WARIS II

Warfarin, Aspirin or Both after Myocardial Infarction (2002)

Design: Multicenter, open-label RCT

 P  < 75 yo, hospitalized for AMI (i.e. SECONDARY prevention)

Excluded: indication or CI for study drugs, malignancy, poor compliance

Mean duration of observation: 4 years

 I
  • Warfarin (target INR 2.8-4.2)
  • ASA 75mg daily + Warfarin (target INR 2-2.5)
 C
  •  ASA 160mg daily
 O Primary outcome: composite of death, non-fatal reinfarction, or thromboembolic cerebral stroke

  • Intention to treat analysis

Versus ASA alone

  • RR for warfarin + ASA: 29% (P = 0.001), NNT = 67
  • RR for warfarin alone: 19% (P = 0.03), NNT = 100
  • NSS in mortality (benefit with non-fatal reinfarction and TE stroke)
    • TE stroke for combination + warfarin alone ~ same (Rate ratio: 0.52)
    • Benefit for reinfarction for combination > warfarin alone
      (Rate ratio: 0.56 for combination vs. 0.74 for warfarin alone)

Safety:

  • NNH for 1 major bleeding episode:
    • 250 for warfarin + ASA
    • 200 for warfarin alone

Take-away points:

  • Main benefit of warfarin + ASA or warfarin alone over ASA for secondary prevention for MI is the:
    Prevention of non-fatal reinfarction and TE stroke

    • No SS difference in mortality
  • But…comes with increased bleeding
    • Increased major bleeding with combination + warfarin > ASA
      • 4 times as many major bleeding
    • Increased minor bleeding with combination
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PEACE ✌

Prevention of Events with Angiotensin Converting Enzyme Inhibiton Trial (2004)

Design:  Double-blinded, Placebo-controlled RCT

Objective: When added to “modern conventional therapy”, does ACEI reduce the rate of nonfatal MI, CV death or revascularization in low risk patients with stable CAD and normal or slightly reduced LV function?

  • HOPE and EUROPA – CAD, vascular dx or diabtests and another CV risk factor – reduced rates of CV death or AMI with ACEI (Ramipril + Perindopril)
    • both trials enrolled patients without a history of HF
 P  N = 8290
> 50 yo, stable CAD, LVEF >40%, toleration of medication and successful completion of the run-in phase with >80% compliance with medication (trandolapril 2mg daily)

  • ~55% patients had documented MI

Excluded: valvular heart dx requriing surgical intervention, CABG or hospitalization for USA within preceding 3 mos (CABG) + 2 mos (USA), female + not using contraception
Median follow up of 4.8 years

 I Trandolapril 4mg daily
 C Placebo
 O  Primary end point: death from CV causes, MI or coronary revasularization

  • Primary endpoint: T: 21.9% vs. P: 22.5% (HR: 0.88-1.06, P = 0.43)
    • Sub-group analysis: NSS
  • BP dropped 4.4 + 0.3/3.6 + 0.2 in trandolapril group after 36 mos (SS difference vs. placebo)
  • NSS for efficacy endpoints – except:
    CHF as primary cause of hospitalization (HR: 0.75 (0.59-0.95), P = 0.02
    Onset of diabetes (HR: 0.83 (0.72-0.96), P = 0.01

Safety:

  • SEs leading to D/C: T: 14.4%, P: 6.5% (P<0.001)
    • Most commonly cough and syncope

Take-away points:

  • SAVE (1992 – captopril), SOLVD (1991 – enalapril): ACEI decreased mortality and rate of development or worsening of symptomatic HF and asymptomatic LV dysfunction + decreased rate of subsequent MI
  • HOPE (2000-ramipril): high risk patients with vascular disease (incl. CAD) or diabetes with NO HF or low EF – ramipril reduced CV death, nonfatal MI, or stroke
  • EUROPA (2003- perindopril): Stable CAD without HF (lower risk than HOPE patients) – perindopril showed reduction in CV death, nonfatal MI, or cardiac arrest
  • PEACE trial patients: more intensive management of risk factors (greater % of patients on lipid lowering therapy and coronary re-vascularized)
  • ?benefit of ACEIs in all patients for CV benefit in “newer era” of MI management
    • Trandolapril – no benefit in “low risk patients” and normal EF who are on optimal therapy for MI management
  • Trandolapril in HF: TRACE (1995): post-MI HF – Trandolapril 4mg daily reduced the risk of CV death, sudden death and progression to severe HF, but no difference in recurrent MI
  • Consider cost – perindopril up to $1.26 per tablet vs. ramipril up to $0.20 per capsule

Reference:

COMMIT/CCS-2 

Title: Clopidogrel and Metoprolol in Myocardial Infarction (2005)

Metoprolol

P: 45852 patients within 24h of suspected acute MI

I: Metoprolol up to 15mg IV then 200mg po daily until discharge or up to 4 weeks in hospital (mean 15 days in survivors)

C: Matching placebo

O:

Primary outcomes:

  • Composite of death, reinfarction or cardiac arrest
  • Death from any cause during scheduled treatment period

Results:

  • No significant difference for both primary outcomes
  • For reinfarction: OR 0.82 (0.72-0.92, p=0.001) – 5 fewer per 1000
  • For ventricular fibrillation: OR 0.83 (0.75-0.93, p=0.001) – 5 fewer per 1000
  • For cardiogenic shock: OR 1.30 (1.19-1.41, p<0.00001) – 11 more per 1000 (mainly during days 0-1 on admission)
  • Overall effect on death, reinfarction, arrest or shock was significantly adverse during days 0-1 and significantly beneficial thereafter. There was substantial net hazard in hemodynamically unstable patients and moderate net benefit in those who were relatively stable (particularly after days 0-1)

Clinical Pearls/Take-home messages:

  • For MI, BB decreases risk for reinfarction and ventricular fibrillation
  • Caution when starting beta-blockers post-MI as increased risk for cardiogenic shock, especially during the initiation of BB
    • Ensure patients are euvolemic and hemodynamically unstable, prior to starting beta-blocker
  • Monitor for cardiogenic shock:
    • LOC, sweating, pale skin, increased HR, decreased BP, respiratory distress (tachypnea, hypoxemia), decrease in urine output