INVEST - Verapamil- vs atenolol-based HTN treatment in CAD

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Pepine CJ, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 2003;290:2805-16.

Bottom line:

  • Although INVEST technically demonstrated "equivalence" of a HTN regimen based primarily on verapamil SR + trandolapril versus atenolol + hydrochlorothiazide in patients with CAD & HTN, this does not generalize to patients with (1) HF or LV dysfunction or (2) recent MI without contraindication for a beta-blocker.

  • Additionally, this likely does not generalize to patients on better evidence-based thiazides (chlorthalidone or indapamide), & possibly not to other beta-blockers.

  • Overall, there was no clinically relevant benefit of the verapamil-based regimen in CAD that would justify using this agent over a beta-blocker in this population.

 

Patients (n=22,576)

  • Included
    • Age 50+ y
    • CAD, clinically stable, defined as any of:
      • Remote MI >3 months ago;
      • Stenosis of >50% of at least 1 coronary artery on angiography;
      • "Classic" angina
      • Ischemia on 2+ non-invasive investigations (EKG, echo, and/or nuclear imaging)
    • Hypertension (HTN)
  • Exclusion
    • HF NYHA functional class IV (I-III could be enrolled)
    • Taking beta-blockers for an MI that occurred <1 year
  • Typical study patient
    • Age 66 y (~33% >70 y)
    • Female 52%
    • Inclusion criteria
      • Angina 67%
      • Coronary stenosis on angiogram 39%
      • MI 32%
      • Abnormal stress test 21%
    • PMHx
      • CABG or PCI 27%
      • Stroke 5%
      • HF (NYHA I-III) 5-6%
      • Current smoker 12%
      • Dyslipidemia 56%
      • Diabetes 28%
    • BP 150/86 mm Hg
    • HR 76 bpm
    • Meds
      • Antiplatelet 57%
      • Lipid-lowering 37%
      • Hormone replacement therapy 18% of women

Interventions

  • Both groups received treatment for HTN to target office-based BP <140/90 mm Hg (<130/85 mm Hg for patients with diabetes or renal dysfunction)
  • I: Verapamil SR-based HTN regimen
    • Step 1: Verapamil SR 240 mg PO once daily (if HF, diabetes, or renal impairment: also add trandolapril 2 mg/d)
    • Step 2: Add trandolapril 2 mg PO daily
    • Step 3: Increase verapamil to 180 mg PO BID & trandolapril to 2 mg PO BID
    • Step 4: Add hydrochlorothiazide 25 mg PO daily
    • Steps 5+: Max doses of verapamil 480 mg/d, trandolapril 8 mg/d, hydrochlorothiazide 100 mg/d, non-beta-blocker non-study antihypertensive
    • At 2 y, 82% on verapamil SR
  • C: Atenolol-based HTN regimen
    • tep 1: Atenolol 50 mg PO once daily (if HF, diabetes, or renal impairment: also add trandolapril 2 mg/d)
    • Step 2: Add hydrochlorothiazide 25 mg PO daily
    • Step 3: Increase both atenolol & hydrochlorothiazide to BID
    • Step 4: Add trandolapril 2 mg/d
    • Steps 5+: Max doses of atenolol 200 mg/d, hydrochlorothiazide 100 mg/d, trandolapril 8 mg/d, non-CCB non-study antihypertensive
    • At 2 y, 77% taking atenolol

