Antiplatelet agents treatment

Transcription

1 Session III Comprehensive management of diabetic patients Antiplatelet agents treatment Chonnam National University Hospital Department of Internal Medicine Dong-Hyeok Cho

2 CONTENTS Introduction Prothrombotic state in diabetes Antiplatelet agents; clinical evidences Resistance to antiplatelet agent Treatment guidelines Summary

3 CVD; global leading cause of mortality FIGURE. Proportion of global NCD deaths under the age of 70, by cause of death, 2008 World Health Organization: Global status report on noncommunicable diseases 2010

4 Vascular complications in DM KDA Diabetes Fact Sheet, 2015

5 DM; accelerated atherothrombosis FIGURE. Hazard ratios (HRs) for vascular outcomes in people with versus those without diabetes at baseline Emerging Risk Factors Collaboration. Lancet. 375(9733): , 2010

6 DM; CAD risk equivalents FIGURE. Kaplan Meier Estimates of the Probability of Death from Coronary Heart Disease in 1059 Subjects with Type 2 Diabetes and 1378 Nondiabetic Subjects with and without Prior Myocardial Infarction. Haffner SM, et al. N Engl J Med. 339(4):229-34, 1998

7 Mechanism of atherothrombosis in DM Jung JH, et al. Diabetes Metab J. 39(2):95-113, 2015

8 Atherosclerosis therapy in diabetes JAMA. 287: , 2002

9 DM; a prothrombotic state FIGURE. Possible pathways involved in the thrombotic state observed in T2DM. Morel O, et al. Atherosclerosis. 212(2):367-76, 2010

10 Platelet dysfunction in DM FIGURE. Mechanisms involved in the platelet dysfunction of diabetic patients. Patti G, et al. Circ J. 78(1):33-41, 2014

11 Platelet activation and prognosis in DM Platelet aggregation following ADP stimuli Platelet aggregation is higher in diabetic than in nondiabetic patients, and insulin-treated diabetic patients have the highest degree of platelet reactivity. The major adverse cardiac event rate was significantly higher in patients with platelet reactivity above the cutoff value compared with those below this cutoff value (37.7 vs. 13.3%, respectively; odds ratio 3.96 [95% CI ]; P < ). Angiolillo DJ. Diabetes Care. 32(4):531-40, 2009

12 Platelet physiology

13 Multiple targets for antiplatelet agents Jung JH, et al. Diabetes Metab J. 39(2):95-113, 2015

14 Aspirin Mechanism of action Membrane Phospholipids Arachidonic Acid COX-1 irreversible Aspirin Prostaglandin H 2 Thromboxane A 2 Platelet Aggregation Vasoconstriction Prostacyclin Platelet Aggregation Vasodilation

15 Low-dose aspirin for 1º prevention in T2DM Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Log-Rank Test, P = 0.16 HR (95% CI): 0.80 ( ) % 4 2 Nonaspirin Aspirin No. at risk Nonaspirin Aspirin years Ogawa H, et al. JAMA. 300(18): , 2008

16 Aspirin in DM & asymptomatic PAD The prevention of progression of arterial disease and diabetes (POPADAD) trial 18.3% 18.2% 6.7% 5.5% Fig. Kaplan-Meier estimates in aspirin and no aspirin groups of proportion of patients who experienced the composite end point of death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or above ankle amputation for critical limb ischemia; and death from coronary heart disease or stroke Belch J, et al. BMJ. 337:a1840, 2008

17 Aspirin for primary prevention in DM TABLE. Clinical trials of aspirin in primary prevention for diabetes Jung JH, et al. Diabetes Metab J. 39(2):95-113, 2015

18 Aspirin for primary prevention in DM META-ANALYSIS of trials examining the effects of aspirin on risk of CVD events in patients with diabetes Effect of aspirin on CHD events Effect of aspirin on risk of stroke Pignone M, et al. Diabetes Care. 33(6): , 2010

19 Aspirin for secondary prevention in DM Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from RCTs Antithrombotic Trialists' (ATT) Collaboration. Lancet. 373(9678): , 2009

20 Aspirin; secondary prevention Effect of antiplatelet treatment* on vascular events** *Aspirin was the predominant antiplatelet agent studied **Include MI, stroke, or death Antithrombotic Trialists' Collaboration. BMJ. 324(7329):71-86, 2002

21 Aspirin; high-dose vs. low-dose Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial High-dose (300~325 mg daily) versus Low-dose (75~100 mg daily) TABLE. Efficacy and safety outcomes for the aspirin dose comparison FIGURE. Kaplan-Meier curves for the primary outcome of cardiovascular death, myocardial infarction, or stroke, for the aspirin dose comparison. Mehta SR, et al. Lancet. 376(9748): , 2010

22 Aspirin; Dose and efficacy Effect of aspirin doses on vascular events in high-risk patients (excluding those with acute stroke) Antithrombotic Trialists' Collaboration. BMJ. 324(7329):71-86, 2002

23 Aspirin for secondary prevention Clinical benefit is clearly superior to the risk of major bleeding in the setting of secondary CVD prevention. Bedrock of antiplatelet therapy for secondary prevention of recurrent ischemic events in patients with atherothrombotic disease, including those with DM. The recommended dose of aspirin for secondary prevention in DM patients with atherosclerotic disease is 75 to 162 mg daily.

