STEMI: Newer Aspects in Pharmacological Treatment

Transcription

1 CHAPTER 14 STEMI: Newer Aspects in Pharmacological Treatment P. C. Manoria, Pankaj Manoria Introduction ST elevation myocardial infarction (STEMI) commonly results from disruption of a vulnerable plaque with superimposed thrombus formation resulting in acute occlusion of the infarct related artery (IRA) which culminates into acute myocardial necrosis. Quick and sustained opening of infarct related artery with good TIMI Grade III flow coupled with good myocardial tissue perfusion is the cornerstone of treatment of STEMI. If the microcirculation is patent, opening of IRA transforms into myocardial tissue perfusion. However, if there is microvascular dysfunction with slow or no flow, opening of the IRA will not produce myocardial tissue perfusion and additional Figure 1 : Myocardial in STEMI Occluded IRA Open IRA IC Adenosine MYOCARDIAL REPERFUSION IN STEMI Open Microcirculation Microvascular dysfunction Myocardial Myocardial No tissue MCE MCE pharmacotherapy has to be utilized to improve it as shown in Fig.1. The major advances in pharmacological treatment are outlined in Table -1 Achievement of quick myocardial Currently, myocardial can be achieved in STEMI in a spell of 2-3 minutes and this indeed is a major achievement. A conjoined triple therapy is utilized for pharmacological targeting all the 3 components of the clot, i.e. fibrin, platelet and thrombin. 1. The fibrin is targeted by bolus fibrinolytic therapy with TNK-tPA 1-3 (.53mg/kg by IV push) which takes 1/2 to 1 minute. 2. The platelets are targeted with aspirin 325 mg orally followed by mg/day and Table 1 : Newer aspects in pharmacological treatment of STEMI Achievement of quick myocardial. Emerging prospects for circumventing the limitations of clopidogrel with newer antiplatelet agents. Prevention of bleeding: A new focus in ACS care. Increasing role of LMWH in STEMI and emerging role of factor Xa inhibitors. Improved outcome of post-fibrinolytic therapy induced hemorrhagic stroke with activated recombinant factor VII a.

2 STEMI: Newer Aspects in Pharmacological Treatment 113 Table 2 : Pharmacological in STEMI TNK-tPA.53 mg/ kg IV push. Aspirin 325 mg orally followed by mg/day plus clopidogrel 3 mg as a bolus dose followed by 75 mg/ day. Enoxaparin 3 mg IV bolus followed by 1 mg/kg subcutaneously twice a day. clopidogrel 3 mg orally followed by 75 mg/ day, which takes another one minute. 3. The thrombin is targeted by LMWH (Enoxaparin) 3 mg IV bolus followed by 1mg/ kg subcutaneous twice a day. The current pharmacological is summarized in Table 2. The above pharmacological regime allowed to be achieved within 2 hours of onset of STEMI in 5% of patients. If the is achieved in the 1 st hour, the golden hour, the infarction may even be aborted. Emerging prospects for circumventing the limitation of clopidogrel After the CLARITY TIMI 3 4 and COMMIT trial, 5 clopidogrel in conjunction with aspirin has become an integral part of therapy for STEMI. Although it provides definite benefit but several limitations of clopiodgrel has erupted out which are shown in Table 3. a. Slow onset of maximal inhibition of platelet aggregation Clopidogrel is a pro drug and is converted to an active metabolite by a complex mechanism. Therefore the onset and peak is delayed (Fig. 2). Prasugrel, a new P 2 receptor antagonist, has a faster onset and earlier peak action (Fig. 2) Table 3 : Limitations of clopidogrel Slow onset of maximal inhibition of platelet aggregation. Irreversible platelet inhibition with slow recovery of function. Inter individual and intra-individual variability in therapeutic response. Increased rate of bleeding. Figure 2 : Onset and peak action of clopidogrel and prasugrel Prasugrel vs. Higher Loading Dose of Clopidogrel in Healthy Subjects (Crossover) IPA (%) 2 M ADP 1 Prasugrel 6/1 N = 41 No ASA 9 7 Clopidogrel 6/ Clopidogrel 3/75 Slow onset of 2 maximal 1 inhibition of platelet -1 aggregation 1/.25 1/.5 1/1 1/2 1/4 1/6 2/ 3/ 4/ 5/ 6/ 7/ / 9/ Day/Time(h) -CLO 3/75--CLO 6/75-PSG 6/1 It is therefore likely that prasugrel may provide better benefit in STEMI compared to clopidogrel. The TRITON-TIMI 3 trial is ongoing in patient with ACS undergoing PCI (both STEMI or NSTEMI) which is comparing prasugrel in a head to head fashion with clopidogrel. The primary end point is a composite of CV death, MI and stroke. AZD 614 is another new P 2 receptor antagonist. It is a direct acting drug and therefore has quick onset and quick offset action. The PLATO trial which is enrolling 16 patients of ACS is in progress and will compare in a head to head fashion AZD 614 with clopidogrel. Cangrelor is the first parenteral P 2 receptor antagonist with a fast onset of action. It is more potent and has a quick offset action also. It is being compared in a head to head fashion with clopidogrel in an ongoing Champion PCI trial. b. Irreversible platelet inhibition with slow recovery of platelet function Clopidogrel is an irreversible antiplatelet agent and if a patient of ACS on aspirin plus clopidogrel needs an emergency CABG, then even if clopidogrel is stopped before CABG, there is increased bleeding with increased peri-operative morbidity and mortality. However, with the new antiplatelet agent like AZD 614 which has a quick onset and quick offset action, the issue may be resolved in future.

