Can Personalized Medicine And An Adaptive Trial Design Salvage This Hard Luck Drug? Reply

Arca Biopharma today announced that it had received FDA clearance to start a phase 2B/3 trial of its novel beta-blocker, Gencaro (bucindolol) for the prevention of atrial fibrillation in patients with heart failure. The GENETIC-AF trial has all the hallmarks of the modern era: the drug will only be tested in patients with a genetic variation that the company believes may predict a positive response to the drug. And the trial will be one of the first to utilize the much-discussed “adaptive” trial design, starting as a phase 2B study and then possibly expanding to a phase 3 study after an interim analysis of the trial data.

But if GENETIC-AF represents the very model of a modern drug, it also serves as a good example of the pitfalls of drug development. Because this drug has been around for a very long time and has had a very troubled history.

Click here to read the full story on Forbes.

 

Michael Bristow, Arca Biopharma President and CEO

 

TACT Principal Investigator Reflects On A Long And Contentious Journey Reply

In a fascinating and important blog post, Gervasio Lamas offers a deeply personal perspective on the long and contentious journey of the Trial to Assess Chelation Therapy (TACT), for which he was the principal investigator.

gervasio-lamasHere are a few quotes from his post, but I can’t urge you strongly enough to read the entire post over on CardioExchange. (Click here for my brief summary of TACT.)

Changing minds is difficult. Unexpected results meet resistance. Out of the mainstream research is subject to heavy criticism. I guess I knew all these truisms when we embarked on the Trial to Assess Chelation Therapy (TACT). Still, I thought we were answering an important clinical question.

To say that this trial was controversial is an understatement. I had previously worked peacefully in other clinical trials, worrying about enrollment, about the DSMB, and about interpretation of data. Not so, here. In retrospect, I had always thought that the adversaries to this study would be the chelation practitioners. After all, they were using an unproven therapy. Why would they want us to show it did not work?

The opposite was true. The chelation practitioners and their main professional organization, the American College for Advancement in Medicine, helped us at every turn. They felt they were doing good, and that bringing chelation to the crucible of a clinical trial would lead to many more patients being helped.

In fact, the principal obstructionists were groups of self-appointed anti-chelation “experts”, who had never administered chelation, had never designed or run clinical trials, but who knew how to make noise and recruit media to their dubious cause – that scientific thought should not be brought to bear on the question of whether chelation was safe and effective.

The gist of the objections to the trial, once legitimate methodological concerns were addressed, was an outcry that, because cardiologists believed that EDTA was quackery, the study had to be negative. Therefore we had done something wrong. Just imagine if this had been stem cells or a new anti-platelet: Kudos all the way, right? Humble chelation got heckles and hecklers. I told my dean at Columbia that people were very upset because they did not like the results. He said “That’s why you do research.”

So now what? Do we recommend chelation? This is where the cautious scientist has to take control. We reported a subgroup, and we have been fooled by subgroups before, so more research has to take place before all of us can jump on this bandwagon.

 

Flu Vaccine May Help Prevent Cardiovascular Events Reply

A new meta-analysis published in JAMA offers the best evidence yet that the flu vaccine may help prevent cardiovascular events.

Jacob  Udell and colleagues analyzed data from 5 published clinical trials in which 6,469 patients were randomized. People who received the flu vaccine had a significantly lower risk of cardiovascular events. The protective effect was largely restricted to people who had had a recent acute coronary syndrome (ACS). Cardiovascular events occurred in 2.9% of people in the vaccination group versus 4.7% of controls (RR 0.64, CI 0.48-0.86, p = .003).

Click here to read the full post on Forbes.

 

New Questions Raised About Italian Cardiologists Already Under Cloud Of Suspicion 1

(This story was updated on Friday, October 4 with a response from Dr. Modena.)

New questions are being raised about the integrity and reliability of research published by a prominent Italian cardiologist and her colleagues. Last November, as previous reported here, Maria Grazia Modena, a former president of the Italian Society of Cardiology, and 8 other Italian cardiologists were arrested as part of a broad investigation into serious medical misconduct at Modena Hospital. To date the Italian authorities have not issued any indictments, but at least one aspect of the investigation appears to involve unauthorized research and failing to obtain informed consent from patients in clinical trials.

