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A. TIMI (Thrombolysis in Myocardial Infarction)

  1. TIMI-1 [1,2]
    1. TPA 2X better than SK at opening infarct related vessel
    2. This correlated with better wall motion in area of infarct vessel
    3. Overall LV EF not affected
  2. TIMI-2 and 2A [3,4]
    1. tPA with immediate (<2 hours) vs delayed vs no PTCA in acute MI
    2. Heparin, ASA 80mg on day 2; randomized to immediate iv metoprolol vs oral on day 6
    3. 6 month mortality in immediate vs. delayed PTCA no significant difference (~5%)
    4. Metoprolol immediate decreased reinfarction and recurrent ischemia (5% vs.12%, p=0.01)
    5. Metoprolol no effect on Left Ventricular Ejection Fraction (LVEF)
  3. TIMI-3 [5]
    1. Efficacy of low dose TPA (0.8mg/kg; max 80mg) in unstable angina and non-Q MI
    2. No difference in MI or death between patients given TPA or placebo
    3. Randomization also catheterization (with PTCA) versus conservative therapy
    4. No effect of catheterization initially (TIMI-3B)
    5. However, 63% of patients in conservative therapy group required catheterization
    6. PTCA group had fewer post-discharge procedures and hospitalizations vs. conservative
  4. TIMI-4
    1. Assess non-invasive methods for predicting recanalization of infarct related artery
    2. Also assessed use of CPK isoforms of MM and MB to predict patency (also troponin C)
  5. TIMI-5
    1. Hirudin (Revasc®) vs. Heparin in acute MI, all patients received aspirin and tPA
    2. Hirudin is a 65 amino acid leech derived thrombin-specific inhibitor
    3. Hirudin showed trend with early improved perfusion and less reocclusion
    4. Death and reinfarction were reduced slightly with hirudin compared to heparin
    5. These data were confirmed in GUSTO IIb trial (see below)
  6. TIMI-6 [65]
    1. Hirudin vs. Heparin in acute MI, all patients received aspirin and streptokinase
    2. Death, recurrent MI, were decreased in hirudin (higher doses) vs. heparin
    3. In this acute MI study, incidence of major hemorrhage was similar in all groups
  7. TIMI-7 [66]
    1. Hirulog in unstable angina - dosing optimization
    2. Hirulog is a recombinant thrombin inhibitor related to hirudin (from leech saliva)
    3. Hirulog has consistent anticoagulation action (direct thrombin inhibition)
    4. Reduction in events, easier APTT optimization, lower bleeding for Hirulog vs. heparin
  8. TIMI-8
    1. Bivalirudin (Angiomax®) versus heparin in unstable angina
    2. Study was terminated prematurely in favor of evaluation in angioplasty
  9. TIMI-9 [67]
    1. Hirudin (Revasc®) versus heparin as adjunctive therapy in acute MI
    2. All patients received thrombolytics
    3. TIMI 9A study stopped early due to increased bleeding with hirudin and high dose heparin
    4. TIMI 9B study showed heparin and hirudin had equal efficacy
  10. TIMI-10
    1. New thrombolytic TNK (tenectaplase) in acute MI
    2. Phase 1 trial with dose escalations; no cerebral bleeding observed
  11. TIMI-11
    1. Enoxaparin (Lovenox®) study in unstable angina
    2. Dose finding study is underway
  12. TIMI-18 [92]
    1. 2220 patients with acute coronary syndromes (ACS) without ST segment elevation
    2. Both unstable angina and MI (ST depression or T wave changes) included
    3. All patients received aspirin, heparin, tirofiban (Aggrastat)
    4. Compared definite catheterization within 48 hours versus as-needed invasive strategy
    5. Primary endpoint: composite of death, MI, or rehospitalization for ACS within 6 months
    6. Definite catheterization group had 15.9% versus 19.4% for as-needed group
    7. Supports use of early invasive strategy with tirofiban in ACS

