A Review of Lifesaving and Antithrombotic Drugs

All about the Autonomic Nervous System

The autonomic nervous system (ANS) provides an autoregulatory function to maintain the body’s hemodynamic homeostasis. These maintenance activities are primarily performed without conscious control or sensation: we don’t need to consciously think about breathing or making our hearts beat.

Much of this regulatory function is located in the medulla oblongata in the brain stem. This explains why patients who are declared brain dead continue to have a heartbeat, and why other elemental body functions remain intact: they’re regulated by the autonomic nervous system and don’t require the higher brain function of conscious thought in order to continue.

The ANS has two opposing (or complimentary) divisions: the sympathetic and parasympathetic systems. The sympathetic system provides the “fight or flight” response when immediate action is required: it’s the gas pedal. The parasympathetic system is the “rest and digest” mechanism. It calms our nerves and slows things down. It’s the brake pedal.

 

All about the Sympathetic Nervous System

The sympathetic nervous system’s “fight or flight“ response is often explained as an evolutionary protective mechanism that developed to help us escape the saber-tooth tigers that were chasing us. Although we’re no longer being chased by tigers, the stressors of modern life stimulate our sympathetic nervous system and cause catecholamine release.

The catecholamines and neurotransmitters of the sympathetic system, noradrenalin (norepinephrine) and adrenalin (epinephrine) have specific receptor sites and elicit a specific response. The sympathetic receptors are alpha, beta (1 and 2) and dopaminergic. Refer to Figure 1 below.

 

Alpha receptors are located in peripheral arteries. When stimulated, they cause vasoconstriction, thereby increasing blood pressure and systemic vascular resistance (SVR). Think of water running through a pipe four inches in diameter: if the amount of water remains the same but the pipe is now only two inches in diameter, the water pressure will be greater.

A common cath lab drug that exhibits pure alpha effects is Neosynephrine® (phenylephrine). This is an alpha agonist that raises blood pressure without causing an increase in heart rate. It’s typically the drug of choice in septic shock when the patient has a heart rate of 120 and BP of 80/40.
Other vasopressor agents like dopamine have both alpha and beta 1 properties. They cause an increase in heart rate as well as BP, thereby increasing myocardial oxygen demand. So if our patient is in cardiogenic shock with a heart rate of 40 and a BP of 80/40, dopamine is a logical choice as a vasopressor since it supports blood pressure and augments the heart’s pumping capability.

Helpful hint:

Before any form of vasopressor is administered, the patient should be adequately hydrated: it’s counterproductive to squeeze an empty container. Remember: without adequate hydration (preload) we can’t attain the stretch on the muscle fibers of the heart. And that can lead to inadequate pumping. Starling’s Law of the Heart states that increasing the stretch on muscle fibers will increase the force of contraction. Think of it as a rubber band: the farther you pull it back (or stretch it) the farther it will fly (and the more it stings if it hits you!).

Beta 1 receptors are located within the myocardial tissues of the heart. Stimulation of these receptors causes an increase in heart rate (chronotrophy) and contractility (inotrophy). The increase in heart rate and contractility causes a subsequent increase in cardiac output, with the unwanted side effect of increased myocardial irritability (think arrhythmias).

Isuprel® (isoproterenol hydrochloride) is a medication with pure beta properties to increase heart rate and contractility. It’s commonly utilized as an ectopy stimulating agent in electrophysiology studies, thereby earning its reputation as a “chemical pacemaker.” It also demonstrates the beta 2 properties of vasodilatation, which can lead to a drop in blood pressure.

In contrast, Levophed® (norepinephrine) is a drug with both alpha and beta properties. It increases BP, systemic vascular resistance (SVR), cardiac output and heart rate. It provides excellent hemodynamic support in critically ill patients.

Beta 2 receptors, located in the lungs, cause bronchodilatation and arterial dilatation when stimulated. Albuterol and terbutaline -- two types of prescribed inhalers -- are beta 2 agonists used to treat bronchospasm in patients with chronic obstructive pulmonary disease (COPD).

As we’ve already noted, beta 1 stimulation works on the heart. And that’s why, when a patient receives a respiratory treatment, his heart rate increases. In most nebulized agents, the medication contains both beta 1 and beta 2 agonists. So we end up with nicely opened lower airways, but an increased heart rate compared to baseline.

Dobutrex® (dobutamine), which is used for heart failure patients, has both beta 1 and beta 2 properties. The beta 1 side increases contractility, or positive inotropic effect, to improve cardiac output, while the beta 2 arterial dilatation effect causes a decrease in preload and afterload. In other words, the two-inch pipe is now four inches.

This reduction in afterload yields less pressure for a failed heart to pump against, decreasing its workload while simultaneously increasing its ability to contract.

Helpful hint for remembering receptor sites: you have one heart: so beta 1. You have two lungs: thus beta 2.

Beta blockers are an entire class of medications dedicated to blocking beta receptor sites. They’re routinely indicated for acute coronary syndrome (ACS) patients. Beta blockers decrease cardiac arrhythmias, heart rate and blood pressure, thereby decreasing myocardial oxygen demand. For this reason they’re also used for blood pressure and heart rate control.

 

Helpful hint: beta blockers should be used with caution in patients with COPD and asthma: remember if you block beta 2, bronchodilitation bronchospasm could be life-threatening in the presence of beta blockade. Beta blockers should not be used in the presence of any atrioventricular
(AV) block.