24 P2Y 12 receptor antagonists Classes Thienopyridines: non-direct, irreversible Nucleotide/nucleoside analogs: direct, reversible Drugs Samoš M1, et al. J Diabetes Res. 2016: , 2016

25 P2Y 12 receptor antagonists FIGURE. Metabolic pathway of P2Y 12 receptor inhibitors Levine GN, et al. Nat Rev Cardiol.11(10): , 2014; Jung JH, et al. Diabetes Metab J. 39(2):95-113, 2015

26 Primary prevention Clopidogrel and aspirin vs. aspirin alone for prevention of atherothrombotic events 15,603 patients with either clinically evident CVD or multiple risk factors clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin followed for a median of 28 months. Primary efficacy endpoint* Secondary efficacy endpoint** 7.3% 17.9% 6.8% 16.7% 0.93 ( ) P= ( ) P=0.04 *Primary efficacy end point: a composite of myocardial infarction, stroke, or death from cardiovascular causes. **Secondary efficacy end point: the first occurrence of myocardial infarction, stroke, death from cardiovascular causes, or hospitalization for unstable angina, a transient ischemic attack, or a revascularization procedure (coronary, cerebral, or peripheral). CHARISMA Investigators. N Engl J Med. 354(16): , 2006

27 Secondary prevention TABLE. Main outcomes of randomized clinical trials investigating clinical efficacy of oral antiplatelet treatment in diabetic patients with acute coronary syndrome or undergoing percutaneous coronary intervention Jung JH, et al. Diabetes Metab J. 39(2):95-113, 2015

28 Intensified antiplatelet regimen in DM FIGURE. Randomized clinical trials evaluating primary efficacy of intensified antiplatelet regimen versus clopidogrel in diabetic patients with acute coronary syndrome. Jung JH, et al. Diabetes Metab J. 39(2):95-113, 2015

29 Glycoprotein IIb/IIIa inhibitors (GPI) Antithrombotic agents preventing the binding of fibrinogen to GP IIb/IIIa receptors Intravenous agents Questionable whether diabetic patients may achieve further clinical benefit from the routine use of GP IIb/IIIa inhibitor in ACS patients. Kristensen SD, et al. Thromb Haemost. 107(2):

30 Glycoprotein IIb/IIIa inhibitors (GPI) TABLE. Characteristics of intravenous glycoprotein IIb/IIIa inhibitors. Kristensen SD, et al. Thromb Haemost. 107(2):

31 Glycoprotein IIb/IIIa inhibitors (GPI) Kristensen SD, et al. Thromb Haemost. 107(2):

32 Phosphodiesterase (PDE)

33 Phosphodiesterase inhibitor PDE2, PDE3, and PDE5 isozymes are accountable for the majority of platelet PDE activity (>90%). In platelets, cyclic adenosine 3,5 -monophosphate (camp) is hydrolysed by PDE3 and PDE2, whereas cyclic guanosine 3',5'-monophosphate is hydrolysed by PDE5 and PDE2. Dual mechanism with increased production of camp (by clopidogrel) and decreased degradation of camp (by PDE inhibitor) synergistically enhances the level of intraplatelet vasodilator-stimulated phosphoprotein-phosphorylation and thus stabilize platelet activation. Jung JH, et al. Diabetes Metab J. 39(2):95-113, 2015

34 Cilostazol Dual inhibitor of PDE3 and adenosine reuptake Widely used selective and reversible PDE3 inhibitor, which is highly expressed in myocardial and vascular smooth muscle cells (VSMCs) and platelets. Also, inhibits adenosine reuptake into erythrocytes, endothelial cells, muscle cells, and platelets, thereby increasing interstitial and circulatory adenosine levels at clinically relevant concentrations (~3 μmol/l). The unique feature of cilostazol may contribute to the observed efficacy profile of cilostazol in platelet reactivity and atheroma progression among DM patients. Jung JH, et al. Diabetes Metab J. 39(2):95-113, 2015

35 Effects of cilostazol on atherosclerosis The Phosphodiesterase Inhibitor Cilostazol Induces Regression of Carotid Atherosclerosis in Subjects With Type 2 Diabetes Mellitus (DAPC Study) TABLE. Changes From Baseline to Year 2 in Mean and Maximum CCA-IMT. Katakami N, et al. Circulation. 121(23): , 2010

