What our goal should be for antihypertensive therapy
There have been two clinical trials in hypertension that have directly addressed the question of whether we would reduce hypertension-related morbidity and mortality by more aggressive compared with less aggressive antihypertensive therapy (Table Trials Addressing What Our Goal for Antihypertensive Therapy Should Be). The first of these was the Hypertension Detection and Follow-up Program (HDFP). This trial was begun in 1972 in the United States and was completed in 1979. The investigators reflected the American, but not the European or Australian, view that it was not ethical after the VA trial was completed to do a placebo-controlled study in hypertensive patients with an elevated diastolic blood pressure. Therefore, HDFP compared the results of treating hypertensive patients to a goal (<90 mmHg if entry diastolic blood pressure was >100 mmHg or a 10 mmHg reduction if entry diastolic blood pressure was 90-99 mmHg) vs usual care. Rather than having a placebo as the control, HDFP compared a group called Stepped Care that was treated with active medication (a diuretic followed by methyldopa, hydralazine, and guanethidine, if needed), and treated to that goal, with a control group whose members were cared for by their primary physicians and treated however vigorously their physicians deemed necessary, the so-called referred care group. The Stepped Care group really should have been called Special Care because these individuals were seen very frequently and received care and surveillance for many problems other than hypertension. The referred care group should have been called Routine Care because these individuals were seen only at the HDFP clinical centers twice in the 5 yr and were otherwise treated per their physicians’ routine. The participants in referred care actually received similar medication but fewer were treated and those who received treatment were certainly less aggressively managed. At the end of the trial, the participants in the Stepped Care group had their diastolic blood pressure lowered to an average of 83 mmHg compared with an average of 89 mmHg in the referred care group. All-cause mortality, the primary end point in HDFP, as well as cardiovascular mortality were both statistically significantly reduced in the Stepped Care vs referred care group. The benefit was seen in all demographic groups except for white women, whose absolute risk was very low. HDFP did not enroll enough white women to be able to show benefit in these relatively low-risk individuals.
The second study looking at the diastolic blood pressure goal of therapy was the Hypertension Optimal Treatment study, completed in 1998. Hypertension Optimal Treatment was specifically designed to determine whether hypertensive patients ages 50-80 with elevated diastolic blood pressure (100-115 mmHg at baseline) would do better if diastolic blood pressure was lowered to <80 mmHg, vs <85 vs <90 mmHg. Hypertension Optimal Treatment was done in a Prospective Randomized Open Label Blinded Evaluation design. In such trials, the drug administered is known to investigators and participants but all end points are evaluated by a committee blinded to the drug actually used or, in this case, the blood pressure goal. All subjects received a dihydropyridine calcium antagonist started at a low dose (5 mg of felodipine) followed by either an angiotensin-converting enzyme inhibitor or β-blocker at low dose, if more therapy was needed to achieve the predetermined goal. The investigator decided which class of drug to add. If the goal was still not reached, further increases in the dose of felodipine to 10 mg (step 3) and then increased doses of the second drug were mandated (step 4). Finally, a diuretic or other therapy was added (step 5) to achieve the study goal. The cohort enrolled was very large (nearly 19,000) and the follow-up was planned to be approx 2-2.5 yr (40,000 participant-yr). The study was extended to an average follow-up of 3.7 yr (71,000 participant yr) when the event rate in all groups was substantially less than predicted. These participants were practically immortal.
The main result in Hypertension Optimal Treatment was disappointing to some because there was no difference in the rates of study end points between these groups. The optimal blood pressure was calculated to be 138/83 mmHg, a strikingly similar finding to that of the HDFP. There was no evidence of an on-treatment diastolic blood pressure under which the event rate rose (i.e., there was no J-point ascertained). In the 1501 subjects with type 2 diabetes, there was a highly statistically significant trend (p < 0.001) for reduced cardiovascular events when diastolic blood pressure was lowered to <80 mmHg. This finding supports the concept that the lower the achieved diastolic blood pressure the better, especially in those with a high absolute risk for events.
In my view, Hypertension Optimal Treatment should not be viewed as a failed study. More than 90% of the cohort, primarily recruited from private practices in 26 countries, had their diastolic blood pressure reduced to <90 mmHg and were able to maintain that level for several years. In fact, more than 50% of those randomized to be treated to a diastolic blood pressure of <80 mmHg achieved this very aggressive goal. The treatment used was conventional and simple to implement. Ordinary doctors treating ordinary patients with ordinary medicines achieved the study blood pressure goals and did so without causing harm. To accomplish this level of success, combination therapy was usually necessary. Only about one third of those who were to be treated to <90 mmHg got to that level with a single agent, and only 26% treated to <80 mmHg reached it with monotherapy. Hypertension Optimal Treatment taught us that practitioners can achieve very aggressive goals, but it often takes multiple drugs to reach those goals. Doctors given goals can achieve them. Although Hypertension Optimal Treatment did not clearly discover a diastolic blood pressure level that was too low, it did show that the subjects treated aggressively did not have more adverse reactions. If anything, the group randomized to and treated to <80 mmHg had an improvement in quality of life and cognitive function, especially when compared with those that were resistant to therapy.
A more recently published trial, the United Kingdom Prospective Diabetes Study (UKPDS), confirmed the substantial benefit of more aggressive compared with less aggressive antihypertensive therapy in type 2 diabetics. In UKPDS, the goal and achieved blood pressure in the control group were both much higher than in Hypertension Optimal Treatment, but the same level of comparative benefit was achieved.
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