Controversy in Treating the Oldest Old With Hypertension: Is the Hypertension in the Very Elderly Trial the Final Answer?

To the Editor: Hypertension is common in the oldest-old individuals and is increasing in prevalence because of the aging population, but whether the oldest old benefit from antihypertensive treatment is unclear.1,2 The evidence is conflicting. The results from the pilot study of the Hypertension in the Very Elderly Trial (HYVET) suggested that treating the oldest old with stage two hypertension (systolic blood pressure (SBP) ≥160 mmHg) reduced the incidence of stroke but increased total mortality.3 Therefore, it is difficult for the oldest-old patients with hypertension and their providers to make decisions on antihypertensive therapy. The final results of the recently published HYVET trial4 could resolve the ongoing conflict and uncertainty about antihypertensive therapy in the oldest old, but misinterpretation of new trial results could happen, so the internal validity, effect size, and the external validity of the HYVET trial were briefly assessed, and the interpretations of the results are shared here with the readers of the Journal of the American Geriatrics Society. The purpose of HYVET was to test whether treating the oldest old with hypertension could reduce the risk of fatal and nonfatal stroke. The trial4 enrolled 3,845 patients aged 80 and older (mean age 83) with SBP of 160 mmHg or greater (mean SBP 173 mmHg) and diastolic blood pressure (DBP) of 90 to 109 mmHg (mean DBP 91 mmHg). The trial patients were randomized to indapamide (1.5 mg) or placebo, and perindopril (2 or 4 mg) or placebo could be added to achieve the target blood pressure of 150/80 mmHg. HYVET was stopped early because the results demonstrated a statistically significant reduction in total mortality (P=.02),4 although the primary outcome (fatal and nonfatal stroke) barely missed statistical significance (P=.06). Heart failure was significantly lower in the treatment group (P<.001). Although the HYVET trial meets many criteria of internal validity,5,6 its early termination could limit the internal validity of the results.7 This is especially problematic given that the stopping criteria in HYVET were not predetermined.8 Interpretation of the results with this consideration is particularly important here given that the results were contrary to the results of a previous meta-analysis2 and the pilot for HYVET.3 Statistical significance does not equate to clinically significant benefit. The magnitude of the benefit is important when applying trial results to clinical practice. For the primary outcome of HYVET,4 absolute risk reduction of stroke was 5.3 per 1,000 patient-years (P=.06), and the number needed to treat per year is 189. For total mortality, absolute risk reduction was 12.4 per 1,000 patient-years (P=.02), and the number needed to treat per year is 81. Whether these results are clinically significant is dependent on individual patients and providers. Extrapolating benefit from hypertension trials to individual elderly patients can be difficult, and the external validity of HYVET to the target population needs to be assessed. HYVET participants were healthier than the general population of the oldest old. When comparing data from HYVET participants with data from the 2006 National Health Interview Survey from the Centers for Disease Control and prevention,9 the participants in HYVET had a lower prevalence of diabetes mellitus (7% vs 18%), coronary disease (12% vs 26%), and stroke (7% vs 11%) than typical Americans aged 75 and older. It would be interesting if HYVET reported how many patients were screened for the final enrollment. By design, HYVET does not address isolated systolic hypertension (SBP≥140 mmHg and DBP <90 mmHg) and mild hypertension (SBP 140–159 mmHg or DBP 90–99 mmHg). Therefore, it is still unknown whether treating the oldest old with isolated hypertension or mild hypertension is beneficial. That treating hypertension in the oldest old is not simple. Some important outcomes such as quality of life of HYVET participants have not been reported. Drug-related adverse effects are another important consideration. Elderly patients often have orthostatic hypotension, postprandial hypotension, dizziness, and falls. The oldest old might have more symptoms if their blood pressure were lowered to or below 140/90 mmHg, the goal of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Overall, HYVET is an important and valid study, but its applicability to most of the oldest old with isolated systolic or mild hypertension is limited. Debates on how to measure the quality of care for this group of elderly patients will continue.10 A new trial that targets isolated systolic hypertension and mild hypertension in the oldest old is urgently needed. Conflict of Interest: Dr. Cheng is a recipient of the Geriatric Academic Career Award from Department of Human Health. Author Contributions: Both authors are contributed equally to this letter. Sponsor's Role: Not applicable.