Another example of beta blockade: when one of my friends has to speak publicly, she develops a redness that begins at her chest and incrementally creeps up her neck to her face. It looks as if her heart is literally pounding out of her chest! People like her benefit from prophylactic beta blockade: she took Inderal® (propranolol) before making speeches and also before her wedding.
Lopressor® (metoprolol) is the beta blocker most commonly administered to patients in the cath lab or ED as part of the acute coronary syndrome (ACS) protocol.

Helpful hint for remembering which meds are beta blockers: most end in “lol.”

Now that we’ve explored the sympathetic receptors and actions of alpha and beta stimulation, it’s clear why epinephrine -- a sympathomimetic drug -- is the first-line advanced cardiac life support (ACLS) medication.

Let’s assume your patient has cardiac-arrested: there’s no perfusing rhythm, no BP, no cardiac output. Epinephrine will vasoconstrict peripheral arterioles and venules, shunt peripheral blood back to the heart in an attempt to raise blood pressure/systemic vascular resistance, and stimulate the beta properties of increasing heart rate and stroke volume.

Epinephrine is also the first-line treatment for anaphylaxis, either in the cath lab for contrast allergy, or as an Epi-Pen® for people who are allergic to bee stings.
Dopaminergic receptors, located in coronary arteries and renal and mesenteric blood vessels, cause dilation of kidney and mesenteric arteries.

Inotropin® (dopamine) is one medication with dose-dependent action. At low dose (0.5-2 mcg/kg/min), dopaminergic receptors are stimulated and renal perfusion is increased. At median dose range (2-10 mcg/kg/min), Inotropin exerts beta effects of increased heart rate and contractility. At the highest doses,(>10mcg/kg/min), the effect is alpha, with peripheral vasoconstriction that raises blood pressure. At this dose Inotropin will have vasopressor, inotropic and chronotropic effects and may increase myocardial oxygen demands on the heart.

Helpful hint: if an IV line infiltrates with Inotropin it can cause sloughing of the skin due to its alpha peripheral constrictive properties. To prevent tissue necrosis, treat as soon as possible with a Regitine® (phentolamine mesylate) injection around the periphery of the infiltration.

A sympathetic wrap-up. Think about the appearance and vital signs of acute myocardial infarction (AMI) patients: they’re afraid they’re going to die, so their “fight or flight” response is stimulated and their sympathetic system is in overdrive.

This is first evidenced by cool, clammy skin caused by alpha stimulation and peripheral vasoconstriction: that’s why their skin is cold, not hot. They may even have a gray or ashen color.

Second, their heart rate (HR) is elevated in part by beta 1 stimulation. The infarcted portion of the myocardium (the ventricular muscle mass) results in a diminished ability to pump effectively, decreasing the stroke volume (SV) and myocardial oxygen
supply.

Our bodies work hard to maintain homeostasis and adequate cardiac output (CO). The equation CO = HR x SV says that organ perfusion pressure or blood pressure must remain adequate to perfuse the brain, heart and major organs. If there’s a drop in stroke volume due to myocardium injury, heart rate must increase to compensate for the decreased stroke volume.

Oxygen is required each time the heart beats. A compromised myocardium is already in oxygen deficit, and an increase in heart rate from beta stimulation puts further oxygen demands on the heart. That’s why your acute MI patient benefits from the administration of a beta blocker like Lopressor®: the beta-blocking action lowers the heart rate, allows for more ventricular filling time, decreases myocardial oxygen demand, improves cardiac output, and may help with arrhythmia suppression.

All about the Parasympathetic Nervous System

The parasympathetic nervous system is the “rest and digest” or “feed and breed” part of the autonomic nervous system. The parasympathetic system innervates the heart via the vagus nerve, or cranial nerve X. The neurotransmitter responsible for parasympathetic stimulation is acetylcholine.
This innervation is limited to the sinoatrial (SA) node and the atrioventricular (AV) junction. There’s very little influence on the ventricles or blood vessels. Parasympathetic stimulation causes a decrease in heart rate and impulse conduction in the heart. Figure 3 details parasympathetic effects elsewhere in the body.

We see the effect of stimulation of the parasympathetic system in the cath lab and recovery area every day. It may happen when the physician is gaining vascular access, sheaths are being pulled, or pressure is being applied to the groin. The heart rate drops and BP falls. The patient becomes diaphoretic and nauseated. And we say the patient is having a vagal response.

What should we do first? Administer a drug to block the parasympathetic stimulation. The drug of choice is atropine, a parasympathetic blocker. Atropine is usually dosed at 0.5-1 mg IV per physician’s order
(A caution: doses of less than .5 mg or more than 2.5 mg can cause a third-degree
heart block).

This is why having atropine readily available at the bedside is part of many institutions’ sheath-pulling policies. It should be the first mode of action in a vagal response, followed by placing the patient in Trendelenburg position and administrating fluids.

Remember groin anatomy of nerve (vagus), artery, vein, ligament. Releasing pressure is not an option until hemostasis is accomplished. Atropine is indicated in symptomatic bradycardia, asystole, and pulseless electrical activity (PEA). Patients who receive atropine will experience dry mouth and pupil dilatation.

You’ll be interested to learn that atropine occurs naturally in the deadly nightshade plant, or Atropa belladonna. The plant gets its name from the Italian word for “beautiful lady” (bella donna): Renaissance-era women used an extract of its berries to dilate their pupils for cosmetic reasons. And US soldiers carry atropine as the antidote for nerve gas exposure.

 

Part 1 Bibliography:

• Braunwald, Eugene. Heart Disease - A Textbook of Cardiovascular Medicine. Vol.1. 5th ed. 1997, ch.13, p.407; ch.21, p.593.