B. ISIS (International Study of Infarct Survival)

  1. ISIS-1
  2. ISIS-2 [6]
    1. SK vs ASA vs SK (1.5 MU)+ASA (160mg) in 17,817 patients; mortality at 5 weeks
    2. First trial to show definite benefit of ASA in treatment of MI - reduced mortality 23%
    3. Aspirin added to SK showed added benefit in acute MI - reduced mortality 46%
    4. Maximal efficacy attained when agents were given within 4 hours of MI
    5. Mortality benefit was still significant effect at 24 hours from onset of MI
  3. ISIS-3 [7]
    1. tPA vs SK vs APSAC (all with ASA 162mg) ± Heparin
    2. 41,299 patients; 92% patients with 12 hours
    3. No significant mortality differences between agents; tPA fewer reinfarctions
    4. Heparin addition definitely decreased recurrent MI's and mortality (but p=0.6)
    5. Mortality benefit seen even with patients treated 6-12 hours from onset of MI
  4. ISIS-4 [46]
    1. 58,000 patients
    2. Magnesium of no benefit in acute MI
    3. Nitrates of no objective benefit in acute MI
    4. Very early ACE inhibition (captopril) appears to improve LV EF and day 35 mortality

C. GUSTO (Global Utilization of SK and TPA for Occluded Coronary Arteries) [9]

  1. GUSTO I
    1. 41,000 patients, 4000 Angiograms performed
    2. Endpoint was 30 day mortality 30d
    3. Treatments: TPA+heparin vs. SK+sc heparin vs SK+iv heparin vs. TPA+SK+ heparin
    4. TPA + Heparin: most rapid opening of vessels in medical trials, lowest mortality ~6%
    5. SK+Heparin: slower to open, poorer EF preservation; mortality ~7%
    6. Catheterization (with angiography) most rapid opening of vessels and best EF
    7. Mortality benefits were maintained at 1 year after treated MI [55]
    8. Cost analysis shows that TPA is overall of cost savings in treatment of MI [45]
  2. GUSTO IIb Study [49,62]
    1. Unstable angina and non-Q wave MI patients
    2. Compared hirudin (direct thrombin inhibitor) with heparin
    3. Also compared primary angioplasty with TPA
    4. Primary angioplasty showed small early benefit over TPA, not seen at 6-months [62]
    5. Primary angioplasty reduces mortality versus medical therapy at 1 year []
  3. GUSTO III [64]
    1. Reteplase is a recombinant mutant TPA lacking finger, kringle-1, and EGF domains
    2. Reteplase has a slower clearance rate compared with normal TPA (alteplase)
    3. In 15,059 patients, no efficacy or safety differences between reteplase and alteplase
  4. GUSTO IV-ACS [90]
    1. 7800 patients with chest pain and ST-depression or raised troponin (T or I) levels
    2. Randomized to placebo, 24, or 48 hours of abciximab
    3. Patients on abciximab had increased risk of MI or death
    4. Thus, in ACS without early revascularization, abciximab is not beneficial [57]
  5. GUSO V [91]
    1. 16,588 patients in first 6 hours of evolving MI with ST-segment elevation
    2. Randomized to full dose reteplase versus half-dose reteplase + abciximab for 12 hours
    3. Half-dose reteplase + abciximab 12 hours may be superior to full dose retaplase
    4. Slightly more bleeding events with combination therapy
  6. Thrombolysis causes more bleeding with fatal outcome in women compared with men [47]

D. GISSI (Gruppo Italiano per lo Studio della Streptochinasi Nell'infarto Miocardico)

  1. GISSI-1 [10]
    1. Streptokinase versus placebo in acute MI in 11,712 patients
    2. In hospital18% reduction in morality with SK given within 6 hours of MI
    3. Benefit 23% in anterior wall MI, insignificant in IMI and Lateral MI
    4. Effects maintained at 12 months
  2. GISSI-2 [11,12]
    1. tPA (100mg over 3 hours) vs SK + s.c. Heparin
    2. 12,490 patients, all on ASA, most on atenolol; given 6 hours from onset of MI
    3. Mortality was 9% with tPA 9% and 8.6% with SK (insignificant difference)
    4. TPA was without heparin; heparin added to SK had no effect (aspirin all groups)
  3. GISSI-3
    1. 20,000 patients
    2. Oral or IV Nitrates are safe but without benefit on objective outcomes at 5 weeks
    3. Nitrates were extremely effective in relieving anginal pain in acute MI
    4. ACE inhibitor (Lisinopril) within 24 hr had lowest post-MI mortality (without nitrates)
    5. Women and patients >70 years showed greatest benefit

E. LATE (Late Assessment of Thrombolytic Efficacy) Trial [13]

  1. 5711 patients, mean age 62; 722% men
  2. Alteplase (recombinant TPA) given to ~50% of patients, all 12-24 hrs post onset of MI
  3. No benefit on mortality when delayed TPA was given

