DAPT - Comparison of 12 vs >12 of DAPT after drug-eluting stent placement

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Mauri L, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.

Bottom line: In patients who go 1 year after drug-eluting stent placement with good adherence to DAPT without a CV or bleeding event, extending DAPT for another 18 months will reduce the risk of MI (NNT 50), but increase the risk of death (NNH 200) & moderate-to-severe bleeding (NNH 112). Benefits are far less impressive in patients receiving 2nd generation drug-eluting-stents, which are the sole drug-eluting stents implanted in current practice.

 

Context

  • Concerns were raised in 2006 about an increased risk of late (month 1-12 after stent placement) & very late (>1 year) stent thrombosis with 1st generation drug-eluting stents (Cypher, Taxus) versus bare-metal stents
    • DAPT duration recommendations at the time were 3-6 months
    • End of 2006: Label change & AHA recommendations for 12 months of DAPT after drug-eluting stent placement
    • True ideal duration of DAPT unknown; further reduction of very late stent thrombosis & resulting MI with durations >12 months?
  • From 2008 onward, newer "2nd generation" drug-eluting stents with faster endothelial healing over the stent & decreased thrombogenicity entered the market
    • Includes everolimus-eluting (Xience) & zotarolimus-eluting (Endeavor, Resolute) stents

Issues with internal validity?

  • Low risk of allocation, performance and detection bias: Randomized, allocation-concealed, double-blind trial analyzed using the intention-to-treat population
  • Unclear risk of attrition bias: ~5% of patients were lost-to-follow-up or withdrew consent

Patients (n=9961)

  • Inclusion
    • >18 y/o
    • PCI with drug-eluting stent placement
    • Received 12 months of DAPT after stent placement
    • Adherence 80%+ during 1st year of DAPT
    • No adverse events during 1st year of DAPT (MI, stroke, repeat coronary revascularization, stent thrombosis, major bleed)
  • Exclusion
    • Life expectancy <3 y
    • Planned surgery in next 30 months requiring antiplatelet discontinuation >14 days
    • Stent diameter <2.25 mm or >4.0 mm
    • Need for oral anticoagulation
    • Switched P2Y12 inhibitor type or dose in first 6 months of DAPT
  • 22.866 screened (11% had events within 1 year) -> 9961 randomized -> 9499 analyzed
  • "Average" patient
    • Age 62 y
    • Female 25%
    • White 91%
    • Indication for PCI: STEMI (10%), NSTEMI (15%), unstable angina (17%), stable angina (38%), other (20%)
    • CV history
      • Prior MI 22%
      • Prior PCI 31%
      • Prior CABG 11%
      • Stroke/TIA 3%
      • HF <5%
      • PAD 6%
    • CV risk factors
      • Current smoker 25%
      • HTN 75%
      • Diabetes 31%
    • PCI characteristics
      • Type of stent
        • 1st generation: Paclitaxel (27%), sirolimus (11%)
        • 2nd generation: Everolimus-eluting (47%), zotarolimus (13%)
      • Other PCI characteristics
        • Treated vessel: Left main (<1%), LAD (41%), RCA (33%), LCx (22%), graft (3%)
        • 1.5 stents
        • Minimum diameter <3 mm 47%
        • Total length 28 mm

Intervention

  • I: DAPT with clopidogrel (2/3) or prasugrel (1/3) x30 months
    • Investigator's choice: Clopidogrel 75 mg/d or prasugrel 10 mg/d (5 mg/d if weight <60 kg)
  • C: DAPT x12 months, then matching placebo
  • Co-interventions
    • Drug-eluting stents used in this trial: 1st generation (Cypher, TAXUS), 2nd generation (Endeavor, Xience)
    • ASA 75-162 mg/d

Generalizability

  • Population: Limited to a relatively low-risk population; individuals with stent placement (for ACS or stable angina) without any CV or bleeding event x12 months
    • Patients with a CV event in this timeframe would inherently be at higher risk & therefore have a larger absolute benefit from prolonged DAPT
    • Patients with a bleeding event in this timeframe would inherently be at higher bleed risk, & therefore have a higher risk of harm from prolonged DAPT
  • Intervention: Most used clopidogrel, but ~1/3 of patients used prasugrel (investigator's choice)
    • Ticagrelor not used in this trial, but risk/benefit of prolonged ticagrelor-based DAPT likely similar to prasugrel (extrapolating from PLATO & PEGASUS ), with additional adverse events with ticagrelor (dyspnea & gout)