• Brunwald, Eugene. Heart Disease - A Textbook of Cardiovascular Medicine. Vol.2. 5th ed. 1997, ch. 38, p.1303.

• Fuster V, Alexander W, O’Rourke R. et al. Hurst’s The Heart. 11th ed. 2004, pp.1361-80.

• Healthworks, Inc. Anatomy and Physiology: Pharmacology Presentation. Essentials of Invasive Cardiology Program. 2007.

Antithrombotic Pharmacology

Here’s a sobering statistic: over 1.5 million people are hospitalized in the US every year with acute coronary syndrome (ACS). And within a year of an initial MI, 38% of women and 25% of men will die. (1)

The good news is that new technologies and treatment strategies have decreased mortality and morbidity rates over the last few decades. Pharmacologic and invasive therapies aimed at safe and effective reperfusion are constantly evolving based on evidence-based standards of care.

In 1960, when my grandfather developed chest pain, “take two aspirin and call me in the morning” was close to the definitive treatment. The 1980’s saw the introduction of thrombolytics or clot busters in the form of streptokinase for coronary arterial reperfusion.

In 1989 a new recombinant form of tissue plasminogen activator (t-PA) was introduced. By 2002, early invasive intervention was the standard of care. And overall in-hospital death rates for acute myocardial infarction fell from 25% in 1970 to 8% in 2002. (2)

Pharmacologic antithrombotic therapy is a hot topic of debate and investigation today. Included are anticoagulants, antiplatelets and thrombolytic agents. When and why are each of these agents used, and how do they function?

To find the answers, let’s revisit what we know about normal clotting in the body.
The ability to achieve hemostasis – the physiologic process by which bleeding is halted - is essential to life. The clotting cascade is a detailed, multistep process that we’ll look at in its simplest form.

The primary focus is on the star player of hemostasis: the platelet. Any disruption in the endothelium of the blood vessel, whether due to a cut in the skin or a ruptured plaque in a coronary artery, causes the release of collagen and tissue factors into the bloodstream.

Platelets circulating in the bloodstream, which in their normal inactive state are smooth and discoid in shape, become activated in the presence of collagen and tissue factor. The platelets change shape and send out spicules that resemble a sea anemone (see Figure 4).

Activated platelets adhere to the site of injury. Thrombin is produced and recruits more circulating thrombin and coagulation factors, setting the stage for large-scale thrombin production. Thrombin converts fibrinogen to fibrin, which leads to clot formation as red blood cells are caught up in a fibrin mesh.

This is great for a cut finger but not so good as a response to a ruptured coronary artery plaque: the thrombus may eventually block flow in that artery completely. Initially this is seen on an electrocardiogram (EKG) as ischemia and T-wave inversion, followed by ST segment elevation indicating injury, and -- if not resolved -- myocardial infarction evidenced by a Q wave, coupled with crushing chest pain and feelings of impending doom.

• Figure 4 Figure 4
• Figure 5 Figure 5
• Figure 6 Figure 6
• Figure 7 Figure 7
•  

Here’s the order of events:

Vasoconstriction
(to reduce blood loss) —>

Platelet adhesion
(to seal the injury site) —>

Platelet activation
(change of shape, transformers) —>

Platelet aggregation
(recruit friends for help) —>

Clot formation
(fibrin mesh where red blood cells and platelets “stick” together) —>

Mission hemostasis accomplished! —>

Possible occlusive thrombus in coronary arteries —>

Myocardial infarction

As you can see in Figure 5, there are many pathways to platelet activation.

 

Platelet aggregation can be inhibited by:

• Inhibitors of thromboxane 2 (TXA2) production, including aspirin and non-steroidal anti-inflammatory drugs (NSAIDs).

• Inhibitors of P2Y12 receptors of adenosine diphosphate (ADP) like Plavix® (clopidogrel), Ticlid® (ticlopidine), prasugrel and cangrelor.

• Direct thrombin inhibitors like Angiomax® (bivalirudin), argatroban, lepirudin and desirudin. These drugs also inhibit plasma coagulation where thrombin plays a key role.

• Inhibitors of glycoprotein llb/llla receptors like ReoPro® (abciximab), Integrilin® (eptifibatide) and Aggrastat® (tirofiban).(3)

The key event in the final stages of blood coagulation is the conversion of fibrinogen to fibrin by the serine protease enzyme thrombin, which is produced in the final stages of coagulation from prothrombin by the action of the enzyme prothombinase. Fibrin is then cross-linked to factor XII to form a blood clot.

The principal inhibitor of thrombin in normal blood circulation is antithrombin III. Antithrombotic pharmacological therapy may prevent clot formation or extension, inhibit platelet aggregation, or break down or “bust” the existing fibrin mesh of a clot. (4)

Anticoagulants prevent clot formation and prevent the extension of an existing thrombus. These include heparin in the form of unfractionated heparin (UFH), low molecular weight heparins (LMWHs) like Lovenox® (enoxaparin), Arixtra® (fondaparinux), and Coumadin® (warfarin), the last of which is not used in the cath lab. Direct thrombin Inhibitors (DTI) like Angiomax® (bivalirudin) and argatroban are also included in the anticoagulants.

Unfractionated heparin (UFH) is derived from the mucosal tissues of meat animals, including pig intestines and bovine lungs. One unit of heparin is the quantity required to keep 1 ml of cat’s blood fluid for 24 hours at 0 degrees Celsius.(5)

Heparin binds to the enzyme inhibitor antithrombin III (AT-III) and causes a shape change that results in its active site being exposed. The activated AT-III then inactivates thrombin and other proteases involved in blood clotting, predominantly factor Xa.

