MATCH

Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial (2004)

Managment of ATherothrombosis with Clopidogrel in High-risk patients

Design: Randomised, double-blind, placebo-controlled trial (Dec 2000 – April 2002)

  • 507 centres (stroke units and neurology departments) in 28 countries
P  N = 7599
High risk patients with recent ischemic stroke or TIA and at least one additional vascular risk factor who were already receiving clopidogrel 75mg dailyInclusion:

  • ischemic stroke or transient ischemic attack in the previous 3 months
    • categorised ischemic stroke with the TOAST classification
  • 1 or more of 5 additional risk factors – previous ischemic stroke, previous myocardial infarction, angina pectoris, diabetes mellitus or symptomatic peripheral arterial disease within the previous 3 years

Exclusion:

  • age < 40 yo
  • severe comorbid conditions
  • increased risk of bleeding (clinical evience of severe hepatic insufficiency, current peptic ulceration, history of systemic bleeding or other history of bleeding diathesis or coagulopathy)
  • scheduled for major surgery or vascular surgery
  • contraindications for aspirin or clopidogrel

Patient characteristics – fairly well balanced between treatment arms

  • Mean age ~ 66 yo
  • 37% female
  • Qualifying event – 21% TIA, 79% ischemic stroke
    • TOAST classification:
      • 34% large artery atherosclerosis
      • 53% small vessel occlusion
      • 2-3% cardioembolism
  • 50% 7 days to 1 month from qualifying event
  • 74% none to slight disability (Modified Rankin scale)
  • 26% ischemic stroke history
  • 19% tia history
  • 5% MI history
  • 78% hypertension
  • 68% diabetes
  • 57% hypercholestermia
  • 48% past or current smoker
  • 80% on aspirin at baseline
I Aspirin 75mg daily (+ Clopidogrel 75mg daily)
Duration of treatment + f/u: 18 months
C Placebo daily (+ Clopidogrel 75mg daily)
Duration of treatment + f/u: 18 months
O Primary endpoint: composite of ischemic stroke, myocardial infarction, vascular death (including haemorrhagic death of any origin) or rehospitalization for acute ischemia (including rehospitalization for TIA, angina pectoris or worsening of peripheral arterial disease requiring therapeutic iintervention or urgent revascularization or transient ischemic attack)

Secondary endpoints:

  • individual and various combinations of the primary endpoint
  • any death
  • any stroke

Safety:

  • incidence of life-threatening bleeding (any fatal bleeding event, a drop in hgb of >50g/L, significant hypotension with need for inotropes (haemorrhagic shock), symptomatic intracranial haemorrhage or transfusion of >4 units of RBC or equivalent amount of whole blood) and major bleeding (defined as significant disabling (with persistent sequalae)), intra-ocular bleeding leading to significant loss of vision or transfusion of <3 units of RBC or equivalent amount of whole blood

Analysis: Intention to treat (irrespective of compliance to protocol)
Power: 80% power, N = 7600 – to detect a 14% relative risk reduction
Funding: Sanofi Synthelabo – undertake site monitoring and data management, and provide input into the study by putting employee into the steering committee

Results:

Efficacy:

  • Primary composite endpoint:
    • RRR: 9.5% (CI: -2 to 19.6%)
  • All stroke NSS
  • Ischemic stroke NSS
  • All-cause mortality NSS

Safety:

  • Life-threatening bleeding:
    • ARR: 1.26% (0.64-1.88) p < 0.0001
    • No early increase in life-threatening bleeding and primary intracranial haemorrhage)
    • No report of haemorrhagic transformations of ischemic stroke
  • GI bleeds
    • Life-threatening: 1.4% vs. 0.6%
    • Major: 1.12% vs 0.29%
  • Fatal bleeds: NSS
  • Symptomatic intracranial haemorrhage:
    • ARR: 0.40% (0.04-0.76)
  • Minor bleeding:
    • ARR: 2.16% (1.51-2.81) p < 0.0001
  • symptomatic intracranial haemorrhage was  more frequent in the aspirin group than in patients allocated placebo; however, in both treatment arms, no haemorrhageic transformations of ischemic stroke were reported as life-threatening bleeding (1.4% vs. 0.6% and 1.12% vs. 0.29%

Take-home points:

  • Aspirin ADDED to clopidogrel (not clopidogrel ADDED to aspirin) resulted in signigifantly higher bleeding with no significant efficacy benefit
  • Patient population are “select high-risk patients”

HYVET

Treatment of Hypertension in Patients 80 years of Age or Older (2008)

Design: Double-blinded, placebo-controlled RCT

  • Intention-to-Treat Analysis
P N = 3845
SBP > 160mmHg
I Indapamide 1.5mg SR daily
* If needed to target BP of 150/80mmHg, perindopril 2 or 4mg daily was added
C Placebo
* If needed to target BP of 150/80mmHg, placebo daily was added
O Primary endpoint: fatal or non-fatal stroke

