic, p=0.75 for diastolic) Symplicity HTN-2 Investigators. The Lancet. 2010.
Catheter-based renal sympathetic denervation in patients with resistant hypertension: 18 month follow-up of the Symplicity HTN-2 trial
Control
6M
12 M
18 M
24 M
M. Esler | AU | 1163
Catheter-based renal sympathetic denervation in patients with resistant hypertension: 18 month follow-up of the Symplicity HTN-2 trial
SBP DBP s P-values < 0.01 at each time point compared to pre procedure values for each group
M. Esler | AU | 1163
Ambulatory blood pressure after catheter-based renal sympathetic denervation in patients with resistant hypertension
F. Mahfoud | DE | 433
Anxiety, depression and quality of life improves in patients with resistant hypertension after renal sympathetic denervation
quality of life improved p<0.01 (SF 12) headache (reported by 60% at baseline) improved p<0.0001, visual analog scale Anxiety (p<0.0001) and depression (p<0.0001) improved (Hospital Anxiety Depression Scale (HADS), in particular in those with clinically relevant anxiety (21%) and depression /17%)
clinically relevant
D. Fischer | DE | 1168
Effect of renal sympathetic denervation on glucose metabolism E. Infante de Oliveira, F. Pinto et al.
Serviço de Cardiologia I & Serviço de Medicina I, Hospital de Santa Maria, CHLN
Hospital Santa Maria Renal Denervation Program
Inclusion Criteria: –
Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus)
–
Stable drug regimen of 3+ more anti-HTN medications
–
HTN confirmed by ABPM
Exclusion Criteria: –
Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention
–
eGFR < 30 mL/min/1.73m2 (MDRD formula), except if in dialysis program
–
Stenotic valvular heart disease for which reduction of BP would be hazardous
–
MI, unstable angina, or CVA in the prior 6 months
HOMA – Homeostatic model assessment
Effect of renal sympathetic denervation on glucose metabolism E. Infante de Oliveira, F. Pinto et al.
Serviço de Cardiologia I & Serviço de Medicina I, Hospital de Santa Maria, CHLN
Hospital Santa Maria Renal Denervation Program • 62 yo lady • Medical history – Severe resistant hypertension • LVH with diastolic dysfunction • Hypertensive retinopathy – Obesity – Hirsutism (minoxidil)
• Medication • Clonidine 0.15 mg 6x/dia • Atenolol 50 1x/dia • Enalapril 40 mg/dia • Nifedipine 120 mg/dia • Hydroclorotiazide 50 mg • Spirinolactone 100 mg
Effect of renal sympathetic denervation on glucose metabolism E. Infante de Oliveira, F. Pinto et al.
Serviรงo de Cardiologia I & Serviรงo de Medicina I, Hospital de Santa Maria, CHLN
ABPM
Hospital Santa Maria Renal Denervation Program
Effect of renal sympathetic denervation on glucose metabolism E. Infante de Oliveira, F. Pinto et al.
Serviรงo de Cardiologia I & Serviรงo de Medicina I, Hospital de Santa Maria, CHLN
Effect of renal sympathetic denervation on glucose metabolism E. Infante de Oliveira, F. Pinto et al.
Serviço de Cardiologia I & Serviço de Medicina I, Hospital de Santa Maria, CHLN
Hospital Santa Maria Renal Denervation Program
Renal Denervation
Metanephrine (urine) (μg/L) Normetanefrine (urine) (μg/L)
Before RDN 270 123
After RDN 60 51
From: Renal Sympathetic Denervation Reduces Left Ventricular Hypertrophy and Improves Cardiac Function in Patients With Resistant Hypertension Brandt MC et al J Am Coll Cardiol. 2012;59(10):901-909
Regression of LVH and Improvement of Diastolic Function Depending on BP Reduction Achieved by RD
Hypertension
ď&#x201A;§ Novel compounds
The interplay of recently discovered components of the reninâ&#x20AC;&#x201C;angiotensinâ&#x20AC;&#x201C;aldosterone system.
Unger T et al. Eur Heart J 2011;32:2739-2747
The therapeutic options for aldosterone antagonism.
Unger T et al. Eur Heart J 2011;32:2739-2747
Van Vark M, et al. Eur Heart J. 2012; 33:2088-2097.
