Criterios de selección y evaluación de los fármacos para la prevención del riesgo cardiovascular. Hipolipemiantes

Transcripción

1 FARMACOLOGÍA CLINICA 6º CURSO Criterios de selección y evaluación de los fármacos para la prevención del riesgo cardiovascular. Hipolipemiantes Dr. Antonio J. Carcas Sansuán

2 Estudio MRFIT (Lancet 1986;2:933 6): Tasa de muerte por CC ajustada por edad y colesterol sérico en varones en USA Tasa de muerte por CC por varones en 6 años Colesterol sérico mg/dl

3 Es beneficioso el tratamiento hipolipemiante? Colesterol muy alto con CC o IM Colesterol moderadamente alto con riesgo elevado de CC o IM Colesterol normal con CC o IM 4S LIPID CARE Prevención secundaria Colesterol alto sin CC o IM Sin historia de CC o IM Colesterol bajo o moderado sin CC o IM WOSCOPS AFCAPS/ TexCAPS ASCOT Pirámide de ensayos recientes: tamaño relativo de los diversos segmentos de la población Prevención primaria

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8 1,7 2,4 3,3 1,9 2,3 3,6

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17 5,1 vs 5,7 4,1 vs 5,3 Seguimiento medio: 4,1 años

18 1,87 vs 2,27 Seguimiento medio: 4,1 años

19 Mayor beneficio en pacientes de mayor riesgo Meta-análisis (Circulation 1998; 97: 946): por cada reducción del 10% del colesterol disminuye 15% eventos coronarios y 11% mortalidad tanto en prevención 1ª como prevención 2ª Riesgo basal y NNT para prevenir un evento coronario por año Estudio (fármaco) 4S (simvastatina) CARE (pravastatina) LIPID (pravastatina) WOSCOPS (pravast.) AFCAPS (lovastatina) Incidencia con placebo 5,2% 2,6% 2,6% 1,5% 1,1% Reducción de riesgo 34% 24% 24% 31% 36% Clinical Evidence NNT

20 Punto de corte según riesgo / beneficio 13% Jackson PR. Br J Clin Pharmacol, 2001; 52:

21 (J Am Coll Cardiol 2006;48:438 45)

22 (J Am Coll Cardiol 2006;48:438 45)

23 (J Am Coll Cardiol 2006;48:438 45) Coronary death or any CV event Eventos evitados 1.65/100/año +0.85/100/año 1.1/100/año 0.86/100/año

24 (J Am Coll Cardiol 2006;48:438 45) Coronary death or myocardial infarction Eventos evitados 0.65/100/año 0.7/100/año 0.75/100/año 0,22/100/año

25 (J Am Coll Cardiol 2006;48:438 45) Stroke Eventos evitados /100/año /100/año 0.01/100/año 0,01/100/año

26 (J Am Coll Cardiol 2006;48:438 45) cardiovascular mortality Eventos evitados 0.02/100/año 0.6/100/año 0.03/100/año /100/año 0.03/100/año

27 Overall mortality (J Am Coll Cardiol 2006;48:438 45)

28 (J Am Coll Cardiol 2006;48:438 45)

29 OBJETIVOS DEL TTO HIPOLIPEMIANTE: CIFRAS DE LDL National Cholesterol Education Program(NCEP)Adult Treatment Panel III (ATPIII) Guidelines Pacientes con CC ó Enfermedad Aterosclerostica periférica ó diabetes ó +2 factores riesgo con >20% de riesgo de crisis coronaria en 10 años (ALTO RIESGO) LDL<100 mg/dl Pacientes +2 factores riesgo con 10-20% de riesgo de crisis coronaria en 10 años (MODERADO/ALTO RIESGO) Pacientes +2 factores riesgo con <10% de riesgo de crisis coronaria en 10 años (MODERADO RIESGO) LDL<130 mg/dl Pacientes con 0-1 factor riesgo (BAJO RIESGO) LDL<160 mg/dl