Results @ mean 2.7 years

  • Vitals @ year 2
    • BP reduction of ~19/10 mm Hg in both groups
    • Achieved BP <140/90 mm Hg: 71.7% vs 70.7%
    • Mean resting HR 73 bpm vs 69 bpm
  • Primary outcome (death, non-fatal MI, non-fatal stroke): 9.9% vs 10.2%, relative risk (RR) 0.98 (0.90-1.06)
    • Death: 7.75% vs 7.9%
    • Non-fatal MI: 1.3% in both groups
    • Non-fatal stroke: 1.2% vs 1.3%
  • Angina:
    • Baseline: 1.5 episodes/week in both groups
    • At 2 years: 1.3 vs 1.6 episodes/week (p=0.02)
  • Adverse events:
    • Lightheadedness: 0.4% vs 0.6%
    • Symptomatic bradycardia: 0.7% vs 1.3%
    • Dyspnea: 1% vs 0.7%
    • Wheezing: 0.2% vs 0.4%
  • Subgroup analyses:
    • Different effect based on whether patients had HF (possibly ~5% absolute risk reduction with beta-blockers in primary outcome) versus those who did not (no difference)
    • Otherwise, no other baseline characteristics had a significant subgroup effect

Generalizability

  • Population widely representative CAD population, with key caveats:
    • First, those with an MI in the last year who were already on a beta-blocker were excluded. Thus, this trial likely selected out patients who may benefit most from beta-blockers.
    • Second, this trial included patients with clinical HF. Notably, although only 5-6% of the population, there appeared to be much worse outcomes in those receiving verapamil subgroup, which is consistent with previous concerns of HF-related mortality due to the negative inotropic effect of non-dihydropyridine CCBs like verapamil. It should therefore be avoided in this population.
    • Third, there was generally poor use of CAD secondary prevention therapies such as ASA & lipid-lowering, & uncharacteristically high use of hormone replacement therapy (55% of enrolled patients were female & 18% of them were receiving HRT despite a confirmed CAD history). This would be expected to increase the underlying risk of primary outcome events in both treatment groups.
  • Multiple considerations regarding the intervention arms are required to interpret the results:
    • First, the interventions represent BP-lowering "regimens" focused on using verapamil or atenolol, rather than a true head-to-head comparison of these agents;
    • Second, although it lowers BP, atenolol seems to reduce the risk of CV events less than antihypertensive agents from other classes in patients with HTN. Similarly, hydrochlorothiazide is a weaker antihypertensive agent & generally has less evidence supporting its use than other thiazides, which have a clearer signal for benefit. This combination may have therefore been disadvantaged versus using a beta-blocker + thiazide combination with more robust supporting evidence (e.g. bisoprolol plus chlorthalidone).
    • Third, adherence to the primary drug of the regimen (verapamil & atenolol) as well as to BP goals was fairly poor, with only 75-80% in each group still taking this drug & only ~70% with BP <140/90 mm Hg at year 2.

Internal validity

  • Low risk of allocation bias due to appropriate sequence generation & allocation concealment (centralized, automated Internet-based randomization with permuted blocks).
  • As this trial was a "prospective, randomized, open-label, blinded-endpoint" (PROBE) trial, it is by default at high risk of performance & detection bias due to knowledge of clinicians & patients of the allocated treatment
    • The risk of performance bias was minimized with a standardized treatment algorithm for HTN & a similarly low proportion of patients (~70%) achieved their BP target. Additionally, few patients had revascularization procedures & there were similar rates of crossover between groups
    • Investigators attempted to minimize the risk of detection bias by adjudication of events by a committee unaware of treatment allocation, however, they could not eliminate this bias as well as if they would have blinded patients and clinicians to allocation to verapamil or atenolol. Given that this was a feasible option with a few minor changes to the study HTN treatment algorithm, it is not possible to give the investigators "a pass" for this.
  • Low risk of attrition bias as analyses followed intention-to-treat principles, & loss-to-follow-up was low at ~2-3% in both groups
  • This trial was technically designed as an equivalence trial, with an equivalence boundary for the relative risk of 0.83-1.20.

ARBs vs ACEIs patients post-MI or at high risk of CVD

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Dickstein K, et al. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:752-60.

The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.

VALIANT: Pfeffer MA, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.

Bottom line:

  • In patients post-MI or at high risk of CVD, telmisartan & valsartan generally prevent CV events as well as ACE inhibitors with similar safety;

  • The combination of ACEI+ARB is no better than monotherapy & increases the risk of adverse events (e.g. hypotension, hyperkalemia & renal impairment);

  • Losartan is inferior to captopril for prevention of CV events.

