Evidence-based hemorheology. Does it exist? Applying evidence from clinical studies to the individual patient

1 Introduction

The practice of medicine has evolved in such a profound way that medical doctors now face substantial hurdles to keep quality of care and manage the ever more expensive resources at their disposal, together with keeping an excellent relationship with their patients.

When one thinks of medical practice, treatment is undoubtedly the most important part, if for no other reason because that is why patients go to see doctors most of the time.

Patients and doctors expect that treatments will do “more good than harm” i.e. that the benefit will overcome any potential risks associated with the treatment. And they also expect that new therapies will replace old ones (because these are inefficient, toxic, etc.).

In order to achieve this, medical decision supporting systems based on high quality clinical evidence should be available to clinicians.

2 Evidence-based medicine

One of the definitions of EBM is that it is “ ...  the integration of best research evidence with clinical expertise and patient values” [4]. In contrast to the traditional paradigm of medical practice, EBM places lower value on unsystematic clinical experience and pathophysiologic rationale, stresses the examination of evidence from clinical research, suggests that interpreting the results of clinical research requires a formal set of rules and, finally, places a lower value on authority than the traditional medical paradigm.

There are two fundamental principles that underline this approach to clinical practice [11]: 1) EBM posits a hierarchy of evidence to guide clinical decision making and 2) evidence alone is never sufficient to make a  clinical decision (clinicians must balance benefits, risks and costs associated with alternative management strategies, and consider their patients’ values and preferences).

The practice of EBM entails a logical and sequential set of steps allowing the use of evidence as a clinical decision supporting system [8]. The EBM practitioner must:

Assess the patient

Probably the most important step – or at least the most innovative – is number 4: “Critical appraise the evidence for its validity, impact and applicability”. This step is crucial to assess and appraise the methodological quality of the individual studies, by addressing 3 aspects of the study:

Internal validity (was the study well designed and conducted?)

Table 1 shows a set of user’s guides to assess a clinical trial. This can be used to find if a specific study is methodologically good and can be used to support clinical decisions.

3 External validity in clinical trials and the example of stroke treatment

Clinical researchers always want to ensure comparability of treatment and control groups. They do this through randomization, concealed allocation, correct blinding, and intention-to treat analyses in their design of the randomized controlled trial (RCT) [3].

They often spend less effort on ensuring the representativeness of trial patients to typical patients in everyday care, but this is absolutely essential if the results are to be useful to the society [10].

The most important methodological details are inclusion and exclusion criteria as well as sub-group analysis [7], because the relative risk reductions (RRRs) estimated in RCTs simply reflect the mean response of a sample to a  treatment. However, because characteristics of individual patients sometimes modulate the treatment effect, the mean response may not always be the same in different patient subgroups [9].

Of course RRR is not the only variable here, for it can only give us the relative efficacy of several interventions for the same disease if the baseline risk (also called the absolute risk) is similar. In Table 2 we give an example of the variations in benefit maintaining the RRR stable at 25% and changing the absolute risk, using stroke as an example.

Of course there are several factors influencing the baseline risk and, through it, the external validity of RCTs:

Context in which the study was conducted (hospital or outpatient)

Concerning biological differences among patients, for example, we know that aspirin for prevention of atherosclerosis (RRR for stroke and coronary disease) is greater in women than in men, that a target diastolic pressure of 80 mm Hg or less reduces events in patients with diabetes but not in the general population, that diuretics for hypertension work better in blacks compared with whites, that in elderly patients influenza vaccine for flu prevention gets a lower immune response and that in breast cancer therapy is dependent on certain gene expression [10].

These considerations apply to stroke treatment as well. And we should expect that, since stroke patients vary in terms of their demographic and clinical characteristics: some are younger, a lot may have hypertension, some may not have dyslipidemia, a few are active smokers, yet others have diabetes, etc.

Some classical papers on stroke treatment confirm this: to examine differential platelet reactivity to low-dose aspirin therapy (81 mg/d for 14 days) by sex, Becker et al. performed an RCT in 571 men and 711 women. Main outcome measure was sex differences in cyclooxygenase-1 direct and indirect platelet activation pathways before and after administration of aspirin [1]. The results showed that there were significant global decreases in platelet reactivity after aspirin therapy that were higher in women than in men.

In the ECST trial [5] 3024 men and women of any age, with some degree of uni or bilateral carotid stenosis and ischemic symptoms (in the previous 6 months had one transient or mild symptomatic ischemic vascular event) were randomized to surgery (n = 1811, 60%) or control (surgery to be avoided for as long as possible, n = 1213, 40%). With a mean follow-up of 6.1 years and main analyses done by intention to treat, several differences were observed [6]: 1) national differences in the time before patient’s investigation – from 3 weeks to 2 months – produced different absolute risk reductions, for example from 19.9% in fast centers to 7.6% in slow centers for ipsilateral ischemic stroke/death in patients presenting with 70–99% stenosis; 2) different use of ancillary surgical techniques during carotid surgery (patch angioplasty vs. intraoperative shunt) from a low percentage in Finland to a high in Germany (with possible different surgical results); 3) even though the baseline data at ECST detected no significant differences, patients who were randomized to endarterectomy but did not have surgery due to medical advice against it (surgeons or anesthetists) fared worse during a 5 year follow-up when compared with patients that were allocated to medical therapy: stroke 36% vs. 18% (p < 0.001), stroke or death 52% vs. 27% (p > 0.0001).

More recently, the American Heart Association/American Stroke Association published a synopsis of its guideline concerning stroke prevention in women, detailing the differences in risk factors for stroke in women [2]. Those were either sex-specific (pregnancy, preeclampsia, or gestational diabetes, oral contraceptive or postmenopausal hormone use) or risk factors that are stronger or more prevalent in women (migraine headache with aura, atrial fibrillation, diabetes, arterial hypertension, depression and/or psychosocial stress).

4 Conclusions

Randomized trials and systematic reviews provide the most reliable data on the effects of treatment and/or prevention.

Their internal validity (i.e. the capability of the study to minimize bias) is of paramount importance, but generalizability of the results is crucial in terms of usefulness for practice.

There is justifiable concern that external validity is often poor in a lot of clinical trials, due mostly to characteristics of patients, complexity of interventions and treatment settings.

Strict requirements for the external validity of RCTs submitted to market approval should be central in its final decision and, to facilitate matters, all RCTs should have a section entitled “To whom do these results apply?”