High levels of triglycerides, a type of fat found in the blood, have been connected to an increased risk of cardiovascular diseases. The question of whether decreasing these levels can reduce the incidence of cardiovascular events has been under investigation. Pemafibrate, a selective peroxisome proliferator–activated receptor α modulator, has been shown to lower triglyceride levels and improve other lipid levels.
In an international, double-blind, randomized, controlled trial involving 10,497 patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride levels of 200 to 499 mg per deciliter), and low high-density lipoprotein (HDL) cholesterol levels (40 mg per deciliter or lower), the effects of pemafibrate were examined. Participants were either assigned to receive pemafibrate or a matching placebo. These patients were already receiving guideline-directed lipid-lowering therapy, or couldn’t undergo statin therapy due to adverse effects, and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes.
The study followed patients for a median period of 3.4 years. After 4 months, pemafibrate had resulted in a decrease of 26.2% for triglycerides, 25.8% for very-low-density lipoprotein (VLDL) cholesterol, 25.6% for remnant cholesterol, 27.6% for apolipoprotein C-III, and an increase of 4.8% for apolipoprotein B. However, the primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), demonstrating no significant reduction in cardiovascular events despite the improved lipid levels.
The overall incidence of serious adverse events was similar between the two groups. However, pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism, and a lower incidence of nonalcoholic fatty liver disease.
In conclusion, despite reducing triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels, pemafibrate did not lower the incidence of cardiovascular events among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels. This suggests that reducing these lipid levels alone may not be sufficient to lower cardiovascular risk, and additional strategies may need to be explored.
The groundbreaking “SUNLIGHTTrial” recently highlighted the potential of the combined treatment of Trifluridine–Tipiracil (FTD–TPI) and Bevacizumab in extending the lifespan of patients with advanced colorectal cancer. The promising phase 3 study builds on prior research suggesting the efficacy of FTD–TPI in these cases, and points to the enhanced potential of FTD–TPI when used in combination with Bevacizumab.
In this trial, 492 adult patients were evenly assigned into two distinct groups. Each patient had received no more than two previous chemotherapy regimens for advanced colorectal cancer. One group received the combination of FTD–TPI and Bevacizumab, while the other was treated with FTD–TPI alone. The trial aimed to analyze overall survival, progression-free survival, and safety outcomes, including the time to the worsening of patients’ Eastern Cooperative Oncology Group (ECOG) performance-status score.
The combination treatment group reported a median overall survival of 10.8 months, a significant improvement compared to the 7.5 months observed in the group treated with FTD–TPI alone. This corresponds to a hazard ratio for death of 0.61, demonstrating a 39% reduction in the risk of death for patients in the combination group (95% confidence interval [CI], 0.49 to 0.77; P<0.001).
Furthermore, combination therapy also showed a remarkable improvement in progression-free survival. Patients in the combination group experienced a median progression-free survival of 5.6 months, more than double the 2.4 months noted in the FTD–TPI group. The hazard ratio for disease progression or death was 0.44, indicating a reduction of the risk by 56% (95% CI, 0.36 to 0.54; P<0.001).
The trial’s safety evaluations revealed that the most common adverse events for both groups were neutropenia, nausea, and anemia. Importantly, no treatment-related deaths were reported. Additionally, the combined therapy also showed a slower time to the worsening of the ECOG performance-status score. The median time to the increase of the ECOG score from 0 or 1 to 2 or higher was 9.3 months in the combination group and 6.3 months in the FTD–TPI group, a reduction in risk of 46% (hazard ratio, 0.54; 95% CI, 0.43 to 0.67).
In conclusion, the Sunlight Trial has shown promising results for patients with refractory metastatic colorectal cancer. The combined treatment of FTD–TPI and Bevacizumab led to significantly longer overall survival and progression-free survival times compared to FTD–TPI alone. Further studies will be needed to confirm these findings and to refine the application of these treatments. Nonetheless, the findings represent a significant stride forward in the battle against advanced colorectal cancer.
Explore the pivotal clinical trials that have shaped our understanding of the role of steroids in the management of septic shock, unveiling the complexities and nuances of this controversial topic.
