BRIDGE - Peri-procedure bridging of anticoagulation of AF patients on warfarin

Douketis JD, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. NEJM 2015;373:823-33.

Bottom line: In patients with AF & CHADS2 score <4 requiring interruption of warfarin, bridging with parenteral anticoagulation increases major bleeding (NNH 53 from bridging) without reducing thromboembolic events.

Patients (n=1884)

  • Randomized 1884, analyzed 1813

  • Included

    • Atrial fibrillation or flutter (paroxysmal or permanent) confirmed by EKG or pacemaker interrogation

    • Non-valvular or valvular AF both eligible

    • CHADS2 score 1 or higher

    • Receiving warfarin for 3+ months with INR 2.0-3.0

    • Undergoing elective invasive procedure felt to require interruption of warfarin

  • Excluded

    • Mechanical heart valve

    • Recent stroke, systemic embolism or TIA (in past 12 weeks) or major bleeding (in past 6 weeks)

    • CrCl <30 mL/min

    • Platelets <100

    • Planned cardiac, brain or spine surgery

  • Baseline characteristics

    • Age 72 y, male (73%), white (91%)

    • CHADS2 score

      • Mean score 2.3

      • 1 (23%), 2 (40%), 3 (24%), 4 (10%), 5 (3%), 6 (<1%)

      • HF/LV dysfunction ~33%

      • HTN 87%

      • Diabetes 41%

      • Prior stroke 8%

      • Prior TIA 8%

      • MI 15%

    • Undergoing procedure classified as having low bleeding risk 89%

    • Labs: INR 2.4, CrCl 88 mL/min

    • Concomitant ASA ~35%

Intervention & comparator

  • I: No bridging

    • Warfarin stopped 5 days before the procedure & restarted evening of surgery or POD 1, without bridging

  • C: Anticoagulant bridging

    • Warfarin stopped 5 days before the procedure & restarted POD0 evening or POD 1

    • Pre-op bridging: Dalteparin 100 units/kg subcut BID started 3 days before the procedure, last dose AM day before procedure (~24h before)

    • Post-op bridging: Dalteparin restarted 12-24h after low-bleeding-risk procedure & 48-72h after high-bleeding-risk procedure; continued x5-10 days until INR 2 or higher once

  • Adherence in both groups was ~86% pre-op & 96% post-op

Results @ day 30-37

  • Not bridging was non-inferior to bridging for the primary efficacy outcome (arterial thromboembolism; a composite of ischemic/hemorrhagic stroke, TIA, systemic embolism)

    • Intention-to-treat (ITT) population: No bridging 04.%, bridging 0.3% (difference 0.1%, 95% confidence interval [95%CI] -0.6% to +0.8%)

      • Stroke: 0.2% vs 0.3%

    • Per-protocol population: 0.3% vs 0.4% (difference 0.0%; 95% CI -0.7% to +0.7%)

  • Not bridging reduced the risk of major bleeding (ITT population): 1.3% vs 3.2% (NNT 53)

    • Minor bleeding: 12.0% vs 20.9% (NNT 12)

  • No difference in all-cause mortality: 0.5% vs 0.4%

Internal validity

  • Low risk of allocation, performance & detection bias

    • Interactive voice-response system

    • Dalteparin & matching placebo in identical vials

    • Blinded adjudication of all outcomes

  • Possible attrition bias due to moderate loss-to-follow-up (3.8%), which is higher than the rate of primary outcome events

  • Non-inferiority trial

    • Non-inferiority margin set as an absolute difference of 1.0% for arterial thromboembolism (wide);

    • Assumed ~1.0% absolute risk of arterial thromboembolism in both groups (actual event rate <1/2 expected);

    • Analysis of both ITT & per-protocol populations, which were nearly identical.

ATTR-ACT - Tafamidis for transthyretin amyloid cardiomyopathy

Maurer MS, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. NEJM 2018;379:1007-16.

