Author + information
- Received April 28, 1999
- Revision received November 12, 2000
- Accepted December 20, 2000
- Published online April 1, 2001.
- William B Hillegass, MD, MPH∗,
- Neal A Dean, BA†,
- Laurence Liao, MD†,
- Rodney G Rhinehart, MD† and
- Paul R Myers, MD, PhD, FACC, FSCAI†,*
- ↵*Reprint requests and correspondence:
Dr. Paul R. Myers, Division of Cardiology, MRBII, Rm. 358, Vanderbilt University, 23rd Ave. S. and Pierce Streets, Nashville, Tennessee 37232-6300
The objective of this study was to test the hypothesis that the intracoronary administration of a direct donor of nitric oxide is a safe and effective method to treat impaired blood flow (no-reflow phenomenon) that occurs during percutaneous transluminal coronary interventions (PTCI).
The absence of blood flow or decreased blood flow in a coronary artery following PTCI despite the presence of a patent epicardial vessel or graft is designated “no-reflow” or “impaired flow.” This alteration in blood flow is a serious complication of percutaneous revascularization strategies that results in an increased incidence of morbidity, myocardial infarction and mortality.
Nineteen consecutive patients undergoing standard percutaneous revascularization procedures complicated by either no-reflow or impaired flow that received intracoronary nitroprusside treatment were studied. One patient had two procedures performed on two separate grafts on two successive days. Interventions were performed on either saphenous vein grafts or native vessels and utilized angioplasty, stent deployment or rotational atherectomy strategies. Following interventions that were associated with impaired flow, varying total doses (of nitroprusside 50 to 1,000 μg) were administered into the coronary artery or saphenous vein graft. The angiographic archives before and after intracoronary administration of nitroprusside were analyzed for TIMI grade flow and a frame count method was used to quantitate blood flow velocity.
Following a PTCI that resulted in either no-reflow or impaired flow, nitroprusside (median dose 200 μg) was found to lead to a highly significant and rapid improvement in both angiographic flow (p < 0.01 compared with pretreatment angiogram) and blood flow velocity (p < 0.01 compared with pretreatment angiogram). No significant hypotension or other adverse clinical events were associated with nitroprusside administration.
The direct nitric oxide donor nitroprusside is an effective, safe treatment of impaired blood flow and no-reflow associated with PTCI. The use of nitroprusside to treat syndromes secondary to microvascular dysfunction may provide a novel therapeutic strategy for treating no-reflow or impaired blood flow following percutaneous interventions.
The “no-reflow” phenomenon has been conventionally described as the persistence of abnormally slow myocardial blood flow in the absence of an angiographically significant coronary artery or vein graft obstruction (1). The phenomenon encompasses states of no flow as well as significantly impaired blood flow. Originally observed in animal models of myocardial infarction, the phenomenon has been observed clinically after percutaneous coronary interventions (PTCI) (1,2). Patients who experience no-reflow or impaired blood flow following PTCI have an increased risk of subsequent myocardial infarction and death (1,2)and can experience increased morbidity during the procedure.
An efficacious treatment of compromised blood flow associated with PTCI remains problematic. Several approaches to the problem have been published, including intracoronary or intragraft injections of verapamil, nitroglycerin, diltiazem, urokinase, abciximab, intra-aortic balloon pumps and papaverine (1–7)or high-velocity injections of intracoronary adenosine (8). Despite some positive results, no-reflow or impaired flow remains a serious problem for PTCI, especially when revascularizing saphenous vein grafts.
The exact mechanisms underlying this clinical condition are not known, but more recent evidence suggests that no-reflow or slow flow is due to dysfunction of the microcirculation at the level of the resistance arterioles. To this end, the no-reflow phenomenon may stem from microvascular dysfunction and vasospasm in this vascular bed due to platelet-derived vasoconstrictors and/or systemic and local release of agents such as endothelin that induce vasospasm. Alternatively, antegrade resistance to arteriolar flow may be compromised by mechanical obstruction from emboli originating from material dislodged from the target vessel.