Both act on the renin-angiotensin system ACE I Effect on RAS
ACE inhibition
ARBs Effects on the AT2 receptors
Plasma renin
Angiotensin II AT1 AT2 Bradykinin Nitric oxide
No change No change
Epstein BJ, Gums JG. Ann Pharmacotherapy. 2005;39:470-480 Messerli FH, Weber MA, Brunner HR. Arch Intern Med. 1996;156:1957-1965
Baseline characteristics of study population (n=158 998) Trial
Year
N
Active treatment
Control
FU, years
HT, %
SBP, mm Hg
Age, years
Incidence rate, control
RENAAL
2001
1513
Losartan
Placebo
3.1
97
153
60
66.0
IDNT
2001
1715
Irbesartan
Amlo or placebo
2.9
100
159
59
54.0
LIFE
2002
9193
Losartan/HCTZ
Atenol/HCTZ
4.8
100
174
67
19.5
ALLHAT
2002
33 357
Lisinopril
Diur or Amlo
5.0
100
146
67
28.5
ANBP-2
2003
6083
Enalapril
HCTZ
4.1
100
168
72
17.1
SCOPE
2003
4937
Candesartan
Placebo
3.7
100
166
76
29.0
Pilot HYVET
2003
1283
Lisinopril
Diuretic
1.1
100
182
84
55.4
JMIC B
2004
1650
Lisinopril or enal
Nifedipine
2.3
100
146
65
6.2
VALUE
2004
15 245
Valsartan
Amlodipine
4.3
100
155
67
24.8
MOSES
2005
1352
Eprosartan
Nitrendipine
2.5
100
152
68
31.0
ASCOT-BPLA
2005
19 257
Amlo/perindopril
Atenolol/BTZ
5.5
100
164
63
15.5
JIKEI HEART
2007
3081
Valsartan
Non-ARB
2.81
88
139
65
6.2
ADVANCE
2007
11 140
Perindopril/Indap
Placebo
4.3
69
145
66
19.8
HYVET
2008
3845
Indap/perindopril
Placebo
2.1
90
173
84
59.3
PRoFESS
2008
20332
Telmisartan
Placebo
2.5
74
144
66
29.1
TRANSCEND
2008
5926
Telmisartan
Placebo
4.6
77
141
67
25.2
CASE-J
2008
4703
Candesartan
Amlodipine
3.3
100
163
64
11.1
HIJ-CREATE
2009
2049
Candesartan
Non-ARB
4.0
100
135
65
14.3
KYOTO HEART
2009
3031
Valsartan
Non-ARB
2.9
100
157
66
7.2
NAVIGATOR
2010
9306
Valsartan
Placebo
6.1
78
140
64
11.5
4.3
91
153
67
23.3
OVERALL
20 trials: All-cause mortality reduction Random effects model
HR (95% CI)
RENAAL IDNT LIFE ALLHAT ANBP-2 SCOPE Pilot HYVET JMIC-B VALUE MOSES ASCOT-BPLA JIKEI HEART ADVANCE HYVET PRoFESS TRANSCEND CASE-J HIJ-CREATE KYOTO HEART NAVIGATOR
1.03 (0.83-1.29) 0.92 (0.69-1.23) 0.88 (0.77-1.01) 1.03 (0.90-1.15) 0.90 (0.75-1.09) 0.96 (0.81-1.14) 0.99 (0.62-1.58) 1.32 (0.61-2.86) 1.04 (0.94-1.14) 1.07 (0.73-1.57) 0.89 (0.81-0.99) 1.09 (0.64-1.85) 0.86 (0.75-0.98) 0.79 (0.65-0.95) 1.03 (0.93-1.14) 1.05 (0.91-1.22) 0.85 (0.62-1.16) 1.18 (0.83-1.67) 0.76 (0.40-1.30) 0.90 (0.77-1.05)
Overall
0.95 (0.91-1.00)
P for heterogeneity 0.266; I 15% 2
0.75 1.33 1 2.0 0.50 RAAS inhibitor better Control better
P
0.03 0.03 0.02
0.032
N=158,998
Van Vark M, et al. Eur Heart J. 2012; 33:2088-2097.