Bottom line:

  • In patients with transthyretin amyloid cardiomyopathy (ATTR-CM) and NYHA functional class 1-2, tafamidis at a dose of 20-80 mg/d reduced the risk of death (NNT 8) & cardiovascular hospitalization (NNT 13) over 30 months.

  • Tafamidis does not appear to reduce mortality, & increases mortality, in patients with NYHA functional class 3 HF at baseline.

  • Tafamidis did not increase overall or any specific adverse effects.

Patients (n=441)

  • Included

    • 18-90 y/o

    • ATTR, wild-type (ATTRwt) or due to a mutation (ATTRm), confirmed by cardiac or extra-cardiac biopsy

    • ATTR cardiomyopathy confirmed by

      • Echo - End-diastolic interventricular septal wall thickness >12 mm

      • Hx of heart failure (HF) with 1+ HF hospitalizations or clinical evidence of volume overload or NT-proBNP 600+ pg/mL

    • 6-minute walk-test (6MWT) distance >100 m

  • Excluded

    • NYHA functional class 4

    • Cause of HF other than ATTR CM, light-chain amyloidosis

    • Receiving other proven/potential therapy for ATTR

      • Hx of liver or heart transplant

      • Diflunisal, doxycycline, tauroursodeoxycholate

    • eGFR <25; ALT/AST >2x ULN; Severe malnutrition (quantified as serum albumin [g/L] * BMI <600)

    • Use of calcium-channel blockers or digoxin

  • Baseline characteristics

    • 74 y/o; male (90%); white (80%), black (14%)

    • ATTRwt (76%), ATTRm (24%)

    • NYHA functional class (FC): 1 (~8%), 2 (~59%), 3 (~33%)

    • Kansas City Cardiomyopathy Questionnaire (KCCQ) 66/100

    • 6MWT distance 350 m

    • BP 115/70 mm Hg (supine & standing)

    • Echo: LVEF 48%, interventricular wall thickness 16.2-16.2 mm

    • NT-proBNP median ~3000

    • Meds: RAAS inhibitor (27%), beta-blocker (29%), diuretic (66-70%), antithrombotic (40%)

Interventions & control

  • I: Tafamidis 20 or 80 mg PO once daily

    • If adverse effect, those randomized to 80 mg/d could be reduced to 40 mg/d

  • C: Matching placebo

  • Adherence: 97% from each group took at least 80% of their doses (assessed by pill count at follow-up visits)

Results @ 30 months

  • Primary outcome of death or CV hospitalization: Win ratio: 1.70 (95% confidence interval [CI] 1.26-2.29)

    • “Win ratio” calculated using the Finkelstein-Schoenfeld method

      • Non-parametric test that compares every patient from the intervention group to every patient in the control group in pairwise fashion;

      • First, pairs are compared based on whether each is alive or dead at last common follow-up (e.g. if patient A followed for 2 years, but patient B dropped out at 1 year, then both are compared at year 1);

      • Second, if both are alive or both dead, then there is a draw, & they are compared based on the rate of CV hospitalizations;

      • The win ratio is a tally of all of these comparisons, where higher scores are better. Because this is a ratio, a confidence interval that does not include 1.00 is statistically significant

  • Death: Tafamidis 29.5%, placebo 42.9% (NNT 8)

    • Hazard ratio (HR) 0.70 (95%CI 0.51-0.96)

    • No significant subgroup difference based on TTR genotype or NYHA FC

  • CV hospitalizations: 52.3% vs 60.5% (NNT 13, relative risk 0.68, 95%CI 0.56-0.81)

    • Rate per patient/year: 0.30 vs 0.46

    • Subgroup based on NYHA class: p<0.001 for interaction; INCREASE with tafamidis in NYHA FC 3

    • Subgroup based on TTR genotype: p=0.11 for interaction'\

  • 6MWT distance vs placebo: +76 m

  • KCCQ vs placebo: +13.6 points (range 0-100, higher scores are better)

  • No difference in overall, serious, or any individual adverse effects

Internal validity

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

    • Computer-generated randomization stratified by TTR status (wild-type or mutant variant), baseline NYHA class

