The appropriate control of hypertension remains

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1 AJH 1999;12: The Effect of Intervention on Antihypertensive Medication Requirements in the Hypertension Optimal Treatment (HOT) Study Daniel W. Jones, Margaret E. Miller, Marion R. Wofford, Douglas C. Anderson, Jr., Mary E. Cameron, Dianne L. Willoughby, Catherine T. Adair, and Nancy S. King Obesity is a significant risk factor for hypertension and the cardiovascular sequelae of hypertension. loss has been shown to be effective in lowering blood pressure in overweight individuals. The purpose of this study was to show the impact of a weight loss intervention on overall medication requirements for obese, hypertensive patients. This was a substudy of the Hypertension Optimal Treatment (HOT) study. HOT study patients who had a body mass index >27 kg/m 2 were randomized to receive either the weight loss intervention, which included dietary counseling and group support, or to serve as the control group. Patients weights and number of medication steps (per HOT protocol) required to achieve target diastolic blood pressure were measured at 3, 6, 12, 18, 24, and 30 months. Patients in the weight loss group lost significantly more weight than the control group only at 6 months ( v kg [mean SD] for weight loss group versus control, respectively, P.05). The weight loss group tended to regain weight after the first 6 months of the study. However, patients in the weight loss group used a significantly fewer number of medication steps than the control group at all time intervals except 3 months. loss appears to be a useful tool in blood pressure management in patients who require medication to control their blood pressure. Am J Hypertens 1999;12: American Journal of Hypertension, Ltd. KEY WORDS: Hypertension, blood pressure, obesity, weight loss, drug treatment. The appropriate control of hypertension remains a challenging problem in the practice of medicine. Hypertension is the leading reason for office visits to primary care physicians. Hypertension is also one of the recognized reversible risk factors for cardiovascular disease, still the leading cause of death in this country. 1 Partly because of better hypertension control, cardiovascular disease death rates have been falling in this country for the last several years. Despite this Received September 17, Accepted April 13, From the Center for Excellence in Cardiovascular-Renal Research (DWH, MEM, MRW, MEC, DLW, CTA, NSK), Division of Hypertension, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi; and the School of Pharmacy (DEA), Department of Clinical Pharmacy Practice, University of Mississippi, Jackson, Mississippi. Address correspondence and reprint requests to Daniel W. Jones, MD, Division of Hypertension, Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS ; djones@medicine.umsmed.edu. This study was supported by a research grant from Astra-Merck by the American Journal of Hypertension, Ltd /99/$20.00 Published by Elsevier Science, Inc. PII S (99)

2 1176 JONES ET AL AJH DECEMBER 1999 VOL. 12, NO. 12, PART 1 TABLE 1. METHOD OF COUNTING MEDICATION STEPS Steps Begin felodipine 5 mg QD Begin enalapril 5 mg QD Begin -blocker (usually metoprolol or atenolol) Increase dose of felodipine Increase dose of enalapril Increase dose of -blocker Add HCTZ (may be done at any point if edema develops) Add a nonprotocol medication The HOT protocol suggested the order for adding medications and making dosage adjustments. The investigator was allowed to alter the order that medications were used based on individual patient needs and responses. Any dose of felodipine, enalapril, or a beta-blocker that was above the starting dose was counted as one step. Nonprotocol medications were counted as one step each regardless of dose. good news, hypertension control rates in general remain much lower than ideal. Of all hypertensives, 30% have good pressure control to 140/90 mm Hg, and only about one half of those treated have control in this range. 1 Those with stage II hypertension and higher are particularly challenging to control. These patients frequently require a greater number of medications and higher doses of medications to achieve adequate blood pressure control. Both side effects and treatment costs are significant problems associated with increasing doses and increasing numbers of medications. 1 Current treatment guidelines call for a combination of lifestyle management and medication in patients with more severe forms of hypertension. Unfortunately, many patients and many practitioners fail to place an appropriate emphasis on lifestyle therapy once medication therapy has been initiated. 1 Among modifications to lifestyle that have been shown to be beneficial, weight loss appears to be the most effective. Body weight and blood pressure are strongly associated. 2,3 Obese patients are more likely to be hypertensive than are lean patients. For some time, we have known that weight loss causes a lowering of the blood pressure. Most weight loss studies have been done in patients on no medications or with borderline or stage I hypertension. 4 The Hypertension Optimal Treatment Study (HOT) was a prospective, randomized trial to determine the optimum lowering of blood pressure in hypertensive patients above the age of 50 years with baseline diastolic blood pressure (DBP) 100 mm Hg. Patients were randomly assigned to achieve a goal DBP of 90, 85, or 80 mm Hg. A stepwise increase in number and dose of medications was used to achieve these DBP goals. This study provided an appropriate setting to examine the effect of weight loss on medication use to achieve goal blood pressures. 5 Previous studies have demonstrated the effect of weight loss on antihypertensive medication requirements in a small group of obese hypertensive patients, 6 in mildly hypertensive obese patients, 7 and in normal weight hypertensive patients. 