Heparin is given as an anticoagulant in the cath lab setting for percutaneous coronary intervention (PCI). UFH is indicated for use with glycoprotein receptor site inhibitor (GPI) drugs like ReoPro® (abciximab), Integrilin® (eptifibatide) and Aggrastat® (tirofiban) as well as with thrombolytic medications like Activase® (alteplase).

Heparin has a short biological half-life of one hour. Its effects are measured in the lab by partial thromboplastin time (aPTT), or the time it takes blood plasma to clot, and activated clotting time (ACT). 2007 AHA/ACC guidelines recommend an ACT of 200-250 as therapeutic during PCI. (6)

Patients who receive heparin are at risk for developing heparin induced thrombocytopenia syndrome (HITS). The effects of heparin can be reversed with protamine.

Heparin was in the news in November 2007 when actor Dennis Quaid’s twelve-day-old twins were mistakenly given 1,000 times the requested dosage of heparin. The drug received more negative press recently due to tainted heparin batches traced to manufacturing facilities in China.

Lovenox® (enoxaparin) is a low molecular weight heparin derived from pig intestine mucosa. Its anticoagulant effect can be directly correlated to its ability to inhibit factor Xa. Lovenox was originally used to treat deep vein thrombosis (DVT) and pulmonary embolus (PE). It’s now used in acute coronary syndrome (ACS) and frequently administered in the ED.

Lovenox has no effect on the international normalized ratio (INR), aPTT, prothrombin time (PT) or ACT, as these tests are insensitive to alterations in factor Xa. Its half-life is 4.5 hours. There is a reduced risk of HITS with Lovenox compared to heparin. Protamine will reverse the effects of Lovenox, but only by 66%. (7)

The ExTRACT-TIMI 25 trial compared the outcomes of patients undergoing PCI who received Lovenox with patients who received UFH. There was a 23% relative risk reduction in the primary composite endpoint of death or nonfatal MI for patients receiving Lovenox compared with those receiving UFH. (8)

Arixtra® (fondaparinux) is the newest anticoagulant approved for use in ACS patients. It’s a synthetic pentasaccharide and a factor Xa inhibitor that selectively binds to antithrombin.

Arixtra has been successfully used to prevent thromboembolic complications in orthopedic surgery and has shown short-term efficacy similar to Lovenox in preventing ischemic events in Non-ST-Elevation Myocardial Infarction (NSTEMI) patients. (9)

The 2007 ACC/AHA guideline update recognizes Arixtra as an anticoagulant agent to be used in conjunction with fibrinolytic agents. It has a predictable anticoagulant response, although it has no effect on INR, aPTT, PT or ACT. The half life of Arixtra is 17 to 21 hours. Trials have shown decreased bleeding complications compared to heparin. There is no antigenicity and very limited risk of HITS. (10)

The OASIS-6 randomized, double blind trial evaluated the efficacy of Arixtra compared with standard anticoagulant therapy in patients with acute ST-elevation myocardial infarction (STEMI). Arixtra was superior to UFH in patients who did not undergo PCI, but patients who underwent PCI and received Arixtra had an increased risk of coronary complications, abrupt closure, no reflow, dissection, new angiographic thrombus, perforation and catheter thrombosis.

In patients treated with conservative therapy, the preferred anticoagulants may be Arixtra, Lovenox for 8 days or for the duration of hospitalization, or UFH for 48 hours, in that order. (6)

Angiomax® (bivalirudin), see Figure 6 above, is a direct thrombin inhibitor anticoagulant. Its active substance is a synthetic peptide that uses hirudin, a natural protein in the salivary gland of leeches, as a prototype. (11)

This is a potent, highly specific, reversible bivalent inhibitor of thrombin and can inactivate both circulating and clot-bound thrombin. It has fast on and fast off activity, with a half-life of 25 minutes. There is no reversal agent.

Angiomax is indicated for patients with unstable angina undergoing percutaneous transluminal angioplasty (PCTA) and for PCI with provisional use of GPIIb/IIIa. It’s also indicated for patients with or at risk of HIT/HITTS who are undergoing PCI.

Dosing is weight-based. Angiomax is intended for use with aspirin. Sheath removal is possible in 1 to 2 hours after discontinuing the infusion. (12)

Helpful hint: If the patient has received UFH, wait 30 minutes before starting Angiomax. if the patient has received LMWH, wait 8 hours before starting Angiomax.

In PCI, Angiomax demonstrated proven efficacy plus fewer bleeding complications for improved outcomes. It was also shown to reduce major hemorrhagic events by 41 to 61% in the ACUITY ACS trial.

In HORIZONS-AMI, Angiomax monotherapy compared to UFH plus GP llb/llla inhibitor was associated with a 24% reduction in the 30-day primary endpoint of net adverse clinical events (all cause death, reinfarction, ischemic target vessel revascularization, or stroke and major bleeding non-CABG). There was also a 40% reduction in 30-day primary endpoint of major bleeding. (13)

Finally, data from the REPLACE-2 and ACUITY trials determined that Angiomax provides cost reductions compared to heparin+GPIIb/IIIa and can be considered an economically attractive antithrombotic medication.

Argatorban is a direct thrombin inhibitor indicated for use as prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia syndrome (HITS). It’s also indicated for patients undergoing PCI who are at risk for HITS and is an effective alternative to heparin in HITS patients. The anticoagulant effect is seen immediately and is monitored with aPTT. Therapeutic aPTT levels are seen in about three hours. Its half-life is 39 to 51 minutes. (14)

Antiplatelet medications decrease platelet aggregation and inhibit thrombus formation. They’re effective in arterial circulation where anticoagulants have little effect. Antiplatelet drugs are classified according to which platelet receptor site is inhibited.

