HOPE, EUROPA, PEACE - ACEIs in CAD & other high-risk patients without HF or LV systolic dysfunction

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Generalizability: Who do these results apply to?

  • HOPE represents a population of patients at high risk of CVD, the majority of whom had stable CAD
  • EUROPA and PEACE represent a stable CAD population
  • All 3 trials specifically excluded patient with clinical HF or LVEF <40% (though HOPE went to lesser lengths to obtain objective evidence of preserved EF)

Interventions

  • I: ACEI
    • HOPE: Ramipril for up to 5 y (median 4.5 y)
      • Initial: 2.5 mg PO HS x1 week,
      • Then increased to 5 mg PO HS x1 week,
      • Then increased to 10 mg PO HS for the duration of the trial
      • Adherence: 79% still taking at final follow-up visit
    • EUROPA: Perindopril for a mean 4.2 years
      • Initial: 4 mg PO daily x2 weeks (started @ 2 mg if age 70+ y),
      • Then increased to 8 mg PO daily
      • Dose could be reduced to 4 mg daily if higher dose not tolerated
      • Adherence: 81% still taking at 3 y follow-up visit
    • PEACE: Trandolapril for a median 4.8 years
      • Initial: 2 mg PO daily x6 months,
      • Then increased to 4 mg PO daily if tolerated
      • Adherence: 74% still taking at 3 y follow-up visit
  • C: Matching placebo

Results

Individually, HOPE and EUROPA demonstrated statistically significant results in their primary outcome, whereas PEACE did not. Results of PEACE originally seemed contradictory, however, a pooled analysis of these trials demonstrated consistent benefits.

Note: The following results are approximately calculated using the pooled relative risks & absolute risk in each study's placebo group.

  • Statistically significant reduction in:
    • Primary outcome (from PEACE, used for pooled analysis): Odds ratio (OR) 0.82, 95% confidence interval 0.76-0.88
      • 10.7% vs 12.8% (NNT 48)
    • All-cause mortality: OR 0.86 (0.79-0.94)
      • HOPE: 10.5% vs 12.2% (NNT 59)
      • EUROPA: 5.9% vs 6.9% (NNT 100)
      • PEACE: 7.0% vs 8.1% (NNT 91)
    • Non-fatal MI: OR 0.82 (0.75-0.91)
      • HOPE: 6.1% vs 7.5% (NNT 72)
      • EUROPA: 5.1% vs 6.2% (NNT 91)
      • PEACE: 4.3% vs 5.3% (NNT 100)
    • Stroke (fatal or non-fatal): OR 0.77 (0.66-0.89)
      • HOPE: 3.8% vs 4.9% (NNT 91)
      • EUROPA: 1.3% vs 1.7% (NNT 250)
      • PEACE: 1.7% vs 2.2% (NNT 200)
    • Hospital admission for HF: OR 0.77 (0.67-0.90)
      • HOPE: 2.6% vs 3.4% (NNT 125)
      • EUROPA: 1.3% vs 1.7% (NNT 250)
      • PEACE: 2.5% vs 3.2% (NNT 143)
    • Revascularization with CABG: OR 0.87 (0.79-0.96)
      • HOPE: 8.2% vs 9.4% (NNT 84)
      • EUROPA: 4.1% vs 4.7% (NNT 167)
      • PEACE: 6.2% vs 7.1% (NNT 112)
  • No statistically significant difference in revascularization with PCI: OR 0.97 (0.89-1.06)
  • Subgroup analyses showed consistent benefit with no significant difference in relative risk reduction between the following subgroups:
    • Low vs high annual CV risk
    • Revascularized or not (p=0.078 for interaction, both groups statistically significantly beneficial)
    • Optimal medical management (ASA+statin+beta-blocker), partially optimized, or not (p=0.357)
    • BP >140/90 vs <140/90

Issues with internal validity?

  • No; all 3 trials were randomized, allocation concealed, double-blind trials with low loss-to-follow-up (<2%) that adhered to the intention-to-treat principle
  • Run-in phase: All 3 trials had a run-in phase prior to randomization lasting 2-4 weeks

ACTION - Nifedipine for stable CAD

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Poole-Wilson PA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): Randomized controlled trial. Lancet 2004;364:849-57.

