Correspondence
Preinfarction Angina
N Engl J Med 1996; 335:59-61July 4, 1996
- Article
To the Editor:
Before medical professionals consider changing their practice of administering thrombolytic agents on the basis of the presence or absence of preinfarction angina, as is suggested by Andreotti et al. (Jan. 4 issue),1 we feel obligated to comment on their study and present more recent data disputing their findings. The study involved a small number of patients (23) treated between 1987 and 1989 and used a less effective regimen of tissue plasminogen activator (t-PA) than is currently used. Nevertheless, after 90 minutes of treatment they obtained a flow of grade 3 (according to the Thrombolysis in Myocardial Infarction [TIMI] classification) in the infarct-related arteries of 86 percent of their patients with preinfarction angina and 73 percent of patients overall — levels of success not achieved in a large-scale study of myocardial infarction.2 One cannot determine whether these angiographic results affected clinical outcomes. In contrast, the first Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial (GUSTO-1) was a large, randomized, prospective study involving four thrombolytic strategies in patients with acute myocardial infarction,3 and it included an angiographic substudy.2 To determine whether preinfarction angina of either recent (seven days or less) or remote (more than seven days) onset affected angiographic and clinical outcomes, we reviewed the clinical and angiographic core laboratory results of the GUSTO study (Table 1Table 1
TIMI Grade 3 Flow and Mortality in Patients with No History of Angina, Angina of Recent Onset, or Angina of Remote Onset.).Our data on substantially more patients than were studied by Andreotti et al. show that preinfarction angina does not affect the likelihood of achieving TIMI grade 3 flow in the infarct-related artery at 90 minutes. Beyond this time, preinfarction angina portends a worse clinical prognosis, especially if the angina is of remote onset. Whether ischemic preconditioning occurs in humans remains uncertain. If it does occur, the mechanism proposed by Andreotti et al. needs to be defined further.
3 ReferencesRaymond Q. Migrino, M.D.
David J. Moliterno, M.D.
Eric J. Topol, M.D.
Cleveland Clinic Foundation, Cleveland, OH 441951
Andreotti F ,Pasceri V ,Hackett DR ,Davies GJ ,Haider AW ,Maseri A . Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N Engl J Med 1996;334:7-12
Full Text | Web of Science | Medline2
The GUSTO Angiographic Investigators
Full Text | Web of Science | Medline3
The GUSTO Investigators
Full Text | Web of Science | Medline
To the Editor:
Andreotti et al. compare the coronary angiograms obtained at base line and at various points after the start of thrombolytic therapy in patients with angina before myocardial infarction with the angiograms obtained in patients without preinfarction angina. They make the intriguing observation that 35 minutes after thrombolysis, there was TIMI grade 3 flow (complete reperfusion) in 64 percent of patients with prior angina as compared with none of those without prior angina.
Previously, we reported that patients with preinfarction angina had smaller infarcts than patients without such angina, as well as a lower incidence of in-hospital death, heart failure, and shock.1 Andreotti et al. note that in our study, when reperfusion was defined as a flow of TIMI grade 2 or 3, there was a trend toward higher rates of coronary perfusion after 90 minutes of thrombolytic therapy among the patients with preinfarction angina than among those without preinfarction angina (81 percent vs. 74 percent, P = 0.11).
We cannot compare our study directly with theirs, since in the TIMI-4 study we do not have angiographic data obtained after 35 minutes of therapy. However, data obtained after 60 minutes are available for 219 patients (approximately half our total study population), and we have now analyzed the TIMI flow grades of patients with and without ischemic pain within 48 hours before their infarctions. Among 79 patients who had angina during that period, 46 percent had TIMI grade 3 flow at 60 minutes, as compared with 34 percent of 140 patients with no angina within the 48 hours before the infarction (Table 1Table 1
Relation of Angina within the 48 Hours before a Myocardial Infarction to TIMI Flow Grades 60 Minutes after the Start of Thrombolytic Therapy.). In addition, patients with angina were less likely to have persistent occlusion (TIMI grade 0) at 60 minutes than those without angina (19 percent vs. 27 percent).Thus, our observations in a cohort of 219 patients support the findings of Andreotti et al. suggesting that recent angina before infarction is associated with more complete reperfusion. Although our results are not as dramatic as theirs, this finding may partly explain the beneficial effects of preinfarction angina on outcome. It should be noted, however, that in our study the absolute difference between the proportion of patients with angina who had TIMI grade 3 flow and the proportion who did not was relatively small (12 percent) and not statistically significant. Whether this difference of 12 percent is enough to explain the profound decreases in infarct size, mortality, and rates of heart failure and shock in TIMI-4 is unknown. Ischemic preconditioning may have played a part. It is also possible that preinfarction angina somehow rendered the thrombus, the coronary arteries, or both more susceptible to thrombolysis.
