The Rapidity of Drug Dose Escalation Influences Blood Pressure Response and Adverse Effects Burden in Patients With Hypertension: The Quinapril Titration Interval Management Evaluation (ATIME) Study

Background  Antihypertensive medication doses are typically increased within several weeks after initiation of therapy because of inadequate blood pressure (BP) control and/or adverse effects.

Methods  We conducted a parallel-group clinical trial with 2935 subjects (53% women, n=1547) aged 21 to 75 years, with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI stages 1 to 2 hypertension, recruited from 365 physician practices in the southeastern United States. Participants were randomized either to a fast (every 2 weeks; n=1727) or slow (every 6 weeks; n=1208) drug titration. Therapy with quinapril, an angiotensin-converting enzyme inhibitor, was initiated at 20 mg once daily. The dose was doubled at the next 2 clinic visits until the BP was lower than 140/90 mm Hg or a dose of 80 mg was reached.

Results  Pretreatment BP averaged 152/95 mm Hg. Patients with stage 2 hypertension reported more symptoms than those with stage 1. The BP averaged 140/86, 137/84, and 134/83 mm Hg in the slow group compared with 141/88, 137/85, and 135/84 mm Hg in the fastgroup at the 3 respective clinic visits. The BP control rates to lower than 140/90 mm Hg at the 3 clinic visits were (slow, fast, respectively) 41.3%, 35.7% (P<.001); 54.3%, 51.5% (P=.16); and 68%, 62.3% (P=.02). In the fast group, 10.7% of participants experienced adverse events vs 10.8% in the slow group; however, 21.0% of adverse events in the fast group were "serious" vs only 12% in the slow group.

Conclusion  Slower dose escalation of the angiotensin-converting enzyme inhibitor quinapril provides higher BP control rates and fewer serious adverse events than more rapid drug dose escalation.

IT IS ROUTINE clinical practice to escalate antihypertensive medication doses (because of inadequate lowering of blood pressure [BP]) and to discontinue BP medication (because of adverse effects attributed to drug therapy) within the first few weeks after initiating or changing drug therapy. Nevertheless, a number of clinical trials of antihypertensive drugs from many drug classes have suggested that maximum BP lowering takes 4 to 6 weeks or longer after initiation of drug treatment.^1-3

It has also long been assumed that hypertension is an asymptomatic condition. Nevertheless, there are studies of a broad range of BPs suggesting that the assumption of drug-induced causality of symptoms is not always correct. In the Systolic Hypertension in the Elderly Program (SHEP) pilot study,⁴ more participants remained on active treatment than placebo at the 1-year follow-up visit. In the Treatment of Mild Hypertension Study (TOMHS),^5-7 patients with stage 1 diastolic hypertension were randomized to the combined active treatment group (multifactorial lifestyle modifications plus 1 of 5 active drug therapies) or to placebo (lifestyle modifications alone).^5-7 Average in-study BP was lower in the combined active drug treatment group (126/78 vs 132/81 mm Hg) where fewer adverse effects and higher quality of life scores occurred compared with the placebo group. These studies, as well as the Hypertensive Optimal Treatment (HOT) study,⁸ raise the intriguing possibility that the adverse-effect burden relates to BP level, and that antihypertensive drugs possibly alleviate more subjective adverse effects than they cause, most likely because they lower BP. We undertook the Quinapril Titration Interval Management Evaluation (ATIME) study to determine whether quinapril, a long-acting angiotensin-converting enzyme (ACE) inhibitor, would result in greater hypertension control rates as well as fewer adverse effects in patients with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) VI stage 1 to 2 hypertension when dose escalation of the ACE inhibitor quinapril was undertaken at a slower pace.

