April 2016

Mei 2016DR GUY ODENTDR ROXANA VOIGT

Oxidatieve stressInflammatieEndotheeldysfunctieRenine angiotensine ald syst activatie

Ct coronaro corpus alienum rechter ventrikelwand

NOAC VKF DOSISSTANDAARD DOSISVERLAAGDE DOSISCI NIERFUNCTIEELIQUIS2 X 5 mg per dag 2 X 2,5 mg per dag -- 2/3 van >80 j, creat > 1,5 mg per dl, < 60 kilo-- creat clear 15 -29Creat clear < 15PRADAXA2 X 150 mg per dag2 x 110 mg per dag -- > 80 j-- verapamil -- creat clear 30 50-- gastritisCreat clear < 30XARELTO20 Mg per dag 15 mg per dag -- creat clear 30-49-- creat clear 15 -29 : caution !!!Creat clear < 15

NOAC VKF TEGENINDICATIESMetalen kunstklepMitraalklepstenoseNierinsufficientie

Wel toegelaten doch niet onderzocht: biologische kunstkleppen, klepherstel of plastie

ELIQUIS 5 MG VKF : terugbetaling

ELIQUIS 2 x 2,5 mg VKF : terugbelating

Pradaxa 2 x 150 mg per dag, vkf , terugbetaling

Pradaxa 2 x 110 mg per dag, vkf , terugbetaling

Xarelto VKF 20 mg per dag, terugbetaling

Xarelto 15 mg , VKF, terugbetaling

Pradaxa : DVT : terugbetaling ( 1 )

Pradaxa : DVT terugbetaling ( 2 )

Pradaxa DVT : terugbetaling ( 3 )

Pradaxa DVT terugbetaling ( 4 )

Pradaxa : longembool : terugbetaling ( 1 )

Pradaxa : longembool : terugbetaling ( 2 )

Pradaxa longembool terugbetaling ( 3 )

Pradaxa : longembool terugbetaling ( 4 )

Eliquis : DVT / LONGEMBOOL

Xarelto : DVT : terugbetaling ( 1 )

Xarelto DVT terugbetaling ( 2 )

Xarelto DVT terugbetaling ( 3 )

Xarelto dvt terugbetaling ( 4 )

Xarelto longembool terugbetaling ( 1 )

Xarelto Longembool terugbetaling (2 )

Xarelto longembool terugbetaling (3 )

Xarelto longembool terugbetaling ( 4 )

Dosering NOAC DVT LONGEMBOOLstartBehandelingPreventieeliquis2 x 10 mg ged 7 dagen 2 x 5 mg per dag ged 6 maand2 x 2,5 mg per dag ged 6 maandXarelto2 x 15 mg per dag 21 dagen 20 mg per dag minstens 3 maandClear 30 49 : 15 of 20 mg per dag Clear 15 -30 : cautionVerlengbaar levenslangPradaxaLMWH ther dosis 5 dagen2 x 150 mg zeker 3 maand Doch 2 x 110 >80 jaar of verapamilClear 30 49 ofwel 2 x 150 ofwel 2 x 110 bij hoger bloedingsrisicoVerlengbaar levenslang

Dabigatran antidotum : PraxbindGehumaniseerd monoklonaal antilichaamfragment dat specifiek bindt aan dabigatran en het antistollingseffect neutraliseert. Onmiddellijke en aanhoudende neutralisatie (tot 12 uur ) van antistollingseffect van dabigatranTwee flacons van 2,5 gram Indicaties: -- voor spoedoperaties/spoedprocedures-- levensbedreigende of oncontroleerbare bloedingen

Perceval sutureless valve

Cardiocel Ozaki klep

Aneurysma aorta descendens

Proprotein convertase subtilisin/kexin type 9(PCSK9)1Serine protease1Synthesised primarily in the liver and enters the circulation1Binds to hepatic LDLR and targets them for degradation, regulating their levels1Reduces LDLR density on the hepatocellular surface and therefore reduces the level of LDL-C clearanceA potential target for intervention in FH and dyslipidemia2Blocking PCSK9 reduces LDLR degradation and therefore increases clearance of LDL-CPCSK9 is a key downregulator of LDLR3

