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From efficacy to safety concerns: A STEP forward or a

step back for clinical research and intercessory 

prayer?: The Study of Therapeutic Effects ofIntercessory Prayer (STEP)Mitchell W. Krucoff, MD, FACC, Suzanne W. Crater, RN, ANP-C, and Kerry L. Lee, PhD Durham, NC 

bHistorically one is inclined to look upon science

and religion as irreconcilable antagonists. . .

I maintain that cosmic religious feeling is the

strongest and noblest incitement to scientific

research . . . Q  Einstein, A. The World  as I See It 

Systematic study of intangible bnoetic1 Q  or bfrontier 2  Q 

healing methods such as intercessory prayer, defined as

b widely practiced therapeutics with no plausible mech-

anism,2  Q  is an area of great public and scientific interest,

as well as of great controversy.3,4  Although prayer is one

of the most ancient of healing practices, the scientific

literature studying prayer is still quite young. In this issue

of the journal, Benson et al report the sixth and largest

prospective, randomized, placebo-controlled study of 

distant prayer cardiovascular patients1,5-8 in the STEP.

It is not surprising that so much of the study of healing

effects of prayer would be pursued in the bhigh tech  Q 

 world of cardiovascular car e,9

as heart disease invariably faces patients, families, and loved ones with the

immediate prospect of death, myocardial infarction, and

stroke, either from the disease or from the procedures

associated with its treatment. In this setting, the cultural

practices of patients, families, and medical staff fre-

quently include the personal use of prayer or solicitation

of prayer with therapeutic intention from other devo-

tees. Previous trials include 3 studies in coronary care

unit populations5-7 and 2 in percutaneous coronary 

intervention populations.1,8 STEP is the first report of 

distant intercessory prayer in patients undergoing

coronary artery bypass surgery.

In the absence of mechanistic insight, attention to thequality of clinical trials science used for the study of an

emotionally and culturally charged btherapy  Q  such as

intercessory pray er 10 becomes critical to the interpret-

ability of study findings and to the utility of such findings

to the practice of medicine. In this regard, the STEP

investigators are to be congratulated for reporting a

large, prospective multicenter study using classic clinical

end points (as defined by the Society of Thoracic

Surgeons database), with rigorous quality control in the

study’s conduct and a thoughtful and rigorous statistical

analysis plan including sensitivity analyses for missing

data. The STEP study is unequivocally a landmark in the

peer review literature on this topic.

 A few study design questions can, nonetheless, be

raised. bConstraints on how intercessory prayer was

provided Q  excluded all but a handful of prayer groups

and may have affected the actual prayers performed by 

those groups. As the authors point out, although on

the one hand this gave rigor to the prayer method

used, it may also have impacted the quality of the

prayer itself and leaves open questions about thegeneralizability of the STEP findings relative to other 

intercessory prayer approaches.

The primary analytic plan also represents some

fundamental trade-offs, as is almost always the case in

clinical trial planning. As the authors carefully explain,

their prospective plan compared Group 1 (prayer but

uncertain) versus Group 2 (no prayer but uncertain)

and independently compared Group 1 (prayer but

uncertain) with Group 3 (prayer and certain). This

structure allows a single feature to be assessed for 

efficacy in each comparison: the effect of adding prayer 

in a double-blind (Group 1 vs Group 2) and the effect of 

certainty versus uncertainty in patients receiving inter-cessory prayer (Group 1 vs Group 3). The trade-offs of 

adopting this analytic plan, however, especially in light

of the data, are relatively unexplored in discussion by 

the authors, and although rethinking the analysis plan

after the data have been examined may be fatally biased,

some discussion of the absence of even secondary 

analyses of all exposure to prayer versus placebo or a

3-way comparison model across the studied groups

might have been helpful to readers.

Defining other features of the study cohort might also

have been revealing. Patients enrolled in the double-

blinded arms might still be inclined to guess or even

From the Duke University Medical Center, Duke Clinical Research Institute, Durham, NC.

Submitted June 27, 2005; accepted June 28, 2005.

Reprint request: Mitchell W. Krucoff, MD, Duke University Medical Center, VAMC, 508 

Fulton Street, Room A3012, Durham, NC 27705.

E-mail: kruco001@mc.duke.edu 

Am Heart J 2006;151:762-4.

0002-8703/$ - see front matter 

n 2006, Published by Mosby, Inc.

doi:10.1016/j.ahj.2005.06.031

Editorial

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believe they know what their treatment assignment

actually was. In elective percutaneous coronary inter-

 vention patients enrolled in a double-blinded prayer 

study, about two thirds of patients not actually assigned

prayer believed that they were.8 In STEP, documentation

of what patients were actually assigned versus what they believed they were assigned in Groups 1 and 2 (uncertain

prayer and uncertain no prayer, respectively) might have

provided insight into the possible role of a placebo effect.

 With excellent clinical science, overall, and a handful

of design criticisms inevitable in clinical studies, the

most striking element of the STEP report is in the

interpretation of the study results showing significantly 

 worsened outcomes in one of the experimental arms.

 While presenting these results clearly and noting them

in discussion, the investigators take an almost casual

approach toward any explanation, stating only that it

bmay have been a chance finding. Q  It is rather unusual to

attribute a statistically significant result in the primary 

end point of a prospective, multicenter randomized trial

to bchance. Q  In fact, such attribution is antithetical to the

 very definition of what a error and statistical certainty 

imply: that the worse outcomes are almost certainly 

related to the therapy and not the play of chance. If the

results had shown benefit rather than harm, would we

have read the investigators’ conclusion that this effect

bmay have been a chance finding, Q  with absolutely no

other comments, insight, or even speculation?

 A more straightforward interpretation might have

been that patients who were asked to hide a clinical

study treatment assignment from their bedside staff  and b who were certain that intercessors would pray for them

had a higher rate of complications, Q  that is, that this

construct appears to do harm. Literally, from the analysis

plan, this bharm Q  is measured relative to the double-

blinded prayer cohort (Group 3, prayer and certain vs

Group 1, prayer and uncertain), although Group 1 itself 

had worse absolute rates of complications than the

standard care, Group 2 (no prayer, uncertain). Second-

ary analyses of the data that might help try to understand

 whether the stress on the patient in the preoperative

period was the key detrimental factor or whether it was

the intercessory prayer per se that may be unsafe in this

patient population were not performed. If spaceconstraints limited the opportunity to present secondary 

analyses, at least some indication of their potential might

have been commented upon.

Compared with the very high level of study design,

conduct, and analysis, the STEP investigators’ interpre-

tation of the study results appears to reflect more the

cultural bias that healing prayer could only seriously be

explored for effectiveness, not for safety issues. Cultur-

ally, bharm Q  resulting from prayer is generally ascribed to

overtly bnegative Q  prayer, such as h ateful prayer,

 voodoo, spells, or other black magic.11 Positively 

intended intercessory prayer is considered a priori to be

only capable of doing good, if it does anything at all. But

this cultural dichotomy is medically problematic and

ethically unacceptable in the setting of a clinical trial

performing structured experimentation on human sub-

 jects. Particularly in the absence of mechanistic insight,

outcome researchers must be vigilant in asking thequestion of whether a well-intentioned, loving, heartfelt

healing prayer might inadvertently harm or kill vulner-

able patients in certain circumstances. Although the

STEP data do not actually prove that prayer had an

untoward effect on coronary artery bypass graft patients,

to simply write off significantly worse outcomes in one

of the experimental arms as the play of chance is in

striking contrast to all the other measures the STEP

coordinating center and investigators took to ensure the

safety of participating patients and quality of the study 

data. Thus, although the STEP investigators used every 

appropriate means of protection of the human subjects

 who participated in their study, the casual approach to

the question of safety in the final data interpretation

promotes a dangerously ambiguous message to inves-

tigators who might be inclined to do research in this area

in the future.

In the study of noetic therapies and, perhaps most

particularly, in the study of intercessory prayer, unique

issues of personal sensitivity, underlying assumptions on

the part of  the investigators, and ethical obligations

abound.9  A pproaching a patient to participate in a

prayer study before a procedure could inadvertently 

alarm a patient, b You mean I’m so sick that I might need

prayer? Q 

Even the assumption that standard clinicaloutcome measures are appropriate end points for 

studies of prayer must be carefully examined; for 

instance, many prayers for the sick contain the implicit

objective of easing the passage of the spirit out of the

body, an outcome which, by Society of Thoracic

Surgeons definition, would be coded as death.

In a randomized single-center study  of prayer in

coronary care unit patients, Harris et al6  w ere supported

by the hospital institutional review board (IRB) to

conduct the study without obtaining informed consent

from patients. The concern leading to this design

element was a deep and thoughtful one: patient

awareness that a study of prayer was ongoing mightprofoundly change the spiritual landscape being studied.

The IRB was duly consulted, and the study design was

approved based on the IRB’s conclusion that this therapy 

bcould not possibly do harm. Q  Although for personal or 

cultural practices assumptions of Divine benevolence

may be both relevant and satisfactory, for clinical

research, such an assumption could only be considered

scientifically naive as in the history of medicine there has

never been a healing remedy that was actually effective

 without having potential side effects or toxicities.

Rigorous thinking is not an indictment of prayer or 

prayer’s potential healing power. Rather, it is respect

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for the complex, redundant, and relatively frail aspects

of human physiology in the setting of coronary 

revascularization. In medical school, almost 30 years

ago, we were taught to define health as a state of 

equilibrium and to understand disease as a fundamental

disequilibrium. Protocol addition of an influence we donot mechanistically understand into a physiologic or even

bmind-body-spirit  Q  disequilibrium such as heart disease

obliges open minded clarity in interpreting the results,

even if the results are not what we intend or expect. Both 

ethically and scientifically, this approach should be no

different for the clinical study of intercessory prayer than

for any other novel therapeutic.

In STEP, the safety of patients and related ethical

obligations to study subjects were conducted, like so

much of the study methodology, at the very highest

level. Informed consent was required, and data and

safety monitoring board oversight was provided. The

data, on the other hand, proved to be counterintuitive.

The assumption imbedded in the analysis plan was that

blinded prayer would be effective and unblinded prayer 

even more effective, with expected complication rates

of 50% in the standard care group, 40% in the blinded

prayer group, and 30% in the unblinded prayer group—

exactly the opposite of what was actually observed. In

the interpretation of obviously counterintuitive findings

as b what may have been chance, Q  the STEP investigators

have allowed cultural presumption to undermine

scientific objectivity. Leading researchers such as the

STEP team should be underlining the imperative that

mechanistically undefinedb

frontier  Q 

therapy research—even well intentioned intercessory prayer—must be

scrutinized for safety issues at an equal or even higher 

level than efficacy measures if medically important and

useful knowledge in this arena is to truly step forward.

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American Heart Journal

April 2006764 Krucoff, Crater, and Lee