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ACC Ranking: 2020 Top Clinical Trials Regarding ACS, TAVI and Heart Failure
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KEYWORDS
clinical trails, ranking

TICO: Ticagrelor With or Without Aspirin in Acute Coronary Syndrome After PCI

The TICO trial showed that ticagrelor monotherapy after 3 months of DAPT was superior at preventing ischemia and bleeding after PCI for ACS.


Description

The goal of the trial was to evaluate ticagrelor monotherapy after 3 months of dual antiplatelet therapy (DAPT) compared with 12 months of DAPT after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS).


Study Design

  • Randomized
  • Parallel
  • Stratification
  • Open-label

Patients undergoing PCI for ACS were randomized to ticagrelor monotherapy after 3 months of DAPT (n = 1,527) versus standard therapy (n = 1,529).

  • Total number of enrollees: 3,056
  • Duration of follow-up: 12 months
  • Mean patient age: 61 years
  • Percentage female: 21%
  • Percentage with diabetes: 27%

Inclusion criteria

  • ACS treated with the ultrathin bioresorbable polymer sirolimus-eluting stent (Orsiro)
  • ≥19 years of age

Exclusion criteria

  • >80 years of age
  • Increased risk of bleeding
  • Need for oral anticoagulation therapy
  • Current or potential pregnancy
  • Hepatic dysfunction
  • Bradycardia

Other salient features/characteristics

  • Clinical presentation: unstable angina 29%, non–ST-segment elevation myocardial infarction (NSTEMI) 35%, STEMI 36%

Principal Findings
The primary outcome, net adverse clinical events (death, MI, stent thrombosis, stroke, target vessel revascularization, or Thrombolysis in Myocardial Infarction [TIMI] major bleeding) at 12 months, occurred in 3.9% of the ticagrelor monotherapy after 3 months of DAPT group compared with 5.9% of the standard therapy group (p = 0.01). Association of ticagrelor monotherapy after 3 months of DAPT vs. standard therapy on the primary outcome: overall hazard ratio (HR) = 0.66, no multivessel disease HR = 0.41, multivessel disease HR = 0.86 (p for interaction = 0.04). Landmark analysis at 3 months for ticagrelor monotherapy vs. standard therapy for the primary outcome: (HR 0.41, p = 0.001).

Secondary outcomes

  • Major bleeding at 12 months: 1.7% of the ticagrelor monotherapy after 3 months group compared with 3.0% of the standard therapy group (p = 0.02)
  • Stent thrombosis at 12 months: 0.4% of the ticagrelor monotherapy after 3 months group compared with 0.3% of the standard therapy group (p = 0.53)
  • TICO-STEMI subgroup analysis: Major adverse cardiac and cerebrovascular events at 12 months: 2.7% of the ticagrelor monotherapy after 3 months group compared with 2.5% of the standard therapy group (p = 0.81)

Interpretation

Among ACS patients who underwent PCI with an ultrathin biodegradable-polymer sirolimus-eluting stent, ticagrelor monotherapy after 3 months of DAPT was superior to standard therapy of DAPT for 12 months. Ticagrelor monotherapy was effective at preventing net composite ischemic and bleeding events. Bleeding events were defined by the TIMI criteria, which by way of reminder includes fatal bleeding, overt bleeding with drop in hemoglobin ≥5 g/dl or a 15% drop in hematocrit, and any intracranial hemorrhage.

This trial is like the similarly designed but placebo-controlled TWILIGHT trial. Neither of these trials addressed if aspirin monotherapy, instead of ticagrelor monotherapy in the 3- to 12-month period, would be equally effective. Ticagrelor monotherapy appears to be an emerging strategy, especially for patients with increased bleeding risk, after a short duration of DAPT.


The EMPEROR-Reduced trial showed that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFrEF (EF ≤40%) on excellent baseline GDMT, irrespective of diabetes status.

Description

The goal of the trial was to assess the safety and efficacy of empagliflozin in patients with symptomatic heart failure with reduced ejection fraction (HFrEF), irrespective of diabetes status.

Study Design

Patients were randomized in a 1:1 fashion to either empagliflozin 10 mg (n = 1,863) or matching placebo (n = 1,867). All the patients were receiving appropriate treatments for heart failure.