Acetylsalicylic acid (aspirin) is a cyclooxygenase inhibitor. Adenosine diphosphate (ADP) receptor inhibitors include Plavix® (clopidogrel) and Ticlid® (ticlopidine). Glycoprotein llb/llla inhibitors include ReoPro® (abciximab), Integrilin® (eptifibatide) and Aggrastat® (tirofiban). Adenosine reuptake inhibitors include Persantine® (dipyridamole). (15)

Acetylsalicylic acid (ASA) is the one drug used to treat cardiac patients whose value is undisputed. Its appropriate dosing regime is currently being debated, however. Its derivatives have been in medical use since antiquity. Sources of salicylic acid can be found in willow bark, myrtle leaves and meadowsweet (Spiraea ulmaria).

In 1835, salicylic acid was successfully synthesized in the laboratory, enabling mass production. Its side effects included mouth, throat and stomach irritation. In 1897 Felix Hoffmann, a German pharmaceutical graduate working for the Bayer Company, invented acetylsalicylic acid, a new formulation without the unpleasant side effects of its predecessor. In 1899, ASA was given the brand name of aspirin, The “A” stood for acetyl, the “spir” came from Spiraea ulmaria, and where the “in” came from is unknown. (16)

Today aspirin is the most widely used cardiac medication, is available without a prescription, and is by far the least expensive. It also provides the greatest return in terms of long-term cardioprotective benefit. A new twist on an old saying: an aspirin and an apple a day keep the doctor away!

Aspirin irreversibly inhibits COX-1 (cyclooxygenase) and modifies the activity of COX-2. This gives it the ability to suppress prostaglandin and thromboxane production. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. (17)

Because heart attacks are primarily caused by blood clots, their reduction with the introduction of small amounts of aspirin has been seen as an effective medical
intervention.

The 2007 ACC/AHA guidelines recommend that ASA be administered to patients with ACS as soon as possible and continued indefinitely. Patients with unstable angina and non-ST elevation MI (UA/NSTEMI) who are treated medically without stenting should receive aspirin indefinitely and Plavix for one to 12 months.

Patients with UA/NSETMI who are treated with bare-metal stents should receive aspirin for at least one month and then indefinitely at lower dose as well as Plavix for one to 12 months. (18)

For patients undergoing coronary artery bypass grafting (CABG), aspirin should be continued while Plavix should be stopped five to seven days before surgery. In UA patients, ASA should be chewed, not swallowed, to hasten its effects in the bloodstream. (19)

Plavix® (clopidogrel), a thienopyridine, is an antiplatelet aggregate medication whose beneficial effects are undisputed. It’s used in combination with aspirin as dual antiplatelet therapy in the majority of cardiac and stroke patients.

Plavix irreversibly blocks the adenosine diphosphate (ADP) receptor site on platelet cell membranes (P2Y12). It’s a prodrug that requires metabolism by the liver for activation. Platelet inhibition can be demonstrated two hours after single-dose administration, but the onset of action is slow, so a loading dose is usually administered. (20)

The hot topic here is not “Should Plavix be given?” but “What dose of Plavix is best?” Debate centers on when to administer the drug, at what dose and for how long. The answers depend on variables of patient presentation (diagnostic case turned interventional or UA/STEMI) and treatment (conservative pharmacological support, invasive plain old balloon angioplasty (POBA), bare-metal or drug eluting stent).

In the CURE trial, pre-treatment with Plavix 300mg at least 24 hours prior to procedure showed a 20% relative risk reduction (RRR) in the primary end points of death, MI, stroke and severe ischemia. Because Plavix must be withheld for five to seven days before surgery, clinicians must weigh the risks and benefits of an early loading dose.

Researchers in the ARMYA-2 trail evaluated whether a 300mg or 600mg loading dose is superior. Patients receiving 600mg at least eight hours prior to PCI had a 50% RRR in periprocedural MI. (21)

For patients treated invasively, the 2007 ACC/AHA guidelines recommend that the duration of Plavix therapy be extended for at least one year after drug-eluting stent placement and ideally up to one year after bare-metal stent placement or medical therapy. ACC/AHA guidelines support the 600mg loading dose, citing more prompt and reliable platelet inhibition. (22)

In 2005, Plavix was reported to be the world’s second-highest selling pharmaceutical, with sales of $5.6 billion US. A one-month supply -- thirty 75mg tablets -- costs around $160 without insurance. (23)
Its high price is a factor for clinicians to consider in making treatment decisions: can the patient afford the medication, and how compliant will he or she be? The patient should not have to choose between food and Plavix.

Just like Cinderella’s slipper, this is not a one-size-fits-all situation. Decisions are multifactorial and need to be evaluated in terms of risk-benefit ratio on an individual basis.

Ticlid® (ticlopidine) is in the same class of medications as Plavix and may be used for patients who are allergic to Plavix or aspirin. Its half-life is 12 hours with a single dose and four to five days with repeated dosing.
The downside of Ticlid – and the reason Plavix is the preferred drug in this class -- is the reported increase in the risk of thrombotic thrombocytopenic purpura (TPP) and neutropenia. Plavix also has a much lower hemorrhagic risk than Ticlid. (24)

Glyoprotein IIb/IIIa inhibitors include ReoPro® (abciximab), which blocks the GP llb/llla receptor and thereby blocks the interaction of fibrinogen with the receptor, the final common pathway to platelet
aggregation.

