The Smoker's Paradox: Insights from the Angiographic Substudies of the TIMI Trials
Background: Despite increased risk for coronary artery disease and acute myocardial infarction (AMI), smokers have a paradoxically lower mortality after thrombolysis for AMI than non-smokers. We determined the clinical risk profiles and coronary flow characteristics of patients in the TIMI trials according to smoking status, focusing on microvascular flow.
Methods: Among 2,573 patients in the TIMI 4, 10A, 10B and TIMI 14 trials, epicardial flow post-thrombolysis was measured using angiographic TIMI flow grades and the corrected TIMI frame count (CTFC). Microvascular flow was measured by TIMI Myocardial Perfusion Grade (TMPG) and, in TIMI 14, the percentage of ST segment resolution.
Results: Clinically, the mean age (54 vs. 62 years), the prevalence of diabetes mellitus (11% vs. 16%) and hypertension (26% vs. 40%), and the 30-day mortality (2.6% vs. 6.2%) were lower among smokers than non-smokers (all p ≤ 0.001). Angiographically, single-vessel disease (48% vs. 40%) and non-left anterior descending infarct arteries (65.4% vs. 60.8%) were more common among smokers (both p ≤ 0.01). Epicardial TIMI grade 3 flow was achieved more often in smokers than non-smokers (61% vs. 56%) and the CTFC was faster (34 vs. 37 frames/sec, both p ≤ 0.01), especially in LAD lesions. However, the frequency of normal microvascular flow (TMPG 3) was similar among smokers and non-smokers (24% vs. 29%, p = 0.16), as was the frequency of complete ST segment resolution (50% vs. 46%, p = 0.29).
Conclusions: Smokers have lower mortality after AMI than non-smokers, due in large part to lower clinical risk profiles and faster epicardial flow. Differences in tissue-level perfusion do not appear to contribute to lower mortality in smokers.
Abbreviated Abstract. After acute MI, active smokers have lower acute mortality than non-smokers that appears to be largely explained by their healthier risk profiles, less extensive coronary disease, and faster epicardial blood flow after thrombolysis. Microvascular injury does not appear to play a major role in the lower mortality risk among smokers.
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- 1.Njolstad I, Arnesen E, Lund-Larsen PG. Smoking, serum lipids, blood pressure, and sex differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation 1996;93450–456Google Scholar
- 2.Mueller HS, Cohen LS, Braunwald E, et al. Predictors of early morbidity and mortality after thrombolytic therapy of acute myocardial infarction. Analyses of patient subgroups in the thrombolysis in myocardial infarction (TIMI) trial, phase II. Circulation 1992;85:1254–1264.Google Scholar
- 3.Barbash GI, White HD, Modan M, et al. Significance of smoking in patients receiving thrombolytic therapy for acute myocardial infarction. Experience gleaned from the international tissue plasminogen activator/streptokinase mortality trial. Circulation 1993;87:53–58.Google Scholar
- 4.Barbash GI, Reiner J, White HD, et al. Evaluation of paradoxic beneficial effects of smoking in patients receiving thrombolytic therapy for acute myocardial infarction: mechanism of the “smoker's paradox” from the GUSTOI trial, with angiographic insights. Global utilization of streptokinase and tissue-plasminogen activator for occluded coronary arteries. Journal of the American College of Cardiology 1995;26:1222–1229.Google Scholar
- 5.Grines CL, Topol EJ, O'Neill WW, et al. Effect of cigarette smoking on outcome after thrombolytic therapy for myocardial infarction. Circulation 1995;91:298–303.Google Scholar
- 6.Gottlieb S, Boyko V, Zahger D, et al. Smoking and prognosis after acute myocardial infarction in the thrombolytic era (Israeli Thrombolytic National Survey). Journal of the American College of Cardiology 1996;28:1506–1513.Google Scholar
- 7.Gomez MA, Karagounis LA, Allen A, Anderson JL. Effect of cigarette smoking on coronary patency after thrombolytic therapy for myocardial infarction. TEAM-2 Investigators. Second multicenter thrombolytic trials of eminase in acute myocardial infarction. American Journal of Cardiology 1993;72:373–378.Google Scholar
- 8.Hasdai D, Lerman A, Rihal CS, et al. Smoking status and outcome after primary coronary angioplasty for acute myocardial infarction. American Heart Journal 1999;137:612–620.Google Scholar
- 9.Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000;101:125–130.Google Scholar
- 10.Lincoff AM, Topol EJ, Califf RM, et al. Significance of a coronary artery with thrombolysis in myocardial infarction grade 2 flow “patency”; (outcome in the thrombolysis and angioplasty in myocardial infarction trials). Thrombolysis and angioplasty in myocardial infarction study group. Am J Cardiol 1995;75:871–876.Google Scholar
- 11.Gibson CM, Ryan KA, Murphy SA, et al. Impaired coronary blood flow in nonculprit arteries in the setting of acute my-ocardial infarction. The TIMI study group. Thrombolysis in myocardial infarction. J Am Coll Cardiol 1999;34:974–982.Google Scholar
- 12.Cannon CP, McCabe CH, Diver DJ, et al. Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) 4 trial. J Am Coll Cardiol 1994;24:1602–1610.Google Scholar
- 13.Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 10A dose-ranging trial. Circulation 1997;95:351–356.Google Scholar
- 14.Cannon CP, Gibson CM, McCabe CH, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Thrombolysis in myocardial infarction (TIMI) 10B Investigators. Circulation 1998;98:2805–2814.Google Scholar
- 15.Antman EM, Gibson CM, deLemos JA, et al. Combination reperfusion therapy with abciximab and reduced dose reteplase: results from TIMI 14. Eur Heart J 2000;21:1944–1953.Google Scholar
- 16.The thrombolysis in myocardial infarction (TIMI) trial. Phase I findings. TIMI study group. N Engl J Med 1985;312:932–936.Google Scholar
- 17.Gibson CM, Murphy SA, Rizzo MJ, et al. Relationship between TIMI frame count and clinical outcomes after thrombolytic administration. Thrombolysis in myocardial infarction (TIMI) study group. Circulation 1999;99:1945–1950.Google Scholar
- 18.Claeys MJ, Bosmans J, Veenstra L, Jorens P, De Raedt H, Vrints CJ. Determinants and prognostic implications of persistent ST-segment elevation after primary angioplasty for acute myocardial infarction: importance of microvascular reperfusion injury on clinical outcome. Circulation 1999;99:1972–1977.Google Scholar
- 19.de Lemos JA, Antman EM, Giugliano RP,et al. ST-segment resolution and infarct-related artery patency and flow after thrombolytic therapy. Am J Cardiol 2000;85:299–304.Google Scholar
- 20.Schroder R, Wegscheider K, Schroder K, Dissmann R, Meyer-Sabellek W. Extent of early ST segment elevation resolution: a strong predictor of outcome in patients with acute myocardial infarction and a sensitive measure to compare thrombolytic regimens. A substudy of the international joint efficacy comparison of thrombolytics (INJECT) trial. J Am Coll Cardiol 1995;26:1657–1664.Google Scholar
- 21.Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation. An intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation 2000;102:2031–2037.Google Scholar
- 22.Madsen MM, Bottcher M, Toftegaard Nielsen T, Czernin J. Altered regulation of the myocardial microcirculation in young smokers. Cardiology 2000;94:91–98.Google Scholar
- 23.Czernin J, Sun K, Brunken R, Bottcher M, Phelps M, Schelbert H. Effect of acute and long-term smoking on myocardial blood flow and flow reserve. Circulation 1995;91:2891–2897.Google Scholar
- 24.Tanaka T, Oka Y, Tawara I, Sada T, Kira Y. Acute effects of nicotine content in cigarettes on coronary flow velocity and coronary flow reserve in men. Am J Cardiol 1998;82:1275–1278, A9.Google Scholar
- 25.Zalokar JB, Richard JL, Claude JR. Leukocyte count, smoking, and myocardial infarction. New England Journal of Medicine 1981;304:465–468.Google Scholar
- 26.Barron HV, Cannon CP, Murphy SA, Braunwald E, Gibson CM. Association between white blood cell count, epicardial blood flow, myocardial perfusion, and clinical outcomes in the setting of acute myocardial infarction: a thrombolysis in myocardial infarction 10 substudy. Circulation 2000;102:2329–2334.Google Scholar
- 27.Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators. Circulation 1995;91:1659–1668.Google Scholar
- 28.Kannel WB, Schatzkin A. Sudden death: lessons from subsets in population studies. Journal of the American College of Cardiology 1985;5:141B–149B.Google Scholar
- 29.Escobedo LG, Zack MM. Comparison of sudden and nonsudden coronary deaths in the United States. Circulation 1996;93:2033–2036.Google Scholar
- 30.Jouven X, Desnos M, Guerot C, Ducimetiere P. Predicting sudden death in the population: the Paris prospective study I. Circulation 1999;99:1978–1983.Google Scholar