36 Triple antiplatelet therapy Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes: A randomized, controlled study Death CV death, MI, or stroke TVR MACCE *TVR; target vessel revascularization, MACCE; major adverse cardiac or cerebral event FIGURE. The Kaplan-Meier curves of cumulative hazard of death (A); cardiovascular death, MI, or stroke (B); TVR (C); and MACCE (D). Han Y, et al. Am Heart J. 157(4):733-9, 2009

37 Resistance to antiplatelet agent Treatment failure: close relationship between HPR or antiplatelet resistance and atherothrombotic events in high-risk patients FIGURE. Therapeutic Window Concept for P2Y 12 Receptor Reactivity Tantry US, et al. J Am Coll Cardiol. 62(24): , 2013

38 High platelet reactivity (HPR) Impact of Platelet Reactivity on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease Angiolillo DJ, et al. J Am Coll Cardiol. 50(16):1541-7, 2007

39 High platelet reactivity (HPR) Thresholds for platelet reactivity to predict clinical events after coronary intervention are different in patients with and without diabetes mellitus TABLE. Multivariate predictors of major adverse cardiac events at 30 days. FIGURE. Incidence of major adverse cardiac events according to the presence of diabetes mellitus and high platelet reactivity Mangiacapra F, et al. Platelets. 25(5):348-56, 2014

40 Aspirin resistance Prevalence : widely variable (5~45%) Mechanisms Floyd CN, Ferro A. Pharmacol Ther. 141(1):69-78, 2014

41 Aspirin resistance and CV morbidity 3.85 (3.08 to 4.80) FIGURE. Risk of any cardiovascular event in aspirin resistant patients Krasopoulos G, et al. BMJ. 336(7637):195-8, 2008

42 Clopidogrel resistance Failure of the molecule to inhibit the target of its action. Ex-vivo measurement of ADP induced platelet aggregation by light transmittance aggregometry Ray S. Indian Heart J. 66(5):530-4, 2014

43 Clopidogrel resistance ADP-induced platelet aggregation Six months recurrent CVS events FIGURE. Study patients (pts) were stratified into quartiles according to degree of platelet activity inhibition in response to clopidogrel treatment. Patients in 4 quartiles were compared with regard to (Lt.) changes in ADP-induced platelet aggregation expressed as percentage of baseline activity and (Rt.) incidence of recurrent major adverse cardiovascular events during a 6-month follow-up. Matetzky S, et al. Circulation. 109(25):3171-5, 2004

44 Management of resistance Several antiplatelet treatment strategies have been developed to optimize platelet inhibition Dose modification of clopidogrel Use of potent P2Y12 inhibitor agents Addition of a third antiplatelet drug (triple therapy) (e.g., cilostazol, PAR-1 inhibitor) Others; compliance, Elimination of interfering substances, etc. Gurbel PA, Tantry US. Circulation. 121(4):569-83, 2010

45 British Male Doctors trial (BMD) Physician s Health Study (PHS) Thrombosis Prevention Trial (TPT) Hypertension Optimal Treatment trial (HOT) Primary Prevention Project (PPP) American Diabetes Association. Diabetes Care. 32 Suppl 1:S13-61, 2009

46 Antiplatelet agents Recommendations Consider aspirin therapy ( mg/day) as a primary prevention strategy in those with type 1 or type 2 diabetes who are at increased cardiovascular risk. This includes most men or women with diabetes aged 50 years who have at least one additional major risk factor (family history of premature atherosclerotic CVD, hypertension, smoking, dyslipidemia, or albuminuria) and are not at increased risk of bleeding. C Aspirin should not be recommended for atherosclerotic CVD prevention for adults with diabetes at low atherosclerotic CVD risk, such as in men or women with diabetes aged <50 years with no major additional atherosclerotic CVD risk factors, as the potential adverse effects from bleeding likely offset the potential benefits. C American Diabetes Association. Diabetes Care. 40 Suppl 1:S75-87, 2017

47 Antiplatelet agents Recommendations When considering aspirin therapy in patients with diabetes <50 years of age with multiple other atherosclerotic cardiovascular disease risk factors, clinical judgment is required. E American Diabetes Association. Diabetes Care. 40 Suppl 1:S75-87, 2017

48 AHA/ASA guidelines for the 1º prevention of stroke Meschia JF, et al. Stroke. 45(12): , 2014

49 대한당뇨병학회진료지침 대한당뇨병학회진료지침, 2015

50 SUMMARY Antiplatelet agents Diabetes Hypercoagulable state Hyper-reactive platelets Antiplatelet regimen Thromboxane inhibitor P2Y 12 receptor antagonists Glycoprotein IIb/IIIa inhibitors (GPI) Phosphodiesterase (PDE) inhibitor Primary and secondary prevention trials for prevention of CVD in diabetes Resistance to antiplatelet agents Treatment guidelines