Intracoronary pharmacotherapy


 * and Al Deibele, M.D. [mailto:wdeibele@charter.net]

Associate Editors-In-Chief: Priyantha Ranaweera, M.D. [mailto:pranawee@bidmc.harvard.edu]; Vijay Kunadian, M.D.

Assistant Editor-In-Chief: Scott P. Williams, [mailto:swilliams@perfuse.org]

Overview
Coupled with the understanding of the importance of preservation of microvascular bed and the inability to progress further on the available systemic pharmacotherapy, there is renewed interest in local drug delivery to achieve higher than usual local drug concentrations.

The most common IC pharmacotherapies are vasodilators, with the most popular being nitroglycerine. There is somewhat frequent use of adenosine and nicardipine, though, most of the experience is mainly on adenosine. Use of verapamil and diltiazem are declining due to the availability of nicardipine.

Despite the lack of randomized trials, the use of IC pharmacotherapies in niche situations, such as prevention and treatment of no-reflow, may prove to be life saving.

The evidence on the use of intracoronary glycoprotein inhibitors is sparse. Until more robust data becomes available, regular use of this class of medications is not recommended.

There has been several studies looking at intracoronary thrombolytics. However there is no evidence to suggest that they are superior to current therapy.

Future studies are expected to address some of the issues in this arena.

Pathophysiology
The process of coronary thrombosis starts at a ruptured or fissured plaque creating an in-situ platelet and fibrin aggregate which progresses to an occlusive thrombus. There is in turn distal embolization of platelet rich thrombi downstream which causes microvascular obstruction and tissue level myocardial ischemia. There are also multiple humoral factors which play a role in setting up the cascade of reversible and irreversible damage at cellular and ultra-structural level. There are multiple pathophysiologic abnormalities that lead to impaired microvascular perfusion including:


 * 1) Epicardial and microvascular spasm
 * 2) Thromboembolism and distal ischemia
 * 3) Neutrophil plugging
 * 4) Swelling and edema of endothelial and myocardial cells
 * 5) Capillary leak
 * 6) Dead cells develop contraction bands (hypercontraction of myocytes)
 * 7) In the setting of reperfusion – hemorrhage in the interstitium
 * 8) Myocytolysis (large vacuoles in cells)  and cell death and removal of dead cells by macrophages, with the beginning of vascular granulation tissue formation  followed by repair-granulation tissue, becoming more fibrous and less vascular over time
 * 9) Heightened alpha adrenergic tone and abnormal neural reflexes
 * 10) Capillary leak – advanced stages
 * 11) Interstitial hemorrhage

The TIMI Frame Count
In this method, the number of cineframes required for dye to reach a distal landmark is counted. This method is a surrogate for velocity of dye traversing the vessel. Slower flow in the culprit artery and in all three arteries has been associated with a higher risk of adverse outcomes including mortality compared to those who had normal flow in non culprit arteries. This simple method has been used in a large number of studies to compare the efficacy of agents targeted to treat the microvasculature. See Google Scholar references here.

TIMI Myocardial Perfusion Grade / Blush Grade (TMPG)
This is a simple semi-quantitative technique that could be conveniently and reliably applied in the cardiac catheterization laboratory, enabling the angiographer to assess tissue level perfusion from the angiogram alone. (34)

TMPG is assessed on a scale of 0-3, according to the following definitions:
 * Normal myocardium (TMPG 3)- Normal ground glass appearance of myocardial blush diffusely, and at the end of the washout phase, dye is only mildly persistent or is gone.
 * Mildly impaired tissue level perfusion (TMPG 2)- Dye enters the myocardium, but accumulates and exits more slowly. At the end of the washout phase, dye in the myocardium is strongly persistent.
 * Moderately impaired tissue level perfusion (TMPG 1)- The dye does not leave the myocardium and there is a stain on the next injection.
 * Severely impaired tissue level perfusion (TMPG 0)- Dye does not enter the myocardium and there is minimal or no blush apparent during the injection and washout phases.