    • Allocation concealed: Allocation by using interactive web-response system

    • Blinding by use of matching placebo

    • Loss to follow-up <0.5% & modified intention-to-treat (mITT) analysis

REDUCE-IT - Icosapent ethyl (EPA) to reduce CV events

Bhatt DL, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. NEJM

Bottom line: In patients with existing ASCVD or diabetes + other CV risk factors, isocapent ethyl (esterified EPA) reduced the risk of CV events (NNT 21) versus placebo over 4.8 years. Conversely, icosapent increased the risk of AF (NNH 72), peripheral edema (NNH 67) and possibly serious bleeding (NNH 167) versus placebo.

It remains unclear how icosapent ethyl works to reduce CV events, or whether it benefits only patients with elevated triglycerides.

Patients (n=8179)

  • Enrolled in 11 countries from November 2011 to August 2016

  • 19,212 screened (10,429 did not meet inclusion criteria) -> 8179 randomized

  • Included

    • Either

      • Secondary prevention: 45+ y/o + established ASCVD, or

      • Primary prevention: 50+ y/o with diabetes + 1 other CV risk factor (male age 55+ y/o or female 65+ y/o; smoker; HTN; HDL-C <1 for men or <1.2 for women; hsCRP >3 mg/L; CrCl 30-60; retinopathy; albuminuria; ABI <0.9 without intermittent claudication)

    • Fasting triglyceride 1.5-5.6 mmol/L (amended in 2013 to 2.3-5.6)

    • LDL-C 1.0-2.6 mmol/L on a stable statin dose for at least 4 weeks

  • Key exclusion criteria

    • HF NYHA functional class 4; life-threatening condition other than CVD with expected prognosis <2y

    • BP >200/100 mm Hg; HbA1c >10.0%; CrCl <30 or need for peritoneal/hemodialysis

    • Planned PCI/CABG

    • Prior pancreatitis; ETOH abuse in past 6 months

    • Meds:

      • Lipid-lowering drugs other than statin +/- ezetimibe (niacin (>200 mg/d), fibrate, omega-3 supplements, bile acid sequestrants, PCSK9 inhibitors

      • Drugs that affect triglycerides & other lipids (tamoxifen, estrogen, progestins, thyroid replacement, systemic steroids.

    • Allergy to fish or shellfish

  • Typical baseline characteristics

    • 64 y/o, male (71%), white (90%)

    • Secondary prevention (71%), primary prevention (29%)

    • Type 2 diabetes (58%)

    • Labs

      • LDL-C 1.9 mmol/L, HDL-C 1.0 mmol/L, trigs 2.4 mmol/L

      • hsCRP 2.2 mg/L

    • Meds

      • Statin (100%): High-intensity (32%), moderate (62%), low (6%)

      • Ezetimibe 6%

Intervention & control

  • I: Icosapent ethyl 2 g PO BID

    • Purified formulation of eicosapentanoic acid (EPA), one of the main omega-3 fatty acids in fish oil;

    • Far exceeds doses found in over-the-counter (OTC) fish oil products, which are typically labeled to contain ~200 mg of EPA/capsule.

  • C: Matching “placebo” containing mineral oil

Results @ median 4.9 years

  • Reduction in primary CV outcome (composite of CV death, MI, stroke, PCI/CABG, or hospitalization for unstable angina [UA]): Icosapent ethyl 17.2% vs placebo 22.0% (NNT 21) & every individual component

    • Hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68-0.83

    • Reduction in 3-point MACE (CV death, MI, stroke): 11.2% vs 14.8% (NNT 28), HR 0.74, 95% CI 0.65-0.83

      • CV death: 4.3% vs 5.2% (HR 0.80, 95%CI 0.66-0.98)

      • Non-fatal or fatal MI: 6.1% vs 8.7% (HR 0.69, 95%CI 0.58-0.81)

