# \` GALLUP INDIAN MEDICAL CENTER YEAR 2005 Ed 11-15-05 Page 1. 

**THROMBOLYTIC AND ANTI-THROMBOTIC**

**THERAPY DRUG PROTOCOLS**

**FOR UNSTABLE CORONARY ARTERY SYNDROMES**

ACUTE ST ELEVATION MYOCARDIAL INFARTION, NON ST ELEVATION MI, AND
UNSTABLE ANGINA

## **INTRODUCTION** 

A.  Outline.

> 1\. **Background**, pathophysiology, and diagnosis of coronary
> syndromes\...Page 1

2.  **Indications** for various drugs in specific coronary
    syndromes..........Page 2

3.  **Contraindications** to thrombolytic
    therapy..............................\...Page 3

4.  **Drug therapy** for acute coronary syndromes:

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a.  T-PA type

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ii. i\. TNK
    (Tenecteplace)................................................\...Page
    5-6

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i.  Activase
    (Alteplace)...................................................Page 4

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iii. 5\. Heparins
     ......................................................................\...Page
     7-8

> 6\. **Anti-Platellet Therapy** (ASA,
> Clopidogrel)...\.............................Page 9

iv. 7\. **GP IIb IIIa**. Platelet
    Inhibitors..............................................Page 10 & 11

    8\. Acute coronary artery syndrome (**ACS**) **flow
    diagram**..................\...Page 12

**B. Pathophysiology of Acute Coronary Syndromes.**

1.  Most acute coronary syndromes (unstable angina, acute MI, etc)
    result from rupture of

> an atherosclerotic plaque, followed rapidly by platelet agglutination,
> then fibrinogen
>
> cross linking, then fibrin clotting. Less commonly by intra-plaque
> hemorrhage.

2.  The severity of the clinical syndrome usually is proportional to the
    amount and activity

> of the thrombus. Hence all patients should receive *anti-platelet and
> anti-thrombotic*
>
> therapy with an intensity equal to their acute syndrome and risk of MI
> and death.

**C. Definition of differing Acute Coronary Artery Syndromes.**

1.  *Diagnosis defines therapy* and is pivotal for optimal therapy and
    outcomes.

2.  **Acute Myocardial Infarction.**

> a\. ***ST elevation* MI (STEMI)**: Typical acute ischemic pain,
> lasting more than 20 min.
>
> unresponsive to O2 TNG etc, and EKG ST elevation in 2 or more
>
> contiguous leads (1mm in limb leads and 2mm in precordial leads)
> usually with
>
> reciprocal ST depression in opposite leads. Cardiac enzymes may be
> negative.

b.  ***Non ST elevation* MI** **(NSTEMI)** Typical acute ischemic pain
    lasting more than 20 minutes and unresponsive to O2, TNG etc, and
    *without* EKG ST elevation, but with 1 mm or more ST depression in 2
    or more contiguous leads. Enzymes may be negative.

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3.  **Unstable Angina/Acute Coronary Syndromes (ACS).** Acute prolonged
    ischemic type chest pain, typical or atypical, in a patient with
    known CAD, or at high risk for CAD, without acute significant EKG
    abnormalities. These patients must be then *risk stratified* for
    therapy by clinical and laboratory markers..

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D.  **Indications for *thrombolytic* and *anti-thrombotic* therapy. (By
    drug)**

> Page 2

1.  **Asprin**

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a.  *All patients* (unless on ASA), 325 mg *chewed and swallowed as soon
    as* *possible*.

2\. **Clopidogrel**

a.  May be used as ASA substitute or adjuvant anti-platelet Tx with ASA

b.  Especially for "high risk" patients with USA syndromes.

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2.  **Thrombolytics; \[Streptokinase, t-PA, or\] TNk; (**requires a plus
    b.below):

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a.  Acute ischemic type chest pain, beginning *less than 6 hours* before
    presentation

> b\. EKG ST elevation in 2 or more leads of at least 1mm and usually
> with reciprocal ST
>
> depression, not known to be old. (***Do not use*** thrombolytic Rx for
> ST **depression** MI.)

b.  No contra-indications are present;

c.  Note: EKG Q-waves, prior unstable angina, and + enzymes are *not*
    contra-indications for *otherwise eligible* patients.