 

Patients

Interventions

  • OPTIMAAL: ARB vs ACEI
    • ARB: Losartan started at 12.5 mg PO daily; increased to target 50 mg PO daily
      • 83% achieved target dose
    • ACEI: Captopril started at 12.5 mg PO TID; increased to target 50 mg PO TID
      • 81% achieved target dose
  • ONTARGET: ARB, ACEI or combination of both
    • ARB: Telmisartan started at 20 mg PO daily; increased to target 80 mg PO daily
      • 87% achieved target dose
    • ACEI: Ramipril started at 2.5 mg PO daily; increased to target 10 mg PO daily (HOPE dose)
      • 82% achieved target dose
  • VALIANT: ARB, ACEI or combination of both
    • ARB: Valsartan started at 20 mg PO BID; increased to target 160 mg PO BID
    • ACEI: Captopril started at 6.25 mg PO TID; increased to target 50 mg PO TID
    • 56% in each monotherapy group achieved target dose, 47% in combination group achieved target doses

Results @ 2-4.7 years

Generalizability & internal validity

  • Design of these trials essentially identical to the original 'ACEI vs placebo' trials that they mimic
    • I.e. high-quality allocation-concealed double-blind RCTs
  • All 3 trials are non-inferiority trials with fair non-inferiority margins and analyses
    • Note: OPTIMAAL is the only of the 3 that does not demonstrate of the ARB (losartan) & in fact points towards significant inferiority to an ACEI
  • As with the 'ACEI vs placebo' RCTs, results of these trials apply to patients that are post-MI, especially those with clinical HF & LV dysfunction, and those at high risk of CVD

HPS - Statins in secondary prevention & patients with diabetes

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Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: A randomised placebo controlled trial. Lancet 2002;360:7-22.

Bottom-line: In patients with existing CVD or diabetes, statin therapy reduced the risk of death (NNT 56) & all major vascular events (NNT 19) over 5 years.

In this population that initially tolerated simvastatin during a 4-6 week run-in phase & was not taking other lipid-lowering therapy, moderate-dose simvastatin did not increase the risk of cancer, cognitive impairment, liver enzyme abnormalities, myalgias or myopathy. 

 

Patients (n=20,536)

  • Included
    • Age 40-80 y
    • Total cholesterol (non-fasting) 3.5+ mmol/L
    • High risk for coronary death based on a past medical history of any of:
      • CAD (past ACS, stable angina, CABG or PCI)
      • Cerebrovascular disease (non-disabling non-hemorrhagic stroke, TIA, carotid endarterectomy)
      • PAD (intermittent claudication)
      • Other arterial surgery or angioplasty
      • Diabetes (type 1 or 2)
      • None of the above, but >65 y/o male with treated HTN
  • Excluded
    • Statin "clearly indicated"
    • Severe HF
    • Chronic liver disease (cirrhosis, hepatitis or ALT >1.5x ULN)
    • Creatinine >200 umol/L
    • Muscle disease (inflammatory muscle disease or CK >3x ULN)
    • Concurrent treatment with cyclosporine, fibrates or high-dose niacin
  • 63,603 screened -> 32,145 entered run-in -> 20,536 randomized -> 20,469 analyzed
  • "Typical" study patient
    • Age >64 y 46%
    • Female 25%
    • PMHx
      • MI 41%
      • Other CAD 24%
      • No coronary hx 35%
        • Cerebrovascular disease 9%
        • PAD 13%
        • Diabetes 19%
        • HTN as only inclusion criterion 1%
    • Lipids: Total cholesterol 5.9 mmol/L, LDL 3.4 mmol/L, apoB 1.14 g/L
    • Meds (CAD subgroup)
      • ASA 63% (77%)
      • ACEI 20% (10%)
      • Beta-blocker 26% (23%)

