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

Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS)⁴⁵

Patients: 4,418 patients, age 65 to 85 years, with a pretreatment systolic blood pressure above 160 mm Hg.

Randomized blood pressure goals. Systolic pressure either lower than 140 mm Hg or 140 to 160 mm Hg.

Results. At 2 years, despite a difference of 9.7/3.3 mm Hg, there was no difference in the primary end point (the combined incidence of cerebrovascular disease, cardiac and vascular disease, and renal failure). Fifty-four patients had died in the strict-treatment group and 42 in the mild-treatment group; the difference was not statistically significant.

Three other trials

Three other trials^46–48 had surrogate end points, but only one of them reported a composite cardiovascular secondary end point.⁴⁶ We will not discuss the other two.^47,48

Cardio-Sis. In the Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica (Cardio-Sis) trial,⁴⁶ 1,111 people without diabetes with systolic pressure higher than 150 mm Hg were randomized to tight control (systolic pressure < 130 mm Hg) vs usual control (systolic pressure < 140 mm Hg) and followed for 2 years with electrocardiography to detect left ventricular hypertrophy.

At a median of 2 years, the systolic blood pressure had declined by an average of 3.8 mm Hg more in the tight-control group than in the usual-control group, and the diastolic pressure by an average of 1.5 mm Hg. There was significantly less left ventricular hypertrophy in the tight-control group. The incidence of the secondary end point of a composite of cardiovascular and renal events was also significantly lower. There was no difference individually in the rates of myocardial infarction, stroke, transient ischemic attack, admission for congestive heart failure, or death.

DISCUSSION: THE DILEMMA OF TREATING AN INDIVIDUAL PATIENT

These data illustrate the dilemma of treating an individual patient whose blood pressure is not at the currently accepted goal while on multiple antihypertensive medications. According to guidelines, therapy should be intensified in this situation. Observational data show a strong graded relationship between blood pressure and cardiovascular events and death, starting with a blood pressure of 115/75 mm Hg. The observational data relating blood pressure to kidney disease are similar. These data support the guideline recommendations that additional medications should be added to reach the promulgated target. Unfortunately, the targeting trials do not define a target, nor do they support the concept that lower is better.

Possible explanations for the negative results

Why does targeting a lower blood pressure not produce the benefit that the observational data lead us to expect?

One possibility is that blood pressure is merely a marker of cardiovascular risk, not a cause of it. This is unlikely, given the temporal relationship, reproducibility, and biologic plausibility that is supported by a very large body of experimental data. However, blood pressure is only one of multiple factors involved in the pathogenesis of vascular and renal disease, and perhaps better attention to other factors such as lipids and smoking may have made the targeting trials underpowered.

Another possibility is that these trials had such strict inclusion and exclusion criteria that they do not represent the general hypertensive population, reducing their external validity.⁴⁹ However, the trials generally enrolled populations at higher risk, in which end points were more likely to occur. This would have enhanced the chance to show a positive effect rather than mask it.

It is possible that antihypertensive medications themselves have unwanted side effects that offset their potential benefit. Medication-related side effects could directly contribute to vascular disease despite their beneficial effect of lowering pressure. There could also be reduced tissue perfusion due to lower blood pressure per se in the face of a diseased vasculature, with the lower pressure directly contributing to organ dysfunction.

Finally, these trials measured brachial pressures to monitor blood pressure. Brachial pressure does not always correlate with central aortic pressure, which is probably a better marker of the overall pressure burden.⁵⁰ It is possible that in these targeting trials, the peripheral blood pressure did not reflect the true central blood pressure and, therefore, significant separation of blood pressures may not have actually occurred.

Targeted vs achieved blood pressures: Analogies with other markers

This contradiction is not an exceptional circumstance in medicine.

For example, in chronic kidney disease, a graded observational relationship exists between decreasing levels of hemoglobin and various adverse outcomes.^51–53 However, targeting a more normal level of hemoglobin compared with a lower one has been shown to be detrimental.^54–57 This implies either that anemia is merely a marker of higher risk or, more likely, that the actual measures used to raise the hemoglobin to higher levels are the culprit. Notably, although targeting a higher hemoglobin concentration vs a lower one was detrimental, achieving a higher hemoglobin was beneficial within each targeted group.^54,58

Another example of harm caused by targeting goals based on observational data is tight glucose control, both acutely in the critically ill⁵⁹ and chronically in patients with type 2 diabetes.⁶⁰ In both cases higher mortality rates ensued.

The same concept may apply to lowering blood pressure. While achieving a lower blood pressure may be more beneficial, targeting a specific goal may be harmful. Given that perhaps 20% of those labeled as hypertensive have resistant hypertension,⁶¹ millions of patients are susceptible to potential harm from targeting a specific goal based solely on observational data. If lower is always better, the randomized trials outlined above should have had more positive outcomes.

It becomes problematic to assign a specific goal for all patients or even groups of patients. The targeting trials do not provide the answer. Based on the observational data it would be optimal to have a blood pressure less than 120/80 mm Hg. This is an observation, not a recommendation. Patients should be assessed on an individual basis, taking into consideration their starting blood pressure, age, medication burden (antihypertensive and otherwise), comorbidities, and ability to comply with a regimen. Given the available data, it is hard to be more specific. In the future it may be possible to identify specific blood pressure targets based on the patient’s genetic makeup, but today that is not possible. Even patients with lower initial blood pressure may benefit from therapy,^62,63 and some experts have advocated blood-pressure-lowering in all, irrespective of the baseline value.¹⁴