FARMACOLOGA CLINICA 6 CURSO -- 2011-2012

Criterios de seleccin y evaluacin de los frmacos para la prevencin del riesgo cardiovascular.

Antihipertensivos
Dr. Antonio J. Carcas Sansun Dpto de Farmacologa. Facultad de Medicina. UAM

Enfermedad cardiovascular: Un desafo mundial

Principal causa de muerte en pases desarrollados y en muchos pases en vas de desarrollo Entre 1970 y 1992 la ECV disminuye lentamente en algunas zonas, sobre todo en Norteamrica, Europa occidental, Australia y Nueva Zelanda La mortalidad por ECV aument recientemente en Europa oriental y central
Sans y cols.: Eur Heart J 1997;18:12311248; American Heart Association: International CVD Statistics, 1998 Brown y cols.: Science 1996;272:629; Reckless: Curr Opin Lipidol 1996;7:356 362

Enfermedad CV: un trastorno multifactorial A

M B I E N T A L E S Lpidos
Obesidad Tabaquismo Dieta Tipo de vida sedentario Factores trombticos

Hipertensin Diabetes
Enfermedad vascular Edad Sexo

Antecedentes familiares

G E N E T I C O S

Pirmide de los factores de riesgo cardiovasculares

Edad Carga de placa ateroesclertica

Marcadores de dao orgnico: HVI. Creatinina elevada. Microalbuminuria. Retinopata. Engrosamiento pared de art. cartida o presencia de placa.

Placa Tabaco HTA Colesterol total (LDL-Col) DM Otros

Factores aterognicos

Factores subyacentes Nutricin/Obesidad Historia familiar Sexo Otros

Como evaluamos el riesgo CV

Prevencin primaria Prevencin secundaria VS Evaluacin del riesgo CV global

Importante para la toma de decisiones teraputicas

Caractersticas de las tablas calibradas del estudio REGICOR: 1) Permite utilizarlas hasta los 74 aos de edad 2) Se proporciona el riesgo exacto en cada casilla 3) Si el HDL est disponible puede corregirse la lectura del riesgo 4) Se usa la clasificacin de la HTA y no slo la TAS 5) Cdigo de colores igual que los vigentes hasta 2003 6) Distingue diabticos de no diabticos

Wilson P et al. Circulation 1998; 97: 1837-1847. Marrugat J et al. Rev Esp Cardiol 2002; 56: 253-61.

Accuracy of risk stratification (according to European Society of Hypertension-European Society of Cardiology [ESH/ESC] guidelines) in hypertensive patients treated in primary care or specialist practice in the CONTROLRISK study.

Physician awareness of CVD prevention guidelines (left panel) and incorporation of guidelines into clinical practice among physicians who stated they were aware of them (right panel).

Objetivos del tratamiento

Disminucin de la morbimortalidad asociada a enfermedad coronaria. Disminucin de la morbimortalidad cerebrovascular: Disminucin de la incapacidad funcional:
Actividades de la vida diaria y autocuidado

Disminucin de enfermedad arterial perifrica Aumento de la supervivencia Mejorar la calidad de vida

Variables de evaluacin
Enfermedad coronaria (CI) :
incidencia de angina o infarto necesidad de revascularizacin

Enfermedad cerebrovascular
Incidencia de ACVA. Grado de dependencia/incapacidad:

Enfermedad arterial perifrica. Calidad de vida. Supervivencia o mortalidad. Variables compuestas:

IAM, ACVA y muerte vascular

Frmacos disponibles para la profilaxis/tratamiento

Antihipertensivos Antiagregantes Anticoagulantes Hipolipemiantes. Beta-bloqueantes Antiarrtmicos

Bases del tratamiento de la hipertensin arterial como factor de riesgo CV

Como definimos la hipertensin arterial?

Fuente: ESH

Porqu se define de este modo la HTA?

Porqu se define de este modo la HTA?

Hypertensive Patients Are at Increased Risk for Cardiovascular Events

Framingham Heart Study - Risk of Cardiovascular Events by Hypertensive Status in Patients Aged
35-64 Years; 36-Year Follow-Up
Biennial Age-Adjusted Rate per 1000

Coronary Disease
Kannel WB JAMA 1996;275(24):1571-1576.

Stroke

Peripheral Artery Disease

Cardiac Failure

Como definimos la hipertensin arterial?

