AFIRE Trial

Current guidelines recommend D(OAC) after completion of combination therapy after 12 months in patients who underwent percutaneous coronary intervention (PCI) and have indication for anticoagulation. In addition single therapy with D(OAC) is indicated for patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) that do not require PCI.

However, these approaches are yet to be supported from randomized clinical trials (RCT).

AFIRE was multicenter, open label and parallel group RCT and funded by Japanese Cardiac Research Foundation. Enrollment criteria were the presence of AF and stable CAD. Patients were required to have CHADs-VASc score of at least 1. In addition they were required to have at least one of the following: A history of PCI (angioplasty with or without stenting) at least 1 year prior to enrollment, a history of angiographically documented CAD (>50% stenosis) not requiring revascularization or a history of coronary artery bypass grafting (CABG) at least 1 year before enrollment. Major exclusion criteria were stent thrombosis, active tumor and uncontrolled hypertension.

Patients were randomly assigned to either monotherapy with rivaroxaban (10 mg once daily if creatinin clearance (CrCl) of 15-49 ml per minute or 15 mg if CrCl>50 ml per minute) or combination therapy with rivaroxaban at the previously stated doses plus an antiplatelet agent (aspirin or P2Y12 inhibitor at the discretion of physician). Primary endpoints were composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization or death from any cause. The primary safety endpoint was major bleeding. The primary efficacy analysis was performed by using modified intention to treat method.

A total of 2215 patients were underwent modified intention to treat analysis. The median follow up period was 24.1 months. The primary endpoint occurred in 89 and 121 patients receiving monotherapy and combination therapy respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). The incidence of the primary safety end point was lower in the monotherapy group than in the combination-therapy group (1.62% vs. 2.76% per patient-year; hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01).

ISAR-REACT 5 Trial

Current guidelines recommend ticagrelor and prasugrel in patients with acute coronary syndromes (ACS). In this randomized clinical trial the efficacy and safety of prasugrel was compared with ticagrelor among patients presented with ACS. This was a investigator initiated, open label, randomized clinical trial and patients were eligible if they present with ACS for which invasive strategy was planned. Patients that were randomized to ticagrelor arm received the loading dose (180 mg loading dose and then 90 mg twice daily) as soon as possible after randomization. On the other hand patients that were randomized to prasugrel arm received the loading dose (60 mg loading dose and then 10 mg once daily) according to the their presentation diagnosis. Those with presented with STEMI received the loading dose as soon as possible after randomization and those with NSTEMI received the loading dose after coronary anatomy was known and before proceeding to percutaneous coronary intervention (PCI). The primary endpoint was the composite of death, MI or stroke at 1 year after randomization. The primary safety endpoint was bleeding according to BARC score.

2012 and 2006 patients were randomized to ticagrelor and prasugrel arm respectively. At 1-year follow-up 15.2% of patients in ticagrelor arm and 12.5% of patients in prasugrel arm discontinued their drugs that they were using at discharge. A primary composite endpoint occurred in 9.1% and 6.8% of patients among ticagrelor and prasugrel arms respectively (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006). In the modified intention-to-treat analysis of bleeding outcome, major bleeding occurred in 5.4% and 4.8% of patients among ticagrelor and prasugrel arms respectively (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46). The lower incidence of composite primary outcomes was driven mainly reduced MI rates in prasugrel arm and this was not at the expense of increased major bleeding. The results were consistent regardless of admission diagnosis.

PARAGON-HF Trial

Heart failure with preserved ejection fraction (HFpEF) is frequently encountered diagnosis in clinical practice and it causes significant morbidity and mortality. Unfortunately there is no convincing evidence from randomized clinical trials for any drug showing efficacy in HFpEF treatment. In this randomized, double blind, active comparator trial, patients older than 50 years, sign and symptoms of heart failure (HF), NYHA II-IV, LVEF >45% within previous 6 months, elevated level of natriuretic peptides, evidence of structural heart disease randomized to either sacubitril-valsartan or valsartan. The primary outcome was composite of total HF hospitalization and death from any cardiovascular cause.

A total of 4822 patients were included to the trial and of those 4796 were included in the efficacy analysis. The median duration of follow up was 35 months. There were 894 primary events in 526 patients among sacubitril-valsartan group and 1009 primary events in 557 patients among valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). Importantly there was suggestion of heterogeneity in treatment effect showing benefit of sacubitril-valsartan in patients with lower LVEF and in women. 15.4% and 16.2% of patients discontinued their randomized drugs for adverse events in sacubitril-valsartan and valsartan arms respectively.

DAPA-HF Trial

Previous studies established the role of SGLT-2 inhibitors in patients with type 2 diabetes for reducing the risk of first heart failure (HF) hospitalization. DAPA-HF trial is designed for evaluating the safety and efficacy of dapagliflozin in patients with HF with reduced EF regardless of presence or absence of diabetes.

Patients were included if they were older than 18 years, had LVEF <40%, NYHA II-III-IV, NT-proBNP >600 pg per milliliter. In addition patients were required to receive guideline-directed HF device and medical therapy. Major exclusion criteria were systolic blood pressure < 95mm/Hg and estimated glomerular filtration rate < 30. Randomized patients were either received dapagliflozin 10 mg once daily or matching placebo. The primary outcome was a composite of worsening HF or death from cardiovascular causes. Worsening HF was defined as either HF hospitalization or urgent visit for IV HF therapy.

4744 patients were either randomized to dapagliflozin or placebo. At screening 42% of patients had type 2 diabetes. The median duration of follow up was 18.2 months. The primary outcome occurred in 16.3% and 21.2% of patients among dapagliflozin and placebo groups respectively (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). All individual components of the composite outcome favored dapagliflozin over placebo. Number needed to treat for dapagliflozin to prevent one primary event was 21. The effect of dapagliflozin on the primary outcome was consistent in all pre-specified subgroups including patients with or without diabetes at baseline. Serious renal adverse events occurred in 1.6% and 2.7% of patients in dapagliflozin and placebo groups respectively.

ENTRUST-AF

Three large randomized trials evaluated the efficacy and safety of DOAC's in patients with AF who had undergone percutaneous coronary intervention PCI. Evidence from these trials established the strategy of using DOAC plus P2Y12 inhibitor and omitting aspirin for reducing bleeding events.

ENTRUST-AF was a open-label randomized, multicenter phase 3b trial evaluating the safety and efficacy of edoxaban-based antithrombotic regimen in patients with AF and undergone PCI. Included patients had anticoagulation indication for AF and successful PCI for stable coronary artery disease or acute coronary syndromes. Patients were randomized to either edoxaban 60 mg once daily (30 mg once daily as required) plus clopidogrel 75 mg once daily (or prasugre of ticagrelor at the discretion of physician) for 12 months or VKA plus clopidogrel 75 mg once daily for 12 months and aspirin for a minimum of 1 months up to 12 months. The primary outcome was composite of major or clinically relevant non-major bleeding. The primary efficacy endpoint was a composite of cardiovascular death, stroke, systemic embolic events, myocardial infarction and definite stent thrombosis.

1506 patients were included and randomized to either treatment arms. The indication of PCI was ACS in 52% of patients. 92% of patients received clopidogrel as a P2Y12 inhibitor. Among patients in VKA group, triple therapy was continued for a mean of 66 days. The median time in therapeutic INR was 63.1%. The primary bleeding event occurred in 17% and 20% of patients among edoxaban and VKA treatment groups respectively (HR for edoxaban 0.83 [95% CI 0.65–1.05], p=0.0010 for noninferiority, margin HR 1.20, p=0.1154 for superiority. Subgroup analysis revealed no variation in treatment effect for primary bleeding outcome among pre-specified baseline characteristics. At 12 months primary efficacy outcomes occurred in 7% and 6% of patients among edoxaban and VKA group respectively (HR for edoxaban 1.06 [95% CI 0.71–1.69]).

COMPLETE Trial

In COMPLETE trial, 'Culprit-Only Revascularization and Complete Revascularizations' strategies were compered in ST-segment elevation myocardial infarction (STEMI) patients with multivessel coronary disease. Complete revascularization was planned during index hospitalization or after discharge (within 45 days). The primary outcome of cardiovascular death or MI at 3 years occurred in 7.8% of the complete revascularization group compared with 10.5% of the culprit-only revascularization group (p = 0.004). This outcome was the same if PCI was performed during (median 1 day) or after the index hospitalization (median 23 days) (p for interaction = 0.62). Cardiovascular death, MI, or ischemia-driven revascularization, as the secondary outcomes, were significantly less in the complete revascularization group (8.9 % vs. 16.7 %, p< 0.001).

Relevant previous trials have demonstrated benefit for complete revascularization, but benefit was mainly due to a reduction in the risk of revascularization. The COMPLETE trial was able to show that complete revascularization was associated with a reduction in 'hard outcomes' since the primary outcome was cardiovascular death or MI. In short, complete revascularization (during or after the index hospitalization) after primary PCI for STEMI is beneficial.

MITRA-FR (2-Year results)

In this study, patients with severe secondary mitral regurgitation were randomized to percutaneous mitral valve repair with MitraClip (n = 152) versus medical therapy (n = 152). Primary outcomes which are defined as death or hospitalization due to heart failure occurred in 54.6 % of the MitraClip group compared with 51.3 % of the medical therapy group (p=0.53). Secondary endpoints were defined as death, hospitalization due to heart failure and death or hospitalization at 24 months. MitraClip device was not associated with a reduction in also secondary endpoints. The average value of the effective regurgitant orifice area (EROA) was 31 mm2 and the left ventricular end-diastolic volume (LVEDV) was 272 cc in the patients included in the study. The degree of mitral insufficiency decreased at least 2 grades in 92% of patients after MitraClip.

In a nutshell, even though MitraClip device significantly decreases the degree of mitral regurgitation, it did not provide superiority to medical treatment in terms of death or hospitalization due to heart failure. This trial contrasts with the COAPT trial, which documented benefit from MitraClip therapy for secondary mitral regurgitation. One reason postulated for this difference is that patients in COAPT had more mitral regurgitation per unit of ventricular volume (i.e., disproportionate mitral regurgitation). In COAPT, the mean EROA was 41 mm2 and the mean LVEDV was 194 cc versus MITRA-FR, where the mean EROA was 31 mm2 and the mean LVEDV was 272 cc.

SWEDEHEART Trial

The registry analysis included 28,812 patients who underwent isolated first-time CABG in Sweden from 2006 to 2015 and were alive six months after hospital discharge. Median follow-up was five years. The registry analyzed the variability rate of use of statins, beta-blockers, RAAS inhibitors and platelet inhibitors over time.

At six months after discharge, data showed statins were dispensed to 93.9 percent of patients, beta-blockers to 91.0 percent, RAAS inhibitors to 72.9 percent, and platelet inhibitors to 93.0 percent of patients. Eight years later the percentages had decreased dramatically to 77.3 percent, 76.4 percent, 65.9 percent and 79.8 percent, respectively. In other findings, researchers observed no major differences in the use of medications between women and men. However, they did note that all drugs were dispensed less frequently to patients over the age of 75.

The reason behind the fall in medications over time could be that in Sweden many CABG patients are not routinely seen by cardiologists beyond six to 12 months after the operation. Another factor may be that CABG relieves symptoms, so patients feel healthy and their motivation to use multiple daily medications wanes over the years.

SYNTAX Trials (10 year results)

The goal of this trial was to compare the relative efficacy of CABG versus DES-PCI (using TAXUS stents) in all-comers with severe three-vessel disease (3-VD) or left main (LM) disease, who were deemed eligible for either CABG or PCI. Primary endpoint was defined as MACCE (all-cause mortality, stroke, MI, or repeat revascularization) at 1, 3, 5, and 10 years. At ten-year follow-up (n=1,689), mortality rates were not different between PCI and CABG groups (27% vs. 24%, respectively). Among those with 3-VD; mortality rates were 28% with PCI vs. 21% with CABG. As for those with LM disease; mortality rates were 26% with PCI vs. 28% with CABG (p for interaction = 0.019).

In conclusion, CABG is a better strategy in multivessel disease and diabetic subgroup by providing a reduction in recurrent revascularization, MI and MI-related mortality in long-term follow-up, whereas PCI is a better and cost-effective strategy in patients with LMCA disease and low syntax scores. Long-term mortality data support PCI for LM disease.

THEMIS Trial

The objective of the THEMIS trial was to evaluate ticagrelor/aspirin compared with placebo/aspirin among patients with stable coronary artery disease (CABG, or history of PCI, or ?50 % stenosis in a major coronary artery) + Type 2 Diabetes mellitus.

The primary efficacy outcome of cardiovascular death, MI, or stroke occurred in 7.7% of the ticagrelor/aspirin group compared with 8.5% of group placebo/aspirin group (p = 0.04). Nonetheless, the primary safety outcome of TIMI major bleeding occurred in 2.2% of the ticagrelor/aspirin group compared with 1.0% of group placebo/aspirin group (p < 0.001). More patients in the ticagrelor/aspirin arm discontinued study medication due to bleeding or dyspnea.

In summary, ticagrelor/aspirin does not appear to have a favorable risk/benefit ratio among patients with stable ischemic heart disease and type 2 diabetes.

THEMIS Trial Sub-study

Among patients with stable coronary artery disease, type 2 diabetes, and prior PCI, ticagrelor/aspirin was associated with a reduction in major adverse ischemic events and an increase in major bleeding events compared with placebo/aspirin. In the subgroup of stable coronary artery disease patients with a history of PCI, ticagrelor/aspirin combination appears to have a favorable risk/benefit ratio.

RAPID-TnT Trial

In patients presenting to the emergency department with chest pain, a 0-1 hour high-sensitivity trop (hs-TnT) strategy (intervention group) and a 0-3 hour hs-TnT strategy (standard group) was compared for primary endpoints of death or myocardial infarction at 30 days. The primary endpoint was observed in 1% of the intervention group and 1% in the standard group (p for noninferiority = 0.006). As for secondary endpoints, the intervention group was found to be significantly better in early discharge from the emergency department and less functional cardiac test requirement (p < 0.001), whereas type 4 a and 5 myocardial infarction were significantly higher in the intervention group (p=0.004). Hospitalization due to arrhythmia, heart failure, stroke or revascularization at 30 days was similar in both groups (p=0.19).

In short, 0-1 hs-TnT strategy was found noninferior to the standard 0-3 hour application. While further study is needed, a rapid protocol utilizing hs-TnT appears to be a safe mechanism to allow for early discharge of low-risk patients from the emergency department.