The ATIME study was a multicenter, randomized, open-label, parallel-group clinical trial funded by Parke-Davis (Morris Plains, NJ) that was conducted in 365 physician offices, all located in the southeastern United States. The first ATIME participant was enrolled on March 18, 1996; the final participant entered the study on December 13, 1996; the last participant completed the study on April 18, 1997. The data coordinating center was located in the Hypertension Center of Wake Forest University Medical School, Winston-Salem, NC, and was responsible for developing the study protocol and case report forms, receiving all study data from clinical sites, adjudicating discrepancies, and preparing all statistical analyses and data reports. There was at least 1 post-randomization visit for each of 4169 subjects; 1234 subjects were considered nonevaluable for the following reasons: (1) ineligible according to study eligibility criteria (n=938); (2) undetermined eligibility because of missing data (n=119); (3) office visits not scheduled in accordance with randomized treatment assignment (n=92); (4) data from 1 clinical site excluded because of quality concerns (n=85). There were a total of 2935 evaluable patients for this report.

Figure 1 displays the design of the study. Potential study subjects underwent 3 qualification visits over a 2-week period with BP eligibility determined at the final (randomization) visit in this sequence. Antihypertensive medication treatment was discontinued or tapered as appropriate at the initial qualification visit. Eligible participants were randomized in a ratio of 1.4:1 to the slow or fast titration groups. A total of 3 post-randomization visits were scheduled for each treatment group. In the fast group, post-randomization clinic visits were at 2, 4, and 6 weeks. In the slow group, clinic visits were at 6, 12, and 18 weeks. All participants received 20 mg of quinapril once daily at randomization. The titration scheme in both groups was accomplished according to the aforementioned visit schedule. If BP normalization (<140/90 mm Hg) was not accomplished at 20 mg, the dose was titrated up to 40 mg, and finally to a maximum dose of 80 mg once daily. If systolic BP (SBP) was higher than 220 mm Hg and/or diastolic BP (DBP) was higher than 115 mm Hg at any visit, the quinapril dose was immediately doubled. If the quinapril was already at the maximum daily dose, open-label add-on therapy could be given or the patient could be withdrawn from the study, at the discretion of the investigator. At each clinic visit, including the randomization visit, a 22-item adverse-effect questionnaire was administered by the clinic nurse. These items represent a subset of the 55-item adverse effect questionnaire administered in the TOMHS study.^5,6 Patients were queried regarding any new or worsening condition since their last clinic visit. If the participant answered yes, additional information was obtained to classify symptom severity as "mild," "moderate," or "severe." Mild symptoms did not interfere with daily activities. Moderate symptoms interfered with but did not preclude execution of most activities. Severe symptoms precluded accomplishment of daily activities. A change in symptom severity between clinic visits was movement of at least 1 severity category in either direction.

Men and women aged 21 to 75 years with SBPs of 140 to169 and DBPs lower than 105 mm Hg or DBPs of 90 to 104 and SBPs lower than 170 mm Hg who provided informed consent were eligible for randomization. Women of childbearing potential had to practice an acceptable contraceptive method.

There were 19 exclusion criteria: (1) taking antihypertensive medication and having an SBP higher than 170 mm Hg or a DBP higher than 105 mm Hg at randomization; (2) taking more than 1 antihypertensive medication; (3) serum creatinine level higher than 123.2 µmol/L (1.4 mg/dL) in men or 114.4 µmol/L (1.3 mg/dL) in women; (4) major disease or life-threatening condition; (5) peripheral edema; (6) planning to move more than 50 miles during the ensuing 3 months; (7) heart failure; (8) previously diagnosed or symptomatic valvular heart disease; (9) prior stroke, myocardial infarction, angina pectoris, or malignant ventricular arrhythmia; (10) predominant cardiac rhythm other than sinus; (11) second-degree or greater heart block; (13) pregnancy, lactation, or planned pregnancy during the next 12 months; (14) intolerance to ACE inhibitors; (15) known secondary hypertension; (16) legally or mentally unable to adhere to the study protocol; (18) malignancy other than skin cancer; or (19) known liver disease or aspartate aminotransferase value more than 1.5 times normal.