Interventions

  • I: Simvastatin 40 mg PO once daily
    • Adherence to >80% of doses: 89% @ 1 y, 82% @ 5 y
  • C: Matching placebo
    • Open-label statin use: 4% @ 1 y, 32% @ 5 y

Results @ mean 5 years

  • LDL
    • @ baseline: 3.4 mmol/L
    • Difference: -1.3 mmol/L @ 1 y, -0.7 mmol/L @ 5 y
  • Death: Simvastatin 12.9%, placebo 14.7% (hazard ratio 0.87, 0.81-0.94), NNT 56
  • Major vascular event (components below): 19.8% vs 25.2% (HR 0.76, 0.72-0.81), NNT 19
    • Non-fatal MI or coronary death: 8.7% vs 11.8%
    • Stroke: 4.3% vs 5.7%
    • Coronary revascularization: 5.0% vs 7.1%
    • Non-coronary revascularization: 4.4% vs 5.2%
  • Adverse effects
    • Cancer: 7.9% vs 7.8%
    • Cognitive impairment: 23.7% vs 24.2%
    • ALT >4x ULN: 0.4% vs 0.3%
    • Unexplained muscle pain/weakness reported at least once: 32.9% vs 33.2%
    • CK
      • 4-10x ULN: 0.2% vs 0.1%
      • >10x ULN: 0.11% vs 0.06%
    • Subgroup analyses demonstrated consistent relative risk reduction in major vascular event across different high-risk inclusion criteria, so absolute benefit dependent on baseline risk. 5-year risk in placebo group (NNT with statin) in relevant subgroups:
      • CAD only: 22.5% (NNT 16)
      • No CAD
        • Cerebrovascular disease: 23.6% (NNT 18)
        • PAD: 30.5% (NNT 14)
        • Diabetes: 18.6 (NNT 23)

Generalizability

  • Represents a wide spectrum of patients with existing vascular disease or diabetes with poor use of other secondary CV prevention interventions, particularly in the CAD subgroup
  • Run-in phase: Placebo x4 weeks, then simvastatin 40 mg/d x4-6 weeks
    • To ensure long-term adherence + "responsiveness" to LDL lowering
    • 36% who entered run-in did not undergo randomization, mostly due to unwillingness or inability to adhere for a planned 5 years
    • Therefore, represents a population that did not have intolerable adverse events after a month of statin therapy

Internal validity

  • Low risk of allocation, performance, detection & attrition bias

    • Central telephone randomization

    • Patients, clinicians, adjudicators unaware of treatment allocation

    • Loss-to-follow-up <0.5%

    • Intention-to-treat analysis

  • High risk of contamination bias

    • By year 5, 32% of patients in placebo group were receiving an open-label statin

    • This acts as a conservative bias, as it attenuates the apparent benefit of statin therapy

Statin dose & CV events

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Bottom-line:

  • In patients with CAD, high-dose statin therapy vs low/moderate statin doses further reduces the risk of CV events by an ~15% (relative risk reduction).

  • In Japanese patients with CAD, moderate-dose statin reduces the risk of CV events and death versus a very low dose by ~19% (relative risk reduction).

 

    Summary of 6 largest trials (n=52,666) 

    statin dose.png

    Latest trial: REAL-CAD summarized below:

    • Design: RCT with open-label, blinded-outcome-adjudication design
    • 13,054 randomized -> 12,413 analyzed in ITT population
    • Included: 
      • Age 20-80 y/o +
      • CAD (history of ACS, prior PCI/CABG, or angiographic coronary artery stenosis >75%) +
      • LDL-C >2.6 mmol/L (excluded if LDL-C >3.0 mmol/L on pitavastatin 1 mg/d during run-in phase)
    • Excluded: Known FH, contraindication to statin, HF NYHA 3-4 or LVEF <30%
    • Baseline characteristics:
      • Age 68 y, male 83%
      • Prior MI 52% (mean 5 years ago), HF 5%, ischemic stroke 7%
      • Statin before run-in: 91%, ASA 92%, ACEI/ARB 67%, beta-blocker 42%
      • LDL-C: before run-in 2.4 mmol/L, after run-in on pitavastatin 1 mg/d: 2.2 mmol/L
    • Interventions: Pitavastatin 4 mg/d (equivalent to ~atorvastatin 20-40 mg/d)
      • Reduced LDL-C by an additional 0.4 mmol/L (18%) vs lower dose
    • Control: Pitavastatin 1 mg/d (equivalent to ~atorvastatin 5 mg/d)
    • Follow-up: 3.9 years (median)