In patients treated with thrombolysis, normal TIMI myocardial perfusion grade 3 flow was associated with improved mortality in the short term. (36) For patients who had thrombolytic therapy for STEMI, at 2 years following thrombolytic therapy, the TMPG was a multivariate predictor of mortality, independent of flow in the epicardial artery. (36)

Patients with TIMI grade 3 flow in the epicardial artery who had a closed microvasculature (TMPG 0/1 flow) had a higher mortality (5.4%) than those with TMPG 2 (2.9%) or TMPG 3 flow (0.7%)(p=0.007). Even among patients with TIMI grade 3 flow, there was a 7-fold increase in mortality dictated independently by the extent of the TMP grading. TIMI myocardial perfusion grade was a predictor of 30-day mortality, independent of gender, age, admission pulse, anterior MI location, the TIMI frame count, and the TIMI flow grade. (37)

In the setting of emergency PCI TMPG was a more potent and accurate predictor of survival than was TIMI flow alone after acute infarct PTCA. Interventions which normalize myocardial blush may in fact reduce mortality, though, only ~30% of pts undergoing PTCA had normal myocardial blush restored. (38)

Myocardial Contrast Echocardiography (MCE)
With no reflow, microbubbles do not enter the myocardium where there is a higher risk of arrhythmia, congestive heart failure, or death. This technique is limited for routine clinical application due to the need of additional equipment, personnel, time and expense. (33)

Intracoronary Pharmacotherapy
The main aim of IC pharmacotherapy is to improve and re-establish effective tissue level perfusion, prior to irreversible changes are triggered. Emphasis is to deliver the drug in the highest possible concentration to the affected area thus potentially minimizing systemic effects and ensuring drug delivery to the affected area in coronary slow-flow or no-reflow states. Administration via the guiding catheter may not achieve adequate dosing because of reflux of drug into the aorta. Ideally they should be administered to the distal vascular bed through a catheter such as a balloon catheter or an ultrafuse catheter.

Non-Endothelium Dependent Vasodilators
Do not require an intact endothelium for vasodilation

Mechanism of Action
These compounds contribute active NO (nitric oxide) a vasodilator.

Nitroglycerin

 * Overview- Nitorglycerin dilates veins, larger arteries and arterioles, and has an antiplatelet action in-vitro. When it is administered systemically Venodilation > arterial dilation.  The exact mechanism of the action of IC nitroglycerin not fully understood. Also, the anti anginal response may be mediated systemically rather than locally. This effect should be differentiated from direct coronary vasodilatory properties.(46)


 * Duration of action- The duration of action is a few minutes.


 * Clinical effects of IC nitroglycerin- Nitroglycerin dilates arteries > 100 mcg, including the areas of stenosis. In higher doses it dilates larger arteries as well. Nitroglycerin, as opposed to dipyridamole, does not cause “steal” phenomenon. (47, 48) In one study, IC nitroglycerin increased normal luminal area of coronary arteries increased by an average of 28% and luminal area in significantly stenotic segments by 29 %. (49)  Smaller coronary arteries (< 1mm diameter) were shown to have a larger percentage dilation compared to larger arteries when given iv or ic. (50,51)  Pretreatment with intracoronary nitroglycerin prevented exercise-induced vasoconstriction of stenotic coronary arteries. (52) Intra coronary nitroglycerin has also been shown to relieve resistant coronary artery spasm not responding to sub lingual nitroglycerin (53)


 * Clinical use- Nitroglycerin is the most commonly used IC vasodilator. Its uses include: suspected or obvious spasm, no-reflow, prophylaxis prior to stenting, prophylaxis in lesions prone to distal embolization, and post PCI angina. Additionally, nitroglycerin is used in conjunction with distal emboli-protection.


 * IC bolus- Nitroglycerin is delivered in 50 – 1000 mcg in boluses.


 * IC infusion-


 * Preparation-


 * Side effects- Side effects of nitroglycerin include: hypotension and headache.


 * Reversing the effects- Hypotension can be relieved with iv fluids and, occasionally, inotropes (eg dopamine).


 * Coronary spasm resistant to nitroglycerine- There have been reports of spasm unresponsive to ic nitroglycerine (200 mcg – 2000 mcg over 10 mts) being successfully treated with ic verapamil (1000 mcg to 1500 mcg given over 10 mts) (54,55)

Sodium nitroprusside

 * Overview: Compared with adenosine, intracoronary nitroprusside produces an equivalent but more prolonged coronary hyperemic response in normal coronary arteries (57)


 * Duration of action: The duration of action is a few minutes, with a drug half life = 2 minutes.