Introduction
Septic shock is a life-threatening condition characterized by a dysregulated host response to infection, leading to circulatory and metabolic abnormalities. The use of steroids in septic shock management has long been a topic of debate among clinicians and researchers. Various clinical trials have been conducted to evaluate the efficacy and safety of steroid administration in septic shock patients. In this article, we will review the landmark clinical trials that have significantly impacted our understanding and approach to steroids use in septic shock management.
1. Reversal of late septic shock with supraphysiologic doses of hydrocortisone (1998)
The trial was a randomized, double-blind, placebo-controlled trial that assessed the effect of low-dose corticosteroids (hydrocortisone) in patients with septic shock who had a poor response to fluid resuscitation and vasopressor therapy. The primary outcome was 28-day all-cause mortality.
Results from the RALES trial showed that low-dose hydrocortisone significantly reduced 28-day mortality in septic shock patients with poor response to initial resuscitative measures. This landmark trial provided the foundation for the use of low-dose corticosteroids in septic shock management.
2. Corticosteroid Therapy of Septic Shock (CORTICUS) (2008)
The CORTICUS trial aimed to evaluate the efficacy of hydrocortisone in septic shock patients, particularly those with relative adrenal insufficiency. The primary outcome was 28-day all-cause mortality.
Contrary to the 1998 trial, the CORTICUS trial found no significant difference in 28-day mortality between the hydrocortisone group and the placebo group. This study raised questions about the universal application of steroids in septic shock and highlighted the need for more research to identify specific patient populations that may benefit from steroid therapy.
3. The HYPRESS Trial (2016)
The HYPRESS trial was a randomized, double-blind, placebo-controlled trial designed to evaluate the effect of hydrocortisone in patients with sepsis but without septic shock. The primary outcome was the development of septic shock within 14 days.
Results from the HYPRESS trial showed that hydrocortisone did not prevent the development of septic shock in sepsis patients without shock at baseline. This study suggested that the routine use of steroids in sepsis without shock may not provide significant clinical benefits.
4. The ADRENAL Trial (2018)
The ADRENAL trial was a multicenter, randomized, double-blind, placebo-controlled trial conducted to assess the efficacy of hydrocortisone in reducing 90-day all-cause mortality in critically ill patients with septic shock. The primary outcome was 90-day all-cause mortality.
The ADRENAL trial found no significant difference in 90-day mortality between the hydrocortisone group and the placebo group. However, the hydrocortisone group experienced a faster resolution of shock and a shorter duration of mechanical ventilation, suggesting that steroids may provide some clinical benefits in septic shock management.
5. The APROCCHSS Trial (2018)
The APROCCHSS trial was a randomized, double-blind, placebo-controlled trial evaluating the effect of hydrocortisone plus fludrocortisone on 90-day all-cause mortality in septic shock patients. The primary outcome was 90-day all-cause mortality.
Results from the APROCCHSS trial demonstrated that the combination of hydrocortisone and fludrocortisone significantly reduced 90-day mortality in septic shock patients compared to placebo. This study provided evidence supporting the use of combined corticosteroid therapy in septic shock management, highlighting the potential benefits of a more comprehensive approach to steroid administration.
6. The VASST Trial (2009)
The Vasopressin and Septic Shock Trial (VASST) was a randomized, double-blind, placebo-controlled trial that investigated the use of low-dose vasopressin in addition to corticosteroids in septic shock patients. The primary outcome was 28-day all-cause mortality.
Although the VASST trial primarily focused on vasopressin, it provided valuable information on the impact of corticosteroids in septic shock management. The trial found no significant difference in mortality between patients receiving vasopressin plus corticosteroids and those receiving norepinephrine plus corticosteroids.
7. The SEPSISPAM Trial (2014)
The SEPSISPAM trial was a multicenter, randomized, double-blind, placebo-controlled study that aimed to evaluate the effect of early administration of drotrecogin alfa (activated) and hydrocortisone in patients with septic shock. The primary outcome was 28-day all-cause mortality.
