Issues and Challenges in ACS Management. Dr.Nakul Sinha MD.DM, FACC. Sahara Hospital, LUCKNOW

Transcription

1 1 Issues and Challenges in ACS Management Dr.Nakul Sinha MD.DM, FACC. Sahara Hospital, LUCKNOW

2 2 Disclaimer Presentation are intended for educational purposes only and do not replace independent professional judgment. Statements of fact and opinions expressed are those of the speakers individually and, unless expressly stated to the contrary, are not the opinion or position of AstraZeneca. AstraZeneca does not endorse or approve, and assumes no responsibility for, the content, accuracy or completeness of the information presented.

3 Outline Major adverse cardiovascular (CV) events in ACS patients New Data from GRACE/Euro Heart Survey in relation to Morbidity and Mortality rate in ACS Epidemiological evidence of ACS/Post ACS patients in India - Disease burden - Risk factor and profile of patients - Morbidity and mortality rate Limitations of Current OAP Issues of anti-platelet resistance Clopidogrel: Insights from CURRENT-OASIS 7 & GRAVITAS Prasugrel: Insights from TRITON-TIMI & TRIGGER-PCI 3

4 4 Global impact of CVD on mortality An estimated 17.1 million people died from CVD in 2004, representing 29% of all global deaths CVD includes CHD (also called CAD). CHD causes more deaths than other major diseases Of CVD deaths, an estimated 7.2 million were due to CHD. World Health Organization. Cardiovascular diseases (CVD), 2009; Datamonitor. Stakeholder Insight: Acute Coronary Syndromes 12/2008; Mackay J, et al. Global burden of coronary heart disease. In: The Atlas of Heart Disease and Stroke. Geneva: World Health Organization; 2004: CAD, coronary artery disease

5 Acute Coronary Syndrome, carries high burden of mortality and morbidity 5 Antman em et all, Circulation 2004;110

6 GRACE ACS Registry Launched in 1999, GRACE is an ongoing observational study designed to recruit a generalizable and unbiased sample of patients with acute coronary syndrome and track their outcomes. As of December 2009, GRACE has enrolled over 100,000 patients at approximately 250 hospitals in 30 countries. 6 6

7 ACS Mortality rates: data from GRACE 7 1. Fox KAA, et al. Nature Clin Pract Cardiol. 2008;5: Tang EW, et al. Am Heart J. 2007;153:29-35.

8 GRACE Registry Post ACS-event mortality grows over time Mortality (%) Mortality (%) Mortality following discharge by initial ECG presentation 1 ST depression Overall mortality at 1 year 2 ST elevation Neither Days from admission 1 year from admission Registry data indicate up to 15% of patients with ACS, may die within 12 months of their initial event Fox KAA, et al. Nature Clin Pract Cardiol. 2008;5: Tang EW, et al. Am Heart J. 2007;153:29-35.

9 Burden of CVD in India, National Commission, Govt of India

10 Coronary Heart Disease is growing rapidly and...is the top contributor to death in India Estimated cases of CHD in India Million cases Top contributors to death in India Percentage Total = 19 million deaths annually +6% p.a Injuries Cardiovascular disease Diabetes Other chronic Cancer Communicable 36 7 Respiratory By 2020, India will have the largest CV burden globally and account for 1/3 rd of deaths ~9% of CHD patients suffer from an ACS event annually, accounting for ~4 million ACS cases in SOURCE: National Health Report-2010, NCMH burden of disease, WHO

11 Earlier onset of CVD in South Asia The INTERHEART study Protective Factors Were Lower In South Asians Than Other Countries Less Moderate-high Intensity Exercise Daily Intake Of Fruits & Vegetables More Elevated Apo-B > A-1 H/O Diabetes The earlier age of AMI in South Asians can be largely explained by higher risk factors at younger age 11 JAMA, 2007