Bottom line: In patients with stable angina already treated with at least 1 maintenance anti-anginal drug, nifedipine for 4.5-6 years did not reduce major CV events.

    Patients

    • Inclusion:
      • Age 35+ y
      • Angina stable for at least 1 month
      • Needing treatment of angina (note: not necessarily uncontrolled or symptomatic at baseline)
      • Plus one of the following
        1. Hx of MI
        2. No hx of MI, but angiographically-confirmed CAD
        3. No hx of MI or angiography, but CAD by positive exercise test or perfusion defect
    • Exclusion
      • Overt HF
      • LVEF <40%
      • Any majr CV event or intervention in the past 3 months
      • Planned coronary angiography or intervention
      • Clinically significant valvular or pulmonary disease
      • Unstable insulin-dependent diabetes
      • Any GI disorder that could impair absorption of long-acting nifedipine formulation
      • Any other condition other than CAD that could limit life expectancy
      • Symptomatic orthostatic hypotension, or supine SBP <90 mm Hg
      • SBP 200+ mm Hg, DBP 105+ mm Hg
      • Renal dysfunction (SCr >2x ULN)
      • Liver dysfunction (ALT/AST >3x ULN)
    • From 1996-1998, ? screened -> 7797 randomized -> 7665 analyzed
    • "Average" patient
      • Age 63.5 y
      • Male 80%
      • Enrollment criterion met
        • Hx of MI ~50%
        • No MI, angiographically-confirmed CAD 33%
        • No MI or angiography, but positive exercise or perfusion defect 17%
      • Current NYHA class II-III symptoms 46%
      • Hx of angina attacks 93%
      • Baseline vitals
        • BP 137/80
        • HR 64
      • Mean LVEF 48%
      • Concomitant meds
        • Any anti-anginal drug 99%
          • Beta-blocker 79%
          • Nitrate (daily maintenance) 38%
          • Nitrate PRN use 56%
        • ASA 86%
        • Statin 63%
        • Any BP lowering 30% - ACEI 20%

    Generalizability: Who do these results apply to?

    • Normotensive individuals with CAD without LV dysfunction, most of whom with a previous MI (of unreported age, but at least 3 months ago), already taking at least 1 daily anti-anginal drug.
    • Does not apply to patients with:
      • Recent MI
      • Angina at rest or with minimal activity
      • Optimized secondary prevention therapy
      • Overt HF or reduced LVEF
      • Patients with uncontrolled HTN

    Interventions

    • I: Nifedipine
      • Initial dose: 30 mg PO once daily
      • If initial dose tolerated, increased to 60 mg PO once daily within 6 weeks
      • Dose could be reduced or interrupted
    • C: Matching placebo
    • The following drugs couldn't be used during the study:
      • Non-study calcium-channel blocker (if on prior to study, 2-week washout before study enrollment)
      • Digoxin (unless used for supraventricular arrhythmias such as afib) or other positive inotropes
      • Antiarrhythmics, class I or III (exceptions: amiodarone or sotalol)
      • Cimetidine
      • Anticonvulsants
      • Antipsychotics
      • Rifampicin

    Results @ planned follow-up of 4.5-6 y (97% of patients met minimal planned follow-up)

    • Effect on vitals
      • BP reduced by ~5/3 mm Hg (not reported; estimated from Figure 2)
        • Patients with BP <140/90: 65% vs 53%
      • HR increased by 1 bpm
    • No statistically significant difference in primary composite outcome and multiple components of this outcome
      • Primary outcome (time to first occurrence of either all-cause death, MI, refractory angina, new over HF, debilitating stroke, or peripheral revascularization): ~22% in both groups (hazard ratio 0.97, 95% confidence interval 0.88-1.07, p=0.54)
      • Death: 8% vs 7.6% (HR 1.07, 95% CI 0.91-1.25)
      • Debilitating stroke: 2% vs 2.6% (HR 0.78, 0.58-1.05)
      • MI: 7.0% vs 6.7% (HR 1.04, 0.88-1.24)
      • Refractory angina (defined as angina at rest, prolonged administration of IV nitrates or equivalent plus a coronary angiogram <1 week after onset of symptoms): 3.9% vs 4.5% (HR 0.86, 0.69-1.07)
      • PCI: 10.1% vs 10.9% (HR 0.92, 0.80-1.06)
    • Certain components of the primary composite outcome were statistically reduced with nifedipine
      • New overt HF: 2.2% vs 3.2% (HR 0.71, 0.54-0.94)
      • Coronary angiography: 23.4% vs 27.8% (HR 0.82, 0.75-0.90)
      • CABG: 7.7% 9.7% (HR 0.79, 0.68-0.92)
    • Subgroups: Of 11 subgroup analyses, only separation of patients based on BP 140/90 or greater vs <140/90 had a significant test for interaction (p=0.015), suggesting benefit of nifedipine in patients with CAD + HTN

    Issues with internal validity?

