MedicalResearch.com Interview with:
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Dr. Richard Dunbar[/caption]
Dr. Richard L. Dunbar MD MS
Assistant Professor of Medicine, Attending Physician, Preventive Cardiovascular Medicine Clinic, Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of MedicineMember, Institute for Diabetes, Obesity and Metabolism,
University of Pennsylvania School of Medicine and
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Dr. Harsh Goel[/caption]
Dr. Harsh Goel
WellSpan Academic Hospitalists
Department of Medicine, York Hospital, PA
MedicalResearch.com: What is the background for this analysis?
Response: Niacin is the first cholesterol lowering treatment to prevent heart attacks and lower long term mortality. It thus provided the first proof that lowering cholesterol reduces cardiovascular risk. However, it is generally poorly tolerated due to almost universal flushing, limiting use. The better-tolerated statin drugs overshadowed niacin, rightly dominating hyperlipidemia therapy. Despite their advantages, statins are far from perfect, leaving important gaps. Firstly, at least 10% of patients simply don’t tolerate statins. Secondly, about 40% of patients have insufficient cholesterol lowering, leaving them far from their target LDL-cholesterol levels. Finally, even though statins lower cardiovascular risk, they by no means eliminate it and significant residual risk remains even in patients who respond to them.
The relatively poor tolerance of niacin motivated development of an extended-release alternative which was dosed very differently from the established cardioprotective regimen used in the Coronary Drug Project (CDP) and the Stockholm Ischemic Heart Disease Study (SIHDS), the two landmark trials that proved niacin's benefits. These trailblazing trials used 3 grams of niacin divided throughout the fed portion of the day as 1 gram thrice daily with meals. In sharp contrast, the alternative regimen was severely handicapped by a profoundly lower dose of only 2 grams per day. Perhaps worse, the alternative regimen dosed all of the niacin at one sitting, at bedtime before the overnight fast, rather than three times a day before meals. We believe these were critical departures from the established cardioprotective niacin regimen, insofar as they severely undermined the alternative regimen’s efficacy. Accordingly, when added to statins, the alternative regimen failed to recapitulate the benefits seen with the established cardioprotective regimen in two recent large clinical trials, the AIM-HIGH trial and the HPS2-THRIVE trial. Besides the inherent flaws of the alternative regimen, there were also major issues with the trial designs which likely contributed to null results.
From a practice standpoint, this is worrisome, because clinicians may draw erroneous conclusions from the trials of the alternative regimen, and thereby deny a significant population of hyperlipidemic patients the benefits of a well-proven cardioprotective therapy, i.e. the population which does not tolerate or does not respond adequately to statins (almost 50% of at risk patients). Hence, we embarked on a critical analysis and review of the alternative regimen with a special focus on the AIM-HIGH and HPS2-THRIVE trials to bring to light the pitfalls of comparing radically different regimens of what is nominally the same drug.
Dr. Amanda Paschke[/caption]
Amanda Paschke, MD
Director, Infectious Disease Clinical Research
Merck Research Laboratories
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Relebactam is an investigational beta-lactamase inhibitor being developed as a fixed-dose combination with imipenem/cilastatin, which is a broad-spectrum antibiotic in the carbapenem class. In preclinical studies, this combination demonstrated antibacterial activity against a broad range of multidrug-resistant Gram-negative pathogens, including those producing extended-spectrum beta-lactamases such as Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and AmpC-producing Pseudomonas aeruginosa. Many of the most concerning infections caused by “superbugs” are caused by Gram-negative bacteria. These bacteria have evolved to be resistant to commonly used antibacterials, and even to antibacterials used as “last resort” treatment, which is why finding ways to treat them has become urgent. The addition of relebactam to imipenem is designed to restore activity of imipenem against certain imipenem-resistant strains of Gram-negative bacteria known to cause serious infections among people who often have other underlying medical conditions, which complicates treatment.
This was a Phase 2, multicenter, randomized, double-blind, non-inferiority study. The study looked at the use of relebactam plus imipenem versus imipenem alone for the treatment of adult patients with complicated urinary tract infections. The primary endpoint for the trial was microbiological response at the completion of IV study therapy. The study met its primary endpoint, demonstrating that the combination of relebactam with imipenem was as at least as effective as imipenem alone for the treatment of complicated urinary tract infections. The trial also demonstrated that the combination of relebactam plus imipenem is well-tolerated, with a safety profile similar to that of imipenem alone in this patient.