1 ReferencesRobert A. Kloner, M.D., Ph.D.
Good Samaritan Hospital, Los Angeles, CA 90017Michael Gibson, M.D.
Chris Cannon, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital, Boston, MA 021151
Kloner RA ,Shook T ,Przyklenk K , et al. Previous angina alters in-hospital outcome in TIMI 4: a clinical correlate to preconditioning? Circulation 1995;91:37-45
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: In patients with acute myocardial infarction receiving t-PA, we found that those with unstable angina during the week before the infarction had higher rates of TIMI grade 3 flow after 35 minutes of treatment and smaller infarcts than patients with no angina or angina more than one week before the infarction. At 90 minutes, reperfusion rates no longer differed significantly between the two groups.
The TIMI-4 data presented by Kloner et al. relate to different thrombolytic regimens but are otherwise comparable to ours, containing angiographic data after 60 minutes and making a prospective distinction between patients with angina and those without angina in the days before infarction. They support a relation between prodromal angina and more frequent early reperfusion during thrombolytic therapy in patients with acute myocardial infarction. We agree that other mechanisms (including “ischemic preconditioning,” collateral circulation, and previous treatments) may also contribute to the smaller infarcts and better clinical outcomes in patients with recent angina.1
We believe the data presented by Migrino et al. in their retrospective analysis are inadequate for the study of preinfarction angina in relation to angiographic and clinical results, mainly because they originate from a large, multicenter study that did not include detailed prospective characterization of the patients' symptoms. Only 8.7 percent of that study population was found to have angina of “recent onset,” whereas studies specifically focusing on symptoms report prodromal chest pain in 24 to 48 percent of patients with acute myocardial infarction2-4; patency at 24 hours was assessed in only 27 patients with recent-onset angina, who received unspecified regimens of streptokinase or t-PA; and the assessment of patency after 90 minutes of therapy was not balanced among the patient groups. Moreover, because early angiography was not performed, the phenomenon revealed in our study could not be investigated.
Our thrombolytic regimen, in the late 1980s, consisted of an intravenous infusion or sequential boluses of t-PA that totaled 100 mg in the first 90 minutes,5 with a 73 percent rate of recanalization to TIMI grade 3 flow at 90 minutes (95 percent confidence interval, 47 to 88 percent), a result consistent with the outcomes after “accelerated” t-PA dosing in the GUSTO-1 study. Our hypothesis that primary angioplasty may be of most benefit in patients with acute myocardial infarction who have large areas of jeopardized myocardium but no recent unstable symptoms can be tested in current cardiologic practice.
We are surprised that Migrino et al. criticized our study mainly with regard to the number of patients and the year of performance and state that rates of patency after thrombolytic therapy should be higher in large trials than in small ones.
5 ReferencesFelicita Andreotti, M.D., Ph.D.
Vincenzo Pasceri, M.D.
Attilio Maseri, M.D.
Catholic University, 00168 Rome, Italy1
Kloner RA ,Shook T ,Przyklenk K , et al. Previous angina alters in-hospital outcome in TIMI 4: a clinical correlate to preconditioning? Circulation 1995;91:37-45
Web of Science | Medline2
Harper RW ,Kennedy G ,DeSanctis RW ,Hutter AM Jr . The incidence and pattern of angina prior to acute myocardial infarction: a study of 577 cases. Am Heart J 1979;97:178-183
CrossRef | Web of Science | Medline3
Muller DW ,Topol EJ ,Califf RM , et al. Relationship between antecedent angina pectoris and short-term prognosis after thrombolytic therapy for acute myocardial infarction. Am Heart J 1990;119:224-231
CrossRef | Web of Science | Medline4
Pasceri V ,Cianflone D ,Finocchiaro ML ,Crea F ,Maseri A . Relation between myocardial infarction site and pain location in Q-wave acute myocardial infarction. Am J Cardiol 1995;75:224-227
CrossRef | Web of Science | Medline5
Khan MI ,Hackett DR ,Andreotti F , et al. Effectiveness of multiple bolus administration of tissue-type plasminogen activator in acute myocardial infarction. Am J Cardiol 1990;65:1051-1056
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Harun Evrengul, Deniz Seleci, Halil Tanrverdi, Asuman Kaftan. (2006) The antiarrhythmic effect and clinical consequences of ischemic preconditioning. Coronary Artery Disease 17:3, 283-288
CrossRef2
Karin Przyklenk, Peter Whittaker. (2005) In Vitro Platelet Responsiveness to Adenosine-Mediated ‘Preconditioning’ is Age-Dependent. Journal of Thrombosis and Thrombolysis 19:1, 5-10
CrossRef3
Shereif H Rezkalla, Robert A Kloner. (2004) Ischemic preconditioning and preinfarction angina in the clinical arena. Nature Clinical Practice Cardiovascular Medicine 1:2, 96-102
CrossRef
