Manreet Kanwar

Role of Phosphodiesterase-5 Inhibitors in Heart Failure: Emerging Data and Concepts

Novel treatment of congestive heart failure (HF) involves utilizing unique pathways to improve upon contemporary therapies. Increasing the availability of cyclic guanosine monophosphate (cGMP) by inhibition of phosphodiesterase-5 (PDE5) is a relatively new, but promising therapeutic strategy. Preclinical studies suggest a favorable myocardial effect of PDE5 inhibitors by blocking adrenergic, hypertrophic and pro-apoptotic signaling, thereby supporting their use in HF. The clinical benefits of acute and chronic PDE5 inhibition on lung diffusion capacity, exercise performance and ejection fraction in humans are emerging and appear promising. Larger, controlled trials are now on-going to assess the safety, efficacy and tolerability of PDE5 inhibitors on morbidity and mortality in patients with both systolic and diastolic heart failure. If the results of these trials are positive, a new avenue for the treatment of HF will open, which will help curtail the societal effects of this costly and morbid disease.

A new Bayesian network-based risk stratification model for prediction of short-term and long-term LVAD mortality.

Existing risk assessment tools for patient selection for left ventricular assist devices (LVADs) such as the Destination Therapy Risk Score and HeartMate II Risk Score (HMRS) have limited predictive ability. This study aims to overcome the limitations of traditional statistical methods by performing the first application of Bayesian analysis to the comprehensive Interagency Registry for Mechanically Assisted Circulatory Support dataset and comparing it to HMRS. We retrospectively analyzed 8,050 continuous flow LVAD patients and 226 preimplant variables. We then derived Bayesian models for mortality at each of five time end-points postimplant (30 days, 90 days, 6 month, 1 year, and 2 years), achieving accuracies of 95%, 90%, 90%, 83%, and 78%, Kappa values of 0.43, 0.37, 0.37, 0.45, and 0.43, and area under the receiver operator characteristic (ROC) of 91%, 82%, 82%, 80%, and 81%, respectively. This was in comparison to the HMRS with an ROC of 57% and 60% at 90 days and 1 year, respectively. Preimplant interventions, such as dialysis, ECMO, and ventilators were major contributing risk markers. Bayesian models have the ability to reliably represent the complex causal relations of multiple variables on clinical outcomes. Their potential to develop a reliable risk stratification tool for use in clinical decision making on LVAD patients encourages further investigation.

Update in treatment options in pulmonary hypertension

Significant developments have occurred in the field of pulmonary hypertension (PH) in the past 2 years, especially in terms of treatment options available. These include: approval of new drugs; evidence for use of initial combination therapies in pulmonary arterial hypertension; approved drugs for use in chronic thromboembolic disease not amenable to, or persistent after surgical thromboendarterectomy; and ongoing clinical trials in PH related to left heart disease and hypoxia. The field continues to evolve and address the challenges in treatment of this multifaceted disease with the aim to provide novel solutions and meet the needs of a growing population with PH. This has led to an extensive body of literature, ranging from case series to prospective, multicenter clinical trials, which will enhance the future of patient outcomes in PH. This contemporary review highlights the key articles in treatment updates for PH for the years 2013 to 2015.

Targeting heart failure with preserved ejection fraction: current status and future prospects

Heart failure with preserved ejection fraction (HFpEF) portrays a significant burden in terms of prevalence, morbidity, mortality, and health care costs. There is a lack of consensus on the basic pathophysiology, definition, and therapeutic targets for therapy for this syndrome. To date, there are no approved therapies available for reducing mortality or hospitalization for these patients. Several clinical trials have recently started to try and bridge this major gap. There is an urgent need to focus on drug and device development for HFpEF as well as to understand HFpEF pathophysiology.

New Drugs and Devices in the Pipeline for Heart Failure with Reduced Ejection Fraction Versus Heart Failure with Preserved Ejection Fraction

Heart failure (HF) is a growing problem in the USA and other industrialized nations. HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) each make up approximately half of the overall HF burden. Although a variety of medical and surgical therapies exist for the treatment of patients with HFrEF, morbidity and mortality remain high, and cardiac transplantation, considered the current gold standard for patients with HFrEF and severe symptoms, is reserved for relatively few eligible patients. Patients with HFpEF have more limited therapeutic options, because no medical therapy to date has been shown to improve survival in these patients. With the rising prevalence of HF and its increasing role in health care expenditure, there is a substantial need for new drug and device therapies for HFrEF and, in particular, HFpEF. This forms the topic of the current review.

Transitioning from parenteral treprostinil to inhaled treprostinil in patients with pulmonary arterial hypertension.

