CHAPTER

14STEMI: Newer Aspects in Pharmacological TreatmentP. C. Manoria, Pankaj Manoria

IntroductionST 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

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 reperfusion

Currently,myocardialreperfusioncanbeachievedin STEMI in a spell of 2-3 minutes and this indeed is a major achievement. A conjoined triple therapy is utilized for pharmacological reperfusion 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-tPA1-3 (0.53mg/kg by IV push) which takes 1/2 to 1 minute.

2. The platelets are targeted with aspirin 325 mg orally followed by 75-160 mg/day and

Table 1 : Newer aspects in pharmacological treatment of STEMI

• Achievementofquickmyocardialreperfusion.

• Emergingprospectsforcircumventingthelimitationsofclopidogrel with newer antiplatelet agents.

• Preventionofbleeding:AnewfocusinACScare.

• IncreasingroleofLMWHinSTEMIandemergingroleof factor Xa inhibitors.

• Improvedoutcomeofpost-fibrinolytic therapy inducedhemorrhagic stroke with activated recombinant factor VII a.

Figure 1 : Myocardial reperfusion in STEMI

MCE

Microvasculardysfunction

MYOCARDIALREPERFUSION IN STEMI

Open Microcirculation

MCE

Myocardialreperfusion

Open IRA

Occluded IRA

IC Adenosine

Myocardialreperfusion

No tissuereperfusion

113STEMI: Newer Aspects in Pharmacological Treatment

clopidogrel 300 mg orally followed by 75 mg/day, which takes another one minute.

3. The thrombin is targeted by LMWH (Enoxaparin) 30 mg IV bolus followed by 1mg/kg subcutaneous twice a day.

The current pharmacological reperfusion is summarized in Table 2.

The above pharmacological regime allowed reperfusion to be achieved within 2 hours of onset of STEMI in 50% of patients. If the reperfusion is achieved in the 1st hour, the golden hour, the infarction may even be aborted.

Emerging prospects for circumventing the limitation of clopidogrel

AftertheCLARITYTIMI384andCOMMITtrial,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 toan active metabolite by a complex mechanism. Therefore the onset and peak is delayed (Fig. 2). Prasugrel, a new P

2Y

12 receptor antagonist, has a

faster onset and earlier peak action (Fig. 2)

It is therefore likely that prasugrel may provide better benefit in STEMI compared to clopidogrel. The TRITON-TIMI 38 trial is ongoing in patient with ACS undergoing PCI (both STEMI orNSTEMI) which is comparing prasugrel in a head to head fashion with clopidogrel. The primary end pointisacompositeofCVdeath,MIandstroke.

AZD 6140 is another new P2Y

12 receptor

antagonist. It is a direct acting drug and therefore has quick onset and quick offset action. The PLATO trialwhich is enrolling16000patientsofACS isin progress and will compare in a head to head fashionAZD6140withclopidogrel.Cangrelor isthe first parenteral P

2Y

12 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 ChampionPCItrial.

b. Irreversible platelet inhibition with slow recovery of platelet function

ClopidogrelisanirreversibleantiplateletagentandifapatientofACSonaspirinplusclopidogrelneedsanemergencyCABG,thenevenifclopidogrel isstoppedbeforeCABG,thereisincreasedbleedingwith increased peri-operative morbidity and mortality. However, with the new antiplatelet agent like AZD 6140 which has a quick onset and quick offset action, the issue may be resolved in future.

Table 2 : Pharmacological reperfusion in STEMI• TNK-tPA0.53mg/kgIVpush.

• Aspirin325mgorallyfollowedby75-160mg/dayplusclopidogrel 300 mg as a bolus dose followed by 75 mg/ day.

• Enoxaparin 30 mg IV bolus followed by 1 mg/kgsubcutaneously twice a day.

Table 3 : Limitations of clopidogrel • Slow onset of maximal inhibition of platelet

aggregation.

• Irreversible platelet inhibition with slow recovery offunction.

• Inter individual and intra-individual variability intherapeutic response.

• Increasedrateofbleeding.