Secondary endpoints: death from any cause, death from cardiovascular causes, death from cardiac causes, death from stroke

Patients:

  • Active treatment: 83.6 + 3.2 yo vs. Placebo: 83.5 + 3.1 yo
  • BP:
    While sitting: 173/90.8
    While standing: 168/88.6
  • Orthostatic hypotension: ~32%
  • HR: 74.5 + 9
  • Cardiac history:
    • CVD ~11.5-12%
    • HTN: 90%
    • Antihypertensive treatment: 64-65%
    • Stroke 6.8%
    • MI: 3.1%
    • HF: 2.9%

Outcomes:

  • Median duration of f/u: 1.8 years
    • Active-treatment:
      25.8% indapamide alone, 23.9% + perindopril 2mg, 49.5% + perindopril 4mg
  • Surrogate markers:
    • Drop in sitting BP:
      Placebo: 14.5+18.5mmHg/6.8+10.5mmHg
      Active treatment: 29.5+15.4mmHg/12.9+9.5mmHg
    • Drop in standing BP:
      Placebo: 13.6+18.9mmHg/7.0+10.9mmHg
      Active treatment: 28.3+16.5mmHg/12.4+10.3mmH
  • Primary endpoint: 30% reduction in the rate (-1 to 51%, P = 0.06)
    • NNT = 11 strokes per 1000 patients treated for 2 years (0-21)
  • Death: 21% reduction in the rate (4-35, P = 0.02)
    • Cardiac-caused death NSS
  • Fatal stroke: 39% reduction in the rate (1-62, P = 0.05)
  • Fatal or non-fatal heart failure: 64% reduction (42-78, P<0.001)
  • Cardiovascular event (death from CV causes or stroke, MI or HF):
    34% reduction (18-47%, P < 0.001)

    • NSS for MI
    • SS for death from stroke (P = 0.06, crosses 1), death from CV causes (P = 0.06, crosses 1) and HF

Safety:

  • NSS in potassium levels, uric acid, glucose, or creatinine
  • Serious ADRs: Placebo (448/1912) vs. Active Tx (358/1933), P = 0.001

CHEP Guidelines:

  • In the very elderly (> 80 yo), SBP < 150mmHg (Grade C)
  • HYVET: BP reduced to 144/77mmHg (15/6.1mmHg lower than placebo group)
    • data safety and monitoring board stopped trial early due to SS efficacy outcomes

Take-away points:

  • ?Restriction to background therapy (more serious ADRs in placebo)
  • HYVET did not study other BP targets – ?benefit vs risk ratio of lower BP targets in this patient population
  • Targeting BP of 150/80 (50% reached target in HYVET after 2 years) with diuretic + ACEI in > 80 yo: SS for reduction in stroke (P=0.06, crosses 1), death from stroke, CV death (P = 0.06, crosses 1), heart failure
    (NSS for MI)

    • Patient population: majority did not have CVD, MI, HF, stroke or orthostatic hypotension – patient population studied was relatively healthy; therefore, results may not be applicable to the general elderly population
  • Safety: tolerability of SBP lowering in higher risk + frailer patients?

MIRACL

Myocardial Ischemia Reduction with Aggressive Cholesterole Lowering (MIRACL)

Design: Randomized double-blinded RCT (2001)

P N = 3086
Adults > 18 yo with unstable angina or Q-wave acute MI
– CP of at least 15 mins duration that occurred at rest or with minimal ertion within the 24 hour period preceding hospitalization and represented a change from their usual anginal pattern
Excluded:
– total cholesterol > 7 mmol/L
– coronary revascularation was planned or anticipated at time of screening 
– PCI within preceding 6 months
– LBBB or paced ventricular rhythm
– NYHA IV CHF
– concurrent tx with other lipid regulating agents except niacin at doses of 500mg/d
– insulin-dependent diabetes
– hepatic dysfunction (ALT > 2x ULN)
– pregnancy/lactation
I Atorvastatin 80mg daily x 16 weeks
between 24-96 hours after hospital admission/presentation of the above
– Compliance 86%
C Matching placebo x 16 weeks
between 24-90 hours after hospital admission/presentation of the above
– 
Compliance 88%
O Primary end point: death, nonfatal acute MI, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization

Secondary end points:
individual occurrence of primary end point, nonfatal stroke, new/worsening CHF requiring hospitalization, worsening angina requiring rehospitalization but without new objective evidence of ischemia, coronary revascularization by surgical or percutaneous means, time to first occurrence of any primary or secondary end point and % of blood lipid levels from baseline to end of study

Patients:

  • 65 yo
  • 85% white
  • 46% unstable angina pectoris, 53% non-Q-wave MI
  • Placebo: 1.4% on lipid-lowering agents vs. Atorvastatin: 0.5% PTA
    – Placebo: 3%, Atorvastatin: 2% after hospitalization
    – ?Difference in baseline risk
  • Baseline mean LDL: 3.2 mmol/L, TG 2.0 mmol/L, HDl 1.2mmol/L