      • Stroke: 2.4% vs 3.3% (HR 0.72, 95%CI 0.55-0.93)

    • Urgent/emergent PCI/CABG: 5.3% vs 7.8% (HR 0.65, 95%CI 0.55-0.78)

    • UA hospitalization: 2.6% vs 3.8% (HR 0.68, 95%CI 0.53-0.87)

  • Death from any cause: 6.7% vs 7.6% (HR 0.87, 95%CI 0.74-1.02 - inconclusive)

Safety

  • Increased:

    • Atrial fibrillation: 5.3% vs 3.9% (NNH 72)

    • Hospitalization for afib/flutter: 3.1% vs 2.1% (NNH 100)

    • Peripheral edema: 6.5% vs 5.0% (NNH 67)

  • Possible increased risk of serious bleeding: 2.7% vs 2.1% (NNH 167; p=0.06)

    • No difference in GI bleeds (1.5% vs 1.1%) or CNS bleeds (0.3% vs 0.2%)

Effect on surrogate outcomes

  • Trigs at year 1: -0.4 vs +0.05 mmol/L (-20% [-0.5 mmol/L] from baseline vs placebo

  • LDL-C at year 1: +0.05 vs 0.18 mmol/L (0.13 mmol/L lower vs placebo)

  • hsCRP at year 2: -0.2 vs +0.5 mg/L (-38% [0.8 mg/L] lower vs placebo

Internal validity

  • Low risk of allocation, performance and detection bias

    • Computer-generated randomization sequence stratified by CV risk group (2o or 1o prevention), use of ezetimibe & geographic region

    • Allocation concealment maintained by central allocation via interactive voice response system

    • Blinding of patients, investigators, clinicians maintained by use of mineral oil “placebo” in control group, which is similar in appearance to the intervention

  • Unclear (potentially high) risk of attrition bias

    • Low loss to follow-up (0.2%) for death

    • High loss to follow-up for non-fatal outcomes, with similar frequency between groups (icosapent ethyl 9.3%, placebo 10.0%)

    • Intention-to-treat analysis.

Other considerations

  • This is not a study of fish oil/omega-3 fatty acid supplements

    • High-quality evidence is exceptionally clear that fish oil/omega-3 fatty acid supplements, such as those sold at pharmacies, health food stores or over the Internet, do NOT reduce the risk of CV events in patients with or without CVD. This has been shown in a meta-analysis of 20 RCTs including 68,680 patients, as well as 2 other recent RCTs (ASCEND & VITAL).

  • The mechanism of action for CV event reduction with icosapent ethyl is unclear

    • Unlikely to be explained by triglyceride reduction

      • Identical CV relative risk reduction (RRR) regardless of baseline triglyceride concentration (<1.7 vs >1.7 or <2.3 vs >2.3 mmol/L);

      • Identical CV RRR regardless of whether achieved trigs <1.7 or 1.7+ mmol/L.

    • Not fully explained by LDL-C increase caused by mineral oil within placebo in comparator group

      • Identical RRR vs placebo patients who had LDL-C increase, decrease, or no change;

      • LDL-C difference of 0.13 mmol/L would only explain a ~3% RR difference based on estimates from the Cholesterol Treatment Trialists’ Collaboration meta-analysis of statins (where 1 mmol/L reduction in LDL-C associated with a ~25% RRR in CV events)

    • Other possible mechanisms include

      • Anti-inflammatory effect (or pro-inflammatory effect of mineral oil in placebo)?

      • Antiarrhythmic effect, or stabilization of cellular membranes?

        • Reduced tertiary outcomes of cardiac arrest (HR 0.52, 95% CI 0.31-0.86) & sudden cardiac death (HR 0.69, 95% CI 0.50-0.96)

      • Antithrombotic effect?

