Lessons Learned From Recent Cardiovascular Clinical Trials: Part II

Vascular Biomarkers and Surrogates in Cardiovascular Disease

“…Factors that may explain their failure include the following: (1) The surrogate does not cause the disease; (2) the surrogate is involved in only 1 pathway in a multiple-pathway disease; (3) the surrogate is insensitive or not affected by the intervention's effect; and (4) the surrogate measures an effect independent from the disease process. 4,11 The Cardiac Arrhythmia Suppression Trial (CAST) illustrates the potential of biomarkers to generate incorrect assumptions in the absence of outcome data. 12 Ventricular premature beats correlate with an increased risk for cardiovascular death.…”

Validity of Vascular Calcification as a Screening Tool and as a Surrogate End Point in Clinical Research

“…25 Another recent reanalysis of scans collected in the whole MESA cohort applying a novel density score showed that it further improves risk discrimination when compared with traditional risk factors and the Agatston score. 26 The gain in discrimination by this score was highly significant but modest (area under receiver operating characteristic curve from 0.700 to 0.711), but the same score allowed a clinically meaningful (+13.9%) improvement in risk reclassification in patients at intermediate risk. Also taking into account the relevant net reclassification improvement of the Agatston score in previous analyses in MESA 11 and in the Rotterdam study, 12 it can be hypothesized that a normal (ie, zero) calcium score as measured by the new density score in patients at intermediate risk may indicate an underlying true risk level low enough to avoid prevention of cardiovascular disease by drug treatment and an elevated score an indication to start or maintain long-term treatment with statins and aspirin.…”

“…27 Mainly because of the high number of low-to-intermediate risk individuals to be enrolled (≈30 000) and the high cost, such a trial never advanced further than the design phase. Although the new calcium density score 26 or other scores can be useful for increasing the discrimination of coronary calcium, it is unlikely that in the medium-term coronary calcification will be properly tested (ie, incorporated in a clinical trial). The degree of improvement in risk discrimination registered in Criqui's reanalysis of MESA, 26 although not trivial, is per se considered insufficient to change guidelines recommendations.…”

“…Such a phenomenon is now attributed to the fact that flecanide interacts with an unexpected translation of the gene coding for the protein-myosin regulatory light chain, a protein which is a crucial component of the contraction of myocardiocytes [25] (Figure S2, IV). Another example of blatant failure is exercise tolerance by the treadmill test as a surrogate for the risk of death in patients with congestive heart failure [26]. Although increasingly applied, vascular calcification is a surrogate whose validity has yet to be proven.…”

Advancing Outcome Measures for the New Era of Drug Development in Cystic Fibrosis

“…Surrogate endpoints are generally used as a substitute for true clinical efficacy measures when the clinical benefit may not be detectable in trials of reasonable cost, duration, or size, or in proof-of-concept or safety trials (30,(46)(47)(48)(49)(50)(51)(52).…”