F. ASSENT Study [83,84]

  1. Assessment of the Safety and Efficacy of a New Thrombolytic (Tenecteplase)
  2. Triple combination mutant (called TNK-TPA) of alteplase (TPA)
    1. Plasma half-life 20 minutes (versus 4 minutes for TPA)
    2. Increased fibrin specificity over TPA
    3. More resistant than TPA to inhibition by plasminogen activator inhibitor-1 (PAI-1)
  3. Can be given as single 30-50mg bolus (0.5mg/kg IV)
  4. ASSENT-2 evaluated equivalence to TPA
    1. 16,949 patients enrolled with acute MI <6 hours duration
    2. Rapid infusion (90 minutes) 100mg alteplase (TPA) versus 30-50mg bolus tenecteplase
    3. Mortality at 30 days 6.18% tenecteplase versus 6.15% TPA
    4. Similar rates of intracranial hemorrhage and all cause stroke
    5. Slightly reduced bleeding and transfusion requirements with tenecteplase versus TPA
    6. Rate of death or nonfatal stroke at 30 days 7.11% tenecteplase and 7.04% TPA
  5. Tenecteplase and alteplase have similar efficacy

G. Assent-3 [93]

  1. Tenecteplase with heparin or enoxaparin or abciximab in MI within 6 hours
  2. 6095 patients randomized
    1. Full dose tenecteplase + enoxaparin x 7 days N=2040; events 11.4%
    2. Half-dose tenecteplase + low dose heparin + 12 hours abciximab N=2017; events 11.1%
    3. Full dose tenecteplase with standard heparin N=2038; events 15.4%
  3. Enoxaparin may be as effective as abciximab and is easier to give

H. TAMI (Thrombolysis and Angioplasty in MI) [14]

  1. tPA + immediate versus delayed angioplasty in acute MI; tPA within 6 hhours
  2. All patients got heparin, ASA, diltiazem, persantine
  3. 197 patients randomized to PTCA, age <70
  4. Mortality 4% in immediate vs. delayed 1% (but p=NS)

I. PAMI (Primary Angioplasty in MI) [15]

  1. 395 patients randomized to angioplasty or TPA
  2. Angioplasty total mortality or nonfatal repeat MI 4.3% vs. 13.5% for TPA
  3. Stroke rate 0.3% with angioplasty; 2.9% with thrombolytics
  4. PTCA probably best for anterior MI, where LV function was highly preserved

J. MITI Trial (Myocardial Infarction Triage and Intervention) [50]

  1. Selected from 12,331 acute MI patients treated with angioplasty or thrombolysis
  2. Primary angioplasty on 1050 patients and thrombolytics on 2095 patients
  3. No significant differences between different treatment groups, or amongst subgroups
  4. High risk patients specifically had essentially identical outcomes
  5. Patients who received thrombolytic therapy had lower costs and fewer procedures
  6. Therefore, in this community cohort, there was no benefit to primary angioplasty

K. VANQWISH Trial [71]

  1. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital Trial
  2. 920 patients with Non-Q-Wave MI randomly assigned to invasive or conservative treatment
  3. Invasive treatment was PTCA ± stenting ± glycoprotein IIb/IIIa inhibitors
  4. Conservative management was based on observation of ischemic events
    1. Thrombolytic agents were given as deemed appropriate
    2. PTCA and/or stenting was withheld unless ischemia was observed
    3. Ischemia was defined as either recurrent in hospital, or in a stress test evaluation
  5. At 23 months average followup, similar serious cardiac event rates in both groups
  6. At 12 months and at hospital discharge, routine angioplasty and revascularization had poorer outcomes than ischemia-directed conservative management
  7. There was a tendency towards higher mortality in invasive group at 23 months
  8. PTCA in non-Q wave MI is indicated only for recurrent ischemia or serious exercise- induced ischemia

L. Primary Angioplasty Versus Streptokinase [85]

  1. 395 patients with MI followed for 5±2 years
  2. 194 received primary angioplasty; 201 received streptokinase (SK)
  3. Mortality 13% in angioplasty versus 24% with SK
  4. Nonfatal reinfarction 6% in angioplasty versus 22% with SK
  5. Readmission for heart failure and ischemia was 101 for angioplasty and 180 for SK
  6. Costs per patient were $16,090 for angioplasty and $16,813 for SK