Results during months 12-30 from stent placement (randomized period)

  • Death, MI, stroke (primary outcome 1): 4.3% with DAPT x30 months, 5.9% with DAPT x12 months, hazard ratio 0.71 (0.59-0.85)
    • Death: 2.0% vs  1.5% (NNH 200, p=0.05)
    • MI: 2.1% vs 4.1% (NNT 50), HR 0.47 (0.37-0.61)
      • Stroke: 0.8% vs 0.9% (p=0.32)
  • Stent thrombosis, definite or probable (primary outcome 2): 0.4% vs 1.4% (NNT 100), HR 0.29 (0.17-0.48)
    • Safety
      • Discontinued study drug: 21.4% vs 20.3% (p=0.18)
      • Moderate-severe bleed (GUSTO definition): 2.5% vs 1.6% (NNH 112)
  • Subgroup analyses: Newer stents have lower risk of CV events & stent thrombosis, as well as lower relative & absolute benefit from prolonged DAPT
    • Benefit of prolonged DAPT on CV events based on stent type:
      • 1st generation NNT <32
      • 2nd generation NNT >77

Other consideration

  • 11 RCTs (n=33,051) have compared DAPT durations ranging from 3 to 48 months following drug-eluting stent placement
    • In 1 meta-analysis of 10 RCTs, "longer" vs "shorter" DAPT duration resulted in
      • Decreased risk of MI by -0.8%/year (NNT 125)
      • Increased risk of 
        • Death by +0.2%/year (NNH 500)
        • Major bleed by +0.6%/year (NNH 167)
  • Subgroups analyses

PEGASUS - Long-term ticagrelor in patients with prior MI

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Bonaca MP, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800.

Bottom line: In patients with prior MI >1 year ago + 1 additional CV risk factor, ticagrelor 60 mg PO BID reduced the risk of MI (NNT 125) & stroke (NNT 250) over 2-3 years, though this was offset by an increased risk of adverse events, including major bleed (NNH 84), dyspnea (NNH 11) and gout attacks (NNH 200).

The "full PLATO" dose of 90 mg BID further increased the risk of adverse events without increasing efficacy over the 60 mg BID dose.

 

    Patients (n=21,162)

    • Inclusion
      • Age 50+ years
      • MI 1-3 y before enrollment
      • 1 or more additional risk factors:
        • Age 65+ years
        • >1 prior MI
        • Multivessel CAD
        • CKD with eGFR <60
        • Diabetes (requiring meds)
    • Exclusion
      • Prior ischemic stroke, intracranial hemorrhage, CNS tumor, intracranial vascular abnormality (e.g. AVM, aneurysm)
      • Prior GI bleed within 6 months
      • Major surgery in past 30 days
      • Bleeding disorder
      • Planned use of oral anticoagulant, P2Y12 inhibitor, dipyridamole, or cilostazol
    • "Average" patient
      • Age 65 y
      • Female 24%
      • White 86%
      • CV history
        • 1.7 y since last MI
        • >1 prior MI 16%
        • Multivessel CAD 59%
        • Prior PCI 83%
        • PAD 5%
      • CV risk factors
        • Current smoker 17%
        • HTN 78%
        • CKD (eGFR <60) 23%
        • Dyslipidemia 77%
        • Diabetes 32%

    Interventions

    • I 1: Ticagrelor 90 mg PO BID (PLATO dose)
    • I 2: Ticagrelor 60 mg PO BID (reduced dose)
    • Control: Placebo
    • Co-interventions:
      • ASA 75-150 mg PO daily 100%
      • Statin 93%
      • ACEI/ARB 80%
      • Beta-blocker 83%

