Novedades en Farmacología Riesgo CV 2010 1
1
José R. González Juanatey
Área Cardiovascular. Hospital Clínico Universitario de Santiago de Compostela J.R.G. JUANATEY C.H.U.Santiago
Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes
J.R.G. JUANATEY C.H.U.Santiago
Blood Pressure, Blood Glucose and Heart Rate in AF and Cardiac Disease. The “J” curve LBP HBP
LBG LHR
•
1
Myocardial Isch Renal failure Hypoperfusion etc J.R.G. JUANATEY C.H.U.Santiago
HBG HHR
mmHg, mg/dL, bpm
Atherosclerosis Vessel rupture Renal failure Cardiac failure Myocardial Isch
Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes
J.R.G. JUANATEY C.H.U.Santiago
Incidence and Unadjusted CV Risk of Events in Deciles of In-treatment SBP Stroke 2
1
0
0 112
121
126
130
133
136
140
144
149
On-treatment SBP (mmHg)
J.R.G. JUANATEY C.H.U.Santiago
160
6
4 5 2
0
112
121
126
130
133
136
140
144
149
160
HR (95% CI)
5
10
Unadjusted risk of events (%)
10
HR (95% CI)
Unadjusted risk of events (%)
Myocardial infarction
0
On-treatment SBP (mmHg)
Sleight, et al., J Hypert 2009; 27: 1360-1369
ROADMAP. Lowest SBP and/or highest SBP reduction quartile are associated with increased CV mortality in CHD patients. The “J” curve effect again Last SBP before event
SBP reduction
1.6
2.5 1.0 1.0
mmHg <122.3 J.R.G. JUANATEY C.H.U.Santiago
122.3126.4
126.4132.2
>132.2
mmHg
<17.3
17.38.1
8.0<0.2
Cohort of patients with pre-existing CHD (1104)
>0.2
Objetivo del tratamiento antihipertensivo Población general hipertensa
) 9 0
H S PA < 140/90 mmHg (E g H m Pacientes diabéticos o de alto/muy alto riesgo m 5 8 PA < 130/80 mmHg 0 8 / 9 3 Pacientes con IR y proteinuria > 1g/24h 1 0 3 1 PA < 125/75 mmHg J.R.G. JUANATEY C.H.U.Santiago
ESH/ESC Guidelines. Rev Esp Cardiol 2007; 60: 968.e1-e94
Reduction in Mortality with Anti-hypertensive Agents: evidence from clinical trials in at-risk hypertensive patients 1
Concomitant pathology (% of patients) HR=0.97 >50% DM/RI 0.91 (0.83-1.00) 0.05 (95% CI: 0.94-1.00; p=0.031) <50% DM/RI 0.97 (0.94-1.01) 0.108 >45% of CVD/CAD 1.01 (0.97-1.05) 0.641 0.89 (0.81-0.99) ASCOT p=0.025 <45% of CVD/CAD 0.93 (0.89-0.97) 0.001 HYVET ASCOT: 19275 Hypertensives (amlodipine/perindopril) HYVET: 3845 Old Hypertensives (indapamide/perindopril) ADVANCE: 11140 Diabetics (perindopril/indapamide)
21 clinical trials (194.621 patients): all-cause mortality reduction
J.R.G. JUANATEY C.H.U.Santiago
0.79 (0.65-0.95) P=0.02
ADVANCE
0.86 (0.75-0.98) p=0.025)
TOTAL
0.87 (0.81-0.94) p<0.001
Active Better
Control Better
Devices in Hypertension. BP changes with renal
sympathetic denervation in patients with refractory HT
J.R.G. JUANATEY C.H.U.Santiago
Devices in Hypertension. BP changes with renal sympathetic denervation in patients with refractory HT SBP 1 Month Change in BP (mmHg)
J.R.G. JUANATEY C.H.U.Santiago
DBP 3 Months 6 Months 9 Months 12 Months
Devices in Hypertension.
