The Blood Pressure "Uncertainty Range" – a pragmatic approach to overcome current diagnostic uncertainties (II)

A tremendous amount of scientific evidence regarding the physiology and physiopathology of high blood pressure combined with a sophisticated therapeutic arsenal is at the disposal of the medical community to counteract the overall public health burden of hypertension. Ample evidence has also been gathered from a multitude of large-scale randomized trials indicating the beneficial effects of current treatment strategies in terms of reduced hypertension-related morbidity and mortality. In spite of these impressive advances and, deeply disappointingly from a public health perspective, the real picture of hypertension management is overshadowed by widespread diagnostic inaccuracies (underdiagnosis, overdiagnosis) as well as by treatment failures generated by undertreatment, overtreatment, and misuse of medications. The scientific, medical and patient communities as well as decision-makers worldwide are striving for greatest possible health gains from available resources. A seemingly well-crystallised reasoning is that comprehensive strategic approaches must not only target hypertension as a pathological entity, but rather, take into account the wider environment in which hypertension is a major risk factor for cardiovascular disease carrying a great deal of our inheritance, and its interplay in the constellation of other, well-known, modifiable risk factors, i.e., attention is to be switched from one's "blood pressure level" to one's absolute cardiovascular risk and its determinants. Likewise, a risk/benefit assessment in each individual case is required in order to achieve best possible results. Nevertheless, it is of paramount importance to insure generalizability of ABPM use in clinical practice with the aim of improving the accuracy of a first diagnosis for both individual treatment and clinical research purposes. Widespread adoption of the method requires quick adjustment of current guidelines, development of appropriate technology infrastructure and training of staff (i.e., education, decision support, and information systems for practitioners and patients). Progress can be achieved in a few years, or in the next 25 years

Is blood pressure reduction a valid surrogate endpoint for stroke prevention? an analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the biomarker-surrogacy (BioSurrogate) evaluation schema (BSES)

<p>Abstract</p> <p>Background</p> <p>Blood pressure is considered to be a leading example of a valid surrogate endpoint. The aims of this study were to (i) formally evaluate systolic and diastolic blood pressure reduction as a surrogate endpoint for stroke prevention and (ii) determine what blood pressure reduction would predict a stroke benefit.</p> <p>Methods</p> <p>We identified randomised trials of at least six months duration comparing any pharmacologic anti-hypertensive treatment to placebo or no treatment, and reporting baseline blood pressure, on-trial blood pressure, and fatal and non-fatal stroke. Trials with fewer than five strokes in at least one arm were excluded. Errors-in-variables weighted least squares regression modelled the reduction in stroke as a function of systolic blood pressure reduction and diastolic blood pressure reduction respectively. The lower 95% prediction band was used to determine the minimum systolic blood pressure and diastolic blood pressure difference, the surrogate threshold effect (STE), below which there would be no predicted stroke benefit. The STE was used to generate the surrogate threshold effect proportion (STEP), a surrogacy metric, which with the R-squared trial-level association was used to evaluate blood pressure as a surrogate endpoint for stroke using the Biomarker-Surrogacy Evaluation Schema (BSES3).</p> <p>Results</p> <p>In 18 qualifying trials representing all pharmacologic drug classes of antihypertensives, assuming a reliability coefficient of 0.9, the surrogate threshold effect for a stroke benefit was 7.1 mmHg for systolic blood pressure and 2.4 mmHg for diastolic blood pressure. The trial-level association was 0.41 and 0.64 and the STEP was 66% and 78% for systolic and diastolic blood pressure respectively. The STE and STEP were more robust to measurement error in the independent variable than R-squared trial-level associations. Using the BSES3, assuming a reliability coefficient of 0.9, systolic blood pressure was a B + grade and diastolic blood pressure was an A grade surrogate endpoint for stroke prevention. In comparison, using the same stroke data sets, no STEs could be estimated for cardiovascular (CV) mortality or all-cause mortality reduction, although the STE for CV mortality approached 25 mmHg for systolic blood pressure.</p> <p>Conclusions</p> <p>In this report we provide the first surrogate threshold effect (STE) values for systolic and diastolic blood pressure. We suggest the STEs have face and content validity, evidenced by the inclusivity of trial populations, subject populations and pharmacologic intervention populations in their calculation. We propose that the STE and STEP metrics offer another method of evaluating the evidence supporting surrogate endpoints. We demonstrate how surrogacy evaluations are strengthened if formally evaluated within specific-context evaluation frameworks using the Biomarker- Surrogate Evaluation Schema (BSES3), and we discuss the implications of our evaluation of blood pressure on other biomarkers and patient-reported instruments in relation to surrogacy metrics and trial design.</p