Nitric oxide is an endothelium-derived compound that has multiple vascular functions, including vasodilation, inhibition of platelet adhesion and anti-inflammatory activity. Nitric oxide is a potent vasodilator in the resistance arteriolar circulation (9)and plays a significant role in the control of coronary blood flow through the microcirculation (10). Although nitrates have traditionally been used as donors of nitric oxide to maximally dilate coronary arteries, significant differences between epicardial arteries and resistance arterioles have been described with respect to the metabolism of exogenous nitrates (11). Metabolism of nitroglycerin by the vascular wall is necessary to derive nitric oxide. However, resistance arterioles are unable to metabolize nitroglycerin to nitric oxide as do large nonresistance vessels (12), and nitroglycerin is relatively less efficacious in eliciting dilation in microvessels compared with large, epicardial vessels. On the other hand, nitroprusside (NTP) is a direct donor of nitric oxide and is reported to require no intracellular metabolism to derive nitric oxide (13). Therefore, we hypothesized that NTP may be efficacious for the treatment of no-reflow primarily through its action as a nitric oxide donor and vasodilation of microvessels. This study reports our initial clinical experience in 20 consecutive percutaneous coronary interventions complicated by no-reflow phenomenon where intracoronary NTP, as a direct nitric oxide donor, was administered.
The interventional procedure databases at the Nashville Veterans Administration Medical Center (VAMC) and Vanderbilt University Medical Center (VUMC) were screened for cases performed between July 1997 and May 1998 with occurrence of no-reflow or impaired flow and the use of intracoronary NTP. Screening these databases identified 20 procedures where 19 patients had received intracoronary NTP for no-reflow. One patient had two procedures done on separate grafts on successive days. To avoid selection bias, consecutive patient cases were analyzed. The cineangiograms or digital archives were subsequently reviewed to confirm the absence of dissection, thrombosis or macroembolization as the explanation for slow coronary flow.
For each of these cases, supplemental demographic and procedural data were recorded. Demographic data included date of birth, gender and race. Preprocedural factors collected were diabetes (insulin-dependent or noninsulin-dependent), prior coronary artery bypass grafting and procedure indication (including angina, acute myocardial infarction, postinfarction angina and silent ischemia). Procedure devices used and pharmacological interventions (drug, delivery, time of delivery and dosage) were recorded.
Impaired blood flow was defined as a reduction in antegrade blood flow (<Thrombolysis In Myocardial Infarction [TIMI] III, thrombolysis in myocardial infarction) following PTCI that was not secondary to abrupt closure, spasm or significant stenosis of the original target lesion (1). All cineangiograms or digital archives were taken at a speed of 15 frames/s. Films from the VAMC were reviewed on the digital system (Camtronics Medical Systems, Hartland, Wisconsin) with its built-in frame counter (also at 15 frames/s) whereas films from VUMC were reviewed on a cineangiogram projector with a frame counter. At least two angiographers assessed each angiogram for modified TIMI grade flow (with the additional division of TIMI II flow into “slow” and “fast” grades) and for quantitative frame counts to maximal opacification of distal landmarks. The two readers each graded the flows as TIMI-0, TIMI-1, TIMI-2 slow, TIMI-2 fast or TIMI-3 flow. The results were averaged using 0, 1, 2, 2.5 and 3, respectively. Frame counts were divided into measured distances for calculation of absolute flow velocities in cm/s. The vessel length was measured with calipers calibrated from the known guide catheter diameter. The least foreshortened view was selected for the cine pairs to measure frame counts before and after NTP administration. Observers assessed flow at baseline prior to intervention, before and after intracoronary or intragraft NTP injections and at the completion of the intervention. The percent change in coronary flow velocity was determined by the formula: where VF= flow velocity measured in cm/s.
Data were also normalized according to the following method: The VFat initial, during no-reflow, post-NTP and at the final angiogram were divided by the maximal VFmeasured at any point during the study. The purpose of normalization was to eliminate variance between the absolute flow rates observed between patients so that each patient would receive equal weighting in the analysis.
The American College of Cardiology/American Heart Association lesion morphology classification was collected. Pre-and postintervention visual percent stenoses were estimated as well as whether the no-reflow was transient or sustained at the end of the procedure.
Patients were continuously monitored during all procedures. Heart rates and blood pressures recorded before and after administration of NTP were determined. The data regarding any effects of intravessel NTP were analyzed to ascertain adverse clinical effects on cardiac hemodynamics.
Management of impaired flow and no flow
All patients received intravessel NTP for treatment of both no-reflow and impaired flow at a dose of at least 50 μg given distal to the target lesion via the angioplasty balloon lumen or, alternatively, through the guide catheter. In general, drug was delivered distal to where there was no apparent angiographic flow via the angioplasty balloon lumen. Drug could be delivered more proximally in slow states. Twenty-seven doses were administered through the guiding catheter; 16 were given distally. Four patients also received other pharmacological interventions, including intracoronary adenosine and/or verapamil, for refractory no-reflow.
