ACTION - Nifedipine for stable CAD

in ,

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.