Figure 2 : Onset and peak action of clopidogrel and prasugrel

100

90

80

70

60

50

40

30

20

10

0

-10

1/0.25 1/0.5 1/1 1/2 1/4 1/6 2/0 3/0 4/0 5/0 6/0 7/0 8/0 9/0

Slow onset ofmaximalinhibitionof platelet

aggregation

Clopidogrel 300/75

Day/Time(h)-CLO 300/75--CLO 600/75-PSG 60/10

IPA (%) 20 M ADPPrasugrel 60/10

Clopidogrel 600/75

N = 41No ASA

Prasugrel vs. Higher Loading Dose of Clopidogrel inHealthy Subjects (Crossover)

114 Medicine Update 2008 Vol. 18

Figure 3 : Variability in platelet responsiveness to clopidogrel

Figure 4 : Primary endpoint of death & ReMI in EXTRACT TIMI-25 trial

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 clopidogrel6. The newer agents like prasugrel, AZD 6140 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 trial7 clearly showed that patient with bleeding has a statistically significant higher mortality. Therefore prevention of bleeding has emergedasanewfocusinACScare8 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 theEXTRACTTIMI-25 trial9, 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 30 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 trial10 in STEMI patients and OASIS-5 trial11 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 0.6 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 90 days (Fig. 6)

Effect of reperfusion strategies on mortality of AMIThe effects of various reperfusion strategies on mortality are seen in (Fig. 7).

The only strategies associated with decreased mortality in STEMI are early pharmacological

Variability in platelet Responsiveness toClopidogrel Among 544 Individuals

Distribution of Adjusted to Baseline Response in Subjects After ClopidogrelN-544112

104968880726456484032241680

Num

ber o

f Pat

ient

s

≤-20 [11,20][-10.0] [31,40] [51, 60] [71,80] [91,100]delta 5µM ADP

Serebruany V. et al. J Am Coll Cardiol. 2005;45:246-251.

Patient to patientvariability

in therapeuticresponse

IIT: Intent-to-treat, RRR: relative risk reduction. RR: Relative Risk

Death or Re-MI (30 days)

Patie

nts

(%)

20

10

0

Enoxaparin Significantly Reduces the Primary Endpoint of Death or non fatal MI Versus UFH

9.912.0

(ITT)

RRR 17%RR: 0.83, 95% CI:0.77-0.90

P= 0.0 00 00 2604UFH (n=10.223)Enoxaparin (n=10.256)

115STEMI: Newer Aspects in Pharmacological Treatment

Both modalities, pharmacological reperfusion or primary PCI, if carried out in the first 3 hours,produce equivalent results. However after 3 hrs to12hours,primaryPCIisdistinctlysuperiortopharmacological reperfusion and is the modality of choice. However because of logistic concerns and financialconstraints,primaryPCIisbeingcarriedout only in 5% of STEMI patients throughout the globe. If patient has cardiogenic shock, primary PCI is themodalityof choice irrespectiveof thetime of presentation.

The CAPTIM trial13 (Fig. 8) showed a very interesting data. There was a slightly lower mortalitywiththrombolysisthanwithPCIinthefirst 2 hours of myocardial infarction in this trial. In

Figure 6 : Recombinant activated factor VIIa in intracranial hemorrhage

Figure 5 : Oasis 5 & 6 Trials combined analysis

Trial Design: Data were pooled from the OASIS-5 and OASIS-6 trials, which comparedfondaparinux (n=16093) with control (n=16077) of either enoxaparin, unfractionaedheparin (UFH), or placebo in patients with ST-elevation and non-ST elevation acutecoronary sundromes.

Death, MI or stroke st 30 daysp < 0.01

Results• At 30 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 < 0.001)• Among patients undergoing non-pimary PCI (n=6634; analysis excludes primary PCI patients), no difference between groups in death, MI or stroke at 30 days for fondaparinux vs enoxaparin/UFH (8..0% ech, p=0.97)• Catheter thrombosis ↑ in fondaparinux group than enoxaparin/UFH group (0.9% vs 0.2%, HR 3.58, p< 0.001) Conclusions• Among patients with acute coronary syndromes, treatment with fondaparinux was associated with lower rate of composite of death, MI or stroke at 30 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 ESC2006

9.18.0

12

8

4

0

%

Fondaparinux Control

OASIS 5 and OASIS 6 Trials Combined Analysis

Increase inhaematoma

volume

Decrease ingrowth ofvolume of

ICH

Death ordisability

Mortality at90 days

69%

55%

49%

54%

29%

18%

18%

18%

29%

16%

14%

11%

3.3%

4.5%

5.8%

Dose

Placebo

40µg/kg.