    Results from 5 largest RCTs

    statin dose outcomes.png

    Results from REAL-CAD

    • Primary outcome (CV death, MI, ischemic stroke or unstable angina requiring hospitalization):
      • Higher dose 4.3%, lower dose 5.4% - 1.1% absolute risk reduction (ARR)
      • HR 0.81, 95% CI 0.69-0.95
    • Death: 3.3% vs 4.2% - 0.9% ARR; HR 0.81, 0.69-0.98
    • MI: 0.6% vs 1.2% - 0.6% ARR; HR 0.57, 0.38-0.83
    • Any muscle complaints: 1.9% vs 0.7% - 1.2% absolute risk increase
    • No difference in rhabdo (<0.1%), CK increase >5xULN (0.7% vs 0.6%) or liver enzyme elevations (2.9% vs 2.7%, p=0.46)

    Meta analysis comparing high- to moderate-dose statins @ mean 2.5 years

    • Systematic review of 10 databases (including MEDLINE, Embase, CENTRAL) to Dec 2010
    • Included 10 RCTs enrolling 41,778 patients
    • Results
      • Statistically significant reduction with higher dose in
        • Coronary death or MI: Relative risk 0.90 (0.84-0.96), low heterogeneity (I^2=0%) in 9 trials
        • Stroke (excluding TIA): RR 0.86 (0.77-0.96), I^2=0% in 10 trials
          • Non-fatal MI: RR 0.82 (0.76-0.90), I^2=0% in 5 trials
      • No statistically significant difference in
        • Death: RR 0.92 (0.83-1.03), I^2=38% in 10 trials
      • Lab abnormalities, elevated
        • Liver enzymes, for ALT: RR 1.57 (1.29-1.91)
        • CK: RR 2.86 (2.02-4.04)
      • Subgroup analysis limited to 3 trials of patients with recent ACS (A-Z, PROVE-IT, Colivicchi et al) found possible reduction in death with higher dose (RR 0.75, p=0.005)

    Article links

    de Lemos JA, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z Trial. JAMA 2004;292:1307-16.

    Cannon CP, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.

    Pedersen TR, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: The IDEAL study: A randomized controlled trial. JAMA 2005;294:2437-45.

    LaRosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.

    SEARCH Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin dialy in 12 064 survivors of myocardial infarction: A double-blind randomised trial. Lancet 2010;376:1658-69.

    Taguchi I, et al. High-dose versus low-dose pitavastatin in Japanese patients with stable coronary artery disease (REAL-CAD): a randomized superiority trial. Circulation 2018;137:1997-2009.

    PRECISION - Comparison of different NSAIDs in patients with arthritis and an increased CV risk

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    Nissen SE, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med 2016;online

    Bottom line: For patients with arthritis and a ~1%/year risk of CVD and low risk of GI bleeds, no NSAID (between celecoxib, ibuprofen or naproxen) is clearly safer. Consider a strategy of using the cheapest NSAID, PRN if possible, and optimizing other strategies to decrease the CV risk of NSAIDs (smoking cessation, statins, BP control, ASA for secondary prevention, etc). NSAIDs should be discontinued in patients who do not receive a noticeable improvement in pain & function from these agents.

     

    Issues with internal validity?

    • Unclear risk of allocation, performance and detection bias  (likely low risk, but inadequate description in protocol and published report)
    • High risk of attrition and contamination bias
      • 68.8% stopped taking the study drug, though no differences in rates or timing between intervention groups
      • 27.4% discontinued follow-up, and 7.2% were outright lost-to-follow-up
      • The above decrease the study's power to find a difference between groups, especially in the ITT analysis, biasing the conclusions towards non-inferiority. With that said, estimates from ITT and on-treatment populations were almost identical

    Special considerations: Non-inferiority trial

    • This study was designed as a non-inferiority safety study to determine that celecoxib was "not much more dangerous" from a CV perspective vs naproxen
    • Criteria to be met to achieve this study's non-inferiority conclusion:
      • Hazard ratio (HR) point estimate <1.12 for the primary outcome
      • Upper limit of HR 97.5% confidence interval <1.33
      • The above had to be met in both intention-to-treat (all patients randomized) and on-treatment populations (events occurring while patient taking study drug + extra 30 days after they discontinued it) to conclude non-inferiority
    • When developing these non-inferiority criteria, assumed would require 762 primary outcome events, and that these would occur at a rate of 2%/year (actual ~1%) & that 40% of patients would discontinue treatment (actual 68%)
      • Actual primary outcome event n=607

    Patients (n=24,081)

    • Included
      • Age 18+ y
      • Need for daily NSAID for arthritis pain
      • Increased risk for/established atherosclerotic cardiovascular disease (ASCVD), defined as any of the following:
        • CAD
        • Cerebrovascular disease
        • Symptomatic peripheral vascular disease
        • Arterial surgery/angioplasty for any ASCVD >3 months prior to randomization
        • Diabetes (extra eligibility criterion for women: on insulin)
        • 3+ ASCVD risk factors from the following: Age >55 y, family history of CVD/stroke, current smoker >15 cigarettes/day, HTN, LVH on EKG, dyslipidemia, microalbuminuria or urine protein:creatinine ratio >2, ABI <0.9, waist:hip ratio 0.90 or greater)
    • Excluded
      • ACS, stroke/TIA or CABG within 3 months
      • HF with NYHA class III-IV symptoms or LVEF 35% or less
      • Planned revascularization procedure
      • Uncontrolled arrhythmia within 3 months
      • BP >140/90 mm Hg
      • Malignancy within 5 years
      • Any significant GI, hepatic, renal or coagulation disorders
      • Concomitant meds: Warfarin, prednisone equivalent >20 mg/d, lithium
    • Screened 31,857 -> randomized 24,222 -> analyzed 24,081
    • "Average" patient
      • Age 63 y
      • Female 64%
      • White 75%
      • Arthritis: OA (90%), RA (10%)
        • HAQ disability score 1.1 (0= no disability, 3= complete disability)
        • Pain visual analog score 54 mm (/100)
      • CV risk category: Primary prevention (77%), secondary prevention (23%)
      • PMHx
        • Current smoker 21%
        • HTN 78%
        • Diabetes 35%
        • Dyslipidemia 63%
      • BP 125/75 mm Hg
      • SCr 80 umol/L
      • Meds
        • ASA 46%
        • Statin 54%
        • DMARD 7%

    Generalizability: Who does this apply to?

    • Middle-aged to elderly adults with arthritis (mainly OA) with a low-intermediate risk of CV events (~10% over 10 years), and minimal non-CV comorbidity
      • Despite enrolling patients with CV risk factors, actual CV event rates were closer to low-intermediate risk (~1%/year), likely resulting from concomitant treatments to lower CV disease & enrolment of a sample of patients generally healthier than the underlying population.