J.R.G. JUANATEY C.H.U.Santiago
Devices in Hypertension. The implantable system for HT (baroreflex activation therapy)
J.R.G. JUANATEY C.H.U.Santiago
Devices in Hypertension. The implantable system for HT (baroreflex activation therapy) Systolic
Diastolic
Baseline=192 mmHg
Baseline=108 mmHg
Change in mmHg
gr/m2
-21
-35 -37
-18
-21
132
116
108
Baseline 3 m
6m
12 months
-38
24 months 36 months
J.R.G. JUANATEY C.H.U.Santiago
LVH Regression
Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes
J.R.G. JUANATEY C.H.U.Santiago
Estabilización vs Regresión de la Ateroesclerosis Coronaria
JAPAN-ACS: IVUS results LDL-C
Pitavastatin 130.9+33.3 Atorvastatin 133.8+31.4
81.1+23.4 84.1+27.4
Change from baseline (%) Hiro T, et al. J Am Coll Cardiol 2009;5 : 293-302 J.R.G. JUANATEY C.H.U.Santiago
Estabilización vs Regresión de la Ateroesclerosis Coronaria Pitavastatina vs Atorvastatina Mean (95% CI) : 1.11 (-2.27 – 4.48)
Pitavastatin better J.R.G. JUANATEY C.H.U.Santiago
Atorvastatin better Hiro T, et al. JACC 2009; 54: 293-302
Apo A-1 Basal: 108.4+18
*p<0.01
HDL-C (mg/dL)
12 Months: 115.7+17.7*
<0.01
<0.001 40.5+9.1
36+5.9
12 Months J.R.G. JUANATEY C.H.U.Santiago
Int J Cardiol 2008; 130: 320-322
Nanoparticle-mediated endothelial cellselective delivery of pitavastatin induces functional collateral arteries (therapeutic angiogenesis)
Pitavastatin
Pitavastatin
Pravastatin
J.R.G. JUANATEY C.H.U.Santiago
Atorvastatin
Fluvastatin
Rosuvastatin
Simvastatin
J Vasc Surg 2010; 52: 412-420
Pitavastatin NT
Pitavastatin NT
Future studies: Randomized Evaluation of Aggressive or moderate Lipid lowering therapy with pitavastatin in NIH ClinicalTrials.gov : NCT01042730
Coronary Artery Disease (REAL-CAD)
Study Objective
To evaluate the prevention of cardiovascular disease by moderate cholesterol lowering therapy or aggressive cholesterol lowering therapy 4mg/day in patients with stable coronary artery disease.
Study Patients
Stable coronary artery disease
Primary Endpoint
Composite outcome consisting of; Cardiovascular death, Non-fatal Myocardial Infarction, Non-fatal Cerebral Infarction, Unstable angina requiring urgent hospitalization
Arms
Pitavastatin 1mg/day
Estimated Enrollment
12,600
Study Period
January 2010 - January 2015 (enrollment; 2 years, follow-up; 3 years)
Informed Consent
Pitavastatin 1mg/day
vs.
Pitavastatin 4mg/day
Pitavastatin 1mg/day Randomized
Pitavastatin 4mg/day
LDL-C<120mg/dL J.R.G. JUANATEY C.H.U.Santiago
Run-in period (≥1 month)
Follow-up period (36 – 60 months)
Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial •
J.R.G. JUANATEY C.H.U.Santiago
1
CV Risk beyond LDL LDL treatment reduces CV Risk Risk factors
Overall RR
Age Gender CV disease HT treat DM
Etc..
Chol T
TG
LDL
Diabetes
HDL
Physical inact
TG
Diet Obesity HT HDL Tobacco
Residual Risk J.R.G. JUANATEY C.H.U.Santiago
CV Risk beyond LDL Etc.. TG Diabetes Physical inact Diet Obesity HT HDL Tobacco
Residual Risk J.R.G. JUANATEY C.H.U.Santiago
CV Risk beyond LDL Etc..