80µg/kg.

160µg/kg.

Recombinant activated factor VIIa for ICH

reperfusion or primary PCI and only these 2modalities are used in our day to day practice.

116 Medicine Update 2008 Vol. 18

Figure 7 : Effects of various reperfusion strategies on outcome in STEMI

a meta analysis14 of 23 randomized trials comparing pharmacological reperfusion with primary PCItherewasaslightlybetterresultswithprimaryPCI.However the point to remember is early reperfusion and early reperfusion should be the goal.

Thus treatment of STEMI has witnessed several newer facets in its pharmacological treatment.

References1. CannonCP,GibsonCM,McCabeCH,etal.TNK- tissue

plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Thrombolysis in Myocardial infarction (TIMI) 10 B investigators.Circulation1998;98:2805-14.

2. 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; 716-22.

3. TanswellP,ModiN,CombsD,DanaysT.Pharmacokineticsand pharmacodynamics of tenecteplase in fibrinolytic therapy ofacutemyocardialinfarction.ClinPharmcokinet2002;41(15); 1229-45.

4. Sobatine MS, Cannon CP, Gibson CM et al; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST- segment elevation. N Engl J Med 2005; 352: 1179-1189.

5. COMMIT (Clopidogrel and Metoprolol in MyocardialInfarctionTrail)CollaborativeGroup.Additionofclopidogrelto aspirin in 45852 patients with acute myocardial infarction: randomized placebo-controlled trial Lancet 2005; 336: 1607-1621.

6. Angiolilo, DJ, Ortiz et al. Variability in Individual Responsiveness to Clopidogrel. Clinical Implications,Management and Future Perspectives. JACC 2007; 49(14):1505 -16.

7. Manoukian SV,Feit F, Mehran R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndrome. An analysis from theACUITYtrial.JACC2007;49(12):1362-68.

8. EikelboomJW,MehtaSR,AnandSS,XieC,FoxKA,YusufS. Adverse impact of bleeding on prognosis in patients with acutecoronary syndromes.Circulation,2006;114(8):774-82.

9. AntmanEM,MorrowDa,McCabeCHetal.EXTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for STEMI N Engl J Med 2006; 354: 1477-1488.

10. 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 2006;295.

11. Comparison of Fondaparunix and Enoxaparin in AcuteCoronary Syndrome. The Fifth Organization to AssessStrategies in Acute Ischemic Syndromes Investigators. NEJM 2006; 354(14): 1464-1476.

12. MayerSA,BrunNC,BegtrupKetal.RecombinantActivatedFactor VII for Acute intracereberal Hemorrhage. NEJM 2005; 352: 777-785.

13. BonnefoyE,LapostolleF,LeizoroviczAetal.Comparisonsof Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction. Lancet 2002; 360: 825-829.

14. KeelyeEC,BouraJA,GrinesCL.Primaryangioplastyversusintravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomized trials. Lancet 2003; 361:13-20.

Figure 8 : Effect of timing of therapy on mortality in AMI

↓ Mortality Mortality ± ↑ mortality on goingevalution

• Invasive- pharmacologic reperfusion.

• Thrombolysis facilitated primary PCI (Assent IV)

• Facilitated thrombolysis (1/2 doses fibrinolytic plus GPllb/llIa I.)• 1/2 dose lytic plus GPllb/llIa I. facilitated Primary PCI

• conjoined triple pharmacological reperfusion.

• Primary PCI

EFFECT OF REPERFUSIONSTRATEGIES ON OUTCOME OF STEMI

Time and Mortality:Primary PCI vs. Thrombolysis

Thrombolysis slightly betterthan PCI in 1st 2-3 Hrs.

Primary PCI

Thrombolysis

Onset of pain to treatment (hrs)

Huber et al. Eur Heart J 2005; 26: 1063-1074

30d-

Mor

talit

y (%

)

8

6

8

6

4

2

0

0 1 2 3 4 5 6 7 8