  • Total screened: 7,220
  • Total number of enrollees: 3730
  • Duration of follow-up: 16 months (median)
  • Mean patient age: 67 years
  • Percentage female: 24%

Inclusion criteria

  • Age ≥18 years
  • Chronic HF, New York Heart Association (NYHA) functional class II/III/IV
  • Left ventricular EF (LVEF) ≤40%
  • HF hospitalization within 12 months
  • N-terminal pro–B-type natriuretic peptide (NT-proBNP ≥600 pg/ml if EF ≤30%; ≥1000 pg/ml if EF 31-35%; ≥2500 pg/ml if EF >35%
  • If concomitant atrial fibrillation, then above thresholds were doubled)

Exclusion criteria

  • Acute coronary syndrome, stroke, or transient ischemic attack (TIA) within 90 days
  • Listed for orthotopic heart transplantation, currently implanted LV assist device (LVAD)
  • Cardiomyopathy based on infiltrative/accumulation diseases, muscular dystrophies, reversible causes, hypertrophic cardiomyopathy, pericardial restriction, peripartum, cardiomyopathy caused by chemotherapy within 12 months
  • Severe valvular heart disease
  • Acute decompensated HF
  • Implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy (CRT) within 3 months

Other salient features/characteristics

  • White 70%, Asian 18%
  • North America: 11%, Europe: 36%, Asia: 13%, Latin America: 34%
  • NYHA functional class II: 75%
  • Mean LVEF: 27%
  • Type 2 diabetes: 50%
  • Estimated glomerular filtration rate (eGFR) <60: 48%
  • Medications: angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker: 70%, angiotensin receptor-neprilysin inhibitor: 19%, mineralocorticoid receptor antagonist: 71%, beta-blocker: 94%
  • ICD: 31%, CRT 12%

Principal Findings

The primary outcome, cardiovascular death or HF hospitalization, for empagliflozin vs. placebo, was 19.4% vs. 24.7% (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65-0.86, p < 0.001)

  • Cardiovascular death: 10% vs. 10.8% (HR 0.92, 95% CI 0.75-1.12)
  • HF hospitalization: 13.2% vs. 18.3% (HR 0.69, 95% CI 0.59-0.81)

Secondary outcomes

  • Total hospitalizations: 388 vs. 553 (p < 0.001)
  • Composite renal outcome (chronic hemodialysis, renal transplantation, profound sustained reduction in eGFR): 1.6 vs. 3.1 (HR 0.50, 95% CI 0.32-0.77, p < 0.01)
  • All-cause mortality: 13.4% vs. 14.2% (HR 0.92, 95% CI 0.77-1.10, p > 0.05)
  • New-onset type 2 diabetes among patients with prediabetes: 11.2% vs. 12.6% (p > 0.05)
  • Change in hemoglobin A1c between baseline and week 52 (patients with diabetes): -0.28 vs. -0.12% (p < 0.05)
  • Systolic blood pressure -2.4 vs. -1.7 mm Hg (p > 0.05)
  • Confirmed hypoglycemic event: 1.4% vs. 1.5%
  • Death/HF hospitalization/emergent or urgent HF visit requiring intravenous treatment or diuretic intensification/deterioration of NYHA class: 32.7% vs. 43% (p < 0.0001)
  • Intensification of diuretics: 15.9% vs. 22.2% (p < 0.0001)
  • Emergent or urgent HF visit requiring intravenous treatment: 6.8% vs. 9.9% (p = 0.0004)
  • Hospitalization for HF requiring cardiac care unit/intensive care unit care: 4.8% vs. 5.7% (p = 0.002)

Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS): Benefit of empagliflozin vs. placebo was maintained across tertiles of baseline KCCQ-CSS for the primary endpoint, total HF hospitalizations and eGFR slope. In addition, benefit of empagliflozin vs. placebo for mean KCCQ-CSS was noted as early as 3 months, and noted to be sustained over 12 months.