        • Reduced MI, stroke, as well as sudden cardiac events & likely increased risk of bleeding

  • Ongoing trials with EPA +/- DHA: STRENGTH (International) , RESPECT-EPA (Japan)

CARMELINA - Linagliptin in type 2 diabetes

Rosenstock J, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: The CARMELINA randomized clinical trial. JAMA

Bottom line: In patients with type 2 diabetes with additional risk for CV or renal adverse events, linagliptin did not reduce the risk of CV events, nephropathy or retinopathy vs placebo over 2.2 years. Linagliptin may increase the risk of acute pancreatitis (NNH 500).

This is consistent with all other trials of DPP-4 inhibitors showing no clinical benefit from this class of medications.

Patients (n=6991)

  • Included

    • Adults with T2DM with HbA1c 6.5-10.0%

    • + antihyperglycemic meds stable for at least 2 months

    • + either high CV or renal risk

      • High CV risk: Existing CAD/stroke/PAD, or micro/macroalbuminuria (urinary albumin:creatinine ratio [UACR] >30 mg/g)

      • High renal risk: eGFR 15-45, or eGFR 45-75 + UACR >200 mg/g

  • Key exclusion criteria

    • ACS/PCI/CABG in last 2 months or PCI/CABG planned

    • Stroke/TIA in last 3 months

  • Typical baseline characteristics

    • 66 y/o, male (62%), white (80%)

    • Diabetes mean duration 15 y, HbA1c 8.0%

    • Ischemic heart disease (27%), HF (27%)

    • eGFR mean 55 mL/min/1.73 m^2: 30-45 (28%), <30 (15%)

    • Meds:

      • Antihyperglycemics: Insulin (58%), metformin (54%), sulfonylurea (32%)

      • ASA (62%), statin (72%), ACEI/ARB (81%)

Intervention & control

  • I: Linagliptin 5 mg PO daily

  • C: Matching placebo

  • Co-interventions: Glycemic control using most available antihyperglycemics (no DPP-4i, SGLT2i or GLP-1 receptor agonists)

Results @ median 2.2 years

Efficacy

  • No reduction in the original primary outcome (“4-point MACE” a composite of CV death, MI, stroke, or hospitalization for unstable angina): Linagliptin 13.3%, placebo 13.2%

    • Hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.88-1.13

    • CV death: 7.3% vs 7.6%

    • Non-fatal MI: 4.5% vs 3.9%

    • Non-fatal stroke: 1.9% vs 2.1%

    • UA hospitalization: 1.2% vs 1.4%

    • Consistent lack of benefit in all subgroups (if anything, HR 1.20 in pts with baseline HbA1c >8%)

  • No effect on death from any cause: 10.5% vs 10.7% (HR 0.98, 95% CI 0.84-1.13)

  • No reduction in kidney outcomes (composite of death due to kidney disease, end-stage renal disease, or sustained -50% eGFR): 6.6% vs 6.5% (HR 0.98, 0.82-1.18)

  • No reduction in retinopathy: 1.0% vs 1.4% (HR 0.73, 95% CI 0.47-1.12)

Safety

  • Serious adverse events: 37.0% vs 38.5%

  • D/C due to adverse event: 10.3% vs 11.5%

  • Possible increase in acute pancreatitis: 0.3% vs 0.1% (NNH 500)

  • No increase in HF hospitalizations: 6.0% vs 6.5% (HR 0.90, 0.74-1.08)

Surrogate outcomes vs placebo

  • HbA1c: At month 3: -0.5%; over entire trial: -0.36%

  • No difference in weight, SBP, DBP, LDL-C, HDL-C

Internal validity

  • Low risk of allocation, performance, detection bias:

    • Computer-generated random sequence;

    • Block-randomized by interactive phone/web system;

    • Participants, clinicians & investigators blinded;

    • Central adjudication of CV & renal events by committee unaware of treatment allocation.

  • Low risk of attrition bias for CV outcomes & death, but unclear for renal outcomes:

    • Low loss-to-follow-up (LTFU) of 0.3% for mortality & 1.3% for CV events, but high (12%) LTFU for kidney outcomes;

    • Modified intention-to-treat (mITT) including all patients as randomized who received study drug for at least 1 dose.