The time from cineangiogram documenting no-reflow to NTP dose was a median of 5 min (range 1 to 20 min, mean 7.3 min) and the time from NTP to follow-up cineangiogram was a median of 2 min (range 0.5 to 31 min, mean 3.9 min). The total time between the cineangiogram documenting no-reflow and the post-NTP angiogram was a median of 7 min.
Discrete variables are presented as percentages and continuous variables as means with standard deviations. The normalized coronary flow velocities were analyzed on initial angiogram, during no-reflow, post-NTP and at the final angiogram.
The normalized flow velocity effects of NTP on impaired flow (no-reflow) and TIMI flow grades were compared using repeated-measures analysis of variance. The subsets of patients with greater than TIMI 0 and TIMI 1 flow were also analyzed to help separate the effects of improvement in coronary flow velocity due to treatment of no-reflow or impaired flow with NTP from that secondary to treatment of the initial total or subtotal occlusion.
Multivariate logistic regression analysis was performed to determine if the NTP dose, delivery method, other medications and time from NTP dose to postcineangiogram were significant independent predictors of the observed change in normalized coronary flow velocities.
Statistical significance was defined as p < 0.05. Statistical analyses were performed using the SPSS (Chicago, Illinois) program.
Study population characteristics
The clinical and procedural characteristics of the patients in whom NTP was administered for no-reflow are shown in Table 1. The target lesion was in a native vessel in 60% of the procedures analyzed, whereas 40% of the procedures were in saphenous vein grafts. Three patients were treated for impaired blood flow following PTCI during an acute myocardial infarction (15%), with the remainder undergoing revascularization for stable angina, unstable angina or postinfarction angina. Most of the revascularization procedures were primary stent deployment (70%). In 16 out of the 20 procedures, the patients received prophylactic abciximab therapy. No patient received “bail-out” abciximab.
The dosing characteristics for either intracoronary or intragraft administration of NTP are summarized in Table 2. The median injection dose was 200 μg of drug with a mean of 2.2 injections per patient for a total of 43 injections. In the majority of cases (63%), drug was given via the guiding catheter with the remainder given distally through the lumen of the angioplasty balloon.
Effects of NTP on no-flow and impaired flow
Percent change in coronary flow velocity comparing pre- and post-NTP treatment
The results of intravascular NTP administration on coronary blood flow velocity (VF, cm/s) (measured using a frame count analysis method; see methods section) were analyzed as the percent change in VFfrom no-reflow to post-NTP treatment for each vessel treated (Fig. 1). In 14 of the 19 patients, there was a positive response to NTP, whereas 5 of the 19 (25%) were nonresponders (Fig. 1). Nitroprusside resulted in a mean 47% (95% CI: 28% to 67%; p = 0.003) improvement in coronary flow velocity (Table 3). In the analysis of the data examining each target vessel injection there was a mean 43% (95% CI: 21% to 65%; p = 0.002) improvement in coronary flow velocity (Table 3).
The effect of NTP on blood flow velocity was not significantly different between graft versus native vessel, atherectomy versus nonatherectomy procedure, or preprocedural angiographic evidence of thrombus being present versus absent by multivariate logistic regression analysis.
Normalized coronary blood flow velocity at the initial angiogram, the angiogram during impaired flow, the angiogram post-NTP and the final angiogram
The absolute coronary flow velocity was determined at the initial angiogram, the angiogram during impaired flow (no-reflow), the angiogram taken post-NTP and at the final angiogram. Because of variability in the absolute flow rates between patients, the VFfor each patient was normalized by dividing the four observed flow velocities by the maximal velocity observed at any point in the procedure. Twelve of nineteen patients had maximal flow at the final angiogram, six of nineteen had maximal flow at the post-NTP angiogram, and one of twenty had maximal flow at the initial angiogram. Normalization allowed expression of the flow velocity as a ratio between 0 and 1 for each time point in each procedure.
Nitroprusside at the final angiogram had elicited a significant improvement in VFby angiographic analysis that was highly significant compared with flow during the initial angiogram and the state of impaired flow or no-reflow (Fig. 2, solid bars; n = 19): initial versus post-NTP, p = 0.04; initial versus final, p = 0.003; impaired flow versus final, p = 0.003; post-NTP versus final, p = 0.017.
Figure 2(hatched bars; n = 15) also presents the data excluding the four patients with no flow at the initial angiogram to separate the possible confounding effect of treatment of the initial lesion on observed flow. There was a significant improvement in VFby angiographic analysis following NTP at the final angiogram compared with initial angiogram and the no-reflow angiogram: initial versus final, p = 0.05; impaired flow versus post-NTP, p = 0.043; impaired flow versus final, p = 0.016. Data were analyzed using analysis of variance for repeated measures.