Interpretation

The results of this trial indicate that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFrEF (EF ≤40%) on excellent baseline guideline-directed medical therapy (GDMT), irrespective of diabetes status. Benefit is primarily driven by a reduction in HF hospitalizations, not mortality. There was an early and sustained benefit on KCCQ-CSS. There was also a benefit in renal outcomes. This is a very important trial, and mirrors similar findings from the DAPA-HF trial for dapagliflozin. Even patients with severe LV dysfunction appeared to benefit. Of note, the DAPA-HF trial was larger, and did show a benefit in cardiovascular and all-cause mortality with dapagliflozin use.

Even though the sodium-glucose cotransporter 2 (SGLT2) inhibitors were introduced as type 2 diabetes management drugs, the results of the EMPA-REG OUTCOME trial and others indicated a clear benefit in HF management. This trial enrolled a dedicated HF population, and conclusively shows a benefit in this patient population, irrespective of diabetes status. These drugs will likely have a prominent role in future HF management guidelines.


VICTORIA: Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction

The VICTORIA trial showed that vericiguat was superior to placebo at improving heart failure outcomes.

Description

The goal of the trial was to evaluate vericiguat compared with placebo among patients with chronic heart failure (CHF) due to reduced ejection fraction (EF). Vericiguat increases soluble guanylate cyclase activity. By stimulating production of cyclic guanosine monophosphate, this may help to improve myocardial and vascular function.

Study Design

  • Randomized
  • Double-blind
  • Parallel

Patients with CHF were randomized to vericiguat (n = 2,526) versus placebo (n = 2,524). Vericiguat started at 2.5 mg daily, increased to 5 mg daily, then 10 mg daily.

  • Total number of enrollees: 5,050
  • Duration of follow-up: 12 months
  • Mean patient age: 68 years
  • Percentage female: 24%

Inclusion criteria

  • CHF; New York Heart Association class II-IV, left ventricular EF <45%, and guideline-directed heart failure therapy
  • Recent heart failure hospitalization or intravenous diuretic use
  • Elevated natriuretic peptides; N-terminal pro–B-type natriuretic peptide (NT-proBNP) ≥1000 pg/ml (≥1600 pg/ml if atrial fibrillation) or BNP ≥300 pg/ml (≥500 pg/ml if atrial fibrillation)
  • Clinically stable (systolic blood pressure ≥100 mm Hg and no intravenous diuretics for 24 hours)

Exclusion criteria

  • Use of long-acting nitrates, phosphodiesterase type 5 inhibitor, riociguat
  • Awaiting heart transplantation, continuous intravenous diuretics, or current/anticipated ventricular assist device
  • Chronic kidney disease (estimated glomerular filtration rate 15 ml/min/1.73 m2) or dialysis
  • Severe pulmonary disease requiring continuous oxygen
  • Severe hepatic insufficiency
  • Correctable cardiac comorbidities

Other salient features/characteristics

  • Mean EF: 29%
  • Target dose of vericiguat achieved in 89%

Principal Findings

The primary outcome, cardiovascular death or hospitalization for heart failure, occurred in 35.5% of the vericiguat group compared with 38.5% of the placebo group (hazard ratio [HR] 0.90, p = 0.019). The risk of the primary outcome for vericiguat vs. placebo: among those aged <75 years (HR 0.84) and those ≥75 years (HR 1.04) (p for interaction = 0.030).

Secondary outcomes

  • Cardiovascular death: 16.4% of the vericiguat group compared with 17.5% of the placebo group (p = 0.27)
  • All-cause death: 20.3% of the vericiguat group compared with 21.2% of the placebo group (p = 0.38)
  • Heart failure hospitalization: 27.4% of the vericiguat group compared with 29.6% of the placebo group (p = 0.048)
  • Serious adverse event: 32.8% of the vericiguat group compared with 34.8% of the placebo group

Interpretaion

Among patients with CHF with recent decompensation, a novel strategy of increasing soluble guanylate cyclase activity with vericiguat was effective. Vericiguat compared with placebo was effective at reducing cardiovascular death or hospitalization for heart failure. There was a possible enhanced benefit among patients <75 years of age. There was no apparent reduction in all-cause mortality with vericiguat compared with placebo. Vericiguat was safe and well tolerated and did not require monitoring of renal function or electrolytes. Vericiguat may represent a novel treatment among patients with recent heart failure decompensation.


