HYVET

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Beckett NS, et al. "Treatment of hypertension in patients 80 years of age or older". The New England Journal of Medicine. 2008. 358(18):1887-1898.
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Clinical Question

Among very elderly patients with hypertension, does active treatment with antihypertensives reduce the rate of fatal or nonfatal stroke when compared with placebo?

Bottom Line

Among very elderly patients (≥80 years) with hypertension, treatment with a diuretic with or without an ACE inhibitor is associated with a trend towards reduced rates of fatal and nonfatal stroke (P=0.06), and a significant reduction in the secondary outcomes of fatal stroke, all-cause mortality, and CV outcomes.

Major Points

Contemporary hypertension trials (including MRC,[1] STOP-Hypertension,[2] STOP-Hypertension-2,[3] and SHEP[4]) have generally excluded the very elderly or have had few enrollees ≥80 years. A 1999 meta-analysis of RCT data found that treatment of hypertension in this age group was associated with a statistically significant reduction in major CV events and HF but no reduction no CV mortaltiy and an increased risk of all-cause mortality.[5] As such, the optimal treatment of hypertension in this age group is unclear.

The 2008 Hypertension in the Very Elderly Trial (HYVET) enrolled 4,761 very elderly individuals predominantly from Eastern Europe or China, who had persistent hypertension, defined as systolic BP 160-199. After a 2-month placebo run-in phase, 3,845 patients were randomized to active treatment or placebo with stratification according to age and sex. Patients in the active treatment arm were given stepwise treatment with a goal BP of <150/80; those in the placebo arm received matching placebo. Stepwise treatment consisted of a diuretic (indapamide sustained release 1.5 mg daily) followed by an ACE inhibitor (perindopril 2 or 4 mg daily), the latter for those whose BP remained uncontrolled with diuretic alone. Additional non-protocol–specified antihypertensives were allowed for up to three months, after which patients were given the option of coming off study or entering open follow-up. The primary outcome was the rate of fatal or nonfatal stroke (excluding TIA). Secondary outcomes included rates of fatal stroke, all-cause mortality, and CV events. The trial was stopped early due to a 21% reduction in all-cause mortality in the active treatment group[6] With a median follow-up of 1.8 years there was a reduction in fatal or nonfatal strokes in the active treatment group, although this was not statistically significant (12.4 vs. 17.7 per 1000 person-years, P=0.06). There were also significant reductions in rates of other secondary outcomes including fatal stroke, HF, and CV events.

Some have interpreted HYVET as a negative study, since the P value for the primary outcome of stroke did not reach statistical significance. However, the study was stopped early due to a 21% reduction in all-cause mortality in the active treatment arm, and this weighs heavily on the results. It is possible that the difference in stroke rates would have reached statistical significance had the trial not been stopped early.[6] Taken together, this possibility combined with the observed reductions in all-cause mortality, HF, and other CV event rates, provides support for the treatment of hypertension in very elderly patients.

The optimal target BP among very elderly patients has yet to be defined. JNC 7 used <140/90, although admittedly that recommendation was based on weak evidence and expert opinion. In that vein, some have expressed significant concerns with over-treatment of hypertension in the elderly, citing the risks of polypharmacy and the fact that elderly patients are prone to hypovolemia and orthostatic syncope, etc. HYVET's use of a goal BP <150/90 differs from that of JNC 7, and while it does not address the issue of optimal BP goal, it provides evidence that treatment to <150/90 is better than no treatment. Results from HYVET and its ilk have led to the JNC 8 recommendation that elderly patients ≥60 years be treated to a goal of <150/90. Expert opinion recommends that for elderly patients who have achieved a target <140/90, there is no compelling reason to adjust treatment.[7]

Guidelines

JNC 8 hypertension guidelines (2014, adapted)[7]

  • In the general population ≥60 years of age, initiate pharmacologic treatment to lower BP at SBP ≥150 mm Hg or DBP ≥90 mm Hg and treat to a goal SBP <150 mm Hg and goal DBP <90 mm Hg. (Strong Recommendation – Grade A)
  • Corollary Recommendation: In the general population ≥60 years of age, if pharmacological treatment for high BP results in lower achieved SBPs (for example, <140 mm Hg) and treatment is not associated with adverse effects on health or quality of life, treatment does not need to be adjusted. (Expert Opinion – Grade E)

Design

  • Double-blind, randomized, placebo controlled-trial
  • N=3,845 (4,761 entered placebo run-in)
    • Active treatment (n=1,933)
    • Placebo (n=1,912)
  • Setting: 195 centers in 13 countries in Europe, Asia, Australia, and N. Africa
    • Four centers were closed for inaccuracies
  • Enrollment: Timeframe not specified
  • Median follow-up: 1.8 years
  • Analysis: Intention-to-treat
  • Primary outcome: Fatal or nonfatal stroke (excluding TIA)

Population

Inclusion Criteria

  • Age ≥80 years
  • Mean sitting BP reading on 2 separate occasions 1 month apart 160-199/90-109 mm Hg
  • Standing SBP ≥140 mm Hg at the visit prior to randomization

Exclusion Criteria

  • Known accelerated hypertension as evidenced by retinal hemorrhages, exudates, or papilloedema
  • Clinical CHF requiring treatment with a diuretic or ACE inhibitor
  • Creatinine >150 umol/L
  • Cerebral or subarachnoid hemorrhage in the prior 6 months
  • Terminally ill
  • Secondary hypertension
  • Gout
  • Dementia
  • Resident of a nursing home
  • Medication contraindication (eg, hyper- or hypokalemia)
  • Unable to stand or walk

Baseline Characteristics

From the active treatment group.