M. Angioplasty with Stents and Abciximab in Acute MI [87]

  1. PTCA + stents + abciximab (gp2b/3a inhitibor) compared with alteplase (thrombolytic)
  2. 140 patients total with acute MI
    1. 71 randomized to stent + abciximab, 69 to alteplase
    2. Evaluations at 6 months
  3. Stents + abciximab led to a reduced infarct size compared to alteplase (14.4% versus 19.4%)
  4. Death, reinfarction or stroke occurred in 23.2% of alteplase group versus 8.5% of stent- abciximab group group at 6 months
  5. Increasing support for PTCA-stent-abciximab for acute Q-wave MI over thrombolysis

MYOCARDIAL INFARCTION - OTHER AGENTS [54]

A. BHAT (Beta-Blockers in Heart Attack Trial) [16]
  1. Propranolol vs. Placebo in 3837 patients with acute MI
  2. Begun 5-21 days post MI
  3. ~25% decrease in mortality at 6 months compared to controls
  4. Similar results in many other trials
  5. Sudden cardiac death lowered by ~50% with ß-blocker use post-MI

B. Other Beta Blocker Trials

  1. Metoprolol has been proven to reduce mortality post-MI given long term [53]
  2. Other agents have been used post-MI and in CHF and reduce mortality
  3. ß-blocker underuse in elderly populations correlated with increased mortality [52]
  4. ß-blockers indicated in essentially all patients post-MI (>200,000 patients studied) [73]

C. ACE Inhibition

  1. CONSENSUS II (Cooperative New Scandinavian Enalapril Survival Study) [17]
    1. Enalapril given within 24 hours to post-MI patients with supine BP >105/60 mm
    2. Dose was escalated beginning at 2.5mg bid then up each day to max 20mg po qd
    3. No improvement in survival during 180d followup post-infarction
  2. SAVE (Survival and Ventricular Enlargement Trial) [18]
    1. Captopril given 3-16 days post-MI in patients with EF <40% without overt CHF
    2. Initial dose 12.5mg po tid escalated to 25mg tid then 50mg tid as tolerated
    3. Captopril decreased MI 25%, cardiovascular death by 21%, CHF by 22%, total death by 19%
  3. See above GISSI-3 and ISIS-4
  4. See below: SOLVD

D. Aspirin (ASA) and/or Warfarin Post-MI [42,43]

  1. Aspirin shows significant prevention of death and cardiovascular events post-MI [40]
  2. This was confirmed in acute MI studies including ISIS-2 [6]
  3. Warfarin has clear efficacy post-MI for decreasing mortality and recurrent MI [41]
  4. Direct comparisons are from older literature and difficult to interpret
  5. Coumadin Aspirin Reinfarction Study (CARS) [63]
    1. ASA 160mg/d vs. ASA 80mg/d + Warfarin 3mg/d vs. ASA 80mg/d + warfarin 1mg/d
    2. 6000 patients evaluated
    3. No benefit of combination therapy over daily aspirin post-MI
  6. Combination Hemotherapy and Mortality Prevention (CHAMP)
    1. ASA 152mg/d vs. ASA 81mg/d + Warfarin (INR 1.5-2.5)
    2. 8000 patients; data in 1998

SURGERY AND CORONARY ARTERY DISEASE

A. Surgical Versus Medical Therapy for CAD [68]
  1. CASS (Coronary Artery Surgery Study) [19]
    1. 780 patients initially with 160 patients actually with Ejection Fraction (EF) 34-50%
    2. 7 year followup with mortality endpoint
    3. No overall survival benefit of surgery for patients with 1V or 2V CAD
    4. At 7 years, survival for 3V CAD with EF 34-50% was 88% surgery versus 65% medicine
  2. VACS (VA Cooperative Study) [20]
    1. 686 patients
    2. 11 year followup
    3. 3V CAD with EF<50% have better survival with surgery than medicine
    4. Left Main disease better with surgery
    5. No LM disease but bad 3V or 2V CAD and multiple risk factors better with surgery
  3. ECSS (European Coronary Surgery Study) [21]
    1. 768 patients
    2. 4 year surgical and 6.5yr medical followup
    3. 3V CAD with EF<50% have better survival with surgery than medicine
  4. Other benefits of Surgery [22]
    1. Relief of Chest Pain
    2. Subjective and objective improvement of functional status
    3. Reduction in drug therapy required for anginal control and activity
    4. Proximal LAD disease better with surgical therapy
    5. Suddent cardiac death 1.6% following surgery vs. ~4.5% with medical control
  5. Summary of Surgical Benefits
    1. 3VD ± Low (<50%) EF
    2. 2VD with proximal LAD lesion (EF <50%) and Symptoms
    3. Left Main Disease
    4. Relief of Pain
    5. Risk of surgical mortality and morbidity increases rapidly with lower EF