Results from the SEPSISPAM trial showed no significant difference in 28-day mortality between patients receiving early administration of drotrecogin alfa and hydrocortisone and those receiving standard care. This study added to the body of evidence suggesting that the benefits of corticosteroids in septic shock management may be limited in certain patient populations and clinical situations.
8. The COIITSS Trial (2012)
The COIITSS trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy of low-dose hydrocortisone in combination with intensive insulin therapy in patients with severe sepsis and septic shock. The primary outcome was the time to shock reversal.
Results from the COIITSS trial demonstrated that low-dose hydrocortisone combined with intensive insulin therapy significantly reduced the time to shock reversal compared to placebo. This study provided further support for the potential benefits of corticosteroids in septic shock management, particularly when used in combination with other therapeutic interventions.
Conclusion
The use of steroids in septic shock management remains a complex and controversial topic. Landmark clinical trials such as RALES, CORTICUS, HYPRESS, ADRENAL, and APROCCHSS have provided valuable insights into the potential benefits and limitations of steroid therapy in this critically ill patient population. While some trials have demonstrated significant mortality reduction and clinical benefits with steroid use, others have not found a clear advantage.
These discrepancies highlight the importance of tailoring treatment strategies to individual patients and specific clinical situations. Future research should focus on identifying patient subgroups that may derive the most significant benefits from steroid therapy and further refining treatment protocols to optimize patient outcomes. By building on the knowledge gained from these landmark trials, clinicians can better navigate the complexities of steroid use in septic shock management and make informed decisions to improve patient care.
Explore the transformative clinical trials that have solidified the role of SGLT2 inhibitors in heart failure management and their potential to redefine the treatment landscape.
Introduction
Heart failure is a complex clinical syndrome associated with significant morbidity and mortality. In recent years, sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a promising new class of drugs with the potential to revolutionize heart failure management. Originally developed for type 2 diabetes treatment, SGLT2 inhibitors have demonstrated significant benefits in heart failure patients. In this comprehensive article, we will review the landmark clinical trials that have shaped the understanding and use of SGLT2 inhibitors in heart failure management.
1. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) (2015)
The EMPA-REG OUTCOME trial was a randomized, double-blind, placebo-controlled trial designed to evaluate the effect of empagliflozin, an SGLT2 inhibitor, on cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease. The primary outcome was a composite of major adverse cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.
Results from the EMPA-REG OUTCOME trial revealed that empagliflozin significantly reduced the primary composite outcome and the risk of hospitalization for heart failure compared to the placebo. This groundbreaking trial was the first to highlight the potential of SGLT2 inhibitors for heart failure management, even in patients without a prior history of heart failure.
2. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS) (2017)
The CANVAS trial aimed to assess the efficacy of canagliflozin, another SGLT2 inhibitor, in reducing cardiovascular events and renal outcomes in patients with type 2 diabetes and a history of or risk factors for cardiovascular disease. The primary outcome was a composite of major adverse cardiovascular events.
The CANVAS trial demonstrated that canagliflozin reduced the primary composite outcome and hospitalization for heart failure compared to placebo. This study further strengthened the evidence supporting the use of SGLT2 inhibitors in heart failure management.
3. Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) (2019)
The DAPA-HF trial was a multicenter, double-blind, randomized, placebo-controlled trial evaluating the efficacy of dapagliflozin, an SGLT2 inhibitor, in patients with heart failure and reduced ejection fraction (HFrEF), regardless of their diabetes status. The primary outcome was a composite of worsening heart failure or cardiovascular death.
The results of the DAPA-HF trial showed that dapagliflozin significantly reduced the primary composite outcome in HFrEF patients, irrespective of their diabetes status. This pivotal trial expanded the potential use of SGLT2 inhibitors to include heart failure patients without type 2 diabetes, broadening their therapeutic impact.
4. Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) (2021)
The EMPEROR-Preserved trial aimed to assess the efficacy of empagliflozin in patients with heart failure and preserved ejection fraction (HFpEF), regardless of diabetes status. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.
The EMPEROR-Preserved trial demonstrated that empagliflozin significantly reduced the primary composite outcome in HFpEF patients, independent of their diabetes status. This landmark trial marked a significant advancement in heart failure management, as it was the first to show a clear benefit of SGLT2 inhibitors in patients with preserved ejection fraction.
5. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DELIVER) (2021)
The DELIVER trial was designed to evaluate the efficacy and safety of dapagliflozin in patients with heart failure and preserved ejection fraction (HFpEF), irrespective of their diabetes status. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.
Results from the DELIVER trial showed that dapagliflozin reduced the primary composite outcome in patients with HFpEF. This study further confirmed the benefits of SGLT2 inhibitors in heart failure patients with preserved ejection fraction, adding to the growing body of evidence supporting their use in this population.
6. Efficacy and Safety of Canagliflozin in Participants With Heart Failure and Preserved Ejection Fraction (CHIEF-HF) (2021)
The CHIEF-HF trial was conducted to evaluate the effects of canagliflozin on health status, functional capacity, and clinical outcomes in patients with heart failure and preserved ejection fraction (HFpEF), regardless of their diabetes status. The primary outcome was the change in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score from baseline to 12 weeks.
The CHIEF-HF trial demonstrated that canagliflozin improved health status, functional capacity, and clinical outcomes in patients with HFpEF. This study further reinforced the role of SGLT2 inhibitors in the management of patients with preserved ejection fraction heart failure.
7. EMPEROR-Reduced: A Pivotal Trial Evaluating Empagliflozin’s Impact on Heart Failure with Reduced Ejection Fraction (2021)
The EMPEROR-Reduced trial (2020) was a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of empagliflozin in patients with heart failure and reduced ejection fraction (HFrEF), regardless of their diabetes status. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.
The results of the EMPEROR-Reduced trial demonstrated that empagliflozin significantly reduced the primary composite outcome in patients with HFrEF, irrespective of their diabetes status. This trial further reinforced the benefits of SGLT2 inhibitors in the management of heart failure patients with reduced ejection fraction and expanded their potential use across a broader range of heart failure patients.
Conclusion
Landmark clinical trials, such as EMPA-REG OUTCOME, CANVAS, DAPA-HF, EMPEROR-Preserved, DELIVER, and CHIEF-HF, have revolutionized our understanding and application of SGLT2 inhibitors in heart failure management. These trials have consistently shown the benefits of SGLT2 inhibitors in reducing hospitalization for heart failure and improving clinical outcomes in both HFrEF and HFpEF patients, regardless of their diabetes status.
As research in SGLT2 inhibitors and heart failure continues to advance, future clinical trials will likely refine our understanding of their optimal use in various patient populations and explore their potential applications in other cardiovascular and renal conditions. By building upon the knowledge gained from these landmark trials, healthcare providers can optimize heart failure management strategies and improve patient outcomes
Atrial fibrillation (AFib) is a prevalent cardiac arrhythmia that significantly elevates the risk of stroke and systemic embolism. As a result, effective anticoagulation therapy is crucial for managing AFib patients. Over the past decade, novel oral anticoagulants (NOACs) have challenged traditional vitamin K antagonists, like warfarin, as preferred therapeutic options. Eliquis (apixaban) is one such NOAC that has revolutionized the landscape of anticoagulation therapy in AFib patients. In this comprehensive article, we delve into the landmark clinical trials that have informed and shaped the use of Eliquis in the management of AFib.
1. Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) (2011)
The groundbreaking ARISTOTLE trial was designed to compare the efficacy and safety of Eliquis (apixaban) with warfarin in patients diagnosed with non-valvular AFib. The primary outcome measured was a composite of stroke and systemic embolism events.
Results from the ARISTOTLE trial revealed that Eliquis was superior to warfarin in the prevention of stroke and systemic embolism while also exhibiting a reduced risk of major bleeding and all-cause mortality. This influential study played an indispensable role in establishing Eliquis as a preferred anticoagulant for AFib patients.
2. Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) (2011)
The AVERROES trial aimed to compare Eliquis (apixaban) with aspirin in AFib patients deemed unsuitable for or unable to tolerate vitamin K antagonist therapy. The primary outcome assessed was the occurrence of stroke or systemic embolism.