Hypertension has more recently been defined as the blood pressure level above which there would be substantial (or clinically significant) benefits from lowering blood pressure

Rose G. Sick individuals and sick populations. Int J Epidemiol 2001; 30: 42732.

Cuando tratamos ?
Criterios para la toma de decisiones sobre cundo tratar la HTA
No considerar la HTA aisladamente sino dentro del perfil total de riesgo cardiovascular. Decidir qu nivel de TA y de riesgo CV global indica el tratamiento.

Evaluacin del riesgo CV en hipertensos

Fuente: ESH Low: Moderate: High: Very High: CVD* 15% 15-20% 20-30% >30% Fatal CVD* < 4% 4-5% 5-8% >8%
*Riesgo a 10 aos

Hypertension Treatment Significantly Reduced Mortality and Morbidity

VA Cooperative Study Group Estimated Cumulative Incidence of All Morbid Events Over 5 Years

Control - Placebo

Active Treatment Groups Diuretic-based regimen and hydralazine

Veterans Administration Cooperative Study Group on antihypertensive agents JAMA 1970;213(7):1143-1152.

Fuente: ESH

Asumiendo un beneficio del 20%, el beneficio a 10 aos ser proporcional al riesgo basal inicial: Riesgo basal RAR NNT 2% 0,4 250 4% 0,8 125 6% 1,2 84 8% 1,6 63 10% 2,0 50

El beneficio de tratar la HTA, es igual en todo tipo de pacientes?

Diferencias entre hombres y mujeres

Puesto que el riesgo basal parece diferente en hombres y mujeres el beneficio podra ser tambin diferente:
INDANA: La reduccin proporcional en el riesgo es similar en ambos sexos. Por tanto el beneficio final depender del riesgo basal.

Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials.
Blood Pressure Lowering Treatment Trialists Collaboration. Eur Heart J 2008; 29:26692680.

Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials.
Blood Pressure Lowering Treatment Trialists Collaboration. Eur Heart J 2008; 29:26692680.

HTA sistlica
Evento CV grave/mortal NNT (5 aos) Hombre Mujer =>70 a. 69-70 a. ECV previa No ECV 18 38 19 39 16 37

Staessen et al. Lancet 2000; 355: 865872

Original Article

Treatment of Hypertension in Patients 80 Years of Age or Older

HYVET Study Group

Study Overview
In this study, patients 80 years of age or older with sustained systolic hypertension were randomly assigned to receive either the diuretic indapamide, with or without the angiotensin-converting-enzyme inhibitor perindopril, or matching placebos, for a target blood pressure of 150/80 mm Hg

N Engl J Med Volume 358(18):1887-1898 May 1, 2008

Mean Blood Pressure, Measured while Patients Were Seated, in the Intention-to-Treat Population, According to Study Group

Beckett NS et al. N Engl J Med 2008;358:1887-1898

Main Fatal and Nonfatal End Points in the Intention-to-Treat Population

RAR= 1,24% NNT/1 ao= 81

Beckett NS et al. N Engl J Med 2008;358:1887-1898

Beckett NS et al. N Engl J Med 2008;358:1887-1898

Anti-hypertensive treatment is twice as effective in preventing complications in diabetics as non-diabetics

Tuomilethto J, N Eng J Med 1999;340:677-684 (redrawn). 60 50 Event/1000 Patient Years 40
57.6

ab Di

c eti

c eti iab nD o n Placebo

Treated

30 20 10

45.1 21.6 27.8 11.9 26.4 19.8

b

31 27.1 12.3 23.5

a b

26.6 22 8.3
a

19.7 15.4
b

0
a

8.3
a

10
b

7.8
b

11.7
a

Overall

Cardiovascular

All CV

Stroke

Cardiac

Fatal events

Non-Fatal events

Cual es la tensin arterial a alcanzar?

La evidencia disponible es fundamentalmente para TAD. La mayora en diabticos (excepto HOT). Estudios disponibles:
HOT UKPDS ABCD-HT ABCD-NT Progress 81 mm Hg 82 78 (beneficio solo en mortalidad total) 75 (beneficio en ACVA) 79 vs 83

 Sabemos que a menor TA, menor riesgo CV hasta un lmite no claramente establecido. Dudosa curva en J.
Major cardiovascular events/1000 patient-years

