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Hypertension guidelines: Treat patients, not numbers

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SPRINT caveats and limitations

SPRINT15 was stopped early, after 3.26 years instead of the planned 5 years. The true risk-benefit ratio may have been different if the trial had been extended longer.

In addition, SPRINT used automated office blood pressure measurements in which patients were seated alone and a device (Model 907, Omron Healthcare) took 3 blood pressure measurements at 1-minute intervals after 5 minutes of quiet rest. This was designed to reduce elevated blood pressure readings in the presence of a healthcare professional in a medical setting (ie, “white coat” hypertension).

Many physicians are still taking blood pressure manually, which tends to give higher readings. Therefore, if they aim for a lower goal, they may risk overtreating the patient.

About 50% of patients did not achieve the target systolic blood pressure (< 120 mm Hg) despite receiving an average of 2.8 antihypertensive medications in the intensive-treatment group and 1.8 in the standard-treatment group. The use of antihypertensive medications, however, was not a controlled variable in the trial, and practitioners chose the appropriate drugs for their patients.

Diastolic pressure, which can be markedly lower in older hypertensive patients, was largely ignored, although lower diastolic pressure may have contributed to higher syncope rates in response to alpha blockers and calcium blockers.

Moreover, the trial excluded those with significant comorbidities and those younger than 50 (the mean age was 67.9), which limits the generalizability of the results.

JNC 8 VS SPRINT GOALS: WHAT'S THE EFFECT ON OUTCOMES?

JNC 84 recommended a relaxed target of less than 140/90 mm Hg for adults younger than 60, including those with chronic kidney disease or diabetes, and less than 150/90 mm Hg for adults 60 and older. The SPRINT findings upended those recommendations, showing that intensive treatment in adults age 75 or older significantly improved the composite cardiovascular disease outcome (2.59 vs 3.85 events per year; P < .001) and all-cause mortality (1.78 vs 2.63 events per year; P < .05) compared with standard treatment.17 Also, a subset review of SPRINT trial data found no difference in benefit based on chronic kidney disease status.18

A meta-analysis of 74 clinical trials (N = 306,273) offers a compromise between the SPRINT findings and the JNC 8 recommendations.19 It found that the beneficial effect of blood pressure treatment depended on the patient’s baseline systolic blood pressure. In those with a baseline systolic pressure of 160 mm Hg or higher, treatment reduced cardiovascular mortality by about 15% (relative risk [RR] 0.85; 95% confidence interval [CI] 0.77–0.95). In patients with systolic pressure below 140 mm Hg, treatment effects were neutral (RR 1.03, 95% CI 0.87–1.20) and not associated with any benefit as primary prevention, although data suggest it may reduce the risk of adverse outcomes in patients with coronary heart disease.

OTHER TRIALS THAT INFLUENCED THE GUIDELINES

Important clinical trials that influenced revised blood pressure guidelines
SPRINT was important for refining the appropriate targets for blood pressure treatment, but several other trials also influenced the ACC/AHA guidelines (Table 3).20–24

SHEP and HYVET (the Systolic Hypertension in the Elderly Program20 and the Hypertension in the Very Elderly Trial)21 supported intensive blood pressure treatment for older patients by reporting a reduction in fatal and nonfatal stroke risks for those with a systolic blood pressure above 160 mm Hg.

FEVER (the Felodipine Event Reduction study)22 found that treatment with a calcium channel blocker in even a low dose can significantly decrease cardiovascular events, cardiovascular disease, and heart failure compared with no treatment.

JATOS and VALISH (the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients23 and the Valsartan in Elderly Isolated Systolic Hypertension study)24 found that outcomes were similar with intensive vs standard treatment.

Ettehad et al25 performed a meta-analysis of 123 studies with more than 600,000 participants that provided strong evidence supporting blood pressure treatment goals below 130/90 mm Hg, in line with the SPRINT trial results.

BLOOD PRESSURE ISN’T EVERYTHING

Other trials remind us that although blood pressure is important, it is not the only factor affecting cardiovascular risk.

HOPE (the Heart Outcomes Prevention Evaluation)26 investigated the use of ramipril (an ACE inhibitor) in preventing myocardial infarction, stroke, or cardiovascular death in patients at high risk of cardiovascular events. The study included 9,297 participants over age 55 (mean age 66) with a baseline blood pressure 139/79 mm Hg. Follow-up was 4.5 years.

Ramipril was better than placebo, with significantly fewer patients experiencing adverse end points in the ramipril group compared with the placebo group:

  • Myocardial infarction 9.9% vs 12.3%, RR 0.80, P < .001
  • Cardiovascular death 6.1% vs 8.1%, RR 0.74, P < .001
  • Stroke 3.4% vs 4.9%, RR = .68, P < .001
  • The composite end point 14.0% vs 17.8%, RR 0.78, P < .001).

Results were even better in the subset of patients who had diabetes.27 However, the decrease in blood pressure attributable to anti­hypertensive therapy with ramipril was minimal (3–4 mm Hg systolic and 1–2 mm Hg diastolic). This slight change should not have been enough to produce significant differences in clinical outcomes, a major limitation of this trial. The investigators speculated that the positive results may be due to a class effect of ACE inhibitors.26

HOPE 328–30 explored the effect of blood pressure- and cholesterol-controlling drugs on the same primary end points but in patients at intermediate risk of major cardiovascular events. Investigators randomized the 12,705 patients to 4 treatment groups:

  • Blood pressure control with candesartan (an ARB) plus hydrochlorothiazide (a thiazide diuretic)
  • Cholesterol control with rosuvastatin (a statin)
  • Blood pressure plus cholesterol control
  • Placebo.

Therapy was started at a systolic blood pressure above 140 mm Hg.

Compared with placebo, the rate of composite events was significantly reduced in the rosuvastatin group (3.7% vs 4.8%, HR 0.76, P = .002)28 and the candesartan-hydrochlorothiazide-rosuvastatin group (3.6% vs 5.0%, HR 0.71; P = .005)29 but not in the candesartan-hydrochlorothiazide group (4.1% vs 4.4%; HR 0.93; P = .40).30

In addition, a subgroup analysis comparing active treatment vs placebo found a significant reduction in major cardiovascular events for treated patients whose baseline systolic blood pressure was in the upper third (> 143.5 mm Hg, mean 154.1 mm Hg), while treated patients in the lower middle and lower thirds had no significant reduction.30

These results suggest that intensive treatment to achieve a systolic blood pressure below 140 mm Hg in patients at intermediate risk may not be helpful. Nevertheless, there seems to be agreement that intensive treatment generally leads to a reduction in cardiovascular events. The results also show the benefit of lowering cholesterol.

Bundy et al31 performed a meta-analysis that provides support for intensive antihypertensive treatment. Reviewing 42 clinical trials in more than 144,000 patients, they found that treating to reach a target systolic blood pressure of 120 to 124 mm Hg can reduce cardiovascular events and all-cause mortality.

The trade-off is a minimal increase in the risk of adverse events. Also, the risk-benefit ratio of intensive treatment seems to vary in different patient subgroups.

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