A Fake and a Fraud: Joachim Boldt, MD

THE EMERGING NEWS of shocking ethics violations and fabricated clinical research by a prominent clinical expert in fluid resuscitation therapy reminds us that no profession is untarnished by the corrupting influences of greed or the drive for self-aggrandizement.

Professor Joachim Boldt is — or rather was — regarded as a world authority on fluid management in surgery and a prolific clinical researcher with more than 200 peer-reviewed articles to his name. Over more than a decade at his academic hospital across the Rhine from Mannheim, Germany, Dr. Boldt has churned out dozens of clinical studies evaluating the functionality and safety of a class of synthetic colloids broadly called hydroxyethyl starch (HES) or “hetastarch.” HES products directly compete with commercial preparations of purified 5% human albumin, the natural water-retaining colloid that comprises roughly two-thirds of our circulating plasma protein content.

In recent years, Dr. Boldt has been an increasingly vociferous advocate of substituting certain synthetic colloids — waxy long-stranded substances derived from corn called HES — for human albumin in surgical fluid volume resuscitation. In numerous commentaries published in leading anesthesia and critical care journals, Dr. Boldt passionately espoused the safety and benefits of newer hetastarch products, while questioning the clinical relevance, value and even the safety of human albumin.

Fraud on the Banks of the Rhine

Then last Oct. 28, the editor of the journal Anesthesia & Analgesia delivered a bombshell.¹ Several concerned readers had written to express doubts about a December 2009 study it published titled “Cardiopulmonary Bypass Priming Using a High Dose of a Balanced Hydroxyethyl StarchVersus an AlbuminBased Priming Strategy.”² The variability in results of a particular cytokine assay was too low to be believed, they argued. So too was the reported variability in blood gas findings in this trial, which randomized 50 patients to receive either an electrolyte-balanced “low-molecularweight” HES product or 5% human albumin and saline in their cardiopulmonary bypass (CPB) pumps prior to open-heart surgery. The lead author of this study was Dr. Joachim Boldt.

Inquiries by the journal led to an investigation by the Rheinland State Medical Board (LÄK), which determined that Dr. Boldt never secured Institutional Review Board (IRB) approval for this trial conducted at his hospital. There were no records documenting subject informed consent. There was no evidence of a randomization process or a follow-up questionnaire as described in the study.

Reported findings from Dr. Boldt’s study perhaps should also have aroused the suspicions of anyone familiar with the major physiological functions of human albumin (see the table, Functions of Human Serum Albumin) or numerous earlier studies clearly associating the use of earlier-generation HES products with impaired hemostasis and excessive blood loss in typically hypothermic, hemodiluted and heparinized patients undergoing cardiac surgery.^3,4 “Highvolume priming of the CPB circuit with a modern balanced HES solution resulted in reduced inflammation, less endothelial damage, and fewer alterations in renal tubular integrity compared with an albumin-based priming,” Dr. Boldt and hisfive co-authors concluded. “Coagulation including platelet function was better preserved with high-dose balanced HES CPB priming compared with albuminbased CPB priming.”

Except their study didn’t actually happen. It now appears that Dr. Boldt made up the results. According to the head of the perfusion team at his hospital, Klinikum Ludwigshafen, no albumin has been used as a priming solution there since 1999. No albumin has been delivered to the cardiac operating rooms “for many years,” the hospital’s pharmacy told LÄK investigators. No original patient data or laboratory findings could be found to support the findings in the study.

In his Oct. 28 letter, the editor of Anesthesia & Analgesia retracted Dr. Boldt’s faked 2009 HES-versus-albumin study. Published editorials in that journal now conclude that the findings were “fabricated.” Dr. Boldt has not denied this. Late last year, he was dismissed from his institution, where he had served as chief of anesthesiology and intensive care.

Meanwhile, the LÄK is continuing its investigation, which it acknowledges could take many months or even years to complete. In late February, the LÄK established that IRB approval could not be verified for 89 of 101 examined studies, including 22 between 1999 and 2009 that were published in Anesthesia & Analgesia. All 89 studies have been declared “unethical” and retracted by a total of 16 U.S. and international journals. An investigating committee commissioned by Klinikum Ludwigshafen is now painstakingly comparing published findings in each of those 89 studies to actual patient and laboratory records to determine whether the reported results were authentic or were faked by Dr. Boldt as well.

What We Don’t Know About Voluven

Whether real or fabricated, the contributions of Dr. Boldt and his hospital account for a substantial share of all HES clinical research literature published during the last decade.Most of his studies presumptively evaluated newer lowmolecular-weight HES products, which have a shorter circulating half-life but also have a less-pronounced adverse impact on platelet function and coagulation factor levels that can impair hemostasis. 5

One of those products is Voluven (6% HES 130/0.4 in 0.9% sodium chloride), manufactured by Fresenius Kabi and launched in the U.S. in September 2008. The prescribing information for Voluven specifies that up to 50 mL/kg — 3.5 liters for the average adult — may be administered per day. This dosing limit far exceeds the recommended daily maximum of 1,500 mL specified for HEXTEND (6% HES in Lactated Electrolyte Injection) or HESPAN (6% HES in 0.9% sodium chloride).

Like other HES products, Voluven is heavily promoted as a less-costly alternative to human albumin. This corn starch-derived synthetic colloid is indeed marginally less costly than albumin. But before substituting Voluven for 5% albumin, physicians and pharmacists arguably should expect to see results from clinically relevant head-to-head comparisons of the two products in sufficiently large randomized studies to detect important differences in the risk of infrequent but potentially serious adverse events. In the setting of major surgery, variation in presenting problems, patient age and underlying comorbidities can make connecting the use of a new agent and adverse outcomes extremely difficult if not impossible without a large randomized trial to overwhelm the effects of these various “confounders.”

In promotional material posted online by Voluven’s U.S. distributor, Dr. Boldt was the senior author on four of the eight clinical studies that evaluated the product in adults. 6 Just two studies in adults compared Voluven with 5% albumin. Both were conducted—if they were conducted at all — by Dr. Boldt and colleagues. In a very implausible coincidence, each of these two studies enrolled 50 subjects, randomized 25:25 to each treatment arm, exactly the same number and randomization as the faked 2009 cardiac surgery trial retracted by Anesthesia & Analgesia.

It thus appears that no credible headto-head clinical trial has been performed in adult subjects to try to ascertain the safety of Voluven in relation to albumin. But there is a second problem that applies equally to other HES products that include HEXTEND, HESPAN and generic equivalents: No clinical trial pitting any of them against albumin has been large enough to identify important but relatively infrequent adverse outcomes. While drug regulators routinely require large studies of new drugs for such common conditions as diabetes, hypertension and prostate disorders, no such standard is applied for novel resuscitative fluids or drugs used in vast numbers of surgeries in often seriously ill patients.

The Human Price of Underpowered Trials

The price paid for this laxity in clinical testing standards has been steep.Consider aprotinin, an antifibrinolytic agent approved in 1993 and marketed for 14 years as Trasylol for use in limiting bleeding in cardiac surgery. This drug was administered to untold thousands of patients until a large Canadian trial finally confirmed suspicions that Trasylol increased the risk of kidney failure, heart attack, stroke and death. The drug was finally withdrawn from the market in 2007.

Closer to home, HES products gained favor in the 1990s as a less-costly alternative to human albumin for CPB pump priming and perioperative volume resuscitation. At an FDA advisory panel meeting in 2002, a colleague and I shared published evidence from several singlecenter “look back” studies showing that rates of serious bleeding and transfusion requirements jumped when surgeons switched from albumin to HES. Shortly thereafter, the U.S. Food and Drug Administration (FDA) amended HES product labeling to include a warning against “use as a cardiac bypass pump prime, while the patient is on cardiopulmonary bypass, or in the immediate period after the pump has been discontinued.”

In both of these unfortunate examples, the requirement of a large adequately powered randomized trial for approval would have exposed infrequent serious risks that individual surgeons and anesthesiologists could not hope to identify in their own very limited and heterogeneous patient pools. And, of course, it would have averted needless harm and lost lives.

Moving Past the Boldt Scandal

The absence of large randomized trials comparing newer HES products like Voluven against albumin has obligated both regulators and clinicians to rely on reviews or meta-analyses of small independent and manufacturer-sponsored trials. Recognizing the grim prospect that an unusually prolific researcher may have fabricated most if not all of his HES-related clinical study findings, investigators in Australia and Canada are now conducting new meta-analyses of the available HES clinical literature that purposely exclude all studies published by Dr. Boldt.

The Canadian group, led by Dr. Ryan Zarychanski, a critical care specialist at the University of Manitoba, recently published a systematic review and meta-analysis assessing renal outcomes and mortality in patients admitted to the intensive care unit (ICU) who received HES solutions or alternative resuscitative fluids, including albumin.⁷ This 2009 review of 22 randomized controlled trials in the online journal Open Medicine determined that patients given HES were significantly more likely to have acute kidney injury (odds ratio 1.90, 95% confidence interval, 1.22- 2.96).In the subset of trials that included patients with severe sepsis or septic shock and in “high-quality” and multicenter trials, there was a trend toward increased risk of death associated with HES.

Shortly after Dr. Boldt’s HES-versusalbumin CPB study was retracted by Anesthesia & Analgesia last October, the authors of this meta-analysis posted the following statement preceding their report:

“ATTENTION: The analysis and conclusions of this article are being revised by the authors. This is due to the journal Anesthesia & Analgesia’s retraction of a paper by Dr. Joachim Boldt, an author in seven of the studies analyzed in this review. As such, the editors of Open Medicine recommend interpreting this review with extreme caution until Zarychanski et al. publish a new analysis and interpretation.”

This group plans to revise its analysis after ongoing investigations resolve questions about the integrity of those seven Boldt studies, among the roughly 200 under scrutiny.

What these meta-analyses cannot fully answer is whether Voluven or other HES products are as safe as human albumin in a broad cross-section of surgical patients, including patients with serious comorbidities such as sepsis or renal insufficiency. To get those answers, one must conduct a large randomized clinical trial. No such trial is currently in progress, but the same consortium of Australian and New Zealand researchers is currently doing the next best thing: a massive 7,000-subject trial comparing 90-day mortality in ICU patients randomized to receive Voluven or saline fluid resuscitation.⁸

This same team in 2004 published the landmark Saline Versus Albumin Fluid Evaluation (SAFE) study of similar size, which documented similar 28-day mortality with administration of albumin and saline in a heterogeneous ICU population. Interestingly, in a cohort of more than 1,200 severe sepsis patients, there was a strong trend toward reduced mortality in those who received human albumin instead of saline (relative risk 0.87, 95% CI, 0.74-1.02).⁹

Next Up for Voluven: Post-Marketing Studies

The FDA approved Voluven in 2007 on the condition that the manufacturer committed to conducting two postmarketing studies:

1. A multiple-dose, randomized controlled trial in subjects with severe sepsis with or without renal dysfunction; and

2. A comparison of Voluven and 5% human albumin in open-heart surgery in 2- to 12-year-old pediatric patients.

Hindsight is always 20/20, but given the absence of any large-scale trials evaluating the safety of Voluven against any other resuscitative fluid, perhaps those trials would better have been completed before approving the product without restrictions or warnings about risks in cardiac surgery or a status of clinical sepsis.

With serious (if not grave) concerns about the validity of several key Voluven trials performed at a single center by a nowdisgraced researcher, there is now an obvious urgency to complete these trials and answer the unanswered safety questions.

Voluven and its class of low-molecularweight HES products are novel by virtue of their lesser effect on the coagulation system than older-generation HES solutions. It specifically restores colloid oncotic pressure where saline or other crystalloids do not.

But in patients who have lost a lot of blood, and particularly in those with serious comorbidities or compromised physiological reserve, I suggest the jury is still out on whether this one-trick colloid is a worthy peer of a humble molecule that is anything but novel.

That would be human albumin, the most abundant and pharmacologically versatile protein in the human bloodstream, and the most perfect colloid nature could create.