Race and sex were self-reported. Isolated systolic hypertension was an SBP of 160 mm Hg or higher and a DBP lower than 90 mm Hg. Obesity was a body mass index (BMI) of 27.8 kg/m² or higher in men and 27.3 kg/m² or higher in women. Blood pressure control was defined as an SBP lower than 140 and a DBP lower than 90 mm Hg. Blood pressure responders were randomized participants manifesting a fall in SBP of 10 mm Hg or those attaining SBP lower than 130 and DBP lower than 85 mm Hg after randomization. An adverse event was a noxious and unintended event that was either observed in or reported by a randomized participant who had received study medication. The event might be related temporally either to immediate or long-term use of the drug, though the drug may not necessarily have caused it. A serious adverse event was an adverse event that was either fatal, life-threatening, or permanently disabling and that required or prolonged inpatient hospitalization, or was a congenital anomaly, cancer, or overdose.

Based on the data of Weir,³ we projected 48% and 74% attainment of BPs lower than 140/90 mm Hg, respectively, in the fast and slow randomized treatment groups. The planned evaluable study sample of 4000 participants afforded 99% power to detect the aforementioned difference in BP control rates using the sample size formula by Fleiss).⁹ In addition, the projected sample size of 4000 provided 99% power to detect a 3–mm Hg difference in SBP lowering between groups at the end of their respective titration periods. With the accrued sample size of 2935, we had 99% statistical power to detect a 1.5–mm Hg between-group difference in change in SBP from baseline. There also was greater than an 80% power to detect a 5% absolute difference in control rates (ie, 65% vs 60%) between the fast and slow titration groups at the end of the study.

Continuous variables are given as means (SDs). The generalized estimating equation procedure of analysis of variance for clustered dichotomous outcomes was used at each visit to test in-study differences in hypertension control and responder rates.¹⁰ The generalized estimating equation method assumes that participants for the same clinical site have correlated BP measurements, but that BP measurements from different sites are independent. The hypothesis of equal rates among study groups was tested by applying a logistic model with a single predictor (treatment group) while adjusting for intrasite correlation. Blood pressure response differences between the slow and fast titration groups were assessed using analysis of variance for clustered continuous outcomes,¹¹ an analytic technique that controls for intrasite correlation of continuous (ie, BP) measurements. In this linear mixed-effects model, subject group was a fixed effect and clinic site was a random effect. Adverse effects were assessed at each visit, stratified by clinic site, using the Mantel-Haenszel χ² statistic to determine between-group differences in the prevalence at baseline as well as in the occurrence or change in severity of an adverse effect after randomization.

Baseline characteristics of 2935 randomized participants are given in Table 1. The slow (drug titration every 6 weeks) and fast (drug titration every 2 weeks) treatment groups were similar on all contrasted characteristics. Figure 2 displays the BP response at each visit for the slow and fast titration groups. In both groups, though the steepest slope of the BP fall was between randomization and visit 1, the downward trend in BP continued through the end of each treatment sequence. Both SBP and DBP were lower at visits 1 and 3 in the slow compared with the fast group (P<.01); at visit 2, there was no significant difference (P=.92) in the reduction in SBP between the 2 groups, although the reduction in DBP in the slow compared with the fast group was of borderline significance (P=.06). Average attained in-study BP levels in the slow group were 140/86, 137/84, and 134/83 mm Hg, respectively, at visits 1, 2, and 3. Over these same visits, average in-study BP was 141/88, 137/85, and 135/84 mm Hg in the fast group. The quinapril doses averaged 20, 29.2, and 35 mg, respectively, at visits 1, 2, and 3 in the slow titration group. In the fast group, the average quinapril doses were 20, 28.3, and 34.5 mg, respectively, at visits 1, 2, and 3. Blood pressure control rates to lower than 140/90 mm Hg are displayed in Figure 3. Similar to the absolute reductions in BP in Figure 2, BP normalization rates were greater at visits 1 and 3 in the slow compared with the fast group, while at visit 2, no significant difference was noted. Within both treatment groups, there was progressively greater BP control to lower than 140/90 mm Hg between randomization and the final study visit.