20 15 10 5 0 10 8 6 4 2 0

Diastolic blood pressure

Minimum = 82.6mm Hg

20 15 10 5 0

Systolic blood pressure

Minimum = 138.5mm Hg

Cardiovascular mortality/ 1000 patient-years

Minimum = 86.5mm Hg

10 8 6 4 2 0
105

Minimum = 138.8mm Hg

70

75

95 100 90 85 80 Mean diastolic blood pressure

120 130 140

150

160 170

180

190

Mean systolic blood pressure

PublishedonlineMarch14,2010

ACCORD Study Design

Randomized multi-center clinical trial Conducted in 77 clinical sites in North America (U.S. and Canada) Designed to independently test three medical strategies to reduce CVD in diabetic patients
BP question: does a therapeutic strategy targeting systolic blood pressure (SBP) <120 mmHg reduce CVD events compared to a strategy targeting SBP <140 mmHg in patients with type 2 diabetes at high risk for CVD events?

ACCORD Double 2 x 2 Factorial Design

Lipid Placebo Fibrate Intensive Glycemic Control Standard Glycemic Control BP Intensive Standard

1383

1374

1178

1193

5128

1370 2753

1391 2765

1184 2362

1178 2371

5123 10,251

5518

4733*
* 94% power for 20% reduction in event rate, assuming standard group rate of 4% / yr and 5.6 yrs follow-up

ACCORD BP Trial Eligibility

Stable Type 2 Diabetes >3 months HbA1c 7.5% to 11% (or <9% if on more meds) High CVD risk = clinical or subclinical disease or 2 risk factors Age (limited to <80 years after Vanguard)
40 yrs with history of clinical CVD (secondary prevention) 55 yrs otherwise

Systolic blood pressure

130 to 160 mm Hg (if on 0-3 meds) 161 to 170 mm Hg (if on 0-2 meds) 171 to 180 mm Hg (if on 0-1 meds)

Urine protein <1.0 gm/24 hours or equivalent Serum Creatinine 1.5 mg/dl

ACCORD BP Protocol
Many drugs/combinations provided to achieve goal BP according to randomized assignment. Intensive Intervention:
2-drug therapy initiated: thiazide-type diuretic + ACEI, ARB, or blocker. Drugs added and/or titrated at each visit to achieve SBP <120 mm Hg. At periodic milepost visits: addition of another drug required if not at goal.

Standard Intervention:
Intensify therapy if SBP 160 mm Hg @ 1 visit or 140 mm Hg @ 2 consecutive visits Down-titration if SBP <130 mm Hg @ 1 visit or <135 mm Hg @ 2 consecutive visits

Baseline Characteristics
Characteristic
Age (yrs) Women % 2 prevention % Race / Ethnicity White % Black % Hispanic % 61 24 7

Mean or % Characteristic
62 48 34 Blood Pressure (mm Hg) On Antihypertensive % Creatinine (mg/dL) eGFR (mL/min/1.73m2) DM Duration (yrs)* A1C (%) BMI (kg/m2)
*

Mean or %
139/76 87 0.9 92 10 8.3
32

Median value

Systolic Pressures (mean + 95% CI)

Mean # Meds Intensive: Standard: 3.2 1.9 3.4 2.1 3.5 2.2 3.4 2.3

Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2

Adverse Events
Intensive N (%)
Serious AE Hypotension Syncope Bradycardia or Arrhythmia Hyperkalemia Renal Failure eGFR ever <30 mL/min/1.73m2 Any Dialysis or ESRD Dizziness on Standing 77 (3.3) 17 (0.7) 12 (0.5) 12 (0.5) 9 (0.4) 5 (0.2) 99 (4.2) 59 (2.5) 217 (44)

Standard N (%)
30 (1.3) 1 (0.04) 5 (0.2) 3 (0.1) 1 (0.04) 1 (0.04) 52 (2.2) 58 (2.4) 188 (40)

P
<0.0001 <0.0001 0.10 0.02 0.01 0.12 <0.001 0.93 0.36

Symptom experienced over past 30 days from HRQL sample of N=969 participants assessed at 12, 36, and 48 months post-randomization

Clinical Parameters assessed at last clinic visit

Intensive Standard P

Potassium (mean mg/dl) Serum Creatinine (mean mg/dl) Estimated GFR (mean mL/min/1.73m2) Urinary Alb/Cr (median mg/g) Macroalbuminuria (%)