8 Therefore, this study was performed to determine whether a dietary behavioral intervention resulting in weight loss would allow fewer medications or lower doses of medication to achieve goal blood pressure in a very obese group of older patients with hypertension stage II or higher. METHODS Methods for the Hypertension Optimal Treatment (HOT) Study have been published previously. 5 Permission for performance of the substudy was obtained from the US HOT Steering Committee. Because the randomization of patients in the HOT Study was based on goal blood pressure, this substudy intervention of weight loss did not adversely affect the main study. Patients were considered eligible for the weight loss substudy if they met the HOT eligibility criteria and had a body mass index (BMI) of 27 kg/m 2 at randomization. Patients were randomized in a single blind fashion to either the weight loss intervention group or the control group. Randomization was done in a blocked fashion to ensure that equal numbers of the three HOT treatment groups were in both the weight loss intervention group and the control group. Patients in the weight loss intervention group were individually counseled by a registered dietitian within 10 days of randomization. During this initial session, patients were counseled on food selection and preparation, and weight reduction goals were established. Total caloric restriction and reduction of fat intake were the only methods used in the weight reduction strategy. Patients were not counseled to exercise. Patients were counseled again at a follow-up session 2 to 4 weeks after the initial counseling session. Patients in the experimental arm also attended twice monthly group support sessions for the first 3 months of study participation, and every 3 to 6 months for the duration of the study. patients were told by research nurses that they should lose weight, but they received no formal diet counseling or group support. s for both groups were measured at 6-month intervals during follow-up required by the HOT protocol. Blood pressure was titrated to the target DBP as specified by the HOT protocol. The number of medication steps required to achieve target DBP was counted at 3 months, 6 months, and at each 6-month interval thereafter. The method for counting medication steps is outlined in Table 1. A sample size of 110 patients with equal numbers in each DBP treatment group was calculated to detect a mean difference of one medication step with a power of 80% at the 0.05 significance

3 AJH DECEMBER 1999 VOL. 12, NO. 12, PART 1 WEIGHT LOSS AND ANTIHYPERTENSIVE MEDICATION 1177 TABLE 2. BASELINE DEMOGRAPHICS Group Group Number Age Gender Male Female Race African-American White (kg) Height (cm) * BMI (kg/m 2 ) SBP (mm Hg) DBP (mm Hg) DBP target group 90 mm Hg mm Hg mm Hg *P.05. level. The Student t test was used to detect differences in the number of medication steps between weight loss and control groups, both for entire groups and stratified by goal blood pressure. Comparisons in systolic and diastolic blood pressures were made using two-way analysis of variance and the Student-Newman-Keuls method for pairwise multiple comparisons. The protocol and consent forms were approved by the Institutional Review Board of the University of Mississippi Medical Center. All patients gave informed consent for both the HOT study and the weight loss substudy. RESULTS A total of 112 patients were enrolled into the weight loss substudy. Baseline demographics are outlined in Table 2. Patients in the weight loss group were significantly taller than those in the control group. No other statistically significant differences in baseline variables were found. Four patients in the weight loss group and five patients in the control group did not complete the study and were excluded from the data analysis. Reasons for the dropouts are found in Table 3. A total of 102 patients, with 51 patients in each group, were included in the data analysis. At three months both groups had lost weight, although the differences were not significant ( v kg [mean SD], P.09 for weight loss group versus control, respectively; see Figure 1). The only significant difference in changes from baseline weight occurred at 6 months ( v kg, P.05 for weight loss group versus control, respectively; see Figure 1). After the first 6 months the TABLE 3. REASONS FOR PATIENT EXCLUSION FROM STUDY DATA Reasons for Drop-Out No. of Patients Serious illness 1 Unable to weigh patient on standard office scales 1 Death 3 Dropout for unknown reasons 4 weight loss group showed a gradual but continuous increase in weight towards baseline, whereas the control group displayed a tendency toward a decrease in weight from baseline. Although the weight loss group did gain weight after the first 6 months, their average weight at 30 months was still less than at baseline. There were no differences in the proportion of patients achieving target DBP at any time interval (Figure 2). There were no significant differences between groups in systolic blood pressure (SBP) or DBP at any time interval even after taking into account the target DBP treatment group (Table 4 and Table 5). Although the weight loss group required fewer medication steps at 3 months, the difference was not statistically significant ( v medication steps for weight loss versus control, respectively, P.23; see Figure 3). However, the weight loss group required significantly fewer medication steps at 6 months ( v medication steps for weight loss versus control, respectively, P.03) and at each time interval after that. As expected, the 90 mm Hg target DBP group used significantly fewer medications than the 80 mm Hg at all time intervals (Figure 4). The 90 mm Hg group also used significantly fewer medications than did the 85 mm Hg FIGURE 1. Mean changes in weight from baseline. The weight loss group lost significantly more weight than the control group at 6 months (P.05).

