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A call for improved reporting on serious adverse events in clinical trials

Schutte, Aletta E.

doi: 10.1097/HJH.0000000000002194
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Hypertension in Africa Research Team (HART), Medical Research Council Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa

Correspondence to Professor Aletta E. Schutte, PhD, Hypertension in Africa Research Team (HART), Medical Research Council Unit for Hypertension and Cardiovascular Disease, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa. Tel: +27 18 299 2444; e-mail: alta.schutte@nwu.ac.za

Following SPRINT (Systolic Blood Pressure Intervention Trial) [1], several investigations including systematic reviews and meta-analyses confirmed that reducing SBP to levels below 140 mmHg markedly reduces the risk of cardiovascular disease and all-cause mortality. In a recent systematic review, Bundy et al. [2] included 42 trials (including 144 220 patients) and showed that randomized groups with a mean achieved SBP of 120–124 mmHg had a hazard ratio for major cardiovascular disease of 0.71 (95% confidence interval 0.60–0.83) compared with groups with a mean achieved SBP of 130–134 mmHg; a hazard ratio of 0.58 compared with those with an achieved SBP of 140–144 mmHg; and a hazard ratio of 0.36 compared with those with a mean achieved SBP of at least 160 mmHg. Similar findings were reported for all-cause mortality. These and other reports call for more intensive control of SBP among adults with hypertension.

Yet in the shadow of this clear benefit of intensive blood pressure control, physicians should weigh the benefit against the risk of serious adverse events – particularly the frail and elderly. A serious adverse event is harmful, fatal or life-threatening, resulting in clinically significant or persistent disability, or requires or prolong hospitalization [3]. With intensive blood pressure lowering such events may include syncope, injurious falls, fractures, acute kidney injury, angio-edema, and hyperkalemia amongst others.

When estimations of excess serious adverse events for all eligible US adults were made by applying the SPRINT intensive blood pressure regimen to the National Health and Nutrition Examination Survey (NHANES) database, 56 100 episodes of hypotension, 34 400 episodes of syncope, 43 400 serious electrolyte disorders and 88 700 cases of acute kidney injury were anticipated per year, compared with standard treatment [4]. These events are balanced by the potential prevention of 107 500 deaths per year. With few other interventions available that could have such an overwhelming public health impact, closer inspection is required to identify cases where serious adverse events are to be expected. With more clarity on patients at risk, careful patient selection can be made prior to implementing intensive treatment.

However, the burden of adverse events because of intensive BP-lowering treatment has received limited systematic analysis, because of two major reasons [5]: the belief that the weight of adverse effects is trivial compared with reduced morbidity and mortality, and the different manners in which adverse events are reported in randomized clinical trials (RCTs). These challenges make quantitative systematic analyses very difficult.

Indeed, a critical limitation in many RCTs reporting serious adverse events is the extremely variable way in which such events are reported. A recent meta-analysis by Thomopoulos et al. [5] on hypertension treatment-attributed adverse events, found that only 15 among 50 RCTs reported all adverse events. Some articles selectively reported adverse events, and often no distinctions were made between mild or scarcely relevant and severe adverse events. There is also a variety of the way adverse events have been ascertained in RCTs. This poor-quality reporting of harmful events in RCTs was found despite an extension of the CONSORT (Consolidated Standards of Reporting Trials) statement in 2004 to improve such reporting, with 10 specific recommendations [3].

In this issue of the Journal of Hypertension, Frey et al.[6] also attempted a meta-analysis to assess the frequencies of serious adverse events associated with different BP targets. However, because of the methodological heterogeneity in reporting serious adverse events, a meta-analysis was not feasible. Studies used different definitions of adverse events, different methods of recording adverse events, diverse follow-up times and study populations. By systematically reviewing seven RCTs (>25 000 participants), they found that intensive treatment was associated with a significant increase in treatment-related adverse events, such as dizziness, syncope, acute kidney injury and hypotension, compared with moderate antihypertensive treatment. Upon their inability to conduct a planned meta-analysis, the authors reiterated the overall need to have precise, uniform definitions of serious adverse events in general, but also for each single adverse event in particular. They added onto the extension of the CONSORT statement [3], by compiling a table with specific descriptors and descriptor details to be included in manuscripts reporting on RCTs. For instance, the authors indicate that the manuscript's ‘Methods’ section should include specifications on defining each type of serious adverse event (with descriptions on grading and assessments), and how event data was collected (how, when, by whom and how many times). In the ‘Results’ section, there should be clear reporting on the number of patients affected (for each type of event), achieved BP at time of event, recurrent events, grading or severity. Their call for improved standardized methods of recording and reporting is urgent in order to accurately compare findings from different trials, and to identify patients in which intensive blood pressure lowering may be more likely to result in adverse events.

Only when addressing these shortcomings in reporting serious adverse events, will we be able to compare the benefit-to-harm ratios of intensive blood pressure lowering more effectively.

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ACKNOWLEDGEMENTS

Sources of support: The author receives financial support from the South African Research Chair Initiative (SARChI) from the National Research Foundation and Department of Science and Technology of South Africa, as well as the South African Medical Research Council.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES

1. Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373:2103–2116.
2. Bundy JD, Li C, Stuchlik P, Bu X, Kelly TN, Mills KT, et al. Systolic blood pressure reduction and risk of cardiovascular disease and mortality: a systematic review and network meta-analysis. JAMA Cardiol 2017; 2:775–781.
3. Ioannidis JP, Evans SJ, Gotzsche PC, O’Neill RT, Altman DG, Schulz K, et al. CONSORT Group. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004; 141:781–788.
4. Bress AP, Kramer H, Khatib R, Beddhu S, Cheung AK, Hess R, et al. Potential Deaths Averted and Serious Adverse Events Incurred From Adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) Intensive Blood Pressure Regimen in the United States: projections from NHANES (National Health and Nutrition Examination Survey). Circulation 2017; 135:1617–1628.
5. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering treatment in hypertension: 8. Outcome reductions vs. discontinuations because of adverse drug events - meta-analyses of randomized trials. J Hypertens 2016; 34:1451–1463.
6. Frey L, Gravestock I, Pichierri G, Steurer J, Burgstaller JM. Serious adverse events in patients with target-oriented blood pressure management: a systematic review. J Hypertens 2019; 37:2135–2144.
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