All-cause mortality: effect of ACE inhibitors Random effects model
HR (95% CI)
P
ALLHAT (lisinopril)
1.03 (0.90-1.15)
ANBP-2 (enalapril)
0.90 (0.75-1.09)
pilot HYVET (lisinopril)
0.99 (0.62-1.58)
JMIC-B (lisinopril, enalapril)
1.32 (0.61-2.86)
ASCOT-BPLA (perindopril)
0.89 (0.81-0.99)
0.03
ADVANCE (perindopril)
0.86 (0.75-0.98)
0.03
HYVET (perindopril)
0.79 (0.65-0.95)
0.02
Overall
0.90 (0.84-0.97) 0.50 0.75 1 1.33 2.0 ACE inhibitor better Control better HR (log scale) Van
0.004
N= 76 615 Vark M, et al. Eur Heart J. 2012; 33:2088-2097.
All-cause mortality: effect of ARBs Random effects model RENAAL (losartan)
HR (95% CI) 1.03 (0.83-1.29)
IDNT (irbesartan)
0.92 (0.69-1.23)
LIFE (losartan) SCOPE (candesartan)
0.88 (0.77-1.01)
VALUE (valsartan) MOSES (eprosartan)
1.04 (0.94-1.14) 1.07 (0.73-1.57)
JIKEI HEART (valsartan)
1.09 (0.64-1.85)
PRoFESS (telmisartan)
1.03 (0.93-1.14)
TRANSCEND (telmisartan) CASE-J (candesartan)
1.05 (0.91-1.22)
P
0.96 (0.81-1.14)
HIJ-CREATE (candesartan)
0.85 (0.62-1.16) 1.18 (0.83-1.67)
KYOTO HEART (valsartan)
0.76 (0.40-1.30)
NAVIGATOR (valsartan)
0.90 (0.77-1.05)
Overall
0.99 (0.94-1.04) 0.50 0.75 1 1.33 2.0 ARB better Control better HR (log scale) Van
0.683
N=82 383 Vark M, et al. Eur Heart J. 2012; 33:2088-2097.
New meta analysis Effects of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Mortality and Cardiovascular Events in Patients Without Heart Failure. A Meta-Analysis of Randomized Clinical Trials in 108,233 patients.
Gianluigi Savarese, MD1, Pierluigi Costanzo, MD1,2, John George Franklin Cleland, MD2, Enrico Vassallo, MD1, Giuseppe Rosano, MD, PhD3, Pasquale Perrone-Filardi, MD, PhD1
Division of Cardiology, Federico II University, Naples, Italy; 2 Academic Cardiology Unit, Hull York Medical School, Cottingham, UK; 3 Clinical and Experimental Research Center, IRCCS San Raffaele, Rome, Italy. 1
Savarese G et al. J Am Coll Cardiol 2013;61/131-142.
RESULTS Results - Composite outcome
ARBs significantly reduced the risk of the composite outcome by 7.0% compared to placebo (p=0.012).
ACE-Is significantly reduced the risk of the composite outcome by 14.9% compared to placebo (p=0.001).
Savarese G et al. J Am Coll Cardiol 2013;61/131-142.
RESULTS Results - All-cause death
No significant effect was found on the risk of all-cause death in ARBs trials (p=0.866).
ACE-Is reduced the risk of allcause death by 8.3% (p=0.008).
Savarese G et al. J Am Coll Cardiol 2013;61/131-142.
RESULTS Results â&#x20AC;&#x201C; New onset of HF
No significant effect was found on the risk of new onset HF in ARBs trials (p=0.866).
ACE-Is reduced the risk of new onset HF by 20.5% (p=0.001).
Savarese G et al. J Am Coll Cardiol 2013;61/131-142.
RESULTS
Results
* p<0.05
Savarese G et al. J Am Coll Cardiol 2013;61/131-142.
Conclusions •
Among RAAS inhibitors, only ACE inhibitors have demonstrated a significant 10% mortality reduction in hypertensive patients (P=0.004).
•
No significant reduction in all-cause mortality nor MI could be demonstrated with ARBs (HR, 0.99 (0.95-1.04); P=0.683).
•
The difference in treatment effect between ACE inhibitors and ARBs was statistically significant (P-value for interaction 0.036).
•
The largest mortality reductions were observed in ASCOT-BPLA, ADVANCE, and HYVET, which studied the ACE inhibitor perindopril (pooled HR, 0.87 [0.81-0.93]; P<0.001).
•
Because of the high prevalence of hypertension, the widespread use of ACE based strategies may result in an important gain in lives saved.
Recent evolution of dual and triple combinations.
Unger T et al. Eur Heart J 2011;32:2739-2747
2007 Guidelines for the Management of Arterial Hypertension European Society of Cardiology European Society of Hypertension European Heart Journal 2007;28:14621536 Journal of Hypertension 2007;25:11051187