ReoPro is manufactured from chimeric monoclonal murine proteins. A chimera is a human-engineered or in vivo mutated protein that is encoded by a nucleotide sequence made by splicing together two or more complete or partial genes from two different species. Among other things, this is a labor-intensive process that helps explain why ReoPro is an expensive product.

ReoPro is dosed by the patient’s weight with no adjustments for renal impairment. A 100kg patient receives a 12.5 cc bolus and an infusion of 17 cc/hr. This patient needs four vials: one for the infusion and three for the 12.5 cc bolus. (26) At $470 per vial, cost of treatment is $1,880.27

Helpful hint: ReoPro vials should be refrigerated and should not be shaken. Inspect the vial visually for particulate matter prior to administration. A non-pyrogenic, low protein binding 0.2 micron filter is used to prepare ReoPro boluses and infusions. Withdraw the contents from the vials with a standard needle, then attach the filter for injection. Don’t pull the drug through the filter: push it through the filter into the IV line (for the bolus dose) or bag.

What subset of patient benefits most from ReoPro administration? As with any drug, efficacy must be evaluated in terms of risk-benefit ratio. There’s a saying in the cath lab that “ReoPro makes it (blood) flow.” There’s a good reason for this: blood does indeed flow in the coronary vessel. But there are also more bleeding risks associated with ReoPro than with other anticoagulant agents.

ReoPro has a demonstrated ability to diminish freshly-formed platelet aggregates, causing the outermost platelets to break away from the collected aggregates and the thrombus to diminish. This distinction sets it apart from other anticoagulants or antiplatelet agents. (28)

ReoPro binds to platelets for the life of the platelet, which is approximately 10 days. If the patient develops bleeding, HITS, or must go immediately to bypass surgery, platelet infusion would be necessary to help reverse the effects of ReoPro.

High-risk STEMI patients who have visible clots and are diabetic should definitely slip their feet into the ReoPro “slipper.” This was demonstrated in the EPISTENT trial.

ACC/AHA guidelines recommend a GP llb/llla inhibitor if an early invasive strategy is used. ReoPro is more enthusiastically recommended in intermediate- to high-risk patients and in combination with aspirin and Plavix in patients who were not pretreated with a GP llb/llla inhibitor and were proceeding to PCI . (29)

Integrilin® (eptifibatide), see figure 7, is an antithrombotic agent that reversibly inhibits platelet aggregation by preventing binding of fibrinogen to the GP lla/lllb receptor. Integrilin helps prevent occlusion of the coronary arteries, thus reducing the incidence of ischemic events.

This is a cyclic hepapeptide derived from a protein found in the venom of the southeastern pygmy rattlesnake. It has a short half-life of 2.5 hours. It’s the third inhibitor of GPllb/llla to find wide acceptance after ReoPro and Aggrastat. (30)

Integrilin is always used in combination with aspirin and/or Plavix and UF or LMW heparin. In patients with UA/STEMI and those undergoing PCI, it has been shown to drive down the risk of ischemic events: clinical trials have demonstrated significant risk reduction before, during and long after PCI. The PURSUIT and ESPRIT trials were pivotal in supporting Integrilin use in PCI, UA/NSTMI and STEMI. (31)

Integrilin is dosed based on patient weight and creatine clearance (CrCl). Infusion is recommended for a minimum of 12 hours. Integrilin comes in premixed bottles for bolus and infusion administration and should be kept refrigerated. (32)

This is the only PCI medication for which there is no mixing involved and two boluses are given. Sometimes the first bolus and infusion are initiated in the ED and the second bolus in the cath lab.

Helpful hint: Administer weight-based heparin and monitor ACTs to achieve a level of 200-250 during PCI, per the latest ACC/AHA guidelines.

Cost of treatment with Integrilin lies between bivalirudin and abciximab. Our 100kg patient with normal CrCl will receive two boluses of 9cc and an infusion of 16cc/hr. This translates into two small vials at $76 each and two 100ml infusion bottles at $230 each to complete the recommended 12 hours of infusion, for a grand total of $612. (33)

Integrilin has been investigated in multiple clinical trials and has been demonstrated to play an important role in conservative and invasive UA/NSTMI management. Data from the CAPTURE, PRISM, and PARAGON B trials suggest that GPIs are more effective in reducing mortality and MI in non-ST-segment elevation ACS (NSTE-ACS) patients with elevated troponin levels, but not in patients with normal troponin levels. (34)

Integrilin has been the most widely used PCI medication in the past, providing excellent results at a fair price: like vanilla ice cream, almost everybody likes it. Where abciximab is expensive and reserved for high-risk patients and bivalirudin came into the marketplace as an alternative to heparin in patients at risk for HITS and has been gaining acceptance as a first line drug in PCI and now STEMI, Integrilin has a universal appeal rooted in evidence-based medicine.

Aggrastat® (tirofiban) is another GP llb/llla inhibitor. It’s a modified version of an anticoagulant found in the venom of the saw-scaled viper Echis carinatus. ACC/AHA guidelines for Aggrastat reflect those of eptifibatide. (35)

Thrombolytic therapy includes the use of drugs to break up or dissolve blood clots -- the main cause of heart attack and stroke -- and reestablish flow. The suffix “lytics” and the term “clot-buster” reflect the action of these drugs.

Thrombolytic medications have saved countless lives. They act on the fibrinolytic system, which is activated by the conversion of plasminogen to the enzyme plasmin (fibrinolysin). This is the enzyme that breaks down the fibrin mesh of clots (Fibrinolysin means “to loosen”).

Streptokinase (SK) and tissue plasminogen activator (tPA) are the most widely used thrombolytic agents for heart attack and stroke.