Dr. Thomas Gaziano[/caption]
Thomas Andrew Gaziano, MD, MSc
Department of Cardiology
Assistant Professor
Harvard Medical School
MedicalResearch.com: What is the background for this study?
Response: Heart failure (HF) is the leading cause of admissions to hospitals in the United States and the associated costs run between $24-47 billion annually. Targeting neurohormonal pathways that aggravate the disease has the potential to reduce admissions. Enalapril, an angiotensin converting enzyme-inhibitor (ACEI), is more commonly prescribed to treat HF than Sacubitril/Valsartan, an angiotensin-receptor/neprilysin inhibitor (ARNI). The latter was shown to reduce cardiovascular death and hospitalizations due to heart failure in a multi-country, randomized clinical (PARADIGM-HF), compared to Enalapril. In order to assess the cost-effectiveness of Sacubitril/Valsartan, compared to Enalapril, in the United States, we created a model population with population characteristics equivalent to the population in the PARADIGM-HF trial. Using a 2-state Markov model we simulated HF death and hospitalizations for patients with a left ventricular ejection fraction (LVEF) of 40% or less.
Dr. Gregg Fonarow[/caption]
Gregg C. Fonarow, MD, FACC, FAHA
Eliot Corday Professor of Cardiovascular Medicine and Science
Director, Ahmanson-UCLA Cardiomyopathy Center
Co-Chief of Clinical Cardiology, UCLA Division of Cardiology
Co-Director, UCLA Preventative Cardiology Program
David Geffen School of Medicine at UCLA
Los Angeles, CA, 90095-1679
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Fonarow: Angiotensin receptor neprilysin inhibitors (ARNI) have been demonstrated to reduce mortality in patients with heart failure with reduced ejection fraction. However, to date, the population level impact of optimal implementation of this therapy in the United States has not been evaluated.
This new analysis estimates that as many 28,484 deaths in heart failure with reduced ejection fraction patients annually could be prevented or postponed with optimal use of angiotensin receptor neprilysin inhibitors (with sensitivity analyses demonstrating a range of 18,230 to 41,017).
Dr. Kenneth Cusi[/caption]
Kenneth Cusi, M.D., F.A.C.P., F.A.C.E.
Professor of Medicine
VAMC staff
Chief, Division of Endocrinology, Diabetes and Metabolism
The University of Florida
Gainesville, FL 32610-0226
MedicalResearch.com: What is the background for this study?
Dr. Cusi: Many patients with prediabetes or Type 2 Diabetes Mellitus (T2DM) are not diagnosed with Nonalcoholic steatohepatitis (NASH), a disease that is the second cause of liver transplantation in the United States. It is also associated with worse cardiovascular disease and harder to control T2DM. We had done in this population a proof-of-concept study published in Nov 2006 in the NEJM. But we lacked a larger, long-term study for definitive proof. This is the largest SINGLE center study, and the longest ever (3 years).
NASH is an overlooked problem for perhaps as many as one-third of patients with Type 2 Diabetes Mellitus. There is now a safe and effective treatment option for patients with T2DM and NASH – pioglitazone will become for NASH what metformin is to the treatment of T2DM: a safe, effective, the “backbone therapy" to which other treatments will be added.
Dr. Steven Woloshin[/caption]
Steven Woloshin, MD
Professor of The Dartmouth Institute
Professor of Medicine
Professor of Community and Family Medicine
New Hamphsire
MedicalResearch.com: What is the background for this study?
Dr. Woloshin: Drug companies are required by law to post results of trials used to support drug applications to the FDA on the clinicaltrials.gov website - but it is not clear whether posted results are complete and accurate. Recent studies attempting to validate posted results by comparing them to corresponding peer reviewed medical journal publications suggest that discrepancies are relatively common. But it is which source is more likely to be correct. We tried to validate posted results against an arguably better gold standard, the drug approval packages from the FDA (ie, the medical and statistical reviews posted on the drugs@fda.gov website). FDA reviews have an advantage over peer reviewed publications: unlike medical journal editors and peer reviewers, FDA has access to the individual participant data from the trials. This means FDA can see all the trials and all the outcomes (avoiding sleective publication) and it means FDA can independently reanalyze according to what they believe to be the best statistical practices (data can be analyzed in many ways - and different decisions, for example, how to account for missing data, can yield very different results).
Prof. Philip Home[/caption]
Professor Philip Home D.M., D.Phil
Professor of Diabetes Medicine
Newcastle University
MedicalResearch.com: What is the background for this study? What are the main findings?
