see also:

• ischaemic heart disease (IHD)
• historic perspectives on medical discoveries
• epidemiology:
  • Am Heart Assoc. prevalence of ischaemic heart disease and cardiac infarcts and cardiac arrest by age group, etc

• angina pectoris clearly described in 18th century by Heberden
• Einthoven 1st described the string galvanometer in 1901
• Cohn introduced the 1st ECG in USA in 1909
• Herrick is generally credited with delineating clinical features of acute coronary thrombosis by reporting the 1st recognised case of non-fatal AMI in USA in 1912.
• Wolferth & Wood introduced ECG precordial leads in 1932 which was a major advance in the ECG diagnosis of ischaemic syndromes
• 1900-1950 Mx of AMI consisted of pain relief, absolute bed rest for 6-8weeks, prevention of thromboembolism & Rx of CCF. Victims of cardiac arrest were virtually never resuscitated as was deemed an irreversible event & the natural history of an irreversible disease.
• Zoll et all in 1950's developed external defibrillators & cardiac pacemakers, providing an effective mechanical approach ro Rx of life threatening arrhythmias.
• Sones in 1959 introduced selective coronary arteriography, which revolutionised the evaluation & Mx of pts with known or suspected IHD.
• In 1960, Kouwenhoven et al published their method of external cardiac massage, which inaugurated the modern era of CPR.
• The realisation that the time between onset of life threatening arrhythmias & initiation of Rx was critical led Day to organise a cardiac arrest team in 1960 & to establish the 1st coronary care unit in 1962 which in 1 year reduced case fatality rates of AMI from 43% to 19%!
• In 1969, advanced prehospital cardiac care was initiated in Belfast, Ireland with the use of Pantridge's mobile coronary care units.
• In 1970, Nagel et al reported the successful use & benefits of prehospital telemetry in the emergency medical system in Miami.
• Cobb et al reported a 60% resuscitation rate & 30% pts eventually discharged home in the Seattle Emergency Medical Service which led to the development of the Emergency Medical Service Systems Acts of 1973 & 1976 which provided funding for the national development of emergency medical systems in the USA.
• Flow-directed balloon-tipped catheter introduced in 1970 further improved Rx of cardiogenic shock in pts with extensive myocardial necrosis.
• In early 1970's coronary artery bypass grafting started to be used in Australia with subsequent annual number of procedures in Aust:
  • < 100 in 1970, rising steadily to ~3,000 by 1980, ~6,000 by 1983, 7,000 in 1986, ~12,000 in 1992
• In 1974, Cohn et al 1st described RV infarction
• late 1970's:
  • beta blockers 1st used for AMI survivors, with subsequent prescribing rates in Australia:
    • 55% in 1984 increasing to 85-90% by 1990
  • aspirin 1st tested in clinical trials for post-coronary pts, with subsequent prescribing rates in Australia:
    • 22% in 1984 increasing to 90-95% by 1990
• In 1980, DeWood et al performed coronary angiography early in course of AMI & demonstrated 87% of those studied with 4hrs of onset of symptoms had total coronary occlusion in the infarct-related artery. This, along with an report by Rentrop on his experience with intracoronary administration of streptokinase lead to desire to develop thrombolytic Rx.
• thrombolytic use in AMI, prescribing rates in Australia:
  • 3% in 1984 increasing steadily to 55% in 1992
• early 1980's, coronary angioplasty introduced, with subsequent annual number of procedures in Aust:
  • <100 in 1983, rising steadily to ~5500 by 1993
• In 1986, introduction of portable 12 lead ECGs made field diagnosis of AMI possible.
• 1990's reports of adverse effects of calcium channel blockers in AMI lead to subsequent reduction in prescribing rates in Australia:
  • 55% in 1984-88 declining to ~30% in 1993
• In 1990's:
  • routine prophylactic lignocaine during AMI increased mortality
  • V-W class I anti-arrhythmic agents given long term after AMI increased mortality
  • ACEI's benefits in AMI shown with subsequent prescribing rates in Australia:
    • ~1% in 1988 rising steadily to 30-35% by 1993
• 1990's: percutaneous coronary intervention in AMI developed with introduction of stents and improved anti-thrombotic Rx using glycoprotein IIb/IIIa platelet inhibitors