VERTIS CV: Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial

The VERTIS CV trial showed that ertugliflozin is noninferior for reducing CV events in patients with T2DM and established CVD. The effects, especially on HF, were consistent with the benefits seen in the SGLT2 inhibitor class.

Description

The goal of the trial was to assess the cardiovascular (CV) safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular disease (ASCVD).

Study Design

Patients were randomized in a 1:1:1 fashion to either ertugliflozin 5 mg (n = 2,752), 15 mg (n = 2,747), or matching placebo (n = 2,747).

  • Total number of enrollees: 8,246
  • Duration of follow-up: 3.5 years
  • Mean patient age: 64.4 years
  • Percentage female: 30%

Inclusion criteria

  • Age ≥40 years
  • T2DM diagnosis according to American Diabetes Association (ADA) guidelines: glycated hemoglobin (HbA1c) 7.0-10.5% (53-91 mmol/mol)
  • Established ASCVD involving the coronary, cerebrovascular, and/or peripheral artery systems
  • Stable on allowable antihyperglycemic agents (AHAs) or on no background AHA for ≥8 weeks prior to study participation

Exclusion criteria

  • History of type 1 DM or ketoacidosis
  • Experiencing a CV event (e.g., myocardial infarction [MI] or stroke) or undergoing coronary or peripheral intervention procedure between the screening visit and randomization
  • Undergoing any CV surgery (e.g., valvular surgery) within 3 months of the screening visit
  • Planned revascularization or peripheral intervention procedure or other CV surgery
  • Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 at the screening visit
  • New York Heart Association class IV heart failure (HF) at screening visit (class III-IV prior to protocol amendment)

Other salient features/characteristics

  • White 88%; Europe: 56%
  • Diagnosis of T2DM: 13 years
  • Baseline low-density lipoprotein: 89 mg/dl
  • Known coronary artery disease: 76%, prior MI: 48%, known CVD: 23%
  • Metformin: 76%; insulin: 48%; glucagon-like peptide-1 (GLP-1): 3.5%
  • Statin: 82%, antiplatelet: 85%
Principal Findings

The primary outcome, CV death, nonfatal MI, or stroke for ertugliflozin vs. placebo: 11.9% vs. 11.9% (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85-1.11, p < 0.001 for noninferiority)

  • CV death: 1.8% vs. 1.9% (p = 0.39)
  • MI: 1.7% vs. 1.6% (p = 0.66)
  • Stroke: 0.8% vs. 0.8% (p = 0.99)

Secondary outcomes

  • HF hospitalization: 2.5% vs. 3.6% (p = 0.006)
  • HbA1c at 18 weeks for 5 mg ertugliflozin vs. placebo: -0.5% (p < 0.0001)
  • HbA1c at 18 weeks for 15 mg ertugliflozin vs. placebo: -0.5% (p < 0.0001)
  • Mean decrease in body weight for ertugliflozin 5 mg vs. placebo: 2.4 kg; for ertugliflozin 15 mg vs. placebo: 2.8 kg
  • Symptomatic hypoglycemic event: 27.2% vs. 28.8%
  • Urinary tract infection: 12.1% vs. 10.2% (p < 0.05)
  • Amputation: 2.0% vs. 1.6% (p > 0.05)

Renal outcomes


  • Renal composite (renal death, dialysis/transplant, doubling of serum creatinine): 3.2% vs. 3.9% (p = 0.08)
  • Doubling of serum creatinine: 3.1% vs. 3.8%

HF outcomes: Time to first HF hospitalization for ertugliflozin vs. placebo, was 0.73 vs. 1.05 events/100 person-years (HR 0.70, 95% CI 0.54-0.90, p = 0.006). The benefit was consistent across ertugliflozin dose. History of HF and EF ≤45%/>45%. Total and recurrent HF events were also reduced in the ertugliflozin arm. On subgroup analysis, effects were more pronounced among patients with eGFR <60 (p = 0.04), presence of macro- or microalbuminuria (p = 0.04), and patients already on diuretic (p = 0.02).

