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Journal of Nutritional & Environmental Medicine (1999) 9, 5-13

EDITORIAL

Is ISIS-4 research misconduct?

DAMIEN DOWNING MBBS

BSAENM, PO Box 3AP, London W1A 3AP, UK

INTRODUCTION

For 40 years now, researchers have been claiming that parenteral magnesium administration may have a beneficial effect on mortality and morbidity in acute myocardial infarction (AMI) [1, 2]. For about the same time, an association has been apparent between magnesium deficiency and prevalence of ischaemic heart disease [3, 4]. By 1992 several small controlled trials had shown a positive result for magnesium therapy in AMI [5-12], and a meta-analysis concluded that it reduced short-term mortality more than any other agent [15]. The same year, the LIMIT-2 study confirmed this with a 24% reduction in mortality in the first 28 days [17] (and 21% in the longer term [18]). Then, in 1995, the very large-scale ISIS-4 study appeared, reporting no benefit from magnesium, and indeed a slight detriment [20]. Very quickly, this study was used to support the argument that magnesium offered no benefit in AMI [21]. and, further, that meta-analysis is intrinsically flawed, and only mega-trials will lead us to the truth [22].

However, there are several clear methodological flaws in the ISIS-4 protocol which call into question both its finding on magnesium, and the more general conclusion that has been drawn concerning mega-trials. The implications of these shortcomings are evidently serious for AMI sufferers, but also therefore for the progress of medical science at large. They also inescapably raise the question of whether ISIS-4 is an instance of misreporting that amounts to research misconduct.

History of Mg in IHD

In 1958, Malkiel-Shapiro reported that magnesium injections appeared to be life-saving in acute myocardial infarction. Sixty- four patients with documented AMI or acute coronary insufficiency were treated with a series of intramuscular magnesium injections (there were no controls). Only one of the patients died within 4-6 weeks of the attack (1.6% mortality), compared to an anticipated average mortality of 19-50% [1].

Similar results were reported a year later by Parsons et al. In that study, 100 patients with acute coronary heart disease, of which at least one-third had AMI, received a series of intramuscular injections of magnesium sulphate. Only one death occurred—a mortality rate of 1%—compared to a mortality of about 30% in controls not given magnesium [2].

In the 1980s a number of small, controlled studies appeared, showing a lower mortality and/or a reduced rate of arrhythmias in the magnesium-treatment groups [5-12]. Although the total number of patients studied in these papers was small (just over 1000 altogether), they did, both individually and when grouped, show a significant benefit from magnesium [17]. There were 2 studies during that period that showed negative results. Abraham [13], which used the lowest Mg dose of any of this set of studies, showed a reduction in tachyarrhythmias, but no change in other cardiac parameters or in mortality. Feldstedt [14] used the highest Mg dose, and found an increase in bradyarrhythmias, heart failure and mortality.

Indeed, both a 1992 meta-analysis [15] and a 1991 overview [16] concluded that there was strong evidence from these studies for a benefit from magnesium. The overview had 5 co-authors, of whom 3 were later on the steering committee of ISIS-4.

In 1992 the LIMIT-2 (second Leicester Intravenous Magnesium Intervention Trial) report appeared [17]. This study randomized 2316 patients, and used a protocol of MgSO4 73mmol IV in the first 24 hours, with start of treatment averaging 3 hours from onset of symptoms. The overall reduction in mortality was 24%.

Then, in November 1993, the results of the extremely large (58,050 patients in 1086 hospitals) ISIS-4 multi-centre study were ‘leaked’ at a cardiology conference in the USA. These appeared to show no benefit for magnesium, and even perhaps a slight worsening of survival. Several months later the Lancet was commenting on why these had not yet appeared in print, and a few months after that they were saying that the result as regards magnesium had already been called into question because of methodological shortcomings in the ISIS-4 study. Then, in March 1995, the Lancet finally published the results [20].