Of the 19 consecutive patients, one had two procedures done on different saphenous vein grafts (graft to posterior descending artery and graft to obtuse marginal artery) on two consecutive days. We therefore submitted these data to an identical analysis, except as 20 consecutive procedures. As with the per-patient analysis, the per-procedure analysis showed that NTP at the final angiogram had elicited a significant improvement in VFthat was highly significant compared to flow during the initial angiogram, flow during the impaired flow or no-reflow state and post-NTP (data not shown).
TIMI flow rate analysis
Analysis of TIMI flow rates showed a significantly enhanced TIMI grade flow comparing no-reflow to the angiogram post-NTP administration (Fig. 3). Examination of TIMI flow rates at the initial angiogram, impaired flow angiogram (no-flow), post-NTP angiogram and final angiogram demonstrated the confounding effect of the initial lesion severity on observed TIMI flow, as seven patients had either TIMI 0 or TIMI 1 flow on the initial angiogram. Therefore data are presented with and without four patients who had TIMI 0 flow at the initial angiogram (Fig. 3)and also as only those patients with TIMI 2 or higher flow at the initial angiogram (Fig. 4).
In the analysis of all 19 patients, NTP elicited a significant increase in TIMI grade flow (Fig. 3, solid bars): initial versus post-NTP, p = 0.013; initial versus final, p = 0.011; no-reflow versus post-NP, p = 0.001; no-reflow versus final, p = 0.001.
In the analysis that excluded procedures with an initial TIMI grade 0 flow, NTP significantly improved TIMI grade blood flow (Fig. 3, hatched bars; n = 15): no-reflow versus post-NTP, p = 0.004; no-reflow versus final, p = 0.009. Data were analyzed using analysis of variance for repeated measures.
Similar to the normalized flow velocity analysis, we submitted the data to both a per-patient analysis and a per-procedure analysis. Nitroprusside at the final angiogram had elicited a significant improvement in TIMI grade flow that was highly significant compared with flow during the initial angiogram, flow during the impaired flow or no-reflow state, and post-NTP (data not shown).
Data were analyzed in those patients with TIMI 2 or higher flow at the initial angiogram (Fig. 4). Nitroprusside had an extremely significant beneficial effect on reestablishing blood flow following the “no-reflow” or impaired flow state (impaired flow compared to post-NTP and final angiograms for patients with ≥TIMI 2 grade flow at the initial angiogram, p = 0.001 and 0.008, respectively). There was a significant decrease in TIMI flow between the initial angiogram and the impaired, no-reflow state (p = 0.03).
Four patients received another pharmacologic agent for impaired blood flow in addition to intracoronary NTP, excluding intracoronary nitroglycerin. Although this sample size of additional agents is too small to draw definitive conclusions, they did not have a significant, independent effect on coronary flow velocity in multivariate logistic regression analysis. Similarly, dose and site of delivery did not have a significant independent relationship with change in normalized coronary flow velocity.
Hemodynamic effects of NTP
Analysis of the hemodynamic data showed no evidence that NTP significantly altered patient blood pressure and heart rate at the doses used (50 to 200 μg per injection) (Table 4). The clinical dose of NTP used was operator-determined on the basis of blood pressure and volume status of the patient. The hemodynamic responses of all patients, together with blood pressures and heart rates, were collected at least 10 min before NTP injection and no later than 30 min postinjection.
Reduced or absent blood flow associated with PTCI is a common and serious complication of percutaneous revascularization strategies, especially those associated with older saphenous vein grafts. Either impaired flow or the absence of flow has been demonstrated to be associated with an increased incidence of myocardial infarction and death (1). Our results suggest a novel therapeutic strategy to treat impaired flow based upon the known actions of nitric oxide on the microvasculature. The principal finding reported in this study was that intravascular administration of a direct donor of nitric oxide markedly decreased the severity of clinically significant, refractory no-reflow associated with percutaneous revascularization.
The treatment of altered blood flow associated with PTCI has primarily utilized direct smooth-muscle vasodilators with varied mechanisms of action, including adenosine, nitroglycerin and calcium antagonists. Kaplan et al. (6), in a study of 36 saphenous vein grafts, found that verapamil was an effective therapy for no-reflow whereas nitroglycerin was not effective in reestablishing flow. Piana et al. (2)also reported that verapamil was effective in improving no-reflow in 89% of cases. Verapamil has also been reported to exert a beneficial effect on microvascular function in low reflow states and enhance myocardial blood flow following a myocardial infarction (14). More recently, high velocity boluses of intracoronary adenosine have been reported to effectively treat no-reflow following vein graft stenting (8).