    • No: Randomized, allocation-concealed, blinded (patients, clinicians, investigators) trial with unclear loss-to-follow-up (~5% terminated study earlier than intended) analyzed using a modified intention-to-treat population (all patients who took at least 1 dose of study drug)
    • Note: No run-in phase

    Additional considerations

    • A deeper look at secondary outcomes and subgroup analyses does not clearly support either the role of nifedipine as a antihypertensive drug in patients with CAD, or as an effective anti-anginal.

      • Antihypertensive: Subgroup analysis demonstrated potential benefit in patients with BP 140/90 mm Hg or greater, but there was no statistically significant reduction in debilitating stroke in the overall study population (the outcome most closely associated with HTN in observational studies).

      • Anti-anginal: Though a reduction in the need for coronary angiography and CABG both suggest a reduction in myocardial ischemia, there was no reduction in the proportion of patients with MI, refractory angina, or PCI.

    • The results of this study conflict with those of the previously-covered CAMELOT trial of amlodipine, which argues against a class effect of dihydropyridine calcium-channel blockers in CAD.

    CAMELOT - Amlodipine, enalapril or placebo in CAD

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    Nissen SE, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217-25.

    Bottom line: In patients with symptomatic, angiographically-confirmed CAD without heart failure symptoms or LV dysfunction, amlodipine, but not enalapril, reduced the risk of ischemia-driven outcomes, including coronary revascularization (NNT 26) and hospitalization for angina (NNT 20), consistent with its anti-anginal mechanism.

    Notably, neither amlodipine or enalapril reduced "hard" clinical outcomes, including death, MI or stroke, compared to placebo over the duration of this trial. This likely reflects a low/intermediate-risk population (e.g. risk of MI ~1.5%/year in placebo group) due to high use of other interventions that reduce CV risk, and short study duration.

     

     

    Patients

    • Inclusion:
      • Adults aged 30-79 requiring coronary angiography for evaluation for chest pain or PCI
      • 1 or more lesions in native coronary artery with >20% stenosis
      • Diastolic BP <100 mm Hg by manual BP measurement (could be taking antihypertensives at time of measurement)
    • Exclusion:
      • Moderate-severe HF
      • LVEF <40%
      • Left main coronary artery stenosis >50%
    • 2865 screened -> 1997 randomized -> 1991 analyzed
    • "Average" patient:
      • 58 y
      • Male 75%
      • White 89%
      • Number of coronary arteries with stenosis >20% - 1 (~30%), 2 (~33%), 3 (~35%)
      • BP 129/77
      • PMHx
        • MI 37-40%
        • PCI 26-30%
        • Angina CCS class 4 - 8-9%
        • HTN 60%
        • Diabetes 17-19%
      • Concomitant meds
        • ASA 95%
        • Statin 83%
        • Beta-blocker ~75%
        • Diuretic 26-33%

    Generalizability: Who do these results apply to?

    • These results apply to patients with angina and angiographically-confirmed CAD without hypertension, most of whom did not have a previous MI, with no/minimal HF symptoms & normal LVEF
    • These results do not apply to patients who:
      • Qualify for the HOPE or EUROPA trials
      • Have HFrEF, or who are post-MI with LV dysfunction

    Interventions

    • Intervention 1: Amlodipine
      • Initial dose: 5 mg PO daily
      • If initial dose tolerated, doubled to 10 mg PO daily at end of week 2
      • If intolerable adverse effect, dose halved & uptitration tried at a later point
      • Titrated to full target dose: 86.7%
      • BP reduced by ~5/2 mm Hg
    • Intervention 2: Enalapril
      • Initial dose: 10 mg PO daily
      • If initial dose tolerated, doubled to 20 mg PO daily at end of week 2
      • If intolerable adverse effect, dose halved & uptitration tried at a later point
      • Titrated to full target dose: 84.3%
      • BP reduced by ~5/2 mm Hg
    • Control: Placebo
    • Co-interventions:
      • Diuretics, alpha-1 blockers, & beta-blockers were permitted
      • Non-study ACEI, ARB & CCBs were not permitted (discontinued over 2-6-week period before study initiation)