    Interventions

    • Celecoxib
      • Initial dose 100 mg PO BID
      • (RA only) dose could be increased to 200 mg PO BID
      • Mean treatment duration: 20.8 months
    • Ibuprofen
      • Initial dose 600 mg PO TID
      • Dose could be increased to 800 mg PO TID
      • Note: In practice, most clinicians will recommend a lower dose than what was used in this trial (usually ~200-400 mg PO TID-QID)
      • Mean treatment duration: 19.6 months
    • Naproxen
      • Initial dose 375 mg PO BID
      • Dose could be increased to 500 mg PO BID
      • Mean treatment duration: 20.5 months
    • Co-intervention for all: Gastroprotection with daily PPI (esomeprazole 20-40 mg)

    Results (reported in the following order: celecoxib, ibuprofen, naproxen)

    ITT analyses (mean follow-up 2.8 years)

    • Death: 1.6% vs 1.8% vs 2.0%
      • Celecoxib vs naproxen: HR 0.80 (0.63-1.00)
    • CV
      • Primary outcome (CV death, non-fatal MI, non-fatal stroke): 2.3% vs 2.7% vs 2.5%
        • Celecoxib vs naproxen: HR 0.93 (0.75-1.13)
        • Ibuprofen vs naproxen: HR 1.08 (0.90-1.31)
      • Major adverse cardiovascular event (primary outcome, coronary revascularization, hospitalization for unstable angina, or TIA): 4.2% vs 4.8% vs 4.3%
        • Ibuprofen vs naproxen: HR 1.11 (0.96-1.29)
      • HF hospitalization: 0.6% in all groups
      • Hospitalization for HTN: 0.3% vs 0.5% vs 0.4%
    • GI - Clinically significant events (GI hemorrhage, obstruction, perforation, or symptomatic gastric/duodenal ulcer): 0.7% vs 0.9% vs 0.7%
      • Celecoxib vs naproxen: HR 0.97 (0.67-1.40)
    • Renal (creatinine increase to >177 umol/L, hospitalization for AKI, or initiation of dialysis): 0.7% vs 1.1% vs 0.9%
      • Celecoxib vs naproxen: HR 0.79 (0.56-1.12)
    • Change in pain visual analogue score from baseline (/100 mm): -9.3 vs -9.5 vs -10.2

    On-treatment analyses (mean follow-up 1.8 y [mean treatment duration + 1 month])

    • Primary outcome: 1.7% vs 1.9% vs 1.8%
      • Celecoxib vs naproxen: HR 0.90 (0.71-1.15)
      • Ibuprofen vs naproxen: HR 1.12 (0.89-1.40)

    Interpretation

    • Caveats to consider
      • The authors performed over 100 analyses including subgroup analyses in addition to the primary non-inferiority analysis, so chance is a plausible explanation for any differences (or lack of differences) in secondary & tertiary outcomes
      • The upper limit of the non-inferiority margin of 1.33 (a 33% relative risk increase) conceptually accepts that NSAIDs could offset the effect of 1-2 interventions to reduce CV events (i.e. CV risk reduction for smoking cessation, ASA, statins, BP & diabetes control are all in the ballpark of a 15-35% relative reduction)
      • Event rates were lower than predicted based on enrolment criteria, likely due to concomitant treatments to reduce CV events
      • Patients discontinued study treatment at a mean 1.7 years, limiting long-term follow-up and assessment of long-term risk
      • No comparison group that received placebo/no NSAID
    • In the context of the above caveats, this study provides some evidence that
      • Celecoxib, ibuprofen and naproxen have similar CV and renal safety profiles at the doses and duration used in this trial, but cannot absolutely refute other studies demonstrating a greater risk with celecoxib;
      • GI event rates between NSAIDs & celecoxib differed only when iron-deficiency anemia of presumed GI origin was added to the predefined outcome of clinically-significant GI events. The difference was not different when considering only serious events. This weakens the rationale for using celecoxib over a non-selective NSAID;
      • Ibuprofen used at doses higher than routinely prescribed may pose a greater risk of CV and non-serious GI events than celecoxib or naproxen. The implications of this for lower doses are unclear;
    • None of the drugs in this study achieved a minimally clinically important change in the pain score (13.7/100). It's likely that a subset achieved a demonstrable reduction in pain, but for the majority of the trial participants, the benefits were non-existent and therefore risks outweighed the benefits.