Coronary blood flow is primarily determined by the resistance-sized arterioles <150 microns in diameter (15). Furthermore, significant differences have been reported between vasomotion of large versus small, resistance-sized arterioles (16). Although the pathophysiology of no-reflow is not exactly known, it is characterized by the failure of perfusion of the coronary microcirculation. Current evidence suggests that no-reflow may represent the complex interaction between abnormal vasomotion of microvessels associated with preexisting atherosclerosis (17–19)and endothelial cell dysfunction in the microcirculation (20). Compromised coronary blood flow in the setting of this underlying pathophysiology may be exacerbated by the release of vasoactive agents from conduit vessels following barotrauma or debulking, activation of inflammatory cells and “showering” of obstructive emboli. Nitric oxide is endogenously produced by the vascular endothelium and has multiple biological actions potentially relevant to no-reflow, including its ability to act as a potent vasodilator, anti-inflammatory agent, and antiplatelet agent (18,21–23). Thus, NTP, a direct nitric oxide donor, may importantly alter the pathophysiology underlying the no-reflow phenomenon. Furthermore, nitric oxide could positively affect latent collaterals or collateral blood flow by eliciting vasodilation (24)or inhibit platelet aggregation in the vascular bed distal to the target lesion.
The central hypothesis tested here, to ascertain if nitric oxide is an effective treatment of no flow or impaired blood flow associated with PTCI, was founded upon previous work comparing the actions of nitroglycerin and NTP in coronary resistance microvessels. Prior studies with intracoronary nitroglycerin may have failed to demonstrate efficacy of the compound as an effective treatment of no-reflow because of the relative inability of resistance arterioles to metabolize nitroglycerin to a nitric oxide or nitrosyl product. This is in contradistinction to the potent vasodilator effects of nitroglycerin on large epicardial arteries. Experimental results have demonstrated that nitroglycerin is a less efficacious dilator of coronary arterioles <100 μM in diameter (17). Therefore, NTP offers an advantage by directly delivering nitric oxide without requiring metabolic processing by the microvascular smooth muscle cells. Compounds with lower oxidation states, such as NTP, release nitric oxide nonenzymatically (11)and offer an advantage over compounds that require enzymatic conversion. An alternative explanation is that the relative efficacy of nitroglycerin as a vasodilator of resistance arterioles may be impaired by autoregulatory effects characteristic of the microcirculation that compensates for nitroglycerin-induced vasodilation (25,26).
This initial clinical observation has several limitations. First, the use of intracoronary NTP was at the discretion of the operator, so there was no consistent dose, site of delivery, time period between cineangiographic injections or recording of blood pressure and heart rate. Thus, concentration response data were not gathered. Second, because this was a retrospective analysis, treatment was not randomized or compared to placebo or another agent. Third, the patients studied are heterogeneous as to the clinical condition for intervention, site of intervention and devices used. The sample size is not adequate to identify clinical settings where NTP is particularly effective or ineffective in reversing no-reflow. Because of the study population size, multivariate analysis may not accurately ascertain if the NTP dose, delivery method, other medications and time from NTP dose to final angiogram are independent predictors of changes in flow velocity. Further data may be needed. The statistical results were identical whether the data were analyzed per patient or per procedure, because one patient had two procedures on two separate grafts on two separate days. Despite these study limitations, the data do suggest that a direct nitric oxide donor such as NTP may be an effective treatment strategy for no-reflow.
The data presented here support the hypothesis that the direct nitric oxide donor NTP is a safe and efficacious agent to treat no-reflow. It remains to be determined if the therapeutic application of nitric oxide biology to no-reflow will result in lower cardiac enzyme levels or survival benefit. Of importance, NTP in doses that do not adversely affect blood pressure appears particularly effective in the treatment of no-reflow in both vein grafts and native coronary arteries undergoing percutaneous revascularization procedures.
The authors are indebted to Briggita Brott, MD, FACC, Vijay Misra, MD, FACC, and Gregory Chapman, MD, FACC, University of Alabama, Birmingham, for their contribution of cardiac catheterization data used in this study.
The authors are indebted to Daniel W. Byrne, Director of Biostatistics and Study Design, General Clinical Research Center, Vanderbilt University Medical Center, Nashville, Tennessee, for his critique of the statistical analyses and design and the interpretation of the results.
- percutaneous coronary interventions
- Thrombolysis In Myocardial Infarction
- Veterans Administration Medical Center
- flow velocity
- Vanderbilt University Medical Center
- Received April 28, 1999.
- Revision received November 12, 2000.
- Accepted December 20, 2000.
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