 * Clinical effects of IC nitroprusside: In one study, 50 mcg delivered IC was shown to be effective in alleviating impaired blood flow and no-reflow associated with PCI. (58) Similarly, 200 mcg produced improved CTFCs among patients with no-reflow and was also associated with a lower incidence of hypotension and bradycardia. (59)


 * Clinical use: Sodium nitroprusside's uses include: suspected or obvious spasm, no-reflow, prophylaxis prior to stenting, prophylaxis in lesions prone to distal embolization. It is also used in conjunction with distal emboli-protection and to treat post PCI angina.


 * IC bolus: 100 mcg IC as a single dose to a total dose of 1000 mcg (1 mg).


 * IC infusion:


 * Preperation:


 * Side effects: Side effects include bradycardia and hypotension, but at a lower rate than observed with nitroglycerin.


 * Reversing the effects:

Adenosine

 * Overview: Adenosine is synthesized in the myocardium in vivo. Intravenous or intracoronary adenosine can reliably increase coronary hyperemia to maximal levels to or even exceeding what is produced by transient ischemia.


 * Mechanism of action: Adenosine increases arterial endothelial cell nitric oxide (NO) through adenosine A2a receptors on the myocytes of resistance vessels. The administration of adenosine is associated with a reduction in both endothelial injury and neutrophil activation. (61)


 * Duration of action: Very brief (5-30 seconds).


 * Clinical Effects: Intra coronary adenosine was shown to improve TIMI frame count measurements in patients with microvascular angina. (64) High-dose intracoronary adenosine in the setting of AMI, was shown to be associated with improved echocardiographic parameters and clinical outcomes. (65)  Several small studies demonstrated an improved microvascular function and reduction in infarct size in the setting of AMI (66,67) In the setting of ACS IC adenosine, compared to saline, was shown to significantly improve left ventricular wall motion and coronary flow.(68)  In a canine model, submaximal dosing did not affect the endocardial to-epicardial blood flow ratio, whereas submaximal doses demonstrated a marked preferential endocardial perfusion. (69)


 * AMISTAD Trials: Largest randomized trials with Adenosine, however the drug was given intravenously.
 * AMISTAD I: Patients with STEMI were treated with thrombolysis and given an infusion of iv 70 mcg/kg/min adenosine infusion, demonstrated a significant reduction in infarct size. (62)
 * AMISTAD II: Largest trial (n=2118). (63) Patients with anterior ST elevation myocardial infarctions were treated with either thrombolysis (60%) or primary PCI (40%) and received IV adenosine 50 mcg/kg/min, 70 mcg/kg/min or placebo.  Patients treated with adenosine demonstrated no reduction in the composite primary end point of death, new congestive heart failure or the first re-hospitalisation for congestive heart failure.  A secondary endpoint of infarct size demonstrated a trend toward a reduction but did not reach statistical significance. The dose used in these two trials was low compared the conventional dose of 140 mcg/kg/min for coronary hyperemia. Also the drug was delivered systemically.


 * IC dosing: The dose needed to induce maximum hyperemia was 16 mcg IC for the left coronary artery and 12 mcg IC for the right coronary artery in a subjects with no CAD. (70)  However in patients with known CAD, the dose varied from 50 mcg to 800 mcg. With increasing dose > 200 mcg, heart block was increasingly encountered. The IC dose of 80 mcg/kg/min produced maximum hyperemia.  With higher doses up to 240 mcg/kg/min there was minimal drop in blood pressure but there was no tachycardia. (71)  In a study comparing various doses of IC adenosine, IV adenosine, ATP and papavarine, it was shown that the IC doses and the IV doses produced comparable vasodilation. How ever IV dosing was associated with more episodes of hypotension and tachycardia and the IC dosing was more less likely to cause tachycardia. Additionally the IC dosing had a propensity to cause bradycardia. (Bernard De Bruyne, MD, PhD; Nico H.J. Pijls, et al, Intracoronary and Intravenous Adenosine 5'-Triphosphate, Adenosine, Papaverine, and Contrast Medium to AssessFractional Flow Reserve in HumansCirculation. 2003;107:1877-1883.)

Low doses ---> effects are confined to subendocardial vessels. High doses ---> transmural vasodilation (60)


 * IC BOLUS: In healthy persons 16 mcg boluses induced maximal hypermeia, but it may be necessary administer larger doses in patients with microvascular dysfunction. (72) Dosages used in studies raged from 16 mcg to 4 mg boluses.  The usual dosages used were 100 mcg boluses to a total dose of 4000 mcg, (73)


 * IC infusion: 10-70 mcg/kg/min with some suggestion that the higher infusion rate may produce better results. Adenosine has a half-life of 6 seconds. Therefore, it can be repeatedly administered when ECG, pulse and blood pressure normalize. (74, 75)


 * Preparation: Add 6 mg of Adenosine to 9 cc of 0.9% NNrmal saline making 600 mcg/ml of the drug. Take 1 cc of this solution and dilute it with 9 cc of normal saline making 60 mcg/ml. Take 1 cc and add 0.9% N saline up to 10 cc yielding 6 mcg ml. Administer paying close attention to the ECG. Immediately before and during administration electrocardiogram can be recorded at a faster speed (100 mm/sec) to assess changes in the PR, QRS, and QT intervals. Because transient bradycardia can occur, consideration should be given to the prophylactic placement of a temporary pacemaker.


 * Side effects: Bradycardia is often seen with the administration of high doses. By increasing the refractory period of the sinoatrial and atrioventricular nodes produces heart block. Unlike with iv use, difficulty in breathing, hypotension, tachycarida, and chest pressure are all uncommon. (76, 77)


 * Reversing the effects: This is not an issue due to short duration of action

Dipyridamole

 * Mechanism of action: Dipyridamole increases interstitial adenosine, resulting in vasodilation. It is thought to divert blood to smaller vessels causing “steeling” from the ischemic areas (as opposed to nitrates).


 * Duration of action: Dipyridamole's duration of action is approximately 30 minutes.


 * Clinical effects:


 * Clinical use: Not used due to the availability of its active form, adenosine. However if needed the clinical usage could be similar to Adenosine.


 * IC bolus:


 * IC infusion:


 * Preparation:


 * Side effects:


 * Reversing the effects: Methyl xanthines reverse the effects of dipyridamole.

Nicardipine

 * Mechanism of action: Compared to nifedipine, diltiazem, and verapamil, nicardipine was the most vascular smooth muscle selective. Nicardipine was also shown to be more specific for coronary arteries than peripheral arteries. (78)


 * Duration of action: Nicardipine's duration of action is 5-6 minutes.


 * Clinical effects: After IV administration of nicardipine, coronary blood flow increased significantly and the mean aortic pressure decreased by 10%. (79) IC nicardipine 200 µg, 10,000 µg diltiazem and verapamil 200 µg were studied on coronary arteries. The effect on epicardial coronary artery diameter was similar among the 3 calcium channel blockers. Two patients who received diltiazem had a transient episode of type 1 second-degree atrioventricular block. Compared to the other two, nicardipine was shown to significantly increase icoronary blood flow velocity and also had a longer duration of effect (5–6 minutes). (80)  Nicardpine 200 mcg IC not only prevented exercise induced vasoconstriction in the atherosclerotic arteries, but also caused vasodilation, in similar proportions to iv administration.  The combination of nitroglycerin and nicardipine has an additive dilatory effect on coronary arteries that is more pronounced in stenotic than nonstenotic vessels (81, 82)  In patients undergoing PTCA, ic infusion of nicardipine protected the myocardium from regional ischemia, allowing a faster recovery of aerobic metabolism after reperfusion. This mechanism appeared unrelated to direct hemodynamic effects of nicardipine. (83)  In contrast to other calcium antagonists such as nifedipine, which depresses myocardial contractility, nicardipine 200 mcg ic, had negligible effects on myocardial contractility. (84)


 * Clinical use: Nicardipine is used: for suspected or obvious spasm, for no-reflow, as prophylaxis prior to stenting, as prophylaxis prior to PCI in lesions prone to distal embolization, as prophylaxis with rotational atherectomy, as part of the flush irrigation of rotational atherectomy. Nicardipine is also used inn conjunction with distal emboli-protection and to treate post PCI angina.


 * IC bolus: 200 mcg as a single dose to a total dose of 1000 mcg (1 mg)


 * IC infusion:


 * Preparation:


 * Side effects: IC nicardipine has minimal systemic or direct myocardial depressant effects (85). It is also associated with a low incidence of bradycardia and hypotension – therefore it may be preferable in patients with low blood pressure.


 * Reversing the effects: Not usually an issue.

Non-Dihydropyridine CCBs

 * Mechanism of action: Non-Dihydropyridine CCBs block L-type calcium channels (vascular smooth muscle, cardiac myocytes, and cardiac sinoatrial and atrioventricular nodes). They also block influx of calcium into muscle cells, smooth muscle, cardiac myocyte relaxation and a-v slowing.

Diltiazem

 * Clinical effects: IC administration of diltiazem was shown to prevent exercise induced vasoconstriction of stenotic coronary arteries. (86)


 * Clinical use: Given the ready availability of Nicardipine, the use of Diltiazem is waning. If needed the clinical usage could be similar to Nicardpine.


 * IC bolus: Diltiazem 200 mcg as a single dose to a total dose of 1000 mcg (1 mg)


 * IC infusion:


 * Duration of action:


 * Preparation: Take 5 mg of Diltiazem in to 9 cc of Normal saline making 500 mcg/ml. Half a ml makes 250 mcg.


 * Side effects: Side effects of diltiazem include: bradycardia, hypotension, and myocardial depression.


 * Reversing the effects:

Verapamil

 * Clinical effects: IC verapamil was shown to improve TIMI flow rates and TIMI frame counts in patients with CAD and improve angiographic outcomes in no reflow states. (87)  Additionally, it has been shown to augment postinterventional coronary blood flow. (88, 89) In patients undergoing PCI < 12 hrs of AMI, early administration of intracoronary verapamil 50-100  mcg prior and the same dose during PCI improved postprocedural myocardial perfusion as evaluated by TMPG (90)  In the VAPOR trial, intragraft administration of 200 mcg verapamil prior to saphenous vein graft PCI reduced no-reflow and was associated with a trend toward improved myocardial perfusion. (91)  Compared to those treated with PTCA alone, verapamil 500 mcg ic after primary PTCA improved microvascular function, leading to better LV functional outcome in patients with AMI (92)  Vasospasm distal to a PTCA site may be resistant to nitroglycerine and was shown respond to Verapamil 100 mcg. (93)  In the setting of ACS, 500 mcg of IC verapamil compared to saline was shown to significantly improve wall motion and coronary flow.(68) IC verapamil was shown to safely terminate reperfusion-induced ventricular tachyarrhythmias  in a rapid manner. However, this effect was not seen for reperfusion-induced VF. (94)


 * Duration of action:


 * Clinical use: Due to ready availability of Nicardipine, this drug is less commonly used. However if needed the clinical usage could be similar to Nicardpine.


 * IC bolus: 200 mcg as a single dose to a total of 1000 mcg (1 mg)


 * IC infusion:


 * Preparation:


 * Side effects: Side effects of IC verapamil include: bradycardia, hypotension, and decline in contractility of the myocardium.  In one study, 500 mcg IC bolus produced a significantly high incidence of hear block and hypotension, with the heart block lasting 3 hours. (68)


 * Reversing the effects:

Papavarine

 * Mechanism of action:


 * Duration of action: Peak effect after 30 sec and a total duration of action of less than 2 to 3 min. Maximal coronary hyperemia for up to 30 seconds.


 * Clinical use: Due to its long duration of action and potential for polymorphic VT, it is not commonly used in the coronary circulation.


 * IC dosing:


 * IC bolus: Total dose that can be given is limited by its relatively slow systemic elimination (half-life, 3-6 hours. 6-12 mg (2mg/ml 0.9% saline). Maximum dosing 30 mg.


 * IC infusion:


 * Preparation:


 * Side effects: Side effects of papavarine include polymorphic VT (0.5% incidence) and hypotension, which may be prolonged due to its longer half life (limiting papavarine's use).


 * Reversing the effects:

Phentolamine

 * Mechanism of action:


 * Duration of action:


 * Clinical effects: 72 hrs following thrombolysis for AMI, alpha-adrenergic blockade IC, using phentolanine attenuated vasoconstriction and postischemic LV dysfunction after PCI. Flow in the uninvolved artery improved following PCI of the culprit artery significantly (by nearly 10 frames) if it was abnormal to begin with. After 15 minutes of observation, however, flow in both the culprit and non-culprit arteries again slowed back down to pre-intervention values which was re-restored after administration of α-blockers. In this study patients initially received thrombolysis followed by angiography 24 hrs later. Also there was no use of glycoprotein inhibitors. (95)


 * Clinical use: Not commonly used clinically.

Endothelium dependent vasodilators

 * Overview: Endothelium dependent vasodilators require and intact endothelium. If the endothelium is diseased or absent then paradoxical vasoconstriction occurs.

Acetyl choline

 * Mechanism of action:


 * Clinical use:

Serotonin

 * Mechanism of action:


 * Clinical effects:


 * Clinical use: