CONCERN: Naproxen vs celecoxib in patients with recent upper GI bleed with an indication for low-dose ASA

Chan FKL, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet [epub ahead of print]

Bottom line:

• Issues in reporting of this trial preclude a fully-informed interpretation of its results

• In patients receiving a PPI & ASA, recurrent upper GI bleed occurred in ~6% of patients also receiving daily celecoxib at a dose of 100 mg BID compared to ~12% of those receiving naproxen 500 mg BID over 18 months.

Patients (n=514)

• Included
  • Presenting with upper GI bleed while on NSAID + low-dose ASA
  • Follow-up endoscopy confirming ulcer healing 8 weeks after GI bleed
  • Negative for H pylori or successful H pylori eradication
  • Ongoing indication for low-dose ASA ("cardiothrombotic diseases" or "multiple CV risk factors")
  • Chronic arthritis pain anticipated to require regular NSAID use
• Key exclusion criteria
  • Erosive esophagitis
  • Gastric outlet obstruction
  • Renal failure (SCr >200 umol/L)
  • Use of anticoagulants
• Typical study patient
  • Age 72 y (>80 y in 24%)
  • Female 46%
  • Indication for NSAID: OA 70%, RA 3%, other 27%
  • Baseline upper GI bleed
    • Gastric origin 55%
    • Required endoscopic therapy ~30%
    • Required blood transfusions 55%
  • ASA indication: Secondary prevention (67%), primary prevention with 10-year CV risk >10% (33%)

Interventions x18 months

• I: Celecoxib 100 mg PO BID
• C: Naproxen 500 mg PO BID
• ~90% in both groups took at least 70% of their doses; ~18% in each group discontinued the study drug before 18 months
• Co-interventions:
  • Esomeprazole 20 mg PO once daily in all patients
  • ASA 80 mg/d (discontinued in ~30% of patients during trial in both groups)

Results @ median 18 months

• Efficacy (not designed or powered to evaluate this)
  • Patient's global assessment of disease activity scale (range 1-5, lower=better):
    • Baseline: 3.0 in both groups
    • Month 18: Celecoxib 2.1 versus naproxen 2.3, p=0.386 for difference between groups
  • Quality of life, pain, use of other analgesics: ?
• Safety
  • Primary outcome - recurrent upper GI bleed (hematemesis/melena or hemoglobin drop >20 g/L+ endoscopically-confirmed ulcers or bleeding erosions): Celecoxib 5.6%, naproxen 12.3% (NNT 15), hazard ratio (HR) 0.44 (0.23-0.82)
    • Fatal recurrent GI bleed: 0 in both groups
  • Major CV event (vascular death, MI or stroke): Celecoxib 4.4% vs naproxen 5.5%, HR 0.78 (0.36-1.73)
• Discontinued treatment before 18 months: Celecoxib 18% vs naproxen 19%

Subgroup analysis (reported in supplement of authors' reply to letter to the editor)

• Primary outcome
  • Continued ASA: Celecoxib 7.2%, naproxen 13.8% (p=.042)
  • Discontinued ASA: 1.4% vs 8.4% (p=.054)
• CV events: 
  • Continued ASA: Celecoxib 5.5% vs naproxen 6.0% (p=.825)
  • Discontinued ASA: 1.5% vs 4.3% (p=.312)

Internal validity

• Unclear/high risk of allocation bias
  • Computer-generated randomization list
  • Attempted to conceal allocation by sealed opaque envelopes, which are easy to subvert through tampering
• Unclear risk of performance/detection bias
  • Proper blinding dependent upon allocation concealment. If sealed opaque envelope method was subverted, then blinding would also be compromised
  • Blinding by "double-dummy" pills not prepared by manufacturer
  • GI & CV outcomes adjudicated by committee blinded to allocated treatment group
• Attrition bias
  • Premature discontinuation occurred in ~18% of patients in each group
  • Modified intention-to-treat analysis for GI safety outcome only counted outcomes that occurred "during treatment," therefore excluding any outcomes occurring after premature discontinuation

Generalizability

• Study conducted in single centre in Hong Kong, with enrolment taking ~10 years (2005-2015)
  • Many changes to GI bleed management (e.g. reduced transfusion threshold) & CV disease management (including ASA prescribing patterns in primary prevention). No reporting or comments on such trends in this publication, which complicates application of these trial results.
• Many aspects of this trial remain unreported, which further complicates application of these results
  • CV risk & indication for ASA?
    • This is the key reporting issue in this trial. The authors do not clearly describe the indication for ASA beyond "cardiothrombotic diseases or multiple coronary risk factors", and do not describe these in their 'baseline characteristics' table. Notably, the authors report that ~30% of patients discontinued ASA during the trial, suggesting that some of these patients had no clear indication for ASA
    • Addendum: The authors reported in a response to letter to the editor that 67% received ASA for secondary prevention, with the remaining 33% receiving ASA for primary prevention in the context of a calculated 10-year risk of a CV event >10%. The benefit of ASA for primary prevention is minimal, & the harms of continuing ASA (especially in these patients who already developed a GI bleed on ASA) likely outweighed any benefit. Furthermore, reported subgroup analyses showed that those who discontinued ASA had a lower risk of CV events, suggesting that mostly the lower-risk primary CV prevention patients discontinued ASA during the trial. 
    • Use of dual antiplatelet therapy (DAPT) was not specifically prohibited during this trial, though its use was not reported
  • Time from initial upper GI bleed to initiating of study NSAID?
    • Addendum: The authors later reported that endoscopy was routinely performed to confirm ulcer healing 8 weeks after the GI bleed, at which point patients were enrolled into this trial.
  • Previous history of NSAID use and efficacy (i.e. previous treatment failures with either study NSAID)?
• Effect of giving no NSAID or NSAID PRN?
  • The majority of patients with OA who use oral NSAIDs in practice do so on a PRN basis. The GI risk related to this kind of usage pattern is likely lower, and may be a reasonable alternative
  • In a previous trial by the same authors of patients with ASA-related upper GI bleed, recurrence using the same definition was <1% over 1 year in patients receiving ASA+PPI
• Clinical importance of primary outcome?
  • The primary outcome of this trial was recurrent endoscopically-confirmed upper GI bleed that presented as either hematemesis/melena or a >20 g/L hemoglobin drop. None of the recurrent GI bleeds in this trial resulted in patient death, and most would be classified as "minor bleeds" under most commonly-used bleeding definitions. As such, impact of these recurrent events on quality of life would be a key domain to measure (but it wasn't).
  • If we accept that this is a clinically-important outcome, the risk remains far too high even with celecoxib, particularly given that only 90% took at least 70% of their doses and that 30% discontinued ASA during the trial.

FOURIER - Evolocumab in patients with CVD

FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. NEJM [online ahead of print]

Bottom line:

• In patients with ASCVD & high CV risk (~5%/year), evolocumab reduced the risk of CV events (NNT 67 over 2.2 years, i.e. ~150/year) with a ~2% risk of injection-site reactions & no other safety concerns.

• LDL-lowering with evolocumab did not reduce the risk of death.

• Although FOURIER is a high-quality trial that conclusively demonstrates that lowering LDL with a PCSK9 inhibitor reduces CV risk, it's not clear from this study for whom this reduction is clinically important enough to justify the substantial cost of these drugs.

• EBBINGHAUS substudy: Evolocumab did not differ in placebo in change in cognitive function over 19 months.

 

Context

• There's been substantial controversy around the LDL hypothesis in the past few years
  • For the longest time, statins were the only lipid-lowering agents with robust evidence of efficacy in reducing the risk of CV events
  • In 2013, American guidelines flipped their recommended approach from "treat to LDL target" to "treat to risk, whereas Canadian guidelines maintained the treat-to-target approach (though emphasis shifted further from non-statins such as fibrates & niacin)
  • In 2015, the IMPROVE-IT trial of ezetimibe in post-ACS patients, though underwhelming some with its fairly unimpressive absolute risk reduction in CV events, provided support for the LDL hypothesis by offering another class of agents which reduces CV risk seemingly via LDL reduction
  • PCSK9 inhibitors, potent LDL-lowering agents, were thus positioned as a "third pillar" for the LDL hypothesis
• Previous meta-analyses, based almost exclusively on statin trials, demonstrated a reduction of CV events with lipid-lowering proportional to LDL reduction; relative risk reduction (RRR) per 1-mmol/L LDL reduction (estimates from Cholesterol Treatment Trialists' Collaboration meta-analysis):
  • Death ~10-15%
  • Major vascular events (MI, stroke, coronary revascularization) ~20-25%
    • Non-fatal MI or coronary death ~20-25%
    • Coronary revascularization ~20-25%
    • Stroke ~10-20%
• The open-label OSLER trial, the largest RCT of evolocumab prior to FOURIER, found a statistically significant reduction in CV events (NNT 82 @ 11 months) with the ~60% reduction in LDL with evolocumab over placebo, but was based on a very small number of outcome events

Patients (n=27,564)

• Included:
  1. Age 40-85 y
  2. Atherosclerotic cardiovascular disease (ASCVD), history of any of the following:
     • MI
     • Non-hemorrhagic stroke (TIA does not count)
     • Symptomatic PAD (claudication + ABI <0.85, peripheral artery revascularization or amputation due to atherosclerotic disease)
  3. LDL (most recent) >1.8 mmol/L or non-HDL >2.6 mmol/L after 2+ weeks of stable lipid-lowering therapy (max-tolerated statin, "preferentially" high-intensity with equivalent of atorvastatin 20+ mg/d +/- ezetimibe)
  4. Fasting triglycerides <4.5 mmol/L
  5. Additional risk factors: 1+ major or 2+ minor
     • Major:
       • Age 65+
       • MI/non-hemorrhagic stroke in prior 6 months
       • Multiple MI/non-hemorrhagic stroke or PAD+MI/non-hemorrhagic stroke
       • Current daily smoker
       • Diabetes
     • Minor
       • Hx non-MI-related coronary revascularization
       • Residual CAD 40+% stenosis in 2+ large vessels
       • HDL (most recent) <1.0 mmol/L
       • LDL (most recent) >3.4 mmol/L or non-HDL >4.1 mmol/L
       • Metabolic syndrome
• Key exclusion criteria (list of all 25 in supplemental appendix)
  1. Any hx hemorrhagic stroke
  2. MI/stroke within 4 weeks
  3. Planned/expected cardiac surgery or revascularization within 3 months
  4. HF NYHA III-IV or last-known LVEF <30%
  5. Uncontrolled/recurrent VT
  6. BP >180/110 mm Hg
  7. eGFR <20
  8. Uncontrolled hypo- or hyperthyroid
• Average study patient
  • Age 62.5 y
  • Male 75%
  • North American 17%
  • Type of ASCVD:
    • MI 81% (most recent median 3.4 y before enrolment)
    • Non-hemorrhagic stroke 19% (most recent median 3.2 y before enrolment)
    • PAD 13%
  • CV risk factors
    • Current smoker 28%
    • HTN 80%
    • Diabetes 37%
  • Labs
    • Total cholesterol 4.3 mmol/L
    • HDL 1.1 mmol/L
    • LDL 2.4 mmol/L
    • Triglycerides 1.5 mmol/L
    • Lipoprotein(a) 37 nmol/L
  • Meds
    • Statins: High-intensity 69%, moderate-intensity 30%, low-intensity <1%
    • Ezetimibe 5%
    • Antiplatelet 92%
    • ACEI/ARB 78%
    • Beta-blocker 76%

Interventions

• I: Evolocumab
  • Either 140 mg q2 weeks or 420 mg q1 month (per patient preference)
• C: Placebo

Results @ 2.2 years

• Lipid parameters
  • LDL, median
    • Baseline: 2.4 mmol/L
    • @ week 48: Evolocumab 0.8 mmol/L, placebo  (-1.45 mmol/L vs placebo, ~60% reduction)
      • <0.65 mmol/L: 42% vs 0%
      • <1.0 mmol/L: 67% vs 0.5%
      • <1.8 mmol/L: 87% vs 18%
  • ApoB reduced by 46% with evolocumab
  • Lp(a) reduced by 27% with evolocumab
• Efficacy
  • No difference in death: 3.2% vs 3.1%, hazard ratio (HR) 1.04 (0.91-1.19)
  • Reduction in composite primary outcome (CV death, MI, stroke, hospitalization for unstable angina, coronary revascularization): 9.8% vs 11.3% (NNT 67), HR 0.85 (0.79-0.92)
    • Reduction in Cholesterol Treatment Trialists "major vascular events": 9.2% vs 11.0% (NNT 56), HR 0.83 (0.77-0.90)
    • Reduction in "key" secondary composite efficacy outcome (CV death, MI, stroke): 5.9% vs 7.4% (NNT 67), HR 0.80 (0.73-0.88)
      • CV death: 1.8% vs 1.7%, p=0.62
      • MI: 3.4% vs 4.6% (NNT 84), HR 0.73 (0.65-0.82)
      • Stroke: 1.5% vs 1.9% (NNT 250), HR 0.79 (0.66-0.95)
      • Hospitalization for unstable angina: 1.7% in both groups, p=0.89
      • Coronary revascularization: 5.5% vs 7.0% (NNT 67), HR 0.78 (0.71-0.86)
• Safety:
  • Only statistically-significant difference: Injection-site reaction: 2.1% vs 1.6% (NNH 200)
  • Serious adverse events: ~25% in both groups
  • Permanent drug discontinuation: 12% vs 13%
  • Any adverse event: 77.4% in both groups
  • Specific adverse events
    • Allergic reaction: ~3% in both groups
    • Neurocognitive event: 1.6% vs 1.5%
    • Cataract: 1.7% vs 1.8%
    • ALT/AST >3x ULN: 1.8% in both groups
    • New-onset diabetes (in those without diabetes at baseline): 8.1% vs 7.7%, non-significant relative risk (RR) 1.05
    • Muscle-related event: 5% in both groups
      • CK >5x ULN: 0.7% in both groups
      • Rhabdomyolysis: 0.1% in both groups
  • Development of evolocumab-binding antibodies in evolocumab group: 0.3% (none were neutralizing antibodies)
• Results consistent within all tested subgroups (including q2 week vs monthly dosing); RRR similar regardless of baseline LDL

Generalizability

• Main consideration that should limit over-generalizing the findings of this trial: High cost of evolocumab (Repatha; ~$8000/year in Canada)
  • NNT to prevent 1 CV event/year ~150 in FOURIER
  • Cost of preventing 1 non-fatal CV event with evolocumab (treating 150 patients/year): ~1.2 million
• Population:
  • Patients in this trial were at very high CV risk (~5%/year) owing to requirement of existing ASCVD + additional risk factors. Extrapolating the NNT/year to lower-risk groups:
    • Secondary prevention or high-risk primary prevention (>2%/year): ~300 (cost ~$2.4 million/non-fatal CV event prevented)
    • Intermediate risk (1-2%/year): 450 (cost ~$3.6 million/non-fatal CV event prevented)
    • Low-risk primary prevention (<1%/year): 800-1500 (cost $7-12 million/non-fatal CV event prevented)
  • Authors did not report the % of patients with FH; if similar to other PCSK9 inhibitor trials, it is likely a small minority of enrolled patients (~3-5%). FOURIER doesn't address long-term effectiveness of lowering LDL with PCSK9 inhibitors in FH & its cost-effectiveness
• Co-interventions
  • Only ~70% were on equivalent of atorvastatin 20 mg/d or more. It's not clear how aggressive clinicians were in trying to optimize statins before enrolling their patients into FOURIER
  • Only 5% were receiving ezetimibe at baseline. In many jurisdictions, a trial of ezetimibe to lower LDL is a prerequisite to initiating a PCSK9 inhibitor. Although the reduction in CV events is modest with ezetimibe, wider use likely would have resulted in a lower baseline CV risk & further reduced the absolute benefit (& increased the NNT) from PCSK9 inhibitors

Internal validity

• Low risk of
  • Allocation bias: Allocated centrally by computer
  • Performance bias: Use of matching placebo, allocation concealment maintained
  • Detection bias: Outcomes adjudicated by central committee unaware of treatment assignment & lipid levels
  • Attrition bias: <0.1% lost to follow-up; analyzed by intention-to-treat
  • Selective outcome reporting bias: All outcomes of interest reported

Additional considerations

• How does evolocumab compare to other lipid-lowering agents?
  • Statins: The effect of evolocumab on outcomes is consistent with the RRR/1-mmol/L LDL reduction with statin monotherapy, except for evolocumab's neutral effect on mortality. The 95% CI for death in FOURIER rules out the 10-15% RRR seen with statins in the Cholesterol Treatment Trialists' Collaboration meta-analysis
  • Beyond low/moderate-intensity statin:
    • High-intensity statin: Maximizing statin dose & lowering LDL by an extra 20-25% (e.g. going from atorvastatin 10 mg/d to 80 mg/d) further reduces the relative risk of a major vascular event by 15% (& are cost-effective for doing this). As with evolocumab, high-intensity statins have not demonstrated a lower risk of death versus moderate-intensity statins
    • Other than evolocumab, only ezetimibe has evidence for reducing CV outcomes beyond statin monotherapy. Fibrates, niacin & CETP inhibitors all failed as add-on to statin therapy
• What does FOURIER mean for lipid targets?
  • Although debate will continue regarding the clinical significance of benefits from increasing lipid-lowering intensity, FOURIER & IMPROVE-IT consistently demonstrate that "lower is better" for LDL, with no clear safe lower limit
  • FOURIER inclusion criteria required patients to have LDL >1.8 mmol/L, but patients achieved similar absolute & relative risk reductions with evolocumab regardless of baseline LDL (from 1.8-2.0 mmol/L to >2.8 mmol/L)
  • Despite most patients in the evolocumab group achieving an LDL <1.8 mmol/L (and most reaching <1.0 mmol/L, half the Canadian LDL target), their CV risk remained elevated at ~4-5%/year. This is a reminder that dyslipidemia is but 1 of many CV risk factors & that achieving LDL targets cannot be the only means of reducing an individual's CV risk

EBBINGHAUS substudy

• Subgroup study of FOURIER (n=1974, 7.2% of study population; 1204 analyzed in primary analysis) evaluating the effect of evolocumab vs placebo on cognitive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB) done at baseline, week 24, annually, & then at the end of the trial
• Primary outcome (spatial working member strategy index of executive function, score ranges from 4-28, lower = better)
  • Baseline: 17.8
  • Last follow-up (median 19 months): Evolocumab 17.5, placebo 17.6
  • Change from baseline: -0.21 vs -0.29 (p<0.001 for non-inferiority)
• Secondary outcomes:
  • Working memory (score 0-270, lower = better)
    • Last follow-up: Evolocumab 20.3 vs placebo 20.1
    • Change from baseline: -0.52 vs -0.93 (p=0.36 for difference)
  • Episodic memory (score 0-70, lower = better)
    • Last follow-up: Evolocumab 24.9 vs placebo 23.6
    • Change from baseline: -1.53 in both groups (p=0.49 for difference)
  • Psychomotor speed (median time, lower = better)
    • Baseline: 356.7 vs 355.1
    • Last follow-up: 361.8 vs 355.7
    • Change from baseline: +5.2 vs +0.9 (p=0.06 for difference)
• Subgroup analyses suggested that evolocumab was worse than placebo in patients with baseline LDL <85 mg/dL, but better than placebo in those with baseline LDL >85 mg/dL (p=0.01 for interaction), though this was not supported by subgroup analysis of secondary outcomes

Fibrates for CV prevention

References: ACCORD Lipid, FIELD

Bottom-line:

• In patients taking a statin, the addition of a fibrate does not significantly reduce the risk of CV events.

• In patients at intermediate-to-high CV risk who are absolutely not able to take a statin, fibrate therapy reduces the relative risk of non-fatal, but not fatal, CV events by ~20%.

  • In my opinion, ezetimibe & bile-acid sequestrants (& soon possibly PCSK9 inhibitors) should be considered before fibrates in these patients.

Patients

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Intervention

• FIELD: Fenofibrate vs matching placebo
  • Fenofibrate given as 200 mg (micronized formulation) PO once daily
  • Non-study lipid-lowering drug: Fenofibrate group 8%, placebo group 17%
  • ~20% in each group discontinued study drug by end of study
• ACCORD Lipid: Fenofibrate + simvastatin vs simvastatin + matching placebo
  • Fenofibrate given as 160 mg PO once daily
  • Average dose of simvastatin 20 mg/d in both groups (open-label, adjusted to lipid targets)
  • Fenofibrate discontinued in 22%, placebo discontinued in 19% by end of study; ~20% in each group discontinued simvastatin by end of study

Results @ ~5 years

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Internal validity

• Both trials at low risk of bias (including allocation, performance, detection, & attrition bias)
  • Central randomization
  • Patients, clinicians, investigators, adjudicators all blinded to treatment allocation
  • Loss-to-follow-up <1%
  • Analyzed using intention-to-treat principles

Generalizability

• FIELD represents the effects of fibrate monotherapy in a population with type 2 diabetes at mostly intermediate risk of CV events (estimated ~10-12% over 10 years)
  • Mechanistically, primarily testing the mechanistic effect of lowering triglycerides by ~30% over placebo, as effect on both LDL & HDL modest
• ACCORD Lipid represents the effects of adding a fibrate to a statin in a higher-risk population of patients with type 2 diabetes (estimated ~25% over 10 years without statin)
  • Again, primarily testing the mechanistic effect of lowering triglycerides, as no discernible effect on LDL or HDL

Other fibrate studies

• VA-HIT: In 2531 men with CAD not receiving a statin, gemfibrozil lowered trigs by ~30% more than placebo. At a median 5.1 years, this resulted in a 4.4% absolute risk reduction in MI or coronary death (NNT 23).
• BIP: In 3090 men with CAD not receiving a statin, bezafibrate increased HDL & lowered trigs by ~15% more than placebo. At a mean 6.2 years, this did not result in a statistically significant effect on MI or sudden death.
• Subgroup analyses from these various trials have provided more confusion than clarity. For example, some studies demonstrate an interaction by baseline triglycerides (VA-HIT, BIP), but not others (FIELD, ACCORD Lipid). The ACCORD Lipid study, but not the BIP trial, found a subgroup interaction based on the combination of low HDL and high trigs.
• A systematic review of 18 fibrate trials, including the ones already mentioned here, found results largely consistent with the FIELD trial:
  • No reduction in death or fatal CV events;
  • Reduction in CV events, entirely driven by non-fatal coronary events (i.e. non-fatal MI & coronary revascularization): Relative risk 0.81 (0.75-0.89);
  • 5% relative risk reduction in coronary events per 0.1 mmol/L reduction in triglycerides;
  • Notably, ACCORD Lipid was the only trial included in this systematic review which had routine statin administration.

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

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

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

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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

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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