  • Demographics: Age 84 years, female sex 61%,
  • Physiologic measurements: Sitting 173/91 mm Hg, standing 168/89 mm Hg, HR 74 BPM, BMI 25 kg/m2
  • PMH: Orthostatic hypotension 8%, HTN 90%, isolated systolic HTN 32%, CVD 11%, stroke 7%, MI 3%, HF 3%
  • Medications: Antihypertensive medications 64%
  • CV risk factors: Smoker 6%, DM 7%
  • Laboratory measurements: Total cholesterol 5.3 mmol/L, HDL 1.35 mmol/L, creatinine 88.6 umol/L, uric acid 280 umol/L

Interventions

Those on antihypertensives at baseline had their medications stopped prior to placebo run-in. Placebo was given for ≥2 months to all patients; those meeting BP goals (see inclusion criteria above) were randomized to a group.

Active treatment
Patients were treated with the following algorithm:
  1. Indapamide SR 1.5 mg daily, then:
  2. Indapamide SR 1.5 mg daily plus perindopril 2 mg PO daily, then:
  3. Indapamide SR 1.5 mg daily plus perindopril 4 mg PO daily
Placebo
Patients received matching placebo.
Adjustments and follow-up
Patients' study drug(s) were adjusted to achieve a goal sitting BP <150/80. Patients were followed every 3-6 months. Additional hypertensive medications could be used for up to 3 months. If these were continued beyond this time frame, patients were removed from the double-blinded assignment. Additionally, those on maximum dosing of their arm with sitting BP ≥220/110 mmHg on two separate occasions were removed from their double-blinded assignment.

Outcomes

Presented as active treatment vs. placebo. P-Y is person-years.

Primary Outcome

Fatal or nonfatal stroke
12.4 vs. 17.7/1000 P-Y (HR 0.70; 95% CI 0.49-1.01; P=0.06)

Secondary Outcomes

Fatal stroke
6.5 vs. 10.7/1000 P-Y (HR 0.61; 95% CI 0.38-0.99; P=0.046)
Mortality
All-cause: 47.2 vs. 59.6/1000 P-Y (HR 0.79; 95% CI 0.65-0.95; P=0.02)
Non-CV or unknown: 23.4 vs. 28.9/1000 P-Y (HR 0.81; 95% CI 0.62-1.06; P=0.12)
CV: 23.9 vs. 30.7/1000 P-Y (HR 0.77; 95% CI 0.60-1.01; P=0.06)
Cardiac: 6.0 vs. 8.4/1000 P-Y (HR 0.71; 95% CI 0.42-1.19; P=0.19)
HF: 1.5 vs. 3.0/1000 P-Y (HR 0.48; 95% CI 0.18-1.28; P=0.14)
MI
2.2 vs. 3.1/1000 P-Y (HR 0.72; 95% CI 0.30-1.70; P=0.45)
HF
5.3 vs. 14.8/1000 P-Y (HR 0.36; 95% CI 0.22-0.58; P<0.001)
CV event
Defined as CV mortality, stroke, MI, or HF.
33.7 vs. 50.6/1000 P-Y (HR 0.66; 95% CI 0.53-0.82; P<0.001)

Adverse Events

Serious
358 vs. 448 events (P=0.001)

Criticisms

  • The high proportion of individuals in China and Eastern European countries (who are at higher risk for stroke) limits the generalizability of the outcomes.[8]
  • No report of how many patients were screened.[8]
  • Incomplete reporting of serious adverse events.[8]
  • It may be unethical to withhold antihypertensives from individuals with a history of stroke or MI.[8]
  • Trial includes explicit sponsorship by affiliate of French pharmaceutical company Servier (manufacturer of perindopril and indapamide) - "Institut de Recherches Internationales Servier".

Funding

  • British Heart Foundation
  • Institut de Recherches Internationales Servier
  • Authors with multiple financial disclosures (including consulting and speaking fees from Servier and Institut de Recherches Internationales Servier)

Further Reading

  1. MRC writers. "Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party." BMJ. 1992;304(6824):405-412.
  2. Dahlof B, et al. "Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension)." The Lancet. 1991;338(8778):1281-1285.
  3. Hansson L, et al. "Randomised trial of old and new antihypertensive drugs in elderly patients: Cardiovascular mortality and morbidity of the Swedish Trial in Old Patients with Hypertension-2 study." The Lancet. 1999;354:1751-1756.
  4. SHEP writers. "Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group." JAMA. 1991;265(24):3255-3264.
  5. Gueyffier F, et al. "Antihypertensive drugs in very old people: A subgroup meta-analysis of randomised controlled trials. INDANA Group." The Lancet. 1999;353(9155):793-796.
  6. 6.0 6.1 Appendix to 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults – Report by the Panel Appointed to the Eighth Joint National Committee (JNC 8)
  7. 7.0 7.1 James PA, et al. "2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the eighth joint national committee (JNC 8)." JAMA. 2014;311(5):507-20
  8. 8.0 8.1 8.2 8.3 Multiple authors. "Correspondence: Treatment of hypertension in the elderly." The New England Journal of Medicine. 2008;359:971-974.