Figure 4 displays the proportions of all participants with BP lower than 140/90 mm Hg at each post-randomization study visit who were controlled for the first time at that visit. Though attrition occurred throughout the study in both groups, and to a greater degree in the slow than the fast titration group, the proportions of individuals attaining BPs lower than 140/90 mm Hg for the first time were similar at visits 2 and 3 in the 2 groups. In the slow titration group, almost 1 in 4 participants at visit 2 and almost 1 in 5 participants at visit 3 had BPs lower than 140/90 mm Hg for the first time.

Response rates were defined as a fall in SBP greater than 10 mm Hg or achievement of BP lower than 130/85 mm Hg. The higher proportion of responders in the slow group attained statistical significance at visit 1 (57.1% vs 51.4%; P < .01) and was of borderline significance at visit 3 (75.4% vs 70.4%; P=.05). At visit 2, there was no significant difference in the proportion of responders between the 2 randomized treatment groups (65.2% vs 65.7%; P=.99).

A greater proportion of participants randomized to the fast than the slow titration sequence remained on the quinapril regimen through visit 3 (73.7% vs 64.5%). However, a similar proportion of participants in the slow (5.0%) and fast (5.2%) groups discontinued quinapril treatment because of an adverse event.

At baseline, none of the 22 adverse effects was more prevalent in persons with JNC VI stage 1 than in those with stage 2 hypertension. However, 6 of 22 symptoms (sleep disturbance [P=.04], cough [P=.03], ringing in the ears [P=.05], flushing, shortness of breath [P=.007], and swelling [P=.06]) occurred more often in individuals with pretreatment stage 2 than in those with stage 1 BP levels. All contrasts were significant at the P<.05 level except for swelling, where the contrast was of borderline significance (P=.06). Of the 22 adverse effects investigated, 4 were present at baseline but, based on relative cumulative presence throughout the study, occurred more frequently in the fast titration group: light-headedness (P=.07); headaches (P=.04); drowsiness (P=.001); and tiredness (P=.03). Neither diarrhea nor nausea was present at baseline but both were more frequent in the fast vs the slow group over the course of the study (P=.08 and P=.02, respectively). These differences are mostly related to differential improvement of adverse effects that were present at baseline. Interestingly, none of the adverse effects that differed between the slow and fast treatment groups was from the constellation of adverse effects that differed by pretreatment JNC VI BP level.

A similar proportion of patients in the 2 groups experienced adverse events (10.8% in the slow vs 10.7% in the fast group). Nevertheless, the frequency distribution of adverse events differed by severity between the 2 treatment groups. Though adverse events of moderate intensity were equally common in the slow and fast treatment groups (37% vs 40%, respectively), the slow group experienced fewer severe (21% vs 12%) and more mild (52% vs 39%) adverse events than the fast titration group.

The highlights of our study findings suggest that slow (every 6 weeks) as opposed to fast (every 2 weeks) drug titration of the ACE inhibitor quinapril results in higher BP control rates and less severe, although not fewer, adverse events. In addition, our documentation of pressure-related symptoms at baseline is consistent with the thesis that hypertension is not an asymptomatic condition, and also supports data from other studies suggesting that patients with hypertension with lower BP report fewer subjective adverse effects and/or tolerate treatment better than placebo.^4-8 It is also notable that there was no overlap in the constellation of adverse effects associated with higher baseline JNC VI BP classification with those that differed between the slow and fast treatment groups after randomization.

