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

COGENT - PPI added to DAPT in patients after ACS/PCI

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Bhatt DL, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363:1909-17

Bottom Line: In patients on clopidogrel + ASA following ACS or stent placement, the addition of omeprazole reduced the risk of clinical GI events (NNT 56 over 6 months), including overt upper GI bleed (NNT 100 over 6 months) with no increase in CV events. Because this trial was stopped early, the benefits (& reported NNTs) may be overestimated.

 

Integrating This Study Into Practice

Despite this uncertainty caused from stopping the trial early, it's reasonable to consider a PPI for the duration of dual antiplatelet therapy in patients without prior GI bleed, especially if they have other risk factors or medications that further increase their risk. PPIs should be mandatory in those with prior GI bleed while taking dual antiplatelet therapy unless contraindicated.

 

Design

Allocation-concealed "superiority" RCT with all (patients, clinicians, outcome adjudicators) blinded, low loss-to-follow-up (3%), analyzed using the intention-to-treat population. 

Study stopped early due to abrupt loss of funding (sponsor went bankrupt), leading to accumulation of only ~1/3 of planned GI primary outcome events.

 

Patients and Setting

  • 15 countries, 393 centers
  • Enrolled between January-December 2008
  • Inclusion criteria:
    1. Age 21+ y/o
      • (designed to have >60% of patients 65+ y/o)
    2. Required DAPT (ASA + clopidogrel) x 12+ months, specifically
      • NSTE-ACS
      • STEMI
      • Coronary stent implantation
  • Key exclusion criteria:
    • Erosive esophagitis, esophageal or gastric varices, non-endoscopic gastric surgery
    • Hx of hemorrhagic stroke, intracranial neoplasm, AVM, aneurysm
    • Active pathological bleeding or hx of hereditary/acquired hemostatic disorder
    • Other indication for gastroprotection (PPI, H2RA, sucralfate, misoprostol)
    • CABG <30 days prior to randomization
    • Cardiogenic shock, refractory ventricular arrhythmias or HF with NYHA class IV at time of randomization
    • Meds
      • >21 days of clopidogrel or another thienopyridine prior to randomization
      • Needs oral anticoagulation
      • Recent fibrinolytic therapy
      • Steroids equivalent to >5 mg/d of prednisone
    • Labs
      • Hemoglobin <100 g/L
      • Platelets <100
  • 4444 screened for eligibility -> 3873 randomized -> 3761 analyzed
  • Average patient:
    • 66 y/o
    • Female 32%
    • Race: White 94%
    • BMI 28
    • CV hx
      • PCI 72%
      • ACS 42%
      • MI 30%
      • PAD 12%
      • Stroke 8%
      • Other vascular disease 50%
    • Hx of GI bleed/ulcer 4%
    • PMHx
      • Current smoker 13%
        • HTN 80%
        • Diabetes 30%
        • Dyslipidemia 78%

 

Intervention and Control

  • Intervention: Omeprazole 20 mg/d
    • Note: Part of proprietary product CGT-2168, which is a fixed-dose combination of clopidogrel 75 mg + omeprazole 20 mg
  • Control: Placebo
  • Co-interventions common to both groups:
    • ASA 75-325 mg/d + clopidogrel 75 mg/d (planned duration of at least 12 months)

 

Outcomes

  • Median follow-up 106 days (max 341 days)
    • Note: Outcomes standardized to 180 days
  • Primary efficacy outcome: Composite upper GI events (ulcer complications [perforation, obstruction, bleed], occult bleeds presumed to be from GI, symptomatic non-bleeding ulcer or erosions
  • Primary safety outcome: Composite CV events (CV death/ischemic stroke/non-fatal MI/coronary revascularization)
  • Subgroup analysis: Outcomes did not differ based on baseline H pylori status or use/non-use of non-ASA NSAIDs (randomization stratified based on these 2 factors)

Outcomes in COGENT trial

 

Key Considerations & Interpretation

Trial stopped early: This trial with otherwise low risk of bias was truncated (stopped early) due to loss of funding. Truncated trials tend to exaggerate effect sizes (overestimate benefits/harms), especially when few events have occurred. It's therefore possible that the observed 1.8% absolute risk reduction (NNT 56) in clinical GI events over 6 months seen with omeprazole versus clopidogrel in COGENT based on only 55 GI events may be an overestimate of the real benefit.

Who does this apply to? 

  • COGENT enrolled patients with new indication for 12 months of DAPT (3/4 PCI, 1/4 ACS), without high-risk features for GI bleed. This is therefore a trial to determine whether routine use of PPIs with DAPT is beneficial in patients at otherwise low risk of GI bleed. Given the issue with stopping early described above, the GI benefits of routinely adding a PPI to DAPT in patients without previous GI bleed/ulcer remain uncertain.
  • This doesn't apply to patients with prior upper GI bleed, where previous trials have demonstrated a large reduction in GI events when adding a PPI to antiplatelet therapy in patients who've previously bled (1, 2). 

Does this trial prove that PPIs don't increase CV risk? 

  • COGENT wasn't designed to demonstrate the absolute CV safety of omeprazole (or to dispel the possible interaction with clopidogrel), and in isolation can't be used to demonstrate safety. Despite this, omeprazole did not numerically increase the risk of CV events in this population at high risk of CV events (4.9% versus 5.7% with placebo).
  • Interpreted in the context of all of the observational and pharmacokinetic evidence, it appears that the association between PPIs & increased CV events may be due to confounding factors (i.e. weight, smoking, and other lifestyle factors that predispose a patient to be prescribed a PPI) rather than a true cause-and-effect.