    Results @ mean 2.75 years

    • Efficacy
      • Death from any cause: Ticag90 5.2%, ticag60 4.7%, placebo 5.2%
        • Ticag90 vs placebo: Hazard ratio (HR) 1.00 (95% confidence interval 0.86-1.16)
        • Ticag60 vs placebo: HR 0.89 (0.76-1.04)
      • Primary outcome (CV death, MI or stroke): Ticag90 7.8%, ticag60 7.8%, placebo 9.0%
        • Ticag90 vs placebo: HR 0.85 (0.75-0.96; NNT 85)
        • Ticag60 vs placebo: HR 0.84 (0.74-0.95; NNT 85)
      • MI: 4.4% vs 4.5% vs 5.3%
        • Ticag90 vs placebo: HR 0.81 (0.69-0.95, NNT 112)
        • Ticag60 vs placebo: HR 0.84 (0.72-0.98, NNT 125)
      • Any stroke: 1.6% vs 1.5% vs 1.9%
        • Ticag90 vs placebo: HR 0.82 (0.63-1.07)
        • Ticag60 vs placebo: HR 0.75 (0.57-0.98; NNT 250)
    • Safety
      • Premature discontinuation: 32.0% vs 28.7% vs 21.4% (NNH 11 & 14, respectively) 
      • Major bleed (TIMI definition): 2.6% vs 2.3% vs 1.1%
        • Ticag90 vs placebo: HR 2.69 (1.96-3.70; NNH 67)
        • Ticag60 vs placebo: HR 2.32 (1.68-3.21; NNH 84)
      • Dyspnea: 18.9% vs 15.8% vs 6.4%
        • Ticag90 vs placebo: HR 3.55 (3.16-3.98; NNH 8)
        • Ticag60 vs placebo: HR 2.81 (2.50-3.17; NNH 11)
        • Severe dyspnea: 0.4% vs 0.4% vs 0.1%
      • Gout: 2.3% vs 2.0% vs 1.5%
        • Ticag90 vs placebo: HR 1.77 (1.32-2.37; NNH 125)
        • Ticag60 vs placebo: HR 1.48 (1.10-2.00; NNH 200)

    Issues with internal validity?

    • No: Randomized, allocation-concealed, double-blind trial with low loss-to-follow-up (~1%) analyzed using the intention-to-treat population

    Additional PEGASUS publications

    • A secondary analysis evaluated the impact of timing of enrolment into PEGASUS relative to previous P2Y12 inhibitor use
      • Test for interaction p<0.001 for primary outcome, no difference in relative risk increase of bleeding
        • Greatest relative risk reduction seen for those within 30 days of previous P2Y12 inhibitor use (HR 0.73, 0.61-0.87 for either ticagrelor dose vs placebo)
          • Primary outcome @ 3 years: Ticagrelor 7.7%, placebo 9.9% (NNT 46)
          • TIMI major bleeding @ 3 years: Ticagrelor 2.5%, placebo 0.7% (NNH 56)
        • No statistically significant benefit in those who discontinued P2Y12 inhibitor 30-365 days before PEGASUS (HR 0.86, 0.71-1.04) & >1 year before pegasus (HR 1.01, 0.80-1.27)
      • Despite a greater relative & absolute risk reduction in those with P2Y12 inhibitor discontinuation <30 days prior to PEGASUS enrolment, ischemic benefit still mostly offset by increased risk of major bleed

    EMPA-REG - Empagliflozin for CV risk reduction in T2DM with hx of CVD

    in ,

    Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

    Bottom line: In patients with T2DM and CVD, empagliflozin (at either dose of 10 mg or 25 mg daily) reduced the risk of death (NNT 39) & CV events (NNT 63) over 3 years.