3\. Choosing the **appropriate lytic drug**; use with urgent Cardiac
Cath: "facilitated PTCA"

> . [Streptokinase]{.underline} (*No longer favored*) [Favors use of
> (TNK type) Thrombolysis]{.underline}
>
> i\. Patient over age 65 Patient under age 50
>
> ii EKG small MI EKG large MI (Especially anterior)
>
> iii\. No prior strep exposure Normal or mildly elevated Troponin
>
> iv\. Symptoms began \> 4 hours ago Symptoms for \< 3 hours
>
> v\. History of prior CVA No history CVA

3.  **Heparins.** (Especially Low Molecular Weight Heparin/LMWH;
    Fondaparinux soon?)

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a.  *Use in all* patients with ACS [unless]{.underline} active bleeding.

b.  Do not give or lower dose if on warfarin, bleeding diathesis, recent
    Streptokinase.

c.  History heparin associated thrombocytopenia (HIT) or high risk of
    hemorrhage.

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4.  Glycoprotein (**GP**) **IIb IIIa Platellet Inhibitors**

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a.  For patients at *highest acute risk* for MI (Most ACS who are
    diabetic): See pages 7-9

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5.  **Nitrate and Beta Blocker therapy.**

> a\. **IV** nitrates may be used starting at 5 ugm/minute in AMI. Use
> sublingual cautiously.
>
> b\. Metoprolol 2.5 to 5 mg IV, one to three doses (max total 15mg),
> over 15 minutes

6.  **Acute Coronary Angiography and PTCA and/or Stenting, and CABG.**

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a.  "Primary" direct PTCA and Stenting: now considered "best practice if
    available."

> i\. Especially indicated for patients especially not Thrombolytic
> eligible.
>
> ii\. Should be available by 12 hours from start of chest pain.

b.  **"Facilitated PTCA": Combined with anti-thrombotic and/or
    thrombolytic therapy.**

> i\. Especially for patients with STEMI over 2 hours from cath lab.

c.  **"Rescue" Angioplasty** for failed thrombolytic therapy.

> i\. Continued pain, ST elevation, or Shock.

d.  CABG may be chosen in patients with multivessel CAD or poor PTCA
    candidates.

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E.  **Contra-indications to thrombolytic** and intense anti-thrombotic
    therapy.

> Page 3.
>
> 1\. **Absolute contraindications:**

a.  Active internal bleeding

b.  Recent intra-cranial or spinal surgery

c.  Recent stroke (6 months) or *any history of intra-cranial*
    hemorrhage, aneurysm, neoplasm, or A-V malformation.

d.  Suspected aortic dissection

e.  Prolonged and traumatic CPR

> f\. Recent vascular, orthopedic, intra-abdominal surgery (2-4 weeks);
> recent major trauma.

2\. **Relative contraindications**:

a.  Presenting BP \> 180/110 or history of poorly controlled severe
    hypertension.

b.  Recent trauma (1 month)

c.  Pregnancy

d.  Active peptic symptoms..

e.  Non-compressible vascular punctures (e.g. subclavian.)

f.  More than brief CPR

g.  Known bleeding diathesis or theraputic coumadin anti-coagulation
    (INR\>2.5)

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3.  3\. **Alternatives to thrombolytic** and intense anti-thrombotic
    therapy

> a\. Urgent cardiac catheterization and re-vascularization
>
> b\. Non-intense anti-thrombotic therapy (e.g. ASA, Clopidogrel, and/or
> LMWH) and ancillary
>
> Anti-ischemic therapy (e.g. beta blocker, I.V. TNG etc.)

4.  **Age;** patients over age 75 have shown to significantly benefit
    from thrombolytic therapy, but

> have a higher risk of hemorrhage. The use of thrombolysis must be
> weighted against high risk of
>
> complications, especially intra-cranial hemorrhagic stroke (mortality
> 25-50%).