Outcomes:

  • Primary endpoint: RR 0.84 (0.7-1.00; P = 0.048)
    • NNT = 39
    • NSS for death, non-fatal acute MI or cardiac arrest with resuscitation
    • ?Primary endpoint made SS by making it composite
    • Risk of recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization: RR: 0.74 (0.57-0.95, P = 0.02)
  • Risk of incidence of non-fatal stroke: RR: 0.41 (0.20-0.87)
  • Risk of incidence of fatal/non-fatal stroke: RR: 0.50 (0.26-0.99)
    • NNT = 22
    • ?SS of fatal stroke alone
  • Surrogate markers
    • LDL increased in placebo by 12%, and decreased in ator by 40%
    • TG increased in placebo by 9%, and decreased in ator by 16%
    • Minor changes in HDL
  • Safety:
    • Increased abnormal liver transaminases
    • NNT = 54

Take-away points:

  •  In acute post-MI (no revascularization), atorvastatin 80mg daily reduced the risk of
    • recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization
    • non-fatal stroke
  • BUT…increased risk of abnormal liver transaminases (>3 times ULN)

SOAP II

Comparison of Dopamine and Norepinephrine in the Treatment of Shock (2010)

Design: Multicenter, RCT

P N = 1679
I Dopamine
*If BP could not be maintained with a dose of 20ug/kg of body weight for dopamine, open label NE, epinephrine or vasopressin could be added
C Norepinephrine
*If BP could not be maintained with a dose of 0.19ug/kg of body weight for NE, open label NE, epinephrine or vasopressin could be added
O Primary outcome: rate of death at 28 days

  • NSS for rate of death
  • Sub-group analysis: dopamine associated with increased rate of death at 28 days among cardiogenic shock, but not septic or hypovolemic shock

Safety:

  • More arrhythmic events among the patients treated with dopamine
    (24.1% vs. 12.4%, p<0.001)

Take-away points:

  • In cardiogenic shock, norepinephrine is associated with less death at 28 days than dopamine

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

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:

DIG

D: Randomized, double-blind, placebo-controlled trial (1997)

P N = 6800, HF and LVEF < 45%, NSR
302 clinical centers in US and CanadaExcluded: afib/flutter, cardiac surgery or PCI within previous 4 weeks or need for cardiac surgery or PCI in near future
I Digoxin
C Placebo
O Efficacy:

  • NSS for death
  • Hospitalizations for worsening HF – RR: 0.72 (0.66-0.79, p<0.001)
  • Subgroup analysis: high risk patients – those with lower EF or enlarged hearts and those in NYHA III or IV – benefit appeared greater

Safety:

  • Most common reasons for suspected digoxin toxicity: ventricular fibrillation or tachycardia, supraventricular arrhythmia, 2nd or 3rd degree AV block

**Retrospective Analysis: Relationship of serum digoxin concentration to mortality and morbidity in the DIG trial** (2005):

For women:

  • 0.5-0.9ng/mL: Beneficial effect of digoxin on morbidity and no excess mortality
  • > 1.2ng/mL (= 1.5 nmol/L): Risk for mortality was greater than placebo

**Association of serum digoxin concentration and outcomes in patients with heart failure (2003): Post-hoc analysis of the DIG trial

For men:

  • 0.5-0.8ng/mL: associated with reduction in mortality
  • 0.9-1.1ng/mL: not associated with reduction in mortality
  • > 1.2ng/mL (= 1.5 nmol/L): higher mortality in men

Take-home messages:

  • Efficacy of digoxin in heart failure:
    • Reducing risk for hospitalizations for worsening HF
  • Monitor digoxin trough levels (30min prior to dose)
    • Levels should at least be 8-12 hours after dose
    • CCS AF guidelines: maximum trough digoxin serum concentration: 1.5 nmol/L
      • DIG trial suggests that > 1.5 nmol/L associated with greater mortality in HF
    • CCS compendium for HF
      • Digoxin trough level in HF patients with severe renal dysfunction: <1nmol/L
      • If rapid deterioration in renal fx, hold digoxin and R/A when stable
      • Role of digoxin: in patients who are in SR + moderate to severe symptoms, despite optimized HF therapy → relieve symptoms + reduce hospitalizations
  • Concurrent atrial fibrillation:
    • Digoxin – target HR of <100bpm
    • Not as effective as controlling HR vs BB or CCBs during exercise
      – should not be used as monotherapy for active patients
    • CCS guidelines for atrial fibrillation:
      If used for treating patients with concomitant LV systolic dysfunction, its use should be dictated by the recommendations of the CCS HF Clinical Guidelines

1.0ng/mL = 1.3 mmol/L – associated with increased mortality in HF