The AVERROES trial demonstrated that Eliquis significantly mitigated the risk of stroke and systemic embolism in comparison to aspirin, while maintaining a similar risk of major bleeding. This study broadened the potential use of Eliquis in AFib patients who could not tolerate or did not respond favorably to traditional anticoagulant therapy.
3. Apixaban in Patients with Atrial Fibrillation and Prior Coronary Artery Disease Undergoing Percutaneous Coronary Intervention (AUGUSTUS) (2019)
The AUGUSTUS trial investigated the safety and efficacy of Eliquis (apixaban) in combination with a P2Y12 inhibitor (such as clopidogrel) in contrast to vitamin K antagonists plus dual antiplatelet therapy (DAPT) in AFib patients with a history of coronary artery disease undergoing percutaneous coronary intervention (PCI). The primary outcomes included major or clinically relevant non-major bleeding and a composite of death or hospitalization.
The results of the AUGUSTUS trial indicated that the combination of Eliquis and a P2Y12 inhibitor substantially reduced the risk of bleeding compared to the vitamin K antagonist plus DAPT group. Furthermore, Eliquis was associated with a lower rate of death or hospitalization. This study helped establish the role of Eliquis in AFib patients undergoing PCI.
4. Efficacy and Safety of Apixaban Compared with Warfarin at Different Levels of INR Control for Stroke Prevention in Atrial Fibrillation (ARISTOTLE-INR Substudy) (2014)
The ARISTOTLE-INR Substudy was an analysis of the ARISTOTLE trial data to evaluate the efficacy and safety of Eliquis (apixaban) compared with warfarin at various levels of international normalized ratio (INR) control in patients with non-valvular AFib. The primary outcomes were the same as those in the original ARISTOTLE trial.
The results of the ARISTOTLE-INR Substudy revealed that the benefits of Eliquis over warfarin were consistent across the entire spectrum of INR control. This important finding reinforced the role of Eliquis as a preferred anticoagulant, offering consistent protection against thromboembolic events in AFib patients regardless of INR control quality.
Conclusion
Landmark clinical trials, such as ARISTOTLE, AVERROES, AUGUSTUS, and the ARISTOTLE-INR Substudy, have significantly contributed to the growing understanding and implementation of Eliquis (apixaban) as a leading anticoagulant therapy for patients with atrial fibrillation. These trials have demonstrated the advantages of Eliquis over traditional therapies in terms of efficacy, safety, and improved clinical outcomes.
As the field of anticoagulation therapy continues to evolve, future clinical trials will likely refine our understanding of Eliquis’ role in AFib management and explore its potential applications in other patient populations. By building upon the knowledge gained from these landmark trials, healthcare providers can optimize anticoagulation strategies and improve patient outcomes for those affected by atrial fibrillation.
Atrial fibrillation (AFib) is the most common sustained cardiac arrhythmia and is associated with an increased risk of stroke, heart failure, and mortality. Over the past few decades, catheter ablation has emerged as a promising treatment for AFib, offering symptom relief and improved quality of life for many patients. In this article, we explore the landmark clinical trials that have played crucial roles in advancing the field of AFib ablation and informing best practices.
Radiofrequency Ablation vs. Antiarrhythmic Drugs as First-Line Treatment of Symptomatic Atrial Fibrillation (RAAFT) (2005)
The RAAFT trial was one of the first randomized controlled trials to compare the efficacy of radiofrequency catheter ablation (RFA) to antiarrhythmic drug (AAD) therapy as first-line treatment for symptomatic paroxysmal AFib. The primary endpoint was the time to first AFib recurrence.
Results from the RAAFT trial showed that RFA was more effective than AAD therapy in preventing AFib recurrence and reducing symptoms. This study laid the foundation for the increasing use of catheter ablation in AFib management.
Catheter Ablation for the Treatment of Atrial Fibrillation (CABANA) (2019)
The CABANA trial was a large-scale, multicenter study designed to compare catheter ablation to drug therapy in patients with symptomatic AFib. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest.
Although the CABANA trial did not demonstrate a significant reduction in the primary composite endpoint, it showed that catheter ablation was associated with a lower rate of AFib recurrence and improvements in quality of life. This trial highlighted the potential benefits of catheter ablation in a broader AFib population.