Effect of baseline renal function: The proportion of patients with chronic kidney disease (CKD) stages 1, 2, and 3 at baseline was 25%, 53%, and 22%, respectively; 60% and 40% of patients had normal and elevated albuminuria, respectively, while 49%, 32%, and 19% were classified into the KDIGO (Kidney Disease Improving Global Outcomes) CKD low-, moderate-, and high-/very high-risk categories.

Event rates were higher for all reported CV outcomes with more advanced kidney disease. For the endpoint of hospitalization for heart failure (HHF)/CV death, a greater benefit was observed among patients with albuminuria with ertugliflozin vs. placebo (33.5% vs. 45.8%, p for interaction = 0.01), and for KDIGO moderate (23.1% vs. 30.3%) and high/very high risk (47.0% vs. 61.1%) for ertugliflozin vs. placebo, respectively (p for interaction = 0.03). A similar finding was noted for the endpoint of HHF.


Interpretation

The results of this trial indicate that ertugliflozin is noninferior to placebo for reducing CV events in patients with T2DM and established CVD. Trends were noted for beneficial effect on renal outcomes, although this was not statistically significant. Subgroup analysis suggested a benefit for HHF and HHF/CV death with ertugliflozin vs. placebo among patients with higher risk (presence of albuminuria, higher KDIGO class).

This is the fourth sodium glucose cotransporter-2 (SGLT2) drug to report on CV outcomes (after empagliflozin, canagliflozin, and dapagliflozin). There appeared to be a consistent class effect with respect to reductions in HF hospitalizations, but major adverse cardiac event reductions were statistically significant only for canagliflozin and empagliflozin. Unlike canagliflozin, no safety signals with respect to amputations were noted. The salutary effects of ertugliflozin appear to be somewhat diminished compared with canagliflozin and empagliflozin; it is unclear if this represents a difference in patient populations between the trials, or a true biological difference in drug efficacy (or other issues). Overall, these are important findings, even as SGLT2 inhibitors are becoming first-line agents for patients with T2DM, and also for patients with HF, with or without DM. These results add to the body of evidence supporting the use of this class in the guidelines.


REALITY: Randomized Trial of Transfusion Strategies in Patients With Myocardial Infarction and Anemia

The REALITY trial showed that a restrictive PRBC transfusion strategy (transfusion for Hgb ≤8 g/dl, goal Hgb 8-10 g/dl) is noninferior to a more liberal strategy (transfusion for Hgb ≤10 g/dl, goal Hgb >11 g/dl).

Description

The goal of the trial was to assess the safety and efficacy of a restrictive versus liberal red blood cell (RBC) transfusion strategy among patients with acute myocardial infarction (AMI) and anemia.

Study Design

Patients with AMI and hemoglobin (Hgb) ≤8 to ≤10 g/dl during admission were randomized in a 1:1 fashion to either a liberal (for Hgb ≤10 g/dl, goal Hgb >11 g/dl) (n = 342) or a restrictive (for Hgb ≤8 g/dl, target Hgb 8-10 g/dl) (n = 324) RBC transfusion strategy. The strategies should be maintained until discharge from hospital or for 30 days, whichever comes first.

  • Total number of enrollees: 666
  • Duration of follow-up: 30 days
  • Mean patient age: 77 years
  • Percentage female: 43%

Inclusion criteria

  • MI (ST-segment elevation MI [STEMI] or NSTEMI)
    • Last ischemic symptoms <48 hours before admission
    • Troponin elevation
  • Anemia: Hb ≤10g/dl but >7 g/dl, at any time of index hospitalization for MI

Exclusion criteria

  • Cardiogenic shock
  • Post-percutaneous coronary intervention (PCI) or post-coronary artery bypass grafting (CABG) MI
  • Transfusion in the previous 30 days
  • Any known hematologic disease
  • Massive bleeding or compromising vital prognosis

Other salient features/characteristics

  • Prior acute coronary syndrome (ACS): 36%
  • Prior PCI: 34%
  • Chronic anemia: 18%
  • On admission: NSTEMI: 70%, coronary angiography: 80%, PCI: 59%, CABG: 4%
  • Mean units of packed RBCs (PRBCs) per patient for restrictive vs. liberal transfusion strategy: 2.9 vs. 2.8
  • At least 1 unit PRBCs: 35.7% vs. 99.4% (p < 0.0001)

Principal Findings

The primary outcome, all-cause death, reinfarction, stroke, and emergency revascularization prompted by ischemia for restrictive vs. liberal transfusion strategy, was 11.0% vs. 14.0% (hazard ratio 0.77, 95% confidence interval 0.50-1.18, p < 0.05 for noninferiority, p = 0.22 for superiority).