**GIMC THROMBOLYTIC THERAPY PROTOCOLS.** Page 4

**GIMC Thrombolytic therapy for STEMI: t-PA (Tissue Plasminogen
Activators)**

**II. ACTIVACE (alteplase) Tissue Plasminogen Activator *(No longer best
practice; use TNK)***

A.  **Dose:**

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1.  Currrent Acute MI dose is both weight based and "*front-loaded"*

2.  Front loaded

> a\. Front loaded refers to the 15mg bolus followed by 50% of dose in
> first 30
>
> minutes, then followed by 35% remainder over 1 hour ("15-50-35")

b.  All patients receive 15 mgm bolus at start, followed immediately by

c.  0.75 mgm/Kgm infusion over 30 minutes; not to exceed 50 mg.

d.  Then 0.5 mgm/Kgm infusion over 60 minutes; not ot exceed 35 mg.

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3.  Weight based dosing

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a.  Patients weighing 70 Kg or more receive full 100 mg. (15-50-35)

b.  See chart for quick calculation of dosing for smaller patients.

> c\. write patient\'s mg dose (i.e. 15-50-35) on nursing notes for
> later reference.

4\. For **massive pulmonary embolism** **the dose is 100 mg over 2 hours
infusion**

B.  **Preparation and Mixture:**

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1.  Open 100 mg box; find 100cc fluid vial, t-PA vial, and double needle
    to "spike" and mix the two together.

2.  "Spike" one end of needle into fluid vial

3.  "Spike" other end of needle into t-PA vial and allow fluid vial to
    drain into t-PA vial.

4.  After fluid has completely dripped into t-PA vial, remove
    needle-empty fluid vial and

> Discard empty fluid vial -- needle assembly

5.  t-PA mixture (100mg in 100cc) is ready for I.V. infusion; attach to
    I.V. infusion set

> on programmable ("IVAC" type) I.V. infusion pump.

C.  **Administration:**

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1.  Bolus 15 mg (7.5cc)

2.  Program double infusion

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a.  30 minute larger dose first, (0.75 mg/kg, not to exceed 50 mg), and
    immediately to be followed by

b.  60 minute smaller dose (0.5 mg/kg, not to exceed 35 mg) infusion.

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3.  Discard any remaining t-PA if physician concurs.

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D.  **Antithrombotic therapy**

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1.  All patients receiving t-PA thrombolytic therapy should receive
    *concurrent* heparin therapy.

2.  Either LMWH heparin (Lovenox) or unfractionated heparin *before or
    during* t-PA

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a.  Bolus followed by routine administration. See page 7 for heparin
    protocols.

**E. PULMONARY EMBOLISM SYSTEMIC THROMBOLYSIS**

1\. 0 or 10 mg bolus, 100 (or 90 mg) IV infusion over **2 hours**.
("Then start Heparin")

**GIMC Thrombolytic Therapy for STEMI; (continued)**

page 5

III\. **TNK (Tenecteplase) tissue plasminogen activator (**best
thrombolytic)

A.  **Introduction**

> TNK is an improved t-PA, a modified recombinant human tissue
> plasminogen activator with increased fibrin specificity, decreased
> blood clearance, *and* resistance to PAI-1 inactivation, allowing a
> single bolus injection. Clinical trials (1.) have demonstrated equal
> efficacy and safety, and fewer dosing errors. The rapid administration
> by single bolus makes this drug **preferable to t-PA (Activase)** for
> most acute MI patients. The clinical indications, contra-indications,
> and ancillary drug therapy - especially concurrent heparin- are
> identical (to t-PA) for TNK

B.  Dosing;

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1.  Like TPA, TNK is weight based. However TNK is *a single bolus*
    injection only.

2.  [Patient\'s Weight TNK dose TNK Volume]{.underline}

> a\. \< 60 Kg 30 mg 6 ml
>
> b\. 60-70 Kg 35 mg 7 ml
>
> c\. 70-80 Kg 40 mg 8 ml
>
> d\. 80-90 Kg 45 mg 9 ml
>
> e\. \>90 Kg 50 mg 10 ml

C.  Preparation

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1.  Review package insert if you are not familiar with this drug and its
    package contents. Patient should have an IV of N saline..

2.  Remove \"shield assembly\" from 10cc syringe*. Note*[;]{.underline}
    do not discard.

3.  Withdraw 10 ml of sterile water from (provided) vial using \"red
    hub\" device.

4.  Gently inject sterile water into TNK vial onto TNK powder.

5.  Gently swirl contents; *do not shake or agitate.* Concentration is 5
    mg/ml. It should be colorless to clear - pale yellow.

6.  When the decision to give TNK is made, **Heparin should be
    administered before or concurrently** with TNK. See page 7 for
    heparin protocols.