B. Surgery Versus Angioplasty for CAD [68]

  1. GABI (German Angioplasty Bypass Surgery Investigation) [23]
    1. CABG 177 patients vs. PTCA 182 patients
    2. Mean 2.2 bypasses/patient vs. mean 1.9 vessels dilated
    3. Equivalent improvement in angina after 1 year
    4. PTCA pts in hospital shorter but required more repeat procedures (44% of PTCA patients)
    5. Peri-procedure Q wave MI more common in CABG (8.1%) vs. PTCA (2.3%)
    6. Anti-anginal medications required in 78% CABG vs. 88% of PTCA groups at 1year
  2. EAST (Emory Angioplasty vs. Surgery Trial) [24]
    1. CABG 194 patients vs. PTCA 198 patients
    2. Endpoints: Death, Q Wave MI, or large thallium reperfusion defect in 3 yrs post-procedure
    3. Endpoints equivalent in PTCA vs. CABG groups
    4. >50% of PTCA vs. ~14% of CABG patients required repeat procedure within 3 years
    5. Angina was found in 20% PTCA patients vs. 12% CABG patients
  3. BARI (Bypass Angioplasty Revascularization Investigation) [48,51,57]
    1. Overall 5 year survival was similar in angioplasty vs. CABG
    2. Overall in-hostpial mortality was ~1.2% (not significantly different between groups)
    3. Subsequent revascularization was 8% in CABG group and 54% in angioplasty group
    4. Diabetics (insulin / non-insulin) had 80% 5 year CABG survival vs. 65% with angioplasty
    5. CABG had better quality of life than angioplasty for >2 vessel CAD [51]
    6. Rest and exertional angina were slightly (~5%) higher in angioplasty than CABG [57]
    7. Overall costs after 5 years were lower for angioplasty only for 2 vessel CAD
  4. RITA-1 (Randomized Treatment of Angina) [74,75,76]
    1. 1011 patients with CAD (45% single and 55% mutlivessel)
    2. Randomly assigned PTCA or CABG
    3. CABG patients cost more initially and had longer periods of recovery
    4. PTCA patients initially required more angina medications and repeat interventions
    5. Most revascularization procedures occurred during the first year
    6. After 7 years of followup, no differences in angina or overall costs

C. Severe, Refractory Angina

  1. Transmyocardial laser revascularization (TMR) used in Class III and IV refractory angina
  2. PACIFIC Trial [88]
    1. 221 patients with reversibloe ischemia Class III or IV
    2. Ineligible for PTCA or CABG
    3. Severe asthma on medical therapy
    4. Randomized to medical therapy ± TMR
    5. TMR improved exercise tolerance, angina, and quality of life
    6. TMR had low morbidity