     

      Patients

      • Inclusion
        • Adults with T2DM
          • No glucose-lowering agents in previous 12 weeks: 7-9%
          • Receiving glucose-lowering agents, stable x12 weeks: 7-10%
        • Established CVD, defined as any of the following:
          • MI >2 months ago
          • CAD (confirmed with angiography)
          • Stroke >2 months ago
          • PAD documented by
            • Limb revascularization or amputation
            • Peripheral artery stenosis >50% on angiography or non-invasive evaluation
            • ABI <0.9 on at least 1 side
      • Key exclusion criteria
        • Cancer within last 5 y
        • Stroke/TIA within 2 months
        • Planned cardiac surgery or PCI in next 3 months
        • BMI >45
        • Blood dyscrasias or any disorder causing hemolysis or unstable RBCs
        • eGFR <30 mL/min/1.73 m^2
        • ALT, AST or ALP >3x ULN
      • 11,531 individuals screened across 590 sites in 42 countries -> 7028 randomized -> 7020 analyzed
      • "Average" patient
        • Age 63 y
        • Male 72%
        • White 72%, Asian 22%, Black 5%, other 1%
        • Geography: Europe 41%, North America 20%, Asian 19%, Latin America 15%, Africa 4%
        • CV risk factors
          • CAD 76% (multivessel 47%)
          • MI 46%
          • CABG 24%
          • Stroke 24%
          • PAD 20%
        • Time since T2DM dx: >10 y (57%), 5-10 y (25%), 1-5 y (16%)
        • Wt 87 kg, BMI 31
        • BP 136/77
        • Lipids: total 4.2, LDL 2.2, HDL 1.1 mmol/L
        • A1c 8%
        • Meds
          • Metformin 74%
          • Insulin 49%
          • Sulfonylurea 43%
          • DPP-4 inhibitor 11%
          • Antihypertensives 95%
            • ACEI 80%
            • Beta-blocker 64%
          • ASA 83%
          • Statin 76%

      Interventions & co-interventions (median 2.6 y)

      • I: Empagliflozin 10 mg or 25 mg
        • A1c lowered by 0.5-0.6% at 12 weeks vs placebo
      • C: Matching placebo
      • Co-interventions:
        • 1st 12 weeks after randomization: No change to glycemic management unles fasting glucose >13.3 mmol/L
        • After 12 weeks: Adjustment to glucose-lowering therapy according to local guidelines

      Results @ median 3.1 y

      • Results for both doses of empaglifozin were similar, and therefore pooled
      • Statistically significant reduction in:
        • The primary outcome (CV death, MI, stroke): Hazard ratio (HR) 0.86, 95% confidence interval 0.74-0.99 (p=0.04)
          • 10.5% vs 12.1% (NNT 63)
        • Death: HR 0.68 (0.57-0.82)
          • 5.7% vs 8.3% (NNT 39)
        • HF hospitalization: HR 0.65 (0.50-0.85)
          • 2.7% vs 4.1% (NNT 72)
      • No statistically significant difference:
        • MI: HR 0.87 (0.70-1.09) - 4.8% vs 5.4%
        • Stroke: HR 1.18 (0.89-1.56) - 3.5% vs 3.0%
        • Coronary revascularization: HR 0.86 (0.72-1.04) - 7.0% vs 8.0%
      • Safety
        • Serious adverse events: 38.2% vs 42.3% (NNT 25, p<0.001)
        • Premature discontinuation: 23.4% vs 29.3%
        • Hypovolemia: 5.1% vs 4.9%
        • Acute kidney injury: 1.0% vs 1.6%
        • UTI: 18.0% vs 18.1% (complicated 1.7% vs 1.8%)
        • Genital infection: 6.4% vs 1.8% (NNH 22)
        • DKA: 0.1% vs <0.1%
        • Hypoglycemia (glucose <3.9 mmol/L or requiring assistance): 27.8% vs 27.9%
      • Numerous subgroup analyses were performed, which demonstrated inconsistent subgroup interactions with the primary outcome and CV death

      Issues with internal validity?

      • No: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up (<0.1%) analyzed using intention-to-treat principles 
      • Run-in: 2-week open-label placebo run-in

      Additional considerations

      • The reduction of CV events became apparent after only 3 months. Previous trials of diabetes drugs or glycemic control goals have never demonstrated a benefit this early, suggesting that the apparent benefit of empagliflozin may have resulted from another mechanism. 
      • The reduction int the primary CV event resulted mainly from a reduction in CV death, but not MI or stroke. This further argues against glycemic control as the beneficial mechanism of empagliflozin.

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

      in

      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

      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.