Abstract
The late breaking trials released at the American Heart Association scientific sessions conference in November in New Orleans, LA covered a wide range of topics, including new devices within the field of heart failure, new registry data on transcatheter aortic valve replacement (TAVR) in intermediate risk patients, and medical management of peripheral arterial disease, coronary artery disease, and hypercholesterolemia. The following review highlights the late breaking trials presented at the conference that will have significant impact on clinical practice.
1
The FUTURE Study: The FUnctional Testing Underlying coronary REvascularization (FUTURE) Study: A “Real World” Comparison of Fractional Flow Reserve-Guided Management Versus Conventional Management in Multi Vessel Coronary Artery Disease Patients
1.1
Background
Fractional flow reserve (FFR) is recommended for identifying hemodynamically relevant coronary artery lesions when there is absence of myocardial ischemia. FFR could modify percutaneous coronary intervention (PCI) strategy in 50% of patients undergoing revascularization, even in those with no evidence for ischemia on non-invasive testing . However, the utility of FFR in guiding different treatment strategies in patients with multi-vessel coronary artery disease (CAD) is unknown.
1.2
Synopsis and main findings
The purpose of the trial was to investigate the superiority of FFR-guided therapeutic management compared with conventional management in patients with multi-vessel CAD. One-year primary composite end points included all-cause mortality, myocardial infarction, repeat revascularization, and stroke. The study was designed as a multicenter, open-label, randomized controlled trial. The initial recruitment plan was to include 1728 patients from 39 centers in France. However, the data safety monitoring board recommended stopping the study due to significantly greater mortality rates in the FFR group. The trial included 941 patients (mean age 65 ± 10 years; 83% male) at that time. Including only patients with available 1-year follow-up resulted in a trend toward higher mortality in the FFR group but that was not a statistically significant difference (3.9% vs 1.8%, p = 0.07). Limiting the analysis to only at the 797 patients followed to the planned 1-year end point, all-cause death was no longer statistically significantly higher in the FFR cohort (p = 0.07).
1.3
Conclusion and clinical implications
The FUTURE trial suggests FFR may not help for treatment decisions in complex, high-risk patients. However, the study was halted prematurely due to safety concerns, which compromised the statistical power of the conclusions. For the time being, FFR should continue to be used in routine interventional practice to guide percutaneous coronary interventions.
2
The REDUCE LAP-HF Trial: Transcatheter Interatrial Shunt Device Provides Sustained Clinical Benefit at One Year in Patients With Preserved or Mildly Reduced Ejection Fraction
2.1
Background
Heart failure with preserved ejection fraction (HFPEF) remains a therapeutic challenge. Elevated left atrial pressure is a near-universal finding in patients with HFPEF, the severity of which is related to both symptoms and outcome . It is hypothesized that decompression of the left atrium in HFPEF patients may improve symptoms and clinical outcomes. Computer simulation was used to demonstrate that an 8 mm interatrial shunt device (IASD) would provide adequate acute LA decompression during exercise. The REDUCE-LAP-HF trial aimed to assess safety and performance at one-year post implant of such an IASD in patients with symptomatic heart failure and left ventricular ejection fraction (LVEF) ≥40%.
2.2
Synopsis and main findings
The open-label, single-arm, phase-1 device trial included 64 patients with New York Heart Association (NYHA) class II-IV heart failure symptoms, LVEF ≥40%, and resting pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or exercise PCWP ≥25 mmHg. The majority of patients were female (66%) with NYHA class II or III symptoms and average LVEF of 47%. 100% of the shunts demonstrated successful left-to-right interatrial flow by echocardiogram at one year and a Qp/Qs ratio stable at 1.28. There were three deaths (4.7%) and one (1.5%) stroke at one year. Follow-up at one year demonstrated significant improvement in NYHA functional status, quality of life, and performance on the 6-min walk test. There was no significant change in LVEF at one year but there was statistically significant increase in cardiac output on invasive measurements. Additionally, there was no significant change in resting PCWP at one year but IASD therapy did provide increased work capacity for a given left atrial pressure.