The key to successful thrombolytic reperfusion therapy is early implementation. Time is muscle, as reflected in the concept of “door to needle time,” the time between a patient’s first symptoms and the first dose of thrombolytic.

One trial showed that patients who receive thrombolytics and subsequently had blood flow restored within one hour had a 1% mortality rate over the next 30 days. Waiting another 30 minutes raised the 30-day mortality rate to 6.4%. After three hours, 80% of benefits were lost, and after 4 hours thrombolytics had virtually no effect in reducing mortality.(36)

Thus the clinical goal is to administer t-PA or streptokinase within 90 minutes of the onset of symptoms. Accomplishing this requires patients to recognize the early onset of symptoms and call for help immediately.

But even with rapid thrombolytic treatment, about 60% of heart attack patients need more intervention to restore blood flow completely. This group requires invasive mechanical intervention in the form of PCI. (37)

Streptokinase -- so named because it was isolated from the streptococcus bacterium -- was the first thrombolytic used in heart attack patients. Introduced in the 1970’s, it made its mark in terms of declining death rates from heart attack.

SK activates both the plasminogen bound to a fibrin clot and the normally inactive plasminogen circulating in the bloodstream, forming plasmin throughout the body. As a result, it both dissolves clots and predisposes bleeding in other organs and tissues. This systemic activity represents the major drawback to SK as a thrombolytic: unwanted and potentially lethal bleeding. (38)

T-PA, or tissue plasminogen activator, converts plasminogen to plasmin. Recombinant rt-PA began clinical trials in 1980 and won Food and Drug Administration (FDA) approval in 1987. It has several advantages over streptokinase. First, t-PA acts almost exclusively on the plasminogen bound to a fibrin clot. In other words, its activity is relatively fibrin-specific: it dissolves clots only and carries a lower risk of systemic bleeding.

All antithrombotic medications carry bleeding risks. Thrombolytics fall in the highest risk category, and there are a number of contraindications to their use. Absolute contraindications for fibrinolysis in STEMI include prior intracranial hemorrhage, suspected aortic dissection, active bleeding, significant closed-head or facial trauma within three months, and known structural cerebral vascular lesion. (39)

The patient’s age, sex, body weight and renal function influence bleeding risk as well. Bleeding events are associated with poorer long-term outcomes. Invasive reperfusion strategies carry fewer bleeding risks.

Heparin UF, bolus and infusion, is recommended in combination with either t-PA or streptokinase.

Choosing among therapies
There’s an increased emphasis today on the concept that pharmacological and interventional strategies should be risk-directed.

The goals for management of NSTEMI patients are rapid and accurate risk stratification, appropriate and institution-specific triage to interventional versus medical strategies, and optimal pharmacological therapy.

High-risk features that direct the clinician toward PCI as the preferred modality include:

• Elevated cardiac markers (troponin and/or CK-MB)

• Elevated inflammatory markers
  (CRP >3)

• age >65

• Presence of ST-T wave changes

• Diabetes

• Thrombosis in Myocardial Infarction (TIMI) risk score >5

• Clinical instability in suspected NSTE-ACS. (40)

2007 ACC/AHA guidelines suggest that prompt mechanical revascularization is associated with the best clinical outcomes. Choosing the most appropriate reperfusion strategy -- PCI or fibrinolysis -- depends on the physician’s assessment of patient risk, the time since the onset of symptoms, and the availability of appropriate PCI and
surgical facilities.

However, the potential mortality benefit associated with PCI might be lost if door-to-balloon time is delayed by more than one hour compared to door-to-needle time for fibrinolytic therapy. For every ten-minute delay in performing PCI, there’s a 1% reduction in the mortality benefit that PCI confers relative to fibrinolysis. (41)

A final thought about our patient So what happened to our patient -- the 60 year old woman, chest pain 10/10, ST elevations in the anterior leads, hemodynamically unstable with a heart rate of 110 and BP of 90/50? The one who “doesn’t look good, is cool and clammy, nauseated and short of breath”?

How her story ends is in many ways determined by where it begins: in other words, on the availability of first-line care. Let’s say she comes to a high-volume interventional cardiology tertiary care center where she receives prompt invasive revascularization with adjunctive pharmacological support and her door-to-device time is 55 minutes.

In this best-case scenario, her EKG returns to normal, she’s pain-free and discharged two days later. In fact she feels so good that she and her husband go ahead and book that cruise they’ve been dreaming of. Sounds like a storybook ending, and it is.

But what if her symptoms present while she’s on that cruise? Her outcome could be very different. Time is muscle, and it takes time to arrange transport from the ship to the nearest hospital. And the hospital may or may not have a cath lab, which means revascularization would come in the form of noninvasive pharmacotherapy with thrombolytics.

Let’s say the patient has an undiagnosed ulcer and develops a GI bleed, is hemodynamically compromised and unstable. In this case she’s transferred to the mainland the next day for cardiac cath, a stent is placed, and her ejection fraction (EF) is 30%. Not a storybook ending at all.

And that brings us back to the point of this article. Medication management in today’s cardiac cath lab is challenging, exciting and demanding, with new meds, equipment and procedures being introduced constantly and ACC/AHA guidelines changing frequently to reflect evidence-based medicine.

Keeping up to date on the why and how of what we do is critical. This knowledge makes it possible for us to understand, embrace and anticipate the pharmacological management of all our cath lab patients.

 

References:

1. www.ClinicalMedicineToday.com, p. 4.

2. http://www.fasebj.org/cgi/content/full/19/6/671e. Clot Busters!! Discovery of Thrombolytic Therapy for Treating Heart Attack & Stroke.

