Interventional Pharmacology—Vasodilators

General (including evidence of efficacy)

Vasodilators

Medications that vasodilate the coronary arteries are frequently used during coronary angiography and intervention. They can generally be classified as:

• Vasodilators that predominantly dilate the epicardial coronary arteries with little or no effect on the microcirculation (e.g., nitroglycerin).

• Vasodilators with mixed activity that dilate both the large epicardial and small resistance arterioles (e.g., nitroprusside).

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• Vasodilators that primarily dilate the coronary microcirculation (e.g., adenosine, calcium channel blockers).

Nitroglycerin

• Nitroglycerin has both direct coronary effects and peripheral hemodynamic effects that can be useful in patients in the catheterization laboratory.

• The principle physiologic action of nitroglycerin is vasodilation, particularly of the systemic veins but also of the coronary and peripheral arteries.

• It is somewhat unique among coronary vasodilators in that it produces vasodilation of larger coronary arteries with little or no dilation of small coronary microvessels. Therefore, it is not effective in the management of microvascular obstruction or the no reflow phenomenon.

• Nitroglycerin has several uses in the catheterization laboratory. Intracoronary (IC) administration is often performed to prevent or treat coronary vasospasm, and augment coronary collateral flow. It can also be helpful in appropriate sizing of balloons and stents.

• When performing cardiac catheterization via the radial approach, intraarterial nitroglycerin is frequently administered prophylactically to prevent radial artery spasm.

• Sublingual or intravenous (IV) nitroglycerin can be used for periprocedural control of hypertension, and for the treatment of patients with angina or decompensated heart failure in the cardiac catheterization laboratory.

Nitroprusside

• Nitroprusside is a potent arterial and venous vasodilator. It produces more balanced arterial and venous dilation compared to nitroglycerin (which is more of a venodilator particularly at low doses). In contrast to nitroglycerin, nitroprusside does not depend on intracellular metabolism for conversion to NO, and can therefore deliver abundant NO to the coronary microcirculation.

• The most important use of IC nitroprusside is in the treatment of slow flow and no-reflow phenomena complicating myocardial infarction and/or percutaneous coronary revascularization. It can also be used as an alternative to adenosine for the induction of hyperemia for the physiological assessment of coronary artery lesions.

• IV nitroprusside is occasionally used in the catheterization laboratory for the management of severe hypertension, acute pulmonary edema/severe decompensated heart failure, and acute mitral or aortic regurgitation

Adenosine

• Adenosine is a potent vasodilator of small coronary resistance arterioles and does not have any vasoactive effects on the large epicardial arteries. Its principle uses in the cardiac catheterization laboratory are: (1) treatment of slow flow/no-reflow, and (2) induction of hyperemia for physiologic assessment of intermediate coronary artery lesions.

• The no-reflow phenomenon is characterized by a reduction in epicardial blood flow despite patency of the vessel, and is due to compromise of the integrity of the microvascular circulation. The pathophysiology may vary depending on the clinical circumstances, but it is primarily due to distal microembolization, vasoconstriction and dysfunction of the microcirculation. No-reflow is most commonly encountered during percutaneous intervention in the setting of acute myocardial infarction or a high thrombus burden, with revascularization of degenerated saphenous vein grafts, and during the use of rotational atherectomy.

• It is clinically important because its presence is associated with increased infarct size, impaired left ventricular function, and increased in-hospital and long-term mortality. One of the most common strategies to manage no-reflow during cardiac catheterization involves the use of vasodilators of the coronary microvasculature, such as adenosine or sodium nitroprusside.

• Maximal coronary hyperemia is required for the physiologic assessment of intermediate epicardial coronary lesions in the catheterization laboratory. Adenosine is the drug of choice for induction of maximal hyperemia when performing fractional flow reserve (FFR) or coronary flow reserve (CFR) measurements.

Calcium channel blockers

• Calcium channel blockers dilate vascular smooth muscle cells, reduce cardiac contractility, and some agents even slow AV node conduction. They lower global myocardial oxygen demand through reductions in myocardial oxygen demand (arterial pressure, heart rate, and contractility). However, their negative inotropic and chronotropic properties may be harmful in patients with severe heart failure or hemodynamic instability.

• IC calcium channel blockers exert their effects predominantly by dilating the small resistance arterioles but may also inhibit platelet aggregation in the microvasculature.

• Compared to adenosine and the nitro-vasodilators, calcium channel blockers are less commonly used during cardiac catheterization and intervention. Their utility in the catheterization laboratory is largely limited to the management of no-reflow, treatment of arrhythmias and the prevention/treatment of radial artery spasm when performing transradial cardiac catheterization.

Administration

Nitroglycerin

• Common routes of nitroglycerin administration in the catheterization laboratory are: intracoronary (IC), intraarterial (IA), sublingual (SL), and intravenous (IV). When given IV, IA, or IC, it has an immediate effect and has a short duration of action of 3 to 5 minutes. SL nitroglycerin is rapidly absorbed with onset of action occurring within a few minutes, maximal effects occurring within 3 to 15 minutes, and effects subsiding within 20 to 30 minutes.

• IV nitroglycerin should be started at low doses, 5 to 20 µg/min, and titrated up 5 to 10 µg every 5 minutes until resolution of angina or control of blood pressure. The rapid decrease in plasma concentration after discontinuation of the infusion is due to its short half-life.

• Optimal IC dosing of nitroglycerin (and many other vasodilators) remains uncertain due to the lack of adequately powered clinical trials. In small studies of patients with coronary artery disease, IC nitroglycerin has been shown to cause coronary artery dilation with doses as little as 5 µg. Moderate doses (50 to 200 µg) produce maximal or nearly maximal dilation, while larger doses (>450 µg) result in no further dilation. Typical doses used in contemporary practice are 100 to 400 µg, which can be repeated every 5 to 10 minutes as blood pressure allows.

• Spasm of the ostium of the right coronary artery or the left main artery may be more effectively treated with sublingual or IV nitrates, since ostial segments may be less exposed to nitroglycerin administered through the diagnostic or guiding catheter.

• For catheterization via the transradial approach, 100 to 200 µg nitroglycerin is commonly given intraarterially to prevent radial artery spasm.

Nitroprusside

• For the treatment of no-reflow, 50 to 100 µg IC bolus can be used and repeated as needed. Cumulative doses >200 µg are safe and effective. Since vasodilators delivered through the guiding catheter may not reach the microcirculation due to no-reflow itself, an infusion catheter can be used to maximize delivery of the drug to the distal microvasculature.

• IV infusion of nitroprusside should begin at 0.5 to 1 µg/kg/min, increasing to no more than 10 µg/kg/min. Invasive arterial pressure monitoring is generally recommended due to its potent hemodynamic effects. The infusion should be limited to 48 hours in duration because cyanide toxicity can occur over time as cumulative doses increase. It should be used cautiously in patients with liver or kidney disease. Tapering the dose of nitroprusside prior to discontinuation is recommended to avoid the possibility of rebound hypertension.

Adenosine

• For the treatment of no-reflow, multiple boluses of high doses of IC adenosine should be administered. Since vasodilators delivered through the guiding catheter may not reach the microvessels due to no-reflow itself, an infusion catheter can be used to maximize delivery of the drug to the distal microvasculature.

• Either IV or IC adenosine can be used to induce maximal hyperemia for the physiologic assessment of coronary artery lesions. IC adenosine achieves maximal hyperemia within 5 to 30 seconds.

• Traditionally 40 to 60 µg is given in the left coronary artery and 20 to 30 µg for the right coronary artery. It appears that there is a dose-effect relationship and higher doses (up to 720 µg) have been shown to increase the sensitivity of FFR.

• IV adenosine is infused at 140 µg/kg/min and produces sustained hyperemia after 1 to 2 minutes. Adenosine hyperemia lasts less than 60 seconds after drug administration has ended.

• For the treatment of reentrant supraventricular arrhythmias, 6 to 12 mg IV boluses are usually administered and repeated if necessary.

• In the Acute Myocardial Infarction STudy of Adenosine (AMISTAD) II trial, IV adenosine (3-h infusion, 50 to 70 µg/kg/min) administered prior to revascularization for acute MI was associated with reduced infarct size, but no improvement in clinical outcomes.

Calcium channel blockers

• A typically used dose of IC verapamil is 200 µg IC bolus, and can be repeated 2 to 4 times as needed. IC nicardipine is typically administered in doses of 200 to 400 µg, and can be repeated if necessary.

• Intraarterial verapamil 3 mg may be given for the prevention of radial artery spasm during transradial catheterization.

Pharmacologic action

Nitroglycerin

• Nitroglycerin produces its major biological effect by releasing nitric oxide (NO). Its actions are, therefore, similar to the endothelium-derived NO; however, it does not require endothelium to exert its action (i.e., endothelium-independent).

• It produces vasodilation by directly relaxing vascular smooth muscle cells in the walls of arteries and veins. The mechanism involves the biotransformation of nitroglycerin to NO, which subsequently activates cyclic GMP and results in smooth muscle relaxation through mechanisms involving intracellular calcium reduction.

• The hemodynamic effects of nitrates are dose-dependent. Systemic veins become near maximally dilated at relatively low doses, while arterial vasodilation occurs at higher doses. At very high doses, arterioles or resistance vessels also dilate.

• Nitroglycerin predominantly dilates the epicardial coronary arteries while having only minimal effect on small coronary resistance vessels (<100 µm in diameter). This differential activity occurs because biotransformation of nitroglycerin in the coronary circulation primarily occurs in the epicardial arteries, while the small coronary arterioles are not capable of converting nitroglycerin to nitric oxide. Since coronary perfusion is predominantly regulated by the coronary microcirculation, nitroglycerin produces only a small and brief effect on coronary flow.

• In addition to vasodilation of epicardial coronary vessels, nitroglycerin dilates and augments coronary collateral blood flow. This is likely due to a combination of factors including nitroglycerin-induced alterations in regional flow and collateral perfusion pressure, reduction in left ventricular wall stress, and direct action on collateral vessel smooth muscle.

• The antianginal effects of nitroglycerin are due to a combination of enhanced oxygen delivery via coronary vasodilation and decreased myocardial oxygen consumption from reductions in left ventricular preload, afterload, and wall tension.

• Nitroglycerin is 60% protein bound, has a half-life of 1 to 4 minutes, and is excreted with urine.

Nitroprusside

• Nitroprusside is an endothelial-independent direct donor of NO. NO activates smooth muscle soluble guanylyl cyclase to form cGMP. Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and resulting in smooth muscle relaxation. It is effective at dilating both the epicardial coronary arteries and the small resistance arterioles.

• The hyperemic response to IC nitroprusside is fast, with peak coronary blood flow occurring within 20 seconds after IC bolus administration, and is more prolonged compared with adenosine.

• Nitroprusside has a very short half-life (seconds to a few minutes).

• Cyanide molecules are released as nitroprusside undergoes metabolism to NO, but cyanide toxicity is rare at clinically used doses. Cyanide is metabolized to thiocyanate in the liver and then eliminated via the kidneys.

Adenosine

• Adenosine is an endogenous purine nucleoside with a very short half-life (5 to 10 seconds). Vasodilation of the coronary arteries occurs through activation of the A2A receptors in vascular smooth muscle cells and is endothelium-independent.

• Activation of the A2A receptor leads to an increase in adenylate cyclase activity and subsequent increase in intracellular cyclic AMP. Its effect is primarily restricted to arterioles <100 µm in size.

• Adenosine also has antiinflammatory properties and inhibits platelet activation and aggregation.

• The electrophysiologic effects of adenosine result from binding to specific A1 receptors, which slow conduction in the sinoatrial node, AV node, and atrial myocytes.

• Methylxanthines (e.g., caffeine, theophylline) are competitive antagonists of adenosine receptors, and thus high doses of adenosine may be necessary in patients using these substances. In contrast, dipyridamole inhibits the breakdown of adenosine and enhances its effect.

Calcium channel blockers

• Calcium channel blockers bind to and block the L-type voltage-gated calcium channels located on vascular smooth muscle cells. The intracellular calcium reduction promotes smooth muscle relaxation and results in vasodilation.

• Calcium channel blockers also bind to calcium channels on cardiac myocytes resulting in reduced cardiac contractility. Certain nondihydropyridine calcium channel blockers bind to receptors on the sinoatrial and AV nodes and decreased nodal conduction.

Clinical Efficacy

Nitroprusside

• No reflow: Nitroprusside has been shown to be a safe and effective therapy for no-reflow during PCI. Various doses of IC nitroprusside have been used in the management of no-reflow and repeated doses may be required to achieve satisfactory coronary flow. It is important to administer the IC nitroprusside into the distal coronary bed via a microcatheter or the lumen of a balloon angioplasty catheter advanced distally.

• High doses (>200 µg) are usually associated with rapid improvements in both angiographic flow and coronary blood flow velocity without significant hypotension or other adverse effects. In cases of refractory no-reflow, the combination of IC adenosine and nitroprusside is safe and may be potentially more effective than adenosine alone. There may also be a role for prophylactic IC nitroprusside in patients at high-risk of developing no-reflow with PCI (e.g. intervention in atretic vein grafts).

• Physiologic assessment of coronary artery lesions: Nitroprusside appears to be a suitable hyperemic stimulus for coronary physiologic measurements, but is used less frequently than adenosine. Compared to IC adenosine, IC nitroprusside produces an equivalent but more prolonged coronary hyperemia (about 25% longer duration) and similar fractional flow reserve (FFR) measurements.

Adenosine

• No-reflow: Studies have shown that IC adenosine is associated with decreased incidence of no-reflow and improved LV function in patients undergoing emergent revascularization for acute myocardial infarction (AMI). Intragraft administration of adenosine is also effective when employed during percutaneous intervention of saphenous vein grafts. Multiple boluses of intragraft adenosine are associated with improvement of no-reflow complicating vein graft interventions.

Physiologic assessment of coronary artery lesions:

• Adenosine may be given either IV or IC for the induction of maximal coronary hyperemia. For most patients it appears that IC adenosine is more or less equivalent to IV adenosine when measuring FFR. However, in few cases, coronary hyperemia may be suboptimal with IC adenosine compared with IV. IV adenosine produces more uniform hyperemia and is generally the recommended approach when performing FFR. IV adenosine has also the advantage of being weight-based and free of operator interference. It is also required for ostial lesions or for the assessment of diffuse disease during pullback recordings.

Calcium channel blocker

• When delivered IC, verapamil, nicardipine, and diltiazem are all effective vasodilators of the coronary microcirculation.

• Verapamil: IC verapamil is associated with significant improvement in myocardial perfusion among patients with angiographic no-reflow undergoing PCI for acute myocardial infarction. The benefits of IC verapamil appear to be similar to those of IC adenosine, but verapamil is associated with higher risk of transient heart block, especially at higher doses and with injection in the right coronary artery. IC verapamil is also associated with improved angiographic outcomes for the treatment and prevention of no-reflow in SVG interventions. Various doses of IC verapamil (50 to 1000 µg) have been used across different trials. It appears that the peak effect on the left coronary system is reached with 1000 ug IC verapamil, with no further increase in coronary blood flow at higher doses.

• Nicardipine: Nicardipine is an attractive choice for the management of no-reflow, since it is a vasoselective dihydropyridine calcium channel blocker with minimal negative chronotropic and inotropic effects. When compared to IC verapamil (200 µg) and diltiazem (1 mg), IC nicardipine (200 µg) appears to offer more potent and prolonged microvascular dilation with less risk of heart block.

• It has been shown to be a safe and highly effective for the reversal of no-reflow during interventions of native and SVG lesions. IC nicardipine is typically administered in doses of 200 to 400 µg, and can be repeated if necessary.

• Diltiazem: IC diltiazem is used by some for the treatment of no-reflow. However, it does not have an approved indication as a vasodilator in the catheterization laboratory currently. Typical starting doses are 50 to 100 µg IC, although doses up to 5 mg have been administered. It has lower negative inotropic effects compared to verapamil.

• IC calcium channel blockers may also be effective for the treatment of epicardial coronary artery spasm, including nitroglycerin-resistant spasm.

Indications and contraindications

Nitroglycerin

Indications for IC nitroglycerin:

• Treatment of spontaneous coronary spasm

• Augmentation of coronary collateral flow

Indications for IV or SL nitroglycerin:

• Periprocedural blood pressure control

• Control of angina in patients with periprocedural myocardial ischemia

• Reduction of preload in patients with decompensated heart failure/pulmonary edema

Indications for IA nitroglycerin:

• Prevention and treatment of radial artery spasm during transradial cardiac catheterization

Contraindications – Systemic nitroglycerin is contraindicated in the following settings:

• Hypotension (systolic blood pressure [SBP] <90 mm)

• Right ventricular infarction

• Concurrent use with phosphodiesterase-5 inhibitors (sildenafil, tadalafil, or vardenafil)

Nitroprusside

Indications for the use of IC nitroprusside during cardiac catheterization/intervention:

• Prevention and treatment of no-reflow

• Induce maximal hyperemia for invasive measurements of coronary reserve

• Treatment of coronary spasm

Indications for the use of IV nitroprusside during cardiac catheterization/ intervention:

• Severe hypertension

• Acute pulmonary edema or severe congestive heart failure

• Acute and/or severe mitral or aortic regurgitation

Contraindications

• Hypotension (SBP <90 mm Hg)

• Concurrent use with phosphodiesterase-5 inhibitors (sildenafil, tadalafil, or vardenafil)

• Hepatic failure is a contraindication to IV nitroprusside due to the inability to detoxify cyanide

• Renal impairment may lead to accumulation of thiocyanate and subsequent toxicity

Adenosine

Indications for the use of adenosine during cardiac catheterization/intervention:

• Prevention and treatment of no-reflow

• Induction of maximal hyperemia for invasive physiologic assessment of intermediate coronary lesions

• Treatment of supraventricular tachycardias

Contraindications

• High-grade AV block or sick sinus syndrome

• Active or severe bronchospastic lung disease

Calcium channel blockers

Indications for the use of calcium channel blockers during cardiac catheterization/intervention:

• Prevention and treatment of no-reflow

• Treatment of epicardial coronary artery spasm

• Treatment of arrhythmias

• Prevention/treatment of radial artery spasm during transradial cardiac catheterization

Contraindications

• Hypotension (SBP <90 mm Hg)

• Bradycardia or high degree of heart block

• Decompensated heart failure/left ventricular dysfunction

Prevention or treatment of coronary spasm induced by catheter, coronary wire, or balloon manipulation. It is also good practice to use IC nitroglycerin to appropriately size balloons and stents prior to deployment.

Undesirable effects

• Nitroglycerin is a very safe and short-acting medication. Primary adverse effects are hypotension, tachycardia, headache, and flushing.

• Nitrate-induced hypotension typically results from combined venous and arterial dilation. Venodilation reduces preload, and hypotension usually responds promptly to intravascular volume infusion. Care should be taken to avoid hypotension when administering nitroglycerin to patients with severe aortic stenosis or significant left main stenosis. Nitroglycerin should not be administered within 24 to 48 hours of phosphodiesterase-5 inhibitor use due to the risk of profound hypotension.

Nitroprusside

• No major adverse effects are usually observed with the administration of IC nitroprusside, except for a transient reduction in blood pressure. As with nitroglycerin, care should be taken to avoid hypotension when administering nitroprusside to patients with severe aortic stenosis or significant left main stenosis.

• Cyanide toxicity is rare with IV nitroprusside, but the risk increases with high doses (>250 µg/min) and prolonged periods of infusion (>48 hours), and in patients in whom elimination is decreased, such as those with hepatic/renal failure. Cyanide/thiocyanate toxicity should be suspected in patients who develop nausea, abdominal discomfort, altered mental status, or convulsions. It is treated with IV sodium nitrite, thiosulfate, and drug discontinuation.

Adenosine

• Since the half-life of adenosine is very short, adverse effects, such as bradycardia, transient AV block, chest pain, dyspnea, headache, and flushing, rarely last more than a few seconds. These side effects are mediated by activation of other adenosine receptors (A1, A2B, and A3). IV dosing may have a higher incidence of flushing, chest pain, and bradycardia/AV block compared to IC adenosine.

• IC verapamil is associated with a greater incidence of transient heart block compared to IC adenosine, especially with injection of the right coronary artery or dominant left circumflex artery.

• IV or IA calcium channel blockers should be avoided in patients with heart failure/severely depressed LV function because of their negative inotropic effects.

Calcium channel blockers

• IC verapamil is associated with a greater incidence of transient heart block compared to IC adenosine, especially with injection of the right coronary artery or dominant left circumflex artery.

• IV or IA calcium channel blockers should be avoided in patients with heart failure/severely depressed LV function because of their negative inotropic effects.

Alternative approaches

Nitroglycerin

Other vasodilators of the epicardial coronary arteries include sodium nitroprusside and acetylcholine. Nitroprusside is also an endothelial-independent donor of NO, but in contrast to nitroglycerin, it does not require enzymatic metabolism to derive NO.

IC nitroprusside, therefore, produces both epicardial and microvascular dilation. Nitroprusside will be covered in detail in the subsequent section. Acetylcholine stimulates muscarinic receptors on coronary endothelial cells. In the presence of normal, “healthy” endothelium, acetylcholine produces coronary vasodilation; but in the setting of dysfunctional endothelium it results in vasoconstriction.

IC acetylcholine can be used as a provocative test to diagnose coronary spasm (and has comparable effectiveness to methylergonovine). It is also used as a research tool to evaluate the endothelium.

Nitroprusside

Nicorandil has a dual mechanism of action: it acts as a (1) nitric oxide donor and an (2) ATP-sensitive potassium channel opener. It produces vasodilation of the epicardial coronary arteries and the small resistance arterioles. In addition, nicorandil has an antiinflammatory effect and reduces production of free radicals. Nicorandil is an effective antianginal medication, and can induce pharmacologic preconditioning and impart cardioprotective effects. Nicorandil has shown some efficacy in reducing no-reflow in the setting of acute myocardial infarction and rotational atherectomy. It is not available in the United States.

Adenosine

Regadenoson, a new selective A2A agonist, produces a similar degree of hyperemia compared to adenosine and has fewer side effects. A single IV bolus of regadenoson (400 µg) has been shown to be as effective as an IV infusion of adenosine for measuring FFR. Sodium nitroprusside is also a suitable hyperemic stimulus for physiologic coronary lesion assessment. Adenosine triphosphate (not available in the United States) and dobutamine have also been used for coronary physiologic measurements. IC papaverine is no longer used for hyperemic stimulation due to the risk of Q-T prolongation and associated arrhythmias.

What's the Evidence?

Amit, G, Cafri, C, Yaroslavtsev, S. “Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial”. Am Heart J. vol. 152. 2006. pp. 887.e9-887.e14. (Single-center RCT of 98 patients with STEMI demonstrating that selective intracoronary administration of a fixed dose of nitroprusside improves 6-month clinical outcomes.)

Levine, GN, Bates, ER, Blankenship, JC. “2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions”. Circulation. vol. 124. 2011. pp. e574-651. (This authoritative PCI guideline contains a nice section on the pharmacologic therapies of no-reflow, along with specific recommendations and tables (in the online supplement) summarizing studies of different coronary vasodilators during elective and primary PCI.)

Levine, GN, Bates, ER, Blankenship, JC. “2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions”. Circulation. vol. 124. 2011. pp. 574-651. (This authoritative PCI guideline contains a nice section on the pharmacologic therapies of no-reflow, along with specific recommendations and tables [in the online supplement] summarizing studies of different coronary vasodilators during elective and primary PCI.)

Nair, PK, Marroquin, OC, Mulukutla, SR. “Clinical utility of regadenoson for assessing fractional flow reserve”. JACC Cardiovasc Interv. vol. 4. 2011. pp. 1085-92. (Small prospective single-center study (n = 25) showing that a single IV bolus of regadenoson is as effective as an intravenous infusion of adenosine for measuring FFR.)

Marzilli, M, Orsini, E, Marraccini, P, Testa, R. “Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction”. Circulation. vol. 101. 2000. pp. 2154-9. (Small RCT [n= 54] showing that intracoronary adenosine administration is feasible and well tolerated in AMI, and that it ameliorates flow, prevents no-reflow and improves ventricular function after primary PTCA.)

De Luca, G, Venegoni, L, Iorio, S. “Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve”. JACC Cardiovasc Interv. 2011. pp. 41079-84. “Small single-center (n= 46) demonstrating that increasing doses of intracoronary adenosine progressively (up to 720 μg) decreased FFR values and increased the percentage of patients with abnormal FFR.”

Levine, GN, Bates, ER, Blankenship, JC. “2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions”. Circulation. vol. 124. 2011. pp. e574-651. (This authoritative PCI guideline contains a nice section on the pharmacologic therapies of no-reflow, along with specific recommendations and tables (in the online supplement) summarizing studies of different coronary vasodilators during elective and primary PCI.)

Taniyama, Y, Ito, H, Iwakura, K. “Beneficial effect of intracoronary verapamil on microvascular and myocardial salvage in patients with acute myocardial infarction”. J Am Coll Cardiol.. vol. 30. 1997. pp. 1193-9. (Small randomized study showing that intracoronary verapamil attenuated microvascular dysfunction and augmented myocardial blood flow in AMI patients undergoing primary angioplasty.)

Vijayalakshmi, K, Whittaker, VJ, Kunadian, B. “Prospective, randomized, controlled trial to study the effect of intracoronary injection of verapamil and adenosine on coronary blood flow during percutaneous coronary intervention in patients with acute coronary syndromes”. Heart. vol. 92. 2006. pp. 1278-84. (Small prospective RCT [n = 100] comparing intracoronary verapamil vs.adenosine vs. saline in ACS patients undergoing PCI, and demonstrating significant and comparable improvement in coronary flow and wall motion index with both verapamil or adenosine with more transient heart block occurring in the verapamil group.)

Huang, RI, Patel, P, Walinsky, P. “Efficacy of intracoronary nicardipine in the treatment of no-reflow during percutaneous coronary intervention”. Catheter Cardiovasc Interv. vol. 68. 2006. pp. 671-6. (Small study showing that intracoronary nicardipine is safe and highly effective in reversing no-reflow during PCI.)

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