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D.  Administration

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1.  Withdraw appropriate patient dose from TNK mixture.

2.  Stand \"shield assembly\" vertical on countertop (green cap down)
    and recap red hub

3.  Remove entire shield assembly including red hub.

4.  TNK is ready to inject as a bolus through a *needleless* hub into a
    saline solution IV line.

5.  Inject TNK as bolus over 5 seconds.

6.  Discard remaining TNK if physician concurs.

7\. For needle hub or \"split septum\" IV system see package insert.

1.  ASSENT-2 Investigators. Single Bolus Tenectase compared to
    front-loaded alteplace in acute myocardial infarction Lancet 1999.
    354:716-722

2\. ACC/AHA 2002 Guideline Update for management of STEMI Circ 2004:
110:588-636

**IV.** ANTI-THROMBOTIC THERAPY: **HEPARIN**S page 7

A. INTRODUCTION

1.  Acute coronary artery syndromes are treated with Heparin (and
    anti-platelet

> Therapy) unless there is a contraindication to heparin (e.g. prior
> Heparin thrombo-
>
> cytopenia or **HIT**) or a substitute anti-thrombotic drug is used.
> Timing and dosing of
>
> Heparin varies with clinical syndrome and if/which thrombolytic drug
> is used.

2.  Low Molecular Weight (Lovenox) or Unfractionated Heparins may be
    used;

> a\. Because of efficacy and ease of administration **LMWH is
> preferred**

3.  Bolus and routine administration dosing depend on the clinical
    syndrome treated.

4\. Fondaparinux pentasaccharide may soon be indicated for ACS.

> B. **Acute *ST- Elevatio*n Myocardial Infarction**; use concurrently
> with TNK (or TPA)

1.  **Low Molecular Weight Heparin (Lovenox)** \[Preferred; see ref
    below\]

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a.  Bolus 30 mg *I.V.* *if Patient under 75 years and no Hx CVA.*

b.  Start 1mg per Kg *sub-Q* 15 minutes later, and then give same dose
    Q12H for 72 hours

c\. PTT monitoring not indicated unless problems with bleeding occur.

2.  **Unfractionated** (regular) **Heparin** \[Some interventionalists
    still prefer UH.\]

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a.  Bolus 4000 Units for weight 70 Kg or greater, or **60 U/Kg.**

b.  Simultaneous infusion of I.V. Heparin in premixed bag

> i . 1000 Units/hour for weight 70 Kg or greater, **12 Units/KG/hour**
> for less than 70 Kg.

c\. Check PTT Q6H with goal PTT 50-75 sec.

d\. Use pre-printed I.V. Heparin orders for nurse adjusted dose per PTT

**C. *Non-ST Elevation* (Non-Q) Myocardial Infarction and Unstable
Angina.**

1.  Low Molecular Weight Heparin **(Lovenox)**

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a.  Start 1 mg per Kg Sub-Q Q12H at diagnosis. No bolus required.

b\. Monitoring of PTT not recommended unless bleeding problems occur.

2.  Unfractionated **Heparin.**

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a.  Same as B.2.. above.

b.  Bolus 4000 Units (60 U/Kg) and infuse 1000 Units (12 U/Kg/ per hour
    I.V.

c\. Check PTT Q6H with therapeutic goal PTT 50-70 sec.

E.  **Heparin induced thrombocytopenia**

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1.  Check CBC with platelet count at least 2X weekly

2.  Consider HIT if count falls \>50% baseline or ct. \<150,000.

3.  D/C Heparin at once, draw antiplatelet antibody, and consider direct
    thrombin inhibitor.

Reference; 1. ASSENT III Trial; Efficacy and safety of tenecteplase
(TNK) in combination with

Enoxaparin (Lovenox). Abciximab, or unfractionated heparin. Lancet Vol
358: 605-13

3.  (ACC/AHA) Practical Implementation of Guidelines for USA/NSTEMI in
    the ED

> Circ 2005; 111:2699-2710

V.  **ANTI-PLATELLET THERAPY.** Page 9

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A.  BACKGROUND.

> 1\. Nearly all acute coronary artery syndromes involve platelet
> agglutination

a.  Often beginning with endothelial dysfunction

b.  Aggravated by acute plaque rupture, fissuring, or unroofing.

c.  Exposed collagen in the plaque rapidly activates Factor VIII.

d.  This rapidly activates platelets and they agglutinate to the exposed
    plaque-Factor 8

e.  The activated platelets rapidly agglutinate to each other via
    fibrinogen binding

> IIbIIIa sites on the platelet.

4.  2\. All drugs with inhibit platelet activation improve outcomes in
    ACS.

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a.  These include ASA, clopidogrel, LMWH's, and IIbIIIa inhibitors.

b.  Other than ASA, Rx therapy requires risk assessment first.

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B.  **ASPRIN.**

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1.  Aspirin has been used in ACAS since ISIS-II, which *demonstrated a
    25% reduction in*

> *mortality even without thrombolytic therapy.*

a.  Mechanism is blockage of the arachadonic acid pathway, inhibiting
    both

> Prostacycline (Vasodilator, decr. platelet agg.) and Thromboxane A2
> (opposite effects)

b.  ASA should be given *as soon as chest pain complaint is k*nown (if
    there is no

> contra-indication), that is within the first 10 minutes of
> presentation.

2.  Asprin inproves outcomes for all (stable and) unstable
    atherosclerotic syndromes;

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a.  Chronic stable CAD, post AMI, Unstable Angina, and AMI.

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3.  A patient on chronic ASA may receive a 81-325mg booster dose in ER.

4.  A patient NOT receiving ASA must be rapidly *ASPIRINIZED.*

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a.  Dose is 325 mg/5 Gr*, chewed and swallowed*, then 81 mg/day

b.  Swallowed with water less effective. (Immediate release ASA only; no
    enteric coat)

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5.  CONTRA-INDICATIONS

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a.  ASA hypersensitivity (e.g. ASA allergy, nasal polyps, etc)

b.  Active UGI bleeding or known active PUD.

c.  Pyrosis or positive stool guiaic are NOT contra-indications.

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C.  **CLOPIDOGREL (Plavix)**

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1.  Clopidogrel has platelet inhibiting effects similar to ASA.

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a.  Initially an ASA substitute for patients with ASA sensitivity or
    active PUD.

b.  Mechanism slightly different from ASA; blocks ADP activation
    pathway.

c.  Very effective when used *with ASA* in CAD patients receiving PTCA
    plus Stent.

d.  Recent CURE Trial demonstrated added benefit of routine Clopidogrel
    Tx

e.  Most beneficial in *"high risk*" USA patients.

f.  Now FDA and ACC/AHA recommended for USA/NQMI; in consideration for
    STEMI.

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2.  Dosing; "load" with 300 mg P.O. in ER. (Four 75 mg tablets.)

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a.  Continue with 75 mg daily for hospital stay to as long as 1 year;
    benefit is durable.

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3.  Indication;

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a.  Any patient not eligible for ASA.

b.  Patients evidencing "high risk" markers with ACS/NSTEMI.

### VI. PLATELET G.P. IIb IIIa PLATELET INHIBITOR page 9

###  "AGGRASTAT " THERAPY PROTOCOL

#### Introduction

1.  Because of intense platelet agglutination in Acute Coronary Ischemic
    Syndromes, anti-

> Platelet therapy with Asprin is always given *unless* specifically
> contra-indicated.

2.  In certain *"high risk"* patients, additional anti-platelet therapy
    with Glycoprotein

> IIb IIIa. Inhibitors is added.

3.  Because of expense and increased bleeding risk, use is restricted to
    special

> "*high risk*" groups (See Acute Chest Pain Syndrome flow diagram page
> 8)

4.  See GIMC Aggrastat *[preprinted orders]{.underline}* attached below
    (next page).

> a\. To be used as "doctor's orders".

5.  In certain circumstances GP IIb IIIa may be used with thrombolytic
    therapy.

6.  Contra-indications to GP IIb IIIa are similar to thrombolytic Rx and
    are listed on page 8.

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A.  **Mixture and Preparation**

> 1\. See Aggrastat preprinted orders; see next page.

B.  **Dosing**

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1.  See Aggrastat preprinted orders; see next page.

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C.  **Administration**

> 1\. See Aggrastat preprinted orders; see next page.

T.E. Richtsmeier MD, FACC

Chief, Cardiology

Revised November 15, 2005