12 Mortality Burden from CVD in India In 1990, estimated 1.17 million deaths from CHD... almost double to 2.03 million by Manifests almost 10 yr earlier in India...52% vs. 23% in west (CVD deaths <70 yrs) Tremendous loss of productive working years due to CVD deaths 9.2 million productive years of life lost in 2000 Expected increase to 17.9 million years in 2030 (almost 10 times of US) , 60% of the world s heart disease population in India. Indians have a high prevalence of risk factors, and have ischemic heart disease at an earlier age than do people in developed countries 12 SOURCE: National Health Report-2010, NCMH burden of disease, WHO Indian J Med Res 124, September 2006, pp Lancet 2008; 371:

13 ACS Registry in India: Insights from CREATE Prospective registry study in 89 centres from 10 regions and 50 cities in India in patients. 13 ACS Diagnosis: 60 6% STEMI Age: Mean age 57 5 years Risk Factors: Smokers (27.9%), Diabetic (30.4%), Hypertensive (37.7%), Previous history of MI (17.5%) 30 day mortality rate: 6.7% Anti-platelet therapy: Monotherapy with Aspirin used in majority >80% Clopidogrel use only in 15%. Lancet 2008; 371:

14 CREATE Registry: Comparison with developed countries Long term ACS data in Indian Patients, like GRACE, currently unavailable and lacking 14 Lancet 2008; 371:

15 Outline Major adverse cardiovascular (CV) events in ACS patients New Data from GRACE/Euro Heart Survey in relation to Morbidity and Mortality rate in ACS Epidemiological evidence of ACS/Post ACS patients in India - Disease burden - Risk factor and profile of patients - Morbidity and mortality rate Limitations of Current OAP Issues of anti-platelet resistance Clopidogrel: Insights from CURRENT-OASIS 7 & GRAVITAS Prasugrel: Insights from TRITON-TIMI & TRIGGER-PCI 15

16 Limitations of Current Anti-platelet therapy Long Time course to achieve maximal inhibition of platelet aggregation. Low level inhibition of platelet aggregation. Individual Variability and Response. Excess of Bleeding during long term prescription. Irreversible nature of Clopidogrel to inhibit P2Y12 receptors on platelets. 16 Angiolillo DA et al. J Am Coll Cardiol. 2007;49:

17 17 Slow metabolic conversion JACC 2007;49:

18 Genetic Factors Polymorphisms of CYP Polymorphisms of GPIa Polymorphisms of P2Y 12 Polymorphisms of GPIIIa Clopidogrel Response Variability Clinical Factors Failure to prescribe/poor compliance Under-dosing Poor absorption Drug-drug interactions involving CYP3A4 Acute coronary syndrome Diabetes mellitus/insulin resistance Elevated body mass index Cellular Factors Accelerated platelet turnover Reduced CYP3A metabolic activity Increased ADP exposure Up-regulation of the P2Y 12 pathway Up-regulation of the P2Y 1 pathway Up-regulation of P2Y independent pathways (collagen, epinephrine, TXA 2, thrombin) 18 Angiolillo DA et al. J Am Coll Cardiol. 2007;49:

19 Number of Patients Individual Response Variability of Clopidogrel Bleeding risk Ischemic risk % Platelet Aggregation (LTA-ADP 20mmol/L) Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:

20 20 Increase the LD of Clopidogrel to achieve better IPA POSSIBLE SOLN

21 21

22 ALBION tested in recent CURRENT OASIS-7 Follow-up of 25,000 patients with ACS either managed medically or with PCI Clopidogrel (600/150mg) vs. Clopidogrel (300/75) on top of ASA (75-325mg) for 7 days and then clopi 75 mg in both grps for 30 days Primary endpoint: time to first occurrence CV Death/ MI/ Stroke 22 N Engl J Med 2010;363:

23 CURRENT OASIS-7 1. In patients with ACS, double dose clopidogrel was not significantly different from standard dose 2. There was an increase in CURRENT-defined major bleeds. 3. No advantage of increasing ASA dose from mg 4. However, in subgroup analysis of ACS pts undergoing PCI, double-dose clopidogrel significantly reduced stent thrombosis and MI. 23 N Engl J Med 2010;363:

24 GRAVITAS Study Design Elective or Urgent PCI with DES* VerifyNow P2Y12 Test hours post-pci PRU 230 R High-Dose Clopidogrel clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel clopidogrel 75-mg daily X 6 months 24 Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months *Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at hrs placebo-controlled All patients received aspirin (81-162mg daily) JAMA, March 16, 2011 Vol 305, No. 11

25 Primary Endpoint: CV Death, MI, Stent Thrombosis 25 GRAVITAS does not support a treatment strategy of high-dose clopidogrel in patients with high residual reactivity identified by a single platelet function test after PCI. JAMA, March 16, 2011 Vol 305, No. 11 Observed event rates are listed; P value by log rank test.

26 26 N Engl J Med. 2001;345:

27 Irreversible P2Y12 Inhibition Advantages Sustained Anti-platelet activity Disadvantages Slow Offset Urgent Intervention Need for Surgery 27 Angiolillo DA et al. J Am Coll Cardiol. 2007;49:

28 28 Clopidogrel and CABG

29 29 Recent USFDA warning on Clopidogrel Poor metabolizers of the drug may not receive full protection from heart attacks, stroke, and cardiovascular death. Tests are available to determine the genetic profile of a key liver enzyme 2C19 and predict whether a patient will ineffectively convert clopidogrel to its active form. Although higher doses of clopidogrel increase antiplatelet response in poor metabolizers, an appropriate dose regimen for these patients has not been established in a clinical outcome trial Advises clinicians to consider other antiplatelet medications or alternative dosing strategies for clopidogrel in patients who are poor metabolizers.

30 30 don t know SWITCH TO PRASUGREL???

31 Endpoint (%) Prasugrel in TRITON TIMI CV Death / MI / Stroke Clopidogrel Prasugrel events P= NNT = TIMI Major NonCABG Bleeds Days Prasugrel Clopidogrel NEJM 357: , events P=0.03 NNH = 167

32 TRITON Patient Population Primary PCI Fibrin-specific agents within 24 hours excluded Non-fibrin-specific agents within 48 hours excluded STEMI Fibrinolytic Rx No Reperf [Did include a significant number of secondary PCI patients 12 hrs-14 days after STEMI angio required] ACS Patient PCI Early Invasive Rx Medical Rx NSTEMI CABG PCI Early Conservative Rx Medical Rx CABG 32 Wiviott SD, et al. N Engl J Med. 2007;357: ; (Wiviott SD, et al. Am Heart J 2006;152:627235

33 ACS Patient Hospital Course TRITON Admission Initial Management Angiography PCI Other Decision Pathways Other Decision Pathways 33 Wiviott SD, et al. N Engl J Med. 2007;357: ; Wiviott SD, et al. Am Heart J 2006;152:627235; Wallentin L, et al. N Engl J Med. 2009;361: ; James S, et al. Am Heart J. 2009;157:

34 Prasugrel comes with increased bleeding tendency Overall in TIMI Major Bleed Subgroup Analysis > 75 yrs <60 kg h/o stroke/ TIA Beneficial more in PCI pts STEMI Diabetes Stent Thrombosis Black Box Warning of increased risk if severe bleed Dose Adjustment required in < 60 kg CI in stroke/ TIA CABG: d/c atleast 7d 34 Effient PI; NEJM 357: , 2007

35 35 Chin et al American Heart Journal July 2010

36 TRIGGER-PCI halted Clopi vs prasugrel in post-stenting stable CAD Very low events and hence no meaningful difference expected ( < 2% at 6M) In stable CAD after PCI, nothing more than DAPT with A+C is required 36

37 Hemorrhage There is a price to pay for greater platelet inhibition and the accompanying reduction Current APT in ischemic events Default 1 Goal 37 Thrombosis

38 38 THANK YOU