ATRIAL FIBRILLATION (AF) TRIALS

A. AF and Stroke Prevention
  1. Risk [25]
    1. RHD associated AF carries a stroke risk ~17% per year
    2. Non-Valvular AF carries a risk ~5% per year
  2. AFASAK [26]
    1. Warfarin INR 2.8-4.2 vs. 75mg ASA qd vs. placebo
    2. Chronic non-RHD AF
    3. 59% stroke decrease with warfarin vs. 13% ASA group
  3. SPAF (Stroke Prevention in Atrial Fibrillation) I [27] and II [28]
    1. Warfarin 1.3-1.8X control (INR ~2.0-4.5) vs. ASA 325mg vs. Placebo
    2. Chronic or intermittant AF
    3. 67% stroke decrease with warfarin vs. 42% with ASA in SPAF I
    4. No significant difference between warfarin and ASA in SPAF II
    5. ASA had decrased risk of complications compared to high dose anti-coagulation
  4. SPAF III [69,70]
    1. ASA + lose fixed dose warfarin far less effective than warfarin INR 2-3 [69]
    2. Nonvalvular AFib patients without cardiovascular risk factors treated with ASA 325mg/d have very low incidence of ischemic and ischemic-disabling strokes [70]
    3. Low risk includes lack of CHF, LVEF>25%, no history of thromboembolism, or female sex at age >75 years
    4. Overall incidence of ischemic stroke in low risk population on ASA was 2.2%/year [70]
  5. BAATAF (Boston Area Anti-Coagulation in Treatment of Atrial Fibrillation) [29]
    1. Warfarin (1.2-1.5X control; INR ~1.7-2.2) vs. Placebo
    2. Non-RHD RF showed 86% stroke decrease with warfarin
  6. VA Study
    1. Warfarin (1.2-1.5X control; INR ~1.7-2.2) vs. Placebo
    2. Non-RHD AF
    3. 72% stroke decrease with warfarin vs. placebo (benefit also to patients >70 yrs old)
  7. Secondary Prevention of Stroke from Atrial Fibrillation (European AF Trial, EAFT) [30]
    1. All patients had non-Rheumatic AFib and were post-TIA or Minor Stroke
    2. Randomized to Coumadin, Aspirin, or palcebo
    3. Placebo group had ~17% adverse events per yr, similar for aspirin
    4. Coumadin very effective with only 8% per year events
    5. Bleeding 2.8% with coumadin (INR 2-4) vs. placebo 0.7% and ASA 0.9% per year
  8. Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study [72]
    1. 677 patients with non-Rheumatic AFib, median age 74 years
    2. Rate of stroke was measured after 1 year in 4 different intervention groups:
    3. MInidose warfarin (1.25mg/d): 5.8% stroke rate at 1 year
    4. Minidose warfarin + aspirin 300mg/d: 7.2%
    5. Aspirin 300mg/d: 3.6%
    6. Adjusted dose warfarin (INR 2.0-3.0): 2.8%
    7. No statistically significant differences, though trends favored adjusted dose warfarin
  9. Cardioversion without Long-Term Anticoagulation [31]
    1. Use of transesophageal echocardiography to detect clots pre-cardioversion
    2. Clots usually form in the atrial, especially the atrial appendage, due to poor blood flow
    3. Absence of clot in atrium predicts good outcome with cardioversion
    4. Presence of clot usually requires 4-6 weeks of anticoagulation prior to cardioversion
    5. Clots may form 3-4 weeks after cardioversion, so warfarin is usually given
  10. Anti-coagulation is not necessary in pure atrial flutter [32]

B. Rate Versus Rhythm Control in AF

  1. Restoration of normal sinus rhythm (NSR) versus rate control (both often desired)
  2. Pharmacological Intervention in AF (PIAF) Trial [89]
    1. 252 patients with AF for 7-360 days randomized to rate or rhythm control
    2. Rate control with escalating levels of diltiazem (other drugs added if needed)
    3. Amiodarone (low dose) used as first line antiarrhythmic
    4. Electrical cardioversion was added in those patients who did not convert on amiodarone
    5. Overall, rate versus rhythm control yielded similar clinical results
    6. However, exercise tolerance is better with rhythm control
    7. Increased drop outs in amiodarone versus diltiazem group due to drug effects

CONGESTIVE HEART FAILURE

A. Ve-HeFT I (Veterans' Administration Heart Failure Trial I) [33]
  1. All male patients on digoxin and diuretics
  2. Hydralazine (75mg qid) + ISDN (160mg/d) versus Prazosin 20mg vs. placebo
  3. Mortality at 2 years was 26% in Hydralazine/ISDN and 34% in placebo and prazosin groups

B. Ve-HeFT II (Veterans' Administration Heart Failure Trial II) [34]

  1. Enalapril versus vasodilator tx (Hydralazine + ISDN) in CHF in men on digoxin + diuretics
  2. Patients had NYHA I-III CHF
  3. 28% reduction in mortality at 2 yrs with enalapril (20mg qd) vs. vasodilator combination

C. The CONSENSUS Trial [35]

  1. Enalapril 2.5-40mg po qd to patients with severe CHF (NYHA IV)
  2. 93% of patients were on digoxin; most were on nitrates and diuretics
  3. At 6 months, enalpril mortality was 25% vs. 44% for placebo

D. The SOLVD (Studies of Left Ventricular Dysfunction) Trial [8,36]

  1. NYHA Class II and III; EF<36%
  2. Enalapril 2.5-20mg po qd vs placebo added to conventional therapy
  3. CHF Deaths decreased 22%, 16% overall lower total deaths at 41.4 months average
  4. In patients with reduced EF and no symptoms of CHF, enalapril improved outcomes [59]
  5. Analysis of large number of ACE inhibitor trials confirms these data [44]