3. www.reopro.com.

4. http://www.fasebj.org/cgi/content/full/19/6/671e.

5. http://enwikipedia.org/wiki/heparin-e.

6. Cohen M, Diez J et al. Pharmacoinvasive Management of Acute Coronary Syndrome: Incorporating the 2007 ACC/AHA Guidelines. The CATH (Cardiac Catheterization and Antithrombotic Therapy in the Hospital) Clinical Consensus Panel Report-III. Journal of Invasive Cardiology, Vol.19, No.12, December 2007, p.530.

7. www.lovenox.com.

8. www.theheart.org. Recent clinical trial data on adjunctive pharmacology in ACS patients undergoing PCI.

9. www.ClinicalMedicineToday.com. Managing Patients with Acute Coronary Syndromes: Evidence Based Approaches to Improve STEMI and UA/NSTEMI Outcomes, p. 8.

10. Cohen M, Diez J et al. Pharmacoinvasive Management of Acute Coronary Syndrome: Incorporating the 2007 ACC/AHA Guidelines. The CATH (Cardiac Catheterization and Antithrombotic Therapy in the Hospital) Clinical Consensus Panel Report-III. Journal of Invasive Cardiology, Vol. 19, No. 12, December 2007, p. 529.

11. Cohen D et al. Economic evaluation of bivalirudin with provisional glycoprotein llB/lllA inhibition versus heparin with routine glycoprotein llB/lllA inhibition for percutaneous coronary intervention: Results from the REPLACE-2 trial. Journal of the American College of Cardiology, November 2004: 44, pp. 1792-1800.

12. www.angiomax.com.

13. Cohen M, Diez J et al. Pharmacoinvasive Management of Acute Coronary Syndrome: Incorporating the 2007 ACC/AHA Guidelines. The CATH (Cardiac Catheterization and Antithrombotic Therapy in the Hospital) Clinical Consensus Panel Report-III. Journal of Invasive Cardiology, Vol.19, No. 12, December 2007, p. 533.

14. http://www.argatroban.com/about/argatroban_htm.

15. http://en.wikipedia.org/wiki/Antiplatelet_drug.

16. http://starryskies.com/articles/dln/1-01/asprin.html. The Science of Aspirin and Willows.

17. http://en.wikipedia.org/wiki/Aspirin.

18. Cohen M, Diez J et al. Pharmacoinvasive Management of Acute Coronary Syndrome: Incorporating the 2007 ACC/AHA Guidelines. The CATH (Cardiac catheterization and Antithrombotic Therapy in the Hospital) Clinical Consensus Panel Report-III. Journal of Invasive Cardiology, Vol.19, No. 12, December 2007, p. 532.

19. www.ClinicalMedicineToday.com. Managing Patients with Acute Coronary Syndromes: Evidence Based Approaches to Improve STEMI and UA/NSTEMI Outcomes, p. 9.

20. http://en.wikipedia.org/wiki/Clopidogrel.

21. www.ClinicalMedicineToday.com. Managing Patients with Acute Coronary Syndromes: Evidence Based Approaches to Improve STEMI and UA/NSTEMI Outcomes, p. 8.

22. Cohen M, Diez J et al. Pharmacoinvasive Management of Acute Coronary Syndrome: Incorporating the 2007 ACC/AHA Guidelines. The CATH (Cardiac Catheterization and Antithrombotic Therapy in the Hospital) Clinical Consensus Panel Report-III. Journal of Invasive Cardiology, Vol.19, No. 12, December 2007, p. 53.

23. Cost information supplied by Eastern Shore Pharmacy, Salisbury, Maryland, February 2008.

24. http://en.wikipedia.org/wiki/Ticlid.

25. http://en.wikipedia.org/wiki/Chimera_%28protein%29.

26. http://reopro.com/news_information/faqs.jsp.

27. Peninsula Regional Medical Center, pharmacy cost list, 2007.

28. http://www.reopro.com/pdf/AB39432_926252_2.28.06.pdf.

29. Cohen M, Diez J et al. Pharmacoinvasive Management of Acute Coronary Syndrome: Incorporating the 2007 ACC/AHA Guidelines. The CATH (Cardiac Catheterization and Antithrombotic Therapy in the Hospital) Clinical Consensus Panel Report-III. Journal of Invasive Cardiology, Vol.19, No. 12, December 2007, p. 529.

30. http://en.wikipedia.org/wiki/Integrilin.

31. http://www.integrilin.com/efficacy_introduction.html.

32. http://www.integrilin.com/full_prescribing_information.html.

33. Peninsula Regional Medical Center, pharmacy cost list, 2007.

34. www.ClinicalMedicineToday.com. Managing Patients with Acute Coronary Syndromes, p. 10.

35. http://en.wikipedia.org/wiki/Aggrastat.

36. Bergman SR, Learch RA, Fox KA et al. Temporal dependence of beneficial effects of coronary thrombolysis characterized by positron tomography. American Journal of Medicine, June 1982: 73, pp. 573-58.

37. www.ClinicalMedicineToday.com. Managing Patients with Acute Coronary Syndromes, p. 3.

38. http://www.fasebj.org/cgi/content/full/19/6/671e. ClotBusters!! Discovery of Thrombolytic Therapy for Treating Heart Attack & Stroke.

39. http://www.madsci.com/manu/ches_thr.htm.

40. www.ClinicalMedicineToday.com. Managing Patients with Acute Coronary Syndromes, p. 3.

41. www.ClinicalMedicineToday.com. Managing Patients with Acute Coronary Syndromes, p. 3.