Cryoballoon vs. Radiofrequency Ablation for Paroxysmal Atrial Fibrillation (FIRE AND ICE) (2016)
The FIRE AND ICE trial compared the safety and efficacy of cryoballoon ablation (a form of pulmonary vein isolation) to RFA in patients with drug-refractory paroxysmal AFib. The primary efficacy endpoint was the time to first AFib recurrence, atrial flutter, or atrial tachycardia.
The results of the FIRE AND ICE trial demonstrated that cryoballoon ablation was non-inferior to RFA in terms of efficacy and safety. This study established cryoballoon ablation as a viable alternative to RFA in the treatment of paroxysmal AFib.
Ablation vs. Amiodarone for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure and an Implanted ICD (AATAC) (2016)
The AATAC trial compared catheter ablation to amiodarone therapy in patients with persistent AFib, congestive heart failure, and an implanted implantable cardioverter-defibrillator (ICD). The primary endpoint was the rate of AFib recurrence at 24 months.
The AATAC trial found that catheter ablation was more effective than amiodarone in maintaining sinus rhythm and reducing the rate of AFib recurrence. Additionally, catheter ablation was associated with fewer hospitalizations and a lower incidence of ICD shocks.
Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4) (2020)
The EAST-AFNET 4 trial evaluated the impact of early rhythm control therapy, including catheter ablation and AADs, compared to usual care in patients with recently diagnosed AFib. The primary outcome was a composite of cardiovascular death, stroke, worsening heart failure, or acute coronary syndrome.
The results of the EAST-AFNET 4 trial showed that early rhythm control therapy led to a significant reduction in the primary composite outcome. This study highlighted the importance of early intervention in AFib management and suggested that early catheter ablation might be beneficial for reducing long-term cardiovascular events.
Catheter Ablation vs. Medical Therapy for Atrial Fibrillation in Heart Failure (CASTLE-AF) (2018)
The CASTLE-AF trial compared catheter ablation to medical therapy in patients with AFib and heart failure with reduced ejection fraction (HFrEF). The primary composite endpoint included all-cause mortality and worsening heart failure events.
The CASTLE-AF trial demonstrated that catheter ablation significantly reduced the primary composite endpoint in patients with AFib and HFrEF. This study reinforced the role of catheter ablation in managing AFib in heart failure patients, emphasizing the potential benefits of this treatment approach in improving clinical outcomes.
Conclusion
Landmark clinical trials in AFib ablation, such as RAAFT, CABANA, FIRE AND ICE, AATAC, EAST-AFNET 4, and CASTLE-AF, have significantly advanced our understanding and treatment of this common cardiac arrhythmia. These trials have helped establish the role of catheter ablation in various patient populations, demonstrated the effectiveness of alternative ablation techniques, and highlighted the importance of early intervention in managing AFib.
As research in the field of AFib ablation continues to evolve, future clinical trials will undoubtedly refine our approach to treating this complex condition. By building upon the knowledge gained from these landmark trials, we can strive to improve patient outcomes and quality of life for those affected by atrial fibrillation.
Heart failure with preserved ejection fraction (HFpEF) is a complex and increasingly prevalent form of heart failure, accounting for nearly half of all heart failure cases. Despite its significance, HFpEF remains a challenging condition to manage and treat, as effective therapies have been limited. In this article, we delve into the landmark clinical trials that have shaped our understanding of HFpEF, its pathophysiology, and the development of targeted treatments.
CHARM-Preserved (2003)
The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved trial was one of the earliest large-scale clinical trials focused on HFpEF. This study assessed the effect of the angiotensin receptor blocker (ARB) candesartan on cardiovascular death and hospitalization due to heart failure in patients with HFpEF.
Results from CHARM-Preserved demonstrated that candesartan modestly reduced heart failure hospitalizations but had no significant impact on cardiovascular mortality. These findings highlighted the need for further research and development of targeted therapies for HFpEF.
I-PRESERVE (2008)
The Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) aimed to evaluate the efficacy of another ARB, irbesartan, in reducing morbidity and mortality in HFpEF patients. Unfortunately, I-PRESERVE results showed that irbesartan did not significantly reduce the composite outcome of death from any cause or hospitalization due to cardiovascular reasons.
