Important Trials

    .

    Cardiovascular

    Ischemic Heart Disease

    • HOPE Trial - Ramipril 10mg PO OD in 10k patients w/ vascular disease or DMII had decreased death rates from: 

       - Cardiovascular causes (6.1 vs. 8.1%)

       - MI (9.9 vs. 12.3%) 

       - Stroke (3.4 vs. 4.9%)

       - All-cause mortality (10.4 vs. 12.2%)

       - Revasc procedures (16.0 vs. 18.3%)

       - Cardiac Arrest, heart failure (8.0 vs. 11.5), DMII complications

    • Comparative effectivness of ARBs for macrovascular complications in DMII    

      • Inclusion: Ontario, DMII, >66yrs

      • Outcome: admission to hospital for acute MI, stroke, heart failure. 

        • Secondary: all cause mortality

      • Telmisartan and valsartan better than irbesartan + no difference between irbesartan and other ARBs such as candesartan, losartan.

      • Telmisartan and valsartan preferred ARBs (funded by Merck + Pfizer)

     

    Secondary Prevention of MI

    ACE Inhibitors

    • SAVE Trial (1992)
      • 2231pts(3-16d post-MI, EF ≤ 40%, No HF) [DB, RCT captopril vs. placebo]
      • Follow-up 42mo:
        • All-cause Mortality: (RRR 20%)
        • Less CV events (RRR 21%)
        • Less HF development (RRR 22%)
        • Less MI (RRR 25%)
      • Notes:
        • Many patients were on BB, and BB provided an independent benefit of ACEi
    • ​AIRE (1993)
      • 2006pts with HF anytime post-MI (DB, RCT, ITT, ramipril vs. placebo)
        • Treated day 3-10 after MI with ramipril or placebo
      • After 6 (minimum) and 15 (average) followup:
        • Mortality: 6% ARR (23% --> 17%)
      • Notes:
        • Many patients were on BB, and BB provided an independent benefit of ACEi
    • HOPE (2000)
      • 9297pts >55yo
        + (1 of CAD / Stroke / PVD / DMII)
        + (1 RF: HTN, Smoking, DMII, Diabetes, Macroalbuminuria)
      • ramipril 10mg vs. placebo
      • Outcomes:
        • hoperesults.png

      • Criticism: Many had suboptimal management with BB, statins, etc..

    Beta Blockers

    • BHAT Trial (1983)
      • 3837pts post-MI (norwegian study) propranolol vs. placebo
      • Follow-up: 27mo
    • CAPRICORN Study
      • patients post-MI with LV dysfunction (EF≤40%) [with or without symptoms of HF]
        • Carvedilol vs. placebo (>80% pts were already on ACEi antiplatlets etc)
      • Secondary endpoint: re-infarction rates better

    Antiplatelet Drugs

    • CURRENT-OASIS 7
      • 75-100mg = 300-325mg of ASA  (325 had more GI bleeds)
      • Conclusion: Use low dose ASA
      • Similar Conclusion in HORIZONS-AMI Trial (revascularized patients)
    • CURE Trial
      • Clopidogrel in Unstable angina to prevent Recurrent Events
      • Clopidogrel+ASA vs. Placebo + ASA in patients with NSTEMI/UA
        • Result: 1.2% ARR in composite death, stroke or MI [from 10.4 to 9.2 per cent (NNT=86)]
        • 1% absolute increase risk of major bleeds (NNH=100)
      • COMMIT Trial
        • Similar to CURE, but in STEMI patients
        • Similar results to CURE
        • No difference in fatal bleeding

     

     

    Lipid Management

     

     

    • JUPITER Trial  (Justification for Use of statins, in Prevention: an Intervention Trial Eval Rosuvastatin)

      • Rosuvastatin in pts with high CRP.

        • Inclusion: 17,802 people, men > 50, and women > 60,  with LDL < 3.4 mmol/L and CRP ≥ 2.0mg.

        • Placebo vs. Rosuvastatin 20mg PO OD.

        • Combind Primary End-Point: MI, Stroke, Arterial Revasc, hospital adm for unstable angina, death from CVD.

      • Results:

        • Stopped after median 1.9y F/U (max 5.0).

        • Rosuvastatin decr LDL by 50% and CRP by 37%.

        • Primary endpoint rates: 0.77 vs. 1.36 per 100 person years.

        • Decreased:

          • MI (0.37--> 0.17)

          • Stroke (0.34 --> 0.18)

          • Revasc for UA (0.77-> 0

          • MI+Stroke+Death from CVD (0.85--> 0.45)

        • S/E: --> no myopathy, no cancer, but highet physician-reported diabetes.

    • ACCORD Trial 

        • ​Simvastatin + Fenofibrate --> No benefit in CVD mortality        
        • Subgroup analysis Possible benefit fibrates in group with high TG (>2.3) and low HDL-C (<0.88) [converted US units]
        • Not as conclusive, weak evidence, only one trial.  (2014)
    • STICH Trial

      • Post-Hoc Analysis: After revascularization, was there a survival difference in patients who had viable myocardium vs. those that had not?

      • Baseline finding of substantial viable myocardium did not have a significant impact on all-cause mortality at 5 years when compared to medical therapy with bypass surgery vs. medical therapy w/o bypass surgery.

      • Implying that viability assessment alone should not be primary deciding factor in treatment.

      • Controversial, a randomized trial assessing outcomes of viable vs. non-viable myocardium never done as of 2014.