Prof. Home: MK1293 is a biosimilar insulin designed with the same amino acid sequence, manufacturing process and formulation as originator insulin glargine (Lantus). This is the clinical proving study in type 1 diabetes, being a 24-week randomized study in 508 participants between MK1293 and Lantus. The primary efficacy endpoint of non-inferiority of HbA1c was met, as was a secondary of equivalence (difference in change from baseline 0.04 (95% CI -0.11, 0.19) %-units), with other measures including hypoglycaemia, insulin antibodies and adverse events also consistent with similarity.
Dr Siddharth Singh[/caption]
Siddharth Singh, MD, MS
Postdoctoral Fellow, NLM/NIH Clinical Informatics Fellowship
Division of Biomedical Informatics
Clinical Assistant Professor of Medicine, Division of Gastroenterology, Department of Internal Medicine,
University of California
San Diego, La Jolla
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Singh: Over the last 4 years, four new medications have been approved for long-term use for weight loss by the FDA. We sought to evaluate the comparative effectiveness and tolerability of these medications through a systematic review and network meta-analysis. Based on 28 trials in over 29,000 overweight or obese patients, we observed that magnitude of weight loss achieved with these agents is variable, ranging from 2.6kg with orlistat to 8.8kg with phentermine-topiramate. Over 44-75% of patients are estimated to lose at least 5% body weight, and 20-54% may lose more than 10% of body weight; phentermine-topiramate was the most efficacious, whereas lorcaserin was the best tolerated.
Anna Therese Lehnich[/caption]
Anna-Therese Lehnich
Zentrum für Klinische Epidemiologie (ZKE)
c/o Institut für Medizinische Informatik
Biometrie undEpidemiologie (IMIBE)
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Sleep disturbances and their consequences are often underestimated but they are of high importance with respect to public health. We were interested in the question whether drugs labeled as sleep disturbing in the summary of product characteristics actually lead to more sleep disorders like difficulties falling asleep, difficulties maintaining sleep, and early morning arousal. To answer this question, we analyzed data of 4,221 persons from Germany.
Dr. Heerspink[/caption]
Doctor Hiddo Lambers Heerspink
Department of Clinical Pharmacy and Pharmacology
University Medical Center Groningen
the Netherlands
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: SGLT2 inhibitors, including canagliflozin, have beneficial effects on multiple cardiovascular and renal risk parameters. This suggests that SGLT2 inhibitors may confer cardiovascular and renal protection. A recent large clinical trial with the SGLT2 inhibitor empagliflozin demonstrated marked reductions in cardiovascular morbidity and mortality and suggested possible renoprotective effects. Whether SGLT2 inhibition slows the progression of kidney function decline independent of its glucose-lowering effect, however, is unknown. We therefore assessed whether canagliflozin slows the progression of kidney function decline by comparing the effects of canagliflozin versus glimepiride on eGFR and albuminuria.
Dr. Catherine Diefenbach[/caption]
Dr. Catherine S. M. Diefenbach MD
Assistant Professor of Medicine
NYU Cancer Center
New York, NY 10016
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Diefenbach: It is well known that age is important prognostic factor in non-Hodgkin’s lymphoma (NHL). Multiple studies have illustrated that elderly lymphoma patients have inferior survival outcomes as compared to their younger counterpart. While the tumor biology is often different in these two groups, and may play a role in this discordancy, elderly patients are often frail or have multiple medical comorbidities. These include geriatric syndromes, such as: cognitive impairment, falls, polypharmacy, and potentially inappropriate medication (PIM) use. All of these may contribute to poor outcomes for elderly patients. In addition, elderly patients are often under-treated for their aggressive lymphoma out of concern for toxicity or side effects, even though the data clearly demonstrates that elderly patients can still benefit from curative intent chemotherapy.
Prof. Neil Carragher[/caption]
Professor Neil Carragher
Principal Investigator Drug Discovery
Institute of Genetics and Molecular Medicine
University of Edinburgh
MedicalResearch.com: What is the background for this study? What are the main findings?
Prof. Carragher: The aim of the study was to generate novel small molecule inhibitors that target breast cancers using a strategy which we named: "dual ligand based phenotypic screening". From initial derivation of a small chemical library based on a promiscuous kinase inhibitor PP1, iterative screening across a suite of breast cancer phenotypic assays guided chemical design towards the novel compound eCF506. eCF506 is a highly potent, orally bioavailable and specific inhibitor of Src Kinase.
Dr. Shipra Arya[/caption]
Shipra Arya MD, SM
Assistant Professor, Division of Vascular Surgery
Emory University School of Medicine
Assistant Professor of Epidemiology (Adjunct)
Rollins School of Public Health
Staff Physician, Atlanta VA Medical Center
Director, AVAMC Vascular Lab and Endovascular Therapy
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Arya: Peripheral Arterial Disease is the next cardiovascular epidemic. It is poorly recognized and not adequately treated compared to heart disease – and research is lacking on the optimal use of statins for PAD patients. Very few randomized clinical trials have been done specifically in PAD patients to assess the impact of statins on cardiovascular outcomes and none on limb related outcomes. The 2013 ACC/AHA guidelines for cholesterol lowering medications recommends high intensity statins for PAD patients extrapolated from the level 2 and 3 evidence and empirically based on CAD and stroke data.
In this study we looked at the amputation and mortality risk based on statin dosage in a large cohort of patients from the VA population and found that high intensity statins are associated with a significant reduction in limb loss (~30%) and mortality (~25%) in PAD patients followed by a smaller risk reduction [~23% for amputation risk reduction and 20% reduction in mortality risk] by low-moderate intensity statins as compared to no statin therapy.
Ms. Leigh Purvis[/caption]
Leigh Purvis, MPA
Director of Health Services Research
AARP Public Policy Institute
MedicalResearch.com Editor’s Note: The May AARP Bulletin has a important article “Black Market Meds Are Flooding the Nation’s Pharmacies And Hospitals” by Joe Eaton, discussing the growing problem of counterfeit medications entering the US pharmaceutical supply chain. Ms. Leigh Purvis of the AARP Policy Institute discussed this important issue for the readers of MedicalResearch.com. Ms. Purvis’ areas of expertise include prescription drug pricing, biologic drugs, and Medicare prescription drug coverage.
MedicalResearch.com: Is pharmaceutical theft and fraud a new or growing problem?
Ms. Purvis: I think it’s safe to say that pharmaceutical theft is a growing problem. Skyrocketing prices have made pharmaceuticals a lucrative target for criminals. Trucks transporting pharmaceuticals are a common target, although some thieves have stolen prescription drugs directly from manufacturers’ warehouses.
Pharmaceutical fraud is also a growing concern. FDA does a great deal to ensure the safety of US pharmaceuticals. However, problems can still arise, particularly when people purchase drugs online.
Dr. Jed Kaminetsky[/caption]
Dr. Jed Kaminetsky MD
Clinical Assistant Professor
Department of Urology
NYU Langone Medical Center
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Kaminetsky: Nocturia is a voiding disorder not well treated by available drugs for overactive bladder and benign prostatic hypertrophy. Desmopressin stimulates the kidneys to concentrate the urine which results in a greatly reduced volume of urine formation for a period of time. Serenity Pharmaceuticals has spent many years developing a low dose nasal spray version of desmopressin called Noctiva specifically for nocturia. The study reported now is a large, placebo controlled phase 3 trial to confirm the statistical efficacy and clinical benefit of this treatment for nocturia.
Dr. Lynda Harris[/caption]
Lynda Harris PhD
Lecturer in Pharmaceutics
University of Manchester
Manchester Pharmacy School
Maternal and Fetal Health Research Centre
Manchester
MedicalResearch.com: What is the background for this study?
Dr. Harris: Pregnancy complications such as pre-eclampsia and fetal growth restriction remain a problem despite advances in antenatal care, and impact heavily on future health: small size at birth is associated with an increased risk of cardiovascular disease and diabetes in later life. Drugs to improve pregnancy outcome are severely lacking, as pregnant women are considered a high risk cohort by drug companies, who fear expensive lawsuits associated with side effects and teratogenicity. The majority of pregnancy complications are caused by a poorly growing or poorly functioning placenta. A number of potential drugs have been identified that enhance placental function in vitro, and improve fetal growth in animal models; however, there is currently no means of restricting their actions to the placenta, and systemic administration of these drugs to pregnant women is not feasible due to the risk of adverse effects in other tissues. To address this issue, we have identified a series of placental “homing peptides” which we have used to create nanocarriers for targeted delivery of drugs to the placenta.
Dr. Martha Rumore[/caption]
Martha M. Rumore, PharmD, JD, MS, LLM, FAPhA
Associate Professor, Social, Behavioral & Administrative Pharmacy
Touro College of Pharmacy
New York, NY 10027
& Of Counsel Sorell, Lenna, & Schmidt, LLP
MedicalResearch.com: What is the background for this study?
Dr. Rumore: The management of lipid therapy is only one component that affects overall cardiovascular outcomes.This study is one of the first to look at the benefits of dose titration versus intensity-based statin therapy. To evaluate whether patients titrated on statin therapy using ATPIII algorithm with an LDL goal of <100mg/dL also met the 2013 ACC/AHA Guideline for Management of Blood Cholesterol goal of ≥40% LDL reduction from baseline compared to inpatients initiated on high-moderate intensity statin (HIS). Other objectives included comparison of algorithms to lower LDL ≥40%, final dose, adverse drug events (ADEs), clinic visits to goal, and cardiovascular event occurrence.
MedicalResearch.com: What are the main findings?
Dr. Rumore: 981 patients were included- 43% were titrated and 57% achieved LDL<100; 38% achieved both LDL <100mg/dL and LDL ≥40% reduction; 58% received HIS and 53% achieved LDL <100; 43% achieved both LDL <100mg/dL and LDL ≥40% reduction.
Initiating patients on High Intensity statins was not more effective than dose titration in achieving <100mg/dL and ≥40% LDL reduction;X2=0.006,N=159,p=0.938. A 50% LDL reduction in patients that also achieved an LDL <100 was 54% and 48%, in titration and HIS groups, respectively; X2=0.611,N=159,p=0.434. The titration group required an average of 4.3 clinic visits to achieve goal, compared to 3.1 visits for HIS; p=0.309; 95% CI(-1.36,1.06).
Dr. Serene Chen[/caption]
Serene I. Chen MD
Dr. Chen is an emergency medicine resident at Highland Hospital, in Oakland, California. She was a student at the Yale School of Medicine when this research was conducted.
MedicalResearch.com: What is the background for this study?
Dr. Chen: To address the rise in U.S. drug shortages, the Food and Drug Administration Safety and Innovation Act (FDASIA) was passed in 2012—and early evidence does suggest that the overall number of new shortages have decreased. However, we found that drugs that are frequently used emergency departments and other acute settings are still affected by more frequent and increasingly prolonged shortages.
Dr. Heli Malm[/caption]
Heli Malm, MD, PhD
Specialist in Obstetrics and Gynecology
Teratology Information Service
Helsinki University and Helsinki University Hospital
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Malm: Animal studies have demonstrated that exposure to SSRIs during early brain development can result in depression-like behavior in adolescence. Today 6% of pregnant women in the US and 4% in Finland are on selective serotonin reuptake inhibitors (SSRIs) at some stage of pregnancy. SSRIs pass the placenta but no prior studies have followed children beyond childhood to monitor the development of depressive disorders, which typically emerge after puberty onset. Results on autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorders (ADHD) have been conflicting.
The study material is based on national register data from Finland. We investigated offspring psychiatric diagnoses, including depression, anxiety, ASD, and ADHD, of nearly 16,000 mothers who had used SSRIs during pregnancy between 1996 and 2010. Children in this cohort ranged in age from 0 to 15 years old. Because maternal psychiatric illness can affect offspring neurodevelopment in the absence of SSRIs, primary comparisons were made between offspring of the SSRI group and offspring of mothers with a psychiatric disorder diagnosis but no antidepressant use.
Children exposed to SSRIs during gestation were diagnosed with depression at an increasing rate after age 12, reaching a cumulative incidence of 8.2% by age 15, compared to 1.9% in the group of children exposed to maternal psychiatric illness but no antidepressants. Rates of anxiety, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) diagnoses did not differ significantly between the two groups.
Dr. Jonathan Slaughter[/caption]
Jonathan Slaughter, MD, MPH
Assistant Professor of Pediatrics
Center for Perinatal Research
Nationwide Children's Hospital/The Ohio State University
Columbus, OH 43205
MedicalResearch.com: What is the background for this study?
Dr. Slaughter: Increasing data has emerged over the last decade showing potential harm following acid suppression use in newborns, older children, and adults. There are virtually no published data that show acid suppression via histamine-2-receptor antagonists (H2RAs) or proton-pump inhibitors (PPIs) is effective for gastroesophageal reflux disease (GERD) treatment or for other indications (stress ulcer prophylaxis, post-operative acid suppression) in healthy or sick newborns. Given the potentially limited effectiveness of these medications and increasing safety concerns following H2RA/PPI use in infants, we wanted to evaluate the frequency and duration of H2RA/PPI use among infants hospitalized within US children's hospital neonatal intensive care units (NICUs) to determine if these drugs appeared to be overused and if use appears to have changed over time. We also evaluated neonatal diagnoses associated with acid suppression to identify targets for future studies that may evaluate the usefulness of acid suppression in neonates following a given diagnosis.
