PP.05.07

Missing Verification of Source Data in Hypertension Research: The HYGIA PROJECT in Perspective

“…In the following, we discuss recently retracted papers in hypertension research, emphasizing the reasons for retraction, and highlight similarities between the retracted articles and the recently published HYGIA PROJECT on bedtime administration of antihypertensive drugs. 1 The PREDIMED study (Prevención con Dieta Mediterránea) was retracted and later republished in 2018. 2,3 Eighty percent of the participants in the PREDIMED study had hypertension, and a subgroup analysis showed that the beneficial effect of intervention in PREDIMED was limited to these 80% with hypertension.…”

“…In contrast, serious problems persist in relation to the HYGIA PROJECT's conclusion that bedtime administration of antihypertensive medications reduced the relative risk of composite cardiovascular events by 45% (95% CIs, 39%-50%), including a 56% (95% CIs, 44%-66%) reduction in cardiovascular mortality. 1 The Hypertension. 2021;78:555-558.…”

“…A problem with HYGIA is the large growth over time in the number of participants reported in Clinicaltrials.gov starting at 5000 participants in 2008, increasing to 15 000 in 2014, 18 000 in 2016, and ending at >19 000 in the recent article. 1 According to the methods paper, 10 700 participants would achieve 95% power to find a 20% reduction in the relative risk for cardiovascular disease at 5 years of follow-up, and an additional 3700 participants with diabetes and 3700 with chronic kidney disease would achieve 90% power to detect a 20% relative risk reduction in these subgroups, respectively. 15 First, designing a study with 90% to 95% power to detect differences in individual subgroups may be questioned from an ethical perspective.…”

“…Although presented as a prospective randomized open-label blinded end point trial in the recent article, 1 the HYGIA methods article stated 15 : "Randomization of participants to treatment-time regimen was done separately for each hypertension medication or combination being tested. Specific trials to evaluate short-term (usually 3-6 months) chronotherapeutic effects on ABPM include, among many others, patients on ramipril, irbesartan, lercanidipine, nebivolol and aliskiren.…”

“…Thus, it seems to us that HYGIA was in fact many small trials, not one large trial, as reported recently. 1 Furthermore, in a 2018 publication, HYGIA was described as a prospective evaluation of participants, without using the term randomization. 17 It is evident from the patient characteristics tables that both articles 1,17 reported data from the same study.…”