Outcomes of Diabetic Patients Following Acute Myocardial Infarction: A Review of the Major Thrombolytic Trials

Bradley RF Bryfogle JW : Survival of diabetic patients after myocardial infarction Am J Med 1956, 20:207–216. ∗ This was one of the first large studies to report mortality rates of diabetic patients after myocardial infarction. The study also looked at the influence of other factors such as hypertension, congestive heart failure, obesity, prior infarctions, gender and age on survival following myocardial infarction.

Partamian JO Bradley RF : Acute myocardial infarction in 258 cases of diabetes: Immediate mortality and five-year survival N Engl J Med 1965, 273:455–461.

Master AM Dack S Jaffe HL : Age, sex and hypertension in myocardial infarction due to coronary occlusion Arch Intern Med 1939, 64:767–786.

Katz LN Mills GY Cisneros F : Survival after recent myocardial Infarction Arch Intern Med 1949, 84:305–320.

Robinson JW : Coronary thrombosis in diabetes mellitus N Engl J Med 1952, 246:332–335.

Smith JW Marcus FI Serokman R for the Multicenter Postinfarction Research Group: Prognosis of patients with diabetes mellitus after acute myocardial infarction Am J Cardiol 1984, 54:718–721.

Garcia J McNamara PM Gordon T Kannell WB : Morbidity and mortality in diabetics in the Framingham population: Sixteen year follow-up study Diabetes 1974, 23:105–111.

Abbott RD Donahue RP Kannel WB Wilson PFW : The impact of diabetes on survival following myocardial infarction in men vs women: The Framingham study JAMA 1988, 260:3456–3460. ∗ The Framingham study revealed a striking trend for increased mortality in diabetic patients following myocardial infarction. Diabetics were shown to have a higher incidence of cardiac failure, recurrent infarction and fatal coronary events. Diabetic women were noted to be at particular risk for adverse events.

Kannel WB Sorlie P McNamara PM : Prognosis after initial myocardial infarction: The Framingham Study Am J Cardiol 1979, 44:53–59.

Sprafka JM Burke GL Folsom AR McGovern PG Hahn LP : Trends in prevalence of diabetes in patients with myocardial infarction and effect on diabetes survival: The Minnesota Heart Study Diab Care 1991, 14:537–543. ∗ The Minnesota Heart Study was a large population-based study that monitored trends in the prevalence of diabetes mellitus, coronary heart disease morbidity and risk factors over a period of 15 years.

Cooper RS Pacold IV Ford ES : Age-related differences in case-fatality rates among diabetic patients with myocardial infarction: Findings from National Hospital Discharge Survey, 1979-1987 Diab Care 1991, 14:903–908. ∗ The National Hospital Discharge Survey raised questions regarding whether diabetes is an independent predictor of mortality following myocardial infarction. This particular study found that after adjustment for age, case-fatality rates from infarction were identical among diabetics and nondiabetics. Younger patients with diabetes, however, had higher mortality rates following myocardial infarction.

Rytter L Troelson S Beck-Nielson H : Prevalence and mortality of acute myocardial infarction in patients with diabetes Diab Care 1985, 8:230–234.

Abbud ZA Shindler DM Wilson AC Kostis JB for the Myocardial Infarction Data Acquisition System Study Group (MIDAS): Effect of diabetes mellitus on short- and long-term mortality rates of patients with acute myocardial infarction: A statewide study Am Heart J 1995, 130:51–58. ∗ This was one of the largest studies to focus on short and long-term survival rates in diabetics following myocardial infarction. Hospital records of 45 595 patients were reviewed. Diabetics had higher mortality rates both in hospital (21.5 versus 19.2%, P<60; 0.001) and during 3-year follow-up (46.7 versus 37.8%) compared with nondiabetics. The impact of diabetes was again found to be more pronounced in younger age groups.

Barrett-Connor E Orchard T : Diabetes and heart disease. In Diabetes in America. Edited by Harris MI Hamman RE. Washington DC: U.S. Govt Printing Office; 1985; Chap XVI 1-41 (DHHS NIH Publ no.85-1468).

Pyrola K Laakso M : Macrovascular disease in diabetes mellitus. In Diabetes in Epidemiologic Perspective. Edited by Marin J Pyrola K Teuscher A. New York: Churchill Livingstone; 1983:183–247.

