SciQuest.org

Paying study subjects is not a new practice, but neither is it uncontroversial. According to regulators, payment should not be so high as to become an “undue inducement,” lest subjects enroll in risky, unpleasant, or degrading trials against their better judgment. But this standard gives IRBs little practical guidance: a sum of money that the wealthy can easily resist may be very tempting for poorer people. Keeping payments low, however, seems unfair to the poor, who submit to trials precisely because they need the money. And whether or not such people are being unduly induced, the larger question is whether they are being exploited.

To exploit people is to take unfair advantage of them, but there is no consensus that current trial arrangements are unfair. Defenders of the status quo argue that people who enroll in trials have agreed to their conditions, that they get paid enough to make it worth their while, and that they are made better off by the arrangement. Nevertheless, there are good reasons to believe that poor subjects are being exploited.

First, poor people are less likely than wealthier ones to get access to the drugs in question, if and when they are approved. Volunteers are unlikely to have full-time employment or, therefore, to have health insurance. Placing the burden of safety testing on the poor appears to contravene article 19 of the Declaration of Helsinki, which states that medical research is ethically justified only if there is a reasonable chance that the population in which it is conducted will benefit from the results.

Second, the U.S. oversight system is not well equipped to monitor a highly competitive, market-based, multinational research industry. The Office for Human Research Protections has no jurisdiction over privately sponsored studies, and the Food and Drug Administration inspects only about 1% of clinical trials.2 IRBs, the most important bodies charged with protecting subjects, were designed primarily to review trial design, risk–benefit ratios, and informed-consent documents. Recent research scandals — which have been uncovered largely by investigative reporters rather than regulators — have concerned a very different set of issues: fraud, conflicts of interest, unfair payment practices, and unsafe or degrading trial conditions. Such problems are magnified still further when studies are conducted at private testing sites and reviewed by for-profit IRBs that are financially dependent on research sponsors.

Third, even though the purpose of phase 1 trials is to test whether new drugs are safe, most sponsors apparently do not provide free care or treatment for subjects who are injured in these trials. In fact, no agency is even tracking injuries in phase 1 trials, much less the long-term health of people who volunteer for many trials over a period of years. A recent study commissioned by the Department of Health and Human Services showed that only 16% of academic health centers provide injured subjects with free care. None compensate injured subjects for pain and suffering or lost wages.3 Although no comparable data are available for private research sponsors, there is little reason to believe that private sponsors are much more generous4; indeed, many include disclaimers in their consent forms indicating that subjects retain responsibility for their own medical care.

Most of these problems can be seen as consequences of the transformation of clinical research into a business. Many subjects in phase 1 trials today see their participation as a job.5 They must pay taxes on their trial income, and sponsors often require them to sign a form acknowledging their status as “independent contractors.” The payment has become high enough to make participating in trials more lucrative than holding a minimum-wage job, even if subjects abide by the requirement that they wait 30 days between trials. Yet subjects get none of the rights or benefits that come with a good job, such as workers’ compensation, the right to unionize, disability benefits, or health insurance. Subjects whose livelihoods depend on trial income are often reluctant to drop out of trials that turn out to be risky or unpleasant, especially if they have traveled some distance to the trial site and have invested a substantial amount of money in accommodations while waiting to enter the trial. Subjects have little incentive to be truthful about their medical history or health status because known medical problems may preclude their participation in a study. Nor do they have anyone to go to with complaints. Many say they are reluctant to complain to sponsors about poor conditions for fear of being excluded from future trials. For similar reasons, they are reluctant to go to a lawyer, even if a trial goes seriously wrong.4

Without actually intending to do so, policymakers have allowed participation in clinical trials to become something very close to a job. Sponsors call subjects’ payments “compensation” to suggest that they are merely reimbursing participants for expenses and inconvenience, even as they fill studies with unemployed people who depend on trial income to make ends meet. They refer to paid subjects as “volunteers,” implying that participation is a freely chosen act of altruism, whereas most subjects indicate that they take part in trials for the money. Regulators allow sponsors to use money to attract subjects but do not require them to provide the kinds of benefits that subjects would demand if they had more power. The result is what one Philadelphia trial subject describes as “a mild torture economy.” “You are not being paid to do something,” he explains. “You are being paid to endure.”5

No potential conflict of interest relevant to this article was reported.