These negative findings raised questions about the efficacy of ARBs in HFpEF and prompted the search for more effective treatment options.
TOPCAT (2014)
The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial investigated the mineralocorticoid receptor antagonist spironolactone’s effectiveness in HFpEF patients. The primary composite outcome included death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure.
TOPCAT’s results were mixed, as spironolactone failed to significantly reduce the primary composite outcome in the overall study population. However, a post-hoc analysis suggested a possible benefit in specific patient subgroups, such as those with elevated natriuretic peptide levels. This trial emphasized the need for better patient selection and personalized therapeutic approaches in HFpEF.
PARAMOUNT (2012)
The Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial was a groundbreaking study that introduced a new class of medications, angiotensin receptor-neprilysin inhibitors (ARNIs). The trial assessed the efficacy and safety of the ARNI sacubitril/valsartan (LCZ696) compared to the ARB valsartan in HFpEF patients.
The PARAMOUNT trial demonstrated that sacubitril/valsartan led to a more significant reduction in the biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) than valsartan alone. Additionally, sacubitril/valsartan was associated with a reduction in left atrial size, suggesting potential benefits in treating HFpEF. These promising results led to further investigation of ARNIs in HFpEF patients.
PARAGON-HF (2019)
Following the encouraging findings from PARAMOUNT, the Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF (PARAGON-HF) trial was designed to evaluate the effect of sacubitril/valsartan on morbidity and mortality in a larger HFpEF population. The primary composite outcome included total hospitalizations for heart failure and death from cardiovascular causes.
Although PARAGON-HF did not demonstrate a significant reduction in the primary composite outcome for the overall population, a subgroup analysis revealed a potential benefit in specific patient populations, such as women and those with a left ventricular ejection fraction closer to 45%. This trial highlighted the importance of further refining patient selection and targeting specific subgroups for optimized HFpEF treatment.
EMPEROR-Preserved (2021)
The EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trial was a landmark study that investigated the efficacy of the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin in reducing cardiovascular death and heart failure hospitalizations in HFpEF patients.
The results of EMPEROR-Preserved showed a significant reduction in the combined risk of cardiovascular death and heart failure hospitalizations with empagliflozin compared to placebo. This trial marked a significant breakthrough in HFpEF treatment, as it was the first to demonstrate a clear benefit with a novel therapeutic agent in this patient population.
Conclusion
The journey to finding effective treatments for HFpEF has been a long and challenging one, with numerous clinical trials conducted over the past two decades. While some trials, such as CHARM-Preserved, I-PRESERVE, and TOPCAT, yielded mixed or disappointing results, others like PARAMOUNT, PARAGON-HF, and EMPEROR-Preserved have paved the way for improved understanding and targeted treatment approaches.
The success of the EMPEROR-Preserved trial with empagliflozin has generated renewed optimism and interest in HFpEF research. It underscores the importance of continued investigation into novel therapeutic strategies and personalized treatment approaches to improve outcomes for patients with heart failure with preserved ejection fraction.
As our understanding of HFpEF continues to evolve, future clinical trials will undoubtedly refine our approach to managing this complex condition, leading to a better quality of life and outcomes for affected individuals.
References:
Yusuf, S., Pfeffer, M. A., Swedberg, K., Granger, C. B., Held, P., McMurray, J. J., … & Ostergren, J. (2003). Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. The Lancet, 362(9386), 777-781.
Massie, B. M., Carson, P. E., McMurray, J. J., Komajda, M., McKelvie, R., Zile, M. R., … & Ptaszynska, A. (2008). Irbesartan in patients with heart failure and preserved ejection fraction. New England Journal of Medicine, 359(23), 2456-2467.
Pitt, B., Pfeffer, M. A., Assmann, S. F., Boineau, R., Anand, I. S., Claggett, B., … & Solomon, S. D. (2014). Spironolactone for heart failure with preserved ejection fraction. New England Journal of Medicine, 370(15), 1383-1392.