TG Diabetes Physical inact Diet Obesity HT
HDL Tobacco
Residual Risk J.R.G. JUANATEY C.H.U.Santiago
Atheroprotective and Vasculoprotective Actions of HDL Reverse cholesterol transport Cellular cholesterol Anti-infectious activity
HDL
Antiinflammator y activity Antiapoptotic activity
Antithrombotic activity Endothelial Antirepair; proteolitic vasodilation activity
J.R.G. JUANATEY C.H.U.Santiago
Antioxidative activity
Innate immune system
Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy (A), Effect of HDL (50 μ/mL, 60 minutes, 37°C) from
(A), Endothelium-dependent relaxations of aortic
healthy subjects (n=10) and diabetic patients (n=33) on endothelial cell NO production as determined by ESR spectroscopy analysis
rings of wild-type mice in response to increasing concentrations of HDL isolated from healthy subjects (n=5) or diabetic patients (n=5) are shown
Diabetics
J.R.G. JUANATEY C.H.U.Santiago
(B)
PBS
P < 0.0001
HDL
HDL Healthy
HDL from Diabetic Patients P = 0.007
(%; aortic rings)
P < 0.0001
Endothelium-dependent Relaxation
(% of buffer- treated cells)
Endothelial NO Production
(A)
HDL from Healthy Subjects
HDL (μg/ml)
Sorrentino SA et al. Circulation. 2010;121:110-122
Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes
J.R.G. JUANATEY C.H.U.Santiago
Prevalence of diagnosed or undiagnosed diabetes
Spain
J.R.G. JUANATEY C.H.U.Santiago
43.3%
Evolución de la prevalencia de Diabetes en las cardiopatías INSUFICIENCIA CARDIACA Incremento 100% (X2)
J.R.G. JUANATEY C.H.U.Santiago
CARDIOPATIA ISQUEMICA Incremento 110% (X2)
Cardiotens 2009
Prevention of CV events by risk factor control in 200 DM Patients treated by 5 years 12.5 for 1 mmol/l LDL reduction 8.2 for 1 mmHg RR reduction 2-3 for 0.9% HbA1c (starting from 7.8%)
J.R.G. JUANATEY C.H.U.Santiago
When hyperglycemia is prolonged during illness, it may have caused cellular damage that cannot be reversed after achieving normoglycemia, as is demonstrated in diabetes (Metabolic Memory/Legacy Effect)
Aspirin for Primary Prevention of CV events in Diabetics Coronary heart disease events
Overall (95% CI)
J.R.G. JUANATEY C.H.U.Santiago
0.91 (0.79-1.05)
Stroke
Overall (95% CI)
0.85 (0.66-1.11)
JACC 2010; 55: 2878-86
The effect of combination lipid therapy in T2 DM The ACCORD Trial Primary Outcome
Proportion with Event (%)
Placebo
Fenofibrate
P=0.32
Years
Accord Study Group. New Engl J Med 2010; 362: 1563
J.R.G. JUANATEY C.H.U.Santiago
Incretin-based therapy GLP-1 R agonists
DPP-4 Inhibitors i.e. Sitagliptin Vildagliptin Saxaglitin Alogliptin ...........
J.R.G. JUANATEY C.H.U.Santiago
GLP-1 Analogues i.e. exenatide
Preserved Human GLP-1 i.e. liraglutide
HbA1c <7.0% + No weight gain + No confirmed hypoglycaemia (minor or major) + Cardiovascular safety J.R.G. JUANATEY C.H.U.Santiago
Patients reaching target (%)
Zinman et al, Diabetologia 2009;52(Suppl 1):S292 (A743)
45 40
39% 32%*
35 30
24%*
25 20
15%**
15
8%**,
8%**,
6%**,
SU
Placebo
TZD
10 5 0
Liraglutide Liraglutide 1.8 mg 1.2 mg (n=1363)
(n=896)
Exenatide
Glargine
(n=231)
(n=232)
(n=490)
(n=524)
(n=231)
Liraglutide 1.8 mg is superior (*p<0.01; ** p<0.0001) Liraglutide 1.2 mg is superior ( p<0.0001) J.R.G. JUANATEYPercentages are from logistic regression model adjusted for trial, previous treatment and with baseline HbA1c and weight as C.H.U.Santiago covariates
Risk of AMI, stroke, HF and death in elderly Medicare patients treated with Rosiglitazone or Pioglitazone Acute Myocardial Infarction Rosiglitazone
Stroke Rosiglitazone
Pioglitazone
Pioglitazone P = 0.18
J.R.G. JUANATEY C.H.U.Santiago
P < 0.001
JAMA 2010; 304: 411-418
Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes
J.R.G. JUANATEY C.H.U.Santiago