     

    Congestive Heart Failure

    • CHARM-Preserved Study
      • Candesartan vs. placebo in diastolic heart failure with preserved systolic function.
        • Inclusion: Heart failure Class II, III, IV + hospitalization for cardiac, and EVEF >40%.
        • Pts were taking B-blockers, diuretics, CCB, spironolactone etc..
        • 36mo follow-up.
      • Result:
        • 1. Significantly fewer hospitalizations for HF.
        • 2. Non-significant reduction trend of composite end-point. (Less death from cardiac causes)
        • 3. NO DIFFERENCE: stroke, MI, coronary PCI
    • DOSE Trial (CHF Diuretic Strategies)
      • Loop diuretics infusion vs. BID dosing AND low dose vs. high dose.
        • Primary Endpoints: global symptoms and patient-reported dyspnea.
        • Used IV furosemide, and converted all other diuretics to furosemide (incl thiazide).
        • 1. Infusion vs. Bolus BID:
          • NO DIFFERENCE in symptoms
          • NO DIFFERENCE in likelihood to change to oral diuretics.
          • NO DIFFERENCE in hospitalizations and serum creatinine.
        • 2. Low dose (IV furosemide equivalent) Vs. High dose strategy (IV lasix * 2.5)
          • High dose strategy --> more fluid loss, more weight loss, less dyspnea, less adverse events, more likely to switch to PO at 48hrs.
          • However: higher creatinine levels in high dose strategy (avg 26 increase), but no difference in outcomes at 60 days.  (CONSINSTENT with prev research: slight worsening renal function acceptable for better symptom management and no change in outcome).
        • No difference in all strategies with: alive and out of hospital days.
    • RALES TRIAL (Spironolactone in CHF)
      • Inclusion: patients with decrased systolic function?, 120 baseline creatinine.
      • Helped reduce rates of hospitalizations, creased cardiac events.
      • HOWEVER: Increased hyperkalemia rates (esp if K+ already high >4.5 and esp if high creatinine).

    Atrial Fibrillation

    • AFFIRM Trial

      • Rate Control vs. Rhythm Control in Patient with Atrial Fibrillation

        • Cardioversion and treatment with antiarrhythmic drugs or rate control.  Used anticoag in both.

        • Primary endpoint: overall mortality

        • 4060 patients rhytm control VS rate control:

          • Survival advantage not significant (5-year mortality 23.8% vs. 21.3%)

          • More patients were hospitalized in rhythm control strategy

          • More adverse drug events in the rhythm control group

        • Side note: majority of strokes occured when warfarin was stopped or subtheraputic.

    • RACE I Trial

      • Rate control vs. Rhythm Control in persistent Atrial fibrillation

      • Rate control is non-inferior to rhythm control.

    • RACE II Trial

      • Atrial Fibrillation: Strict (<80bpm) rate control vs. Lenient (<110bpm) rate control

        • Primary outcome: Composite death from cardiovascular causes.

        • Incidence 12.9% in lenient-control vs. 14.9 in strict control.

        • Frequency of adverse symptoms were the same, but success to reach target higher in lenient control (97.7 vs. 67.0%), and fewer total visits (75 vs. 684).

          • However, actual HR in both groups were 75 and 86 bpmrespectively

          • Thus, the trial was not that lenient

          • Few patients had HR > 100 bpm

     

     

    Resuscitation

    • SAFE Trial
      • Albumin vs. NS for fluid resuscitation in ICU
        • Multicenter, randomized, double-blinded study to compare effect of fluid resuscitation with albumin or saline on mortality in ICU.​ 
        • 4% Albumin vs. Normal Saline
        • 7000 Patients randomized:
          • No difference in relative risk of death.
          • No difference in days spent in ICU
          • No difference in days spent in hospital.
          • No difference in mechanical ventilation.
          • No difference in days of renal replacement therapy.
        • Subgroup Analysis:
          • Small benefit in using albumin in:
            • Severe Sepsis (0.87 relative risk reduction vs. NS)
            • ARDS (0.93 RRR vs. NS)
          • Increase in death at 2 years in patients with TBI (Traumatic Brain Injury)
            • Albumin increases ICP.
    • Finfer 2011:
      • Albumin = mortality benefit at 28 days in pts with severe sepsis 
      • Subgroup: no difference in pts with or without hypoalbuminemia.
    • FEAST Study (Fluid Expansion as Supportive Therapy)
      • African 3141 children presenting with febrile illness randomized to:
        • Fluid Bolus (20-40mL/kg) vs. Maintenance (albumin or crystalloid)
      • Result: Bolus = worse outcomes (from CV collapse, not from overload)
      • Result: No difference albumin vs. crystalloid

     

     

    PE/DVT

    • CLOT Trial
      • LMWH vs. oral anticoagulation for prevention of recurrent VTE in cancer patients.
        • Compared: Dalteparin 200 IU/kg SC OD x 5-7 days + coumarin x6months (target INR 2.5)
          VS
          Dalteparin alone 200 IU/kg SC  OD for x1 month followed by 150 IU/kg x5months.
        • Outcomes:
          • 0.48 hazard ratio (half the people developed recurrent VTE in LMWH vs. coumarin)
            Dalteparin vs. Coumarin group:
          • No difference in major bleeding risk (6% vs. 4%)
          • No difference in ANY bleeding (14% vs. 19%)
          • Mortality at 6 months: (39% vs. 41%).

    Nephrology

    • SHARP Trial (Study of Heart And Renal Protection)
      • Statin + Ezetimibe decreased CVD rates in patients with CKD.  (only indication for statin+ non-statin lipid lowering).
      • However, there was no statin-only arm in this trial.
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