• In 1980, De Wood et al demonstrated that AMI occurred because of complete occlusion of a coronary artery with thrombus. This led to the introduction of thrombolytic Rx as a Rx for AMI.
• Hartzler in 1983 showed that in his study, percutaneous transluminal coronary angioplasty resulted in > 90% of arteries successfully opened (cf. 80% with thrombolytic Rx).
• GISSI-1(1986) & ISIS-2 (1988) confirmed that Rx with streptokinase significantly reduced 14-21day in-hospital mortality after AMI from 13% to 11% and then to 8% when combined with aspirin - esp. if it was given EARLY, within 1st 3hrs.
• A European study (1985) showed that coronary patency was improved at 90min after thrombolytic Rx - 70% with t-PA & 55% with SK. It was thus presumed that t-PA would have an additional benefit over SK in terms of mortality.
• However, GISSI-2 (1990) & ISIS-3 (1992) failed to show any benefit of t-PA over SK.
  • It showed that SK + aspirin can save 26 lives per 1000 pts treated.
• By 1990, evidence accrued that IV heparin was needed with t-PA to maintain coronary patency. Without IV heparin, patency at 18hrs was only 52% - similar to SK in other trials.
• re-occlusion rates with angioplasty as high as 18% were reported (Topol, 1990) whereas re-occlusion rates in thrombolytic Rx was only 5-6%.
• In 1993, results of the GUSTO study (41,021 pts) showed a remarkable consistency in survival benefit for accelerated t-PA with IV heparin (1% absolute difference in mortality - eg. 6.9% vs 7.9% in other words 36 lives saved per 1000pts Rx cw 26 lives saved with SK) compared with the other arms of the study.
  • the other arms of the study were:
    • SK + S/C heparin
    • SK + IV heparin
    • SK + t-PA + IV heparin
• Although t-PA had a slightly higher disabling stroke rate than SK, the difference was only 1 patient per 1000 treated & thus in the pts with ant. infacts < 75yrs old @ <4hrs there was clear net beneficial effect of t-PA vs SK.
• On this basis, it was recommended that on a cost-benefit analysis, accelerated dosing of t-PA with IV heparin & oral aspirin should be used for acute anterior infarcts in pts < 75yrs old & < 4hrs from onset of most severe pain, or where SK was C/I but thrombolytic Rx was still indicated.
• In addition, an angiographic substudy was undertaken comparing infarct artery patency at 90min in each of the arms (approx. 290pts in each arm studies):
  • accelerated t-PA pts had significantly higher patency (81% cf 54-60% for SK pts)
  • confirmed that patency at 90min was associated with preserved LV function & survival
  • pts Rx with accelerated t-PA had better overall LV function with higher ejection fraction, lower end systolic volume index, fewer abnormal cords & significantly higher percentage of pts had normal wall motion (29% cf 19%) at both 90min & 5-7 days.
• In 1993, the LATE study showed evidence that even in pts with convincing evidence of AMI when given t-PA 6-12hrs after onset of pain, there was 30% reduction in mortality & a 22% reduction in mortality if given between 12-24hrs after onset. In pts where there was doubt about the diagnosis, t-PA increased mortality when given after 12hrs.
• in 1995, a meta-analysis showed that primary angioplasty resulted in a lower short-term (6-month) mortality rate than fibrinolysis (3.7% versus 6.4%, and also lowered the composite endpoint of mortality and reinfarction (6.1% versus 11%) in 7 combined randomized studies but provided no advantages in improving these 2 individual endpoints in any of 17 trials that tested the effects of angioplasty after lysis, whether it was performed immediately after lysis, soon after lysis, or after a time delay.
• In 1997, the GUSTO III study compared reteplase vs alteplase for AMI.
  • No significant difference in efficacy or safety but reteplase easier to administer as double bolus vs bolus then infusion.
• In 1999, the ASSENT-2 study compared single bolus tenecteplase with front-loaded alteplase and showed:
  • equivalent in effect on 30D mortality post-AMI
  • similar intracranial bleeding
  • less non-intracranial bleeding
  • better mortality in sub-group of pts Rx after 4hrs presumably as it is more fibrin specific than alteplase which in turn showed similar improvements in GUSTO III trial when it was compared with the less fibrin-specific reteplase

