Alteplase for stroke: money and optimistic claims buttress the “brain attack” campaign

Both doctors and the public are becoming more alert to potential conflicts of interest, and an increasing number of journals now require competing interest statements from their authors and reviewers. In this article Jeanne Lenzer uses the example of guidelines produced by the American Heart Association to discuss some of the questions that can arise when interests conflict

As doctors and the public become more aware of conflicts of interest involving study bias,¹ publication bias,² and industry gift giving³ they turn to credible non-profit organisations for sound medical recommendations. Unfortunately, many groups (and their individual panellists) that serve as arbiters of inconclusive data may also suffer from conflicts of interest.⁴,⁵

One such conflict is self referencing bias. An example of this is in specialty guidelines for colon cancer screening, where radiologists recommend barium enemas while gastroenterologists recommend colonoscopy. A more important conflict arises when corporations with a financial stake in the recommendations issued by a non-profit making organisation provide financial support for that organisation.

In this paper I examine an example of such a conflict, in which a treatment recommendation that could cost more lives than the disease itself was supported by statistics from only one randomised controlled study. Additionally, poor outcomes and dissenting opinion appear to have been obscured. This recommendation may have been made in a true spirit of unbiased scientific inquiry, but the appearance of dispassionate analysis was eroded by large donations from a drug company to the organisation making the recommendation and payments for research and lecture fees to its individual expert panellists.

Summary points

• The American Heart Association rated the thrombolytic agent alteplase (tPA) as a class I (definitely recommended) intervention for stroke despite controversy about its safety and efficacy

• Most of the association's stroke experts have ties to the manufacturers of alteplase

• Genentech, the US manufacturer of alteplase, contributed over $11m to the American Heart Association in the decade before its recommendation on alteplase

• Following public scrutiny, the American Heart Association recently withdrew statements that alteplase for stroke “saves lives”

• Seemingly impartial organisations that issue professional guidelines may have ties to the manufacturers of recommended interventions

The recommendation and the doubts

In August 2000 the American Heart Association upgraded its recommendation of alteplase (tPA) for stroke from optional (class IIb) to definitely recommended (class I)⁶ despite continuing controversy about the safety and efficacy of the treatment. The concerns include the following:

• Most randomised, controlled trials show that thrombolytics increase mortality in acute ischaemic stroke^7–11

• The recommendation was based on one trial: the National Institute of Neurological Diseases and Stroke (NINDS) trial.¹² In this trial many more patients in 90-180 minute treatment arm had mild stroke scores at baseline, while more in the placebo arm had worse scores (see table)¹²

• The external validity of this particular trial is questionable since the proportion of patients enrolled in the 0-90 minute group was artificially increased through study design criteria¹³

• Chance alone could explain the benefit shown in this single study⁸,⁹,¹³

• Efficacy in expert hands is not the same as clinical effectiveness in usual clinical practice⁸

• One fifth of patients initially diagnosed with stroke by expert stroke teams were subsequently found not to have strokes.¹⁴ Exposing such patients to alteplase would incur all the risks with none of the benefit

• Even assuming effectiveness, the clinical impact is marginal, with only 0.4% of patients potentially benefiting from alteplase.¹⁵

These concerns and others have caused the Canadian Association of Emergency Physicians to conclude, “Further evidence is necessary to support the widespread application of stroke thrombolysis outside of research settings.”¹⁰ The American Academy of Emergency Medicine similarly concluded:“Objective evidence regarding the efficacy, safety, and applicability of tPA for acute ischemic stroke is insufficient to warrant its classification as standard of care.¹⁶ After an urgent request from concerned members,¹² the American College of Emergency Physicians is considering a policy statement that supports a much more restrictive recommendation of alteplase for stroke than represented by the class I recommendation of the American Heart Association. According to college national board member, Susan Nedza, “Leaders in emergency medicine are raising significant scientific, ethical and implementation issues” (personal communication, February, 2001).

Statistics and spin

The American Heart Association first classified alteplase as an optional (class IIb) intervention after the Food and Drug Administration approved its use in ischaemic stroke in 1996. In 2000 alteplase was upgraded to a definitely recommended intervention (class I) after further review of reports after the National Institute of Neurological Diseases and Stroke trial.

Another observational study, the “standard treatment with alteplase to reverse study” (STARS),¹⁷ was favourably considered despite the fact that it had strong ties to the manufacturer of alteplase (all sites were part of the Genentech-sponsored “alteplase thrombolysis for acute noninterventional therapy in ischemic stroke” (ATLANTIS) trials). It was not an “effectiveness” study (since it involved experts who had participated in the prior randomised controlled trials) and it relied on voluntary site reporting (results from 31% of ATLANTIS sites were not included).

Rather strikingly, on the other hand, the association made no mention of the Cleveland area experience,¹⁸ which reported catastrophic results with community use of alteplase for stroke: patients treated with alteplase had twice the death rate of similar patients not treated. Unlike STARS, the Cleveland study had minimal ties to the manufacturer, represented true community practice, and, most important, did not reflect selective reporting, as it included all non-Veterans Administration patients treated for stroke in the city of Cleveland.

Advocates of alteplase have dismissed clinical trials outside of the National Institute of Neurological Diseases and Stroke trial as heterogeneous and note that the American Heart Association guidelines encourage adherence to the protocols of the National Institute of Neurological Diseases and Stroke. However, critics caution that selective emphasis of a single study is scientific folly: “There are numerous examples in medicine where a single small study (or even a few studies) seemed to support a promising hypothesis, but subsequent larger work failed to confirm that benefit (or showed substantial harm).”¹³

Verification of data thwarted

Attempts to obtain raw data from the National Institute of Neurological Diseases and Stroke trial or the alteplase thrombolysis for acute noninterventional therapy in ischemic stroke part A trial have been unsuccessful. Drs Clark (ATLANTIS) and Marler (National Institute of Neurological Diseases and Stroke) and Genentech have turned down requests for the raw data. A formal Freedom of Information Act request for the data from the National Institute of Neurological Diseases and Stroke trial has been filed with the Food and Drug Administration, but a preliminary response from the administration's legal counsel was negative.

Making the raw data available for scrutiny seems all the more prudent given that Genentech provided the data monitoring services for the National Institute of Neurological Diseases and Stroke trial. A clinical review by the Food and Drug Administration of a pilot study for the trial indicates that some of Genentech's data calculations were inaccurate: “In calculation of infarct volume . . . the volumes exceed not only the volume of a cerebral hemisphere, but even the volume of the entire cranial vault.”¹⁹

Although the provision of data monitoring services by Genentech may not have caused data errors, the refusal of the trial investigators to release their raw data and of Genentech to describe the function it fulfilled in providing such services makes data verification impossible. This is of particular interest since some potentially important data (such as primary endpoint mortality at 24 hours) were never published.

Bloated claims: the “brain attack” campaign

In the mid 1990s the American Heart Association launched a major initiative known as the “brain attack” campaign. This term was encouraged so clinicians and patients would think of stroke as an emergency on a par with myocardial infarction, or “heart attack.” This campaign rested on the touted value of alteplase.

This is how alteplase for “brain attack” was described in American Heart Association literature²⁰: “A clot-busting drug that helped revolutionise heart attack treatment, tPA holds enormous potential for the treatment of ischemic stroke, which accounts for 70 to 80 percent of all strokes. It is estimated that tPA could be used in 400 000 stroke cases per year to save lives, reduce disability and reverse paralysis. Yet tPA is now only being used in some 4000 to 6000 cases annually.”

The statement “save lives” is not supported by data from any fibrinolytic trial. No trial has ever shown a reduction in mortality from alteplase use in stroke, but several have shown substantially increased mortality. American Heart Association president, Dr Rose Marie Robertson, withdrew this statement when its inaccuracy was pointed out in conjunction with questions about potential conflicts of interest.²¹

The American Heart Association and potential conflicts of interest

In the late 1990s there were rumours in the medical community that Genentech had paid for the national headquarters of the American Heart Association. Although some dismissed this as an urban myth, the rumours proved true. Minutes of the American Heart Association board of directors' meeting on 18 October 1991 confirm that Genentech contributed $2.5m (£1.8m, €2.8m) to build the association's headquarters in Dallas. Further research shows that Genentech's contributions to the American Heart Association have totalled $11m (£7.8m, €12.6m) over the past decade.²⁰,²¹

Dr Robertson has argued that Genentech's contributions had no effect on American Heart Association guidelines. She stated that the panellists were “independent” and required to file conflict of interest statements.²¹ Since no conflict of interest statements were published with the American Heart Association's Guidelines 2000, physicians and the public may reasonably conclude that the association and its panellists were free of competing interests. However, the association will not release the conflict of interest statements for public inspection and verification.

A panel of nine was responsible for the guidelines, eight supporting alteplase and one dissenting. Independent investigation for this article shows that six of the eight panellists who supported alteplase for stroke as a class I recommendation had ties to the manufacturer. Four panellists received lecture fees as members of the Genentech speakers bureau; one serves as a consultant to Boehringer Ingelheim, a “development and marketing partner” with Genentech in producing and distributing alteplase; and two received research funding from Genentech (some panellists had more than one form of relationship with Genentech.) Only two of the panellists who supported the upgraded classification had no ties to the manufacturer. Dr Jerome Hoffman, the lone dissenting panellist, also had no industry ties.

Two panellists initially denied receiving Genentech funding or fees. One, who received lecture fees, acknowledged speaking for Genentech only after being told of evidence of his relationship: “I didn't realise I was officially on the speakers bureau.” When asked the time frame of his lectures, he responded, “Mostly between 1997 and 2000.” Another panellist denied being a principal investigator on a Genentech-sponsored trial, only acknowledging this role after being told that a coauthor had identified him as a principal investigator and after receiving a copy of the original article listing him as such. He said he had enrolled only a few patients, then withdrew from the study and didn't realise his name was listed as a principal investigator in JAMA.

Some argue that industry gifts or funding do not usually result in distorted science.²² However, manufacturers' sponsorship of clinical trials is increasing,²³ and treatment benefits have been shown to be overstated in sponsored trials,¹ while risks are understated,²⁴ and undesired data are more likely to be suppressed.²⁵

Delayed publication, missing data

A single Genentech sponsored trial, alteplase thrombolysis for acute noninterventional therapy in ischemic stroke (ATLANTIS) part A,²⁶ prospectively replicated many of the methods of the National Institute of Neurological Diseases and Stroke trial, including its enrolment of a subgroup of patients in a 0-3 hour window. (The overall trial measured outcomes with alteplase given 0-6 hours after onset of symptoms.) Part A was negative: alteplase did not improve stroke recovery but did dramatically increase mortality rates (at 30 days 18% of patients given alteplase had died versus 4% of those given placebo). Inclusion of a 0-3 hour subgroup of patients was done, according to lead author Dr Wayne Clark, to “see if we could replicate the results of the National Institute of Neurological Diseases and Stroke [trial]” (personal communication, September 2000). Yet no subgroup analysis of the 0-3 hour cohort was described in the final publication. Furthermore, the results of part A were not published for six years after the trial's completion, even after results from both the National Institute of Neurological Diseases and Stroke trial (conducted concurrently) and a second phase of the same trial (part B) were released.²⁶

Dr Clark, responding to an inquiry about the cause of the delayed publication of part A, said; “The investigators asked several times to publish it. I guess the company thought that it might somehow bias the ongoing 3 to 5 hour study [part B]. But I don't have a good answer for you.”

Genentech has declined to respond to Dr Clark's statements saying they won't comment on “unsubstantiated rumours” (personal communication, Shelly Schneiderman, Genentech, August, 2001).

Suppressed dissent: the disappearing of Dr Hoffman

Dr Jerome Hoffman, one of the nine experts empanelled by the American Heart Association to develop the guidelines, provided the sole dissent to the organisation's recommendation. The eight other panellists were known to support alteplase for stroke from prior publications. After his expert testimony at the guidelines meeting he was asked by the American Heart Association to provide a written commentary expressing the basis of his dissent. Although he submitted this paper at least a year before the final guidelines were released, it was never published and the guidelines did not mention it. In addition to removing Dr Hoffman's name from the list of authors of the guidelines (at his request), the association also, for unexplained reasons, removed his name from the list of expert panellists.²⁷ This deprived the scientific community of knowledge about the basis for Dr Hoffman's dissent and it obscured an important signal that any dissent existed at all.

Chameleon ethics

Although a study to verify the outcomes of National Institute of Neurological Diseases and Stroke could benefit the public, it could only harm those who stand to gain financially. A revealing history of such risks comes from Genentech itself. Dr Elliott Grossbard, a Genentech scientist, vigorously opposed a head to head study of alteplase and streptokinase for myocardial infarction. He put Genentech's position bluntly: “We don't know how another trial would turn out. And if we don't come out ahead, we would have a tremendously self-inflicted wound . . . [another study] may be a good thing for America, but it wasn't going to be a good thing for us.”²⁸

Although good science has long relied on dissection of prior studies and data verification, this value has been stood on its head in the name of “ethics” by those with a financial stake in the outcome. Both Dr Clark and Genentech have opposed further studies of alteplase in stroke, stating they would be “unethical” in view of the National Institute of Neurological Diseases and Stroke trial results. Critics point out that another study is crucial regardless of outcome. If benefit is found far greater physician compliance with the American Heart Association guidelines could be expected. If the outcome were negative, it would seem that caution is in order.

Not just Genentech and the American Heart Association

Industry funding of non-profit healthcare and professional organisations is widespread. The attorneys general of 16 states and the Corporation Counsel for Washington, DC issued a report in 1999 about the increasing number of ties between non-profit organisations and pharmaceutical companies. They concluded that the public was given “false and misleading” messages as a result.²⁹ A few examples of such sponsorships include the American Cancer Society, which is funded by AstraZeneca, Johnson and Johnson, Bristol-Myers Squibb, Eli Lilly, and other manufacturers of diagnostic tests and treatments for prostate cancer. Breast Cancer Awareness Month is funded by AstraZeneca, the manufacturer of Nolvadex (tamoxifen), while Eli Lilly, manufacturer of fluoxetine (Prozac) along with 17 other manufacturers of psychoactive drugs, provided $11.72m (£8.3m, €13.4m) to the National Alliance of the Mentally Ill.

Conclusions

Expert guidelines are expected to be objective, impartial, and independently derived. Sponsorship from organisations that stand to gain from recommendations favourable to their products threatens to undermine such objectivity. Given the profitability of drugs and medical devices, such neutrality is badly needed. Professional societies, particularly those with influence on medical practice, should adopt rigorous standards with regard to industry sponsorship. Such standards should avoid all appearance of potential bias, enabling critical analysis to be conducted in an environment independent of profit motives, providing equal opportunity to test inexpensive therapies with expensive ones, and encouraging open criticism in a forum of dispassionate scientific debate.

Table.

More patients treated with alteplase than those treated with placebo had mild strokes at baseline in the 91-180 minute group, while those with the worst strokes were more likely to be in the placebo group. Mean scores overall were also lower at baseline for patients given alteplase

Baseline NIHSS scores	Alteplase (%)	Placebo (%)
0-5	19.0	4.2
>20	18.3	27.5

From table 3.¹²