Goal-directed antihypertensive therapy: Lower may not always be better
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.
KEY POINTS
- 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.
NINE TRIALS WITH RENAL PRIMARY END POINTS
African American Study of Kidney Disease and Hypertension (AASK)23
Patients: 1,094 African Americans with presumed hypertensive renal disease and a measured glomerular filtration rate between 20 and 65 mL/min/1.73 m2.
Randomized blood pressure goals. Mean arterial pressure 92 mm Hg or less vs 102 to 107 mm Hg.
Results. At 4 years, the two groups had average blood pressures of 128/78 and 141/85 mm Hg, respectively. The groups did not differ in the rates of the primary end points—ie, the rate of change in the measured glomerular filtration rate over time or the composite of a 50% reduction in glomerular filtration rate, the onset of end-stage renal disease, or death.
Comments. Several issues have been raised about the internal validity of this trial.
So-called hypertensive kidney disease in African Americans (as opposed to European Americans) may be a genetic disorder related to polymorphisms of one or more genes on chromosome 22q. Initial data implicated the MYH9 gene, which encodes non-muscle myosin heavy chain II.24,25 More recent data implicate the nearby APOL1 gene encoding apolipoprotein L126 as more relevant. These polymorphisms have a much greater prevalence in African Americans and appear responsible for the higher risk of idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy in this population.24–26 Therefore, in African Americans, hypertension may in fact be the result of the kidney disease and not its primary cause, which may explain why in this and other African American populations stricter control of blood pressure did not produce a renal benefit.27,28
Also, there is the possibility of misclassification bias. A secondary analysis of data obtained by ambulatory monitoring showed that of the 377 participants whose blood pressure appeared to be under control when measured in the clinic, 70% actually had masked hypertension, ie, uncontrolled hypertension outside the clinic.29 The real difference in blood pressure between groups may well have been different than that determined in the clinic.
In addition, a prespecified secondary analysis showed no difference in the rates of cardiovascular events and death between the groups.30 However, the study was not designed to have the statistical power to detect a difference in cardiovascular events. Moreover fewer cardiovascular events occurred than expected, further reducing the study’s power to detect a difference.
Toto et al31
Toto et al reported similar results in an earlier trial in 87 hypertensive patients (77 randomized), predominantly African American, and similar concerns apply.
Lewis et al32
Patients: 129 patients with type 1 diabetes.
Randomized blood pressure goals. A mean arterial pressure of either no higher than 92 mm Hg or 100 to 107 mm Hg.
Results. At 2 years, despite a difference of 6 mm Hg in mean arterial pressure, the glomerular filtration rate (measured) had declined by the same amount in the two groups. The study was underpowered for this end point. Patients in the group with the lower goal pressure were excreting significantly less protein than those in the other group, but they were received higher doses of an angiotensin-converting enzyme (ACE) inhibitor—in this case, ramipril (Altace).
The Appropriate Blood Pressure Control in Diabetes (ABCD) trials33–35
Patients: 950 patients with type 2 diabetes mellitus and either normal or high blood pressure.
Randomized blood pressure goals. Either intensive or moderate therapy (see Table 1).
Results. At 5 years, creatinine clearance (estimated) had declined by the same amount in the two groups. However, fewer of the hypertensive patients had died in the intensive-therapy group.34 Similarly, normotensive patients had less progression of albuminuria if treated intensively.33
In the ABCD Part 2 with Valsartan (ABCD-2V) trial in normotensive patients,35 therapy with valsartan (Diovan) did not affect creatinine clearance but did reduce albuminuria. However, 75% of the patients in the moderate-treatment group were untreated.
Schrier et al36
Patients. 75 hypertensive patients with autosomal-dominant polycystic kidney disease and left ventricular hypertrophy.
Randomized blood pressure targets. Less than 120/80 mm Hg vs 135/85 to 140/90 mm Hg.
Results. After 7 years, despite a difference in average mean arterial pressure of 11 mm Hg between the groups (90 vs 101 mm Hg), there was no difference in the rate of decline of creatinine clearance. The left ventricular mass index decreased by 21% in the lower-target group and by 35% in the higher-target group (P < .01).
Modification of Diet in Renal Disease (MDRD) trial37,38
Patients: 840 patients whose measured glomerular filtration rate was between 13 and 55 mL/min/1.73 m2.
Randomized blood pressure targets. A target mean arterial pressure of less than 92 mm Hg vs less than 107 mm Hg.11,37
Results. After 2.2 years, the mean difference in mean arterial pressure was 4.7 mm Hg. There was, however, no difference in the rate of decline in the glomerular filtration rate.
In a 6-year follow-up, significantly fewer patients in the lower-blood-pressure group reached the end point of end-stage renal disease or the combined end point of end-stage renal disease or death.38 The rate of death, however, was nearly twice as high in the lower-blood-pressure group (10% vs 6%). The blood pressure and treatment during follow-up were not reported.
Comments. Internal validity is an issue, since the blood pressure and therapy during follow-up were unknown, and more patients received ACE inhibitors in the lower-blood-pressure group during the trial. Further, the higher death rate in the lower-blood-pressure group is worrisome.