2.3
Conclusion and clinical implications
The implantation of the IASD appears to be safe through one-year follow-up. Patients show a clinically meaningful reduction in normalized PCWP and meaningful improvements in NYHA class, exercise capacity, and quality of life. The long-term effects on right-sided chambers are undetermined. Randomized trials are required to determine the true value of this novel therapy.
2
The REDUCE LAP-HF Trial: Transcatheter Interatrial Shunt Device Provides Sustained Clinical Benefit at One Year in Patients With Preserved or Mildly Reduced Ejection Fraction
2.1
Background
Heart failure with preserved ejection fraction (HFPEF) remains a therapeutic challenge. Elevated left atrial pressure is a near-universal finding in patients with HFPEF, the severity of which is related to both symptoms and outcome . It is hypothesized that decompression of the left atrium in HFPEF patients may improve symptoms and clinical outcomes. Computer simulation was used to demonstrate that an 8 mm interatrial shunt device (IASD) would provide adequate acute LA decompression during exercise. The REDUCE-LAP-HF trial aimed to assess safety and performance at one-year post implant of such an IASD in patients with symptomatic heart failure and left ventricular ejection fraction (LVEF) ≥40%.
2.2
Synopsis and main findings
The open-label, single-arm, phase-1 device trial included 64 patients with New York Heart Association (NYHA) class II-IV heart failure symptoms, LVEF ≥40%, and resting pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or exercise PCWP ≥25 mmHg. The majority of patients were female (66%) with NYHA class II or III symptoms and average LVEF of 47%. 100% of the shunts demonstrated successful left-to-right interatrial flow by echocardiogram at one year and a Qp/Qs ratio stable at 1.28. There were three deaths (4.7%) and one (1.5%) stroke at one year. Follow-up at one year demonstrated significant improvement in NYHA functional status, quality of life, and performance on the 6-min walk test. There was no significant change in LVEF at one year but there was statistically significant increase in cardiac output on invasive measurements. Additionally, there was no significant change in resting PCWP at one year but IASD therapy did provide increased work capacity for a given left atrial pressure.
2.3
Conclusion and clinical implications
The implantation of the IASD appears to be safe through one-year follow-up. Patients show a clinically meaningful reduction in normalized PCWP and meaningful improvements in NYHA class, exercise capacity, and quality of life. The long-term effects on right-sided chambers are undetermined. Randomized trials are required to determine the true value of this novel therapy.
3
EUCLID Trial: Effects of Ticagrelor Compared With Clopidogrel in Patients With Peripheral Artery Disease
3.1
Background
Peripheral artery disease (PAD) is considered a systemic manifestation of atherosclerosis affecting over 200 million people worldwide and associated with both cardiovascular and limb morbidity and mortality . Antiplatelet therapy is recommended for all patients with PAD and clopidogrel is superior to aspirin . Ticagrelor is an antiplatelet agent that has proven benefits over clopidogrel in patients with acute coronary syndrome. The aim of the EUCLID study was to determine if long-term monotherapy with ticagrelor versus clopidogrel reduces the rate of composite cardiovascular (CV) death, myocardial infarction (MI), or ischemic stroke in patients with symptomatic PAD.
3.2
Synopsis and main findings
The EUCLID study was a multicenter, double blind trial that included 13,885 patients with symptomatic PAD randomized to receive ticagrelor 90 mg twice a day or clopidogrel 75 mg daily. The primary efficacy endpoint of composite cardiovascular death, MI, or ischemic stroke occurred in 751 of 6930 patients (10.8%) receiving ticagrelor versus 740 of 6955 (10.6%) receiving clopidogrel (p = 0.65). There was no significant difference in major or minor bleeding between the two groups.