Although the ISIS-4 mega-trial has been put forward as a demonstration that magnesium lacks any benefit in acute infarction, it could equally be argued that it clarifies the mechanism involved, and indicates how and when it should be administered. This did not deter the BMJ from publishing, the following week, two editorials both stating that meta-analysis must be regarded as flawed, that the truth will only emerge from mega-trials, and that we now know ‘the truth’ about magnesium—that it is ineffective [21, 22]. In retrospect this begins to appear over-hasty to say the least.

The flaws in ISIS-4

There are several major criticisms that have been made of the ISIS-4 protocol, and although some elucidatory research has been done since it appeared, much of the literature that validates these criticisms was available before ISIS-4 was implemented—indeed it is largely cited by the ISIS-4 team members in the 1991 overview mentioned above [16]. The principal methodological criticisms are that the administration of magnesium was:

Too much

The beneficial cardiovascular effects of magnesium include a lowering of blood pressure through vasodilatation, a slowing of the heart rate, and reduced excitability of myocardium. Excessive dosages will cause harmful hypotension and bradycardia, and possibly heart block and failure. In ISIS-4, hypotension was more frequent in patients given magnesium, as were heart block and heart failure, and cardiogenic shock. These findings are very similar to—and indeed could have been predicted from—those in the study by Feldstedt et al. [14], but were not seen in any of the other studies. The small studies in the 1980s and early 1990s [5-14] used a wide range of doses of magnesium, almost all of them between 32 and 73 mmol in the first 24 hours (Fig. 1). The notable exceptions were the studies by Abraham et al. [13] which employed 10 mmol and reported strictly limited effects, and the Feldstedt et al. paper which used 80 mmol and showed changes consistent with magnesium toxicity.

In ISIS-4 a total of 80 mmol of Mg was administered in the first 24 hours, which is more than in any other study, but exactly the same as that used in Feldstedt. Figure 1 (modified from Seelig and Elin [24]) plots the outcome, in terms of percentage change in mortality, against Mg dosage, in published studies up to and including ISIS-4. The addition of the LIMIT and ISIS-4 papers to those published before 1991, when ISIS-4 began data gathering, does not significantly alter the best-fit curve to be derived from these data points, which show that, unsurprisingly, it is possible to overdose magnesium.

ISIS4 Figure 1

Fig. 1

Paper

Mg dose

% effect

Year

Reference

1

Abraham

10

25

1987

13

2

Ceremuzynski

32

-69

1989

12

3

Bertschat

40.5

-50

1989

10

4

Rasmussen

50

-61

1986

6

5

Thorgersen

50

-63

1995

39

6

Morton

60

-50

1984

5

7

Singh

65

-50

1990

11

8

Smith

65

-71

1986

8

9

Schecter

67

-88

1990

9

10

Schecter

67

-83

1990

9

11

LIMIT-2

73

-24

1992

17

12

Barghava

73

0

1995

40

13

Flather

80

0

1991

 

14

Feldstedt

80

20

1991

14

15

ISIS-4

80

6

1995

20

FIG. 1. Outcome in published studies up to and including ISIS-4.

The ISIS-4 published protocol document [19] contains no discussion of the choice of magnesium dosages, nor any rationale for the injudiciously high dosage used. Dosage-finding studies were conducted, and cited, for captopril and mononitrate [25, 26], but not for magnesium. The steering committee of ISIS-4 clearly knew about the studies that make up the above curve—several of them put their name to a 1991 overview of them [17]. By choosing a dose of magnesium that had previously been shown to produce toxicity signs and an increase in mortality, the designers appear to have put patients at risk, and probably a substantial number of patients died as a direct result. At best, they must be open to accusations of wilful carelessness in the dosage selection for one of their interventions—but only for one of the three.

Too late

Magnesium protects against many of the complications that can occur in acute MI, but it is well established that, to be effective, administration should begin as soon as possible after the onset of symptoms. This becomes particularly important when thrombolysis is performed, because successful thrombolysis re-establishes blood-flow to damaged myocardium, and the consequent reperfusion injury can itself be harmful. Magnesium protects against this, but only if it is given early enough.

Epidemiological and laboratory studies indicate that low tissue magnesium levels can contribute to the development of coronary heart disease [27-29]. When AMI occurs, magnesium levels in myocardium fall dramatically, allowing an influx of calcium into cells, leading to increased risk of arrhythmia and to potentiation of irreversible cell damage [30-32]. Magnesium administered parenterally protects against these injuries to the heart and their complications; this was clearly demonstrated by the series of studies between 1980 and 1995 cited above [5-14], none of which (excluding the LIMIT-2 study) involved the use of thrombolysis.

When, as in the LIMIT and ISIS-4 studies, thrombolysis is performed, a further therapeutic role for magnesium is called into play. Reperfusion injury describes a sequence of events that result from restoration of blood supply to infarcted areas of myocardium, which includes damage mediated by free-radicals and by calcium overload [33]. The consequences include myocardial stunning and arrhythmias, and the death of previously viable cells. Magnesium, given in appropriate doses and with appropriate timing, protects against these effects also [34-37].

In streptokinase thrombolysis, achieving 50-60% restoration of arterial patency takes approximately 90 minutes from the beginning of thrombolysis (a figure cited in the full ISIS-4 paper). As soon as blood flow is re-established, reperfusion injury will start to occur. For magnesium to protect against this, it needs to be present in effective concentration before this time; it therefore needs to be administered early enough. In a proportion of unthrombolysed patients, spontaneous reperfusion will nevertheless occur during the first few hours after AMI, with reperfusion injury resulting from this also. Timing of magnesium therapy in relation to both reperfusion and onset of symptoms is therefore important. The crucial importance of timing was examined thoroughly in four animal studies [35-38] and one further human study [39], all of which appeared in 1995, so were not available to the ISIS-4 researchers. Nonetheless, it does not take a scientist to appreciate that if a therapeutic agent is not present in the body when a harmful event occurs it cannot moderate the effects of that event. In summary, the clear finding of these studies was that delaying the start of magnesium therapy to 1 hour after the start of thrombolysis removed or severely diminished the protective effect of magnesium.

In the LIMIT-2 study [17,18], the median time from onset of symptoms to randomization was 3 hours. Allocation to thrombolysis and/or magnesium therapy then occurred simultaneously, so that magnesium was always given early, and begun no later than thrombolysis. The reduction in 28-day mortality for those allocated to magnesium vs controls was 24%. In ISIS-4 the median time from onset of symptoms to randomization was 8 hours, and a maximum gap of 24 hour s from onset of symptoms to magnesium (or other) therapy was set. Moreover, thrombolysis was required to be started before randomization, and therefore magnesium therapy could take place. The ISIS-4 paper states: "For patients receiving both fibrinolytic and magnesium infusions, the magnesium was begun within 2 h of the start of the fibrinolytic in about half of all randomized patients" [20]. The finding of the ISIS- 4 study was that magnesium conferred no protection.

Although both the ISIS-4 paper and Yusuf and Flather, in their BMJ editorial [21], have argued that reperfusion would have been almost simultaneous with magnesium in a large proportion of patients, it is in fact clear that considerably more than half of the magnesium-allocated patients would not have received it until after the 1-hour point. Given that the protocol stated that "Study treatment was generally to be started immediately after the early lytic phase (i.e. the first hour or so) of any fibrinolytic regimen", it further seems clear that in respect of magnesium administration the protocol was violated in over 50% of ISIS- 4 subjects [42]. As Woods succinctly stated in his 1995 review of the subject [23]; "The study was not designed to test for an effect of magnesium on reperfusion injury and cannot retrospectively be made to do so." Equally, given the permitted delay between onset of symptoms and start of therapy, it was not designed to test for an effect of magnesium on ischaemic injury either.

Too quick

Apart from the effects of magnesium on myocardial damage and mortality from ischaemia and reperfusion, there is a separate direct effect on the risk of tachyarrhythmias. This has been shown to operate both in AMI and in other, non-cardiac, disorders [43, 44]. Tachyarrhythmias can occur immediately, as a result of ischaemia and/or reperfusion, or later on for a variety of reasons. The need to maintain magnesium levels does not cease after the first few hour s of infarction, therefore.

The earliest studies of Mg in heart disease [1,2] used intramuscular injections. Those published between 1980 and 1991 [5-14] used intravenous infusions with or without initial slow intravenous ‘bolus’ injections, treatment lasting 24 hours in three of these [8,12, 14], 36 hours in one [5] and 48 or 72 hours in the remainder. Of the 24-hour studies two showed a substantial decrease in mortality, the exception being Feldstedt, which used the same ‘overdosage’ of magnesium as ISIS-4. All of the 36-72 hour studies showed an improvement in mortality. The two subsequent studies, LIMIT and ISIS-4, both limited magnesium administration to 24 hours; neither found an improvement in the rate of arrhythmias requiring treatment.

No laboratory or human studies have since been conducted to determine the importance of magnesium duration (in contrast to the timing of magnesium onset), nor has the timing of arrhythmias in relation to magnesium therapy in the studies cited been accessible to post-hoc analysis. At present, therefore, we can only say that this aspect of magnesium therapy requires further study to achieve certainty. When Teo et al. [16] reviewed the effects of magnesium in 1991, however, 4 of the 7 trials that they considered had given magnesium for more than 24 hours, and none for less. Apart from Feldstedt all had used a smaller dosage of magnesium than ISIS-4 did. All but one of the 7 studies showed a reduction in arrhythmias. The ISIS-4 protocol gave no reason for choosing, from the range of previous study models available to them, the maximum dose of magnesium, given over the minimum duration of infusion.

Too uncontrolled

In contrast to the assertion by several theorists that ISIS-4 amounts to conclusive evidence that large-scale trials are necessary to establish the truth regarding treatment effects, outweighing meta-analysis and demonstrating its shortcomings, the very validity of the study as a mega-trial has been questioned. The point has been made that ISIS-4 was conducted in 1086 hospitals in 31 countries—an average of 53 patients per hospital. Inevitably, there will have been wide variations in social and physical settings between hospitals, leading to wide variations in implementation of the study protocol—and thus to a reduction in the homogeneity of the results. Given this, it has been suggested that ISIS- 4 could best be regarded as 1000 + small trials rather than one large one. As such, the appropriate statistical models for analysis of the results would be different. Antman [42, 45] observed that, for examining pooled data from multiple studies, the fixed effects model assumes homogeneity among the trials, whereas the random effects model allows for variability between them. The most noticeable difference between these two models is typically that the confidence intervals for the treatment effects are greater with the random effects model. Applying this comparison of statistical tools to the studies up to and including LIMIT, ISIS-4 and the 1995 trial by Schecter [46] (looking at the effect of magnesium in subjects considered unsuitable for thrombolytic therapy), Antman found an odds ratio for magnesium vs control of 1.02 (0.96-1.08) by the fixed effects model but 0.59 (0.39-0.90) by the random effects model—a striking difference. Were such an analysis to be utilized for an internal analysis of the results of ISIS-4, the conclusions might have been very different.

A similar point applies to the consideration of individual patients in large-scale trials; as Woods states, "the simplicity of the design imposes a reductionist model on any treatment effect—one size fits all" [23]. Readers of this journal more than most are likely to appreciate this point concerning the individuality of patients, and the reductionist effect of fitting all of them, regardless of treatment needs, into a rigid randomization protocol. Some studies since ISIS-4 have begun to look at the possibility that magnesium might be appropriate for sub-sets of AMI patients [46-48]. The use of different study models, together with appropriate statistical methods based on heterogeneity rather than assuming homogeneity, offers hope of identifying such groups of patients and serving them better in future.

But the most interesting such observation to emerge from analysis of ISIS-4 and the other studies relates to the influence on treatment effects of control group mortality. This underlying mortality may be influenced by a variety of factors—in many studies on AMI, for instance, non-trial nitrate therapy is allowed at the discretion of treating doctors, without resulting in exclusion from the trial. Indeed it is clear that ethical considerations would make it difficult to withhold such measures for the sake of a study. In ISIS-4 60% of patients received such non-trial treatment. The unsurprising finding, in general, is that the lower the control mortality, the less benefit can be derived from treatment—otherwise we would expect negative mortality rates in treated groups—and the greater the size of study groups needed to establish any treatment effect.

In Fig. 2, the magnitude of treatment effect is plotted against control mortality for 15 studies including ISIS-4; the curve (in this case a logarithmic trendline) crosses the zero line at about 3% control mortality. In a similar analysis Antman [42] found that the regression curve for treatment effect reached zero at a control mortality of approximately 7%. A reasonable inference might be that there is an inescapable—and so far untreatable, by magnesium or anything else—mortality rate from AMI of around 5%, which is borne out by the average treatment group mortality in all these studies of 4.9%.

The consequence for the ISIS-4 study, with a control mortality of about 7%, is that despite its large size it was a poor instrument for detecting treatment effects. While this would also appear to have been the case, to a lesser degree, for captopril and mononitrate, it was especially true for magnesium due to the factors discussed above.

Conclusions

Considering all these factors together, it appears that the effect in the case of ISIS-4 has been to produce a classical Type II error. This goes against conventional statistical wisdom, which says that the only real protection against such errors lies in large numbers. It has further led to a shift in the consensus view of meta-analysis, based on an acceptance that ISIS-4 was right, and the clear inference that meta-analysis is therefore fundamentally flawed. This must now be questioned.

The lack of discussion of magnesium treatment choices in either the ISIS-4 protocol paper or the full report makes it impossible to draw any conclusions regarding the thinking or motives of the steering committee. But the outcome of ISIS-4 does have to be regarded as a good one for the researchers (evidence that large-scale studies work, and that many more will be needed) and for the principal funders (evidence that captopril works, but mononitrate and magnesium do not).

ISIS4 FIGURE 2

Fig. 2

Paper

Control

Treatment

   

Mortality %

Effect as %

1

Abraham

2

25

2

Ceremuzynski

13

-69

3

Bertschat

5

-50

4

Rasmussen

17

-61

5

Thorgersen

6

-63

6

Morton

5.5

-50

7

Singh

15

-50

8

Smith

15

-71

9

Schecter

17

-88

10

Schecter [41]

15

-83

11

LIMIT-2

10

-24

12

Barghava [40]

8

0

13

Flather

7

0

14

Feldstedt

5.5

-20

15

ISIS-4

7

6

FIG. 2. The magnitude of treatment effect plotted against control mortality for the 15 studies culminating in ISIS-4.

Every major study these days involves a press release announcing the results. These are the scientific equivalent of the work of ‘spin doctors’ in government. A further cause for concern regarding ISIS-4 is the way in which the results were released, in November 1993, in the form of a press release embargoed until the first day of the American Heart Association meeting in Atlanta, at which the preliminary results were presented to the meeting. At this time, according to the final paper (which appeared somewhat later, in March 1995), it was only 9 weeks since randomization had ended, and only 81% of follow-up data was available for analysis. Already though, the tone of the press release makes it clear how the authors wished their report to be viewed: Dr Rory Collins, the ISIS- 4 coordinator, said "These results will disappoint those who had trusted the positive claims from previous small trials of magnesium and nitrates."

In an editorial in 1991 we discussed the issue of ‘Tabloid Science’: ‘the public, bombarded with health stories alongside politics, sport and the rest of the news, have no opportunity to acquire an overview of the research evidence; each story is displaced from memory by the next, or the one after that, and perception of the truth is ephemeral, immediate and partial, and often trivialized’ [49]. In this context, the combination of the ISIS-4 report and the way it was presented to the world looks like a deliberate and so far very successful strategy. Those who had trusted the previous studies were indeed disappointed, though not necessarily in the way meant by Dr Collins, and the impact on clinical care has been substantial. If they are not deliberate, then the multiple anomalies in the design and execution of ISIS-4, whose effects all accumulate towards an underestimate of the usefulness of magnesium, must indicate startling ignorance and/or negligence on the part of the ISIS- 4 authors. Either this was bungling or it was research misconduct.

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