Primary Care Corner with Geoffrey Modest MD: Hypertensive Treatment in Patients at Intermediate Risk

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By Dr. Geoffrey Modest

Recently 2 articles were in the NEJM from the HOPE-3 study, looking at cholesterol and blood pressure lowering in people at “intermediate-risk”, using a 2×2 factorial design. The blog Friday looked at the lipid arm of the study. This one will evaluate the hypertension group (see DOI: 10.1056/NEJMoa1600175). Study funded by Canadian Instit of Health Research and a drug company)

Details:

  • 12,705 people in 21 countries/6 continents (eligibility criteria: men ≥​ 55 yo/women ≥​ 65, with at least one of: elevated waist-to-hip ratio, history of low HDL, current or recent smoking, dysglycemia, family history of premature CVD, mild renal dysfunction; also women ≥​​60 yo with 2 or more of these criteria), without baseline cardiovascular disease (CVD) and intermediate risk (defined at annual risk of approx 1%, per the INTERHEART risk score, a score from 0-49, where the low-risk group had a score ≤ 9), randomized to candesartan 16mg plus hydrochlorthiazide 12.5mg vs placebo.
  • Median age 66, 46% female, 87% with elevated waist-to-hip ratio, mean BMI 27, 27% current/recent smokers, 6% diabetes, mean HDL 44.7 mg/dl, mean LDL 127.8, triglycerides 128.8, hs-CRP 2.0, INTERHEART risk score of 14.5, 29% Chinese/27% Hispanic/20% White/15% South Asian/2% Black, 22% on a BP med and 11% on aspirin)
  • Initial 4 week run-in period where people got both rosuvastatin and the BP med (candesartan/HCTZ) to make sure they were tolerated. the most common adverse effect was hypotension in 2%
  • First coprimary outcome: composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke; second coprimary outcome: the first one plus revascularization, heart failure, and resuscitated cardiac arrest. and, they added a secondary outcome: the second coprimary outcome plus angina with evidence of ischemia
  • Follow-up 5.6 years
  • Results:
    • Mean blood pressure at baseline was 138.1/81.9 mmHg, achieving decrease of 6.0/3.0 mmHg with active meds over placebo. By the end of the study 76.8% were taking the active med and 75.7% the placebo
    • Candesartan/HCTZ (vs placebo) resulted in:
      • First coprimary outcome: in 260 people (4.1%) vs 279 (4.4%), a nonsignificant 7% reduction [HR 0.93 (0.79-1.10, p=0.40)]
      • Second coprimary outcome: in 312 people (4.9%) vs 328 (5.2%), a nonsignificant 5% reduction [HR 0.95 (0.81-1.11, p=0.51)]​
    • ​The prespecified subgroup of those in the upper third of systolic pressure (>143.5/mean 154.1) did have significantly lower reductions:
      • The newly added secondary outcome: in 129 people (6.0%) vs 172 (8.3%), a 28% reduction [HR 0.72 (0.57-0.90)], with significant decreases in stroke (42%)
      • First coprimary outcome: 27% decrease (HR 0.73, 0.56-0.94)
      • Second coprimary outcome: 24% decrease (HR 0.76, 0.60-0.96)​
      • And, the trend of benefit in the upper third over the middle and lower thirds had p=0.02 for the first coprimary outcome and p=0.009 for the second.
    • And, there actually was a trend to harm in lowering the blood pressure in the lowest tertile (<131.5 mmHG; mean 122.2)
    • The curves pretty completely matched until about year 7, when there may have been some splaying of the curves [hard to interpret: there would need to be longer follow-up to see if that curve separation continued or this was a blip]
    • As with the lipid arm, there was no evidence of any significant interaction of the combination of meds: the results were essentially the same in those on BP meds plus placebo vs BP meds plus statin
    • No difference in new-onset diabetes, or pretty much any of the other adverse outcomes other than symptomatic hypotension, dizziness or lightheadedness in 3.4% vs 2.0% in placebo; but no difference in syncope, renal dysfunction, serum potassium levels, and no difference in serious unexpected reactions or permanent discontinuation of meds.

So, a few thoughts:

  • This population was at lower actual risk of CVD events than most prior trials [e.g. 2.2% in the SPRINT trial (see blog below) vs 0.8% for the first coprimary outcome and 0.9% for the second in the above HOPE-3 study]. These other trials also achieved more blood pressure reduction [e.g. 15/8 in comparing the intensive vs standard arms of the SPRINT trial, vs 6/3 in this study]
  • So, there may be several explanations for the lack of benefit in the HOPE-3 trial:
    • They looked at a relatively healthy group, who experienced fewer events than in most of the prior studies. So, it may be that a longer follow-up period would yield a different clinical outcomes. supporting evidence includes:
      • The fact that those at higher risk on subgroup analysis, the tertile with the highest initial blood pressure, did the best
      • The likely increasing benefit over time (at least to my looking at the graphs) could support achieving statistically significant benefit in extended follow-up
      • And, they used lower doses of meds than in other studies and achieved much lower blood pressure decreases, so the effect might well take longer to see
    • Again, my conclusion from this study, as with the prior blog on the lipid arm, is that lifestyle changes are really crucial. This population was overweight, had higher lipids than what probably really is “normal” (at least normal for a non-CVD prone population), had many smokers, how much exercise they did/not reported. And the actual achieved lowering of blood pressure was pretty small (and, per other studies, an amount achievable with pretty much any of the lifestyle interventions individually, let alone in combination)
    • In terms of meds, the study does support using meds (though secondary analysis, albeit pre-specified) for those with systolic blood pressure >143.5/mean 154.1​ (though I would still really promote the lifestyle changes first)
    • I think one of the confusing issues with blood pressure goals is that they may be different in patients taking meds vs through life-style changes. So, though the target BP in those on meds is perhaps around 140/80 in diabetics and somewhat lower in others, the targets may be even lower in those doing lifestyle changes (losing weight, lower sodium DASH-type diet, exercise, etc.). And, it is not just the adverse events/collateral damage from the meds. My guess is that the lifestyle changes actually reverse the abnormal physiology creating hypertension and are not just lowering the blood pressure through vasodilation, decreasing angiotensin, decreasing intravascular/interstitial fluid, etc., as is done by the meds.
    • So, bottom line, I think it is important not to be swayed by the guidelines promoting treatment only in those with pretty high blood pressures (>140 or >150 systolic), or be inured to the fact that so many of our patients do have supraphysiologic blood pressures but below medication-treatable. We should be pretty aggressive about even low levels of increased blood pressure (e.g., the old “mild” or “prehypertensive” groups, which as noted by a few epidemiologic studies, comprise the largest group with hypertension-related morbidity/mortality). And meds still play a role at least in intermediate risk patients with systolic BP >143 (or, mean of 154), if that level remains after optimizing lifestyle changes. And it still may be useful in those with lower levels, though we need a more extended follow-up period in those in this HOPE-3 study.

For other relevant blogs, see:

https://stg-blogs.bmj.com/bmjebmspotlight/category/hypertension/ for a review of several blogs on hypertension

https://stg-blogs.bmj.com/bmjebmspotlight/2015/11/19/primary-care-corner-with-geoffrey-modest-md-tighter-blood-pressure-control-the-sprint-trial/​ for an assessment of the SPRINT trial, which found significant benefit to a lower blood pressure target.

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