4 1178 JONES ET AL AJH DECEMBER 1999 VOL. 12, NO. 12, PART 1 FIGURE 2. Proportion of patients achieving target diastolic blood pressure. group at all time intervals except at 3 and 12 months. There were no significant differences between the 80 mm Hg and 85 mm Hg groups. A comparison of medication steps between the weight loss and control groups stratified by target DBP group revealed no significant interaction between the two factors. DISCUSSION The principal finding of this study was that the addition of a dietary intervention weight loss with drug therapy reduces the number of drugs or dose of drugs to reach goal DBP in a group of older, very obese patients with stage II and III hypertension. A surprising finding was that this effect on medication requirements lasted beyond the period of weight loss. Several other studies have shown that weight loss decreases antihypertensive medication requirements in hypertensive patients. Darne et al showed that hypocaloric dieting reduced the medication requirement score in obese patients after 10 months. 6 The Darne TABLE 4. STRATIFIED ANALYSIS OF DIASTOLIC BLOOD PRESSURES* Months 80 mm Hg 85 mm Hg 90 mm Hg Baseline * Mean SEM. There were no significant differences in pairwise comparisons of diastolic blood pressures between treatment groups stratified by the HOT treatment group. study is smaller (n 54) and shorter than the present study. Davis et al demonstrated that weight loss increased the likelihood that a patient will be controlled on monotherapy in a follow-up to the Trial of Antihypertensive Intervention and Management (TAIM). 7 In that study, no attempts were made to measure the amount of medication being used. Patients in this study were younger, less obese, and had lower baseline blood pressure (143/93 mm Hg) than those in the present study. A study by Imai et al was important in demonstrating the benefit of weight loss in hypertensive patients of normal weight. 8 They demonstrated an effect on blood pressure and the amount of medication required to control blood pressure. In a less structured study, Cohen et al showed that diet counseling by family practice residents made no difference in the number of antihypertensive medications. 9 However, simply counting the number of medications does not take into account the dosages used. The present study differs from the previous studies in duration, severity of the hypertension, or the older age of the population. Our study adds to the evidence that weight loss is beneficial in a challenging group of patients. Clinicians often work hardest at achieving weight loss in the mildly to moderately overweight, with a goal of avoiding medication use. This study confirms that modest weight loss in the very overweight and very hypertensive can have substantial benefit. Another unique feature of this study is the opportunity to observe the effect of weight gain on blood pressure medication requirements after weight loss. Despite regaining the weight, those who lost more weight initially required less blood pressure medication at 30 months. Reasons for this carry-over effect from weight loss are not clear. There are at least three potential explanations. First, because the design of the study did not allow for decreasing the dose or number of medications when a patient s blood pressure was consistently below goal pressure, this might have influenced the difference in medication dose to persist despite weight regain. Those who consistently stayed at 5 to 10 mm Hg below goal blood pressure did not have medication doses or numbers of medications decreased per the protocol. If this effect had been significant, those with weight loss should have demonstrated lower blood pressures. This was not the case. Mean treatment blood pressures were the same for both the weight loss intervention group and the control group within each DBP goal group. Second, a more likely explanation for the persistent difference in the number of medication steps may be related to compliance. Those in the intervention group were seeing health care professionals more frequently than those in the control group. Both groups saw

5 AJH DECEMBER 1999 VOL. 12, NO. 12, PART 1 WEIGHT LOSS AND ANTIHYPERTENSIVE MEDICATION 1179 TABLE 5. STRATIFIED ANALYSIS OF SYSTOLIC BLOOD PRESSURES* 80 mm Hg 85 mm Hg 90 mm Hg Months Baseline * Mean SEM. There were no significant differences in pairwise comparisons of systolic blood pressures between treatment groups stratified by the HOT treatment group. nurses every 3 to 6 months. Only the weight loss intervention group saw a dietitian or other health care professionals every 1 to 2 months. Most of the sessions were led by a dietitian, but occasionally the sessions included a physician. During the group sessions, patients in the weight loss intervention group had the opportunity to ask questions and to discuss dietary changes. More frequent access to health care professionals may have enhanced compliance with medications as well as lifestyle therapy. Pill counts were the major marker for compliance in the study. There were no differences between the two groups in regard to pill counts. Third and last, a more appealing potential explanation might be some unexplained physiologic change brought on by the weight loss that had a persistent effect The primary limitation of our study relates to methodology. The lack of a downward titration of medication makes interpretation somewhat more difficult. Also, weight loss studies typically use blood pressure as the primary endpoint. The number of steps of medications is not a typical marker for success. The method we used for counting the number of steps underestimates somewhat the total medication dosages used. If dosages of all medications could be converted to a single dosage equivalent, it would allow a more accurate comparison. The study has importance primarily in two areas. The first has to do with the effect of using fewer medications in patients with hypertension. Most antihypertensive agents have side effects that are dosedependent. Lower doses mean fewer side effects, which should enhance compliance. Cost of medication is certainly related to the number of medications used and, usually, to dose as well. Both decreasing side effects and decreasing cost should significantly enhance compliance. FIGURE 3. Mean number of medication steps by dietary intervention group. FIGURE 4. Mean number of medication steps by diastolic blood pressure treatment group. The 80 mm Hg group used significantly fewer (P.05) medication steps than the 90 mm Hg group at all time intervals. The 85 mm Hg group used significantly fewer (P.05) medication steps than the 90 mm Hg group at 6, 18, 24, and 30 months. There were no significant differences between the 80 mm Hg and 85 mm Hg groups.