Source Information

Dr. Elliott is a professor at the Center for Bioethics at the University of Minnesota, Twin Cities. Dr. Abadie is an anthropologist and independent scholar who recently completed a research fellowship in the Bioethics Research Program, Mayo Clinic, Rochester, MN.

Time for health news that is warm and fuzzy!

A new study reported in the Journal of American College of Cardiology shows that a big mug of hot cocoa can reverse vascular dysfunction in patients with diabetes, suggesting a therapeutic potential of cocoa in this patient population.

Prior studies have shown that flavanol-containing foods, including cocoa, certain fruits and vegetables, tea, and red wine, have beneficial effects on LDL oxidation, platelet aggregation, insulin sensitivity, endothelial function, and blood pressure. These researchers show that the reversal of diabetic endothelial dysfunction with cocoa is comparable to intermediate- and long-term interventions using exercise and various medications, including insulin, pioglitazone, ACE inhibitors, and statins. They also found that over time the good effects persisted. Even if cocoa could enhance lifestyle and medication benefits in diabetics, it would be significant in how we approach this diabetes epidemic.

This study was not designed to determine the molecular mechanism of action but there is an indigenous population in Panama (Kuna Indians) that consumes a large amount of cocoa rich in flavanols. Despite their diet that also has a large amount of salt, they have a very low prevalence of heart disease, stroke, diabetes, and cancer compared with Kuna Indians living in Panama City.

It is important to know that the doses of flavanol in the cocoa were much higher than what we are drinking. The high-flavanol cocoa used in this study–which provides much more flavanol than the typical US dietary intake of 20 to 100 mg daily–is not sold in the supermarket.

It looks like an opportunity for a Mars or Hersheys manufacturer to me.

Why do people wear eyeglasses? The answer is simple - they have a bad eyesight and unfortunately they can’t live without prescription spectacles. Actually, they can live but the most of the benefits may be unreachable for them if they do not see well. Even a blurred image of your lover will not attract your anymore and the things that were once sharp and clear (provided your eyesight has worsened) do not bring you such a feeling as they used to. Anyway, there are always many wayouts of such a situation.

The first thing that comes up to your mind can be a surgical interference but as a matter of fact not all the operations end successfully and there is always risk to lose your eyesight at all! Besides, eyesight operation costs a substantial sum of money and the majority of people can not afford this.

Wearing lenses is really a step forward in comparison with wearing eyeglasses as they are practically invisible and they do not “spoil face”. Besides when you are wearing lenses you can also
buy sunglasses and enjoy the sun like all other people do. But lenses demand a careful and timely attention: a holder and a solution.

Simple plastic and cheap metal eyeglasses are still very popular today and not because they are really cheap in comparison with other solutions for your eyesight but also because they are practical, need minimal attention and if you choose the right glasses for your face - it won’t spoil your look, may even make it better!

Clinical Outcomes

At 30 days, patients who were assigned to receive bivalirudin alone, as compared with those who were assigned to receive heparin plus a glycoprotein IIb/IIIa inhibitor, had a significantly reduced rate of net adverse clinical events (9.2% vs. 12.1%; relative risk, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005), owing to a lower rate of major bleeding (4.9% vs. 8.3%; relative risk, 0.60; 95% CI, 0.46 to 0.77; P<0.001), with similar rates of major adverse cardiovascular events (5.4% and 5.5%, respectively; relative risk in the bivalirudin group, 0.99; 95% CI, 0.76 to 1.30; P=0.95) (Table 3 and Figure 2). In a post hoc analysis, with the exclusion of large hematomas from the protocol definition, the rate of major bleeding was reduced from 7.8% with heparin plus glycoprotein IIb/IIIa inhibitors to 4.7% with bivalirudin (P<0.001). Bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, also reduced hemorrhagic complications as defined by the TIMI and GUSTO scales, thrombocytopenia, and the need for blood transfusions (Table 3). Among patients in the control group, the peak activated clotting time did not differ significantly between those with major bleeding and those without major bleeding (median, 273 seconds and 263 seconds, respectively; P=0.12).
Treatment with bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in significantly lower 30-day rates of death from cardiac causes (1.8% vs. 2.9%; relative risk, 0.62; 95% CI, 0.40 to 0.95; P=0.03) and death from all causes (2.1% vs. 3.1%; relative risk, 0.66; 95% CI, 0.44 to 1.00; P=0.047); rates of reinfarction, target-vessel revascularization, and stroke were not significantly different (Table 3 and Figure 2). There were no significant differences in the peak creatine kinase level or creatine kinase MB fraction between the bivalirudin group and the group that received heparin plus glycoprotein IIb/IIIa inhibitors (median peak creatine kinase level, 1433.0 U per liter and 1428.5 U per liter, respectively; P=0.79; median peak creatine kinase MB fraction, 162.8 U per liter and 160.1 U per liter, respectively; P=0.98). There were no significant interactions between the treatment assignment and either preprocedural unfractionated-heparin use or clopidogrel loading dose with respect to major adverse cardiovascular events or major bleeding (Table 4).
Among 3124 patients in whom stents were successfully implanted, the overall rate of stent thrombosis at 30 days did not differ significantly between the group that received bivalirudin and the group that received heparin plus a glycoprotein IIb/IIIa inhibitor (2.5% and 1.9%, respectively; P=0.30). However, in a prespecified analysis, within the first 24 hours, stent thrombosis occurred in 17 more patients in the bivalirudin group than in the group receiving heparin plus a glycoprotein IIb/IIIa inhibitor (1.3% vs. 0.3%, P<0.001), whereas between 24 hours and 30 days, stent thrombosis occurred in 7 fewer patients in the bivalirudin group (1.2% vs. 1.7%, P=0.28). Nonetheless, patients in whom PCI was performed and who were assigned to receive bivalirudin rather than heparin plus a glycoprotein IIb/IIIa inhibitor had lower 30-day rates of death from cardiac causes (1.8% vs. 2.8%; relative risk, 0.63; 95% CI, 0.40 to 0.99; P=0.045), major bleeding (5.1% vs. 8.5%; relative risk, 0.59; 95% CI, 0.46 to 0.77; P<0.001), and net adverse clinical events (9.2% vs. 12.2%; relative risk, 0.75; 95% CI, 0.62 to 0.92; P=0.005).

Among the 25 patients in whom stent thrombosis developed within 24 hours, 2 patients died (8.0%), including 1 in each randomized group. In the entire study cohort, of the 93 patients who died within 30 days, death was preceded by major bleeding in 26 patients, 8 of whom were in the bivalirudin group (hazard ratio for death among patients with vs. those without major bleeding, 9.12; 95% CI, 5.73 to 14.52; P<0.001) and by definite stent thrombosis in 5 patients, 1 of whom was in the bivalirudin group (hazard ratio for death among patients with vs. those without definite stent thrombosis, 5.54; 95% CI, 2.24 to 13.69; P<0.001).
Discussion

In this prospective, randomized trial involving patients with ST-segment elevation myocardial infarction who were undergoing primary PCI, treatment with the direct thrombin inhibitor bivalirudin (with glycoprotein IIb/IIIa inhibitors administered in 7.2% of the patients because of suboptimal results of the PCI), as compared with treatment with heparin plus the routine use of glycoprotein IIb/IIIa inhibitors, improved event-free survival at 30 days, owing to a significant reduction in major bleeding. The rates of major adverse cardiovascular events were similar in the two treatment groups. Bivalirudin reduced the rate of major bleeding, as classified not only by the protocol definition but also by the laboratory-based TIMI scale and the clinical GUSTO scale, and in addition reduced the rates of thrombocytopenia and blood transfusion, despite the significantly higher peak activated clotting time among patients treated with bivalirudin. Moreover, random assignment to bivalirudin alone as compared with heparin plus glycoprotein IIb/IIIa inhibitors significantly reduced the rates of death from cardiac causes and from all causes at 30 days.

The reduction in mortality with bivalirudin as compared with heparin plus glycoprotein IIb/IIIa inhibitors in the present trial may be attributable to the prevention of iatrogenic hemorrhagic complications. Previous trials have documented the independent relationship between major bleeding (with or without blood transfusions) and subsequent death.16,17,18,19 Major bleeding was a more powerful predictor of death than periprocedural myocardial infarction after PCI in the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events 2 (REPLACE-2) trial, and the reduction in bleeding with bivalirudin as compared with heparin plus glycoprotein IIb/IIIa inhibitors resulted in a trend toward reduced late mortality after PCI among the relatively low-risk patients in that study.27 In the present trial, more deaths occurred after major bleeding (26 deaths) than after reinfarction (10) or definite stent thrombosis (5). The 40% relative reduction in major bleeding in the bivalirudin group as compared with the group that received heparin plus a glycoprotein IIb/IIIa inhibitor, with similar rates of ischemic complications, may thus explain the observed improvement in survival with bivalirudin in patients with ST-segment elevation myocardial infarction, who are at higher risk than the patients in the REPLACE-2 trial. Moreover, anticoagulation with bivalirudin reduced the occurrence of severe thrombocytopenia, which has also been strongly associated with death among patients with ST-segment elevation myocardial infarction and with PCI.14,15

Among patients in whom a stent was successfully implanted, assignment to bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in 17 more episodes of stent thrombosis within the first 24 hours, representing a significant 1.0% absolute increase, which was partially offset by 7 fewer events in the patients treated with bivalirudin between 24 hours and 30 days (absolute reduction, 0.5%). The early increase in stent thrombosis with bivalirudin alone may be explained by adenosine diphosphate–induced platelet activation before maximal thienopyridine blockade of the P2Y12 receptor28 or by residual thrombin activity after the discontinuation of bivalirudin. However, although the increase in acute thrombotic events probably underlies the increased risk of major adverse cardiovascular events that was noted on the first day among patients treated with bivalirudin, the overall 30-day rates of reinfarction were not increased — 1.8% in each group — and only 2 of the 93 deaths in the study occurred after acute stent thrombosis (1 in each randomized group). The prognostic implications of acute stent thrombosis that occurs early in the hospital phase in closely monitored patients who have undergone primary PCI for ST-segment elevation myocardial infarction and that affects a previously infarcted myocardial territory may thus differ from the implications of subacute stent thrombosis or acute thrombosis that occurs after discharge from the hospital in patients who have undergone elective PCI and whose left ventricular function was well preserved. Most important, the rate of death from cardiac causes (including deaths due to stent thrombosis) among patients who were treated with heparin plus a glycoprotein IIb/IIIa inhibitor surpassed that among patients treated with bivalirudin by day 7, and by 30 days, a significant 37.9% relative reduction in death from cardiac causes (an absolute decrease of 1.1%) was seen in the group treated with bivalirudin. Further investigation is warranted to determine whether the risk of early stent thrombosis can be mitigated by treatment with more rapidly acting and potent thienopyridine agents,29,30 a longer course of bivalirudin, or both, without increasing the risk of bleeding. Pending such studies, the 1% incremental risk of stent thrombosis within the first 24 hours, with no significant difference in the rates at 30 days, must be placed in the context of the decrease in the rate of major bleeding and the subsequent 1% absolute reduction in mortality from cardiac causes that were achieved with the abbreviated use of bivalirudin (i.e., only during PCI) as compared with heparin plus glycoprotein IIb/IIIa inhibitors.

The present study has several strengths, including the enrollment of a broad cross section of patients. Nonetheless, several limitations should be noted. First, the logistic complexities of the trial necessitated an open-label design, introducing potential bias. However, compliance with the protocol procedure and the study medications was high, and the rate of provisional use of glycoprotein IIb/IIIa inhibitors in the bivalirudin group was low and similar to that in the double-blind REPLACE-2 trial.20 The relative reductions in hemorrhagic complications with bivalirudin as compared with heparin plus glycoprotein IIb/IIIa inhibitors in the present trial were also similar to those in the REPLACE-2 trial.20 Potential bias was further mitigated by the use of blinded core laboratories and a clinical-event adjudication committee that required original-source documentation for event verification. Second, a heparin bolus was administered in the emergency room to approximately two thirds of the patients, with bivalirudin most commonly started in the cardiac catheterization laboratory 30 minutes later, before PCI. Interaction testing, however, showed that administration of bivalirudin significantly reduced major bleeding independently of preprocedural administration of heparin, and preprocedural administration of heparin before bivalirudin was associated with a weak trend toward reduced major adverse cardiovascular events at 30 days. Third, the trial was underpowered for low-frequency end points, including death. However, the mechanistic underpinnings for the observed reduction in the rate of death with bivalirudin (i.e., reduced risks of bleeding, transfusion, and thrombocytopenia), in concert with the consistency of our results with those of earlier studies,20,21,22,23 provide reassurance that this finding is probably valid. Fourth, reinfarction may be difficult to detect after primary PCI, although the nearly identical peak levels of cardiac enzymes after PCI in the two treatment groups suggest that there was no difference in the rate of reinfarction. Finally, although an independent, unblinded statistical monitoring group has found no interactions between the type of stent used and the randomly assigned study drug for the primary 30-day end points, longer-term follow-up, including unblinding of the stent randomization data at 1 year, is required to evaluate thoroughly the effect of bivalirudin in patients with ST-segment elevation myocardial infarction who are undergoing primary PCI.

In conclusion, our trial shows that in patients with evolving ST-segment elevation myocardial infarction who are undergoing primary PCI, the use of bivalirudin alone, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, results in significantly reduced 30-day rates of major bleeding and increased event-free survival.

Supported by the Cardiovascular Research Foundation, with grant support from Boston Scientific and the Medicines Company.

Dr. Stone reports receiving consulting fees from Medtronic, GlaxoSmithKline, Eli Lilly, and Bristol-Myers Squibb and grant support from Boston Scientific, the Medicines Company, and Abbott Vascular. Dr. Guagliumi reports receiving consulting fees from or serving on advisory boards for Abbott Vascular and Boston Scientific and receiving grant support from Medtronic and Boston Scientific. Dr. Dudek reports receiving lecture fees from Nycomed. Dr. Gersh reports receiving consulting fees from or serving on advisory boards for AstraZeneca, Bristol-Myers Squibb, Abbott Laboratories, and Boston Scientific and having equity interest in CV Therapeutics. Dr. Pocock reports receiving consulting fees from and serving on an advisory board for the Medicines Company. Dr. Kirtane reports receiving consulting fees from or serving on advisory boards for Abbott Vascular, Medtronic, and Boston Scientific and receiving lecture fees from the Medicines Company and Alphamedica. Dr. Mehran reports receiving lecture fees from Boston Scientific and the Medicines Company. Dr. Parise reports being employed by the Cardiovascular Research Foundation. No other potential conflict of interest relevant to this article was reported.

* The investigators, institutions, and research organizations participating in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial are listed in the Appendix.

Source Information

From Columbia University Medical Center and the Cardiovascular Research Foundation, New York (G.W.S., G.D., A.J.K., H.P., R.M.); Charité Campus Benjamin Franklin, Berlin (B.W.); Ospedali Riuniti di Bergamo, Bergamo, Italy (G.G.); Silesian Center for Heart Disease, Lodz, Poland (J.Z.P.); LeBauer Cardiovascular Research Foundation and Moses Cone Hospital, Greensboro, NC (B.R.B.); Jagiellonian University, Krakow, Poland (D.D.); Rabin Medical Center, Petach Tikva, Israel (R.K.); Universitätsklinikum Schleswig-Holstein, Lübeck, Germany (F.H.); Mayo Clinic, Rochester, MN (B.J.G.); London School of Hygiene and Tropical Medicine, London (S.J.P.); and New York–Presbyterian Hospital/Weill Cornell Medical Center, New York (S.C.W.).

Address reprint requests to Dr. Stone at Columbia University Medical Center, Cardiovascular Research Foundation, 111 E. 59th St., 11th Fl., New York, NY 10022, or at gs2184@columbia.edu.

References

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27. Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention: an analysis of the REPLACE-2 trial. Am J Cardiol 2007;100:1364-1369. [CrossRef][Medline]
28. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005;111:1153-1159. [Free Full Text]
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30. Greenbaum AB, Ohman EM, Gibson CM, et al. Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEP-AMI) angiographic trial. Am Heart J 2007;154:702-709. [CrossRef][ISI][Medline]

This is the opposite of EverythingHealth. Why anyone would need this object of destruction is a mystery to me. Coming soon to a gun show near you! (Hat tip to Ray B. for this)