Gruppo Italiano per lo Studio della Streptochinasi nell'Infarcto Miocardico (GISSI): Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction Lancet 1986, i:397–402.

Second International Study of Infarct Survival (ISIS-2) Collaborative Group: Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2 Lancet 1988, ii:349–360. ∗ ISIS-2 was one of the first large thrombolytic trials which clearly demonstrated a benefit among diabetic patients receiving streptokinase for acute myocardial infarction. Benefits appeared to be greater in diabetics compared with nondiabetics, showing relative mortality reductions of 31 versus 23%.

LATE Study Group: Late assessment of thrombolytic efficacy (LATE) study with alteplase 6-24 hours after onset of acute myocardial infarction Lancet 1993, 342:759–766.

EMERAS (Estudio Multicentrico Estreptoquinesa Republicas de America del Sur) Collaborative Group: Randomized trial of late thrombolysis in patients with suspected acute myocardial infarction Lancet 1993, 342:767–772.

Wilcox RG von der Lippe G Olsson CG Jenson G Skene AM Hampton JR : Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis (ASSET) Lancet 1988, ii:525–530.

ISIS-3 (Third International Study of Infarct Survival) Collaborative Group: ISIS-3: A randomized trial of streptokinase vs tissue plasminogen activator vs anistreplase and aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction Lancet 1992, 339:753–770.

ISAM (Intravenous Streptokinase in Acute Myocardial Infarction) Study Group: A prospective trial of intravenous streptokinase in acute myocardial infarction (ISAM): Mortality, morbidity and infarct size at 21 days N Engl J Med 1986, 314:1465–1471.

Mueller HS Cohen LS Braunwald E Forman S Feit F Ross A et al.: Predictors of early morbidity and mortality after thrombolytic therapy of acute myocardial infarction: Analysis of patient subgroups in the Thrombolysis Myocardial Infarction (TIMI) Trial, Phase II Circulation 1992, 85:1254–1264. ∗ Subgroup analysis of patients enrolled in phase II of the TIMI trial showed persistently higher mortality rates in diabetics treated with alteplase, heparin and aspirin, compared with nondiabetics. Interestingly, diabetic patients randomized to invasive treatment strategies had particularly high mortality rates.

Barbash GI White HD Modan M van de Werf F , for the Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial: Significance of diabetes mellitus in patients with acute myocardial infarction receiving thrombolytic therapy J Am Coll Cardiol 1993, 22:707–713. ∗ Data from the International Tissue Plasminogen Activator/Streptokinase Mortality Trial raised some intriguing questions about whether diabetics vary in their responsiveness to specific thrombolytic treatment regimens.

Kouvras G Cokkinos D Spyropolous M : Increased mortality of diabetics after acute myocardial infarction attributed to diffusely impaired left ventricular performance as assessed by echocardiography Jpn Heart J 1989, 29:1–9.

Granger CB Califf RM Young S Candela R Samaha J Worley S and the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group: Outcome in patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents J Am Coll Cardiol 1993, 21:920–925. * A study published by the TAMI study group assessed outcomes in diabetic patients receiving thrombolytic therapy, using angiographic follow-up. The study also stratified patients according to type of diabetes treatment received. Thrombolytic therapy was found to be equally effective in achieving early patency in diabetics, without increased risk for stroke or hemorrhage.

Woodfield SL Lundergan CF Reiner JS Greenhouse S Thompson MA Rohrbech SC : Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: The GUSTO-1 experience. J Am Coll Cardiol 1996 (submitted). * A landmark paper from the GUSTO study with angiographic follow-up which demonstrated comparable 90-min patency rates after thrombolysis in diabetics and nondiabetics. Although not statistically significant, there appeared to be a trend for higher reocclusion rates 5-7 days post-infarction. Diabetics showed consistently lower hyperkinesis in non-infarct zones. Those receiving early, elective invasive intervention were found to have higher overall mortality rates. The reasons for this are unclear.

Singer DE Moulton AW Nathan DM : Diabetic myocardial infarction: Interaction of diabetes with other preinfarction risk factors Diabetes 1989, 38:350–357.

Stone PH Muller JE Hartwell T Rutherford JD Parker CB and the MILIS Study Group: The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: Contribution of both coronary disease and diastolic left ventricular dysfunction to adverse prognosis J Am Coll Cardiol 1989, 14:49–57. * Eighty-five diabetic patients were assessed during the course of an acute infarction with serial evaluation of left ventricular fuction. Diabetics had a higher incidence of post-infarction angina, infarct extension, heart failure and death despite smaller infarct size, and similar left ventricular ejection fractions. The authors postulate that diastolic left ventricular dysfunction may contribute to the adverse outcomes observed in diabetics.