It is important to note that our findings in favor of slow titration were not explained by differential drug dose exposures because the quinapril dose was virtually identical at each post-randomization visit in the 2 groups. Also, the differential follow-up in the 2 treatment groups potentially biases toward a greater likelihood of detecting adverse effects and adverse events in the slow compared with the fast group. Thus, the finding of fewer adverse effects and equivalent adverse events in the slow group is even more notable. In addition, it is unlikely that the higher dropout rate in the slow titration group explained our findings of higher BP control rates for this group given that a significant number of individuals were coming under initial control at visit 3 (final study visit) in both treatment groups. The higher proportion of individuals remaining on treatment in the fast compared with the slow treatment group seems counterintuitive and merits comment. The final study visit in the slow group took place 18 weeks after randomization or 12 weeks after treatment had ended in the fast group. Thus, total follow-up was much longer in the slow treatment group. These data might be interpreted as providing justification for a brief "interim" BP check visit near the midpoint of the every 6-week follow-up as a strategy to encourage patients to complete the initial drug titration phase.

We can only speculate as to why fewer adverse effects were experienced and the severity of the adverse events was less bothersome in the slow than in the fast titration group. The lower BP readings at each clinic visit or possibly the less steep downward BP trajectory in the slow group likely contributed, at least in part, to this finding.

Perhaps the most important aspect of our study is the impact our findings will have on physician and patient beliefs regarding the relationship of hypertension, drug therapy, and subjective adverse effects reported by the patient. According to the recent Third National Health and Nutrition Examination Survey,¹² there are 43,180,000 people with hypertension in the US adult population, 32,174,000 of whom are being treated with drugs, but only 10,743,000 of whom have achieved BP control to lower than 140/90 mm Hg. Given the more stringent BP goals for persons with diabetes mellitus, renal insufficiency, and heart failure (<130/85 mm Hg), and the even more aggressive therapeutic goal for patients with hypertension and with greater than 1-g/d proteinuria (<125/75 mm Hg),¹³ even fewer people with hypertension than suggested by the above numbers are actually at goal BP. Though there are many reasons for poor BP control in the free-living population, the ATIME study findings offers a drug-titration strategy that may minimize the occurrence of adverse effects as well as improve BP control rates in drug-treated hypertension.

The time-honored practice of assessing BP responses every couple of weeks and, if the BP reduction is inadequate, to escalate the drug dose or to substitute another drug in its place, is not supported by our findings. Regardless of our findings, however, the important question is, what is the benefit of more rapid BP lowering? Most people with hypertension, particularly those with stage 1 or 2 BP elevations, are at risk for pressure-related complications over the long-term (years). Moreover, the benefits of rapid BP lowering/normalization remain ill defined. Our findings suggest that rapid dose-escalation not only does not yield tangible improvements in BP control or subjective well-being, but rather is associated with less desirable outcomes on these 2 potentially important clinical parameters.

The ATIME study suggests suboptimal therapeutic decisions and clinical outcomes for those with hypertension treated with drugs if the health care provider and/or patient believe that (1) hypertension is always asymptomatic; and/or (2) subjectively perceived symptoms are usually attributable to drug therapies. If either of these 2 beliefs is held by the provider and/or conveyed to the patient, clinical decisions (ie, down-titration or discontinuing therapy with currently prescribed drugs) will be made that are not likely to reduce or ameliorate pressure-related symptoms. A slower pace of antihypertensive medication dose up-titration can potentially improve important patient outcomes in patients with hypertension treated with ACE inhibitor monotherapy, and probably with other antihypertensive medications as well. In the absence of any proven benefit from rapid BP lowering accomplished over a few weeks, a slower drug dose titration strategy as used in the ATIME study seems reasonable.

Accepted for publication December 20, 1999.

This investigator-initiated study was funded entirely by Parke-Davis, Morris Plains, NJ.

Reprints: John M. Flack, MD, MPH, Wayne State University School of Medicine, University Health Center, 4201 St Antoine, 2E, Detroit, MI 48201 (e-mail: jflack@intmed.wayne.edu).