3 114 Medicine Update 2 Vol. 1 Figure 3 : Variability in platelet responsiveness to clopidogrel Figure 4 : Primary endpoint of death & ReMI in EXTRACT TIMI-25 trial Variability in platelet Responsiveness to Clopidogrel Among 544 Individuals Distribution of Adjusted to Baseline Response in Subjects After Clopidogrel N Number of Patients [-1.] [11,2] [31,4] [51, 6] [71,] [91,1] delta 5µM ADP Serebruany V. et al. J Am Coll Cardiol. 25;45: Patient to patient variability in therapeutic response Patients (%) 2 1 Enoxaparin Significantly Reduces the Primary Endpoint of Death or non fatal MI Versus UFH Enoxaparin (n=1.256) 9.9 P= Death or Re-MI (3 days) UFH (n=1.223) IIT: Intent-to-treat, RRR: relative risk reduction. RR: Relative Risk (ITT) RRR 17% RR:.3, 95% CI: c. Inter-individual and intra-individual variability in therapeutic response to clopidogrel (Fig. 3) Some patients of STEMI despite intake of adequate dosage of clopidogrel continue to get ischemic events and stent thrombosis and an important reason believed to be responsible for this is the inter-individual or intra-individual variability in therapeutic response to clopidogrel 6. The newer agents like prasugrel, AZD 614 and cangrelor which are more potent and provide additional antiplatelet effect even on top of clopidogrel may provide solution to this but at present there is no data available on this. Prevention of bleeding: A new focus in ACS care The ACUITY trial 7 clearly showed that patient with bleeding has a statistically significant higher mortality. Therefore prevention of bleeding has emerged as a new focus in ACS care and attempt are being made to provide antithrombotic treatment with minimal or no bleeding. Increasing role of LMWH enoxaparin and emerging role of Xa inhibitor fondaparunix in STEMI. After the EXTRACT TIMI-25 trial 9, enoxaparin has become an integral part of therapy of STEMI. The trial showed a statistically significant reduction in the primary end point of death or Re-MI at 3 days by 17% and also a statistically significant (Fig. 4) reduction in the secondary end point of death, MI and urgent revascularization by 19% with enoxaparin as compared to UFH. No doubt, enoxaparin is associated with slight increase in bleeding (not intracranial hemorrhage) compared to UFH but when we consider efficacy plus safety, the balance hits in favor of enoxaparin. Fondaparunix is a factor Xa inhibitor and has been tested head to head with UFH in OASIS-6 trial 1 in STEMI patients and OASIS-5 trial 11 in NSTEMI patients. The combined analysis of both the trials has shown that fondaparunix has same efficacy but less bleeding compared to UFH (Fig. 5). Post fibrinolytic intracranial hemorrhage Fibrinolytic therapy is associated with intracranial hemorrhage in.6 to 1.4% of patients and this is associated with higher morbidity and mortality. Of late, there has been exciting results with recombinant activated factor VIIa in intracranial hemorrhage. 12 It limits amount of bleeding, reduces risk of death and improves survivor s functional outcome at 9 days (Fig. 6) Effect of strategies on mortality of AMI The effects of various strategies on mortality are seen in (Fig. 7). The only strategies associated with decreased mortality in STEMI are early pharmacological