Treprostinil is a potent prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH, World Health Organization Group I). Previously, treprostinil was available only in subcutaneous (SC) or intravenous (IV) formulations. Availability of an inhaled formulation of treprostinil has provided clinicians with an alternative to continuous SC or IV treprostinil in appropriate patients. Stable PAH patients whose quality of life has been dramatically impacted by side effects of parenteral therapy or those who have had recurrent, life-threatening bloodstream infections but are otherwise responding well to treatment may be the candidates for continuing prostacyclin therapy with inhaled treprostinil. However, there is little clinical experience with transitioning patients from parenteral to inhaled treprostinil. We present the results of two cases that highlight important considerations in transitioning patients from parenteral to inhaled therapy, including the pharmacologic and clinical equivalence of formulations, dose titration of formulations and suggested criteria for patient selection.

Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially life-threatening condition characterized by obstruction of pulmonary arterial vasculature by acute or recurrent thromboemboli with subsequent organization, leading to progressive pulmonary hypertension and right heart failure. Until relatively recently, CTEPH was a diagnosis made primarily at autopsy, but advances made in diagnostic modalities and surgical pulmonary endarterectomy techniques have made this disease treatable and even potentially curable. Although published guidelines are available, in the absence of randomized controlled trials regarding CTEPH there is a lack of standardization, and treatment options have to be individualized.

Low Accuracy of the HeartMate Risk Score for Predicting Mortality using the INTERMACS Registry Data.

Selection is a key determinant of clinical outcomes after left ventricular assist device (LVAD) placement in patients with end-stage heart failure. The HeartMate II risk score (HMRS) has been proposed to facilitate risk stratification and patient selection for continuous flow pumps. This study retrospectively assessed the performance of HMRS in predicting 90 day and 1 year mortality in patients within the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). A total of 11,523 INTERMACS patients who received a continuous flow LVAD between 2010 and 2015 were retrospectively categorized per their calculated HMRS to predict their 90 day and 1 year risk of mortality. The performance of the score was evaluated by the area under curve (AUC) of the receiver operator characteristic. We also performed multiple regression analysis using variables from the HMRS calculation on the INTERMACS data. The HMRS model showed moderate discrimination for both 90 day and 1 year mortality prediction with AUCs of 61% and 59%, respectively. The predictions had similar accuracy irrespective of whether the pump was axial or centrifugal flow. Multivariable analysis using independent variables used in the original HMRS analysis revealed different set of variables to be predictive of 90 day mortality than those used to calculate HMRS. HMRS predicts both 90 day and 1 year mortality with poor discrimination when applied to a large cohort of LVAD patients. Newer risk prediction models are therefore needed to optimize the therapeutic application of LVAD therapy. Patient selection for appropriate use of LVADs is critical. Currently available risk stratification tools (HMRS) continue to be limited in their ability to accurately predict mortality after LVAD. This study highlights these limitations when applied to a large, comprehensive, multicenter database. HMRS predicts mortality with only modest discrimination when applied to a large cohort of LVAD patients. Better risk stratification tools are needed to optimize outcomes.

Macitentan (Opsumit) for the treatment of pulmonary arterial hypertension

The endothelin pathway is a key pathway for the pathogenesis of pulmonary arterial hypertension (PAH). Antagonism of this pathway is recommended as initial therapy in low-risk patient with PAH to inhibit fibrosis, cell proliferation, and inflammation caused by endothelin. Prior to October 2013, ambrisentan, a selective ETA receptor antagonist and bosentan, a dual ETA/ETB antagonist, were the only currently available agents for PAH targeting the endothelin pathway. Based on the results of the SERAPHIN trial, macitentan (brand name Opsumit®), a new ETA/ETB antagonist, has been US FDA approved to delay disease progression and reduce hospitalizations for PAH. SERAPHIN is the first ERA trial to use an event-driven strategy with a composite primary end point of morbidity or mortality. Previous trials have focused on short-term outcomes, such as improved 6-min walk distance and WHO functional class.

Pulmonary hypertension in potential heart transplant recipients: current treatment strategies.

Purpose of reviewPulmonary hypertension associated with left heart disease is the most commonly encountered form of pulmonary hypertension and is associated with a poor prognosis. As the global burden of heart failure grows, this associated disease can be a major impediment to those patients undergoing cardiac transplantation, given its association with post-transplant right ventricular failure. Unfortunately, the pathophysiology of pulmonary hypertension secondary to left heart failure remains poorly understood, thereby rendering targeted treatment strategies largely undefined. In this review, we provide a review of the currently available literature in this unique patient population. Recent findingsThe current focus on better defining the underlying pathophysiology and standardizing diagnostic and therapeutic approaches to pulmonary hypertension associated with left heart disease need to be interpreted and made applicable in the context of clinical practice. Given the relative paucity of successful, targeted pharmacological options, there is an increasing evidence that device-based therapies, used in conjuncture with medical therapy, may help in lowering the pulmonary pressures by causing sustained left ventricular unloading. SummaryPulmonary hypertension in the context of left heart disease is the most common form of pulmonary hypertension encountered in clinical practice and is associated with worse prognosis in patients being considered for cardiac transplantation. Therapies targeting left ventricular unloading, as well as pulmonary vascular remodeling, are being increasingly studied and used in daily practice.