30 Es necesario disminuir la cifra de colesterol LDL a cifras <100 mg/dl? Hasta cuanto?

31 Los ensayos clínicos realizados evalúan la eficacia de dosis fijas de estatinas, en ningún caso la disminución de la morbimortalidad al alcanzar una cifra determinada de LDLc. Post-CABG. Circulation 2000; 102: pacientes aleatorizados reducir el LDL a o a mg/dl necesidad de revascularización a los 4 años: 6,5% vs 9,2% (p = 0,03)

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33 Majority of LDL-C Lowering Occurs at the Lowest Statin Dose Atorvastatin 10/20/40/80 mg 211 mg/dl* Simvastatin 10/20/40 mg 219 mg/dl* Daily Dose 38% 28% 10 mg 20 mg 46% 51% 54% 35% 41% 16% with 3 Titrations 13% 40 mg 80 mg *Mean baseline LDL-C. At the time of this study, the maximum dose for simvastatin was 40 mg. Adapted from Jones P et al. Am J Cardiol 1998;81:

34 The diminishing returns of the hypothesized log-linear relationship Paciente con mayor riesgo CV Paciente con menor riesgo CV Hayward, R. A. et. al. Ann Intern Med 2006;145:

35 Mortalidad coronaria a 25 años en el estudio 7 países según la colesterolemia Tasa de mortalidad coronaria, % Europa del norte USA Sur Europa continental Serbia Sur Europa Mediterránea Japón 2,6 5,15 7,75 (100mg/dl) (200mg/dl) (300mg/dl) Kromhout D. Eur Heart Journal 1999; 20: Colesterolemia total, mmol/ l

36 First, assessment of baseline risk should be based on any type of occlusive vascular event (rather than on coronary events alone), since lowering LDL cholesterol with a statin lowers the risks not just of coronary events but also of revascularisation procedures and of ischaemic strokes. Secondly, treatment goals for statin treatment should aim chiefly to achieve substantial absolute reductions in LDL cholesterol (rather than to achieve particular target levels of LDL cholesterol), since the risk reductions are proportional to the absolute LDL cholesterol reductions. Full compliance with available statin regimens can reduce LDL cholesterol by at least 1 5 mmol/l in many circumstances, and hence might be expected to reduce the incidence of major vascular events by about one third.

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38 Cambios en LDLc-HDLc y riesgo CV Am J Cardiol 2008;101[suppl]: 58B 62B

39 Influencia de marcadores de inflamación en el riesgo CV AFCAPS/TexCAPS Low LDL Subgroups Low Low LDL, LDL, Low Low hscrp hscrp Low Low LDL, LDL, High High hscrp hscrp [A] [B] RR Statin Effective Statin Not Effective However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hscrp but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. Ridker et al, New Engl J Med 2001;344:

40 Influencia de marcadores de inflamación en el riesgo CV To improve detection of individuals at increased risk for cardiovascular disease, physicians often measure high sensitivity C-reactive protein (hscrp), an inflammatory biomarker that reproducibly and independently predicts future vascular events and improves global risk classification, even when cholesterol levels are low. Prior work has shown that statin therapy reduces hscrp, and that among stable coronary disease patients as well as those with acute ischemia, the benefit associated with statin therapy relates not only to achieving low levels of LDL, but also to achieving low levels of hscrp. In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / TexCAPS trial*, we observed that those with low levels of both LDL and hscrp had extremely low vascular event rates and that statin therapy did not reduce events in this subgroup (N=1,448, HR 1.1, 95% CI ). Thus, a trial of statin therapy in patients with low cholesterol and low hscrp would not only be infeasible in terms of power and sample size, but would be highly unlikely to show clinical benefit. In contrast, we also observed within AFCAPS/TexCAPS that among those with low LDL but high hscrp, vascular event rates were just as high as rates among those with overt hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1,428, HR 0.6, 95% CI ). *Ridker et al N Engl J Med 2001;344:

41 Influencia de marcadores de inflamación en el riesgo CV ALGUNOS HECHOS: 1. El tratamiento con estatinas reduce la PCRhs y este descenso se relaciona con el beneficio de las estatinas. 2. AFCAPS / TexCAPS: - Pacientes con cifras bajas de LDL y PCRhs tenían un riesgo muy bajo de eventos y en ellos las estatinas no reducían el riesgo (N=1,448, HR 1.1, 95% CI ). - Pacientes con cifras bajas de LDL pero altas de PCRhs el riesgo era tan alto como en pacientes con hiperlipidemia y en este subgrupo las estatinas reducían significativamente el riesgo (N=1,428, HR 0.6, 95% CI ). *Ridker et al N Engl J Med 2001;344:

42 Cannon et al. N Engl J Med 2004; 350:

43 Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/dl hscrp > 2 mg/l 89,890 89,863 Screened 4 week Placebo Run-In 17,802 Randomized Reason for Exclusion (%) LDL-C > 130 > 130 mg/dl mg/dl hscrp < 2.0 mg/l Withdrew Consent 54 Diabetes 1 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dl <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to to Placebo 8,857 8,600Completed Study Lost Lost to to follow-up 8,864 8,600 Completed Study Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in in Efficacy and Safety Analyses Ridker et al NEJM 2008

44 LDL (mg/dl) LDL decrease 50 percent at 12 months HDL (mg/dl) HDL increase 4 percent at 12 months hscrp (mg/l) hscrp decrease 37 percent at 12 months TG (mg/dl) TG decrease 17 percent at 12 months Months Months

45 PEP: combined myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes

46 Statins and the Development of Diabetes HR (95% CI) WOSCOPS Pravastatin 0.70 ( ) PROSPER Pravastatin 1.34 ( ) HPS ASCOT-LLA PROVE-IT Simvastatin Atorvastatin Atorvastatin VS Pravastatin 1.20 ( ) 1.20 ( ) 1.11 ( ) JUPITER Rosuvastatin 1.25 ( ) Statin Better Statin Worse

47 Understudied Subgroups Women Age > 70 Black, Hispanic, Other Low Risk Subgroups Framingham Risk < 10 % LDLC < 100 mg/dl BMI < 25 mg/m2 No Hypertension N HR (95%CI) 6, ( ) 5, ( ) 5, ( ) 8, ( ) 6, ( ) 4, ( ) 7, ( ) No metabolic Syndrome 10, ( ) Elevated hscrp Only 6, ( ) All Participants 17, ( ) Rosuvastatin Superior Rosuvastatin Inferior

48 Number Needed to Treat (5 year) Endpoint All FRS<10 FRS>10 Primary Endpoint Primary Endpoint, Mortality MI, Stroke, CABG/PTCA, Death MI, Stroke, Death Benchmarks: Statins for hyperlipidemia 5-year NNT Diuretics 5-year NNT Beta-blockers 5-year NNT Aspirin Men 5-year NNT Aspirin Women 5-year NNT

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50 Lp-PLA2 y riesgo en el estudio ARIC From Society for Heart Attack Prevention and Eradication.

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52 Effects of antilipemic medications on lipoproteins and inflammatory biomarkers Vanhecke et al. Rev Cardiovasc Med. 2009;10(1):51-58

53 CP&T. Vol 83 Nº 3 March

54 JUPITER Can we improve and simplify guidelines for primary prevention?

55 JUPITER Can we simplify guidelines for statin therapy? 1. Strong recommendations for diet, exercise, and smoking cessation for any patient with or at risk for cardiovascular disease. 2. If there is prior MI, stroke, or known CVD, treat 3. If the patient is diabetic or has a very strong family history of premature atherothrombosis, treat 4. If LDLC > 160, TC:HDLC > 6, or hscrp > 2, treat 5. Beyond these recommendations, referral to lipid specialist or cardiologist for further evaluation.