1. Stein E et al. N Engl J Med. 2012;366:11081118; 2. Duff CJ et al. Biochem J. 2009;419:577584; 3. Lo Surdo P et al. EMBO Rep. 2011;12:13001305;4. Horton JD et al. J Lipid Res. 2009;50(suppl):S172S177

Model of LDLR Bound to PCSK94

64

Clinical trial data support achieving lower levels of LDL-C, regardless of baseline LDL-C[To convert, 100 mg/dL=2.59 mmol/L].ACS, acute coronary syndrome; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol.Rosenson RS. Exp Opin Emerg Drugs 2004;9:26979; LaRosa JC, et al. N Engl J Med 2005;352:142535; Cannon CP, et al. N Engl J Med 2015;372:238797.4SpboLIPIDpbo4SS40CAREpboHPSpboLIPIDP40CAREP40HPSS40TNTA10TNTA80PROVE-IT TIMI 22P40PROVE-IT TIMI 22A80IMPROVE-ITS40+EZEIMPROVE-ITS40

ACS studyStable CAD study

Although large-scale statin trials have demonstrated significant reductions in CV risk, there are many patients who have a CV event despite receiving statin therapyThere is increasing evidence that larger reductions in LDL-C are associated with greater improvements in CV morbidity and mortalityThe studies shown here have demonstrated a generally linear relationship between event rates and on-treatment LDL values over a wide range of LDL from 194 down to 54 mg/dL [5.02 to 1.53 mmol/L]The linear relationship between lower LDL-C levels and reduction in CV events was also observed in the IMPROVE-IT ezetimibe trial3Importantly, there is no level of LDL that has been studied below which further LDL reduction has not shown benefit

Studies:4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events Trial; HPS, Heart Protection Study; CV, cardiovascular; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LIPID, Long-term Intervention with Pravastatin in ischemic Disease; PROVE IT-TIME 22, Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22; TNT, Treating to New Targets.

Abbreviations:LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol.

References:Rosensen RS. Exp Opin Emerg Drugs 2004;9:26979.LaRosa JC, et al. N Engl J Med 2005;352:142535.Cannon CP, et al. N Engl J Med 2015;372:238797.

Every 1 mmol/L reduction in LDL-C reduces annual CV risk by up to 28%, regardless of mechanismData from studies of non-statin lipid-lowering medications superimposed upon data from the Cholesterol Treatment Trialists Collaboration (CTTC) 2005 meta-analysis. The IMPROVE-IT trial was adequately powered to show the efficacy on incremental LDL-C lowering on CV outcomes. [To convert, 100 mg/dL=2.59 mmol/L].CV, cardiovascular; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C, low-density lipoprotein cholesterol.CTT Collaboration. Lancet 2005:366;126778; CTT Collaboration. Lancet 2010;376:167081; Cannon CP, et al. N Engl J Med 2015;372:238797.There is no evidence of any lower LDL-C threshold

CTTC trials (statin)

Niacin

Diet/unsaturated fatty acid

Ileal bypass

Bile acid resin

Ezetimibe

FibrateMore LDL lowering and risk reductionReduction in CV events (%)01020304050

IMPROVE-IT

1020304050607080Reduction in LDL-C (mg/dL)

LDL-C has been validated as a modifiable risk factor through > 30 years of research Trials with statins provided a large volume of data regarding the relationship between LDL-C reduction and reduction in CV events in a variety of patient populations and baseline LDL-C values Very similar results were seen with studies over decades with non-statin interventions such as niacin, bile acid sequestrants, fibrates and even surgical approaches, all of which showed that, when LDL-C was appreciably lowered, and there were no off-target adverse effects on other lipid fractions or other parameters, then there was a corresponding reduction in risk Some more recent trials had very small LDL-C reductions and non-significant reductions in CV events, but were inadequately powered to test the LDL-C hypothesisIn contrast, the IMPROVE-IT study was adequately powered for CV events and shows that further LDL-C reduction with a non-statin added to a statin further reduces CV events2The data shown are from studies of non-statin lipid-lowering medications superimposed upon data from the Cholesterol Treatment Trialists Collaboration (CTTC) 2005 meta-analysis. Circle/square size is proportional to sample sizeTo convert: 100 mg/dL = 2.59 mmol/L

Abbreviations:CV, cardiovascular; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C, low-density lipoprotein cholesterol.