    Results @ 2 years

    • Statistically significant reduction in the primary outcome with amlodipine, but not enalapril, versus placebo
      • Amlodipine vs placebo: Hazard ratio 0.69 (0.54-0.88)
      • Enalapril vs placebo: HR 0.85 (0.67-1.07)
      • Amlodipine 16.6%, enalapril 20.2%, placebo 23.1%
    • Beneficial effects of amlodipine versus placebo on primary outcome driven by softer, "ischemic" outcomes
      • Coronary revascularization: 11.8% vs 15.7% (NNT 26, p=0.03)
      • Hospitalization for angina: 7.7% vs 12.8% (NNT 20, p=0.002)
    • No statistically significant difference between groups in "hard" clinical outcomes (listed as amlodipine, enalapril, placebo):
      • All-cause mortality, MI or stroke: 3.3%, 3.4%, 4.7%
        • All-cause mortality: 1.1%, 1.2%, 0.9%
        • Non-fatal MI: 2.1%, 1.6%, 2.9%
        • Stroke or TIA: 0.9%, 1.2%, 1.8%
      • Hospitalization for HF: 0.5%, 0.6%, 0.8%
    • Safety:
      • Discontinued study medication: 29.3%, 35.1%, 31.1% (differences between groups not statistically significant, p=0.07)
      • Hypotension: 3.3%, 9.5%, 3.2% (NNH 16 for enalapril vs placebo)
      • Cough: 5.1%, 12.5%, 5.8% (NNH 15 for enalapril vs placebo)
      • Peripheral edema: 32.4%, 9.5%, 9.6% (NNH 5 for amlodipine vs placebo)

    Issues with internal validity?

    • No: Randomized, allocation-concealed, blinded (patients, clinicians & outcome adjudicators) trial with low loss-to-follow-up (<0.5%) analyzed using the intent-to-treat population.
    • Notes:
      • Minor baseline imbalances in baseline characteristics, e.g. age (amlodipine 57.3 y vs enalapril 58.5 y) & history of MI (amlodipine 37.4% versus enalapril 40.3%) do not suggest compromised allocation concealment or impact results
      • 2-week placebo run-in period to exclude non-adherent patients (took <80% of doses).

    Testing: Coronary artery calcium to risk stratify in primary prevention

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    What the test entails

    • Single Computer tomography (CT) scan of the chest using either electron beam CT (EBCT) or multidetector CT (MDCT)
    • A radiologist or cardiologist evaluates the CT images and quantifies calcification of the coronary arteries (a marker of atherosclerotic plaque buildup) using the Agatston score

    Evidence

    A 2004 meta-analysis identified the coronary artery calcium (CAC) score as an independent risk factor for coronary artery disease events (coronary death, non-fatal MI or revascularization)

    • CAC score: odds ratio (OR) for coronary heart disease event
      • No calcification (0): OR 1 (reference)
      • Low (1-100): OR 2.1
      • Medium (101-400): OR 5.4
      • High (>400): OR 10

    The Multi-Ethnic Study of Atherosclerosis (MESA) population-based cohort provides the best evidence for use of the coronary artery calcium (CAC) score in risk stratification.

    • In a primary prevention cohort that included patients with a low (<5%), intermediate (5-20%) and high (>20%) 10-year risk of CVD based on the Framingham risk score, the CAC score was a statistically significant predictor of coronary or total CV events, but added little extra accuracy to the Framingham risk score used alone.
      • Indescriminate testing is the main limitation of these results. There is little value in obtaining a CAC score in a patient who is at low risk of a CV event based on their risk factors. Similarly, a CAC score is unlikely to reclassify a patient with a high Framingham score down into a low-risk category that doesn't warrant treatment.
    • To account with the limitations of the above study, the MESA investigators evaluated the performance of the CAC score (& other novel risk markers) in a sub-cohort of 1330 patients without diabetes with an "intermediate" Framingham score (10-year risk of coronary artery disease of 5-20%) over a median follow-up period of 7.6 years.
      • Addition of CAC score to the Framingham risk score correctly reclassified
        • ~25% of patients from an intermediate- to high-risk group (i.e. changed their estimated 10-year risk of a coronary event from 5-20% to >20%)
        • ~40% of patients from the intermediate- to low-risk group

