Healthy Skepticism Library item: 17728

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Publication type: Journal Article

Lu TF, Landmesser U, Ruschitzka F
Standing firm-the European Heart Journal, scientific controversies and the industry
European Heart Journal 2010 Apr 24;
http://freepdfhosting.com/4f161330ef.pdf

Abstract:

The scientific process
Science is not a continuous process, but rather, one which
advances in leaps and bounds, moving forward only to experience
setbacks as unexpected, new information becomes available.
Knowledge thus develops with conjectures and refutations as
Karl R. Popper,1 the eminent philosopher of science, once said.
As Thomas H. Huxley put it, the tragedy of scientific inquiry is
that a beautiful hypothesis may be slain by an ugly fact.2 Knowledge
therefore is never stable; in fact, even the most elegant theory may
be disclaimed by surprising new data. All our assumptions, theories
and concepts must continually withstand falsification attempts
through novel insights and unexpected findings, and the longer
they survive, the better and more useful they are.
Many concepts have been disproved by appropriately powered
trials, one of the more prominent examples being the CAST
trial3 which falsified the assumption that suppression of premature
ventricular beats will prevent sudden death. Similarly, in heart
failure stimulation of left ventricular function with either catecholamines
or their derivatives as well as stimulators of myocardial
second messengers such as cAMP increased rather than decreased
mortality, although symptoms and physical performance were
improved.4 The series of negative trials was just recently complemented
by the ILLUMINATE trial5 using torcetrapib, a cholesterol
ester trans-protein inhibitor, to increase the plasma levels of protective
high-density lipoproteins which unexpectedly led to
increased mortality in the active treatment group.
However, it is not merely the efficacy of drugs, interventions,
or devices which requires continual critical monitoring: safety
has become the new efficacy as the scientific community has experienced
surprising findings with molecules used for noncardiovascular
indications. In fact, while cyclooxygenase-2 inhibitors
were increasingly used to the benefit of patients afflicted osteoarthritis
or other conditions, the APPROVe (Adenomatous Polyp Prevention
on Vioxx) trial,6 which was designed to expand the
indication of this promising and novel class of drugs, revealed an
unexpected increase in myocardial infarctions in the actively
treated group. Together with a previously published second
analysis of the VIGOR-trial,7 this led to the withdrawal of rofecoxib
or VioxxR by Merck, its manufacturer, on 30 September 2004.
Consequently, the safety of all other drugs in this class as well as
all non-steroidal anti-inflammatory drugs was in question and new
trials such as PRECISION were launched to test this very issue.8
The contribution of industry
The pharmaceutical industry has made immense investments in
developing novel drugs-and obviously had and still has to deal
with the risks involved. If a drug is proved to be effective, the
efforts of industry were always rewarded by substantial sales, in
most cases to the benefit of the respective company as well as
the patients in need. It goes without saying that the pharmaceutical
industry has contributed enormously to the impressive progress of
medicine and cardiology in particular over the last 50 years: aspirin
developed by Bayer, beta-blockers by ICI, ACE-inhibitors by
Squibb, statins by Merck and Bristol, Myers & Squibb and thereafter
many others such as angiotensin Type 2 receptor antagonists by
Merck and later Takeda, Novartis and AstraZeneca are just a
few of the most prominent examples that have changed our
daily practice. Similarly, pacemakers, implantable defibrillators, balloons,
and stents would not be part of our therapeutic armamentarium,
had they not have been developed by innovative
manufacturers in close collaboration with academic researchers.
Challenges and successes
With the increasing success of drug development, however, things
became a bit more difficult, especially in cardiovascular medicine.
Today, novel drugs not only have to prove better and better efficacy,
but must also provide impeccable safety. This has made it
increasingly difficult to introduce novel cardiovascular drugs into
the market. The development of many molecules had to be
stopped prematurely because of a less than perfect side effect
profile or because of disappointing efficacy. For example, the
promising adenosine type 1 receptors antagonist rolofylline
which was expected to improve prognosis in acute heart failure
by interfering the tubulo-glomerular feedback never saw the light
of clinical practice because the pivotal trial could not confirm
the results of the phase I and II studies. For the manufacturer, in
this case Merck Inc., this proved to be a considerable setback. In
fact, such events may significantly affect the future strategy of the
company, its organization and the careers of many of its employees.
Thus, along the road of research and development of pharmaceuticals
and devices, the hopes and fears of scientists within
industry and academia may create serious conflicts of interest.
Unmet needs
Despite the tremendous progress in cardiovascular medicine that we
were fortunate enough to witness in recent decades, there are still
many unmet needs, for instance in diabetes. Indeed, although
aspirin, statins, and inhibitors of the renin–angiotensin system are
effective in this patient population, risk remains high. This has led to
development of several novel treatment strategies, among them the
so-called thiazolidinediones or PPAR-y activators. These drugs
exert an array of effects in the cardiovascular system as well as in
lipid and glucose metabolism and hence created high hopes that the
devastating natural history of diabetes could be favourably influenced.
Thiazolidinediones were thus promising from the start.
However, troglitazone, which was marketed in 1998 in the USA
and later in Europe, soon came under intense scrutiny because
of a rare, yet potentially fatal hepatotoxicity.9 The next available
molecules of this class, rosiglitazone and pioglitazone, seemed to
lack these side effects and were thus rapidly approved for clinical
use by the FDA and the EMEA, while troglitazone was withdrawn
from the market. Both drugs undoubtedly exerted beneficial
effects on a variety of surrogate endpoints such as high density
lipoproteins, markers of inflammation and plasma glucose levels.
However, in the case of rosiglitazone, unfavourable signals were
noted in several trials suggesting that the drug might be associated
with water retention, an increased incidence of heart failure and
possibly myocardial ischaemia. These concerns were discussed
both by the registration agencies and clinical scientists, particularly
after the meta-analysis of Nissen andWolski10 had been published.
Nevertheless, the discussion continued due to the lack of a sufficiently
large and adequately powered clinical trial.
The culprit
In a recent issue of the European Heart Journal, Komajda et al.11
published another analysis on the cardiovascular effects of rosiglitazone
reporting an increased incidence of congestive heart failure
in the RECORD trial. The paper was accompanied by an editorial
authored by Steve Nissen,9 an acknowledged expert in the field.
Editorials are meant to be provocative in order to stimulate scientific
discourse. To this end, the European Heart Journal aims to
foster open debate on scientific issues for its readership and regularly
invites reviewers and key opinion leaders to elaborate on published
articles. The journal also defines its position in this forum
through the following disclaimer: ‘The opinions expressed in this
article are not necessarily those of the editors of the European
Heart Journal or of the European Society of Cardiology’-they
might, but they don’t have to.
Unexpected mail
On 21 February 2010, the Editor-in-Chief of the European Heart
Journal received a letter from Dr Moncef Slaoui, the chairman of
research and development of GlaxoSmithKline, the manufacturers
of rosiglitazone. In his communique´, he urged the journal not to
publish the online editorial in print. The journal’s editorial board discussed
the issue and unanimously agreed that such a demand was
unacceptable. However, representatives of the manufacturer were
invited to express their position in the journal, to allow for an
open scientific debate. Obviously, such an offer also had to
involve the editorialist, Steve Nissen, and thus the European Heart
Journal is pleased to publish both the statement of GlaxoSmithKline
as well as the response to their criticism by Steve Nissen.
Standing firm
Science is an interactive process and that is why journals are
optimally positioned to promote this process. Communicative
reasoning within the scientific community is the hallmark of the
scientific process as Habermas12 put it. Scientists know what a
good argument is and will consider its merits and evidence, if
put forward by knowledgeable colleagues, may they work in academia
or in the industry. However, we cannot suppress concerns,
data or divergent opinions-we must consider them and argue
with data, numbers and plausibility. Only through such a discourse
can progress evolve.