4 STEMI: Newer Aspects in Pharmacological Treatment 115 Figure 5 : Oasis 5 & 6 Trials combined analysis % Trial Design: Data were pooled from the OASIS-5 and OASIS-6 trials, which compared fondaparinux (n=1693) with control (n=1677) of either enoxaparin, unfractionaed heparin (UFH), or placebo in patients with ST-elevation and non-st elevation acute coronary sundromes OASIS 5 and OASIS 6 Trials Combined Analysis Death, MI or stroke st 3 days p <.1. Fondaparinux 9.1 Control Results At 3 day follow-up, composite of death, MI or stroke in fondaparinux group vs control Major bleeding at 9 days in fondaparinux group vs control (2.1% vs 3.4%; p <.1) Among patients undergoing non-pimary PCI (n=6634; analysis excludes primary PCI patients), no difference between groups in death, MI or stroke at 3 days for fondaparinux vs enoxaparin/ufh (..% ech, p=.97) Catheter thrombosis in fondaparinux group than enoxaparin/ufh group (.9% vs.2%, HR 3.5, p<.1) Conclusions Among patients with acute coronary syndromes, treatment with fondaparinux was associated with lower rate of composite of death, MI or stroke at 3 days compared with control group, wich was mixture of no antithrimbin, UFH, and enoxaparin No efficacy benefit with fondaparinux in PCI cohort but catheter thrombosis was increased with fondaparinux Presented at ESC26 Figure 6 : Recombinant activated factor VIIa in intracranial hemorrhage Dose Placebo 4µg/kg. µg/kg. 16µg/kg. Recombinant activated factor VIIa for ICH Increase in haematoma volume 29% 16% 14% 11% Decrease in growth of volume of ICH 3.3% 4.5% 5.% Death or disability 69% 55% 49% 54% Mortality at 9 days or primary PCI and only these 2 modalities are used in our day to day practice. 29% Both modalities, pharmacological or primary PCI, if carried out in the first 3 hours, produce equivalent results. However after 3 hrs to 12 hours, primary PCI is distinctly superior to pharmacological and is the modality of choice. However because of logistic concerns and financial constraints, primary PCI is being carried out only in 5% of STEMI patients throughout the globe. If patient has cardiogenic shock, primary PCI is the modality of choice irrespective of the time of presentation. The CAPTIM trial 13 (Fig. ) showed a very interesting data. There was a slightly lower mortality with thrombolysis than with PCI in the first 2 hours of myocardial infarction in this trial. In

5 116 Medicine Update 2 Vol. 1 Figure 7 : Effects of various strategies on outcome in STEMI Figure : Effect of timing of therapy on mortality in AMI EFFECT OF REPERFUSION STRATEGIES ON OUTCOME OF STEMI Time and Mortality: Primary PCI vs. Thrombolysis Mortality Mortality ± mortality conjoined triple pharmacological. Primary PCI Facilitated thrombolysis (1/2 doses fibrinolytic plus GPllb/llIa I.) 1/2 dose lytic plus GPllb/llIa I. facilitated Primary PCI Thrombolysis facilitated primary PCI (Assent IV) on going evalution Invasivepharmacologic. 3d-Mortality (%) Primary PCI Thrombolysis Thrombolysis slightly better than PCI in 1st 2-3 Hrs. Huber et al. Eur Heart J 25; 26: Onset of pain to treatment (hrs) a meta analysis 14 of 23 randomized trials comparing pharmacological with primary PCI there was a slightly better results with primary PCI. However the point to remember is early and early should be the goal. Thus treatment of STEMI has witnessed several newer facets in its pharmacological treatment. References 1. Cannon CP, Gibson CM, McCabe CH, et al. TNK- tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 1B trial. Thrombolysis in Myocardial infarction (TIMI) 1 B investigators. Circulation199; 9: ASSENT-2 Investigators. Single- bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double blind randomized trial. Lancet 1999; 354; Tanswell P, Modi N, CombsD, Danays T. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmcokinet 22; 41 (15); Sobatine MS, Cannon CP, Gibson CM et al; CLARITY- TIMI 2 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with STsegment elevation. N Engl J Med 25; 352: COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trail) Collaborative Group. Addition of clopidogrel to aspirin in 4552 patients with acute myocardial infarction: randomized placebo-controlled trial Lancet 25; 336: Angiolilo, DJ, Ortiz et al. Variability in Individual Responsiveness to Clopidogrel. Clinical Implications, Management and Future Perspectives. JACC 27; 49 (14): Manoukian SV,Feit F, Mehran R, et al. Impact of major bleeding on 3-day mortality and clinical outcomes in patients with acute coronary syndrome. An analysis from the ACUITY trial. JACC 27; 49 (12): Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation, 26; 114(): Antman EM, Morrow Da, McCabe CH et al. EXTRACT- TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for STEMI N Engl J Med 26; 354: The OASIS-6 Trial Group. Effects of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST- segment Elevation Myocardial Infarction. The OASIS-6 Randomized Trial. JAMA 26; Comparison of Fondaparunix and Enoxaparin in Acute Coronary Syndrome. The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. NEJM 26; 354(14): Mayer SA, Brun NC, Begtrup K et al. Recombinant Activated Factor VII for Acute intracereberal Hemorrhage. NEJM 25; 352: Bonnefoy E, Lapostolle F, Leizorovicz A et al. Comparisons of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction. Lancet 22; 36: Keelye EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomized trials. Lancet 23; 361:13-2.