By Nortin Hadler, MD

In a single generation, the evidentiary basis for the practice of medicine has grown from a dream to a massif. No longer need physicians rely solely on experience and opinion in formulating diagnostic and therapeutic approaches to the care of the patient.

However, for any given clinical challenge, the available science is never flawless, monolithic or comprehensive, nor is it likely to be durable in the face of newer studies.

The international medical community has mounted two approaches to sorting the wheat from the chaff: One targets the doctor in convening committees to formulate guidelines for patient care. The other targets the patient for evaluating options, so-called informed medical decision making. Both approaches are now sizable undertakings clothed in organizational imprimaturs and girded by self-promotion.

But they are largely parallel undertakings with work products that can cause considerable cognitive dissonance on the part of the patient and the physician. In a recent article in the British Medical Journal [1] the Guideline Development Group convened by the National Institute for Health and Clinical Excellence (NICE) summarized the thinking behind the guidance it was offering regarding the management of STEMI. This is an object lesson in such cognitive dissonance.

STEMI is the acronym denoting an acute coronary syndrome with ST-segment elevation on electrocardiogram.  STEMI is commonly thought to be the best indication for PCI; angioplasty with or without stenting. For all other forms of acute coronary syndromes that have been subjected to scientific testing for efficacy PCI has proved disappointing [2]. The same can be said for stable angina although PCI is still considered reasonable when all else fails.

But in the setting of an acute STEMI, this guidance document from NICE is in step with guidelines promulgated by other agencies [3] recommending urgent invasive revascularization whenever possible.

The basis for NICE guidance on STEMI:

The actual wording of the recommendation is to “offer coronary angiography, with follow-on primary PCI if indicated, as the preferred coronary reperfusion strategy for people with acute STEMI if: presentation is within 12 hours of onset of symptoms and primary PCI can be delivered within 120 minutes of the time when fibrinolysis can be given.” The term “offer” denotes that the Guideline Development Group is “confident that, for the vast majority of patients, an intervention will do more good than harm, and be cost effective [4].” Regardless of the patient’s age, comorbidities, or cardiac status if the patient has an acute STEMI, don’t dither; get thee to the catheterization suite. “Evidence from an individual patient data meta-analysis” supports no other option.

Of course, the recommendation to “offer” PCI in the setting detailed above is hardly an exercise in informed medical decision making. The patient is in pain, scared to death and not likely to take comfort in analytic thinking. This recommendation underlies national agendas to cleave minutes of the time to get to the hospital and seconds off the door-to-balloon time. It influences the thinking of doctors, policy makers, and the public regarding the treatments of all acute coronary syndromes.

Is the “offer” based on science, prescience or presumption?

In the full report of the Guideline [4], the Guideline Development Group is quick to admit, “No specifically designed randomized controlled trial or observational study has addressed the issue of the extent to which primary PCI-related time delay (and other factors such as presentation delay and a person’s risk profile) diminishes the advantages of primary PCI over fibrinolysis.” This is an extraordinary admission from a Group that insists that PCI be “offered” to any patient suffering an acute STEMI.

If angioplasty, with or without stenting, was a pharmaceutical instead of a procedure (device), is there any regulatory agency that would license it without a randomized controlled trial demonstrating adequate efficacy?

The “STREAM Trial” was a multicenter randomized controlled trial supported by Boehringer Ingelheim. The results, known to the Guideline Development Group [5], were published in the New England Journal of Medicine 3 months before the Guideline was issued [6]. Nearly 2000 patients were randomized to either PCI or fibrinolysis 1-3 hours after the onset of symptoms of their STEMI. The primary endpoint was a composite of death, shock, congestive heart failure or reinfarction up to 30 days.

This endpoint occurred in 12.4% of the patients treated with fibrinolysis and 14.3% in the primary PCI group. This is not a statistically or clinically significant difference. Neither was the difference in each component of the composite outcome. By the way, almost all patients subjected to PCI were rewarded with stent placement – but to no discernible avail.

Furthermore, earlier randomized controlled trials of this nature are similar in design and result to STREAM [7]. The Development Group found none of these trials persuasive.

There is no perfect trial given the vagaries of the clinical arena. The STREAM authors themselves want readers to consider their trial no more than exploratory and emphasize that their design excluded STEMI patients with symptoms for <1 hour. They refer to studies that are far less sound in design but that suggested the contrary result, such as the Danish (DANAMI) observational studies.

The Danish took advantage of their national registry to compare outcomes as a function of the time it took to transfer the patient from the community to a hospital with the facilities to perform PCI. It turned out that the sooner the better. However, there are many biases in such a study design, not the least of which is that the more stable the patient the more likely they were to be transferred expeditiously [8].

Perhaps that explains the seemingly contrary result when the American CathPCI Registry was analyzed [9]. Based on the records of over 95,000 patients with STEMI, between 2005 and 2009, there had been a decline in the delay in getting the patient from arrival at hospital to PCI from about 90 minutes to 60 minutes. But there has been no discernible decline in risk-adjusted in-hospital or 30-day mortality.

The conclusion of the authors of this study, and of the accompanying commentary [10], as with the STREAM authors, was there was still nothing wrong with the theory. After all, in animal experiments the window of time in which ischemia from coronary artery occlusion is reversible is this brief. Hence, while we have done well reducing the door-to-balloon time, we still need to reduce the delay from the onset of symptoms to treatment.

Data torturing

Given this level of conviction, the Guideline Development Group felt compelled to probe the entire body of science before dismissing PCI for acute STEMI as but another common practice that is advisable based only on “experience and opinion”, the rationale for nearly all correlative recommendations in the Guideline. In the past several decades, biostatisticians have developed methodologies that make such analyses commonplace.

The clinical literature is replete with “systematic reviews” and “meta-analyses” usually undertaken because the particular literature is robust but the results are varied – often characterized by small-effects that are often contradictory. Trying to tease valid insights from such a jumble is a daunting task that some consider more telling in the undertaking than in the result; if one need resort to such an exercise, it is highly unlikely that there is any clinically meaningful truth in hiding. But many a statistician does not share my compunction, including those employed by NICE and most agencies promulgating guidelines.

As stated above, the Guideline recommendation is “based on evidence from an individual patient data meta-analysis.” This was a complicated exercise [4]. The investigators established criteria for studies they considered likely to be informative, studies comparing PCI with fibrinolysis for STEMI in various clinical settings. Many assumptions were in play since none of the studies directly addressed the hypothesis regarding the timing of PCI for STEMI. Rather than analyze individual studies, they culled 12 meta-analyses from the literature. However, they decided that they would base their meta-analysis of these meta-analyses on the 6 that allowed for a calculation of the relative reduction in the risk for an adverse outcome if PCI was delayed. Of the other meta-analyses, 4 were excluded because they “only reported absolute risk reduction.”

I understand their reasoning from the perspective of biostatistics. From a clinical perspective, these are disconcerting criteria upon which to base any recommendation. Absolute risk reduction is critical to informed medical decision making. For example, the information that an intervention leads to a 50% reduction in the risk of death is inadequate without the absolute numbers.

One’s ears would perk up if this is based on a randomized controlled trial with 1000 patients, where 200 were dead within a year untreated, but only 100 if treated. But one might think twice if it was 20 dead untreated and only 10 treated. One might wonder if the latter result was reproducible. One might wonder if it was worth the hassle and risks of treatment in the first place since the chances of survival were nearly as great without the intervention. Remember, this is not a lottery. We are talking about a controlled trial. It is as if one were to be nearly as likely to win the lottery without buying a ticket.

Realize that randomized controlled trials of PCI versus fibrinolysis cannot avoid the same bias that plague the observational studies; it’s more challenging to undertake PCI quickly in the unstable patient than to expeditiously inject a fibrinolytic agent. Despite this bias, the absolute risk reduction from intervening within an hour of arrival at the hospital in the 4 meta-analyses excluded from the Guideline analysis is far from dramatic:

Study 1: The absolute survival benefit of angioplasty compared with fibrinolysis decreased by 0.24% for every additional 10-minute delay [11].

Study 2: When all 20 studies were included, a non-significant trend was seen between primary PCI-related time delay and mortality between primary PCI and fibrinolytic therapy (n = 7,239; absolute 0.5% decrease for every 10-minute delay; p <0.22), with equipoise at 88 minutes [12].

Study 3: As PCI-related time delay increased, the absolute mortality reduction favoring primary PCI decreased significantly (n = 7,419; 0.94% decrease for every additional 10-minute delay; p = 0.006) [13].

Study 4: When the trials with the longest and shortest delays were excluded, the benefit of PCI…was nullified after a delay of 62 min, and every additional 10-min delay produced a 1.1% increase in mortality (p =0.01) [14].

So if we whisk a hundred or more patients with a very acute STEMI off to the PCI instead of injecting a lytic agent, we may do some special good for one for all that effort. Of course, PCI is has significant risks that are more frequent than that.

Doc, what would you do if you were me?

This query is the essence of the doctor-patient relationship in the 21^st Century. It demands an understanding of the limitations of the informative science and an appreciation of the values of the patient. And it demands a trusting and empathic therapeutic contract. The goal is simply and solely to benefit the individual patient.

Guidelines need to be re-named; at best they are a statement of the degree to which a small number of individuals, always handpicked individuals, can reach a consensus regarding the inferences that can be drawn from the science relevant to a particular clinical challenge. This is another form of clinical contract designed to benefit a group or population patients but driven by the values of the handpicked individuals and often by the values of the pickers. It’s hard to imagine that such a contract is without conflicts of interest, and easy to demonstrate their likelihood – particularly easy in cardiology [15].

As a clinician, I am neither surprised nor outraged; could one expect anything more of a small group with a vested interest in the topic. These are the considerations that should weigh heavily in discussions of health care finance and health care reform. If some august governmental body were to declare interventional cardiology and cardiovascular surgery for coronary artery disease a failed experiment that should no longer be supported, I would applaud and display the scientific basis for the shift in policy.

But that’s not my goal in this analysis. This is an object lesson. After  eons when physicians had only “opinion and experience” to offer the patient, we have so much more. We can turn the clinic into a place of enlightened dialogue between patient and physician. We can meld the few scientific certainties and the many clinical uncertainties into options that serve the needs of the patient – the one individual who is entitled to the wherewithal to make whatever decision is most suitable [16].

Nortin Hadler, MD, is a professor of Medicine and Microbiology at the University of North Carolina – Chapel Hill.  Much of his scholarship has focused on issues in employee health and safety. Hadler is the author of numerous articles and essays and a series of a popular books on the state of medicine today. His most recent work, Citizen Patient, was published earlier this year.

References

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2. Navarese EP, Gurbel PA, Andreotti F, et al. Optimal timing of coronary invasive strategy in non-ST-segment elevation acute coronary syndromes. A systematic review and meta-analysis. Ann Intern Med 2013; 158: 261-70.
3. Krumholz HM, Anderson JL, Bachelder BL, et al. ACC/AHA 2008 performance measures for adults with ST-elevation and non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures. Circulation 2008;118:2596-2648.
4. National Institute for Health and Care Excellence. The acute management of myocardial infarction with ST-segment elevation. (Clinical guideline 167) 2013. http://guidance.nice.org.uk/CG167
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14. Hadler NM. The Citizen Patient. Reforming health care for the sake of the patient, not the system. University of North Carolina Press, 2013.
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