References:FDA Briefing Document (EMDAC) June 10 2015. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs /EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM452354.pdf. [Accessed 9 July 2015].Cannon CP, et al. N Engl J Med 2015;372:238797.

Background on CHD and HypercholesterolemiaCHD is the single most common cause of death in the US and Europe1,2Hypercholesterolemia is a major modifiable risk factor in the development of CHD3Despite the multitude of treatment options, the prevalence of hypercholesterolemia and associated CHD remain high1Statin therapies have demonstrated CV event reduction by ~ 25% despite a higher percentage of patients achieving LDL-C goals4-6

CHD = coronary heart disease; US = United States; CV = cardiovascular; LDL-C = low density lipoprotein-cholesterol.

Roger VL, et al. Circulation. 2012;125:e2-e220.Allender S, et al. European Cardiovascular Disease Statistics. European Heart Network. 2008.National Cholesterol Education Program. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf. Accessed April 22, 2013.Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.LaRosa, JC, et al. N Engl J Med. 2005;352:1425-1435.

Main Points:CHD affects approximately 16 million Americans and is the single most common cause of death in both the United States (US) and Europe.1,2According to a report issued by the National Cholesterol Education Program in 2001, low density lipoprotein-cholesterol (LDL-C) is a major cause of CHD, and LDL-lowering therapies can reduce the risk for CHD.3Despite the multitude of treatment options, the prevalence of hypercholesterolemia and associated CHD remain high. About 100 million Americans have a total cholesterol > 200 mg/dL; about 34 million Americans have a total cholesterol > 240 mg/dL.1Statin therapies have demonstrated cardiovascular (CV) event reduction by only ~ 1/4, despite achievement of LDL-C goals.4-6

References:Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics 2012 Update: a report from the American Heart Association. Circulation. 2012;125:e2-e220.Allender S, et al. European Cardiovascular Disease Statistics. European Heart Network. 2008.National Cholesterol Education Program. Detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III): Executive summary. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf. Accessed April 22, 2013.Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001-1009.Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.LaRosa, JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.71

Psck-9 functie

Combo-therapy

Statin-intolerantMono-therapyHeFH

Long-term safety and efficacyOpen-labelExtension

HoFH

Phase 2(N = 168)Phase 3(N = 300)Phase 2(N = 629)Phase 3(N = 1,700)Phase 2(N = 1,400)Phase 2/3(N 67)Phase 2/3(N = 125)Phase 2(N = 406)Phase 3(N = 600)Phase 3(N = 905)Phase 3(N = 27,500)SecondaryPrevention

Phase 3(N = 950)

Phase 2(N = 157)Phase 3(N = 300)Athero

Phase 3(N 3,500)Phase 3(N = 500)PROFICIO

Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations

Amgens Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations (PROFICIO) has undertaken a broad range of Phase 2 and Phase 3 clinical investigations to evaluate the safety and efficacy of AMG 145.

LDL-C reduction to achieve therapeutic goals as a function of starting value*And/or 50% LDL-C reduction from baseline LDL-C when target levels cannot be achieved.[To convert, 100 mg/dL=2.59 mmol/L].CV, cardiovascular; CVD, cardiovascular disease; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol.Reiner Z, et al. Eur Heart J 2011;32:1769818.Nordestgaard BG, et al. Eur Heart J 2013;34:347890.Many FH and CVD patients will need an LDL-C reduction beyond 50% to obtain therapeutic targets, according to ESC/EAS guidelines1

Starting LDL-C% reduction to reach target LDL-Cmmol/L70>605.26.2657050604.45.2606540503.94.4556035403.43.945552535

An absolute reduction to an LDL-C level