  • All-cause mortality: 5.6% vs. 7.7% (p > 0.05)
  • Recurrent MI: 2.1% vs. 3.1%
  • Emergency revascularization: 1.5% vs. 1.9%

Secondary outcomes for restrictive vs. liberal transfusion strategy

  • Acute renal failure: 9.7% vs. 7.1% (p = 0.24)
  • Infection: 0% vs. 1.5% (p = 0.03)
  • Acute lung injury: 0.3% vs. 2.2% (p = 0.03)
  • Length of stay: 7.0 vs. 7.0 days (p = 0.84)
  • Total 30-day hospital costs: €11,051 vs. €12,572 (p = 0.1)

Interpretation

The results of this trial indicate that a restrictive PRBC transfusion strategy (transfusion for Hgb ≤8 g/dl, goal 8-10 g/dl) is noninferior to a more liberal strategy (transfusion for Hgb ≤10 g/dl, goal Hgb >11 g/dl). In addition, infections and acute lung injury were higher with a more liberal strategy. Total blood utilization and costs were both lower with the restrictive strategy; this strategy was considered cost-dominant.

This is an important trial, and argues against the 10/30 rule that was once commonly practiced post-ACS. One minor point is that transfusions are frequently administered for Hgb ≤7 in clinical practice in the United States; the threshold studied in this trial was slightly higher (8 g/dl), possibly due to lack of equipoise for Hgb levels ≤7 g/dl. Similar results in favor of a restrictive strategy have been noted for post-cardiac and noncardiac surgery patients.

POPular TAVI: Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic-Valve Implantation

The POPular TAVI (antiplatelet therapy) trial showed that aspirin alone was preferential to aspirin plus clopidogrel after TAVR.

Description

The goal of the trial was to evaluate aspirin alone compared with aspirin plus clopidogrel among patients who underwent transcatheter aortic valve replacement (TAVR) and did not have a long-term indication for oral anticoagulation.

Study Design

  • Randomized
  • Parallel
  • Open-label

Eligible patients who underwent TAVR were randomized to aspirin alone (n = 331) versus aspirin and clopidogrel for 3 months (n = 334).

  • Total number of enrollees: 690
  • Duration of follow-up: 12 months
  • Mean patient age: 80 years
  • Percentage female: 50%
  • Percentage with diabetes: 24%

Inclusion criteria

  • Patients who underwent TAVR and did not have an indication for anticoagulation therapy

Exclusion criteria

  • Implantation of a drug-eluting stent within the last 3 months or bare-metal stent within the last month

Principal Findings

The primary co-outcome, all bleeding (minor, major, and life-threatening or disabling bleeding) at 12 months, occurred in 15.1% of the aspirin alone group compared with 26.6% of the aspirin plus clopidogrel group (p = 0.001).

The primary co-outcome, nonprocedure-related bleeding at 12 months, occurred in 15.1% of the aspirin alone group compared with 24.9% of the aspirin plus clopidogrel group (p = 0.005).

Secondary outcomes

  • Cardiovascular death, nonprocedure-related bleeding, stroke, or myocardial infarction at 12 months: 23.0% of the aspirin alone group compared with 31.1% of the aspirin plus clopidogrel group (p for noninferiority < 0.001, p for superiority 0.04)
  • Cardiovascular death, stroke, or myocardial infarction at 12 months: 9.7% of the aspirin alone group compared with 9.9% of the aspirin plus clopidogrel group (p for noninferiority = 0.004, p for superiority 0.93)
  • VARC major bleeding at 12 months: 2.4% of the aspirin alone group compared with 7.5% of the aspirin plus clopidogrel group (p < 0.05)
  • VARC major, life-threatening, or disabling bleeding at 12 months: 5.1% of the aspirin alone group compared with 10.8% of the aspirin plus clopidogrel group (p < 0.05)
  • Symptomatic aortic valve thrombosis at 12 months: 0.9% of the aspirin alone group compared with 0.3% of the aspirin plus clopidogrel group (p = nonsignificant)
  • Increased aortic valve gradient >10 mm Hg at 12 months: 3.0% of the aspirin alone group compared with 3.3% of the aspirin plus clopidogrel group (p < 0.05)