4.3 1.1 74.8 12.6 6.6

4.4 1.0 80.6 14.9 8.7

0.17 <0.0001 <0.0001 <0.0001 0.009

Primary & Secondary Outcomes

Intensive Standard Events (%/yr) Events (%/yr) Primary Total Mortality Cardiovascular Deaths Nonfatal MI Nonfatal Stroke Total Stroke
208 (1.87) 150 (1.28) 60 (0.52) 126 (1.13) 34 (0.30) 36 (0.32) 237 (2.09) 144 (1.19) 58 (0.49) 146 (1.28) 55 (0.47) 62 (0.53)

HR (95% CI)
0.88 (0.73-1.06) 1.07 (0.85-1.35) 1.06 (0.74-1.52) 0.87 (0.68-1.10) 0.63 (0.41-0.96) 0.59 (0.39-0.89)

P
0.20 0.55 0.74 0.25 0.03 0.01

Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the primary outcome, revascularization and unstable angina (HR=0.95, p=0.40)

Stroke Results
Intensive BP management reduced the rate of two closely correlated secondary end points: total stroke (p=0.01) and nonfatal stroke (p=0.03). Assuming that this finding was real, the number needed to treat to the lower SBP level to prevent one stroke over 5 years was 89. These effects would be consistent with meta-analyses summarizing the impact of a 10 mm Hg reduction in SBP on strokes from observational studies (relative risk=0.64) and drug treatment trials (relative risk=0.59).

Primary Outcome by Pre-defined Subgroups

Also examined DBP tertiles (p=0.70) and number of screening meds (p=0.44)

Conclusions
The ACCORD BP trial evaluated the effect of targeting a SBP goal of 120 mm Hg, compared to a goal of 140 mm Hg, in patients with type 2 diabetes at increased cardiovascular risk. The results provide no conclusive evidence that the intensive BP control strategy reduces the rate of a composite of major CVD events in such patients.

Pacientes con HTA y sin DM

Over a median follow-up of 20 years (IQR 193203), systolic and diastolic blood pressure were reduced by a mean of: - 235/89 mm Hg (SD 106/70) in the usual-control group -273/104 mm Hg (110/75) in the tight-control group - between-group difference: 38 mm Hg systolic [95% CI 2452], p<00001; and 15 mm Hg diastolic [0624]; p=0041).

RAR= 4,6 % NNT/1 ao= 22

Existen diferencias entre los diferentes antihipertensivos?

Blood Pressure Lowering Treatment Trialists' Collaboration
Lancet 2003 Nov 8;362(9395):1527-35

Blood Pressure Lowering Treatment Trialists' Collaboration

Lancet 2003 Nov 8;362(9395):1527-35

Blood Pressure Lowering Treatment Trialists' Collaboration

Lancet 2003 Nov 8;362(9395):1527-35

Monoterapia o tratamiento combinado?

CHD
Rbasal RRR ARR NNT Rbasal

ACVA
RRR ARR NNT

Hombres

10%

46%

4,6%

22

5%

58%

2,9%

34

Mujeres -65 aos -TA 150/90 -3 frmacos d

5%

46%

2,3%

40

4%

58%

2,3%

43

TA RR-EC (mmHg) a) 1 frmaco a dosis estndar b) 1 frmaco x2 dosis c) 2 frmacos de clase diferente
*Riesgo basal: 10%

RR-ECV

NNT-EC*

NNT-ECV*

5 6 9

25% 29% 40%

35% 40% 54%

40 35 25

29 25 19

NNT dosis doble vs Asociacin: 4

Limitaciones de los ensayos clnicos en HTA

En la mayora de los estudios se seleccionan pacientes de riesgo CV elevado y la extrapolacin a poblaciones con otro riesgo es dudosa. La mayora de los estudios tienen poco poder para evaluar las variables secundarias. Los programas teraputicos frecuentemente no son iguales a los utilizados en la prctica clnica. El cumplimiento en los ECs es mucho mayor que en la prctica. Los ECs duran 4-5 aos en el mejor de los casos, mientras que la esperanza de vida puede ser de 20-30 en edad adulta. Es difcil extraer conclusiones sobre riesgos individuales.

Ms importante que el frmaco utilizado es el conseguir el tratamiento y control de todos los pacientes

Fuente: JNC

Fuente: ESH

NICE Clinical Guideline 18 (partial update,2006

Gua de 2007 para el manejo de la hipertensin arterial ESH/ESC

Gua de 2007 para el manejo de la hipertensin arterial ESH/ESC

Posibles combinaciones de antihipertensivos.

Las combinaciones de eleccin en la poblacin hipertensa general se representan con lneas gruesas.

Gua de 2007 para el manejo de la hipertensin arterial ESH/ESC