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ACC Ranking: 2020 Top Clinical Trials Regarding ACS, TAVI and Heart Failure
ACC
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).
Patients undergoing PCI for ACS were randomized to ticagrelor monotherapy after 3 months of DAPT (n = 1,527) versus standard therapy (n = 1,529).
Inclusion criteria
Exclusion criteria
Other salient features/characteristics
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
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.
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.
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.
Inclusion criteria
Exclusion criteria
Other salient features/characteristics
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)
Secondary outcomes
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.
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.
Inclusion criteria
Exclusion criteria
Other salient features/characteristics
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
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.
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).
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).
Inclusion criteria
Exclusion criteria
Other salient features/characteristics
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)
Secondary outcomes
Renal outcomes
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.
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.
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.
Inclusion criteria
Exclusion criteria
Other salient features/characteristics
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).
Secondary outcomes for restrictive vs. liberal transfusion strategy
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.
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.
Eligible patients who underwent TAVR were randomized to aspirin alone (n = 331) versus aspirin and clopidogrel for 3 months (n = 334).
Inclusion criteria
Exclusion criteria
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
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.
Patients were randomized in a 1:1 fashion to either colchicine 0.5 mg daily or matching placebo.
Inclusion criteria
Exclusion criteria
Other salient features/characteristics
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).
Secondary outcomes for colchicine vs. placebo
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.
Colchicine Reduces Cardiovascular Events in Chronic Coronary Disease
N Engl J Med. | Oct 29,2020
Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Imp...
N Engl J Med. | Dec 29,2020
Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction
N Engl J Med. | Mar 31,2020
Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients...
Circulation. | Nov 13,2020