Interpretation

Among patients who underwent TAVR and did not have an indication for anticoagulation, aspirin alone was associated with a reduction in all bleeding and nonprocedure-related bleeding compared with aspirin plus clopidogrel. This benefit was largely due to a significant reduction in major bleeding events. Aspirin alone compared with aspirin plus clopidogrel was also associated with noninferiority regarding adverse ischemic events (cardiovascular death, stroke, or myocardial infarction). Valve function appeared to remain similar within 12 months.

The results of this study are similar to the ARTE trial. A limitation of the trial is open-label design. This trial casts some doubt on the arbitrary practice of dual antiplatelet therapy after TAVR.


LoDoCo2: Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease 2

The LoDoCo2 trial showed that colchicine improves CV outcomes (primarily MI and ischemia-driven revascularization) among patients with chronic coronary disease compared with placebo. However, there was a signal towards higher non-CV mortality with colchicine.

Description

The goal of the trial was to assess the safety and efficacy of colchicine in patients with chronic coronary disease.

Study Design

Patients were randomized in a 1:1 fashion to either colchicine 0.5 mg daily or matching placebo.

  • Total number of enrollees: 5,522
  • Duration of follow-up: 28.6 months (median)
  • Mean patient age: 66 years
  • Percentage female: 15.3%

Inclusion criteria

  • Age 35-82 years
  • Evidence of coronary disease on invasive coronary angiography or computed tomography
  • Angiography or a coronary artery calcium score of ≥400 Agatston units on a coronary artery calcium scan
  • Clinically stable condition for ≥6 months

Exclusion criteria

  • Moderate-to-severe renal impairment
  • Severe heart failure
  • Severe valvular heart disease
  • Known side effects from colchicine

Other salient features/characteristics

  • History of acute coronary syndrome: 84%
  • Prior coronary revascularization: 84%
  • Single antiplatelet: 67%, dual antiplatelet: 23%, statin: 94%

Principal Findings

The primary outcome, cardiovascular (CV) death, myocardial infarction (MI), stroke, ischemia-driven revascularization, for colchicine vs. placebo, was 6.8% vs. 9.6% (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.57-0.83, p < 0.001).

  • MI: 3.0% vs. 4.2% (p = 0.01)
  • Ischemic stroke: 0.6% vs. 0.9% (p = 0.2)
  • Ischemia-driven revascularization: 4.9% vs. 6.4% (p = 0.01)
  • CV mortality: 0.7% vs. 0.9% (p > 0.05)

Secondary outcomes for colchicine vs. placebo

  • CV death, MI, stroke: 4.2% vs. 5.7% (p = 0.007)
  • All-cause mortality: 2.6% vs. 2.2% (p > 0.05)
  • Non-CV death: 0.7 vs. 0.5 events/100 patient-years (HR 1.51, 95% CI 0.99-2.31)
  • Hospitalization for pneumonia: 1.7% vs. 2.0%

Interpretation

The results of this trial indicate that colchicine improves CV outcomes among patients with chronic coronary disease compared with placebo. Reductions were noted in MI and ischemia-driven revascularization. However, there was a signal towards higher non-CV mortality with colchicine. Etiology was unclear, but hospitalizations for infections and pneumonia were similar between the two arms.

These are interesting findings. The COLCOT trial showed a benefit in ischemic outcomes among a similar high-risk population. In that trial, there was a neutral effect on death (1.8% vs. 1.8%) and benefit was predominantly driven by a reduction in urgent revascularizations. COPS was a smaller trial in ACS patients that showed a similar benefit in revascularization, but with a significantly higher risk of non-CV mortality (5 vs. 0, p = 0.02). It is unclear if this is a true signal or a chance finding, but will need to be carefully assessed going forward. Discontinuations due to side effects are frequent with colchicine; in this trial, 15% did not undergo randomization after enrollment in the run-in phase due to side effects.



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