• beta blockers 1st used for AMI survivors in the 1970's, with subsequent prescribing rates in Australia:
  • 55% in 1984 increasing to 85-90% by 1990
• Norwegian Multicenter Study (1981):
  • 1,884 pts timolol 5-10mg bd vs placebo days 7-28 post AMI, F/U @ 33 & 72months:
    • 39% reduction in mortality
    • 28% reduction in reinfarction
• BHAT (1982):
  • 3,837 pts propranolol 20-80mg tds vs placebo days 5-21 post-AMI:
    • terminated at 24 months because:
    • 28% reduction in mortality
• MIAMI (1985):
  • 5,778 pts metoprolol 15mg IV then 200mg/d orally 15days vs no beta blocker:
    • non-signif. 13% reduction in mortality
• ISIS-1 (1986):
  • 16,027 pts atenolol 5-10mg IV then 100mg/d orally vs no beta blocker:
    • decreased mortality from vascular causes by 15% throughout 1st year post-AMI
• TIMI-IIB (1991):
  • 1,434 pts Rx with rtPA + aspirin: 3x5mg IV metoprolol then 50-100mg bd orally vs delayed (D6-8) metoprolol 50-100mg bd:
    • no difference in mortality at 6 & 42 days, but no. of deaths were small
    • 2.7% in immediate group had nonfatal reinfarction vs 5.1% in delayed group
    • at 6 days, but not at 42 days (no difference by then):
      • 19% in immediate group had recurrent chest pain vs 24% in delayed group
• metanalysis of trials performed prior to thrombolytic Rx + aspirin introduced (1993):
  • 13% reduction in mortality in pts Rx early with beta blockers although these pts had higher incidence of hypotension, bradycardia & bronchospasm, but these side effects were reversed by ceasing beta blocker Rx & bradycardia responded to atropine if clinically indicated.
  • JAMA 1993 260: 1910-6
• metanalysis of trials (1996):
  • beta blockers during AMI: 28,970pts, 13% reduction mortality
  • beta blockers after AMI: 24,298 pts, 23% reduction mortality
  • NEJM Nov 28 1996 335(22): 1660-1667

• CONSENSUS II (1992):
  • 6090pts IV enalaprilat 1mg then 2.5-20mg orally vs placebo post-AMI:
    • terminated due to:
      • possible adverse effect in high-risk subgroup of elderly pts who had early hypotensive reactions - this may have been due to IV dose!!
      • high probability that enalapril was no better than placebo
• SAVE (1992):
  • asymptomatic pts with LV ejection fraction < 40% 3-16days post-AMI - captopril vs placebo:
    • 19% reduction mortality at 42months
    • 37% reduction in severe heart failure
• AIRE (1993):
  • clinical CCF within 3-10days AMI: ramipril vs placebo:
    • 27% reduction in mortality
    • 19% reduction in combined endpoint of death, severe heart failure, AMI or stroke
• GISSI-3 (1994):
  • 19,394 pts lisinopril 5-10mg/d vs usual care for 42days post-AMI:
    • 12% reduction in mortality
• TRACE (1995):
  • LV ejection fraction < 35% 3-7 days post-AMI: trandolapril vs placebo:
    • 24% reduction in sudden death
    • 29% reductio in progression to severe heart failure
• ISIS-4 (1995):
  • 58,050pts captopril 6.25-50mg bd vs placebo for 28days post-AMI:
    • 7% reduction in mortality at 35days which persisted for 1 yr

• GISSI-3 (1994):
  • 19,394 pts IV GTN then transdermal GTN or usual care for 6wks post-AMI:
    • non-significant 6% reduction in mortality
    • lower rates of post-infarctional angina & cardiogenic shock
  • NB. many placebo pts also received IV GTN too thus may have obscured true benefit
• ISIS-4 (1995):
  • 58,050pts oral isosorbide mononitrate 30-60mg daily vs placebo for 4wks post-AMI:
    • non-significant 3% reduction in mortality
    • reduced chest pain but not cardiogenic shock
    • caused headache & hypotension severe enough to require termination of Rx
  • NB. many placebo pts also received IV GTN too thus may have obscured true benefit

• nifedipine:
  • TRENT (1986):
    • 4,491pts nifedipine 10mg qid vs placebo post-suspected AMI:
      • non-significant 7% increase in mortality at 1 month
  • SPRINT I (1988):
    • nifedipine vs placebo post AMI:
      • non-significant increase in mortality of 7%
  • SPRINT II (1993):
    • 1,358 pts nifedipine 20mg tds post AMI:
      • terminated as nonsignificant 33% increase in early mortality
  • metanalysis of nifedipine trials post-AMI (1995):
    • 8,350pts 16% increase in mortality, possible dose-related relationship evident!
• non-dihydropyridines:
  • verapamil:
    • DAVIT I (1984), DAVIT II (1990), CRIS (1996):
      • verapamil post-AMI
        • no significant effect on mortality however, in DAVIT II, 20% reduction in mortality in 1st major events due to cardiovascular causes
    • metanalysis:
      • no significant decrease in mortality (RR 0.93 with 0.78-1.10 95% CI)
      • 19% reduction in re-infarction
  • diltiazem:
    • MDPIT (1988):
      • 2,466 pts post AMI:
        • nonsign. 2% increase in mortality
        • pts with pulm. congestion ⇒ 41% increase in cardiac events
        • pts without pulm. congestion ⇒ 23% decrease in cardiac events
        • cardiac events = death from cardiac causes or nonfatal reinfarction
        • need further study of subgroups to determine if chance or causal.
• in US National Registry of MI b/n 1990-1993:
  • 30-40% of 240,989 pts with AMI were given Ca channel blockers!!!