E. Acute Infarction Ramipril Efficacy (AIRE) [60,61]

  1. 603 patients post-MI randomized to ramipril (302 patients) or placebo
  2. Mean time from MI to randomization was 5 days
  3. At hospital discharge, 14% of ramipril and 5% of placebo patients were not receiving drug
  4. At 1, 6 and 12 months, ramipril had a >35% risk reduction of death
  5. At 24 months, reduction was not significant, but there were many more deaths in placebo
  6. Therefore, ACE inhibition with ramipril post-MI was highly effective in reducing death
  7. Ramipril (2.5-5.0mg bid) also reduced CHF episodes and overall morbidity

F. Trandolapril Cardiac Evaluation Study (TRACE) [81,82]

  1. 6676 patients with acute MI and ejection fraction <35%
  2. Randomized to trandolapril or placebo after MI
  3. Minimum treatment and followup was 2 years
  4. Life expectancy increased from 4.6 years (placebo) to 6.2 years for trandolapril
  5. No decrease in benefit of treatment with time

G. Evaluation of Losartan in the Elderly (ELITE I and II) Studies [58,86]

  1. Use of Losartan, an Angiotensin II Receptor Blocker (ARB)
  2. ELITE I [58]
    1. Patients >64 years old with NYHA Class II-IV (95% were II and III) CHF, EF<40%
    2. 722 ACE inhibitor naive patients randomized to losartan 50mg qd or captopril 50mg tid
    3. Discontinuations were 12% for losartan, 20% for captopril
    4. Death and/or hospital admissions for CHF were 9.4% for losartan, 13.2% captopril (p=0.075)
    5. No difference in renal dysfunction, which was primary endpoint
    6. NYHA Class improved equally in both groups
  3. ELITE II [86]
    1. Patients 60 years or older, NYHA Class II-IV with EF<40%
    2. 3152 patients randomized to losartan 50mg qd or captopril 50mg tid
    3. Median followup 555 days
    4. Mortality was similar in the two groups (p>0.05)
    5. Discontinuation due to adverse events lower with losartan (9.7%) than captopril (14.7%)
    6. Cough leading to discontinuation 0.3% in losartan group, 2.7% in captopril
  4. Conclusion from the ELITE studies is efficacy similarity between ACE-I and ARB

H. ß-Adrenergic Blocker Studies

  1. Metoprolol in Dilated Cardiomyopathy (MDC) [77]
  2. Carvidilol [78,79]
    1. Two trials have shown reduction in mortality and morbidity
    2. Slow escalation of drug is required
  3. Cardiac Insufficiency Bisoprolol Study (CIBIS II) [80]
    1. 2647 patients with Class III or IV CHF with EF <35%
    2. All patients received diuretics + ACE inhibitors
    3. Initiate bisoprolol 1.25mg/d or placebo; maximum bisoprolol 10mg/d
    4. Mortality reduction 34% and sudden death reduction 44% with bisoprolol
    5. Generally well tolerated therapy
    6. Main effect on arrhythmia reduction

I. Hydralazine - Captopril Comparison Study (Hy-C) [37]

  1. Captopril /ISDN versus Hydralazine/ISDN NYHA Class III/IV
  2. One year survival increased in captopril versus hydralazine group

J. Digoxin Studies

  1. PROVED [38]
    1. Prospective Randomized Study of Ventricular Failure and the Efficacy of Digoxin
    2. Digitalis has been shown to decrease mortality from CHF
    3. Mortality reduced only when used in combinations with diuretics (eg. furosemide)
  2. RADIANCE: Digoxin and ACE Inhibitors [39]
    1. Randomized assessment of Digoxin on Inhibotrs of the ACE Enzyme
    2. Digitalis + ACE Inhibitors versus ACE inhibitor therapy alone in EF 35% Class II or III CHF
    3. Addition of digoxin improved symptoms, ejection fraction, delayed progression of CHF
  3. Digitalis Investigation Group [56]
    1. Largest prospective, randomized controlled study to date (6800 patients)
    2. Patients with EF < 45% in main trial group (average ~28%)
    3. Mainly Class II and III CHF followed over an average of 37 months
    4. Digoxin reduced overall hospitalizations but not overall mortality
    5. Trend toward reduced death attributable to worsening CHF

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