The new questions center on the same issue of research misconduct and the possibility that informed consent was not obtained from patients. The  questions– which were brought to my attention by a reader– center on a number of significant inconsistencies and highly improbable statements and statistics in a report of a purported randomized controlled trial published in the journal Heart in 2010. The questions raised about the paper lead to the inevitable suspicion that the trial very likely was not randomized and that patient consent may  not have been properly obtained.

Click here to read the full story on Forbes.

Realistic Expectations For New ‘Breakthrough’ Blood Pressure Technology Reply

Early trials of renal denervation, the innovative new catheter-based blood pressure lowering technology,  have resulted in extremely impressive drops in systolic blood pressure in the range of 30 mm Hg. These results have sparked a great deal of excitement in the hypertension community and stirred the interest of a multitude of medical device companies. Some experts have proclaimed renal denervation a potential “cure” for resistant hypertension, perhaps enabling a significant number of patients to eliminate all drug therapy. Other expanded uses of the technology in more moderate forms of hypertension and other diseases are under active consideration. Now, however, a new analysis of the available data suggests the troubling possibility that renal denervation may not be nearly as effective in cutting blood pressure as had been suggested in the earlier trials. Rather than reducing systolic blood pressure by 30 mm hg, the new analysis suggests that a more realistic estimate of the effect of renal denervation may be a much more modest reduction of about 11 mm Hg.

A paper published online in Heart  demonstrates that the large reductions in blood pressure seen so far in clinical trials of renal denervation may be a consequence of certain key aspects in the design of these trials. The apparent blood pressure lowering effect of renal denervation has been greatly magnified because the trials have been uncontrolled, unblinded, and have utilized office-based blood pressure measurements rather than the far more reliable and consistent ambulatory blood pressure monitoring (ABPM).

Click here to read the full story on Forbes.

New Actelion Drug Found Safe And Effective In Pulmonary Arterial Hypertension– But Does It Save Lives? Reply

Macitentan, a new drug for pulmonary arterial hypertension (PAH), appears to be safe and effective, but it is unclear whether it offers any significant advantages over currently available drugs.  The drug, a dual endothelin-receptor antagonist, is under development from Actelion as an enhanced version of bosentan (Tracleer). The results of a phase 3 trial, SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), have now been published in the New England Journal of Medicine.

In the trial, 742 patients with PAH were randomized to one of three groups: a daily dose of 3 mg of macitentan, a daily dose of 10 mg of macitentan, or placebo. The primary endpoint (the time to the first occurrence of a composite endpoint of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension) was significantly reduced in the two treatment arms:

Click here to read the full post on Forbes.

Actelion

American Heart Association Announces Late-Breaking Clinical Trials Reply

AHA 2013 logoThere are still a few days left in August and the European Society of Cardiology meeting doesn’t start until this weekend in Amsterdam. Nevertheless, the American Heart Association has released the list of late-breaking clinical trials for the annual meeting in November.

Late-Breaking Clinical Trials 1: Acute Cardiovascular and Cerebrovascular Care

  • Sunday, Nov 17, 2013, 4:00 PM – 5:19 PM

Moderators:

  • Lance Becker, Philadelphia, PA
  • Stephen Bernard, Melbourne, Australia

4:00 PM: Nitrites in Acute Myocardial Infarction

  • Nishat Siddiqi, Univ of Aberdeen, Aberdeen, United Kingdom
  • Discussant: Kenneth Bloch, Boston, MA

4:13 PM: Blood Pressure Reduction Among Acute Ischemic Stroke Patients: A Randomized Controlled Clinical Trial

  • Jiang He, Tulane Univ, New Orleans, LA
  • Discussant: Cathy A Sila, Cleveland, OH

4:35 PM: Randomized Clinical Trial of Pre-hospital Induction of Mild Hypothermia in Out-of-Hospital Cardiac Arrest Patients Using a Rapid Infusion of 4oC Normal Saline

  • Francis Kim, Univ of Washington, Seattle, WA
  •  Discussant: Maaret Castrén, Stockholm, Sweden

4:57 PM: Target Temperature Management 33°C versus 36°C after Out-of-hospital Cardiac Arrest, a Randomized, Parallel Group, Assessor Blinded Clinical Trial

  • Niklas Nielsen, Helsingborg Hosp, Lund Univ, Helsingborg, Sweden
  •  Discussant: Benjamin S Abella, Philadelphia, PA

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Late-Breaking Clinical Trials 2: Prevention: From Schools to Countries