6 1180 JONES ET AL AJH DECEMBER 1999 VOL. 12, NO. 12, PART 1 The other area of potential importance relates to the mechanism for hypertension associated with obesity. The lag time in blood pressure effect with weight regain may have some implications regarding the mechanism of the relationship of blood pressure and weight, as well as the benefit of weight loss on blood pressure. Future studies are needed to ascertain the mechanism. In conclusion, we have demonstrated that a dietary intervention leading to short term weight loss caused older, very obese, stage II and III hypertensive patients to require fewer steps of medication to reach a goal DBP. Despite regain of weight, the positive effect of weight loss on medication use persisted for up to 30 months. loss appears to be a useful tool in blood pressure management in patients who require medications to control their blood pressure. REFERENCES 1. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch. Intern. Med 1997;157: Jones DW: Body weight and blood pressure. Effects of weight reduction on hypertension. Am. J. Hypertens 1996;9:50s 54s. 3. Jones DW, Kim JS, Andrew ME, Kim SJ, Hong YP: Body mass index and blood pressure in Korean men and women: the Korean National Blood Pressure Survey. J. Hypertens 1994;12: Dustan HP: Cardiovascular consequences of obesity. Chin Med J (Engl) 1992;105: Hansson L, Zanchetti A: The Hypertension Optimal Treatment (HOT) Study patient characteristics: randomization, risk profiles, and early blood pressure results. Blood Press 1994;3: Darne B, Nivarong M, Tugaye A, et al: Hypocaloric diet and antihypertensive drug treatment. A randomized controlled clinical trial. Blood Press 1993;2: Davis BR, Blaufox MD, Oberman A, et al: Reduction in long-term antihypertensive medication requirements. Effects of weight reduction by dietary intervention in overweight persons with mild hypertension. Arch Intern Med 1993;153: Imai Y, Sato K, Abe K, Sasaki S, Nihei M, Youshinaga K, Sekino H: Effects of weight loss on blood pressure and drug consumption in normal weight patients. Hypertension 1986;8: Cohen MD, D Amico FJ, Merenstein JH: reduction in obese hypertensive patients. Fam Med 1991;23: Maxwell MH, Heber D, Waks AU, Tuck ML: Role of insulin and norepinephrine in the hypertension of obesity. Am J Hypertens 1994;7: Su HY, Sheu WH, Chin HM, Jeng CY, Chen YD, Reaven GM: Effect of weight loss on blood pressure and insulin resistance in normotensive and hypertensive obese individuals. Am J Hypertens 1995;8: Kaplan NM: The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 1989;149: Delva P, Pastori C, Provoli E, Degan M, Arosio E, Mohtesi G, Steele A, Lechi A: Erythrocyte Na( )-H exchange activity in essential hypertensive and obese patients: role of excess body weight. J Hypertens 1993; 11: Diez J, Ruilope LM, Rodicio JL: Is insulin-like growth factor 1 a determinant of renal haemodynamics in obesity hypertension? J Hypertens 1993;11(Suppl 5):S192 S Ribstein J, du Cailar G, Mimran A: Combined renal effects of overweight and hypertension. Hypertension 1995;26: Hall JE, Brands MW, Dixon WN, Smith MJ Jr: Obesityinduced hypertension: renal function and systemic hemodynamics. Hypertension 1993;22: