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Ann Thorac Surg 2000;70:883-888
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Nitroglycerin is preferable to diltiazem for prevention of coronary bypass conduit spasm

^a Department of Cardiothoracic Surgery, Boston, Massachusetts, USA
^b Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA

Address reprint requests to Dr Shapira, Department of Cardiothoracic Surgery, Boston Medical Center, 88 E Newton St, Boston, MA 02118,
e-mail: oshapira{at}bu.edu

Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. Diltiazem is widely used to prevent radial artery spasm after coronary bypass grafting (CABG). However, recent in vitro and in vivo studies have shown that nitroglycerin is a superior conduit vasodilator compared to diltiazem. A clinical comparison of these agents in patients undergoing CABG has not been previously performed.

Methods. One hundred sixty-one consecutive patients undergoing isolated CABG with the radial artery were prospectively randomized to 24-hour intravenous infusion of nitroglycerin or diltiazem followed by 6-month treatment with a daily dose of isosorbide mononitrate (n = 84) or diltiazem CD (n = 77). Analyses were performed on "intention-to-treat" basis.

Results. Crossovers because of low cardiac output, complete heart block, or sinus bradycardia occurred in 5 patients in the diltiazem group and none in the nitroglycerin group (p = 0.05). Operative mortality (nitroglycerin, 1.2% versus diltiazem, 1.3%), major morbidity (14% versus 16%), perioperative myocardial infarction (1.2% versus 0%), peak serum creatinine phosphokinase MB fraction levels (27 versus 21 U), intensive care unit stay (34 ± 19 versus 38 ± 30 hours) and total hospital length of stay (4.7 ± 1.4 versus 4.7 ± 1.3 days) were similar (p = not significant for all). Cardiac pacing was required more often in the diltiazem group (28% versus 13%, p = 0.01). Follow-up longer than 2 months was available in 145 patients (90%). Follow-up mortality (nitroglycerin, 1.2%; diltiazem, 1.3%), myocardial infarction (6%, versus 5%), and reintervention (8% versus 6%) rates and average angina class (1.3 ± 0.7 versus 1.1 ± 0.4) were similar (p = not significant for all). Thallium stress test obtained in 117 patients showed abnormal perfusion in the radial artery territory in only 4 patients (3%), 2 in each group (p = not significant). Treatment with diltiazem was more costly ($16,340 versus $1,096).

Conclusions. Nitroglycerin is preferable to diltiazem for prevention of conduit spasm. Nitroglycerin is safe, effective, better tolerated, and less costly than diltiazem, and therefore, should be the agent of choice.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
The goal of coronary artery bypass grafting (CABG) is to provide with durable blood flow to all the territories of ischemic myocardium. The superior long-term patency rate of internal thoracic artery grafts compared with saphenous vein grafts is well documented [1]. Improved patency rates have been shown to translate into improved long-term survival and cardiac-related event-free survival [1]. Recently, several investigators have shown that the use of two internal mammary grafts, particularly when grafted into two left-sided coronary arteries, further improves long-term results, compared with use of a single internal mammary artery [2]. These observations triggered the usage of multiple arterial conduits for CABG.

The radial artery was first introduced as an alternative arterial conduit in the early 1970s, only to be abandoned shortly thereafter because of early graft failure related to accelerated intimal hyperplasia and vasospasm [3, 4]. The use of the radial artery was recently rejuvenated with encouraging early and midterm results attributable to modifications in harvesting techniques and routine prolonged administration of antispasmodic agents. With respect to the latter, diltiazem is the most frequently used agent [5–9].

However, recent in vitro and in vivo studies have shown that nitroglycerin is a superior conduit vasodilator compared to diltiazem [10–12]. Canver and colleagues [13] used ultrasonography and Doppler studies to document a strong vasodilatory response to oral nitroglycerin in both grafted and in situ internal mammary arteries. Gurevitch and colleagues [14] used long-acting nitrates for prevention of composite arterial conduit spasm in a small clinical study. However, a systematic comparison of nitroglycerin and diltiazem following CABG has not been performed. This study was designed to compare the efficacy and safety of nitroglycerin and diltiazem for prevention of arterial conduit spasm in a prospective randomized fashion.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Patients
A total of 161 consecutive patients undergoing isolated CABG using the radial artery at Boston Medical Center between January 1998 and May 1999 were provided with informed consent and were enrolled. Four patients over the same time period declined enrollment. Patients undergoing concomitant valve or other procedures were excluded. Patients were then randomized by means of the last digit of their medical record number to 24-hour intravenous infusion of either nitroglycerin (American Regent Laboratories, Inc, Shirley, NY; n = 84) or diltiazem (Baxter Healthcare Corp, Deerfield, IL; n = 77), followed by 6 months of treatment with a daily extended-release isosorbide mononitrate (Imdur, Warrick Pharmaceuticals Corp, Reno, NV) or diltiazem CD (Cardizem CD, Hoechst, Marion, Roussel, Inc, Kansas City, MO), respectively. The study was approved by the Boston Medical Center Institution Review Board.

Surgical technique
All operations were performed using near-normothermic (34°C) cardiopulmonary bypass with heparin-bonded circuits. Distal anastomoses were performed during a single aortic-cross clamp period. Myocardial protection was achieved using cold antegrade and retrograde blood cardioplegia enhanced with topical cooling (4°C saline).

Drugs
For patients randomized to diltiazem, a loading dose (0.1 mg/kg during 20 minutes) followed by an intravenous infusion (0.1 mg · kg^-1 · min^-1) was started after induction of anesthesia. On the first postoperative day a short-acting oral diltiazem (diltiazem HCl, Blue Ridge Laboratories, Inc, Kansas City, MO) replaced the infusion using four daily divided doses. If the drug was well tolerated (normal sinus rhythm, stable hemodynamics), the long-acting preparation was given once a day for 6 months at the same daily dose as the short- acting agent. For patients randomized to nitroglycerin, a continuous intravenous infusion of 0.1 µg · kg^-1 · min^-1 was started after induction of anesthesia without any loading dose. The infusion rate was adjusted to maintain a mean systemic blood pressure of 60 to 80 mm Hg. After 24 hours, a short-acting oral isosorbide dinitrate (Isordil, Geneva Pharmaceuticals, Inc, Broomfield, CO) replaced the intravenous infusion in three divided doses with the total daily dose equivalent to a 24-hour infusion. If the drug was well tolerated (stable blood pressure without orthostatic hypotension, no headache), the long-acting preparation (Imdur) was prescribed daily for 6 months at an equivalent daily dose. Patients not tolerating their originally assigned medication (ie, hypotension, low cardiac output, conduction system abnormalities) crossed over to the other medication.

Data collection
All patients underwent a medical history and physical examination. Clinical data were collected from the medical record by personnel not familiar with the randomization scheme. Data included age and gender, Canadian Cardiac Society angina class, elective/nonelective nature of the operation (nonelective operation was defined as an operation that had to be performed immediately after or within a few hours after catheterization), history of previous CABG, and clinical history of hypertension, diabetes mellitus, previous cerebral vascular accident, and previous myocardial infarction. The extent of coronary artery disease (number of major vessels with a percent stenosis 50%) and left ventrintensive care unitlar ejection fraction were recorded from the preoperative cardiac catheterization. Operative details were also recorded including total number of grafts, number of arterial grafts, use of the internal mammary artery, cardiopulmonary bypass time, and aortic cross-clamp time.

Short-term follow-up
We used The Society of Thoracic Surgeons guidelines to define postoperative morbidity and mortality. Clinical events that occurred within 30 days of operation (or within the same admission if the patient remained hospitalized for more than 30 days) were recorded including: (1) death from any cause, (2) postoperative myocardial infarction (defined as a new Q wave recorded in the 12-lead electrocardiogram, creatinine phosphokinase (CK) MB fraction more than 50 U, or a new permanent wall motion on echocardiogram, (4) occurrence of atrial fibrillation of any duration, (5) postoperative cerebral vascular accident (defined by clinical history and computed tomography scan of the brain, (6) reoperation for bleeding, (7) use of cardiac pacing, and (8) use of inotropic drugs (dopamine > 2 µg · kg^-1 · min^-1, dobutamine, milrinon, and epinephrine). The decision to initiate cardiac pacing or inotropic support was based on established practice guidelines for care of postoperative patients and was made by personnel aware of the treatment assignment. Other recorded measurements included duration of ventilator support, length of intensive care unit stay, and length of hospitalization, and total serum levels of CK and CK-MB, which were measured routinely upon arrival to the intensive care unit, and 8 and 16 hours later. Additional serum CK levels were obtained only if clinically indicated.

Long-term follow-up
Long-term follow-up was achieved by direct telephone contact with the patient, the family, and the primary care physician at three time points—2 months, 6 months, and 1 year postoperatively. Follow-up data included (1) total mortality, (2) operative-related complications, (3) myocardial infarction, (4) angina class using the Canadian Cardiovascular Society classification, (5) cardiac reintervention, (6) a thallium-201 stress test performed 3 to 6 weeks after the operation by a cardiologist who was blinded to the treatment assignment, and (7) cost analysis based on the actual hospital pharmacy cost for a 6-month treatment regimen of the respective drugs.

Statistical analysis
On the basis of our previous observational study [9], the present study was planned to have 80% power to detect an increase in the need for postoperative cardiac pacing from 20% to 40% in patients treated with diltiazem with a sample size of 150 patients ( = 0.05).

The principal end points of the study include major adverse cardiac events such as mortality, major morbidity, myocardial infarction, use of inotropic agents, and reintervention. Major morbidity was defined as all postoperative major complications excluding uncomplicated atrial fibrillation (eg, myocardial infarction, cerebral vascular accident, reoperation for bleeding, major respiratory complications, sternal infection). Reintervention was defined as the need for diagnostic cardiac catheterization, percutaneous transluminal angioplasty, or repeat CABG. The secondary end points include incidence of cardiac pacing, CK levels, ventilator support, length of intensive care unit and hospital stay, abnormal perfusion in the radial artery territory in the thallium-201 scan, and cost.

Data were analyzed on an "intention-to-treat" basis. Data are expressed as mean ± standard deviation or as absolute number with percentage. The two-tailed Student’s t test was used to analyze continuous variables. Categorical variables were analyzed using ² with Yate’s correction or Fisher’s exact test when appropriate.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Patient characteristics
A total of 161 patients enrolled into the study. Eighty-four patients were randomized to receive nitroglycerin and 77 to receive diltiazem. Crossovers because of hemodynamic or conduction side effects occurred in 5 patients in the diltiazem group and none in the nitroglycerin group (p = 0.05). Two patients with low left ventricular ejection fraction had persistent low cardiac output (cardiac index. < 2.0 L/min) that required inotropic support and resolved after switching to nitroglycerin. Three patients required prolonged cardiac pacing because of heart block (2 patients) or severe sinus bradycardia (1 patient). These conduction abnormalities resolved after switching to nitroglycerin. The patient characteristics are listed in Table 1 and demonstrate that the two treatment groups were well-matched with respect to clinical variables known to influence operative outcome. The two groups also received comparable operations and these data are listed in Table 2.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Single or bilateral internal mammary arteries have become the conduits of choice for coronary revascularization because of the well-established superior long-term patency rates and improved long-term clinical outcomes, compared to saphenous vein [1, 2]. However, the use of bilateral internal mammary arteries may be medically contraindicated in some patients, and even when used as composite grafts, two internal mammary arteries may not be sufficient to allow complete arterial revascularization. Thus, other arteries have been extensively evaluated as alternative conduits for CABG.

The radial artery is an attractive arterial conduit for CABG for several reasons. First, it is easy to harvest in parallel with the internal mammary artery. In addition, there is often sufficient length to allow grafting of any target vessel. Finally, the radial artery caliber is well-matched to that of most coronary arteries and its thick muscular wall affords easy surgical handling [5–9]. Recent studies also suggest improved inherent physiologic properties of the radial artery, similar to those of the internal mammary artery [15]. Thus, single and bilateral radial arteries are increasingly used as the second arterial conduit of choice (after the internal mammary artery) with encouraging early and midterm results [3–9, 16–20].

The major disadvantage of the radial artery is its propensity for vasospasm documented both clinically [3–5, 16–20], and in studies using organ-chamber methodology [21, 22]. Enhanced reactivity of the radial artery to norepinephrine, serotonin, angiotensin II, and endothelin I compared to internal mammary artery has been documented in vitro [21, 22]. Clinical and angiographic (eg, the "string" sign) evidence of radial artery spasm are well recognized [3–9, 16–20]. Thus, most surgeons (although not all [8]), emphasize the necessity for pharmacologic intervention to prevent vasospasm when these conduits are used [5–9, 16–20]. The drug of choice to prevent vasospasm is still a matter of controversy.

The calcium channel antagonist diltiazem has been empirically selected by most surgeons [5–9, 16–19]. Diltiazem belongs to the benzothiazepine group of calcium channel-blocking agents [23]. All calcium antagonists bind to the _1c subunit of the L-type calcium channel, which is the main pore-forming unit of the channel [23]. The L-type calcium channel is present in cardiac muscle, vascular smooth muscle, nonvascular smooth muscle, and other tissues. Blockage of L-type channels in vascular tissues results in relaxation of vascular smooth muscle and vasodilation [23]. L-type channel blockage in the heart, however, results in negative inotropic and chronotropic effects [23]—a distinct disadvantage after CABG. Thus, up to 30% to 40% of patients undergoing CABG and treated with diltiazem may experience hypotension, bradycardia, or heart block requiring a reduction in dose, discontinuation of the drug, or temporary pacing [6, 9]. Moreover, use of diltiazem does not completely eliminate spasm. In early and midterm angiographic studies radial artery spasm was identified in 1% to 9.7% [5, 16–20]. Also, 6 months after the operation only 40% to 60% of patients were still compliant with the drug [6, 9]. These clinical observations triggered the evaluation of the effect of other antispasmodic agents on the radial artery.

Cable and colleagues [10] demonstrated that diltiazem and verapamil had little effect on radial artery receptor-dependent and receptor-independent contraction, whereas nifedipine and nitroglycerin were much more effective. In another study, He [24] demonstrated that the use of verapamil and nitroglycerin solution to prepare the radial artery grafts maximally preserves endothelial function. Spreti and colleagues [11] studying patients after CABG and documented severe serotonin-induced radial artery vasospasm despite treatment with diltiazem that was completely reversed with intracoronary nitroglycerin administration. Recently, we have shown that nitroglycerin is a much more potent vasodilator of the radial artery than diltiazem [12], both in vitro and in vivo. We also found these observations applied equally to other CABG conduits such as the internal mammary artery and saphenous vein. This experimental data suggested that nitroglycerin should be considered in place of diltiazem for the prevention of radial artery spasm. However, clinical data to support this position were lacking. The present study extends these basic observations to the clinical arena, demonstrating that nitroglycerin produces equivalent or better outcomes in patients undergoing radial artery bypass grafting.

Principal in-hospital and follow-up clinical end points such as mortality, major morbidity, myocardial infarction, use of inotropic agents, the need for cardiac catheterization, and reintervention were equivalent between the study groups. Also similar were the secondary end points of peak serum CK levels, intensive care unit stay, and total hospital length of stay. However, nitroglycerin was much better tolerated than diltiazem in the immediate postoperative period. In 5 patients, diltiazem had to be switched to nitroglycerin because of low cardiac output or conduction abnormalities. There were no crossovers from nitroglycerin to diltiazem. Also, cardiac pacing was required significantly more often in patients treated with diltiazem, although implantation of a permanent pacemaker was not necessary. Finally, nitroglycerin was not only effective and safe, but also much less costly. Six-month treatment with diltiazem was 16-fold more costly than nitroglycerin.

Study limitations
Several factors in the study design might have introduced bias. Patients were randomized by their last digit of the medical record as opposed to a computer-generated random number technique. This resulted in 7 more patients in the nitroglycerin group. Also, the decision to initiate inotropic support or cardiac pacing was made by personnel aware of the treatment assignment. Finally, midterm follow-up was available for only 90% of patients at 2 months and 38% at 12 months.

As described in the Patients and Methods section the study population size was based on the risk of cardiac pacing. Overall clinical outcomes (both in-hospital and long-term) were very good, with very low complication rates in both groups. Thus, it is possible that the study population was too small to detect small but significant differences in clinical outcomes between the groups.

One potential limitation of this study was the lack of routine coronary angiography. Coronary angiography remains the gold standard to assess graft patency. In the current era, however, it is very difficult to justify coronary angiogrpahy for study purposes only. Therefore, a thalium-201 stress test was used as a corollary to evaluate graft patency. We found a very low rate of abnormal perfusion to the radial artery territory in both groups, confirming other studies reporting early radial artery angiographic patency of 90% to 95% [7, 16–20].

A major potential limitation of the use of nitrates is the well-known phenomenon of nitrate tolerance, the cause of which remains unclear [25]. It is not related to altered pharmacokinetics, because drug plasma levels remain the same or even higher after prolonged use compared with the initial therapy [26]. Although it is clear that loss of some hemodynamic effects invariably occurs, other vascular effects persist during therapy, and abrupt cessation of treatment may be associated with withdrawal symptoms [25]. Similar to the variability of different vessel responses to nitroglycerin, there are differences in the susceptibility of veins, arteries, and arterioles to develop nitrate tolerance, and that arterial or arteriolar response may persist although venous tolerance exists [15, 27]. Recent ultrasonographic studies in young individuals treated with high-dose nitrates suggested that nitroglycerin tolerance might not affect the brachial artery [28]. Currently, the most effective strategy to avoid or minimize the degree of tolerance development is to use regimens that provide for a protracted nitrate-free interval each day. To address this issue we have used in this study a single daily dose of the long-acting preparation isosorbide mononitrate that when taken in the morning, delivers high nitrate levels during the day with a low nitrate interval during the night. Plasma nitrate levels increase rapidly during the first hour after dosing, peak at 4 hours, and gradually decrease to the nadir 24 hours after administration. Chrysant and colleagues [29] documented the safety of this protocol, reporting no exercise test decrements occurring immediately before the next dosing in patients with angina. This regimen may be particularly useful given the well-known circadian variation of myocardial ischemic events with increased incidence during the morning hours related to increased sympathetic drive and other factors [30].

In summary, given the in vitro and in vivo experimental data and the clinical data from this study, we conclude that nitroglycerin compares favorably with diltiazem in the prevention of conduit spasm. Nitroglycerin also offers the advantage of a reduced side effect profile and less cost than diltiazem. On the basis of these observations, we submit that nitroglycerin is the agent of choice in the prevention of coronary bypass conduit spasm.

	References

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