Goal-directed antihypertensive therapy: Lower may not always be better

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ABSTRACTAt least 16 treatment trials have been done in which patients were randomly assigned different blood pressure goals in an attempt to better define specific target pressures. We critically review the data.


  • Observational data indicate that lower blood pressure is better than higher, and many trials have confirmed that treatment of hypertension is beneficial. Guidelines have set specific goals based on the observational data.
  • Surprisingly, randomized controlled trials have not shown a lower target to offer significant clinical benefit, and suggest the potential for harm with overly aggressive therapy.
  • The optimal blood pressure on treatment for an individual patient remains unclear.



A 50-year-old African American woman with type 2 diabetes mellitus, hypertension, hyperlipidemia, and chronic kidney disease presents for a follow-up visit. The patient had been treated with hydrochlorothiazide 25 mg/day and enalapril (Vasotec) 20 mg twice daily until 6 weeks ago. At that time her blood pressure was 160/85 mm Hg, and amlodipine (Norvasc) 10 mg/day was added to her regimen. Her other medications include glipizide (Glucotrol), metformin (Glucophage), lovastatin (Mevacor), fish oils, aspirin, calcium, and vitamin D. Her current blood pressure is 145/80 mm Hg; her serum creatinine level is 1.5 mg/dL, and her urine albumin-to-creatinine ratio is 180 mg/g.

In hypertensive patients who have diabetes or chronic kidney disease, guidelines1 call for intensification of antihypertensive therapy to reach a goal blood pressure of less than 130/80 mm Hg. What data exist to support these guidelines? And what should the clinician do?


Often, clinicians are faced with hypertensive patients whose blood pressure, despite treatment, is higher than the accepted goal. Often, these patients are elderly and are already taking multiple medications that are costly and have significant potential adverse effects. The dilemma is whether to try to reach a target blood pressure listed in a guideline (by increasing the dosage of the current drugs or by adding a drug of a different class) or to “do no harm,” accept the patient’s blood pressure, and keep the regimen the same.1,2

The current goal blood pressure is less than 140/90 mm Hg for all but the very elderly, with more intense control recommended for patients at high risk, ie, those with diabetes mellitus, chronic kidney disease, or atherosclerotic cardiovascular disease.1

While it appears to be in the patient’s best interests to follow such guidelines, review of available data indicates that this it not necessarily so, and may even be harmful.


Many observational studies have found that the higher one’s blood pressure, the greater one’s risk of cardiovascular events and death. Indeed, meta-analyses of these trials, which involved more than 1.5 million people, demonstrate a strong, positive, log-linear relationship between blood pressure and the incidence of cardiovascular disease and death.3–5

Further, there is no evidence of a threshold pressure below which the risk is not lower (ie, a “J-point”), starting with 115/75 mm Hg. A J-point may exist for diastolic blood pressure in elderly patients with isolated systolic hypertension6 and in patients with coronary artery disease.7 Otherwise, the observation is clear: the lower the blood pressure the better. For every 20 mm Hg lower systolic blood pressure or 10 mm Hg lower diastolic blood pressure, the risk of a cardiovascular event is about 50% less.4,5

Observational analyses also show a strong, graded relationship between blood pressure and future end-stage renal disease.8,9 Post hoc analyses indicate that chronic kidney disease progresses more slowly with lower achieved blood pressures, especially in those with higher degrees of proteinuria.10–12

However, observational data do not prove cause and effect, nor do they guarantee similar results with treatment. This requires randomized controlled trials.


Initial trials were aimed at determining whether hypertension should even be treated. A 1997 meta-analysis of 18 such trials comparing either low-dose diuretic therapy, high-dose diuretic therapy, or beta-blocker therapy with placebo involved 48,000 patients who were followed for an average of 5 years.13 The rates of stroke and congestive heart failure were consistently reduced, although only low-dose diuretic therapy reduced the risk of coronary heart disease and death from any cause.

More recent trials enrolled people not considered hypertensive who were randomized to receive either active drugs or placebo, or no treatment. Other trials attempted to assess non-pressure-related effects of specific agents, using other antihypertensive agents in the control group. Still other randomized controlled trials compared one agent or agents with other agents while attempting to attain equivalent blood pressure between groups. Frequently, however, there was some blood pressure difference.

Meta-analyses of most of these trials conclude that the major benefit of antihypertensive therapy—reducing rates of cardiovascular morbidity and mortality—comes from a lower attained blood pressure, irrespective of which agent is used.14–18 Exceptions exist, however. For example, specific drug classes are indicated after myocardial infarction, and in congestive heart failure and proteinuric chronic kidney disease.10,19–21


The overriding theme of these observational data is that a lower blood pressure, whether attained naturally or with treatment, is better than a higher one from both the cardiovascular and the renal perspective.

What remains unclear is what blood pressure should be aimed for in a particular patient or group of patients. Is it a specific pressure (eg, 140/90 mm Hg), or does the change from baseline count more? Should other factors such as age or comorbidity alter this number?

Several randomized controlled trials have addressed these questions by targeting different levels of blood pressure. We are aware of at least 16 such trials in adults, including 13 with renal or cardiovascular primary end points and three with surrogate primary end points.

An unavoidable design flaw of all of these trials is their unblinded nature. Consequently, nearly all of them carry a Jadad score (a measure of quality, based on randomization and blinding)22 of 3 on a scale of 5.


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