• VW class I drugs:
  • CAST (1991):
    • encainide, flecainide or moricizine long term:
      • encainide or flecainide group terminated at 10mths:
        • of 1498 pts treated, 89 died:
          • 59 of arrhythmia (43 taking drug, 19 on placebo)
          • 22 of other cardiac causes (17 taking drug, 5 on placebo)
          • 8 of noncardiac causes
      • moricizine group terminated later:
        • higher mortality in initial 14 day period & small probability that drug would deccrease mortality even if trial completed
  • metanalysis of 18 long term trials of 6300pts post-AMI Rx with V-W class I drugs (1993):
    • 21% increase in mortality
• amiodarone:
  • trials are more promising but more limited
  • BASIS (1990):
    • 212pts with complex VE's: amiodarone 1000mg 5 days then 200mg/d vs placebo:
      • reduction in arrhythmic events
      • 61% reduction in overall mortality at 1 yr
  • metanalysis (1993) of 9 trials 1557pts, 21% reduction in mortality
  • CAMIAT:
  • EMIAT:
• sotalol:
  • UK l-sotalol trial (1982):
    • no significant reduction in either mortality or sudden death
  • SWORD (1995):
    • 3121 pts with LV dysfunction postAMI: d-sotalol vs placebo
    • terminated as increase mortality

• LIMIT-2 (1992):
  • 2,316 pts with AMI: IV MgSO4 8mmol over 5min then 65mmol over 24h vs placebo:
    • Mg started at same time as thrombolytic Rx
    • median time from onset of chest pain to randomisation was 3hrs
    • 36% pts received thrombolytic Rx
    • 24% reduction in mortality
• metanalysis (1993):
  • IV MgSO4 conferred 39% reduction in mortality, 27% reduction in heart failure
• ISIS-4 (1995):
  • 58,050 pts with AMI: IV MgSO4 8mmol over 15min then 72mmol over 24h vs placebo:
  • Mg started “after the 1st hour or so of thrombolytic Rx”
  • median time from onset of chest pain to randomisation was 8hrs
  • 70% pts received thrombolytic Rx
  • nonsignif. 6% increase in mortality
  • significant increases in: heart failure, death due to cardiogenic shock, bradycardia
  • this contradiction of earlier studies may be due to the longer time between start of myocardial reperfusion & the achievement of therapeutic serum Mg levels
  • however, even in subgroups no significant reductions in mortality were found:
    • pts Rx < 6h after onset of pain
    • pts receiving Mg within 2h of thrombolytic Rx
    • pts receiving neither thrombolytic Rx nor aspirin

• ISIS-1: atenolol in AMI Lancet 1986 2: 57-66
• TIMI-IIB: immediate vs delayed metoprolol Circulation 1991 83:422-37
• CAST: encainide or flecainide in VE suppression. NEJM 1991 324: 781-8
• LIMIT-2: IV MgSO4 in AMI. Lancet 1992 339: 1553-8
• ANZ J of Med supplement - Thrombolysis '93.
• Goodman & Gilman 8th ed. 1990.
• GISSI-3: lisinopril, transdermal nitrate in AMI. Lancet 1994 343: 1115-22
• ISIS-4: early oral captopril, mononitrate & IV magnesium in AMI Lancet 1995 345:669-85
• Wood AJJ Adjunctive drug Rx of AMI - evidence from clinical trials NEJM Nov 28 1996 335(22): 1660-1667
• GUSTO III: reteplase vs alteplase in AMI. N Engl J Med 1997: 337: 1118-23
• TIMI 10B: TNK vs front-loaded alteplase in AMI Circulation 1998 98:2805-14
• ASSENT-1: TNK, tenecteplase in AMI. Am Heart J 1999 137:786-91
• ASSENT-2: tenecteplase vs alteplase in AMI. Lancet 28 Aug 1999 354: 716-722