Jaffe AS Spadaro JJ Schechtman K Roberts R Geltman EM Sobel BE : Increased congestive heart failure after myocardial infarction of modest extent in patients with diabetes mellitus Am Heart J 1984, 108:31–37.

Regan TJ Lyons MM Ahmed SS Levinson GE Oldewurtel HA Ahmad MR : Evidence for cardiomyopathy in familial diabetes mellitus J Clin Invest 1977, 60:885–899.

Lomuscio Castagnone M Vergani D Verzoni A Beltrami A Ravaglia R : Clinical correlation between diabetic and non diabetic patients with myocardial infarction. Cardiologia 1991 46:543–554.

Malmberg K Ryden L : Myocardial infarction in patients with diabetes Eur Heart J 1988, 9:259.

Ulvenstam G Aberg A Bergstrand R Johansson S Pennert K Vedin A : Long-term prognosis after myocardial infarction in men with diabetes Diabetes 1985, 34:787.

Savage MP Krolewski AS Kenien GG Lebeis MP Christlieb R Lewis SM : Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor Am J Cardiol 1988, 62:665–669.

Gray RP Yudkin JS Patterson DL : Enzymatic evidence of impaired reperfusion in diabetic patients after thrombolytic therapy for acute myocardial infarction: A role for plasminogen activator inhibitor? Br Heart J 1993, 70:530–536. ∗ This study compared the activity of plasminogen activator inhibitor (PAI-1) in diabetic and nondiabetic patients with acute myocardial infarction, to determine if PAI-1 activity influences reperfusion after thrombolytic therapy. Diabetics had higher PAI-1 activity post-infarction and longer times to peak creatine kinase-MB enzyme.

Zarich SW Nesto RW : Diabetic cardiomyopathy Am Heart J 1989, 118:1000–1011. ∗ A good, comprehensive review of the literature on diabetic cardiomyopathy.

Colwell JA Halushka PV Sarji KE Lopes-Virella M Sagel J : Vascular disease in diabetes: Pathophysiological mechanisms and therapy Arch Intern Med 1979, 139:225–230.

Colwell JA Lopes-Virella M Halushka PV : Pathogenesis of atherosclerosis in diabetes mellitus Diab Care 1981, 4:121–133. ∗ A review of the factors thought to contribute to the pathogenesis of atherosclerosis in diabetics. Mechanisms of endothelial dysfunction, arachadonic acid metabolism, alterations in platelet dysfunction and fibrinolysis are described.

Kannel W : Lipids, diabetes, and coronary heart disease: Insights from the Framingham study Am Heart J 1985, 110:1110–1117.

Davi G Catalano I Averna M Notarbartolo A Strano A Ciabattoni G et al.: Thromboxane biosynthesis and platelet function in type II diabetes mellitus N Engl J Med 1990, 322:1769–1774.

Alessandrini P McRae J Feman S Fitzgerald GA : Thromboxane biosynthesis and platelet function in type I diabetes mellitus N Engl J Med 1988, 319:208–312.

Davi G Rini GB Averna M Nova S De Fede G Pinto A : Thromboxane B2 formation and platelet sensitivity to prostacyclin in insulin-dependent, and non-insulin dependent diabetics Thromb Res 1982, 26:359–370.

Halushka PV Mayfield R Colwell JA : Insulin and arachidonic acid metabolism in diabetes mellitus Metabolism 1985, 34 (suppl 1):32–36.

Harrison HE Reece AH Johnson M : Effect of insulin treatment on prostacyclin in experimental diabetes Diabetologia 1979, 18:65–68.

Valentovic M Lubawy W : Impact of insulin or tolbutamide treatment on 14C-arachidonic acid conversion to prostacyclin and/or thromboxane in lungs, aortas, and platelets of streptozotocin-induced diabetic rats Diabetes 1983, 32:846–851.

Sagel J Colwell JA Crook L Laimins M : Increased platelet aggregation in early diabetes mellitus Ann Intern Med 1975, 82:733–738.

Mustard JF Packman MA : Platelets and diabetes mellitus N Engl J Med 1984, 311:665–667.