3.3
Conclusion and clinical implications
Ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events in patients with symptomatic PAD. The clinical benefits of ticagrelor compared with clopidgrel in patients with ACS cannot and should not be extrapolated to PAD. Ultimately, more studies like EUCLID are needed to determine the optimal medical and non-pharmacological therapy to prevent CV and limb-related events.
4
HOPE-3 Trial: The Effect of Blood Pressure and Cholesterol Lowering on Cognition
4.1
Background
Cognitive impairment and dementia affect 5% to 7% of patients over 60 years old. Elevated blood pressure is associated with cognitive impairment. In addition, statins were linked to short-term memory loss in observational studies but not in randomized controlled studies. The HOPE-3 study was initially designed to evaluate the effects on cardiovascular (CV) events by lowering of blood pressure and LDL cholesterol in 12,705 intermediate CV risk patients . The current post hoc analysis of the HOPE-3 study evaluated the cognitive effects of lowering blood pressure, LDL cholesterol, or both.
4.2
Synopsis and main findings
A total of 1626 patients completed cognitive and functional assessments at both baseline and the end of the study. The median follow-up was 5.6 years. The primary outcome of cognitive decline assessed using the Digit Symbol Substitution Test (DSST) was not different between treatment arms. Post hoc analyses showed non-significant trends toward beneficial effects of the blood pressure intervention in patients with a baseline systolic reading greater than 145 mmHg and of rosuvastatin in those with a baseline LDL cholesterol level greater than 140 mg/dL. Only a combination treatment for blood pressure lowering and LDL lowering in patients who have both hypertension and elevated LDL cholesterol at baseline was found to reduce the mean change of DSST.
4.3
Conclusion and clinical implications
The study failed to demonstrate that lowering blood pressure and or LDL cholesterol results in significantly less decline in cognitive or functional status. Only in patients with high systolic blood pressure and high LDL cholesterol at baseline did treatment with both rosuvastatin and a blood pressure-lowering agents result in significantly slower cognitive decline. The clinical implications of the present analysis is that the beneficial cognitive effects of blood pressure and LDL cholesterol lowering can be anticipated only for patients with baseline elevated blood pressure and LDL cholesterol.
5
PRECISION Trial: Cardiovascular Outcomes With Celecoxib Vs Ibuprofen or Naproxen
5.1
Background
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed class of drugs in the world. The use of COX-2 inhibitors for treatment of arthritis were part of a fierce debate and underwent criticism after post marking approval surveillance of one such agent rofecoxib (Vioxx; Merck) demonstrated an excess of myocardial infarctions and strokes. Celecoxib remained on the market under the condition that the manufacturer conduct a cardiovascular safety trial. The PRECISION trial aimed to evaluate the cardiovascular safety of celecoxib by comparing it with two common non-selective NSAIDs naproxen and ibuprofen.
5.2
Synopsis and main findings
The study enrolled 24,081 patients with arthritis who also had established cardiovascular disease or were deemed to be at high risk for cardiovascular (CV) disease. The patients were randomized to celecoxib, naproxen, or ibuprofen. After mean treatment duration of 20 months, the primary endpoint of composite CV death, nonfatal myocardial infarction (MI) or nonfatal stroke occurred in 2.3% of the celecoxib-treated patients, 2.5% of the naproxen group, and 2.7% of the ibuprofen group in the intention-to-treat analysis (p < 0.001 for noninferiority in both comparisons). No significant differences emerged for any of the components of the composite endpoint, nor from a range of additional secondary endpoints with the exception of serious gastrointestinal events, which were significantly lower in the celecoxib group compared with the other two groups. Renal events and hospitalizations for hypertension were both significantly lower for celecoxib versus ibuprofen.
5.3
Conclusion and clinical implications
Numerically fewer events occurred with celecoxib than ibuprofen, meeting all noninferiority criteria. These findings challenge the widely held view that naproxen provides superior cardiovascular safety. Despite the limitations of the trial, the findings may require a careful review to determine whether changes in labeling or regulatory status of these drugs are warranted.
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