  • Monday, Nov 18, 2013, 9:00 AM -10:28 AM

Moderators:

  • Donna K Arnett, Birmingham, AL
  • Lynne Braun, Chicago, IL

9:00 AM: Promotion of Cardiovascular Health in Preschool Children: 36-month Cohort Follow-up

  • Jaime Céspedes, Fundación CardioInfantil Insto de Cardiología, Bogotá, Colombia
  • Discussant: Gerard R Martin, Washington, DC

9:22 AM: Randomized Trial of Social Network Lifestyle Intervention for Obesity: MICROCLINIC Intervention Results and 16-Month Followup

  • Eric L Ding, Harvard Sch of Public Health, Boston, MA
  • Discussant: Lawrence J Appel, Baltimore, MD

9:44 AM:  Multifaceted Intervention to Improve Medication Adherence and Secondary Prevention Measures (Medication Study) After Acute Coronary Syndrome Hospital Discharge

Michael Ho, VA Eastern Colorado Health Care System, Denver, CO

Discussant: Nancy Albert, Cleveland, OH

10:06 AM: China Rural Health Initiative – Sodium Reduction Study: the Effects of a Community-Based Sodium Reduction Program on 24hr Urinary Sodium and Blood Pressure in Rural China

  • Nicole Li, The George Inst for Global Health, Sydney, Australia

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Late-Breaking Clinical Trials 3: Medical and Surgical Approaches to Improving Heart Failure Outcomes

  • Monday, Nov 18, 2013, 10:45 AM -12:13 PM

Moderators:

  • Frederick A Masoudi, Aurora, CO
  • Adrian F Hernandez, Durham, NC

10:45 AM: Atrial Antitachycardia Pacing and Managed Ventricular Pacing Reduce the Endpoint Composed by Death, Cardiovascular Hospitalizations and Permanent Atrial Fibrillation Compared to Conventional Dual Chamber Pacing in Bradycardia Patients: Results of the Minerva Randomized Study

  • Giuseppe Boriani, Univ of Bologna, Policlinico S.Orsola-Malpighi, Bologna, Bologna, Italy
  • Discussant: Anthony Tang, Victoria, BC, Canada

11:07 AM: Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE AHF) Trial

  • Horng H Chen, MAYO Clinic, Rochester, MN
  • Discussant: Marco Metra, Brescia, Italy

11:29 AM: Severe Ischemic Mitral Regurgitation: Is it Better to Repair or Replace the Valve?

  • Michael A Acker, Hosp of the Univ of Pennsylvania, Philadelphia, PA
  • Discussant: Timothy J Gardner, Newark, DE

11:51 AM: Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT)

  • Marc A. Pfeffer, Brigham & Women’s Hosp, Harvard, Boston, MA
  • Discussant: Margaret M Redfield, Rochester, MN

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Late-Breaking Clinical Trials 4: Therapeutic Advances in Coronary and Peripheral Vascular Disease.

  • Monday, Nov 18, 2013, 3:45 PM – 5:13 PM

Moderators:

  • John G Harold, Washington, DC
  • Mark A Creager, Boston, MA

3:45 PM: One Year Mortality in STEMI Patients Randomized to Primary PCI or a Pharmaco-invasive Strategy. The Stream 1 Year Follow-up

  • Peter Sinnaeve, Univ of Leuven, Leuven, Belgium
  • Discussant: Harold Dauerman, Burlington, VT

4:07 PM: Secretory Phospholipase A2 Inhibition with Varespladib and Cardiovascular Events in Patients with an Acute Coronary Syndrome: Results of the VISTA-16 Study

  • Stephen Nicholls, South Australian Health and Medical Res Inst, Adelaide, Australia
  • Discussant: Philippe Gabriel Steg, Paris, France

4:29 PM: Randomized Comparison of Endovascular Revascularization Plus Supervised Exercise Therapy Versus Supervised Exercise Therapy Only in Patients With Peripheral Artery Disease and Intermittent Claudication: Results of the Endovascular Revascularization and Supervised Exercise (ERASE) Trial

  • Farzin Fakhry, Erasmus MC, Rotterdam, Netherlands
  • Discussant: Mary McDermott, Chicago, IL

4:51 PM: A Randomized Multicenter Clinical Trial of Renal Artery Stenting in Preventing Cardiovascular and Renal Events: Results of the CORAL Study

  • Christopher J Cooper, Univ of Toledo, Toledo, OH
  • Discussant: Thomas Zeller, Bad Krozingen, Germany
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Late-Breaking Clinical Trials 5: New Strategies for Atrial Fibrillation Patients: Rhythm and Thrombosis

  • Tuesday, Nov 19, 2013, 10:45 AM -12:03 PM

Moderators:

  • Augustus O Grant, Durham, NC
  • Keith A Fox, Edinburgh, United Kingdom

10:45 AM: RADAR-AF Trial. A Randomized Multicenter Comparison of Radiofrequency Catheter Ablation of Drivers versus Circumferential Pulmonary Vein Isolation in Patients with Atrial Fibrillation

  • Felipe Atienza, Hosp Gregorio Maranon, Madrid, Spain
  • Discussant: Mark Link, Boston, MA

11:07 AM: A Randomized Trial Comparing Genotype-Guided Dosing of Warfarin to Standard Dosing: The EU Pharmacogenetics of Anticoagulant Therapy (EU-PACT) Warfarin Study

  • Munir Pirmohamed, Univ of Liverpool, Liverpool, United Kingdom

11:17 AM: The Clarification of Optimal Anticoagulation through Genetics (COAG) Trial

  • Stephen E. Kimmel, Univ PA Sch of Med, Philadelphia, PA

11:27 AM: Discussant of EU-PACT Warfarin Study and COAG Trial: Patrick T. Ellinor, Boston, MA

11:41 AM: ENGAGE AF-TIMI 48 Primary Results

  • Robert P Giugliano, Brigham and Women’s Hosp, Boston, MA
  • Discussant: Elaine Hylek, Boston, MA

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Faint PRAISE: 13 Year Delay In Publication Of A Major Clinical Trial Sparks Criticism Reply

13 years after first being presented the results of the PRAISE-2 trial finally have been published in JACC: Heart Failure. The trial itself is now largely irrelevant to current clinical practice, as the hypothesis it tested has long been abandoned, but the long delay in publication may serve to bring even more awareness to the issue of the delay or complete absence of publication of many clinical trials.

An accompanying editorial, by Marc Pfeffer and Hicham Skali, is highly critical of the delay:

Although standards for conduct and reporting of clinical trials have improved since 2000, the failure to fully vet the results of a clinical trial of human volunteers in a peer-reviewed journal was and remains unacceptable.

PRAISE-2 had its origins in the first PRAISE trial, which was first presented in 1995 and subsequently published in the New England Journal of Medicine in 1996. In that trial there was no difference between amlodipine (Norvasc, Pfizer) and placebo in the rate of mortality or cardiovascular hospitalization in patients with heart failure. However, a prespecified subgroup analysis turned up the highly surprising result that heart failure patients with a nonischemic etiology who received amlodipine had a highly significant 46% reduction in the risk of death compared with placebo patients.

Click here to read the full post on Forbes.

Milton Packer

Milton Packer

Recent €23 Million Biotech IPO Relied Heavily On Questionable Research 2

A successful €23 million initial public offering  (IPO) last week was based on highly questionable research, according to a group of UK physicians who have scrutinized the available data. In addition, one of the researchers, a prominent European cardiologist, failed to disclose in a key paper that he helped to start, and held a significant interest in, the company, Cardio3 BioSciences.

On July 4 Cardio3 BioSciences, a biotechnology company focusing on cardiac stem cell therapy, said that it had raised €23 million in an IPO on the NYSE Euronext Brussels and NYSE Euronext Paris. The company’s main product is called C-Cure, which it defines as “a unique cell therapy aimed at repairing damaged tissue and improving heart function, clinical outcomes and quality of life.” C-Cure uses uses pre-programmed cardiac progenitor cells to treat heart failure. As described by the company, “the supporting science is the result of Mayo Clinic innovation leading to advanced product development, manufacturing scale-up, and clinical trial execution by Cardio3 BioSciences catalyzed by ongoing collaboration facilitated through Mayo Clinic Ventures.”

The company plans to use the IPO money for a Phase III trial, following what the company describes as “positive Phase II results, recently published in the Journal of the American College of Cardiology.”

But the phase II results are a bit more complicated, according to Darrel Francis and colleagues (who last week published a paper highly critical of a different stem cell group). Francis et al have identified numerous errors in the paper which raise serious questions about the validity of the data and whether any useful conclusions can be drawn from the paper.

One striking finding– obvious once it has been pointed out– is that the authors report at different times different number of patients enrolled in the trial. The text of the paper says 48 patients were randomized, Figure 1 lists 47, and Table 1 lists 45 (42 men and 3 women).

Click here to read the full story on Forbes.

 

 

Paper Raises Hundreds Of Questions About The Integrity Of Stem Cell Research Group 2

Serious questions have been raised about the integrity and validity of research performed by a well-established German stem cell research group. A paper published in the International Journal of Cardiology exhaustively details a multitude of discrepancies and contradictions in papers from the researcher’s group. Further, the revelation of such widespread misconduct may lead to broader disturbing questions about the reliability of scientific publications and the ability of the clinical research system to police itself.

In “Autologous bone marrow-derived stem cell therapy in heart disease: Discrepancies and contradictions,” Darrel Francis and colleagues scrutinize 48 papers from the research group of Bodo-Eckehard Strauer. According to Francis et al, the 48 papers from Strauer’s group contained reports on only 5 actual clinical studies, or “families” of reports, and that duplicate or overlapping reports were common. The paper contains details about more than 200 errors in the papers, including contradictory descriptions of the design, protocol and results of the trials. Francis et al write:

“Readers cannot always tell whether a study is randomised versus not, open-controlled or blinded placebo-controlled, or lacking a control group. There were conflicts in recruitment dates, criteria, sample sizes, million-fold differences in cell counts, sex reclassification, fractional numbers of patients and conflation of competitors’ studies with authors’ own.

Contradictory results were also common. These included arithmetical miscalculations, statistical errors, suppression of significant changes, exaggerated description of own findings, possible silent patient deletions, fractional numbers of coronary arteries, identical results with contradictory sample sizes, contradictory results with identical sample sizes, misrepresented survival graphs and a patient with a negative NYHA class.”

Click here to read the full post on Forbes.

Bodo-Eckehard Strauer

New Anticoagulant Found Safe And Effective In Acute Venous Thromboembolism 1

In a large clinical trial the new oral anticoagulant apixaban (Eliquis, Pfizer and Bristol-Myers Squibb) was at least as effective as standard therapy and caused fewer bleeding complications in patients with acute venous thromboembolism. The results of the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) trial are being presented on Monday at the annual meeting of the International Society on Thrombosis and Haemostasis in Amsterdam and are being published in the New England Journal of Medicine. (The embargo on the trial was lifted early by the Journal after being broken by Reuters.)

Click here to read the full story on Forbes.

 

 

Novartis Acknowledges Employees Participated In ‘Independent’ Trials Reply

Novartis has acknowledged that employees of the company participated in five “independent” investigator-initiated post-registration trials without disclosing their relationship to the company. The company said that a broader “comprehensive investigation with independent third party experts is ongoing” but that it has “provided an update” to Japanese medical societies and to the principal investigators of the five trials.

The new statement from Novartis admits that “one of our former employees [presumably Shirahashi] had varying levels of involvement in five investigator initiated valsartan trials in Japan.” The statement also disclosed that “a second former employee (who reported to the first former employee) had involvement which was limited to one of these trials.” Novartis said that independent investigation is continuing but that so far there has been no indication of a “specific company strategy to integrate the first former employee into the five valsartan investigator initiated trials.” However, the investigation has revealed

that some of this former employee’s superiors in Japan knew of his participation in these trials and were supportive of him in these activities. They believed that employees of a business that had academic titles could perform clinical research support as academics, without any conflict of interest issues arising. In addition, there is no indication that any of his supervisors knew or approved of the incomplete disclosure of his affiliation in the published papers for these studies.

Click here to read the full story on Forbes.

 

İsviçre Basel'deki Novartis binası

 

 

Amgen Trial Fails To Show Benefit Of Anemia Drug In Heart Failure Patients Reply

Deutsch: Amgen als Sponsor der Tour of California

 

The bad news continues for Aranesp (darbepoetin alfa), Amgen’s long-acting erythropoietin-stimulating agent. The drug is intended to stimulate red cell blood production in patients with anemia. Amgen today announced the top line results of a large phase 3 heart failure trial of the drug and said  the trial had failed to meet its primary endpoint.

 

The RED-HF (Reduction of Events With Darbepoetin Alfa in Heart Failure) Trial, which started in 2006, had randomized 2,278 patients with heart failure and anemia to receive either Aranesp or placebo.

 

Click here to read the full story on Forbes.