    Bottom line

    • Patients who should NOT get CAC scoring (low likelihood of altering management)
      • Low Framingham score
      • High Framingham score
      • Patients already receiving primary prevention therapies
      • Patients who have already made a decision for/against medical therapy for primary prevention
    • Patients for whom CAC scoring could be useful
      • Intermediate Framingham score + patient undecided about initiating therapy, or wishing for further stratification
      • High Framingham score + undecided about therapy
    • Clinicians can integrate the CAC score with traditional clinical risk factors to estimate a patient's 10-year CV risk using this calculator.

     

    Prepared by: Ricky Turgeon BSc(Pharm), ACPR, PharmD

    Last updated: 9 Sept 2016

    Calcified LAD

    NORSTENT - Drug-eluting versus bare-metal stent for CAD (short)

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    Bonaa KH, et al. Drug-eluting or bare-metal stents for coronary artery disease. N Engl J Med 2016 [online]

    Bottom-line: In patients with CAD who received PCI with coronary stent placement and received DAPT with ASA + clopidogrel x9 months, there were no difference in death or MI whether patients received 2nd-gen drug-eluting stents or bare-metal stents. 

    Drug-eluting stents reduced the need for further revascularization by 3.3% (absolute) at 6 years.

    Also worth mentioning: Regardless of stent type implanted, patients received 9 months of dual-antiplatelet therapy (DAPT; with clopidogrel). Despite this, patients with drug-eluting stents had lower risk of stent thrombosis than those with bare-metal stents. Combined with the evidence showing no statistically-significant difference in stent thrombosis risk between 3 vs 12 months of DAPT in patients with 2nd-generation drug-eluting stents, this provides evidence against using bare-metal stents in patients with increased risk of bleeding to permit shorter DAPT duration.

     

    Context:

    Patients (n=9013)

    • Multicenter (all 8 Norwegian PCI cneters); every person who got PCI in Norway Sept 2008-Feb 2014 potentially eligible for this trial
    • Inclusion:
      • Adults presenting with stable angina or ACS with lesion in native coronary arteries or coronary-artery grafts amenable to stent implantation
    • Exclusion:
      • Previous coronary stent
      • Bifurcation lesion requiring 2+ stent technique
      • On warfarin
      • Life expectancy <5 y due to condition other than CAD
    • 12,425 eligible -> 9013 randomized
    • Average patient
      • 63 y/o
      • Male 75%
      • Smoker ~35%
      • Diabetes ~13%
      • PCI indication: stable angina 30%, UA 12%, NSTEMI 31%, STEMI 27%
      • Multivessel disease 40%
      • Procedure characteristics: 1-2 stents implanted, total length ~27 mm

    Interventions

    • I: Drug-eluting stent (DES)
      • ost common: Everolimus-eluting (Promus 67%, Xience 15%), zotarolimus-eluting (Endeavor Resolute 11%)
    • C: Bare-metal stent (BMS)
      • Most common: Driver 43%, Integrity 22%, Liberte 18%)
    • Co-interventions common to both groups:
      • ASA 75 mg/d indefinitely
      • Clopidogrel 75 mg/d x9 months
      • Other secondary prevention therapy per current guidelines

    Results @ ~6 years

    • No significant difference in primary outcome (death, non-fatal spontaneous MI)
      • DES 16.6% vs BMS 17.1% (p=0.66)
    • Other non-significant secondary outcomes:
      • Death: 8.5% vs 8.4%
      • Spontaneous MI: 11.4% vs 12.5%
      • Stroke: 3.4% vs 3.0%
    • Statistically-significantly different secondary outcomes:
      • Any revascularization (CABG or PCI): 16.5% vs 19.8% (p<0.001, number needed to treat 31 at 6 years)
      • Definite stent thrombosis: 0.8% vs 1.2% (p=0.05)

    Issue with internal validity?

    • No: Allocation-concealed, open-label RCT analyzing intention-to-treat population, 0% lost-to-follow-up
      • Low risk of allocation, performance, detection or attrition bias