Almer L Nilsson IM : Fibrinolysis in diabetes mellitus Acta Med Scand 1975, 198:101–106.

Fuller JH Keen H Jarrett RJ Omer T Meade TW Chakrabarti R : Haemostatic variables associated with diabetes and its complications BMJ 1979, 2:964–966.

Mayne EC Bridges JM Weaver JA : Platelet adhesiveness, plasma fibrinogen, and factor VIII levels in diabetes mellitus Diabetologia 1970, 6:436–440.

Ferguson JC Mackay N Philip JD Sumner DJ : Determination of platelet and fibrinogen half-life with (75 SE) selenomethionine. Studies in normal and diabetic subjects Clin Sci Mol Med 1975, 49:115–120.

Juhane-Vague I Roul C Alessi MC Ardissone JP Hein M Vague P : Increased plasminogen activator inhibitor in non-insulin dependent diabetes: Relationship with plasma insulin Thromb Haemost 1989, 61:370–373.

Auwer XJ Bouillon R Collen D Geboers J : Tissue plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus Atherosclerosis 1988, 8:68–72.

Sane DC Stump DC Topol EJ Sigmon KM Keriakes DJ George BS et al.: Correlation between baseline plasminogen activator inhibitor levels and clinical outcome during therapy with tissue plasminogen activator for acute myocardial infarction Thromb Haemost 1991, 65:275–279.

Hamsten A De Faire U Walldius G Dahlen G Szamosi A Landou C : Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction Lancet 1987, i:3–8.

Oswald GA Yudkin JS : Hyperglycemia following acute myocardial infarction: The contribution of undiagnosed diabetes Diab Med 1987, 4:69–71.

Opie LH : The glucose hypothesis: Relation to acute myocardial ischemia J Mol Cell Cardiol 1970, 1:107–115.

Hearse DJ Stewart DA Chain EB : Diabetes and the survival and recovery of anoxic myocardium J Mol Cell Cardiol 1975, 7:397–415.

Yudkin JS Oswald GA : Hyperglycemia, diabetes and myocardial infarction Diabetic Med 1987, 4:13–18. * A good discussion of hyperglycemia, ketosis and stress hormone responses and their possible contributions to the adverse outcomes of diabetics following myocardial infarction.

Khaja F Walton JA Jr Brymer JF Lo E Osterberger L O'Neill WW : Intracoronary fibrinolytic therapy in acute myocardial infarction. Report of a prospective randomized trial N Engl J Med 1983, 308:1305–1311.

Rogers WJ Mantle JA Hood WP Jr Baxley WA Whitlow PL Reeves RC : Prospective randomized trial of intravenous and intracoronary streptokinase in acute myocardial infarction Circulation 1983, 68:1051–1061.

Fibrinolytic Therapy Trialists' (FTT) Collaborative Group: Indications for fibrinolytic therapy in suspected acute myocardial infarction: Collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients Lancet 1994, 342:311–322. ∗ This study was an aggregate analysis of the major thrombolytic trials. Analysis of subgroup data on diabetic patients showed clear benefit from thrombolytic therapy, resulting in reductions in mortality proportional to that seen in nondiabetics. Though not statistically significant, absolute benefits of therapy appeared to be greater in diabetics.

Lynch M Gammage MD Lamb P Nattrass M Pentecost BL : Acute myocardial infarction in diabetic patients in the thrombolytic era Diab Med 1994, 11:162–165. * The authors looked at 208 diabetic patients suffering acute myocardial infarction. The study showed that thrombolytic therapy conferred major benefits on diabetics. Positive correlation was found between mortality and admission glucose values. Careful glycemic control during the peri-infarct period, however, did not affect short-term mortality.

Lee KL Woodlief LH Topol EJ Weaver D Betriu A Col J : Predictors of 30 day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients Circulation 1995, 91:1659–1668.

Czyzk A Krolweski AS Szablowska S Alot A Kopczynski J : Clinical course of myocardial Infarction among diabetic patients Diab Care 1980, 3:526–529.

Gwilt DJG Petri M Lewis PW Nattrass M Pentecost BL : Myocardial infarct size and mortality in diabetic patients. Br Heart J 1985 54:466–472.

Factor SM Okun EM Minase T : Capillary microaneurysms in the human diabetic heart N Engl J Med 1980, 302:384–388.

Fischer VW Barner HB Leskiw ML : Capillary basal laminar thickness in diabetic human myocardium Diabetes 1979, 28:713–719.

Mintz GS Painter JA Pichard AD : Atherosclerosis in angiographically ‘normal’ coronary artery reference segments: An intravascular ultrasound study with clinical correlations J Am Coll Cardiol 1995, 25:1479–1485.

Greaves M Preston FE : Haemostatic abnormalities in diabetics in Diabetes and Heart Disease. Edited by Jarred RJ. Amsterdam: Elsevier 1984:47–80.

Shaw S Pegrum CD Wolff S et al.: Platelet adhesiveness in diabetes mellitus J Clin Path 1967, 20:845–847.

Fleischman AR Beirenbaum ML Stier A Somol H Watson PB : In vivo platelet function in diabetes mellitus Thromb Res 1976, 9:467–471.

Fuller JH Keen H Jarrett RJ Omer T Meade T Chakrabarti R et al.: Haemostatic variables associated with diabetes and its complications BMJ 1980, 2:964–970.

Hamberg M Svensson J Samuelsson JB : Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides Proc Natl Acad Sci USA 1975, 72:2991–2996.

Ingerman-Wojenski C Silver MJ Smith JB Macarack E : Bovine endothelial cells in culture produce thromboxane as well as prostacyclin J Clin Invest 1981, 67:1292–1296. ∗ This study showed that vascular reactivity to eicosanoids (thromboxane and endoperoxide analogues) was markedly increased in both the aorta and coronary vessels of diabetic rats. The hearts of these animals also tended to develop arrhythmias more frequently, at higher perfusion pressures.

Roth DM Reibel DK Lefer AM : Vascular responsiveness and eicosanoid production in diabetic rats Diabetologia 1983, 24:372–376.

Barbash GI Hod H Roth A Miller HI Rath S Har Zahav Y : Correlation of baseline plasminogen activator inhibitor activity with patency of the infarct related artery after thrombolytic therapy in acute myocardial infarction Am J Cardiol 1989, 64:1231–1235.

Reilly CF Fujita I Mayer EJ Siegfried ME : Both circulating and clot-bound plasminogen activator inhibitor-1 inhibit endogenous fibrinolysis in the rat Arterioscler Thromb 1991, 11:1276–1286.

Lucore CL Sobel BE : Interactions of tissue type plasminogen activator with plasma inhibitors and their pharmacologic implications Circulation 1988, 77:660–669.

Egeberg O : The blood coagulability in diabetic patients Scand J Clin Lab Invest 1963, 15:533–538.

Rao AK Pratt C Berke A Jaffe A Ockene I Schreiber TL : Thrombolysis in Myocardial Infarction (TIMI) Trial Phase-I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase J Am Coll Cardiol 1988, 11:1–11. ∗ The authors found that risk for coronary reocclusion within 7-10 days of alteplase infusion appeared to be inversely related to baseline functional fibrinogen level, with the magnitude of its drop to andir level and to peak levels of fibrin degradation products. Diabetics showed modest differences in peak fibrin degradation products, compared with nondiabetics.

Stump DC Califf RM Topol EJ Sigmon K Thornton D Masek R : Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. The TAMI study group Circulation 1989, 80:1222–1230.

Gwilt DJ Petri M Nattrass M Pentecost BL : Effect of intravenous insulin infusion on mortality among diabetic patients after myocardial infarction BMJ 1984, 51:626–636. ∗ This study found no differences in the extent of infarct size, occurrence of heart failure arrhythmias and mortality following myocardial infarction, when comparing diabetic patients with adequate glycemic control and inadequate glycemic control.

Roth A Koffler M Viskin S Shargorotski B Bernfeld D Laniado S : Does adequate control of diabetes in the preinfarction period improve the short-term postinfarction course? J Diab Complications 1992, 6:218–222.

Liedtke AJ : Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart Prog Cardiovasc Dis 1981, 23:321–336.

Vik-Mo H Mjos OD : Influence of free fatty acids on myocardial consumption and Ischemic injury Am J Cardiol 1981, 48:361–366.

Sobel BE Corr PB Robinson AK : Accumulation of lysophosphoglycerides with arrhythmogenic properties in ischemic myocardium J Clin Invest 1978, 62:546–553.

Carmamelli B : Retinal hemorrhage after thrombolytic therapy [Letter]. Lancet 1991, 8753:1456–1457.