Solomon, S. D., Zile, M., Pieske, B., Voors, A., Shah, A., Kraigher-Krainer, E., … & Packer, M. (2012). The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. The Lancet, 380(9851), 1387-1395.
Solomon, S. D., McMurray, J. J., Anand, I. S., Ge, J., Lam, C. S., Maggioni, A. P., … & Lewis, E. F. (2019). Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. New England Journal of Medicine, 381(17), 1609-1620.
Anker, S. D., Butler, J., Filippatos, G., Ferreira, J. P., Bocchi, E., Böhm, M., … & Pocock, S. J. (2021). Empagliflozin in heart failure with a preserved ejection fraction. New England Journal of Medicine, 385(16), 1451-1461.
2006
APAF STUDY
A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation (AF)
randomized controlled trial
M
Objective: To compare the relative efficacy of circumferential pulmonary vein ablation (CPVA) & antiarrhythmic drug therapy (ADT) in the treatment of patients with paroxysmal atrial fibrillation (PAF) who have already failed antiarrhythmic drugs
198 patients
Inclusion criteria: Patients >18 or <70 years with (1) creatinine concentration < 1.5mg/dl (2) h/o atrial fibrillation for > 6 months (3) AF burden > 2 episodes/ month in the last 6 months
Circumferential pulmonary vein ablation (n=99)
86
VS
Antiarrhythmic drug therapy (n=99)
PRIMARY OUTCOME
% patients free from recurrent atrial tachyarrhythmias P<0.001
SECONDARY OUTCOMES
22
22
93
% patients free from recurrent atrial tachyarrhythmias after repeat ablation.
35
35
95
95
Patients with sinus rhythm at 1 year % P=0.08
87
Conclusion: Among patients with paroxysmal atrial fibrillation, CPVA is more successful than ADT for prevention of paroxysmal atrial fibrillation with few complications
C Pappone et al. JACC 2006,48(11):2340-2347
2021
ANTLER TRIAL
Maintenance or discontinuation of antidepressants in primary care
Multicenter, randomized, double-blind trial
M
Objective: To assess the effects of maintenance
antidepressant therapy, as compared with discontinuation of treatment, in patients taking antidepressants
478 patients
Inclusion criteria: Participants 18 to 74 years of age with >2 prior episodes of depression or took antidepressants for > 2 years
Maintenance group
(n=238)
39
39
x
Discontinuation group (n=240)
PRIMARY OUTCOME
Relapse of depression %
HR 2.06; 95% CI, 1.56 to 2.70; P< 0.001
SECONDARY OUTCOME
56
56
4.1
PHQ-9 score at 12 weeks Diff: 2.2; 95% CI, 1.5 to 2.8
6.3
3.1
GAD-7 score at 12 weeks Diff: 2.4; 95% CI, 1.8 to 3.0
5.3
4
Adverse events %
3
Conclusion: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy.
G Lewis et al. NEJM 2021; 385:1257-1267
2019
ANTHARTIC TRIAL M
Prevention of early Ventilator-Associated
Pneumonia after cardiac arrest
Multicentre, randomised, double-blind, placebo-controlled
Objective: To investigate whether in post out-of-hospital cardiac arrest (OOHCA) patients treated with targeted temperature management, does the use of empirical antibiotics prevent early ventilator-associated pneumonia.
194 patients
Inclusion criteria: Patients ≥ 18 years of age hospitalized in the ICU after OOHCA with shockable rhythm,& treated with targeted temperature management of 32 to 34°C
Antibiotic Group (N=99)
19
PRIMARY OUTCOME
Control Group
(N=95)
Rate of early ventilator-associated pneumonia %
HR 0.55; 95% CI, 0.31 to 0.92; P=0.003
SECONDARY OUTCOME
34
34
4
Rate of late VAP %
5
4
Urinary tract infection %
3
Conclusion: A 2-day course of antibiotic therapy with amoxicillin- clavulanate in patients receiving a 32-to-34°C targeted temperature management strategy after out-of-hospital cardiac arrest with initial shockable rhythm resulted in a lower incidence of early ventilator- associated pneumonia than placebo.
B François et al. NEJM 2019;381:1831-42
